Final Professional

2021

Ghulam Murtaza Hamad

Punjab University College of Pharmacy, Lahore, Pakistan
Session 2016-21
 Table of Contents

01 Rational Use of Drugs 01

02 Introduction to Essential Drugs 39

03 Drug Utilization Evaluation / Drug Utilization Review 53

04 Clinical Pharmacokinetics 68

05 Pharmaceutical Care, its Scope, Management of Care Plan 113

06 Clinical Therapeutics 138

07 Clinical Toxicology 151

08 Safe Intravenous Therapy & Hazards of IV Therapy 159

09 Non-Compliance 168

Disease Management
5) Central Nervous System Unit 173
6) Infectious Diseases 182
10 7) Endocrinology Unit 243
8) Oncology Unit 295
9) Nephrology Unit 326
10) Hematology Unit 334

11 Past Papers 347

12 References 353

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Chapter 1 – Rational Use of Drugs

RATIONAL USE OF DRUGS

Rational means Logical, Sensible, Reasoned or Perceptive

DRUG USAGE
 Drugs have been used in diverse societies and cultures. Drugs have been
used for medical, recreational and social purposes. Pharmacists are well
educated regarding conventional drug usage, Meaning by drug
interactions, ADRs, ADEs. A few pharmacist know about herbal and
homeopathic medications. Similarly, most of the life-threatening events,
such as poison control are dealt in poison control centers or hospitals.
 Nevertheless, pharmacist is the custodian of the drugs and know almost
all aspects of the drugs. Unfortunately, pharmacist – most important
professional regarding drug information, is not taking a leading role or is
not being given.
 But what about the perception of people regarding the drug name. How
they classify it. What in their perception is considered a drug.
 Patients receive medications appropriate to their clinical needs, in doses
that meet their own individual requirements, for an adequate period of
time, and at the lowest cost to them and their community. (WHO, 1985).

RATIONAL PRESCRIBING AND PRESCRIPTION WRITING

 Once a patient with a clinical problem has been evaluated and a
diagnosis has been reached, the practitioner can often select from a
variety of therapeutic approaches.
 Medication, surgery, psychiatric treatment, radiation, physical therapy,
health education, counseling, further consultation and no therapy are
some of the options available, of these options, drug therapy is by far
the most frequently chosen. In most cases this requires the writing of a
prescription.
 Most important aspect in rational drug usage is;
PATIENT EDUCATION
 Patient education is based on learning and learning involves three
processes:
1. Knowledge – acquire, understand, reinforce.

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2. Attitude (affective) – based on ones’s feelings, perceptions,

beliefs, emotions.
3. Behavior – knows, feels and act– in association with social and
environmental factors.
DEMANDS OF RATIONAL PRESCRIBING
 Rational prescribing demands that patient receives;
­ Drugs appropriate to their needs
­ Doses that meet their individual requirements
­ For an adequate period of time
­ At the lowest cost to them and to the community.
 Appropriate indication – appropriate drug
 Appropriated route of administration, dosage and duration –
appropriate patient
 Appropriate patient information – appropriate evaluation.

RATIONAL PRESCRIBING CRITERIA

 Like any other process in healthcare, writing a prescription should be
based on a series of rational steps:
1. Make a specific diagnosis
2. Consider the pathophysiologic implication of diagnosis
3. Select a specific therapeutic object
4. Select a drug of choice
5. Determine the appropriate dosing regimen
6. Devise a plan for monitoring the drug’s action and determine an end
point for therapy, Correct dispensing – appropriate packaging and
dispensing
7. Plan a program of patient education – to ensure patient compliance.
Five `RIGHTS' OF MEDICATION
 Do the right things right
1. Right patient
2. Right drug
3. Right dose
4. Right route
5. Right frequency

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FACTORS THAT CONTRIBUTE TO IRRATIONAL USE OF DRUGS

IMPACT OF INAPPROPRIATE USE OF DRUGS

 It can be seen in many ways:
1. Reduction in the quality of drug therapy leading to increased
morbidity and mortality.
2. Waste of resources leading to reduced availability of other vital
drugs and increased costs.
3. Increased risk of unwanted affects such as adverse drug reactions
and the emergence of drug resistance, e.g., malaria or multiple
drug resistant tuberculosis.
4. Psychosocial impacts, such as when patients come to believe that
there is "a pill for every ill". This may cause an apparent increased
demand for drugs.

PROBLEMS WITH RATIONAL USE OF DRUG

IRRATIONAL DRUG USE – PRESCRIBING AND DIAGNOSIS
1. Complex disease or health problem
­ Patients has many symptoms but is embarrassed to talk about the
main one, so the situation does not get addressed.
2. Lack of basic diagnostic Modalities or tests
­ Prescriber does not do a physical exam and prescribe drugs based on
(objective findings) verbal information.

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3. Overworked Prescribers
­ In a health facility, only one prescriber and 300 patients visit per day
for consultation.
4. Lack of basic diagnostic equipment
­ No microscope to examine urine or blood samples.
­ No X-ray machine or MRI machine to test for tuberculosis, tumor
location and size.
5. Prescribing un-necessary medical therapy
­ Prescribing drug for no medical indication
­ Drug duplication (aspirin + clopidogrel) for prophylaxis
­ Treating avoidable ADRs.
6. Not prescribing drug for any ailment or ignoring few ailments for which
drug can be prescribed
­ Un-treated condition of the patient, bothering the patients, not
giving prophylactic therapy.
7. Prescribing old drug by habit, less efficacious than newer efficacious
drugs
­ E.g., prescribing digoxin, when more efficacious drugs exist.
8. Prescribing old drug by habit, less safe than newer drugs
­ Prescribing diamicron, while more advance formulation exist,
diamicron MR more safe.
9. Not identifying patient condition, which is refractory to drug, not
switching to a better drug
­ E.g., Erythromycin which still interacts with statins, so patient does
not get the effects due to concomitant administration of a drug,
while azithromycin do not.
10.Prescribing inappropriate dose, dosage, frequency and duration of
therapy
­ Antibiotic is prescribed as injectable for 2 days.
11.Prescribing drug with considering drug-drug interaction, drug –food
interaction, contraindications
­ Digoxin with verapamil
­ Fexofenadine with orange juice
­ Milk with ciprofloxacin
­ Beta-blocker in asthma and bradycardia.
12.Prescribing drug without giving necessary instructions to the patients
­ Avoid Ciprofloxacin and tetracycline with milk and antacids.

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­ Insulin prescribed without proper instructions.

IRRATIONAL DRUG USE – PRESCRIBING ISSUES
1. Prescribing expensive drugs when low-cost equivalents are available
­ Ampicillin injection is given when patient can be cured using tablets
only.
2. Selecting wrong drug for patient’s illness
­ Anti-diarrheal drug is prescribed when patient is dehydrated and only
require re-hydrating solution (ORS).
3. Prescribing several drugs when few drugs can provide the same effect
­ Sulfadoxine/pyrimethamine and paracetamol is prescribed when
patient has only fever not malaria.
4. Prescribing drugs when disease is self-limiting and patient would be
fine without taking any drug
­ Ampicillin or antibiotic is prescribed when patient has simple cold
without fever and sore throat.
5. Prescribing drugs without dose adjustments in elderly and infants or
any other specific condition
­ Not adjusting dose of theophylline in infants.
6. Prescribing drugs without adjusting dose in disease conditions
­ No adjustment of drugs in renal disease and liver disease.
­ Reduce dose of beta-blocker to 50% if GFR 10 – 50 mL/min.
­ Reduce dose of verapamil and erythromycin in Liver impairment.
7. Prescribing old drugs without updating drug information from
authentic and un-biased source
­ Diamicron is being given to patients when more advance Diamicron
MR is available with improved efficacy and safety profile.
8. Dose tapering for the drugs which require dose tapering
­ Benzodiazepines, corticosteroids and opioids.
9. Prescribing without taking into account the risk vs benefit ratio of the
drugs being prescribed
­ For example, in general population – lactating women, pregnancy,
pediatrics and geriatrics.
IRRATIONAL DRUG USE – DISPENSING
1. Wrong interpretation of prescription
­ Ampicillin prescribed but amoxicillin is dispensed.
2. Wrong quantity dispensed

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­ Artemether/lumefantrine (Coartem) is prescribed – 4 tablets 2 times

daily – a total of 24, but only 16 tablets were dispensed without
telling the patient, which only lasts for 2 days.
3. Incorrect or inadequate labelling
­ Sulfadoxine/pyrimethamine is dispensed (white tablets) with no
proper labelling on the container – which means patient fails to
remember or will be confused if taking more than 2 drugs with same
kind of color and shape.
4. Incorrect or insufficient dispensing information
­ Patient (child) is prescribed paracetamol 500 mg, but is provided 250
mg tablets with telling the parents to give two tablets.
5. Un-sanitary/unhygienic practices
­ Tablets were retrieved for counting to give 20 tablets – a few tablets
fell on the floor and were picked up and dispensed to the patients.
6. Dispensing near expiry medicine
­ Medicines that will be expired in 2 days and were given for 7 days
treatment.
7. Dispensing in similar kind of container with almost similar labelling
pattern
­ Avoid using same containers for similar shape and color tablets or
capsules to avoid confusion on patient’s part.

COMMON ERRORS
1. Prescribing exceedingly high dose
2. Prescribing more toxic drugs than necessary
3. Prescribing an unnecessary drug
4. Prescribing a drug that will lead to drug-drug interaction
5. Prescribing drugs with no proven benefits
6. Prescribing expensive medicines even when cheaper and equipotent are
available
7. Prescribing parenteral dosage form when oral formulation is proved to
be more beneficial
8. Poor prescription writing
9. Usage of certain drugs by the patients for minor ailments without
consulting the physician
10.Usage of potent drugs in high doses to obtain quick relief for the
sufferings

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11.The patients do not complete the prescribed regimen and cease the
administration halfway through the course when the symptoms begin to
subside
12.Omission of needed information – DDIs, Antacids and Iron with
tetracycline/cipro absorption
13.Inappropriate drug prescription - prescribing anti-psychotic drug for drug
induced Parkinson symptoms, metoclopramide
14.Prescribing laxatives for reduced bowel activity – associated with anti-
histamines (diphenhydramine), anti-depressants (amitriptyline), anti-
psychotic drug (thioridazine)
15.Prescribing anti-hypertensive associated with the use of NSAIDs.

NON-COMPLIANCE AND IRRATIONAL USE

 Four types of non-compliance leading to medication error:
1. The patient fails to obtain medication
2. The patient fails to take medication
3. The patient prematurely discontinues medication
4. The patient (or another person) takes medication inappropriately.
For example, the patient share a medication with others for any of
several reasons.

REASONS OF IRRATIONAL DRUG USAGE

1. Lack of sources to provide un-biased information regarding currently
used medicines – practitioners rely on medical representatives for the
information
2. Lack of proper training for the medical students and physicians in writing
proper prescriptions
3. Lack of diagnostic facilities in a hospital – difficulties for a prescriber to
reach a conclusion
4. Patients want quick relief from the ailments – pressure on prescriber to
prescribe a drug for a self-limiting symptoms
5. Due to ineffective control of drug regulatory authorities – availability
and dispensing of prescription drugs as over the counter drugs
6. Prescribers are influenced by manufacturers – incentives for prescribing
their drugs
7. Patients have more liberty to decide whether to purchase all the drugs
or only a few of them.

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 Chapter 1 – Rational Use of Drugs

DRUG USE IN DEVELOPING COUNTRIES

Examples of Strategies for

Outcomes Causes of IDU Challenges
IDU Improvement

Substandard Drug marketing

drugs, & profiteering, Provide Tec-
International Finances,
Lack of Access unreliable Patents and Assis. &
Level Priorities
Med-info. Trade funding
High prices agreements

Budgetary
constraints, Budgetary
National Substandard weak laws & constraints,
Poor health indices regulations, NDP & A
Level drugs poor
poor infrastructure
infrastructure

Drug Unreliable
shortages, Drug Lack of trained
supplies, bad
Health Loss of confidence & expired Committees manpower,
procurement
System Level wastage of resources drugs Essential Budgetary
practices, poor
Drugs list constraints
Lack of MIS infrastructure

Poly
Lack of
pharmacy, Training,
Prescriber Drug wastage, drug knowledge, Lack of
wrong drugs,
Level resistance patient S.T.G training
over
overload
prescribing

Lack of
Inadequate
Dispenser Drug wastage, drug Knowledge, Lack of
patient Training
Level resistance Patient training
counseling
overload

High cost of Community

Drug resistance, drug Poverty, Illiteracy,
Patient & drugs, outreach,
dependence Increased illiteracy, traditional
Community sharing of Advertising,
costs of treatment, culture, self medicines,
Level drugs, self posters,
Death medication Poverty
medication, Leaflets

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CONSEQUENCES OF IRRATIONAL DRUG USE

1. Irrational use of novel antibiotics can lead to the development of
resistance.
2. Irrational drug use does not produce desired therapeutic outcome –
additional pain and discomfort to the patient.
3. Patient and the government has to bear the increased cost of treatment.

AVOIDABLE MISTAKES
1. Prescribing multiple drugs
2. Prescribing to keep up with the latest fad
3. Prescribing an older drug out of habit
4. Prescribing to satisfy the expectations of the patients
5. Prescribing out of pressure from pharmaceutical companies
6. Prescribing without making proper diagnosis
7. Prescribing without proper instructions – dose, dosage form, frequency
and duration.

PROBLEMS WITH IRRATIONAL USE OF INJECTIONS

 Un-necessary use of Injections are associated with:
­ Higher costs
­ Increased need of trained staff
­ Increased time to administer the drug
­ Possible transmission of serious pathogens
­ Increased risk of adverse drug reactions – abscess formation
­ Patient’s discomfort.
 General use of injections should be restricted to followings:
­ Oral administration is not tolerable and is not possible.
­ If there is a clear absorption problem; vomiting and severe diarrhea.
­ Drug of choice is only available in parenteral dosage form, e.g.,
insulin and gentamicin.
­ High concentrations are needed and is not achievable via oral route,
e.g., meningitis.
­ Urgent treatment is required due to severe and rapidly progressing
illness, e.g., septicemia.
­ Patient is unlikely to comply with oral therapy.

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EDUCATIONAL, MANAGERIAL AND REGULATORY STRATEGIES FOR

INTERVENTION IN RATIONAL DRUG USE

Strategies Interventions Targeted category of persons

-Technical assistance
W.H.O, World Bank and Various
International -Drug Donations
international organizations
-Funding
-Drug registration
-Ministry of Health
-Essential drug list
-Ministry of Health
Regulatory -Laws and regulations restricting
-Ministry of Health and other
dispensing, prescribing & the entire
relevant ministries and agencies
pharmaceutical industry
-Storekeepers, Administrators,
-Establishing a priority list for drug
purchasers and Health workers
procurement
-All health Units
-Establishing Drug Committees
-Accounts and Purchasers
-Establishing price indicators
Managerial -Drug Use supervisors
-Standard operating procedures for
-Administrators, purchaser and
dispensing and drug storage
unit Heads
-Standard diagnostic and treatment
-Store keepers and Dispensers
guidelines
-Prescribers
-Medical and in-service training
-Formal training (curriculum review) for all Health workers
Educational -Continued Medical Education -All Health workers
-Increased supervision and support -Patients and community
Guidelines Prescribing as per guidelines Doctors, Pharmacists, Nurses
-Available medicine as per the
Essential Hospitals, Doctors, Pharmacists,
guidelines for majority of
Medicine List Nurses
population
-Establishing a priority list for drug -Storekeepers, Administrators,
procurement purchasers and Health workers
-Establishing Drug Committees -All health units
Drug and -Establishing a drug utilization -Accounts and Purchasers
Therapeutic information system for monitoring -Drug Use supervisors
Committee and evaluation -Administrators, purchaser and
-Establishing procedures for unit Heads
selection, procurement and -Store keepers and Dispensers
distribution -Prescribers
-Drug Information Centers -Medical and in service training for
Un-biased -Continued Medical Education all Health workers
Drug -Increased supervision and support -Patients and community
Information -Medical Journals, Newsletter, -Administrators, Units Heads and
Treatment Guidelines Purchasers

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CHALLENGES TO RATIONAL DRUG USE

1. WIDESPREAD IRRATIONAL PRESCRIBING
 Despite the growing body of knowledge on rational use interventions,
numerous studies have documented the continuing widespread
irrational prescribing of drugs.
2. INJECTION THERAPY
 can also be an example of irrational drug use.

3. LIMITED KNOWLEDGE
 Knowledge alone is not enough to change behavior, and that complex
and multifaceted solutions are needed.
4. EXPENSIVE NEW DRUGS
 Many new drugs and second-line drugs are very expensive and
accordingly unaffordable for many governments and consumers.
5. EDUCATION AND TRAINING
 Drugs and therapeutics committees may have difficulty to run in
situations where medical and pharmacy training is still very
traditional; with much emphasis on drug knowledge and very little on
public health, prescribing skills, drug management and patient care.
6. INFLUENCE OF PHARMACEUTICAL REPRESENTATIVES
 Doctors often gets visits from these representatives introducing new
drugs or reminding doctors of their products.
 Doctors should stick to the principles of rational prescribing.

7. CONSUMER DECISION
 The consumer takes the final decision about whether and where to
seek health care, what medicine is actually taken, how much and
when, and from what source.
 These decisions are influenced by knowledge, culture, drug
promotion and personal finances.
8. INDEPENDENT DRUG INFORMATION
 Independent drug information and public education about drug use
are complicated and costly and have always been underserved and
underfunded.
 They also tend to be organized by NGOs thus with informal networks
and objective evaluation of interventions and publication of the

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results are not easily arranged.

9. LACK OF INDEPENDENT DRUG INFORMATION AND ADVICE
 Worldwide, some 50% of people fail to take their medicines correctly.
Part of the problem is that self-medication is widespread.
10. PROFIT MOTIVES AND PRESSURE TO PLEASE PATIENTS
 Purchases of drugs in certain localities take place in the private
sector, where prescribing and selling functions are often combined.
 Profit motives and pressure to please the patient can lead to over-
treatment of mild illnesses, overuse of injections and misuse of anti-
infective drugs.

RATIONAL DRUG USE BY CONSUMERS

 Establishing effective drug information systems to provide independent
and unbiased drug information, including on traditional medicine to the
general public and to improve drug use by consumers.
PROGRESS
 An extensive review by WHO of public education on drugs provided
valuable insight into strategies used, and their strengths and weaknesses
(Public Education in Rational Drug Use: A Global Survey).
 WHO guide to investigating drug use in the community has contributed
to a growing body of knowledge on consumer understanding, attitudes
and practices regarding drug use. (How to Investigate Drug Use in
Communities).
 Experiences with independent drug bulletins are being shared with
developing countries through networks such as the International Society
of Drug Bulletins.
 Development of drug information centers. These are important source
of independent drug information. Linking these centers electronically
contributes to sharing of information and experience.

WHO GUIDE TO GOOD PRESCRIBING

1. Make diagnosis
2. Set therapeutic goal for the individual patient
3. Decide on the therapeutic approach
4. Choose a drug class
5. Choose a generic drug within a class
6. Individualize dose, formulation, frequency, and duration

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7. Verify suitability of chosen drug

8. Write prescription
9. Inform patient
10.Monitor for effects and adverse effects
11.Alter prescription, if necessary.

CHARACTERISTICS OF GOOD AND BAD PRESCRIBING

GOOD PRESCRIBING BAD PRESCRIBING
Effective Ineffective
Safe Unsafe
Patient centered and individualized Not patient centered
Acceptable to patient Not suitable for patient
Appropriate (not too little or too much) Inappropriate
Addresses expectations of patient Causes patient distress and harm
Judicious use of resources Higher cost
Well informed (evidence based) Poorly informed
Based on unbiased information Based on biased information
Low vulnerability to outside influences Vulnerable to outside influence

RATIONAL DISPENSING
THE ROLE OF DISPENSERS IN PROMOTING RATIONAL DRUG USE
 Identify who can be a dispenser
 Identify factors that influence dispensing
 Describe methods to enhance dispenser-patient communications
 Identify ways to influence a dispenser's behavior.

PRESCRIBER AND DISPENSER

 In the real world of drug use (rational and irrational)

PRESCRIBER
 A Prescriber is anyone with a recommendation for treatment.
DISPENSER
 A Dispenser is anyone who gives out a treatment.
DISPENSERS
 Pharmacists, pharmacy technicians
 Pharmacy assistants
 Nurses, nurse aids

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 Doctors
 Drug sellers
 Shopkeepers
 Family members.
DISPENSER REQUIREMENT
KNOWLEDGE / SOURCE OF INFORMATION
 Drug information
 Product information
 Consultation
SKILLS
 Communication skill
 Promotional/marketing techniques
OTHERS
 Supply
 Dispensing equipment
 Dispenser-prescriber relationship
 Status/role in the health care system
DISPENSING PROCESS
 Receive prescription
 Interpret prescription
 Retrieve medication/ingredients
 Prepare and process
 Communicate with patient
 Ensure patient's understanding
 Monitor compliance by patient
 Keep records.

POTENTIAL ERRORS AND PROBLEMS

 Wrong interpretation of prescription (or diagnosis)
 Retrieval of the wrong drug from stock
 Wrong dosages
 Inadequate packaging/labeling
 Inaccurate counting, compounding
 Inadequate or nonexistent labeling
 No knowledge of proper drug compliance

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 Insufficient knowledge of the disease process

 Insufficient time to talk with patients about their drugs
 Inability to communicate to patients about therapy
ASSESSING DISPENSING CONDITIONS
 Dispensing point conditions
 Dispensing time? Communication time?
 How often do errors occur?
 Who is responsible for dispensing?
 Dispensing training in country?
 Salaries and wages for dispensers?
 Dispensing packaging?

ROLES OF PHARMACIST IN ENSURING RATIONAL DRUG DISPENSING

 Procurement
 Distribution
 Prescribing
 Information
 Additional roles:
­ Communication with physician
­ Treatment guidelines
­ Research on prescribing and utilization
­ Consumer education
PHARMACIST ROLE IN APPROPRIATE DISPENSING
FRAUDULENT PRESCRIPTIONS
 Legitimate prescription with alterations made by patient
 Stolen prescription pads of a legitimate prescriber but with contact
changes
 Drug seekers who phone for their own prescriptions and use their own
phones for verification
 Drug abusers who use stolen pad to write prescriptions
 Individuals present themselves at emergency to obtain controlled
substance prescription to modify it later or copy for re-use
STEPS THE PHARMACIST MUST TAKE TO ENSURE THE VALIDITY OF
PRESCRIPTIONS
I. ENSURE THAT ONLY STATE-AUTHORIZED PRESCRIBERS WRITE/ORDER
PRESCRIPTIONS

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 The DEA defines a practitioner as a physician, dentist, podiatrist,

veterinarian, state-registered practitioner.
 The pharmacist must know the laws in each state/province, if presented
with a prescription from that state.
 If the pharmacist is presented with a questionable prescription, he or
she may want to use the contact information on the prescription.
 States have the authority to determine the scope of treatment by
prescribers.
 States may restrict the ability of certain practitioners to write
prescriptions only for certain indications or specific conditions — for
example, dentists being restricted to treatments related to oral health.
 If the pharmacist has questions regarding whether a valid prescriber-
patient relationship exists, he or she may contact the prescriber or ask
the patient when they last saw the prescriber, or ask other general
questions related to the interaction with the prescriber.
 Verify prescriber registration #.
II. PRESCRIPTION MONITORING PROGRAM (PMP)
 In US, every state has PMP - generally track every controlled substance
dispensed in the state and include patient name, controlled substance
name and quantity, date dispensed, prescriber and pharmacy identity.
 The pharmacist must be judicious in accessing information in the PMP.
The pharmacist must never abuse the privilege of reviewing the
information in the database.
 The pharmacist should access information only when a prescription is
presented.
 The pharmacist must always adhere to federal and state privacy and
security laws, and act in a professional, ethical manner.
III. REVIEW OF PRESCRIPTION
 The pharmacist must take the time to comprehensively review the
prescription order the patient presents. The pharmacist may conduct the
following review steps in any order:
­ Review the prescription order for any changes or alterations.
­ Both handwritten and computer-generated prescriptions are
subject to alteration.
­ Check if the prescription appears to be a photocopy that might
indicate duplication of the original order by the patient.

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­ The pharmacist should specifically examine the date of the order,

the quantity and strength; and signature on the prescription
order to ensure that the prescriber’s handwritten signature is
included on the prescription as required by the DEA.
­ Any alterations must be brought to the attention of the
prescriber,
­ In the case of Schedule III-V medications, a pharmacist may
contact the prescriber to authorize a verbal telephone order for
prescriptions.
­ The pharmacist may not receive oral authorization for a Schedule
II controlled substance prescription.
­ Obtain treatment plan. If customers are submitting prescriptions
for large quantities of drugs.
­ Review the date issued, Review the medication, strength, dosage
form and quantity.
­ Document, document, document! The pharmacist regularly hears
this mantra for many actions taken in the pharmacy, but
documentation is even more important when verifying a
controlled substance prescription. The pharmacist must document
the steps they have taken to verify the prescription, including any
calls to the prescriber(s), conversations with the patient,
medication history review, and PMP access and review on the
prescription itself or in the pharmacy management system.
PHARMACY CONTROLS TO ENSURE APPROPRIATE DISPENSING
1. The pharmacist should take necessary actions to prevent widespread
prescription drug abuse and ensure appropriate dispensing in the
pharmacy.
2. Receive and validate prescription (print, DEA#, Date, Doctor name,
License # etc.)
3. Understand and interpret prescription (patient, medicine, dose)
4. Identify area prescribers who most often prescribe narcotic or dubious
prescriptions and review these prescriptions carefully
5. Communication by the pharmacist to both the prescriber and patient is
necessary because it may uncover rational reasons for prescribing .
6. Once the pharmacist identifies the prescribers and patients who should
be flagged, the pharmacist and pharmacy staff must ensure that all

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federal and provincial laws and regulations, and other protections, are
maintained when doing so
7. The pharmacist should implement a substance order management and
inventory system to closely monitor receipt and dispensing of drugs.
8. Prepare and label items for issue (self-checking, double checking,
counter checking, FEFO not FIFO, read the label twice), do not select
medicine based on color or place of the container, do not open many
containers at the same time.
9. Measure the tablets or capsules without touching them, use spatula,
clean white paper or lid of the container
10.Label should be kept upward while pouring medicine from container
11.Make final check and record actions taken
12.The pharmacist should review logbooks, perpetual inventory, invoices,
receipts and other pharmacy distribution records to flag excessive
ordering or dispensing by certain pharmacists or on certain shifts.
IMPROVING PATIENT COMPLIANCE WITH THERAPY
 Dispenser-patient communication
 Packaging for patient use
 Labeling
 Written information
DISPENSER-PATIENT COMMUNICATION
 Dispensers communicate with patients how to take drugs
 Ensuring their understanding is very important.
CONCLUSION
 Dispensing is a critical part of drug use
 Dispensing is often neglected in training and EDP programs
 Interventions exist to improve dispensing
 Patients benefit from better dispensing.

DRUG USE PROBLEM

 Drug misuse means using drugs in a way that harms you or causes you to
harm others. You can misuse illegal drugs, prescription drugs, or over-
the-counter drugs.
 Most of the time, a drug problem starts with casual use. You may not
think there will be a problem if you use a drug once or twice.

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 But drug use can become a drug problem and drug dependency, and it
sometimes happens quickly.
 The use of medications in both developed and developing countries
often shows a striking discrepancy with principles of clinically acceptable
practice.
 In most developing countries the sources of misuse range from travelling
drug peddlers and small grocery shops to prescribers in teaching
hospitals.
STEPS TO LEARN ABOUT THE DRUG USE PROBLEMS

1. EXAMINE
 Identify a priority drug use issue (e.g., poly-pharmacy, un-necessary
medication)
­ Which potential problems carry the highest clinical risk (DDIs)
­ Which involve expensive or widely used drugs (steroid use by GPs)
­ Which are potentially the easiest to correct (treatment guidelines
and EDL to avoid un-necessary medication)
 Collect data to measure current practices (how and what options are
available to collect data)
­ Which source of data will give you the best information (hospital
staff, patient, GPs)?
­ How large a sample is necessary to get reliable information?
­ What are the groups of interest e.g., doctors and nurses or public
sector and mission facilities?

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2. DIAGNOSE
 Identify specific problems and causes and describe in detail apparent
problems in drug use.
­ What specific practices are the problems (poor storage, lack of
knowledge, drug administration, adverse event)
­ What is an ideal practice (gold standard)?
­ Who are the most important providers, e.g., the influence
leaders in the community, or those with the best or worst
practices?
­ Are there high-risk patients, e.g., pregnant mothers or young
children?
 Identify the apparent causes of the problem.
­ What social and cultural factors influence practices?
­ Providers knowledge and belief
 Cultural forces and peer practices
 Patient demand and practices
­ How do economic constraints influence providers and patients?
 Identify constraints to change
­ Economic factors prevent change
­ Drug supply factors will hinder change
­ Work environment
3. TREAT
DESIGN AND IMPLEMENT INTERVENTIONS
 Select target behaviors to change and design an intervention program.
­ Which behaviors can be changed most cost effectively?
­ What are the possible economic consequences?
­ What are the most appropriate interventions, given their different
costs, complexities, and chances of success?
­ What personnel is required, and what training will they need?
 Acceptability and Effectiveness
­ Conduct pilot tests to determine the acceptability and
effectiveness of an intervention.
 Implement in stages
­ Implement the intervention and collect data to measure changes.
­ Is the intervention implemented as expected?
­ How can program impacts be measured?
­ Are the data reliable?

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4. FOLLOW UP
 Measure Changes in outcomes and evaluate the intervention's success.
­ Was the intervention implemented as planned, e.g., the number
of educational sessions or supervisory visits?
­ What are the measurable changes, e.g., in knowledge, beliefs,
patient satisfaction, clinical results, expenditures, etc.?
­ How cost effective is the intervention compared to other
strategies?
­ How generalizable are the results to other settings?
 Feedback results.
­ To program personnel, to providers, and to consumers, to
encourage them to maintain and increase positive changes.
­ Use results to improve the impact of the program or to guide
decisions about other problems to investigate.

COLLECTION OF DATA TO LEARN ABOUT DRUG USE

 Collect data to learn about the exact nature of the problem, and to find
out some of its underlying causes.
 Drug use encounter, a term which we use to describe the period of
interaction between a health provider who is offering care (including
pharmaceuticals) and a patient who is seeking care.
 Drug use encounters can occur in many places including:
­ Hospital inpatient units ­ Traditional healers'
­ Hospital outpatient practices
clinics ­ Licensed pharmacies
­ Health centers ­ Drug retail shops
­ Private physicians ­ Marketplace stalls
 Drug use encounters may involve many different individuals in
recommending and selecting therapies, including:
­ Physician ­ Pharmacist
­ Nurse ­ Pharmacy clerk
­ Clinical officer ­ Shopkeeper
­ Traditional healer ­ Trader
­ Injectionist ­ Patient
­ Dresser /Attendant ­ Relative or friend

METHODS OF COLLECTING DATA

 Selection of method to be used depends on:

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­ The nature of the problem

 How complex is the behavior involved?
 How much is known about the problem already?
­ The objectives of collecting data
 Is the objective describing a problem, measuring change, or
monitoring performance?
 How much information is needed to choose among possible
interventions?
­ The availability of resources
 Are technical experts available to assist in processing and
analyzing data?
 Is there an existing source of data?
­ The time available
 How much time can be spent in gathering data?
 Is there a need to demonstrate short-term change?
 The data can be of two types;
I. Qualitative data
II. Quantitative data
QUANTITATIVE DATA
 Quantitative data, are numeric data collected in the form of counts,
rates, or classifications. Quantitative data are very useful for finding
out what practices are happening in a given situation, and how
often they are happening. These data can therefore be used to identify
specific problems or to measure the success of interventions to change
these problems.
 Opportunities for collecting quantitative data include:
­ Routinely reported data: The least costly alternative if data are
already available, reliable, and suitable to describe the problem
being studied.
­ Data gathered from record systems: Large samples of data can
often be collected retrospectively from medical or pharmacy
record systems at relatively low cost - the quality of the data may
be low since the data were often collected for other purposes.
­ Sample surveys: The most widely used method for collecting
health data, surveys gather information, once or at multiple points
in time, about a sample of people, health facilities, or events (e.g.,
prescribing encounters)

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 Quantitative methods describe drug use patterns, or pinpoint specific

problems that need attention.
 However, quantitative methods are usually not good for
understanding why these patterns or problems exist.
 Qualitative techniques are better suited to examine underlying feelings,
beliefs, attitudes, and motivations.

SOURCES OF QUANTITATIVE DATA ON DRUG USE

LOCATION OF DATA DATA SOURCES USEFUL FOR STUDYING
RETROSPECTIVE: Drug supply
Public Sector -Aggregate patterns of drug
orders
Administrative use and expenditures
- Stock cards
Offices, Medical -Comparative use of
- Shipping and
Stores drugs within therapeutic classes
delivery receipts
RETROSPECTIVE: Patient -Aggregate patterns of drug use
registers and expenditures
- Health worker logs - Drug use per case, overall
Health Facility,
- Pharmacy receipts and by group (age, sex, health
Clinical Treatment
- Medical records problem, etc.)
Areas and Medical
PROSPECTIVE: - Provider-specific prescribing
Record Departments
- Patient observations patterns
- Patient exit surveys - Features of patient prescriber
- Inpatient surveys interaction
RETROSPECTIVE: Pharmacy logs
- Aggregate patterns of drug
- Prescriptions retained in
use and expenditures
Health Facility pharmacies
- Dispensing practices
Pharmacies PROSPECTIVE:
- Features of patient-dispenser
- Patient exit surveys
interaction
- Patient observations
RETROSPECTIVE: Prescriptions - Private sector prescribing
retained in pharmacies practices drug sales without
Pharmacies and PROSPECTIVE: prescription
Retail Drug Outlets - Customer exit surveys - Self-medication practices
- Customer observations - features of customer sales
- "Simulated visits" attendant interaction
RETROSPECTIVE: Family
- Total community drug use-
medical records
care-seeking behavior
- Household surveys
Households - Self-medication practices
PROSPECTIVE:
- Family drug use
- Household drug audits
- Patient compliance
- Family medical records

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QUALITATIVE DATA
 Qualitative methods are based on talking to people or observing their
behavior. Qualitative methods often involve trained interviewers or
observers. However, managers and policy makers can use qualitative
methods to assess the factors that underlie a problem so that they can
decide how to solve it. Managers themselves do not need to know how
to carry out qualitative techniques, but only what these techniques are
and how they may be useful.
I. INTERVIEWS
OVERVIEW
 An extended discussion between a respondent and an interviewer based
on a brief interview guide that might cover between 10-30 topics.
 Guided by a list of open-ended topics rather than a set of fixed
questions, and the respondent is continually probed to provide more
depth and detail on these topics.
 Issues of interest to the respondent are allowed to emerge - often
completed with key informants, who may be opinion leaders or other
people in a special personal or professional position who are expected to
provide insights into the perspective of a group.
SCOPE
 A few (5-10) in-depth interviews with people who reflect the feelings of
a particular group will often be enough to get a feel for the important
issues.
 If the target population is diverse, generally 5-10 interviews would be
held with members of each important subgroup.
STRENGTHS
 Helps in establishing trust between the interviewer and respondent.
 Particularly useful with less educated or illiterate respondents, and in
cultural groups where abrupt, direct questioning is considered
inappropriate.
 Can generate unexpected insights or new ideas and information,
because the topics covered depend on the opinions and feelings of the
respondent.
WEAKNESSES

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 Time-consuming compared to more structured questionnaires.

 Analysis of large amounts of open-ended data can be difficult.
 Key informants may say what is socially acceptable or what they believe
the interviewer wants to hear.
 Interviewers must be well-trained to avoid bias and well-informed about
the material discussed.
II. DISCUSSIONS
OVERVIEW
 Moderated discussion about a defined set of topics among a small
number of participants (usually 6-10), who share key characteristics like
age, gender, or job.
 Focus groups typically last for 1-2 hours, and the conversation is usually
recorded so that details can be reviewed later.
 Participants talk under the guidance of a moderator who keeps the
discussion focused, ensures that everyone participates, and tries to
encourage the participants to discuss topics in-depth.
 An assistant, who does not take part in the discussion, takes notes about
the topics discussed, points of agreement and disagreement, and the
non-verbal interactions of the participants.
 An informal location (e.g., restaurant) and a relaxed atmosphere
encourages open, free-flowing conversation.
SCOPE
 The number of FGDs conducted depends on the target population; if the
target population is homogeneous, fewer groups are needed, but if the
population is diverse, generally 2-4 groups would be held for each
important subgroup.
 Subgroups are usually defined on the basis of factors like urban-rural
location; level of prescriber training; type and size of health facility; or
even quality of previous practices (e.g., health workers who follow
standard treatment norms vs. those who do not).
STRENGTH
 Useful in finding out how people behave and why they behave
differently.

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 Inexpensive to conduct and quick to organize; often the entire process

of planning, recruiting participants, holding discussions, and analyzing
data can take place in as little as 2-3 weeks.
 The exchange of ideas and the support of other participants encourage
participants to express feelings and beliefs.
 Can be very useful in anticipating responses or misunderstanding about
educational materials prepared for an intervention.
WEAKNESSES
 Because participants are not chosen randomly and because only a few
groups are held, opinions and attitudes may not represent the larger
population.
 The success of focus groups depends on the skill of the moderator in
encouraging meaningful discussion among participants.
 The analysis of focus group data can be very subjective and highly
influenced by the biases of the analyst.
 FGDs are good at finding out the direction of behavior, but they only
indicate frequency of behavior in very general terms.
 Some discussions may distort or exaggerate feelings of certain
participants, or they may be dominated by a few strong-willed
individuals.
III. OBSERVATIONS
OVERVIEW
 Systematic observations by trained observers of a series of encounters
between health providers and patients.
 Data can be recorded as a list of observed behaviors and impressions, or
by scoring each interaction on a predetermined set of indicators and
scales.
 In a typical study, a trained observer would first get to know the health
providers to be observed and would introduce a non-threatening reason
for the observations, in order to make their behavior as natural as
possible.
 Observers sometimes keep a diary to record their feelings about the
setting being observed and features of patients or providers that seem
related to observed practices.
SCOPE

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 Observation studies vary greatly in scope. If we want to quantify the

frequency of certain behaviors, the number of encounters observed
needs to be rather large, at least 30 or more in each category of interest
 If we want to understand the typical features of clinical episodes, a few
days' observation in five or six carefully selected settings might be
enough.
STRENGTHS
 Observations are the only feasible way to learn systematically about
what happens during the complex interactions between persons seeking
care and medical providers.
 They are the best method to study issues like patient demand, the
influence of sales attendants on customers' selection of products, or the
quality of communication between prescribers and patients.
 Because health providers are seen in their working environment,
observers can gain insights about behavior that are impossible for an
outsider to obtain.
WEAKNESSES
 Presence of observers may cause shifts towards socially appropriate
behavior; however, in many settings observers "blend in" over time.
 Observation studies require skilled observers, who can make people feel
at ease, and also be careful and unbiased in reporting their observations.
 Observation is less useful when the behaviors of interest occur
infrequently or for only a subgroup of encounters (e.g., for specific age
groups or diagnoses)
IV. QUESTIONNAIRES
OVERVIEW
 Questionnaires contain a fixed set of items that are asked to a large
sample of respondents selected according to strict rules to represent a
larger population.
 Questionnaires are usually administered by interviewers trained to
collect this kind of information in a standardized way.
 Can focus on material that is factual, such as what respondents know, or
on factors that are harder to quantify like attitudes, opinions, or beliefs.
 In contrast to an in-depth interview, all questions are identified in
advance, and each respondent is asked precisely the same questions.

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 Answers are often limited to a fixed set of response categories; if

questions are open-ended, they are coded later according to fixed
criteria.
SCOPE
 Questionnaire surveys usually include at least 50-75 respondents from
the target population.
 If the target population has several subgroups with potentially different
levels of knowledge, attitudes, or opinions, then the sample would
usually include at least 50-75 randomly selected persons from each
subgroup.
 The required sample size depends on the nature of the target
population, how the sample is drawn, the desired degree of accuracy,
and available resources.
STRENGTHS
 Questionnaires are familiar and understandable to most people,
including health managers and respondents.
 Skills required to develop survey forms, design samples, collect and
process data, and analyze results are often locally available.
 Questionnaire surveys are the best method to find out:
1. The frequency of specific behaviors
2. The relative strength of different attitudes and opinions
3. Characteristics of the target population.
WEAKNESSES
 Attitudes and opinions are often difficult to quantify.
 People will sometimes give an answer when asked a direct question,
even if the question is irrelevant or if none of the responses apply.
 Many respondents tend to answer what they feel interviewers expect to
hear.
 Results are sensitive to which questions are asked, and how they are
worded.
 For populations that are not homogeneous, the samples needed are
large, requiring many interviewers or a long period of time to collect the
data.

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SAMPLING TO STUDY DRUG USE

OBJECTIVES
 Describe the principles on which sampling is based
 Identify and describe different sampling methods
 Select a sample of health facilities from a list using at least two different
methods
 Compare the results of the methods
 Instruct others how to sample for drug use studies.

SAMPLING
 Sampling is a process by which we study a small part of a population to
make judgments about the entire population.
 Sampling involves selecting a number of units from a defined
population.
SAMPLING DEFINITIONS
SAMPLING UNIT
 The thing that is sampled: for example, a person, clinical episode, or
health facility.
STUDY POPULATION
 All the sampling units that could possibly be included in the sample.
SAMPLING FRAME
 A list of all the available sampling units in the study population.
REPRESENTATIVE SAMPLE
 A representative sample has all the important characteristics of the
study population from which it is drawn.
SAMPLING METHODS
 Two categories of sampling methods
­ Non-probability sampling
­ Probability sampling
1. NON-PROBABILITY SAMPLING
 Non-probability sampling does not involve random selection. Does that
mean that non-probability samples are not representative of the
population? Not necessarily. But it does mean that non-probability
samples cannot depend upon the rationale of probability theory.

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 With non-probability samples, we may or may not represent the

population well, and it will often be hard for us to know how well we
have done so.
I. CONVENIENCE SAMPLING
 Study units available at the time of data collection are selected for the
sample.
 Example: I would include in this category the traditional "man on the
street" (of course, now it is probably the "person on the street"),
interviews conducted frequently by television news programs to get a
quick (although nonrepresentative) reading of public opinion. I would
also argue that the typical use of college students in much psychological
research is primarily a matter of convenience.
II. QUOTA SAMPLING
 Different categories of sample units are included until a certain number
has been reached in each category. In quota sampling, you select people
non-randomly according to some fixed quota. There are two types of
quota sampling: proportional and non-proportional:
 Proportional Quota Sampling
­ For instance, if you know that population has 40% women and
60% men, and you want a total sample size of 100, you will
continue sampling until you get those percentages.
­ So, if you have already got the 40 women for your sample, but not
the sixty men, you will continue to sample men but even if
legitimate women respondents come along, you will not sample
them because you have already "met your quota.
 Non-Proportional Quota Sampling
­ In this method, you specify the minimum number of sampled units
you want in each category. here, you are not concerned with
having numbers that match the proportions in the population.
­ Instead, you simply want to have enough to assure that you will
be able to talk about even small groups in the population
2. PROBABILITY SAMPLING
 A probability sampling method is any method of sampling that utilizes
some form of random selection.
 In order to have a random selection method, you must set up some
process or procedure that assures that the different units in your
population have equal probabilities of being chosen.

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 Humans have long practiced various forms of random selection, such as

picking a name out of a hat.
I. SIMPLE RANDOM SAMPLING
 Used in situations where the number of sampling units is relatively
small.
 Process of Simple Random Sampling:
­ Identify all possible units available for sampling
­ Decide on the size of the sample
­ Choose units by a lottery method or use computers to generate
random numbers.
II. SYSTEMATIC SAMPLING
 Systematic sampling with equal probability:
­ Numbered list of all possible units
­ # units  desired sample size = sampling interval
­ Random # x sampling interval = random start
­ Round number up to choose sample unit
­ Add sampling interval to random start for subsequent units.
 Systematic sampling with probability proportional to size:
­ Units are sorted in decreasing order by some measure of size (like
population or number of visits)
­ Calculate the cumulative total
­ Cumulative total  sample size = sampling interval
­ Random # x sampling interval = random start
­ Add sampling interval to previous total for subsequent units.
III. STRATIFIED SAMPLING
 Used when the sampling frame contains clearly different categories
(strata), For example,
­ Urban and rural facilities
­ Facilities with and without doctors
­ Government and mission facilities.
 Process of Stratified Sampling:
­ Organize the list of sampling units by stratum
­ Select units within each stratum using a random method (simple
random sampling or systematic sampling).
 It ensures that you will be able to represent not only the overall
population but also the sub-groups.
IV. CLUSTER SAMPLING

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 Used when, for logistic reasons, it is easier to select sample units in

groups.
 Process of Cluster Sampling:
­ Select a cluster of sample units – area or geographical. Example:
health center with multiple prescribers or Islamabad, Rawalpindi.
­ Include the entire cluster or select a subsample or Select a
random sample unit to start each cluster (a house, a patient, etc.)
­ Include neighboring sample units until a certain cluster size is
reached.
V. MULTISTAGE SAMPLING
 Combine the simple methods described earlier in a variety of useful
ways that help us address our sampling needs in the most efficient and
effective manner. When we combine sampling methods, we call this
multi-stage sampling.
 Randomly select primary sampling units at the first stage:
­ Specific communities
­ Specific health facilities
 Within the primary sampling units, randomly select the final sampling
units at the second stage:
­ Drug use encounters
­ Patients
­ Prescribers
 Sometimes in complex samples, additional stages are needed. For
example, consider the idea of sampling Punjab Province residents for
face-to-face interviews. We might sample various districts throughout
the province – cluster sampling but still difficult So, we might set up a
stratified sampling process within the clusters.
 In this case, we would have a two-stage sampling process with stratified
samples within cluster samples cities and then districts.

DRUG USE INDICATORS

 Appropriate use of drugs is one essential element in achieving quality of
health and medical care for patients and the community as a whole.
 To improve drug use practices:
­ An essential tool for such work is an objective method to measure
drug use in health facilities that will describe drug use patterns
and prescribing behavior.

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­ The drug use indicators are intended to measure specific aspects

of the behavior of health providers in health facilities in a
reproducible manner, irrespective of who measures them
or when the measures are taken.
WHO/INRUD (WORLD HEALTH ORGANIZATION/INTERNATIONAL NETWORK OF
RATIONAL USE OF DRUGS)
 Developed drug use indicators to be used as measures of performance in
three general areas related to the rational use of drugs in primary care.
They are called core drug use indicators.
TYPES OF INDICATORS
 Prescribing indicators
 Patient care indicators
 Health facility indicators
1. PRESCRIBING INDICATORS
 The indicators of prescribing practices:
­ Measure the performance of health care providers.
­ Measure several key dimensions for appropriate use of drugs.
 Include practices observed in a sample of clinical encounters taking place
at outpatient health facilities for the treatment of acute or chronic
illness.
 These encounters can be observed
­ Retrospectively
­ Prospectively
AVERAGE NUMBER OF DRUGS PER ENCOUNTER
 Purpose - To measure the degree of polypharmacy.
 Prerequisites - Combination drugs are counted as one.
 Calculation - Average, calculated by dividing the total number of
different drug products prescribed, by the number of encounters
surveyed. It is not relevant whether the patient actually received the
drugs.
 Example - In health centers in Indonesia patients are prescribed an
average of 3.3 drugs per consultation.
PERCENTAGE OF DRUGS PRESCRIBED BY GENERIC NAME
 Purpose - To measure the tendency to prescribe by generic name.

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 Prerequisites - Investigators must be aware of actual names used in the

prescription rather than only having access to the names of the products
dispensed.
 Calculation - Percentage
 Example - In health units in Nepal an average of 44% of drugs are
prescribed by generic name.
PERCENTAGE OF ENCOUNTERS WITH AN ANTIBIOTIC/INJECTION PRESCRIBED
 Purpose - To measure the overall level of use of two important, but
commonly overused and costly forms of drug therapy.
 Prerequisites - A list must be available of all the drug products which are
to be counted as antibiotics; investigators must be instructed about
which immunizations are not to be counted as injections.
 Calculation - Percentages
 Example - In dispensaries in Nigeria 48% of all outpatient encounters
were prescribed one or more antibiotics, while an injection was
prescribed during 37% of all consultations.
PERCENTAGE OF DRUGS PRESCRIBED FROM ESSENTIAL DRUGS LIST OR
FORMULARY
 Purpose - To measure the degree to which practices conform to a
national drug policy.
 Prerequisites - Copies of a published national essential drugs list or local
institutional formulary to which data on prescribed drugs can be
compared.
 Calculation - Percentage
 Example - In dispensaries in Tanzania on average 88% of drugs
prescribed appeared on the national essential drugs list.
2. PATIENT CARE INDICATORS
 To understand way drugs are used it is important to consider what takes
place at health facilities from both the provider's and the patient's
perspectives. Patients - with a set of symptoms and complaints, and with
expectations about the care they will receive - leave with a package of
drugs or with a prescription to obtain them in the private market.
 The patient care indicators - what patients experience at health facilities,
and how well they have been prepared to deal with the pharmaceuticals
that have been prescribed and dispensed.

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AVERAGE CONSULTATION TIME

 Purpose - To measure the time that medical personnel spend with
patients.
 Prerequisites - accurate recording - the time between entering and
leaving the consultation room. Waiting time is not included.
 Calculation - Average, calculated by dividing the total time for a series of
consultations, by the number of consultations.
 Example - In Malawi patients spend an average of 2.3 minutes with
health workers in the consultation room.
AVERAGE DISPENSING TIME
 Purpose - To measure the average time that personnel dispensing drugs
spend with patients.
 Prerequisites - accurately recording the average time patients spent with
pharmacists, - the time between arriving at the dispensary counter and
leaving. Waiting time is not included.
 Calculation - Average, calculated by dividing the total time for dispensing
drugs to a series of patients, by the number of encounters.
 Example - In health centers in Tanzania patients spend an average of 78
seconds receiving their drugs.
PERCENTAGE OF DRUGS ACTUALLY DISPENSED
 Purpose - degree to which health facilities are able to provide the drugs
which were prescribed.
 Prerequisites - Information on which drugs were prescribed, and
whether these drugs were actually dispensed at the health facility.
 Calculation - Percentage,
 Example - In health facilities in Nepal, 73% of prescribed drugs were
actually dispensed at the health facility.
PERCENTAGE OF DRUGS ADEQUATELY LABELLED
 Purpose - degree to which dispensers record essential information on
the drug packages they dispense.
 Prerequisites - Investigators must be able to examine the drug packages
as they are actually dispensed at the health facility.
 Calculation - Percentage,

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 Example - In Region A only 10.2% of drugs dispensed were adequately

labelled.
PATIENTS' KNOWLEDGE OF CORRECT DOSAGE
 Purpose - effectiveness of the information given to patients on the
dosage schedule of the drugs they receive.
 Prerequisites - Access to a written prescription or to a patient card
against which patients' knowledge on the dosage schedule can be
checked
 Calculation - Percentage,
 Example - In 23 health facilities in Bangladesh 63% of patients were able
to repeat the correct dosage schedule of the drugs they had received.
3. HEALTH FACILITY INDICATORS
 The ability to prescribe drugs rationally is influenced by many features of
the working environment.
 Two particularly important components
­ An adequate supply of essential drugs
­ Access to unbiased information about these drugs.
AVAILABILITY OF COPY OF ESSENTIAL DRUGS LIST OR FORMULARY
 Purpose - extent to which copies of the national essential drugs list or
local formulary are available at health facilities.
 Prerequisites - A national essential drugs list or a local formulary must
exist for that level of care.
 Calculation - Yes or no, per facility.
 Example - In Country A only 28% of health facilities had a copy of the
national list of essential drugs.
AVAILABILITY OF KEY DRUGS
 Purpose - availability at health facilities of key drugs - common health
problems.
 Prerequisites - A short list of 10-15 essential drugs must be compiled
that should always be available.
 Calculation - Percentage, available/stock * 100
 Example - In health centers in Nigeria, on average 62% of 14 key
essential drugs were actually in stock.

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STUDY DESIGN OF DRUG USE INDICATOR

 Three main objectives
­ To describe current treatment practices
­ To compare performances of individual facilities and prescribers
­ Monitor drug use behaviors
SELECTION OF FACILITY
 The first activity is to select the type of health facilities to be studied,
drawing randomly from a larger group of facilities. Prescribing indicators
measure aspects of outpatient treatment. They are designed for use in
health centers, dispensaries or hospital outpatient departments, both
public and private.
 In general, a single drug use study would focus on one type of facility, so
that the results make sense. The prescribing indicators are less useful in
inpatient settings, or in specialty outpatient clinics in referral hospitals
where the drug use patterns are more complex.
TYPE OF PRESCRIBING ENCOUNTER TO BE INCLUDED
 In addition to general medical visits for acute or chronic illness, there
can be separate clinics for well-child visits, pre-natal and post-natal
visits, dental visits, specialist consultations, and so forth. Adult,
paedreatics, new patients or re-attendants. Treatment practices for
these different types of encounters can be quite different.
 A study which mixes different types of encounters in an unsystematic
way will produce results that are difficult to interpret. Indicators studies
should be restricted to a sample of general illness encounters,
representing a mix of health problems and ages.
CHOOSE – RETROSPECTIVE OR PROSPECTIVE DATA
RETROSPECTIVE
 Drawing random encounters from historical medical records
 If adequate resources of retrospective data exist
 Include – clinical registers, treatment records and copies of prescriptions
 Method of selecting random sample of patient encounter
 Specific names and routes of drug administrations
 Major weakness – incomplete.
PROSPECTIVE

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 Data from the patients as they present for the treatment in patient care
and facility indicators always require the collection of prospective data.
 Prospective data is often complete and generally collected over a short
period of time.
 Major weakness:
­ May exist biases
­ Seasonality, peculiarities in staffing
­ Providers know they are being observed
­ Results in socially desirable directions
SAMPLE SIZE OF DRUG USE INDICATORS
 Studies of drug use practices sometimes use an incorrect unit of analysis.
 Prescribing practices in a group of health facilities can be thought of in a
variety of different ways which include:
­ Areas or locations - a sample may include different regions or
districts; or within a single region, it might include urban, peri-
urban and rural areas.
­ Health facilities - a sample may be drawn from a number of health
facilities of the same type, or from different types of facilities such
as hospital outpatient departments, polyclinics and health
centers.
­ Health providers - sometimes it will be possible to know the
identity and background of the individual providers (doctors,
nurses, paramedical workers, pharmacists) who treated patients
in the sample, and to examine provider-specific differences in
treatment patterns;
­ Prescribing encounters - encounters are collected from several
health facilities in the sample and studied as a whole.

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INTRODUCTION TO ESSENTIAL DRUGS

DEFINITION
Essential medicines, as defined by the World Health Organization, are the
“medicines that satisfy the priority health care needs of the population"

THE CONCEPT OF ESSENTIAL MEDICINES

 A limited range of carefully selected essential medicines leads to better
health care, better drug management, and lower costs. These are the
medications to which people should have access at all times in sufficient
amounts. The prices should be at generally affordable levels.
 These essential medicines should be:
­ Available at all times
­ In adequate quantities
­ In appropriate dosage forms
­ At affordable prices.

EDL BACKGROUND
 Twenty-eighth World Health Assembly in 1975, EDL idea was
materialized. The Director General pointed out that the selection of
essential drugs would depend on the health needs and on the structure
and development of the health services of each country. Lists of
essential drugs should be drawn up locally, and periodically updated,
with the advice of experts in public health, medicine, pharmacology,
pharmacy and drug management. By resolution WHA 28.66 the
Assembly requested the Director-General to advise Member States on
the selection and procurement, at reasonable costs, of essential drugs
corresponding to their national health needs.
 Following wide consultation, an initial Model List of Essential Drugs was
included in the first report of the Expert Committee on the Selection of
Essential Drugs in 1977. The concept of essential drugs was quickly taken
up by Member States: by the end of 1998 about 140 countries had
developed their own national lists of essential drugs, often in
combination with standard treatment guide-lines and stratified
according to the level of care. Many countries have also successfully

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applied the concept to teaching hospitals and facilities providing

specialized care. Health insurance schemes increasingly use national lists
of essential drugs as a reference.

HISTORY
 The first WHO EDL was published in 1975 – including 220 medicine and
vaccines. List is revised every two years by WHO expert committee. In
2002, revised procedure approved by WHO. Revisions were made
essential to provide up to date information due to constant change in
medical needs of population and due to availability of newer medicines.
 The term essential drug list (EDL) was replaced by essential medicine list
(EML), due to wrong notion of general pubic as specific drugs as
potential of abuse. Requirement of EML may vary from country to
country and even with in a state – essential drugs one country may not
be essential to another due to disease prevalence and economic
conditions. Keeping this in view, WHO made a list of EML which serve as
a guide for other countries to develop their own. WHO gave freedom to
the countries to add or delete drugs as per their requirements.

RATIONALE BEHIND THE ESTABLISHMENT OF EDL

 Advancement of science and technology gave birth to numerous brands
of drugs – indiscriminately marketed sans taking into account health
care needs of local population. Another important and major concern is
that population belonging to the rural areas could not access the
essential drugs.
 The reality that for millions of people – particularly poor and
disadvantaged – the medicine are unavailable, unaffordable, unsafe and
improperly used.
 More than 156 countries have a national list of essential drugs, out of
which 81% have been updated in the last 5 years and one third in two
years. In 2007, 30 years after the introduction of essential medicine
concept, a model EML for children was also introduced. But it does not
mean that drugs mentioned are limited, thus it should not be viewed
that those drugs that do not find a mention in EML are not useful.

EDL IN PRACTICE
 Model lists have proved to be valuable in improving the quality of health
care and reducing costs. Better quality of care is achieved when the list

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of essential drugs is linked to evidence-based treatment guidelines,

especially when the supply system guarantees the availability of the
selected drugs. Treatment guidelines can also focus training and serve as
a standard for supervision and medical audit; prescribers become more
familiar with the drugs and can better recognize adverse drug reactions.
Lower costs are achieved through selecting cost-effective treatment.
 A limited range of drugs in the supply system may lead to economies of
scale and competition between manufacturers, further reducing the
costs. Market approval of a pharmaceutical product is usually granted on
the basis of efficacy, safety and quality and rarely on the basis of a
comparison with other products already on the market, or cost.
However, in some developing and most developed countries the
majority of drug costs are covered by public funds or through health
insurance schemes. Most public drug procurement and insurance
schemes have mechanisms to limit procurement or reimbursement of
drug costs.
 An evaluation process is therefore necessary, based on a comparison
between various drug products and on cost/benefit considerations. The
advantage of a new treatment over the existing one is then compared to
its extra cost. Such information has proved very helpful in taking
informed decisions about the selection of essential drugs. The model list
is intended to help with this evaluation.

EDL CONCEPT AND RATIONALIZATION OF DRUG USE IN HEALTH CARE

 Greater international coordination – whether drug donations are
needed. Shorter lists are valuable in emergency situations. Model lists
are informational and educational tools for health professionals and
consumers. Addresses issued related to drug use. Helpful in developing
strategies of drug procurement, supply, donations, financing, research
priorities for drug use in specific diseases.
RECENT TREND
 The first lists - a means to guide the procurement of drugs. In recent
years, more emphasis has been placed on the development of treatment
guidelines as the basis for drug selection and supply, and on the
evidence underlying the development of those treatment guidelines.

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EDL AND DEGREE OF EXPERTISE

 Now many medications which require a high degree of expertise to
ensure safe and effective use. Adequate specialist skills and
complementary resources are needed before the introduction of some
classes of drugs.
 Examples of situations where specialist control of drug use is necessary
are:
­ The use of reserve antimicrobials for multidrug-resistant bacteria.
­ Establishing adequate regimens for treatment of tuberculosis and
leprosy.
­ The use of antineoplastic and immunosuppressive drugs. The use
of antiretroviral drugs.
­ The use of antimicrobial, antifungal and antiviral agents for the
treatment of opportunistic infections in immunocompromised
patients.

PRINCIPLES UNDERLYING THE CONCEPT OF EDL

 Medicine list only comprises a selected number of medicines that could
be used effectively in treating numerous conditions in majority of
population. These limited drugs can be procured, distributed and utilized
in a more rational, economic and efficient manner.
 Since the drugs in the list have proven benefits, efficacy and safety, the
prescribers should be trained and educated in the use of drugs. The
personnel involved in the health care system should educate patients
regarding their drug therapy which becomes easy with limited number
of drugs.

EDL – A COMMON CORE

 A tentative identification of a “common core” of basic drugs which have
universal relevance and applicability with the full understanding that
exclusion does not imply rejection.
 This does not imply that no other drugs are useful, but simply that these
basic drugs, when used in accordance with appropriate therapeutic
guidelines, are the most cost-effective for meeting the health care needs
of majority of the population.
 In certain situations, there is a need to make available additional drugs
essential for rare diseases. (orphan drugs)

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MODEL LIST OF ESSENTIAL MEDICINE

 The classification of drugs has been done based on the therapeutic
indication. The model list comprises of 27 classes in alphabetic order.
Each class of therapeutic agent have been further subdivided
­ E.g. anti-infective drugs are subdivided into anthelmintics, anti-
fungal and anti-bacterial.
 The drugs that are mentioned in the list are those that are commonly
used and easily available dosage forms.
ESSENTIAL MEDICINES WHO MODEL LIST
1. Anesthetics
1.1 General anesthetics and oxygen
1.1.1 Inhalation medicines
Halothane Inhalation
Isoflurane Inhalation
Nitrous oxide Inhalation
Oxygen Inhalation (medicinal gas).
1.1.2 Injectable medicines
Ketamine Injection: 50 Mg (as hydrochloride)/ml in 10-ml
vial.
Propofol Injection: 10 mg/ml: 20 mg/ml.
1.2 Local anesthetics
□ Bupivacaine Injection: 0.25%; 0.5% (hydrochloride) in vial.
Injection for spinal anesthesia: 0.5%
(hydrochloride) in 4-ml ampoule to be mixed
with 7.5% glucose solution.
□ Lidocaine Injection: 1%; 2% (hydrochloride) in vial.
Injection for spinal anesthesia: 5%
(hydrochloride) in 2-ml ampoule to be mixed
with 7.5% glucose solution.
Topical forms: 2% to 4% (hydrochloride).
Lidocaine + Epinephrine (Adrenaline) Dental cartridge: 2% (hydrochloride) +
epinephrine 1:80 000.
Injection: 1%; 2% (hydrochloride or sulfate) +
epinephrine 1:200 000 in vial.
Complementary List
Ephedrine Injection: 30 mg (hydrochloride)/ml in 1-ml
ampoule.
(For use in spinal anesthesia during delivery, to
prevent hypotension).
1.3 Preoperative medication and sedation for short-term procedures
Atropine Injection: 1 mg (sulfate) in 1-ml ampoule.
□ Midazolam Injection: 1 mg/ml.
Oral liquid: 2 mg/ml [c].
Tablet: 7.5 mg; 15 mg.
Morphine Injection: 10 mg (sulfate or hydrochloride) in 1-ml
ampoule.

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 The square box symbol (□) is primarily intended to indicate similar clinical performance
within a pharmacological class.
 Where the [c], symbol is placed next to the complementary list it signifies that the
medicine(s) require(s) specialist diagnostic or monitoring facilities, and/or specialist medical
care, and/or specialist training for their use in children.
 The generic names of drugs have been used which is accompanied by their respective doses
and available dosage forms.

Clinical guidelines and a list of essential medicines lead to better prevention and care

CRITERIA FOR SELECTING EDL

 The selection of drugs should be based on the experience rather than on
opinion. These medicines with long history of safety and efficacy
determined by clinical studies should be included. Inclusion of fewer
drugs should be made only when these drugs offer any significant
advantage over the existing ones. The quality, bioavailability and
stability should be the set standards.
 The choice of essential medicines depends on several factors, including
the disease burden and sound & adequate data on the efficacy, safety
and comparative cost- effectiveness of available treatments.
 Stability in various conditions, the need for special diagnostic or
treatment facilities and pharmacokinetic properties are also considered
if appropriate. Most essential medicines should be formulated as single
compounds. Fixed-ratio combination products are selected only when
the combination has a proven advantage in therapeutic effect, safety or
compliance over single compounds administered separately.
- Examples of combination medicines that have met these criteria
include new formulations for tuberculosis and malaria.
 In cost comparisons between medicines, the cost of the total treatment,
and not only the unit cost of the medicine, is considered. Cost and cost-

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effectiveness comparisons may be made among alternative treatments

within the same therapeutic group but will generally not be made across
therapeutic categories (for example, between treatment of tuberculosis
and treatment of malaria). The absolute cost of the treatment will not
constitute a reason to exclude a medicine from the Model List that
otherwise meets the stated selected criteria.
- The patent status of a medicine is not considered in selecting
medicines for the Model List. In cases where two drugs bear close
resemblance with respect to efficacy, stability, bioavailability etc.
then the drug with thorough investigation should be selected:
- Which has more appealing PK parameters.
- Which can be prepared in appreciable quantity and quality at an
affordable cost.
 The cost to benefit ratio is an important criteria, in simple terms rather
than unit cost – total cost of the treatment should be taken into account.
 WHO maintains that a single drug or an active ingredient should find a
mention in EML. The fixed combination drugs should be mentioned only
when they offer relatively better therapeutic efficacy, safety patient
compliance etc.
 If pharmaceutical dosage form is the criteria for selecting drugs, then the
following guidelines should be considered:
- The dosage form which has appreciable utility and widely
available should be selected.
- PK profile and extent of bioavailability.
- Stability of the dosage form under the storage conditions
prevalent in the area.
- Dosage forms for special groups like pediatrics, geriatrics and
pregnancy.
- The controlled and sustained release forms of short acting drugs
should find a mention only accompanied with justifiable
documentation.
FACTORS AFFECTING EDL CRITERIA
1. Pattern of prevalent diseases
2. The treatment facilities
3. The training and experience of the available personnel
4. The financial resources
5. Genetic, demographic and environmental factors.

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6. Some drugs are considered essential only if a therapeutic program is

planned to address the diseases for which these drugs are used.
- For example, the cytotoxic drugs are essential only if a
comprehensive cancer treatment program is planned. Such a
program requires adequate hospital, diagnostic and clinical
laboratory facilities for its implementation.
7. In contrast, the drugs used in palliative care are always essential, even
when a comprehensive cancer treatment program does not exist.

CONSIDERATION OF PHARMACEUTICAL DOSAGE FORM

 As a general rule, pharmaceutical forms are selected on the basis of their
general utility and wide availability internationally. In many instances, a
choice of preparations is provided, particularly in relation to solid dosage
forms. Tablets are usually less expensive than capsules, but, while cost
should be taken into account, the selection should also be based on a
consideration of pharmacokinetics, bioavailability, stability under
ambient climatic conditions, availability of excipients, and established
local preference.
 In a few instances where there is no uniformity of tablet strength (for
example acetylsalicylic acid and paracetamol), a dosage range is
provided from within which suitable tablet strengths should be selected
on the basis of local availability and need. Specific pediatric dosages and
formulations are included in the list only when indicated by special
circumstances. In many instances, dosage is specified in terms of a
selected salt or ester, but in others (for example chloroquine) it is
calculated, in accordance with common practice, in terms of the active
moiety.
 For certain drugs with short half-lives that are rapidly metabolized, such
as carbamazepine, calcium-channel blockers and theophylline,
conventional-release dosage forms must often be taken three or four
times a day to maintain drug levels in the required narrow range.
Sustained release dosage forms can reduce the frequency of drug
administration, thereby improving compliance and, often, the
therapeutic effectiveness of the drug by maintaining a more constant
drug level than can be obtained using traditional dosage forms. Because
the preparation of sustained-release products is difficult and requires
special expertise, a proposal to include such a product in a national list
of essential drugs should be justified by adequate documentation.

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STEPS IN THE DEVELOPMENT OF EDL

1. Prioritize a list of common problems/diseases being treated in the
hospital and determine the first choice of treatment for each problem.
2. Draft, circulate for comment, and finalize the formulary list.
3. Develop policies and guidelines for implementation.
4. Educate staff about the formulary list and monitor implementation.
5. Managing a formulary list (EML): adding and deleting drugs.

PRINCIPLES OF EML MANAGEMENT

1. Select drugs according to the needs of patients.
2. Select drugs of choice for the conditions identified.
3. Avoid duplications, both therapeutic and pharmaceutical (dosage
forms).
4. Use explicit selection criteria, based on proven efficacy, safety, quality
and cost.
5. Use evidence-based information whenever possible.
6. Be consistent with national EMLs and STGs.
7. Consider requests for the addition of new drugs only when made by
health-care staff, not by the pharmaceutical industry.
8. Require that requests for the addition of new drugs are justified using
documented evidence on efficacy, relative efficacy, safety and
comparative cost-effectiveness and that the person requesting any new
drug declare any conflict of interest.
9. Carry out annual systematic reviews of all therapeutic classes to avoid
duplication.

QUALITY ASSURANCE OF EDL

 Priority should be given to ensuring that the available drugs have been
made according to good manufacturing practices and are of generally
recognized quality. This requires knowledge of and confidence in the
origin of the product. The risks of procuring drugs from anonymous
sources cannot be over stressed.
 It is recommended that drugs should be purchased directly from known
manufacturers, their duly accredited agents or recognized international
agencies known to apply high standards in selecting their suppliers.
 Quality assurance of drugs, as embodied in product development, good
manufacturing practice and subsequent monitoring of quality
throughout the distribution chain to utilization, is a crucial element in

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any essential drug program. The importance of the bioavailability of

drugs in the assessment of their quality.

PHARMACO-VIGILANCE AND EDL

 Little is known about the clinical consequences of different prescribing
patterns between countries or between regions within a country.
Systematic and comprehensive data are available on the use of drugs
after they have been marketed, However, data are often not used to
their full potential or in accordance with generally accepted criteria.
 Moreover, data on the effects of overdose and uncommon or long-term
adverse effects are usually not available at the time of registration. To
optimize the usefulness and/or benefits of drugs in actual use,
continuing pharmaco-vigilance is needed.

BENEFITS OF EDL
1. The concept helps to focus the national revenue to the essential
medicines, required by majority of the drugs thereby decreasing the
foreign exchange.
2. This concept is basically concerned with increasing the availability of
essential drugs to the hardest populations residing in the rural areas.
3. The essential drugs list proves to be beneficial which eases the problems
encountered drug prescription. Moreover, limited no. of drugs in the list
ease the process of dispensing and enhance the patient compliance.
4. Due to limited no. of essential drugs mentioned in the list, their
procurement, supply and storage can be made in systemic manner. This
ultimately assures continuous supply, effective management of stock
and reduction in waste.
5. The essential drug concept though indirectly may prove to be beneficial
in reducing the poverty, the easy availability of the health care and
improves the standard of living.
ADVANTAGES
 Better procurement policies
 Better transport and management
 Recusing the cost of procurement
 Effective monitoring and evaluation of pharmaceutical use
 Effective control of pharmaceuticals in public circulation

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 Enforcing rational prescribing by focusing on limited list of

pharmaceuticals.
COMPULSORY TO ONLY PRESCRIBE DRUGS UNDER THE MODEL
 It allows the countries, states or even hospital to compile an EML of their
own according to their needs (WHO model list serve as a guide)
 The list being flexible can be regularly updated to keep up with the rapid
advancements made in the field of pharmacy.
A CONTINUAL PROCESS
 The selection of essential drugs is a continuous process, which should
take into account changing public health priorities and epidemiological
conditions, as well as progress in pharmacological and pharmaceutical
knowledge.
 It should be accompanied by a concomitant effort to supply information
and provide education and training to health personnel in the proper
use of the drugs.

STEPS IN REVIEW OF APPLICATIONS TO THE MODEL LIST

1 Summary of application posted on WHO Medicines website.
2 Specialist assessment of comparative efficacy, safety and cost-
effectiveness.
3 Review of assessments by Expert Committee member (“presenter”);
formulation of draft recommendation.
4 Review of draft recommendation by relevant Expert Advisory Panel
members; and posted on WHO Medicines website.
5 Review by presenter, prepares final draft recommendation.
6 Discussion of draft recommendation and proposed text for WHO Model
Formulary by the Expert Committee.

PAKISTAN DRUG POLICY

1 The specific objective of the National Drug Policy are as under:
a. To develop and promote the concept of essential drugs ensure
regular, uninterrupted and adequate availability of such drugs of
acceptable quality and at reasonable prices.
b. To inculcate (educate/teach) in all related sectors and personnel
the concept of rational use of drugs with a view to safeguarding
public health from over-use, mis-use or inappropriate use of
drugs.

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c. To encourage the availability and accessibility of drugs in all parts

of the country with emphasis on those which are included in the
National Essential Drugs List.
d. To attain self-sufficiency in formulation of finished drugs and to
encourage production of pharmaceutical raw materials by way of
basic manufacture of active ingredients.
e. To protect the public from hazards of substandard, counterfeit
and unsafe drugs.
f. To develop adequately trained manpower in all fields related to
drugs management.
g. To develop a research base particularly for operational and
applied research with a view to achieving the above-mentioned
objectives.
h. To develop the pharmaceutical industry in Pakistan with a view to
meeting the requirement of drugs within the country and with a
view to promoting their exports to other
2 In order to ensure availability of safe, effective and quality products at
reasonable prices.
3 Pakistan has a fairly modern legislation namely the Drugs Act, 1976.
4 Under this law comprehensive rule have also been framed on various
aspects of drug control.
5 The law provides a system of licensing of each manufacturing house and
registration of all finished drugs with a view to ensuring efficacy, safety
and quality of the drugs sold in the market.
6 For licensing and registration Central Licensing and Registration Board
comprising of experts from the field of medicines and pharmacy are
established.
7 Quality Control is ensured through inspection and laboratory services.
8 The law also provides for compliance of Good Manufacturing Practice by
the manufacturers, for fixing drug prices and for regulation of imports,
export, and sale of drugs.
9 Under this Act, the manufacturing, registering and import/export are
regulated by the Federal Government whereas the sale is regulated by
the Provincial Governments.

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NATIONAL ESSENTIAL DRUGS LIST (NEDL)

PREPARATION OF NEDL
 The Federal Government and each provincial government until 1993 had
their own lists of drugs for purchases for the government institutions.
 There was urgent need to prepare a National list of Essential Drugs of
Pakistan with graded lists for various levels to be implemented uniformly
both at the Federal and Provincial levels.
 A National Essential Drugs List of Pakistan was thus prepared in 1994 in
view of the health needs of the country with the help of specialists
organizations in the field of medicines and pharmacy from all over the
country.
BULK PURCHASES FOR HEALTH INSTITUTIONS
 Bulk purchases of drugs for all government and semi-government health
institutions shall be made in accordance with this list.
 Effective and well-organized operating systems shall be developed for
procurement and distribution of such drugs for the population. This shall
envisage quantification of the actual needs for drugs and effective
logistics for supply.
PROMOTION OF ESSENTIAL DRUGS CONCEPT
 The Essential Drug Concept and the National Essential Drug List will be
promoted in the public and private sector. Policy will be geared to
increase share of essential drugs in local production and to make such
drugs available at affordable prices where-ever needed. Efforts will also
be made to promote rationality in essential drug prescribing and use. To
encourage this, Drug Information Sheets in line with those of WHO
model providing concise, accurate and comprehensive information shall
be prepared and widely circulated.
 A comprehensive public information shall be launched to enhance
understanding and acceptance of the Essential Drugs Concept by the
patient and the health care personnel. The doctors in the public sector
shall be persuaded to prescribe rationally cost-effective drugs from the
Essential Drugs List.
 Unbiased information about drugs shall be published and widely
circulated to the Federal and Provincial Health Institutions. A system of
audit and accountability shall also be introduced.

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REVIEW OF NEDL
 Periodically reviewed and revised every year and made more pragmatic
by a committee that includes competent specialists in clinical medicine,
pharmacology and pharmacy and from other related fields and
published.
CRITERIA FOR SELECTION OF EDS
 For the selection of essential drugs and for establishing a national
program for the use of essential drugs, the guidelines and criteria
recommended by the WHO shall be followed.
AVAILABILITY OF EDS
 Essential drugs which could be in short supply - establishment of hospital
pharmacy for manufacture of such drugs and also by providing
incentives to the local industry
CONSTITUTION OF HOSPITAL PHARMACY AND THERAPEUTIC COMMITTEE
 All teaching divisional and district hospitals shall constitute “Pharmacy
and Therapeutic Committees” to monitor and promote rational use of
drugs in the hospitals.
GENERIC NAMES FOR EDS
 Only generic names will be used for drugs in the NEDL all public sector
drug lists, inventory sheets and tender documents.

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Chapter 3 – DUE / DUR

DRUG UTILIZATION EVALUATION (DUE) /

DRUG UTILIZATION REVIEW (DUR)

Acronyms associated with the evaluation of medications use;

DRUG USE REVIEW (DUR): 1969, prescription drugs. Retrospective evaluation
to monitor medication use patterns (trends) and it was quantitative.
ANTIBIOTIC USE REVIEW (AUR): 1978, Retrospective evaluation of antibiotic
use and it was also quantitative. It was limited to identifying pattern of use.
DRUG USE EVALUATION (DUE): 1986, Multidisciplinary involvement.
Expansion of AUR to all drugs. It was limited to the evaluation of prescribing
and outcome only.
MEDICATION USE EVALUATION (MUE): 1992, Expansion of DUE to include all
medications. Evaluation expanded to include all aspects of medication use:
Prescribing, dispensing, administration, monitoring etc.

DEFINITION
“MUE is a performance improvement method that focuses on evaluating and
improving medication – use processes with the goal of optimal patient
outcomes.”
 MUE may be applied to a medication or therapeutic class, disease state
or condition, a medication-use process (prescribing, preparing and
dispensing, administering, and monitoring), or specific outcomes. It is a
potential tool in the evaluation of health care system, with main
objective to ascertain drug use in society.
 Casual observation, as well as more systematic study of prescribing
practices, frequently reveals a pattern of diversity among prescribers in
the treatment of even the most common conditions.

SPECIFIC POPULATION
 Elderly – incorrect use of medication and poly-pharmacy
 Children – poor development of functions and most of the drugs are
intended for adults.

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IMPROVED OUTCOMES
 Decrease in Potential hazards
 Decrease in Un-necessary finances
 Thus, it is necessary to have a periodic review of the pattern of drug
utilization to ensure safe and effective treatment.

PURPOSE
 The purpose of DUR is to ensure drugs are used appropriately, safely and
effectively to improve patient health status.

RISING IMPORTANCE OF DUE

 All these factors contribute to the increasing importance of DUE.
­ The boost in the marketing of new drugs
­ Wide variations in the pattern of drug prescribing and
consumption
­ Growing concern about the delayed adverse effects,
­ Increasing concerns regarding the cost of drugs and
­ Volume of prescription.

CRITERIA
 Predetermined criteria for appropriate drug therapy are compared
against a patient’s or a population’s records. Non-adherence to criteria
results in drug therapy changes.
 In addition, continual improvement in the appropriate, safe and
effective use of drugs has the potential to lower the overall cost of care.
 DUR allows the pharmacist to document and evaluate the benefit of
pharmacy intervention in improving therapeutic and economic
outcomes while demonstrating the overall value of the pharmacist.
 Prospective DUR often relies on computerized algorithms to perform key
checks including drug interactions, duplications or contraindications with
the patient’s disease state or condition.

ISSUES REQUIRING DUE

 Poly-pharmacy is one problem; providers may use three, four, five, and
sometimes more medicines to treat the most trivial conditions for the
sake of satisfying a patient’s need to receive medicines (or the
pharmaceutical seller’s need for profit). Other reasons for poly-

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pharmacy include lack of diagnostic competence or confidence and an

inadequate knowledge of treatment regimens.
 Other common medicine use problems are choosing incorrect
medicines, prescribing the incorrect dose, prescribing medicines that
cause adverse drug reactions (ADRs) or medicine interactions, and using
more expensive medicines when less expensive medicines would be
equally or more effective.

GENERAL AIM
 A system of improving the quality of medicine use in hospitals and
clinics, is an ongoing, systematic, criteria-based program of medicine
evaluations that will help ensure the appropriate use of medicine.
 A DUE can be structured so that it will assess the actual process of
administering or dispensing a medicine (i.e., appropriate indications,
dose, medicine interactions) or assess the outcomes (i.e., cured
infections, decreased lipid levels.)

OBJECTIVES
1. Promoting optimal medication therapy
2. Preventing medication-related problems
3. Evaluating the effectiveness of medication therapy
4. Improving patient safety
5. Establishing interdisciplinary consensus on medication-use processes
6. Stimulate improvements in medication-use processes
7. Ensure standardization in medication-use processes
8. Enhancing opportunities, through standardization, to assess the value of
innovative medication-use practices from both patient-outcome and
resource-utilization perspectives
9. Minimizing procedural variations that contribute to suboptimal
outcomes of medication use
10.Identifying areas in which further information and education for health
care professionals may be needed
11.Minimizing costs of medication therapy. These costs may be only partly
related to the direct cost of medications themselves
12.When medications are selected and managed optimally from the outset,
the costs of complications and wasted resources are minimized, and
overall costs are decreased

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13.Meeting or exceeding internal and external quality standards (e.g.,

professional practice standards, accreditation standards, or government
laws and regulations)
14.Enhancing accountability in the medicine use process.

SCOPE OF DRUG USE EVALUATION

 Drug use evaluation (DUE) aims to understand how and why drugs are
used so as to improve appropriate drug use and the health outcome.
 DUE can be aimed to analyze the present and the developmental trends
of drug usage at various levels of the health care system, whether
national, local or institutional.
 DUE may evaluate drug use at a population level, based on the
demographic details.
 These studies are used to calculate the reported adverse drug reactions,
to monitor the utilization of various categories of drugs, to monitor the
regulatory activities.
 Drug utilization data may be used to produce crude estimates of disease
prevalence, such as cardiovascular disease.
 Drug utilization data may be also used to plan drug importation,
production, and distribution, and to estimate drug expenditures.

NEED OF DRUG UTILIZATION RESEARCH

 The aim is to facilitate the rational use of drugs in populations. In
individual patients, the rational drug use implies the prescription of a
well-documented drug in an optimal dose on right indication at an
affordable price.
 It is important to realize that inappropriate use of drugs represent a
potential hazard to the patients and an unnecessary expense. It is
difficult to understand the rational use of drug without the knowledge
on how drugs are being prescribed.
 DUE contributes to:
­ Rational drug use by describing the drug use pattern and
interventions.
­ Helps in understanding how drugs are being used by making
estimates of number of patients exposed to drugs, describing and
estimating to what extent the drugs are used at certain area,
whether overused or underused.

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­ It compares the observed patterns of drug use with current

recommendations or guidelines.
­ Feedback is provided to the prescribers based on the drug
utilization data collected.
­ Drug utilization research enables to assess whether interventions
undertaken improves the drug use by monitoring and evaluating
patterns of drug use.

TYPES OF DRUG USE INFORMATION

DRUG BASED INFORMATION
 Detailed information is usually required to answer clinically important
questions which may involve aggregation of drug use at various levels,
and information on indications, doses and dosage regimens.
PROBLEM BASED INFORMATION
 The question must be addressed to know more about the problem that
is being managed instead of knowing about the particular group of drugs
used for any condition.
PATIENT INFORMATION
 Demographics and other information will be useful for the studies. The
age distribution has critical importance in some cases e.g., to know
whether the drug is being used in an age group different from that in
which clinical trials were performed.
 The co-morbidities of the patient group may be important in
determining treatment choice and adverse effects. For example in the
management of hypertension in asthma patients, beta blockers should
be avoided.
PRESCRIBER INFORMATION
 The differences in the drug prescribing often lack rational explanations.
This type of information helps to determine the prescribing behavior
which is often helpful to understand how and why drugs are prescribed.

ROLE OF PHARMACIST IN DUE

 Pharmacists, by virtue of their expertise and their mission of ensuring
proper medication use, should exert leadership role and work
collaboratively with other members of the healthcare team in the
ongoing process of medication-use evaluation and improvement.

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 Responsibilities of pharmacists in the MUE process include;

­ Developing an operational plan for MUE programs and processes
that are consistent with the health system’s overall goals and
resource capabilities.
­ Working collaboratively with prescribers and others to develop
criteria for specific medications and to design effective
medication-use processes.
­ Reviewing individual medication orders against medication-use
criteria and consulting with prescribers and others in the process
as needed.
­ Managing MUE programs and processes.
­ Collecting, analyzing, and evaluating patient-specific data to
identify, resolve, and prevent medication-related problems.
­ Interpreting and reporting MUE findings and recommend changes
in medication-use processes.
­ Providing information and education based on MUE findings.

A STEP WISE APPROACH TO DUE

I. ESTABLISH RESPONSIBILITY
 Drug therapeutic committee (DTC) monitor DUEs in hospital and clinics.
The DTC must establish procedures that will govern the committee in its
activities concerning medicine use review and evaluation.
 DTC must establish a plan, outlining which medicines will be a part of the
DUE process. This plan needs to be updated and evaluated each year.
II. DEVELOP SCOPE OF ACTIVITIES
 The scope can be extensive or it can focus on a single aspect of
pharmaceutical therapy.
 Methods to identify medicine use problems includes:
­ ABC or vital, essential, nonessential (VEN) analysis, defined daily
dose analysis, ADR reports, medication error reports, antibiotic
sensitivity results, procurement studies, hospital and primary care
clinic indicator studies, patient complaints or feedback, and staff
feedback.
 DTC must concentrate on the most important medicines, those with the
highest potential for problems, to get the most return on the work
involved. These high priority areas would include:
­ High-volume medicine use

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­ Medicines with a low therapeutic index

­ Medicines with a high incidence of ADRs
­ Expensive medicines.
ABC ANALYSIS
 Most pharmacists and managers know that only a few drug items
account for the greatest drug expenditure. ABC analysis is the analysis of
annual medicine consumption and cost in order to determine which
items account for the greatest proportion of the budget.
 It can reveal:
­ High usage items for which there are lower-cost alternatives on
the list or available in the market.
 This information can be used to:
­ Choose more cost-effective alternative medicines
­ Identify opportunities for therapeutic substitution
­ Negotiate lower prices with suppliers.
­ Measure the degree to which actual drug consumption reflects
public health needs and so identify irrational drug use, through
comparing drug consumption to morbidity patterns.
­ Identify purchases for items not on the hospital essential
medicines list i.e. the use of non-formulary medicines.
VEN ANALYSIS
 VEN analysis is a well-known method to help set up priorities for
purchasing medicines and keeping stock. Drugs are divided, according to
their health impact, into vital, essential and non-essential categories.
 VEN analysis allows medicines of differing efficacy and usefulness to be
compared, unlike ABC and therapeutic category analyses, where only
drugs of similar efficacy or action can be compared.
­ Vital drugs (V): Potentially life-saving or crucial to providing basic
health services.
­ Essential drugs (E): Effective against less severe but significant
forms of disease, but not absolutely vital to providing basic health
care.
­ Non-essential drugs (N): Used for minor or self-limited illnesses;
these may or may not be formulary items and efficacious, but they
are the least important items stocked.

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DEFINE DAILY DOSE (DDD)

 The analysis of medicine consumption in terms of unit quantities can
help to identify over- and under-use of individual medications or
therapeutic groups.
 The defined daily dose (DDD) methodology converts and standardizes
readily available product quantity data, such as packages, tablets,
injection vials, bottles, into crude estimates of clinical exposure to
medicines, such as the number of daily doses.
 The DDD is the assumed average daily maintenance dose for the
medication’s main indication. The DDD is based on the average
maintenance dose for adults, but it can be adjusted for pediatric
medicine use.
 Converting aggregate quantities available from pharmacy inventory
records or sales statistics into DDDs roughly indicates how many
potential treatment days of a medicine have been procured, distributed
or consumed.
 The medicines can then be compared, using units such as:
­ No. of DDD per 1000 inhabitants per day, for total drug
consumption
­ No. of DDD per 100 beds per day (100 bed-days), for hospital use
EXAMPLE
 If the calculations for amoxicillin show that there were 4 DDDs per 1000
inhabitants per day, this suggests that on any given day, for every 1000
persons, 4 adults received a daily dose of 1 g of amoxicillin.
 This interpretation assumes that the prescribed daily dose (the quantity
actually prescribed to a patient) is the same as the defined daily dose,
although this may not, in fact, be the case.
CALCULATION STEPS
1. Find out the total amount of medicines used or procured in one year in
terms of the number of units (tablets, capsules, injections) and the
strength (mg, g (gm), IU)
2. Calculate the total quantity consumed in one year in terms of mg/g/I.U.
by multiplying the number of units (tabs, caps, inj.) by the strength of
dose
3. Divide the total quantity by the assigned DDD for that medicine

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4. Divide the total quantity by the number of patients (if known) or by the
population.
𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 (𝑚𝑔) 𝑠𝑜𝑙𝑑 𝑖𝑛 𝑜𝑛𝑒 𝑦𝑒𝑎𝑟
DDI/1000 people / day =
𝐷𝐷𝐷 (𝑚𝑔) 𝑥 365 𝑑𝑎𝑦𝑠 𝑥 #𝑝𝑒𝑜𝑝𝑙𝑒
IMPORTANT CATEGORIES
 Medicines that are critically important categories; cardiovascular,
emergency, toxicology, oncology, intravenous medicines, and narcotic
analgesics
 Antimicrobial medicines, both prophylactic and therapeutic Injections
 Medicines undergoing evaluation for addition to the formulary
 Medicines used for off-label indications
 Medicines used for high-risk patients.
III. ESTABLISH CRITERIA, DEFINE AND ESTABLISH THRESHOLD
 Establishing criteria is the single most important procedure in a DUE.
Criteria for the use of any medicine should be established by the DTC
using relevant evidence-based literature sources and recognized
international and local experts.
 The criteria for any DUE should reflect what is in the country’s STGs
(assuming that they have been developed correctly) and any medicine-
use protocols that exist. Credibility of the DUE relies on criteria that are
based on evidence-based medicine. Criteria must be developed with and
accepted by the medical staff for the process to be credible
 After developing criteria, the DTC must establish a threshold or standard
(benchmark) against which the criteria will be judged.
 A threshold refers to the percentage of charts or records that will meet
or exceed the established criteria for the medicine. Ideally, this
threshold will be 100 percent, but realistically, a smaller percentage will
be more appropriate to account for exceptions to routine medicine
prescribing. Therefore, a threshold of 90 to 95 percent is typically used
for many criteria, but each instance must be carefully analyzed before
reaching a conclusion.
 A comprehensive list of indicators for appropriate medicine use includes
the following components:
PROCESS INDICATORS
 Indications — Specific uses for the medicine in question

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 Dose — Specific doses for any approved indication for appropriate

duration
 Quantity dispensed — Correct number of doses administered
 Preparation — Steps involved with preparing a medication for
administration
 Monitoring — Laboratory test necessary and intervals of testing during
the use of the medicine
 Contraindications — Known contraindications
 Drug interactions — Significant medicine interactions, including
medicine-medicine, medicine-food, and medicine-laboratory
 Administration — Specific steps necessary to administer a medicine,
especially for injectables
 Patient education — Instructions and education that a patient should
receive with the medicine
OUTCOME INDICATORS
 Specific outcomes to be realized from medicine use
 Lowered blood pressure, stabilized blood glucose, and fewer migraine
and asthma attacks
 Decreased visits to the emergency room, decreased hospitalizations
 Improved patient quality of life (obtained from questionnaires).
PHARMACY ADMINISTRATION INDICATORS
 Correct cost to patient
 Accurate billing records
 Accurate dispensing records
 Appropriate use of generic medicines or therapeutic equivalents
 Appropriate use of formulary medicines
 Appropriate quantity dispensed.
IV. COLLECT DATA AND ORGANIZE RESULTS
 DUEs can be accomplished as prospective evaluations, or they can be
performed retrospectively.
­ A prospective analysis involves the collection of data as the
medicine is being prepared or dispensed to the patient.
­ Retrospective analysis is done using chart reviews or other data
sources to review medicine use according to indicators and
criteria prepared in advance.

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 The advantage of a prospective review is that the pharmacist (or other

reviewer) can intervene at the time the medicine is dispensed to prevent
errors in, for example, dosage, indications, or interactions.
 Retrospective evaluation, which may involve more of the reviewer’s
time or require access to medical records, is best accomplished when
the reviewer has time away from the patient care areas and distractions.

DUE CATEGORIES
I. PROSPECTIVE DUE
 Prospective review involves evaluating a patient's planned drug therapy
before a medication is dispensed.
 In this process the pharmacist can identify and resolve problems before
the patient receives the medication. Pharmacists routinely perform
prospective reviews by assessing a prescription medication's dosage and
its directions and reviewing patient information for possible drug
interactions or duplicate therapy.
 A prospective study watches for outcomes, such as the development of
a disease, during the study period and relates this to other factors such
as suspected risk or protection factor(s).
 Prospective DUE commonly addresses:
­ Drug-disease contraindications
­ Therapeutic interchange
­ Generic substitution
­ Incorrect drug dosage
­ Inappropriate duration of drug treatment
­ Drug-allergy interactions and clinical abuse/misuse.
 All efforts should be made to avoid sources of bias such as the loss of
individuals to follow up during the study. Prospective studies usually
have fewer potential sources of bias and confounding than retrospective
studies.
II. CONCURRENT DUE
 Concurrent review is performed during the course of treatment and
involves the ongoing monitoring of drug therapy to ensure positive
patient outcomes.
 It presents pharmacists with the opportunity to alert prescribers to
potential problems and to intervene in areas such as drug- drug
interactions, duplicate therapy, and excessive or insufficient dosing.

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 This type of review allows therapy to be altered for a patient if

necessary.
 Concurrent DUE commonly addresses:
­ Drug-drug interactions
­ Excessive doses
­ High or low dosages
­ Duplicate therapy
­ Drug-disease interactions
­ Over and under utilization
­ Drug-age precautions
­ Drug-gender precautions
­ Drug-pregnancy precautions.
III. RETROSPECTIVE DUE
 A retrospective DUE is the simplest to perform since drug therapy is
reviewed after the patient has received the medication. A retrospective
review may detect patterns in prescribing, dispensing, or administering
drugs to prevent recurrence of inappropriate use or abuse and serves as
a means for developing prospective standards and target interventions.
 In retrospective DUE, patient medical charts or computerized records
are screened to determine whether the drug therapy met approved
criteria and aids prescribers in improving care for their patients,
individually and within groups of patients, such as those with diabetes,
asthma, or high blood pressure.
 Retrospective DUE commonly addresses the issues:
­ Therapeutic appropriateness
­ Over and under utilization
­ Appropriate generic use
­ Therapeutic duplication
­ Drug-disease contraindications
­ Drug-drug interactions
­ Incorrect drug dosage
­ Inappropriate duration of treatment
­ Clinical abuse/misuse.

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DEVELOP RECOMMENDATIONS AND ACTION PLAN

 After completing the data analysis, information is presented to the DTC
and a decision is made as to the appropriateness of the information in
the DUE.
 The DTC also must decide on whether to continue, discontinue, or
expand the functions of the DUE in question.
 All medicines that do not meet the thresholds must be evaluated
carefully and plans must be made to improve the use of the medicine
relative to the criteria.
 Recommendations should be prepared for the DTC to address the
following:
­ Inappropriate medicine use
­ Unacceptable patient outcomes
­ Methods to resolve any medicine use problem.
 Interventions to improve medicine use might include:
­ Education, including letters to practitioners, in-service education,
workshops, newsletters, and face-to-face discussions
­ Implementation of medicine order forms
­ Prescribing restrictions
­ Formulary manual changes
­ Change (or better enforcement) of the STGs.

CONDUCT DUE FOLLOW UP

 Follow-up in every DUE is critical to ensure resolution of any unresolved
medicine use problems. If the problems are not resolved, then the DUE
will have little usefulness to the health care system.
 As a part of a follow-up plan, the DTC must assess the need to continue,
modify, or stop the DUE activity depending on the results of each
specific medicine review.
 All programs within the DTC should be evaluated yearly. This complete
evaluation is necessary to look comprehensively at the entire program
and analyze its merits and its utility in improving medicine use.
 Programs that do not have a significant impact on medicine use should
be redesigned so that they can provide measurable improvements.
 Without improvements in medicine use and patient outcomes, the time
spent on DUE will be of no value.

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WHEN DUES GO WRONG

 Lack of authority and organization — The DUE must have a clear
organizational structure defined including, for example, what person
develops criteria, collects data, and reports results.
 Poor problem prioritization — Poor prioritization may lead to work on
medicine use problems that may be insignificant and make meaningful
results difficult to obtain.
 Poor documentation — All activities should be documented with a
report in the DTC minutes, and this report should be distributed to the
medical staff as necessary; documentation should clearly discuss results
and recommendations of each DUE.
 Inadequate follow-up — This problem is one of the most frequent to
occur with DUE; follow-up and resolution of every problem must be
accomplished with every DUE.
 Overly intrusive data collection and evaluation — This process can
consume many individuals’ time and must be kept to a minimum to
accomplish the task of the DUE; DUEs in general must not take a
significant amount of time away from patient care.

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DRUG USE EVALUATION CRITERIA FOR CIMETIDINE

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CLINICAL PHARMACOKINETICS

THERAPEUTIC DRUG MONITORING (TDM)

DEFINITION
“A branch of clinical pharmacy/pharmacology that deals with the
measurement of medication concentration in the blood, mainly drugs with
narrow therapeutic range”
 TDM is commonly used to help clinicians monitor and maintain drug
levels within therapeutic window – drug concentration range in which
drug exerts its clinical effect with minimal adverse effects for most
patients.
NEED OF TDM
 Drugs with narrow therapeutic index – drug efficacy difficult to establish
clinically (lithium, phenytoin and digoxin)
 For patients with impaired clearance of drugs, e.g., renal failure
 Patients disease that can make drug toxicity unpredictable, e.g.,
theophylline in chronic obstructive pulmonary disease
 For drugs, whose efficacy is difficult to establish, e.g., phenytoin
 Change in co-medications (quinidine decrease digoxin clearance)

PURPOSE OF TDM
 Optimizing patient drug therapy and clinical outcome while minimizing
the risk of drug induced toxicity.
THERAPEUTIC INDEX
 An index for measuring safety of drugs.
- Must be >1 for drug to be usable.
 Digitalis has a TI of 2
 Penicillin has TI of >100

𝐿𝐸𝐷
𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝐼𝑛𝑑𝑒𝑥 (𝑇𝐼) =
𝐸𝐷
 LED50 is the lethal dose that causes death in 50% animal under
experiment.
- If TI is wide – the drug is safe, If TI is narrow – the drug is toxic.

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𝐿𝐸𝐷
𝑀𝑎𝑟𝑔𝑖𝑛 𝑜𝑓 𝑆𝑎𝑓𝑒𝑡𝑦 =
𝐸𝐷
 Difference between usual effective dose and dose causing life
threatening effects.
THERAPEUTIC WINDOW
 A more clinically relevant index of safety, describes the dosage range
between the minimum effective therapeutic concentration or dose, and
the minimum toxic concentration or dose.
PHARMACOKINETIC PARAMETERS VITAL FOR TDM
 Bio-availability (F)
 Volume of distribution (Vd)
 Clearance (Cl)
 Half-life (T1/2)
 Protein binding

FACTORS DETERMINING IDEAL THERAPEUTICS

 If immediate effect is needed, a loading dose (LD) must be given to
achieve a desired concentration.
­ The LD is determined by the volume of distribution (Vd)
­ To maintain the concentration requires a maintenance dose
regimen
­ The maintenance dose-rate is determined by the Cl
­ The fluctuations within a dosing interval are determined by the
half-life (t1/2)
CLINICAL PHARMACOKINETICS AND TDM
 Both are associated and help in data analysis and interpretation with
suitable prognostic decisions. Data demonstrate that patients suffer
fewer side effects than those who are not monitored.
 Mostly useful for drugs if clearance of drug changes as the concentration
changes.
 Population pharmacokinetics will be useful in preparing initial dosage
guidelines for TDM drugs.
 From dosing point of view
­ CL – determines the maintenance dose rate
­ Vd – determines the loading dose (LD)
­ t1/2 – determines dosing interval and time to steady state

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 TDM is useful in drugs:

­ With a narrow therapeutic index
­ Which are highly protein bound
­ Which are liable to interact
­ In which the metabolite might be toxic
DRUG CONCENTRATION AND TDM
 Drug concentration at the site of action cannot be routinely measured,
but the desired or adverse effects may correlate better with plasma or
blood concentrations than they do with dose.
SITUATION THAT WARRANT TDM
 When it is difficult to distinguish between the progress of the disease
and pharmacological effects of drugs, a good relationship exist between
drug plasma concentration and response.
 For limited number of drugs there is better relationship between plasma
drug concentration and response rather than dose and response Thus,
plasma drug concentration has become valuable surrogate index of drug
exposure.
PRE-REQUISITES OF TDM
 Need to know:
­ Time the blood sample was taken
­ Time dosage was received
­ Dose, duration, dosage form
­ Patient demographics
­ Co-medications
­ Indication for monitoring
­ Pharmacokinetics and therapeutic range of the drug.
LIMITED VALUE OF TDM
 There is no well-defined therapeutic plasma concentration range.
 The formation of pharmacologically active metabolites of a drug
complicates the application of plasma drug concentration data to clinical
effect unless metabolite concentrations are also considered.
 Toxic effects may occur at unexpectedly low drug concentrations as well
as at high concentrations – unpredictable toxicity.
 There are no significant consequences associated with too high or too
low levels.

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COMMONLY MONITORED DRUGS

ROLE OF HEALTH PROFESSIONALS IN A TDM SERVICE

CLINICIAN
 Prescribes appropriate drugs, provides initial dose regimen and monitor
response.
CLINICAL PHARMACIST
 Revises the dosage regimen and provides a plan for TDM.
 Interprets the results and design a new regimen on individual basis.
CLINICAL CHEMIST
 Verifies the sample and perform drug analysis.
NURSE
 Guides sampling, sends the sample, monitors clinical response.
MINIMUM DATA REQUIREMENT OF TDM
 Dose regimen (including dose, frequency and route)
 Date and time of last dose given/taken
 Information on sample
 Sampling time.

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THERAPEUTIC DRUG MONITORING FORM

INDICATIONS OF TDM
 Low therapeutic index
 Poorly defined clinical end point
 Non-compliance
 Therapeutic failure
 Wide variation in the metabolism of drugs
 Major organ failure
 Individualizing drug therapy
 Monitoring and managing drug interactions
 Prevention of adverse drug effects

TDM PROCESS
I. APPROPRIATE INDICATION
 To ensure that sufficient drug is reaching the drug receptor to produce
the desired response (which may be delayed at onset).
 To ensure that drug (or metabolite) concentrations are not so high as to
produce symptoms or signs of toxicity.

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 To guide dosage adjustment in clinical situations in which the

pharmacokinetics are changing rapidly (e.g., in neonates, children or
patients in whom hepatic or renal function is changing).
 To define the pharmacokinetic parameters and concentration-effect
relationships of new drugs.
II. ACCURATE PATIENT INFORMATION
 Accurate information about the patient (name, identification number,
age, gender and pathology)
 The drug therapy (dose, formulation and route of administration, length
of therapy, date and time of last dose)
 The specific questions to be investigated and the date and time of the
sample are essential for proper interpretation.
III. A BIOLOGICAL SAMPLE
 A biological sample that can provide clinically meaningful measurement.
 An appropriate specimen:
­ An appropriate specimen is obviously a prime necessity for
effective TDM.
­ Serum or plasma samples are normally used, although whole
blood is the preferred matrix for many immunosuppressive drugs
(e.g., cyclosporine) as the drug is concentrated in red cells.
 The Request
­ Always ensure clinician expectations.
 Laboratory Measurement
­ Should be performed within a useful time frame.
IV. TIME TO SAMPLE
 Timing of the specimen is also important. For TDM to be meaningful, the
patient should be in steady-state on the present dose of the drug.
however, when suspected toxicity is being investigated, waiting to attain
steady-state is clearly contraindicated.
 The time taken to reach steady-state is determined by the elimination
half-life of the drug. In practice, samples are taken after drug dosing has
continued for at least four half-lives.
 The plasma concentration after 3.3 half-lives is 90 percent of the
predicted steady-state. This may be taken as the minimum time for
sampling after starting the drug or changing the dose.
 For drugs with a long half-life (e.g., digoxin, phenobarbitone), two weeks
or more may be required before steady-state samples can be taken,

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especially if renal function is poor and the drug is renally excreted (e.g.,
digoxin)
 Regular monitoring is useful:
­ When optimizing dosage initially
­ When other drugs are added to or subtracted from a regimen to
guard against known or unexpected interactions
­ When renal or hepatic function is changing.
 Occasionally, sampling at the time of specific symptoms may detect
toxicity related to peak concentrations, for example, carbamazepine and
lithium.
V. COMMUNICATING LAB RESULTS
 Analytical technique used
 Units of measurement
 Therapeutic concentration
 Clinical interpretation
­ The optimum range of drug concentrations for a particular patient
is a very individual matter, depending to some extent on the
severity of the underlying disease process.
­ Difficulties arise when, having made a measurement for no
particularly good reason on a stable patient, the clinician discovers
that the result is outside the target range and feels compelled to
do something about it.
­ Drug concentrations above the target range do not invariably
require a reduction in dosage. For immune suppressants it may be
necessary in some patients to run levels above the target range to
avoid rejection of a heart transplant.
­ For other drugs it may be that if the patient is symptom-free, a
careful search for signs of toxicity should be made. If no evidence
is found, the patient may be best served by doing nothing.
­ Although for some drugs (e.g., phenytoin), continued monitoring
for the development of long-term undesirable effects is advisable.
­ Similarly, drug levels below the target range in a patient who is
well, and free from symptoms, do not require an increased dose,
although in some cases (e.g., digoxin), they may provide evidence
that the drug is no longer necessary and stopping it under medical
supervision is worth trying.

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VI. DOSING
 After dose adjustment (usually after reaching a steady state)
 Assessment of adequate loading dose (after starting phenytoin
treatment)
 Dose forecasting to help predict a patient's dose requirements
(aminoglycosides)
 There are a number of implicit assumptions, namely that:
­ The correct dose was given at the stated time
­ An accurate measurement of the drug concentration was
­ made
­ An accurate recording of the time of sample collection was made,
and Steady-state concentrations have been achieved. errors in any
of these may result in erroneous dosage predictions.
VII. MONITORING
 Assessing compliance
 Diagnosing under treatment
 Diagnosing failed therapy.
INTERPRETATION OF DRUG CONCENTRATION DATA
 When interpreting TDM data, a number of factors need to be
considered.
I. SAMPLING TIMES
 When TDM is carried out as an aid to dose adjustment, the
concentration should be at steady state.
II. CAPACITY LIMITED CLEARANCE
 If a drug is eliminated by the liver, it is possible for the metabolic
pathway to become saturated. Initially the elimination is first-order, but
once saturation of the system occurs, elimination becomes zero-order.
 This effect is not seen at normal therapeutic doses and only occurs at
very high supratherapeutic levels, which is why the kinetics of some
drugs in overdose is different from normal. However, one important
exception is phenytoin, where saturation of the enzymatic pathway
occurs at therapeutic doses.
III. INCREASING CLEARANCE
 Normally, proportion of the total concentration of drug which is protein
bound is constant. However, this situation is not seen in one or two
instances (e.g. valproate and disopyramide).

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 As the concentration increases the plasma protein binding sites becomes

saturated and the ratio of unbound drug to bound drug increases.
 The elimination of these drugs increases disproportionate to the total
concentration since elimination is dependent on the unbound
concentration.
IV. THERAPEUTIC RANGE
 In TDM, a therapeutic range is usually used as a guide to the optimum
concentration. Should not be taken as absolute.
 Some patients may respond to levels above or below these ranges,
whereas others may experience toxic effects within the so-called
therapeutic range.
 These ranges are only adjuncts to dose determination, which should
always be done in the light of clinical response.
FACTORS AFFECTING TDM
1. Patient demographics
2. Patient Compliance
3. Individuals capacity to distribute / metabolize / excrete the drug
4. Genetic factors
5. Concomitant disease, Tropical disease and nutritional deficiencies
6. Alternative system of medicine
7. Ethnic differences and extrapolation of the normal range
8. Alcohol and Tobacco use
9. Quality of medication
10.Control of drug assay
11.Medication or sampling errors
12.Laboratory errors
13.Cost effectiveness

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1. DIGOXIN
INTRODUCTION
 Digoxin is a cardiac glycoside used in the treatment of mild to moderate
heart failure and for ventricular response rate control in chronic atrial
fibrillation.
MECHANISIM OF ACTION
 Most widely used of the digitalis glycosides. Acts (heart) by increasing
the force of contraction (+ve ionotropic effect) and decreasing
conduction through the atrio-ventricular node. (-ve dromotropic effect)
and -ve chronotropic effect.
CLINICAL USES
 Mainly used is in the treatment of atrial fibrillation by slowing down the
ventricular response, although it is also used in the treatment of heart
failure in the presence of sinus rhythm.
THERAPEUTIC PLASMA CONCENTRATION
 Considerable variation between patients, historically plasma digoxin
concentrations of 1 to 2 mcg/L (ng/mL) were generally considered to be
within the therapeutic range. (non-CHF)
 Data now indicate that a therapeutic range of 0.5 to 0.9 mcg/L is
indicated for patients with CHF.
 This lower target range is based on the fact that most patients with left
ventricular dysfunction do not demonstrate additional therapeutic
benefits from higher digoxin concentrations.
 In atrial fibrillation, the goal for digoxin is rate control. Rate control is
achieved by atrioventricular (AV) nodal blockade and may require higher
digoxin concentrations.
PHARMACOKINETICS
ABSORPTION
 Digoxin is poorly absorbed from the gastro-intestinal tract, and
dissolution time affects the overall bioavailability.
 The two oral formulations of digoxin have different bioavailabilities:
F (tablets) = 0.7 , F (liquid) = 0.8
DISTRIBUTION

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 Digoxin is widely distributed and extensively bound – high volume of

distribution.
 Digoxin volume of distribution can be estimated using the equation:
7.3 L/kg (ideal body weight (BWt)
­ which is derived from population data.
 However, distribution is altered in patients with renal impairment, and a
more accurate estimate in these patients is given by:
Vd = 3.8 x ideal BW + (3.1 x clearance (mL/min)
 Distribution time 6 -8h, Thus sampling for TDM should be done not more
than 6 hours post dose.
ELIMINATION
 Digoxin is eliminated primarily by renal excretion of unchanged drug
(60–80%), but some hepatic metabolism also occurs (20–40%).
 The population average value for digoxin clearance is:
Digoxin clearance (mL/min) = 0.8 x BW + creatinine clearance (mL/min)
 In healthy individuals, the metabolic clearance of digoxin is 0.57 to 0.86
mL/kg/min, and the renal clearance is approximately equal to or a little
less than creatinine clearance.
 CHF reduces the metabolic clearance of digoxin to about one-half its
usual value and may reduce the renal clearance slightly as well.
However, patients with severe congestive heart failure have a reduced
hepatic metabolism and a slight reduction in renal excretion of digoxin:
Digoxin clearance (mL/min) = 0.33 x BWt + (0.9 creatinine clearance (mL /min)
TIME TO SAMPLE
 Ideally obtained 7 to 14 days after a maintenance regimen is initiated or
changed. Ensures steady state on the current dosing regimen.
 Samples may be obtained before steady state is achieved but be
cautious in assessing the relationship between the current dosing
regimen and the eventual steady-state concentration.
 In addition, in patients with end- stage renal disease it may take 15 to 20
days to achieve steady state be- cause of the prolonged half-life.
 Samples can be obtained within 24 hours of an initial loading dose may
help confirm the relationship between the digoxin plasma concentration
and pharmacologic response or establish the apparent volume of

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distribution when plasma samples are obtained this early, however, they
are of little value in evaluating the maintenance regimen.
USUAL DOSE AND DOSE INTERVAL
 Atrial fibrillation and flutter: rapid digitalization — 0.75-1.5 mg orally
over 24 hours in divided doses; maintenance, according to renal function
and loading dose, 125-250 mcg daily
 Heart failure, for patients in sinus rhythm, 62.5-125 mcg once daily.

FACTORS AFFECTING CONCENTRATION

 Renal elimination, so extra care needed in patients with impaired renal
function and in the elderly.
 Antacids, cholestyramine and dietary fiber decrease absorption.
 Enzyme inducers (e.g., phenytoin and rifampicin) increase nonrenal
clearance.
 Small changes in dose may result in either loss of efficacy or serious
adverse effects; bioavailability may vary considerably between
preparations, so care needed if changing preparation.
TOXIC EFFECTS
 Gastrointestinal (nausea, vomiting, diarrhea or constipation, abdominal
pain)
 Neurological (headache, fatigue, insomnia, confusion, vertigo)
 Visual disturbances (blurred vision, color casts and colored halos are
classic signs of digoxin toxicity)
 Cardiac (bradycardia, atrioventricular block, ventricular tachycardias and
other arrhythmias)
 Toxicity is related to drug concentration but is exacerbated by
hypokalemia (take care when diuretics are co-administered).
PRACTICAL IMPLICATIONS
 Congestive heart failure, hepatic and renal diseases all decrease the
elimination of digoxin.
 In addition, hypothyroidism increases the plasma concentration
(decreased metabolism and renal excretion) and increases the sensitivity
of the heart to digoxin.
 Hyperthyroidism has the opposite effect. Hypokalemia, hyperkalemia,
hypomagnesaemia and hypoxia all increase the sensitivity of the heart to
digoxin.

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KEY PHARMACOKINETIC PARAMETERS

Parameter Key point
Optimum sampling time Pre-dose (trough sample) or >6 hours post-dose
Time to peak 1 hour (oral, plasma)
Route of elimination 36 hours with normal renal function
Elimination half-life (3.8) (weight in kg) + (3.1) (Clcr in mL/min)
Time to steady state 7-10 days
Protein binding 25%
0.8-2.0 μg/L (1.0-2.6 nmol/L)
Target range
In heart failure: 0.5-1.0 μg/L (0.6-1.3 nmol/L)

DRUG IINTERACTIONS
Drugs which cause INCREASED serum Drugs which cause DECREASED serum
digoxin levels digoxin levels
Amiodarone, Anticholinergic drugs, Antacids, Cholestyramine,
Diltiazem, Spironolactone, Quinidine Domperidone, Kaolin-pectin

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2. THEOPHYLLINE
INTRODUCTION
 Theophylline (an alkaloid) belongs to methylxanthine group of drugs.

MECHANISIM OF ACTION
 Relaxes smooth muscle and relieves/prevents bronchoconstriction.

CLINICAL USES
 Mild diuresis
 Central nervous system stimulation
 Cerebrovascular vasodilatation
 Increased cardiac output
 Bronchodilatation - major therapeutic effect of theophylline.

PHARMACOKINETICS
DISTRIBUTION
 Extensively distributed throughout the body, with an average volume of
distribution based on population data of 0.48 L/kg.
 Theophylline does not distribute very well into fat, and estimations
should be based on ideal body weight.
 A two-compartment model best describes theophylline disposition, with
a distribution time of approximately 40 min.
ELIMINATION
 A first-order process primarily by hepatic metabolism to relatively
inactive metabolites.
 The population average for clearance - 0.04 L/h/kg, but this is affected
by a number of diseases/drugs/ pollutants.
 Neonates metabolize theophylline differently, with 50% being converted
to caffeine. Therefore, in neonatal apnea of prematurity, a lower
therapeutic range is used.
 Usually 5–10 mg/L since caffeine contributes to the therapeutic
response.
USUAL DOSE AND DOSE INTERVAL
 Modified release preparations: 200-500 mg every 12 hours; children 2-6
years: 60-120 mg every 12 hours; children 6-12 years: 125-250 mg every
12 hours.

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FACTORS AFFECTING CONCENTRATION

 Rate of metabolism affected by many factors (e.g., hepatic disease,
other drugs, dietary factors, smoking)
 First-order elimination kinetics at target concentrations, zero-order at
higher concentrations.
 Concentrations increased in heart failure, cirrhosis and viral infections
and by erythromycin, cimetidine, ciprofloxacin
 Concentrations decreased in smokers, chronic alcoholics and by drugs
that induce hepatic metabolism (e.g., phenytoin, carbamazepine,
rifampicin)
MONITORING PARAMETERS
 An accurate and thorough patient history.
 Take special note the following conditions:
­ Smoking history
­ Previous theophylline therapy
­ CHF or other serious cardiac disease
­ Hepatic disease
­ Drug interactions: macrolide antibiotics, quinolones, cimetidine.
SERUM THEOPHYLLINE LEVEL MONITORING
 If the patient has taken a theophylline product within the previous 24
hours, obtain a level before administering any IV theophylline.
MONITORING IV THEOPHYLLINE
 Obtain theophylline levels at 1, 7 and 24 hours after initiating IV therapy
and every 24 hours while receiving IV theophylline.
MONITORING ORAL THEOPHYLLINE
 When initiating oral therapy obtain theophylline levels daily until stable.
TOXIC EFFECTS
 Mild/moderate effects (nausea, headache, jitteriness) are common
within the target range
 More serious effects (tremor, agitation, insomnia, diarrhea, palpitations,
tachycardia, cardiac arrhythmias, seizures, cardiorespiratory arrest)
occur with increasing frequency at plasma concentrations above 20
mg/L (110 μmol/L)

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PRACTICAL IMPLICATIONS
 Intravenous bolus doses of aminophylline need to be given slowly
(preferably by short infusion) to avoid side effects due to transiently high
blood levels during the distribution phase.
 Oral doses with sustained release preparations can be estimated using
population average pharmacokinetic values and titrated proportionately
according to blood levels and clinical response.
 Sustained release preparations may provide 12h cover. However, more
marked peaks and troughs are seen with fast metabolizers (smokers and
children).
KEY PHARMACOKINETIC PARAMETERS
Parameter Key point
Trough: immediately before next dose
Optimum sampling
Peak: 4-8 hours post-dose (modified release preparations)
time
2 hours post-dose (rapid-release)
1-2 hours post-dose (rapid-release)
Time to peak
4-8 hours post-dose (modified release)
Route of elimination Hepatic metabolism (<20% renally)
Elimination half-life 3-9 hours
Time to steady state 2-3 days (oral dosing, adults)
Protein binding ~50%
Target range 10-20 mg/L (55-110 μmol/L)

DRUG INTERACTIONS
 Acyclovir
 Allopurinol
 Calcium channel blockers
 Quinolones

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3. GENTAMICIN
INTRODUCTION
 Gentamicin is an aminoglycoside used to treat a wide variety of aerobic
infections in the body.
MECHANISIM OF ACTION
 Disruption of protein synthesis by irreversible binding to the 30S
ribosomal subunit of susceptible organisms.
CLINICAL USES
 Broad spectrum antibiotic active against aerobic Gram-negative
organisms and some Gram-positive organisms.
 Used in treatment of serious infections sometimes with a penicillin or
metronidazole (or both).
 Used in combination with other antibiotics in endocarditis.

THERAPEUTIC RANGE
 Gentamicin has a low therapeutic index, producing dose related side
effects of nephro- and ototoxicity.
 The use of TDM to aid dose adjustment if these toxic effects which
appear to be related to peak and trough plasma levels are to be avoided.
 It is generally accepted that the peak level (drawn 1 h post-dose after an
intravenous bolus or intramuscular injection) should not exceed 12 mg/L
and the trough level (drawn immediately pre-dose) should not exceed 2
mg/L.
 The above recommendations relate to multiple daily dosing of
gentamicin. If once daily dosing is used, then different monitoring and
interpretation parameters may apply.
PHARMACOKINETICS
DISTRIBUTION
 Gentamicin is relatively polar and distributes primarily into extracellular
fluid. Thus, the apparent volume of distribution is only 0.3 L/kg.
 Gentamicin follows a two-compartment model with distribution being
complete within 1 h.
ELIMINATION
 Elimination is by renal excretion of the unchanged drug.
 Gentamicin clearance is approximately equal to creatinine clearance.

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PRACTICAL IMPLICATIONS
 Therapeutic range is based on peak (1 h post-dose to allow for
distribution) and trough (pre-dose) concentrations.
INITIAL DOSAGE
 This may be based on the patient's physiological parameters. Gentamicin
clearance may be determined directly from creatinine clearance.
 The volume of distribution may be determined from ideal body weight.

SINGLE DOSE (STAT) AND ONCE DAILY (OD) GENTAMICIN REGIMEN

 Dose: 5mg/kg OD (Maximum daily dose: 480mg)
 Administration: In 100ml normal saline or glucose 5% infused over
60mins.
ADVANTAGES
 High peaks are more effective in achieving bacterial kill
 Long post antibiotic effect therefore not necessary to have levels above
the mean inhibitory concentration (MIC) all day
 Reduced risk of nephrotoxicity due to washout period allowed by
infrequent dosing
 No greater risk of ototoxicity
 Monitoring of levels is simpler
 Less nursing time required to administer the antibiotic
INDICATIONS FOR OD REGIMEN
 Severe sepsis of unknown cause and/or oliguria
 Intra-abdominal sepsis
 Urological sepsis
 Hospital acquired pneumonia
EXCLUSION OF OD REGIMEN
 Significant renal impairment
 Pregnant patients
 Endocarditis
 Patients with cystic fibrosis
 Patients with severe burns
However,

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 A second dose may be given after a 24-hour Interval if there is no clinical

improvement and providing the renal function has not become
impaired.
 Should once daily gentamicin be required for more than two doses, this
should be guided by serum trough levels.
 Unless for specific conditions i.e. infective endocarditis and neutropenic
sepsis, gentamicin should not be given > 5 days as this increase the risk
of toxicity.
ONCE DAILY DOSING
 There are theoretical arguments for once daily dosing of gentamicin,
since aminoglycosides display concentration-dependent bacterial killing,
and a high enough concentration to minimum inhibitory concentration
(MIC) ratio may not be achieved with multiple dosing. Furthermore,
aminoglycosides have a long post-antibiotic effect.
 Aminoglycosides also accumulate in the kidneys, and once daily dosing
could reduce renal tissue accumulation.
 Initial dosage for a once daily regimen is 5–7 mg/kg/day for patients with
a creatinine clearance of >60 mL/min.
 This is subsequently adjusted on the basis of blood levels. However,
monitoring of once daily dosing of gentamicin is different to multiple
dosing.
 One approach is to take a blood sample 6–14 h after the first dose and
plot the time and result on a standard concentration-time plot (the
Hartford nomogram, Nicolau et al., 1995).
 Once daily dosing of gentamicin has not been well studied in pregnant or
breastfeeding women, patients with major burns, renal failure,
endocarditis or cystic fibrosis. Therefore, it cannot be recommended in
these groups and multiple daily dosing should be used.
ONCE DAILY DOSE IN RENAL IMPAIRMENT
 Dose: 3 mg/kg OD
 Administration: In 100ml normal saline or glucose 5% infused over
60mins
 In patients receiving ≥ 2 doses, a post dose gentamicin level should be
collected 18 –24 hours after the last dose (i.e., a pre-dose level)
MONITORING FOR ONCE DAILY REGIMEN

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 Aim for a pre-dose (trough) level of < 1mg/L.

 Take a pre-dose level (18-24hours) before giving the next dose.
 Clearly mark on the request form how many hours after the dose the
sample has been taken.
 Unless patients are at risk of nephrotoxicity due to pre-existing renal
impairment or are receiving multiple nephrotoxic agents (E.g some
chemotherapy agents).
 Do not wait for the result to come back before giving the next dose,
adjust the regimen around the next and subsequent dose if applicable
 Post dose (peak) levels are not required.
 When the first dose of gentamicin has been given in the evening or
night, the level should be taken by 15:00 hr the following day if this falls
within 18–24-hour window and sent for analysis immediately.
RENALLY IMPAIRED
 Await assay result and give dose when level <1mg/L.
 Always monitor renal function carefully by checking urine output daily
and serum creatinine levels 2 –3 times per week, especially for courses
longer than 5 days duration.
 Risk of toxicity increases when duration of the treatment course exceeds
5 days.
 Prolonged courses of gentamicin must only be given only when there is a
clear clinical need e.g. endocarditis.
MULTIPLE DAILY DOSE SYNERGISTIC REGIMEN FOR INFECTIVE ENDOCARDITIS
 Dose: 1mg/kg every 12 hours (Max 240mg/day)
 Administration: IV injection in 10-20ml saline or glucose 5% over at 3–5
mins IV infusion in 50ml normal saline or glucose 5% infused slowly over
20mins –30mins
 Gentamicin is given in low doses primarily for its synergistic effect with
beta-lactam antibiotics.
 Regular monitoring of serum levels is important to ensure that there is
enough drug is present throughout a 24-hour period to act with the
beta-lactam.
 Because gentamicin may be given for several weeks in this context, it is
also important to ensure that the drug is being adequately renally
excreted.

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 Baseline audiometry is recommended for patients who require extended

treatment (>2 weeks) with this agent
MONITORING FOR SYNERGISTIC DAILY MDR
 Take pre-dose (trough level) sample before giving the 3rd or 4th dose
after commencement. This should also be the case after any dose
adjustment.
 Post-dose (peak level) should be taken 1 hour after the end of the
infusion.
 For streptococcal/enterococcal endocarditis infections aim for:
 Pre-dose levels: <1mg/L
 Post-dose levels: 3-5mg/L
Serum levels Actions
Pre-dose level <1mg/L Continue current regimen
Post-dose level around 3-5mg/L Re-check levels after a further 3 or 4 doses
Omit further doses until level <1mg/L
Pre-dose level >2mg/L
Increase the dosing interval to 24-hourly
Post dose level 5mg/L or above
Re-check levels after a further 3 or 4 doses
Increase dose and remain on 12 -hourly dosing
Pre-dose level <1mg/L
interval
Post dose level <3mg/L
Re-check levels after a further 3 or 4 doses
CONVENTIONAL MULTIPLE DOSE REGIMEN
 Multiple daily doses therapeutic regimen has largely been superseded by
once daily gentamicin regimen and is generally not recommended.
Except for pregnant patients, patients with cystic fibrosis or severe burns
 Dose: 3-5mg/kg in divided doses (8 -12 hourly)
 Administration: IV injection in 10-20ml saline or glucose 5% over at 3–5
mins IV infusion in 50ml normal saline or glucose 5% infused slowly over
20mins –30mins.
MONITORING FOR CONVENTIONAL MDR
 Both pre and post dose levels are required.
 Take pre-dose (trough level) sample before giving the 3 rd or 4th dose
after commencement. This should also be the case after any dose
adjustment.
 Pre-dose (trough level) should be taken 8 or 12 hours after the previous
dose for tds and bd regimens respectively.
 Post-dose (peak level) should be taken 1 h after the end of the infusion.

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 Aim for pre-dose (trough) level < 2mg/L

 For most infections, aim for post-dose level of 5 –10mg/L
Pre-dose
Actions
Level
Continue current regimen.
Ensure the patient is responding clinically.
< 2mg/L
Further pre-dose level to be monitored twice weekly so long renal
function is stable
Increase dosing interval i.e. from tds to bd provided renal function is
2 – 3 mg/L
unchanged.
Further gentamicin doses should be withheld until level <1mg/L.
> 3 mg/L If further doses are required, re-start with increased
interval/decreased dose.

Post-dose Level Actions

Check previous dose(s) have been given as prescribed.
Below Target If the low post-dose level appears genuine, gentamicin is sub-
therapeutic. Consider increasing the dose
Ensure level is not taken via an intravenous catheter that is
used for the administration of the antibiotic as this will give
High Levels false high level.
Consider reducing the dose (and the dose frequency). Final
action dependent on trough level also.
Pre-dose level <
2mg/L (normal)
Post dose level Reduce the Dose
is above target
range
Both pre-dose Omit next dose
and post-dose Review need for further gentamicin
levels are above Consider increasing the interval between doses
target range Restart gentamicin when pre-dose level <2mg/L

FACTORS AFFECTING CONCENTRATION

 Large, highly polar molecule
 Very poor oral bioavailability – must be given parenterally
 Not metabolized, excreted renally
 Short plasma half-life (2-3 hours) unless renal function impaired

TOXIC EFFECTS
 Vestibular and auditory damage (often irreversible)
 Nephrotoxicity (reduces excretion and may precipitate vicious cycle)

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KEY PHARMACOKINETIC PARAMETERS

Parameter Key point
Peak: 1-hour post-dose (30-60 minutes after
Optimum sampling time
infusion complete)
Time to peak 1 hour
Route of elimination >90% excreted renally
Elimination half-life 2-3 hours with normal renal function
Time to steady state 10-15 hours with normal renal function
Protein binding <10%
Once-daily/extended dose regimes:
Seek local advice for specific regime
Target range Multiple-dose regimes:
Trough: <2 mg/L (<1 in endocarditis)
Peak: 5-10 mg/L (3-5 in endocarditis)
DRUG INTERACTIONS
 Abacavir
 Acetaminophen
 Acetylcholine
 Zonisamide
 Zidovudine
 Warfarin

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4. LITHIUM
INTRODUCTION
 Lithium is effective in the treatment of acute mania and in the
prophylaxis of manic depression (bipolar disorder).
MECHANISIM OF ACTION
 Specific mode of action not known; may increase tryptophan uptake and
serotonin synthesis.
CLINICAL USES
 Treatment and prophylaxis of mania, bipolar disorder and recurrent
depression
 Aggressive or self-mutilating behavior.

PHARMACOKINETICS
DISTRIBUTION
 Lithium is unevenly distributed throughout the body, with a volume of
distribution of approximately 0.7 L/kg.
 Lithium follows a two-compartment model with a distribution time of 8
h (hence, the 12-h sampling criterion).
ELIMINATION
 Lithium is excreted unchanged by the kidneys.
 Clearance is approximately 25% of creatinine clearance since there is
extensive reabsorption in the renal tubules.
 In addition to changes in renal function, dehydration, diuretics
(particularly thiazides), angiotensin-converting enzyme inhibitors (ACE
inhibitors) and non-steroidal anti-inflammatory drugs (NSAIDs) (except
aspirin and sulindac) all decrease lithium clearance.
 Conversely, aminophylline and sodium loading increase lithium
clearance.
USUAL DOSE AND DOSE INTERVAL
 Lithium carbonate is the typical salt used: 400-1200 mg daily initially
with serum concentration monitoring 12 hours post-dose to fall within
the target range; adjust as required
 Elderly usually require lower doses
 Once dose stabilized, switch from divided to single doses
 Lithium carbonate 200 mg = lithium citrate 509 mg

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FACTORS AFFECTING CONCENTRATION

 Wide bioavailability variation between preparations; changing therapy
should be monitored as for initiation of therapy
 Lithium competes with sodium for reabsorption in renal tubules –
altered sodium balance or fluid intake may precipitate toxicity
 Interaction with diuretics – thiazides decrease excretion
 Renal impairment reduces excretion.

MONITORING THERAPY
 Monitoring of serum levels and other tests should be carried out as
follows:
­ ECG: Annually for patients with cardiac disease
­ Weight and BMI: Annually
­ Renal Function: 6 monthly (3 monthly if eGFR <60)
­ Full blood count: 6 monthly
­ Thyroid function: 6 monthly
­ Lithium level: 3 monthly (5-7 days after change in dose and brand)
INTERPRETATION OF SERUM LITHIUM LEVEL
 12-h (post dose) levels above 1.2mmol/l are considered to be toxic and
levels below 0.4mmol/L are ineffective.
 In adults, if Lithium serum levels are kept in the range of 0.4-0.8mmol/L,
then lithium is usually well tolerated with minimal side effects. To
control the acute phase, levels may need to be around1.0mmol/L.
 Levels at or above 0.7mmol/L are reported as being more effective then
lower doses.
 For most patients, the range of 0.4-0.8mmol/L is appropriate for
prophylaxis
THE CONCENTRATION IS LOW (E.G. < 0.6 MMOL/L)
 If the person is well and the concentration is consistently low, but the
normal for that individual, a dose alteration is not required.
 If the patient is unwell and a series of concentrations have been
bordering on the lower end of the range:
­ Assess compliance
­ Re-check concentration after five days
­ Increase dose if appropriate

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THE CONCENTRATION IS WITHIN THERAPEUTIC RANGE (E.G. 0.6–0.8

MMOL/L)
 If the person is well and tolerating, no action is required.
 If the person is well but complains of dose related side effects:
­ Investigate and exclude possible reasons for increased lithium
concentrations, especially if these are higher than the normal for
the individual.
­ If appropriate try a small dose reduction with assessment of
clinical response.
 If the person is unwell increase the dose to within the acute treatment
range (0.8–1.2 mmol/L). Liaise with a specialist if there is no response or
adverse effects develop.
THE CONCENTRATION IS HIGH (TYPICALLY > 1.0 MMOL/L), BUT WITH NO
SIGNS OF TOXICITY)
 Investigate possible explanations for high concentration. Correct where
possible and re-check the concentration.
 If the concentration is one of several which have bordered on being too
high, encourage fluids, re-check level after five days and consider a dose
decrease.
 If there is no clear explanation for the high concentration; re-check and
investigate renal function.
REASONS FOR CHANGES IN MEASURED SERUM LITHIUM LEVELS
VARIATION IN SAMPLING TIME
 For example, a sample is taken at 18 hours post dose but is usually
measured at 12 hours.
CHANGE IN DOSE REGIMEN
 For example, if the dose is switched from once daily to twice daily the
12-hour post dose concentration will be changed.
COMPLIANCE ISSUES
 Poor compliance is common as patients have a tendency to stop taking
lithium if they feel well, or to reduce adverse effects such as tremor.
RENAL FUNCTION

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 A decrease will raise lithium concentrations.

 An increase reduces lithium concentrations
INTERACTING DRUGS
 NSAIDs, ACE inhibitors and diuretics may raise concentrations and the
risk of toxicity may be exacerbated with dehydration, vomiting and
diarrhea, and change in salt/fluid balance.
OTHER
 Dehydration, GI upset (vomiting and diarrhea), or change in salt or fluid
balance may alter lithium concentrations and increase the risk of drug
interactions.
 Crash diets, change to vegetarian diet (with much lower sodium content)
and physical illness are often associated with increases.
 Brand changes. Different brands and dosage forms (slow-release vs
normal release) have variable bioavailability. Always prescribe the same
brand and formulation of lithium.
TOXIC EFFECTS
 Renal impairment (risk of vicious circle as drug is renally excreted)
 Hypothyroidism
 Nephrogenic diabetes insipidus
 Hyponatremia potentiates toxicity (avoid thiazide diuretics)
 Hyperparathyroidism rare
 CNS disturbances (ataxia, tremors, lethargy, sedation, dysarthria,
confusion, seizures) are an indication of toxicity
 Chronic dosing:
­ Toxicity >1.5 mmol/L requires intervention
­ Lithium concentrations >2.0 mmol/L consider hemodialysis.
PRACTICAL IMPLICATIONS
 Should not be prescribed unless facilities for monitoring plasma lithium
concentrations are available.
 Lithium excretion is a first order process, changes in dosage result in a
proportional change in blood levels.
 Blood samples should be drawn 12 h after the evening dose, since this
will allow for distribution and represent the slowest excretion rate.

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 Population pharmacokinetic data (particularly the volume of

distribution) cannot be relied upon to make initial dosage predictions,
although renal function may give an approximate guide to clearance.
KEY PHARMACOKINETIC PARAMETERS
Parameter Key point
Optimum sampling time 12 hours post-dose
Time to peak 2-4 hours (longer with sustained-release forms
Route of elimination Renal excretion only
10-35 hours (elderly have decreased renal function
Elimination half-life
and typically longer half-lives)
Time to steady state 3-7 days of chronic dosing
Protein binding 0%
Usually: 0.4-1.0 mmol/L
Elderly: 0.4-0.8 mmol/L
Target range Acute bipolar disorder: up to 1.2 mmol/L
(Lithium concentration is always expressed as
mmol/L [equivalent to mEq/L])
DRUG INTERACTIONS
 Benzodiazepines
 Abatacept
 Acetaminophen
 Acetazolamide
 Acyclovir

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5. PHENYTOIN
INTRODUCTION
 Phenytoin is an anticonvulsant drug used in the prophylaxis and control
of various types of seizures.
MECHANISIM OF ACTION
 Limits spread of seizure activity through effects on the sodium channel
of neuronal wall membranes.
CLINICAL USES
 Widely used alone and in combination with other anticonvulsants
 All forms of epilepsy except absence seizures
 Prophylaxis in neurosurgery or severe head injury
 Fosphenytoin, a phenytoin prodrug, for IV use in status epilepticus
 Used to treat trigeminal neuralgia if carbamazepine inappropriate.

PHARMACOKINETICS
DISTRIBUTION
 Phenytoin follows a two-compartment model with a distribution time of
30–60 min.
 The apparent volume of distribution is 1 L/kg.
ELIMINATION
 The main route of elimination is via hepatic metabolism. However, this
metabolic route can be saturated at normal therapeutic doses. This
results in the characteristic non-linear dose/concentration curve.
 Therefore, instead of the usual first-order pharmacokinetic model, a
Michaelis– Menten model, used to describe enzyme activity, is more
appropriate.
 Rate of metabolism = (Vmax ⋅ C) / (Km + C), where Vmax is the maximum
rate of metabolism in mg/d, C is the phenytoin concentration in mg/L,
Km is the substrate concentration in mg/L, and where the rate of
metabolism = Vmax /2.
­ Km is the plasma concentration at which metabolism proceeds at
half the maximal rate.
­ Vmax is the maximum rate of metabolism of phenytoin and is more
predictable at approximately 7 mg/kg/day.

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USUAL DOSE AND DOSE INTERVAL

 150-300 mg per day initially, adjust according to response and plasma
concentration, usual dose 200-500 mg daily
 Child: initially 5 mg/kg in two divided doses to typically 4-8 mg/kg
(maximum 300 mg)
 Fosphenytoin is equivalent to phenytoin in a weight ratio of 3:2; doses
are stated in phenytoin equivalents (PE) (e.g., 1.5 mg Fosphenytoin = 1.0
mg PE)
 Fosphenytoin (status epilepticus): 20 mg (PE)/kg initially, then 50-100
mg (PE)/minute; maintenance 4-5 mg (PE)/kg daily in 1 or 2 divided
doses with trough plasma concentration monitoring; consult local
guidance for children
FACTORS AFFECTING CONCENTRATION
 Metabolized by CYP2C9 (90%) and 2C19 (10%), limited capacity
 Saturation kinetics (nonlinear or zero-order kinetics) – i.e., small changes
in dose may lead to disproportionate changes in plasma phenytoin
concentrations
 Individuals vary as to when their kinetics become nonlinear
 Valproate displaces protein-bound phenytoin.

MONITORING THERAPY
 Essential to monitor therapy to enable informed and safe-dosage
changes
 There is no dose-effect relationship
 Saliva concentrations reflect plasma concentrations
 Free plasma concentrations best reflect effect
 Dose changes should be made judiciously
 Be aware of drug interactions.

TOXIC EFFECTS
 Poor side-effect profile limits use
 Neurotoxicity (nystagmus, dysarthria, diplopia, ataxia)
 Chronic side effects may be disabling or disfiguring (e.g., ataxia or
gingival hyperplasia, acne and hirsutism)
PRACTICAL IMPLICATIONS
 Since the dose/concentration relationship is non-linear, changes in dose
do not result in proportional changes in plasma concentration.

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 Using the Michaelis–Menten model, if the plasma concentration is

known at one dosage, then Vmax may be assumed to be the population
average (7 mg/kg/day), since this is the more predictable parameter to
calculate Km.
 Care is needed when interpreting TDM data and making dosage
adjustments when phenytoin is given concurrently with other
anticonvulsants, since these affect distribution and metabolism of
phenytoin.
KEY PHARMACOKINETIC PARAMETERS
Parameter Key point
In steady state this is not too important as the
Optimum sampling time effective half-life is long, a trough sample if on short-
term Fosphenytoin
Time to peak 3-12 hours (dose and formulation dependent)
Route of elimination Hepatic metabolism (>95%)
Elimination half-life 6-24 hours (up to 60 hours if metabolism saturated)
Time to steady state 2-6 days of chronic dosing
Protein binding ~92%
Total phenytoin: 5-20 mg/L (20-80 μmol/L)
Free phenytoin: 0.5-2.0 mg/L (2-8 μmol/L)
Target range
Vmax: 100-1000 mg daily (variable in children)
Km: 1-15 mg/L (4-60 μmol/L) (variable in children)
DRUG INTERACTIONS
 Abacavir
 Abatacept
 Aceclofenac
 Benzodiazepines

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6. CARBAMAZEPINE
INTRODUCTION
 Carbamazepine is an anticonvulsant used to treat various types of
seizures and pain resulting from trigeminal neuralgia.
MECHANISIM OF ACTION
 Probable blocking of use-dependent sodium channels, inhibiting
repetitive firing.
CLINICAL USES
 Partial and secondary generalized tonic-clonic seizures
 Primary generalized tonic-clonic seizures
 Prophylaxis of bipolar affective disorder, mania and as a mood stabilizer
 Effective for pain relief in trigeminal neuralgia

PHARMACOKINETICS
DISTRIBUTION
 Carbamazepine is distributed widely in various organs, with the highest
concentration found in liver and kidneys.
 Carbamazepine is 70–80% protein bound and shows a wide variation in
the population average apparent volume of distribution (0.8–1.9 L/kg).
ELIMINATION
 Carbamazepine is eliminated almost exclusively by metabolism, with less
than 2% being excreted unchanged in the urine.
 Elimination is a first-order process, but carbamazepine induces its own
metabolism (auto-induction).
 Auto-induction begins in the first few days of commencing therapy and
is maximal at 2–4 weeks.
 Since clearance changes with time, so does half-life, with reported
values as long as 35 h after a single dose, decreasing to 5–7 h on regular
dosing.
ABSORPTION
 Absorption after oral administration is slow, with peak concentrations
being reached 2–24 h post-dose (average 6 h).
 Absorption is incomplete, with bioavailability estimated at
approximately 80% (F = 0.8).

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FACTORS AFFECTING CONCENTRATION

 Metabolized to the active epoxide by CYP3A4
 Liver disease reduces clearance
 Increased clearance in children and pregnancy, reduced in old age.

USUAL DOSE AND DOSE INTERVAL

 Epilepsy: initially 100-200 mg 1-2 times daily, increasing to 0.8-1.2 g daily
in divided doses (lower doses in children also age-dependent, lower
initial dose in elderly); up to 2 g may be needed
 Prophylaxis of bipolar disorder: usually 400-600 mg daily in divided
doses, maximum 1.6 g daily
 Trigeminal neuralgia: initially 100 mg 1-2 times daily, increasing to 200
mg 3-4 times daily in divided doses, up to 1.6 g daily.
MONITORING THERAPY
 Relationship between plasma concentration and effect complicated by
active metabolites (CBZ-epoxide); CBZ-epoxide measurement may be
helpful in assessing adherence
 Monitoring is essential when seizure control is difficult to attain, but
some patients can be managed effectively with minimal concentration
monitoring.
 Blood count, renal and hepatic monitoring is needed.

PRACTICAL IMPLICATIONS
 Use of pharmacokinetic equations is limited, due to the autoinduction
effect.
 However, there are a number of important practical points:
­ Blood samples should not be drawn before the steady state,
which will not be achieved until 2–4 weeks after starting therapy
to allow for auto-induction, or 3–4 days after subsequent dose
adjustments.
­ When sampling, the trough level should be measured because of
the variable absorption pattern.
­ Complex calculations are not helpful, but as a rule of thumb each
100 mg dose will increase the plasma concentration at the steady
state by approximately 1 mg/L in adults.
­ A number of other drugs (including phenytoin) when given
concurrently will affect carbamazepine metabolism and
subsequent blood levels

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KEY PHARMACOKINETIC PARAMETERS

Parameter Key point
Optimum sampling time Pre-dose (trough sample)
Time to peak 4-8 hours (longer with sustained-release forms)
Route of elimination Hepatic metabolism (~3% excreted renally)
10-20 hours (shorter in children or in patients on
Elimination half-life
enzyme-inducing drugs)
21-28 days after initiation until auto-induction is
Time to steady state
complete; 2-6 days on chronic dosing
Protein binding ~75%
Target range 4-12 mg/L (17-50 μmol/L)
DRUG INTERACTIONS
 Aceclofenac
 Abacavir
 Abatacept
 Zolpidem

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7. PHENOBARBITAL
INTRODUCTION
 Phenobarbital is a long-lasting barbiturate and anticonvulsant used in
the treatment of all types of seizures, except for absent seizures.
MECHANISIM OF ACTION
 Enhances the effect of GABA by opening the chloride channel at the
GABA receptor.
CLINICAL USES
 All forms of epilepsy except absence seizures
 Phenobarbital used as second-line treatment in status epilepticus.

PHARMACOKINETICS
DISTRIBUTION
 Phenobarbital readily distributes into most body tissues and is 25 - 50%
protein bound.
 The population-average volume of distribution is 0.7–1 L/kg.

ELIMINATION
 Phenobarbital is primarily (80%) metabolized by the liver, with
approximately 20% being excreted unchanged in the urine.
 Elimination is a first-order process but is relatively slow with a
population average clearance of approximately 0.004 L/h/kg.
USUAL DOSE AND DOSE INTERVAL
 60-180 mg at night; 5-8 mg/kg for children

TIME TO SAMPLE
 Phenobarbital has a half-life of approximately five days; as a result,
plasma samples obtained within the first one to two weeks of therapy
yield relatively little information about the eventual steady-state
concentrations.
 For this reason, routine plasma Phenobarbital concentrations should be
monitored two to three weeks after the initiation or a change in the
Phenobarbital regimen.
 Plasma samples obtained before this time should be used either to
determine whether an additional loading dose is needed (e.g., when
plasma concentrations are much lower than desired), or whether the

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maintenance dose should be withheld (e.g., Phenobarbital

concentrations are much greater than desired).
 Once steady state has been achieved, the time of sampling within a
dosing interval of phenobarbital is not critical; plasma concentrations
can be obtained at almost any time relative to the phenobarbital dose.
 As a matter of consistency, however, trough concentration are generally
recommended and if phenobarbital is being administered by the
intravenous route,
 Care should be taken to sample at least one hour after the end of the
infusion to avoid the distribution phase.
FACTORS AFFECTING CONCENTRATION
 Phenobarbital induces its own metabolism
 Phenytoin and valproate decrease clearance
 Renal impairment decreases clearance.

TOXIC EFFECTS
 Sedation is a common early side effect, tolerance develops
 Hyperkinesia and behavioral disturbances in children
 Nystagmus and ataxia
 Megaloblastic anemia
 Osteomalacia

MONITORING THERAPY
 Tolerance occurs
 Poor correlation between drug concentration and effect
 Target range must be interpreted flexibly
 Very low phenobarbital concentrations may have a significant
anticonvulsant effect and withdrawal may provoke breakthrough
seizures.
PRACTICAL IMPLICATIONS
 In view of the long half-life, single daily dosage is possible with
phenobarbital.
 Samples for therapeutic monitoring may be drawn any time during a
dose interval, since concentration fluctuation between doses is minimal.
 However, the patient should be at the steady state, which takes 2–4
weeks (1–2 weeks in children).

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KEY PHARMACOKINETIC PARAMETERS

Parameter Key point
Optimum sampling time Not important at steady state
Time to peak 0.5-4.0 hours
Route of elimination ~70% hepatic metabolism
Elimination half-life 80-120 hours
17-25 days of chronic dosing; however, metabolic
Time to steady state induction will require dose changes and the
establishment of a new steady state
Protein binding ~50%
Target range 10-40 mg/L (40-160 μmol/L)
DRUG INTERACTIONS
 Benzodiazepines
 Acetazolamide
 Abatacept
 Abacavir

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8. SODIUM VALPORATE OR VALPORIC ACID

INTRODUCTION
Valproic acid is an anticonvulsant used to control complex partial seizures and
both simple and complex absence seizures.
MECHHANISIM OF ACTION
 Several possible mechanisms including increased GABA turnover and
limiting of voltage dependent sodium channels.
CLINICAL USES
 All forms of epilepsy
 Primary generalized epilepsy; drug of choice in generalized absences,
myoclonic, tonic-clonic, focal atonic and tonic seizures
 Acute mania associated with bipolar disorder.

PHARMACOKINETICS
DISTRIBUTION
 Valproate is extensively bound to plasma protein (90–95%),
 Unlike other drugs, it can saturate protein binding sites at
concentrations greater than 50 mg/L, altering the free fraction of drug.
 Therefore, the apparent volume of distribution of valproate varies from
0.1 to 0.5 L/kg.
ELIMINATION
 Elimination of valproate is almost entirely by hepatic metabolism, with
less than 5% being eliminated by the kidneys.
 As a result of the saturation of protein binding sites and the subsequent
increase in the free fraction of the drug, clearance of the drug increases
at higher concentrations.
 Therefore, there is a non-linear change in plasma concentration with
dose
USUAL DOSE AND DOSE INTERVAL
 600 mg daily in two doses after food, increasing by 200 mg daily every
three days to a maximum of 2500 mg daily; usual dose 1000-2000 mg
daily.
 Mania: initially 750 mg daily in 2-3 divided doses increased according to
response; usual dose as above

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 Migraine prophylaxis: initially 200 mg twice daily, increased if necessary

to 1200-1500 mg daily in divided doses.
FACTORS AFFECTING CONCENTRATION
 Saturable protein binding results in dose-dependent free-fraction
increases, hence variability across the dosage interval
 Clearance increased by carbamazepine, phenytoin and phenobarbital
 Clearance depends on free fraction and influenced by displacement by
endogenous metabolites (e.g., free fatty acids, affected by
hypoalbuminemia)
 Non-linear total valproic acid kinetics, but free valproic acid kinetics are
linear.
TOXIC EFFECTS
 Hepatotoxicity
 Pancreatitis
 Weight gain common
 Nausea, vomiting (reduced with enteric-coated forms)
 Hyperammonemia
 Thrombocytopenia

MONITORING THERAPY
 Monitor full blood count and liver function
 The evidence is against monitoring plasma concentrations in epileptic or
bipolar disorder patients as there is wide intraindividual variation in
concentrations with no relationship to therapeutic effect; toxicity may
be related to longer half-life metabolites.
PRACTICAL IMPLICATIONS
 In view of the lack of a clear concentration–response relationship and
the variable pharmacokinetics, there are limited indications for the
measurement of valproate levels.
 In most cases, dosage should be based on clinical response.
 Valproic acid can take several weeks to become fully active, so
adjustment of doses must not be made quickly.
 In a few cases where seizures are not controlled at high dosage, a
plasma level may be helpful in confirming treatment failure.
 If monitoring is to be undertaken, levels should be drawn at steady state
(2–3 days). A trough sample will be the most useful, since wide
fluctuations of blood levels may occur during a dose interval.

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KEY PHARMACOKINETIC PARAMETERS

Parameter Key point
Optimum sampling time Pre-dose (trough sample)
1-4 hours (longer with enteric-coated forms:
Time to peak
3-8 hours)
Route of elimination ~95% hepatic metabolism
Elimination half-life 9-16 hours (monotherapy)
Time to steady state 3-7 days of chronic dosing
Protein binding ~95%
There is little evidence for the 50-100 mg/L
(350-700 μmol/L) range often cited, or the range
Target range of 50-125 mg/L (350-870 μmol/L) cited for bipolar
disorder monitoring; plasma concentrations show
poor correlation with effect
DRUG INTERACTIONS
 Acetylsalicylic acid
 Carbamazepine
 Felbamate
 Erythromycin
 Lamotrigine
 Lorazepam

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9. CYCLOSPORIN
INTRODUCTION
 Cyclosporine is a steroid-sparing immunosuppressant used in organ and
bone marrow transplants as well as inflammatory conditions such as
ulcerative colitis, rheumatoid arthritis, and atopic dermatitis.
MECHANISIM OF ACTION
 Inhibits calcineurin phosphatase and limits T-cell activation.

CLINICAL USES
 Treatment of transplant rejection in patients previously receiving other
immunosuppressive agents
 Treatment of severe psoriasis, atopic dermatitis, ulcerative colitis and
rheumatoid arthritis when conventional therapy is ineffective or
inappropriate.
PHARMACOKINETICS
DISTRIBUTION
 Ciclosporin is highly lipophilic and is distributed widely throughout the
body with a volume of distribution of 4–8 L/kg.
 There is variable distribution of cyclosporin within blood since the whole
blood concentration is approximately twice the plasma concentration.
Within plasma, cyclosporin is 98% protein bound.
ELIMINATION
 Ciclosporin is eliminated primarily by hepatic metabolism, with wide
inter-individual variation in clearance (0.1–2 L/h/kg).
 In children these values are approximately 40% higher, with a resulting
increased dosage requirement on a milligram per kilogram basis.
 In elderly patients or patients with hepatic impairment a lower clearance
rate has been observed
USUAL DOSE AND DOSE INTERVAL
 Following transplantation (oral): 10-15 mg/kg daily for 1-2 weeks
postoperatively then reduced gradually to 2-6 mg/kg daily for
maintenance in two divided doses.
 In dermatology: 2.5 mg/kg daily in two divided doses increasing to 5
mg/kg daily if response not achieved, guided by renal function (measure
serum creatinine)

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FACTORS AFFECTING CONCENTRATION

 Metabolized by CYP3A4
 Multiple metabolites, but no evidence that metabolites make a
significant contribution to pharmacological effect
 Dosage adjustment needed in hepatic disease
 Widely varying pharmacokinetics between patients.

TOXIC EFFECTS
 Renal dysfunction is a serious adverse effect
 Raised blood pressure and hyperlipidemia
 Adverse cosmetic effects (gingival hyperplasia and hypertrichosis)
 Overimmunosuppression associated with infection and neoplasia.

MONITORING THERAPY
 Narrow therapeutic index and variable pharmacokinetics means that
monitoring is essential for safe use of the drug
 Whole blood samples used as drug is concentrated in red cells (EDTA
anticoagulant)
 Recommended sample times are trough or 2-hour post-dose
 Target concentrations vary with time after transplantation, transplant
type, other immunosuppressives, sample time and analytical method.
PRACTICAL IMPLICATIONS
 In addition to the wide inter-patient variability in distribution and
elimination pharmacokinetic parameters, absorption of standard
formulations of ciclosporin is variable and incomplete (F = 0.2–0.5 in
normal subjects).
 In transplant patients this variation in bioavailability is even greater and
increases during the first few months after transplant. Furthermore, a
number of drugs are known to interact with ciclosporin.
 All these factors suggest that therapeutic drug monitoring will assist in
optimum dose selection, but the use of population averages in dose
prediction is of little benefit, due to wide inter-patient variation.
DRUG INTERACTIONS
 Aceclofenac
 Abatacept
 Abacavir
 Zolpidem

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KEY PHARMACOKINETIC PARAMETERS

Parameter Key point

Trough (C0) or 2 hours post-dose (C2) whole
Optimum sampling time
blood sample
Time to peak 1-6 hours
Hepatic metabolism
Route of elimination
<1% excreted renally
Elimination half-life 18-25 hours
Time to steady state 2-6 days
Protein binding ~90%
Varies widely with sample time, transplant type
Target range
and time after transplantation

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10. VANCOMYCIN
INTRODUCTION
 Vancomycin is a glycopeptide antibiotic used to treat severe but
susceptible bacterial infections such as MRSA (methicillin-resistant
Staphylococcus aureus) infections.
MECHANISIM OF ACTION
 Inhibits cell wall synthesis in susceptible organisms.

CLINICAL USES
 Glycopeptide antibiotic with bactericidal activity against aerobic and
anaerobic Gram-positive bacilli, including multiresistant Staphylococci
(MRSA)
 Used in prophylaxis and treatment of endocarditis and other serious
infections caused by Gram-positive cocci
 Oral administration for Clostridium difficile infections.

PHARMACOKINETICS
DISTRIBUTION
 Volume of distribution of vancomycin is 0.7L/kg.
ELIMINATION
 Major route of elimination is via urine, 70-90% excreted unchanged in
urine.
USUAL DOSE AND DOSE INTERVAL
 By intravenous infusion: 1.0-1.5 g every 12 hours (over 65 years, 500 mg
every 12 hours or 1 g once daily). Child: 15 mg/kg every 8 hours,
maximum 2 g daily.
FACTORS AFFECTING CONCENTRATION
 Large, highly polar molecule
 Very poor oral bioavailability – must be given parenterally except in
pseudomembranous colitis
 Not metabolized, excreted renally
 Short plasma half-life (4-6 hours) unless renal function impaired

TOXIC EFFECTS
 Neutropenia, thrombocytopenia

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 Nephrotoxicity and ototoxicity rare, enhanced risk if high doses or used

with an aminoglycoside
 Rashes including toxic epidermal necrolysis.
MONITORING THERAPY
 Concentration monitoring required.

KEY PHARMACOKINETIC PARAMETERS

Parameter Key point
Peak: 1-hour post-dose (30-60 minutes after
Optimum sampling time infusion complete)
Trough: immediately before next dose
Time to peak 1 hour
Route of elimination 80% excreted renally
4-7 hours with normal renal function
Elimination half-life
(longer in the elderly)
Time to steady state 20-35 hours with normal renal function
Protein binding <10%
Trough: 10-15 mg/L (15-20 mg/L for endocarditis)
Target range
Peak: 25-50 mg/L

DRUG INTERACTIONS
 Aceclofenac
 Acyclovir
 Abacavir
 Acetaminophen

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PHARMACEUTICAL CARE

DEFINITION
“Pharmaceutical care is that component of pharmacy practice which entails the
direct interaction of pharmacist with the patient for the purpose of caring for
that patient’s drug related needs”
OR
“It describes specific activities and services through which an individual
pharmacist cooperates with a patient and other professionals in designing,
implementing and monitoring a therapeutic plan that will produce specific
therapeutic outcomes for the patient”

PHARMACEUTICAL CARE PROCESS

ASSESSMENT
 The main goal is to establish a full medication history and highlight
actual and potential drug related problems.
CARE PLAN
 This should clearly state the goals to optimize care and the
responsibilities of both the pharmacist and the patient in attaining the
stated goals.
EVALUATION
 This reviews progress against the stated patient outcomes.

PHARMACEUTICAL CARE – KEY POINTS

CARE PLAN
 A care plan is developed for each of the patient's medical conditions
being managed with pharmacotherapy.
SUCCESSFUL CARE PLAN
 Successful care plan is clear, measurable goals of therapy which include
a parameter, desired value (s), and a timeframe for achieving them.

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GOAL OF THERAPY
 Goal of therapy is desired response or endpoint that you and your
patient wants to achieve from pharmacotherapy.
INTERVENTIONS
 To resolve the drug therapy problems
 To achieve goals of therapy
 To prevent drug therapy problems

INITIATING NEW DRUG THERAPY

 Initiating new therapy and discontinuing drug therapy or changing the
product and/or dosage regimen.
ADDITIONAL INTERVENTIONS
 Patient education
 Medication compliance reminders/devices
 Referrals to other health care providers
 Monitoring equipment to measure outcome parameters

SCHEDULING A FOLLOW-UP EVALUATION

 Scheduling a follow up evaluation with the patient to determine the
outcomes of pharmacotherapy at a clinically appropriate time.
DOCUMENTATION
 Documentation of the care plan establishes the relationships between
the goals of therapy, and interventions designed to achieve the goals.

SCOPE OF PRACTICE WITHIN PHARMACEUTICAL CARE

ROLE
 it has evolved from an emphasis on prevention of drug-related problems
to expanded roles of pharmacists in the triage of patient’s:
­ Treatment of routine acute illness
­ Management of chronic diseases
­ Primary disease prevention.
FUNCTION
 The implementation of pharmaceutical care services a redesign of
professional workflow.
 The assignment of technical functions to technical personnel under
direct supervision of a responsible pharmacist.

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UNIQUENESS OF CARE PLAN

 Pharmaceutical care plan includes:
­ Clinical pharmacy
­ Patient counseling
­ Pharmaceutical services

ESSENTIAL COMPONENTS OF PHARMACEUTICAL CARE

1. Pharmacist-patient relationship.
2. Pharmacist’s workup of drug therapy (PWDT).
3. Documentation of pharmaceutical care.
1. PHARMACIST-PATIENT RELATIONSHIP
 Professional relationship must be established and maintained.
 Patient-specific medical information must be collected, organized,
recorded, and maintained.
 Patient-specific medical information must be evaluated and a drug
therapy plan developed mutually with the patient.
 The pharmacist assures that the patient has all supplies, information and
knowledge necessary to carry out the drug therapy plan.
 The pharmacist reviews, monitors, and modifies the therapeutic plan as
necessary and appropriate, in concert with the patient and healthcare
team.
2. PHARMACIST WORK-UP OF DRUG THERAPY (PWDT)
 Provision of pharmaceutical care is centered around this, although
the methods used for this purpose may vary.
 Components are:
I. Data collection
II. Develop or identify the CORE pharmacotherapy plan
III. Identify PRIME Pharmacotherapy problems
I. DATA COLLECTION
 Collect, synthesize and interpret relevant information
 Patient’s demographic data: age, sex, race etc.
 Pertinent medical information
 Medical history (current and past)
 Family history
 Dietary history
 Medication history (prescription, OTC, allergies)

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 Physical findings (weight, height, B.P)

 Lab results (serum drug levels, potassium levels, serum creatinine
levels relevant to drug therapy)
 Patient complaints, symptoms and signs.
II. DEVELOP OR IDENTIFY THE CORE PHARMACOTHERAPY PLAN
CORE PHARMACOTHERAPY PLAN
 C = Condition of patient
­ it may include nonmedical conditions or need and is thus not a
reiteration of the current medical problem.
 O = Outcome desired for the condition or need
­ Patient outcomes (generally five category of patient outcomes)
 Mortality  Economic
 Morbidity  Quality of life
 Behavior
­ Therapeutic end points (surrogate markers; disease-oriented
evidence)
 A therapeutic end point represents the pharmacological or
therapeutic effects that is expected, ultimately, to achieve
the desired outcome.
 More than one end point is usually needed to achieve an
outcome-for example, both near normal glycemic control
and normalization of blood pressure are necessary to
significantly reduce the risk of ESRD.
 R = Regimen to achieve desired outcome
­ Therapeutic regimens
 Existing therapy
 Initial therapy
­ Goal setting and behavior regimens
 Identify the type of new goal set, such as the following:
 Start a new positive action- exercise program
 Increase the frequency or intensity of a positive
action- drink 2 more cups of water
 Stop or decrease- stop smoking
 Continue an action that is perfect- continue to
exercise 30 minutes a day, every day.
 E = Evaluation parameters
­ Efficacy parameters

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­ Toxicity parameters
 ADRs
 Allergic reactions
 Toxicity not occurring
III. IDENTIFY PRIME PHARMACOTHERAPY PROBLEMS
PRIME PHARMACOTHERAPY PROBLEMS
 P = Pharmaceutical Problems
­ Dose, route, duration, form, timing, frequency etc.
 R = Risk to Patient
­ Known contraindications
­ Hypersensitivity/allergy
­ Drug-induced problems
­ Common/serious ADRs
 I = Interactions (Drug-drug, drug-food, drug-disease, drug-lab, etc.)
 M = Mismatch (Drug without indication, indication without drug, actual
barriers to implement PCP)
 E = Efficacy issues (suboptimal selection of pharmacotherapy, minimal
or no therapeutic effectiveness, medication availability, compliance or
administration considerations)
3. DOCUMENTATION OF PHARMACEUTICAL CARE
 Formulate a FARM note or SOAP note to describe or document the
interventions needed or provided by pharmacist.
FARM NOTE
 F = Findings
­ Patient specific information that leads to the identification of
pharmacotherapy problem or indication for pharmacist’s
intervention.
 A = Assessment
­ Pharmacist’s evaluation of the findings (severity, priority or
urgency of the problem, short-term and long-term goals of the
intervention)
 R = Resolution
­ Actual or proposed action plans by the pharmacist. The
intervention options may include
 Counselling or educating the patient.

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Making recommendations for the patient and


caregiver.
 Informing the prescriber.
 Making recommendation to the prescriber.
 With-holding medication or advising against use.
 M = Monitoring and follow up
­ The parameters and timing of the follow-up monitoring to assess
the safety, efficacy and outcome of the intervention.
­ It includes
 Parameters to be followed
 Intent of the monitoring
 Ways of the monitoring
 Frequency of the monitoring
 Duration of monitoring
 Anticipated or desired findings
 Decision points to alter therapy

SOAP NOTE
 This is used primarily by physicians.
 S = Subjective findings
­ Means only what the patient tells you (e.g., symptoms,
attributions, etc.) or what you know to have occurred in the
past (e.g., a medication change you made based on a
telephone conversation with the patient)
 O = Objective findings
­ Includes results of physical examination and interval test data
 A = Assessment
­ Diagnosis or possible explanations for patient’s medical
problem
 P = Plan
­ Drug regimen or surgical procedures.

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CLINICAL AND ECONOMIC IMPACT OF PHARMACEUTICAL CARE

PRACTICE
 Pharmaceutical care practice saves patients and the health care system a
significant amount of money and produces a positive savings to cost
ratio. More the number of drugs consequently increases the cost.
 Many factors may contribute to the cost of therapy:
­ Drug therapy problems
­ Ineffective drug therapy
­ Additional drug therapy (sometimes to resolve the problems)
­ Dosage is too low
­ Dosage is too high
­ Adverse drug reactions
­ Non-compliance
­ Level of patient complexity
 When a practitioner can save a clinic visit, an employee workday, or an
emergency room visit, the practitioner has saved the patient and the
health care system a substantial amount of money.
 With the pharmaceutical care practitioner resolving drug therapy
problems and thus making the patient's pharmacotherapy more
effective and safer, physician office visits primarily to respond to
medication-related issues are avoided
 One of the responsibilities of the pharmaceutical care practitioner is to
refer the patient to another practitioner if he/she is in need of other
expertise which saves the patient from suffering and experiencing future
problems and can also save the health care system a tremendous
number of medical services (costs) in the future.

PRACTITIONER’S RESPONSIBILITIES
1. The pharmaceutical care practitioner's responsibility is to determine that
all of the patient's drug-related needs are met at all times. This means
that:
­ All of a patient's drug therapy is used appropriately for each
medical condition
­ The patient's drug therapy is the most effective available
­ The patient's drug therapy is the safest possible
­ The patient is able and willing to take the medication as intended.

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2. The pharmaceutical care practitioner's responsibilities include the

identification, resolution, and prevention of drug therapy problems.
3. The pharmaceutical care practitioner's responsibilities are to ensure that
the goals of therapy are met for each of the patient's medical conditions
and desired outcomes are achieved.
4. These responsibilities are fulfilled by caring for each patient as an
individual in a way that benefits the patient, minimizes harm, and is
honest, fair, and ethical.
5. The pharmaceutical care practitioner fulfills these clinical responsibilities
by meeting the standards for professional and ethical behavior
prescribed within the philosophy of pharmaceutical care practice.
6. The standards for professional behavior include providing
pharmaceutical care at a specified standard of care, being ethical in all
decision-making, displaying collegiality, collaborating, maintaining
competency, applying research findings where appropriate, and being
sensitive to limited resources.
7. It is the pharmaceutical care practitioner's responsibility to hold
colleagues accountable to the same standards of professional
performance. The success of the practice will depend upon it.
8. Do the very best you can for every patient. In all cases, do no harm. Tell
the patient the truth. Be fair. Be loyal. Recognize that the patient is the
ultimate decision maker. Always protect your patient's privacy.
9. Understand who the patient is and what he/she wants from the
practitioner.
10.Assess each patient’s medical conditions and associated drug therapies
for appropriate indication, effectiveness, safety and the patient’s
compliance.
11.Identify drug therapy problems because they interfere with achieving
the goals of therapy.
12.Develop a plan that establishes the desired goals of therapy for each of
the patient’s medical conditions.
13.Make appropriate interventions to resolve drug therapy problems,
achieve the goals of therapy and prevent drug therapy problems from
occurring.
14.Follow-up with the patient to evaluate the results of pharmacotherapies,
recommendations, and other interventions

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15.Continue to manage your patient's drug therapy until the goals of

therapy are achieved.
THE PRACTITIONER'S PHILOSOPHY OF PRACTICE
 A philosophy of practice is a set of values that guides the behavior of a
professional. It helps the practitioner determine what is important, how
to set priorities, and how to make clinical decisions and judgments.
 The philosophy of practice prescribes how a practitioner should practice
on a daily basis. It is a set of rules the practitioner must follow to meet
the standards of practice.
THE RESPONSIBILITY TO CARE
 Within the context of health, care derives from two different—but
complementary—concerns:
1. The technical dimensions of taking care of patients.
2. Caring for or about a particular patient, thereby demonstrating a
concern for and commitment to the well-being of another person,
usually a stranger.
PATIENT-CENTERED APPROACH
 Patient-centeredness places the patient at the center of attention, at all
times, in all situations, regardless of the practitioner's demands, time
constraints, or personality characteristics.
 Patient-centeredness prescribes the behavior of the practitioner toward
the patient during the patient care process.
 When thinking and acting in a caring manner with the patient at the
center of the practice, practitioners will:
­ Place the patients' needs, wants, and preferences before their
own
­ Serve as advocates and do what is best for the patient, regardless
of what it requires on their part
­ Treat patients as individuals—be sensitive to cultures and belief
systems, without being patronizing or condescending
­ Respect patients' time and priorities by committing full attention
to them
­ Remain conscious of patients' value system and be prepared to
identify and resolve ethical dilemmas in an honest and
straightforward manner.

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THE PATIENT'S ROLE

 Establishing therapeutic relationship with the patient to provide optimal
care
 Quality of care depends on quality of relationship developed with the
patient
 Strong relationship helps retrieval of necessary information from the
patient for clinical decision making
 The relationship established will be a unique. Both practitioner and
patient bring values, experiences and expectations to the therapeutic
relationship
 Developing successful relationships involves skills that can learned and
improved daily
 Treating the patient in a confidential manner is the greatest respect
afforded to him /her.
THERAPEUTIC RELATIONSHIP
 The therapeutic relationship is a partnership or alliance between the
practitioner and the patient formed for the purpose of optimizing the
patient's medication experience.
 The therapeutic relationship requires recognition of certain
responsibilities on the part of the patient and the practitioner. It is based
on trust, respect, authenticity, empathy, and commitment.
BUILDING THE THERAPEUTIC RELATIONSHIP
 Characteristics and Behaviors Associated with the Therapeutic
Relationship are given in table.
Characteristics about yourself Behaviors you manifest toward your patient
Honesty/authenticity/open communication Putting the patient's needs first
Offering reassurance
Empathy/sensitivity
Seeing the patient as a person
Patience and understanding Mutual respect/trust
Competence Cooperation/collaboration
Assuming responsibility for interventions Caring
Building confidence
Supporting the patient
Being held accountable for the decisions and
Offering advocacy
recommendations made
Paying attention to the patient's physical and
emotional comfort

THE PATIENT’S RIGHTS

 What the patient can expect

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 Patients expect you to care about what they want

 Patients will expect you to put their needs first before you own
 Patients expect compassion and understanding of them as individuals
 The Patient Expects You to Possess the Technical Knowledge and the
Clinical Experience and Confidence It Takes to Apply that Knowledge to
Their Individual Case
 Patients Expect to Receive the Appropriate Medication for Their Medical
Problems, and They Expect the Medication to Work
 Patients Will Expect You to Be Realistic and Honest About What They
Can Expect from Their Medications
 Patients Will Expect You to Be Their Advocate for All Their Drug-Related
Needs
 Patients Will Expect You to Be Accountable for the Decisions You Make
and the Advice You Give
 Patients Will Expect You to Know When to Refer Them to Someone with
Different Expertise
THE PATIENT'S RESPONSIBILITIES
 Provide you with accurate and complete information
 Participate in the establishment of goals of therapy
 Contribute to the care plan as agreed upon (act on the education and
instructions they received, collect important outcome parameters, keep
appointments)
 Maintain a diary of medication use, signs, and symptoms, and test
results if needed to evaluate effectiveness, safety, and compliance
 Notify you of changes and/or problems with their drug therapy so you
can act on them before they become harmful
 Ask questions whenever they arise. In , you will be introduced to a
number of specific techniques that will help you to develop a
therapeutic relationship with your patients.
ISSUES OF CONFIDENTIALITY
 Maintaining a patient's privacy is the greatest test of the respect a
practitioner gives a patient
 Patient confidentiality has always been a concern in health care.

THE PATIENT'S MEDICATION EXPERIENCE

 The patient's medication experience is the sum of all the events a
patient has in his/her lifetime that involve drug therapy.

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 This is the patient's personal experience with medications. This lived

experience shapes the patient's attitudes, beliefs, and preferences about
drug therapy. It is these characteristics that principally determine a
patient's medication taking behavior.
 The patient's medication experience consists of three related entities:
­ The patient's description of the experience he/she has had with
medications
­ A comprehensive medication history, including immunizations,
allergies, adverse drug reactions, and social drug use patterns
­ A complete record of the patient's current medications and
associated medical conditions.

ASSESSMENT
1. The purpose of the assessment is to determine if the patient's drug-
related needs are being met and if any drug therapy problems are
present
2. Know your patient by understanding his/her medication experience
before making any decisions about his/her drug therapy
3. Elicit only relevant information necessary to make drug therapy
decisions
4. Always assess the patient's drug-related needs in the same systematic
order:
­ First determine if the indication is appropriate for the drug
therapy
­ Second, evaluate the effectiveness of the drug regimen for the
indication
­ Third, determine the level of safety of the drug regimen. Only
after determining that the drug therapy selected or being used by
the patient is appropriately indicated, effective, and safe, should
you evaluate the patient's compliance with the medication.
5. Documentation includes the clinician's assessment of how well the
patient's drug-related needs are being met and a description of the drug
therapy problems present
PURPOSE, ACTIVITIES, AND RESPONSIBILITIES
 The purpose of the assessment is to determine if a patient's drug-related
needs are being met.

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 Activities and Responsibilities: the practitioner gathers, analyzes,

researches and interprets information about the patient, the patient's
medical conditions, and the patient's drug therapies. Individuals can
have drug-related needs whether they are taking medications or not.

Activities Responsibilities
Meet the patient Establish the therapeutic relationship
Determine who your patient is as an
individual by learning about the reason for
Elicit relevant information from the patient the encounter, the patient's demographics,
medication experience, and other clinical
information
Determine whether drug-related needs are
Make rational drug therapy decisions using
being met (indication, effectiveness, safety,
the
compliance)
Pharmacotherapy Workup Identify drug therapy problems

STANDARD OF PATIENT CARE

 Collection of Patient-Specific Information
 Meeting the patient
 Introducing yourself
 Physical environment
 Taking notes
 Eliciting Information from the Patient.
 Patient Information Required for the Assessment

Patient's medication
Demographic information Clinical information
experience
Patient's attitude toward
taking medication and
description of wants, Reason for the encounter
concerns, understanding,
beliefs, and behaviors
Medication history
Age Weight, height Gender Immunization history
Pregnancy status Living Allergies and adverse drug Relevant medical history
arrangements Occupation reactions Social drug use
Special needs
Current medication record
Medical conditions—all
related drug therapies Review of systems
(indication—product-
dosage-outcome)

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 Getting started
 Reason for the encounter
 Patient demographics

DRUG THERAPY PROBLEM

DRUG THERAPY PROBLEMS: TERMINOLOGY
“A drug therapy problem is any undesirable event experienced by a patient
which involves, or is suspected to involve, drug therapy, and that interferes
with achieving the desired goals of therapy”
COMPONENTS OF A DRUG THERAPY PROBLEM
1. An undesirable event or risk of an event experienced by the patient. The
problem can take the form of a medical complaint, sign, symptom,
diagnosis, disease, illness, impairment, disability, abnormal laboratory
value, or syndrome. The event can be the result of physiological,
psychological, sociocultural, or economic conditions.
2. The drug therapy (products and/or dosage regimen) involved.
3. The relationship that exists (or is suspected to exist) between the
undesirable patient event and drug therapy. This relationship can be the
consequence of drug therapy, suggesting a direct association or even a
cause and effect relationship, or to require the addition or modification
of drug therapy for its resolution or prevention.

•Assessment
Follow-up
•Follow-up
•Signs & symptoms •Care plan evaluation
•Goals of therapy •Patient outcomes

Follow-up Follow-up

CATEGORIES OF DRUG THERAPY PROBLEMS

 Seven distinct types of drug therapy problems have been identified that
may potentially lead to an undesirable event that has physiologic,
psychological, social, or economic ramifications. These include:
1. Unnecessary drug therapy
2. Need additional drug therapy
3. Ineffective drug
4. Dosage too low

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5. Dosage too high

6. Adverse drug reaction (ADR)
7. Non-compliance

FOLLOW UP EVALUATION
 The purpose of the follow-up evaluation is to determine the patient's
outcomes in relation to the desired goals of therapy.
 Parameters that reflect both effectiveness and drug safety must be
evaluated.
 The evaluation of effectiveness of pharmacotherapy includes
measurable improvement in clinical signs and symptoms and/or
laboratory values.
 The evaluation of the safety of pharmacotherapy includes evidence of
adverse drug reactions and/or toxicity.
 Patient compliance and its influence on outcomes are determined during
the follow-up evaluation.
 The outcome status of the patient's medical condition being treated or
prevented with drug therapy is determined and described.
 The patient is reassessed to determine if any new drug therapy
problems have developed.
 The follow-up evaluation is the step in which actual results and
outcomes from drug therapies are documented.
PURPOSE, ACTIVITIES, AND RESPONSIBILITIES OF FOLLOW UP

Activities Responsibilities
Elicit clinical and/or laboratory evidence of
actual outcomes and compare them to Evaluate effectiveness of pharmacotherapy.
goals of therapy.
Elicit clinical and/or laboratory evidence of
adverse effects or toxicity to determine Evaluate safety of pharmacotherapy.
safety of drug therapy.
Make a judgment as to the clinical status of
Document clinical status and any changes in
the condition being managed with
pharmacotherapy that are required.
pharmacotherapy.
Assess patient compliance and identify if
Assess patient for any new problems. any new drug therapy problems have
occurred.
Schedule next follow-up evaluation. Provide continuous care.

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EVALUATION
 The Practitioner Evaluates the Patient's Outcomes and Determines the
Patient's Progress Toward the Achievement of the Goals of Therapy,
Determines If Any Safety or Compliance Issues Are Present, and Assesses
Whether Any New Drug Therapy Problems Have Developed
MEASUREMENT CRITERIA
 The patient's outcomes from drug therapies and other interventions are
documented.
 The effectiveness of drug therapies is evaluated, and the patient's status
is determined by comparing the outcomes within the expected
timeframe to achieve the goals of therapy.
 The safety of the drug therapy is evaluated.
 Patient compliance is evaluated.
 The care plan is revised, as needed.
 Revisions in the care plan are documented.
 Evaluation is systematic and ongoing until all goals of therapy are
achieved.
 The patient, family and/or care-givers, and health care providers are
involved in the evaluation process, when appropriate.
DETERMINING THE CLINICAL OUTCOME STATUS
 The terminology used to describe clinical outcome status resulting from
drug therapies is precise and represents both the decisions and actions
on the part of the pharmaceutical care practitioner.
 The standard pharmacotherapy outcome status terms describe two
characteristics of the patient's drug therapy:
­ The progress, or lack of progress, in achieving the desired goals of
therapy at the time of the follow-up evaluation
­ The action, if any, taken to adjust the patient's drug therapies.
I. RESOLVED
 The patient's desired goals of therapy have been successfully achieved,
and drug therapy can be discontinued.
II. STABLE
 The patient's goals of therapy have been achieved, and the same drug
therapy will be continued to optimally manage the patient's chronic
disease.
III. IMPROVED

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 Measurable progress is being realized in achieving the patient's goals of

therapy.
 Goals have not been completely achieved at this time; however, no
changes in drug therapy will be implemented at this time because more
time will be required to observe the full benefit from this drug regimen.
IV. PARTIAL IMPROVEMENT
 The evaluation indicates that some positive progress is being made in
achieving the patient's goals of therapy, but adjustments in drug therapy
are necessary at this time in order to fully meet all of the goals of
therapy by the next scheduled follow-up evaluation.
V. UNIMPROVED
 The practitioner's clinical evaluation is that, to date, little or no positive
progress has been made in achieving the patient's goals of therapy, but
further improvement is still anticipated given more time. Therefore, the
patient's care plan will not be altered at this time.
 Thus, the unimproved status evaluation is dependent on the timing of
the follow-up evaluation.
VI. WORSENED
 The practitioner's evaluation describes a decline in the health of the
patient despite an adequate therapeutic trial using the best possible
drug therapy for this individual. Because the goals of therapy are not
being achieved, changes in the patient's drug therapies are necessary at
this time.
VII. FAILURE
 The practitioner's evaluation indicates that the present care plan and
associated drug therapies have been given at adequate dosages and for
an adequate amount of time, yet they have failed to help the patient
achieve the goals of therapy.
 Therefore, the present therapy should be discontinued and alternate
pharmacotherapy initiated. In these situations, the desired outcomes
have not been realized and the initial treatment is considered to have
failed.
VIII. EXPIRED
 The fact that the patient dies while receiving drug therapy is
documented in the pharmaceutical care record. Any important
observations about contributing factors, especially if they are drug-
related, should be noted.

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ACQUIRING THE KNOWLEDGE YOU NEED TO PRACTICE

 The expertise of the pharmaceutical care practitioner is focused in the
disciplines of pharmacology, pharmacotherapy, and pharmaceutical care
practice.
 The knowledge you will need to provide pharmaceutical care can be
categorized into three types:
­ Knowledge about the patient
­ Knowledge about diseases
­ Knowledge about drug therapies.
 The scope of knowledge about patients can be grouped into personal,
social, and physiological information.
 The scope of knowledge about diseases can be grouped into
characteristics of the disease, intent of treatment, and goals of therapy.
 The scope of knowledge about drug therapies can be grouped into
characteristics of the drug, actions of the drug in the patient, and the
outcomes of drug therapy.
 The knowledge you need can most effectively and efficiently be learned
within the structure of the Pharmacotherapy Workup and then applied
in the patient care process.
 The most useful approach to learning this knowledge is to begin with
those patient characteristics, diseases, and drug therapies that are most
commonly seen in practice.
BECOMING FAMILIAR WITH WHAT YOU NEED TO KNOW
 The knowledge you must learn, integrate, and use in practice can be
classified into three broad categories:
­ Knowledge about patients
­ Knowledge about diseases
­ Knowledge about drugs.
 All three categories of knowledge are equally important, however your
unique expertise will lie in drug therapies. Because you will be using this
knowledge to make patient-specific decisions, you will always think
about and apply it in a specific order:
­ Understand the patient
­ Understand the patient's disease
­ Illness, or medical condition
­ Understand the drug therapy used to treat the medical condition.

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 Although it will be necessary to gain knowledge in a number of different

sciences, the foundation of your knowledge will be:
­ How drugs work (pharmacology)
­ How drugs are used to treat and prevent diseases
(pharmacotherapy)
­ How we apply this knowledge to help patients (pharmaceutical
care practice).
COMMON CONDITIONS NEED TO BE KNOWN
 Hypertension  Esophagitis  Otitis media
 Hyperlipidemia  Pain—general  Anxiety
 Osteoporosis  Asthma  Insomnia
 Diabetes  Arthritis pain  Headache pain
 Vitamin/dietary  Bronchitis  Cardiac
supplements  Sinusitis dysrhythmias
 Allergic rhinitis  Menopausal
 Depression symptoms
PHARMACOTHERAPEUTIC KNOWLEDGE NEEDED FOR PHARMACEUTICAL CARE
PRACTICE
 Characteristics of the drug:
­ Description of the drug ­ Mechanism of action
Efficacy ­ Sites of action
­ Dosage regimen ­ Toxicology
­ Dose ­ Contraindications
­ Dosing interval, ­ Adverse effects
Frequency, Duration ­ Precautions
 Activity of the drug in the patient:
­ Bioavailability ­ Drug administrations
­ Physicochemical ­ Pharmacokinetics
properties ­ Pharmacodynamics
­ Formulations and ­ Time course of the
dosage forms effect
THE OUTCOMES OF DRUG THERAPY
 Therapeutic process Effectiveness: The therapeutic effect—expected
beneficial pharmacological effects of the drug on the course of the
patient's disease or illness.

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 Improvement: Improvement in signs, symptoms, and/or laboratory

findings.
 Safety: Detrimental pharmacological effects of the drug on the patient
 ADRS: Undesirable or harmful effects and adverse drug reactions

ACQUIRING THE CLINICAL SKILLS YOU NEED TO PRACTICE

 The clinical skills required to practice pharmaceutical care include:
­ Obtaining information from the patient
 Obtaining information from patients requires observational,
interview, and physical assessment skills
­ Applying knowledge to individual patients
 Applying knowledge to individual patients allows you to
generate hypotheses, solve problems, and make rational
and logical decisions about the patient's pharmacotherapy.
­ Communicating with patients and colleagues, and being reflective
in practice.
 Learn how to be reflective in practice to learn the most you
can from every patient experience and become proficient at
presenting patient cases so you can learn from your
colleagues.
 Reflective skills allow you to convert clinical experience into
clinical knowledge.
DOCUMENTATION IN PRACTICE
 Documenting the care provided in practice reflects commitment to the
patient, adherence to practice standards, and the desire to learn from
clinical experience.
 Refers to all the patient-specific information, the clinical decisions, and
the patient outcomes that are recorded for use in practice.
GUIDELINES FOR DOCUMENTING PHARMACEUTICAL CARE
 Timely
 Precise
 Concise
 Complete
REASONS TO DOCUMENT CARE IN PRACTICE
 Meeting the Documentation Standard for Patient Care

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 Being Effective and Efficient at Patient Care

 Legal Purposes
 Communication Purposes
THE PHARMACEUTICAL CARE PATIENT CHART
 The patient chart is a record of the information collected by
practitioners, the decisions made, the actions taken, and the outcomes
that result, at the time these events occur.

PATIENT CASE PRESENTATION

CHIEF COMPLAINT (CC)
 A brief statement of the reason why the patient consulted the physician,
stated in the patient’s own words.
HISTORY OF PRESENT ILLNESS (HPI)
 Complete description of the patient’s symptoms:

PAST MEDICAL HISTORY (PMH)

 Includes serious illnesses, surgical procedures, and injuries the patient
has experienced previously.
FAMILY HISTORY (FH)
 Includes the age and health of parents, siblings, and children. For
deceased relatives, the age and cause of death are recorded.
SOCIAL HISTORY (SH)
 Includes the social characteristics of the patient as well as the
environmental factors and behaviors that may contribute to the
development of disease.
MEDICATION HISTORY (MEDSH)
 Should include an accurate record of the patient’s current use of
prescription medications, nonprescription products, and dietary
supplements.
ALLERGIES (ALL)
 Allergies to drugs, food, pets, and environmental factors (e.g., grass,
dust, pollen) are recorded.
REVIEW OF SYSTEMS (ROS)
 Starting from the head and working toward the feet and may include the
skin, head, eyes, ears, nose, mouth and throat, neck, cardiovascular,

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respiratory, gastrointestinal, genitourinary, endocrine, musculoskeletal,

and neuropsychiatric systems.
PHYSICAL EXAMINATION
 A physical examination is a routine test performed by primary care
provider (PCP) to check your overall health.

PATIENT FOCUSED APPROACH IN CARE PLAN

IDENTIFICATION OF REAL AND POTENTIAL DRUG THERAPY PROBLEMS
 The first step in the patient-focused approach is to collect pertinent
patient information, interpret it properly, and determine whether drug
therapy problems exist.
 Analogous to documenting the subjective and objective patient findings
in the Subjective, Objective, Assessment, Plan (SOAP) format.
 It is important to differentiate the process of identifying the patient’s
drug therapy problems from making a disease-related medical diagnosis.
 After the drug therapy problems are identified, the clinician should
determine which ones are amenable to pharmacotherapy.
 Alternatively, one must also consider whether any of the problems could
have been caused by drug therapy.
DETERMINATION OF DESIRED THERAPEUTIC OUTCOMES
 After pertinent patient-specific information has been gathered and the
patient’s drug therapy problems have been identified, the next step is to
define the specific goals of pharmacotherapy.
 The primary therapeutic outcomes include:
­ Cure of disease (e.g., bacterial infection).
­ Reduction or elimination of symptoms (e.g., pain from cancer).
­ Arresting or slowing of the progression of disease (e.g.,
rheumatoid arthritis, HIV infection).
­ Preventing a disease or symptom (e.g., coronary heart disease)
 Other important outcomes of pharmacotherapy include:
­ Not complicating or aggravating other existing disease states.
­ Avoiding or minimizing adverse effects of treatment.
­ Providing cost-effective therapy.
­ Maintaining the patient’s quality of life.
DETERMINATION OF THERAPEUTIC ALTERNATIVES
 After the intended outcome has been defined, attention can be directed

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toward identifying the types of treatments that might be beneficial in

achieving that outcome.
 The clinician should ensure that all feasible pharmacotherapeutic
alternatives available for achieving the predefined therapeutic
outcome(s) are considered before choosing a particular therapeutic
regimen.
DESIGN OF AN OPTIMAL INDIVIDUALIZED PHARMACOTHERAPEUTIC PLAN
 The purpose of this step is to determine the drug, dosage form, dose,
schedule, and duration of therapy that are best suited for a given
patient.
 Individual patient characteristics should be taken into consideration
when weighing the risks and benefits of each available therapeutic
alternative.
 Reasons for avoiding certain drugs in therapeutic plan should be known.
­ Some potential reasons for drug avoidance include drug allergy,
drug–drug or drug–disease interactions, patient age, renal or
hepatic impairment, adverse effects, poor compliance, pregnancy,
and high treatment cost.
 Specific dose selected may depend upon the indication for drug use
­ For example: The dose of aspirin used to treat rheumatoid
arthritis is much higher than that used to prevent myocardial
infarction.
 Other factors that influence drug selection are:
­ Tolerance –may affect the adherence
­ Economic
­ Psychosocial
­ Ethical
 These all factors must be given due consideration in designing
pharmacotherapeutic regimen
IDENTIFICATION OF PARAMETERS TO DETERMINE OUTCOME
 Identify the clinical and laboratory parameters necessary to assess the
therapy for achievement of the desired therapeutic outcome and for
detection and prevention of adverse effects.
 The outcome parameters selected should be:
­ Specific
­ Measurable
­ Achievable

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­ Directly Related to the therapeutic goals.

­ Defined endpoint i.e., Time bound.
 The acronym SMART has been used (Specific, Measurable, Achievable,
Related, and Time bound).
PATIENT EDUCATION
 The concept of pharmaceutical care is based on the existence of a
covenantal relationship between the patient and the provider of care.
 For chronic diseases such as diabetes mellitus, hypertension, and
asthma, patients may have a greater role in managing their diseases
than do health care professionals.
 Self-care is becoming widespread as increasing numbers of prescription
medications receive over-the counter status.
 For these reasons, patients must be provided with sufficient information
to enhance compliance, ensure successful therapy, and minimize
adverse effects.
 Patients who accept the offer of counseling, pharmacists should
consider including these items:
­ Name and description of the medication (which may include the
indication).
­ Dosage, dosage form, route of administration, and duration of
therapy.
­ Special directions or procedures for preparation, administration,
and use.
­ Common and severe adverse effects, interactions, and
contraindications (with the action required should they occur).
­ Techniques for self-monitoring.
­ Proper storage.
­ Prescription refill information.
­ Action to be taken in the event of missed dose.
COMMUNICATION AND IMPLEMENTATION OF PHARMACOTHERAPEUTIC PLAN
 The most well-conceived plan is worthless without implementation
because of inadequate communication with prescribers or other health
care providers.
 Permanent, written documentation of significant recommendations in
the medical record is important to ensure accurate communication
among practitioners.

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 Oral communication alone can be misinterpreted or transferred

inaccurately to others. Especially in the case of Look-a-like Sound-a-like
(LASA) drugs.

PHARMACIST ROLE IN PHARMACEUTICAL CARE

 Role of Pharmacist in Pharmaceutical care involves:
1. Patient assessment
2. Education and counseling
3. Patient specific pharmacist care plan
4. Drug treatment protocol
5. Dosage adjustment
6. Prescriptive authority

STANDARDS FOR PROFESSIONAL BEHAVIOR

 The Standards for Professional Behavior have been given in the table
below:

# Category Standard

The practitioner evaluates his/her own practice in relation to

I Quality of care professional practice standards and relevant statutes and
regulations.
The practitioner's decisions and actions on behalf of patients
II Ethics
are determined in an ethical manner.
The pharmaceutical care practitioner contributes to the
III Collegiality professional development of peers, colleagues, students, and
others.
The practitioner collaborates with the patient, family and/or
IV Collaboration care-givers, and health care providers in providing patient
care.
The practitioner acquires and maintains current knowledge in
V Education pharmacology, pharmacotherapy, and pharmaceutical care
practice.
The practitioner routinely uses research findings in practice
VI Research
and contributes to research findings when appropriate.

The practitioner considers factors related to effectiveness,

VII Resource allocation
safety, and cost in planning and delivering patient care.

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CLINICAL THERAPEUTICS

ANTIBIOTIC ESSENTIALS
FACTORS IN ANTIBIOTIC SELECTION
1. ANTIBIOTIC SPECTRUM
 Refers to the range of micro-organisms an antibiotic is usually effective
against and is the basis for empiric antibiotic therapy.
 Antibiotic susceptibilities are a guide to predicting antibiotic
effectiveness in blood/well vascularized organs. In vitro testing does not
always predict in vivo effectiveness.
2. TISSUE PENETRATION
 Antibiotic tissue penetration depends on properties of the antibiotic,
e.g. lipid solubility, molecular size and tissue, e.g. adequacy of blood
supply, presence of inflammation.
 Antibiotic tissue penetration is rarely problematic in acute infections due
to increased microvascular permeability from local release of chemical
inflammatory mediators.
 In contrast, chronic infections, e.g. chronic pyelonephritis, chronic
prostatitis, chronic osteomyelitis and infections caused by intracellular
pathogens often rely on chemical properties of an antibiotic, e.g. high
lipid solubility, small molecular size for adequate tissue penetration.
 Antibiotics cannot be expected to eradicate organisms from areas that
are difficult to penetrate or have impaired blood supply, such as
abscesses, which usually require surgical drainage for cure.
 Implanted foreign materials (prosthetic parts) associated with infection
usually need to be removed for cure, since microbes causing infections
associated with prosthetic joints, shunts, and intravenous lines produce
a slime/biofilm on plastic/metal surfaces that permits organisms to
survive despite antimicrobial therapy.
3. ANTIBIOTIC RESISTANCE
 Bacterial resistance to antimicrobial therapy may be classified into
following:
­ Natural/intrinsic ­ Absolute
­ Acquired ­ Agent specific
­ Relative

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NATURALLY/INTRINSICALLY RESISTANCE
 Pathogens not covered by the usual spectrum of an antibiotic are
termed e.g. 25% of S. pneumoniae are naturally resistant to macrolides.
ACQUIRED RESISTANCE
 A previously susceptible pathogen that is no longer susceptible to an
antibiotic e.g. ampicillin resistant H. influenzae.
INTERMEDIATE LEVEL (RELATIVE) RESISTANCE
 Manifests as an increase in minimum inhibitory concentrations (MICs)
but are susceptible if achievable serum/tissue concentrations greater
than MIC, e.g. penicillin-resistant S. pneumonia.
ABSOLUTE RESISTANCE
 Manifested as sudden increase in MICs during therapy and cannot be
overcome by higher-than-usual antibiotic doses, e g , gentamicin-
resistant P. aeruginosa.
AGENT-SPECIFIC RESISTANCE
 Most acquired antibiotic resistance is, not a class specific, and is usually
limited to one or two species.
 Resistance is not related, per se, to volume or duration of use Some
antibiotics have little resistance potential i.e. “low resistance” potential
even when used in high volume; other antibiotics can induce resistance,
e.g. “high resistance” potential with little use.
4. SAFETY PROFILE
 Whenever possible, avoid antibiotics with serious/frequent side effects.
5. COST
 Switching early from IV to PO antibiotics is the single most important
cost saving strategy in hospitalized patients.
 The institutional cost of IV administration (~Rs./dose) may exceed the
cost of the antibiotic itself.
 Antibiotic costs can also be minimized by using antibiotics with long half-
lives, and by choosing monotherapy over combination therapy.
FACTORS IN ANTIBIOTIC DOSING
RENAL INSUFFICIENCY
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therapeutic ratio,”
 Dosing strategies are frequently based on formula-derived estimates of
creatinine clearance, rather than precise quantitation of glomerular
filtration rates.
 Dosage adjustments
­ Antibiotics with narrow toxic-to-therapeutic ratios, and for
patients who are receiving other nephrotoxic medications or have
preexisting renal disease.
 Initial and Maintenance Dosing in Renal Insufficiency
­ For drugs eliminated by the kidneys, the initial dose is unchanged,
and the maintenance dose/dosing interval are modified in
proportion to the degree of renal insufficiency (CrCl).
 Dosing adjustment problems in renal insufficiency can be circumvented
by selecting an antibiotic with a similar spectrum that is eliminated by
the hepatic route.
 Aminoglycoside dosing
­ Single daily dosing—adjusted for the degree of renal insufficiency
after the loading dose is administered–has virtually eliminated the
nephrotoxic potential of aminoglycosides, and is recommended
for all patients, including the critically ill (except enterococcal
endocarditis, where gentamicin dosing every 8 hours may be
preferable)
­ Aminoglycoside-induced tubular dysfunction is best assessed by
quantitative renal tubular cast counts in urine, which more
accurately reflect aminoglycoside nephrotoxicity than serum
creatinine.
HEPATIC INSUFFICIENCY
 Antibiotic dosing for patients with hepatic dysfunction is problematic
since there is no hepatic counterpart to the serum creatinine to
accurately assess liver function.
 In practice, antibiotic dosing is based on clinical assessment of the
severity of liver disease.
 For practical purposes, dosing adjustments are usually not required for
mild or moderate hepatic insufficiency.
 For severe hepatic insufficiency, dosing adjustments are usually made
for antibiotics with hepatotoxic potential.

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COMBINED HEPATIC AND RENAL INSUFFICIENCY

 There are no good dosing adjustment guidelines for patients with
hepatorenal insufficiency.
 If renal insufficiency is worse than hepatic insufficiency, antibiotics
eliminated by the liver are often administered at half the total daily
dose.
 If hepatic insufficiency is more severe than renal insufficiency, renally
eliminated antibiotics are usually administered and dosed in proportion
to renal function.
DOSING STRATEGIES IN RENAL AND HEPATIC INSUFFICIENCIES
RENAL INSUFFICIENCY
 If creatinine clearance 40-60ml/min: Decrease dose of renally –
eliminated antibiotic by 50% and maintain the usual dosing interval.
 If creatinine clearance 10-40ml/min: Decrease dose of renally-eliminated
antibiotic by 50% and double the dosing interval.
 Alternative: Use antibiotic eliminated / inactivated by the hepatic route
in usual dose.
HEPATIC INSUFFICIENCY
 Decrease total daily dose of hepatically-eliminated antibiotic by 50% and
maintain the usual dosing interval.
 Alternative: Use antibiotic eliminated /inactivated by the renal route in
usual dose.
MODE OF ANTIBIOTIC AND EXCRETION / EXCRETORY ORGAN TOXICITY
 The mode of elimination/ excretion does not predispose to excretory
organ toxicity per se, e g , nafcillin (hepatically eliminated) is not
hepatotoxic, and it’s main side effect is nephrotoxicity (interstitial
nephritis).
 In contrast, oxacillin (renally eliminated), is not nephrotoxic and its main
side effect is hepatotoxicity (hepatitis).
MICROBIOLOGY AND SUSCEPTIBILITY TESTING
OVERVIEW
 In vitro susceptibility testing provides information about microbial
sensitivities of a pathogen to various antibiotics and is useful in the

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guiding therapy.
LIMITATIONS OF MICROBIOLOGY SUSCEPTIBILITY TESTING
 In vitro data do not differentiate between colonizers and pathogens.
Before responding to a culture report from the microbiology laboratory,
it is important to determine whether the organism is a pathogen or a
colonizer in the clinical context As a rule, colonization should not be
treated.
 In vitro data do not necessarily translate into in vivo efficacy. Reports
which indicate an organism is “susceptible” or “resistant” to a given
antibiotic in vitro do not necessarily reflect in vivo activity. In vitro
susceptibility testing is dependent on the microbe, methodology, and
antibiotic concentration. In vitro susceptibility testing by the
microbiology laboratory assumes the isolate was recovered from blood,
and is being exposed to serum concentrations of an antibiotic given in
the usual dose Since some body sites e.g. bladder urine contains higher
antibiotic concentrations than found in serum, and other body sites.
PK/PD AND OTHER CONSIDERATIONS IN ANTIMICROBIAL THERAPY
BACTERICIDAL VS BACTERIOSTATIC THERAPY
 For most infections, bacteriostatic and bactericidal antibiotics inhibit/kill
organisms at the same rate and should not be a factor in antibiotic
selection.
 Bactericidal antibiotics have an advantage in certain infections, such
endocarditis, meningitis, and febrile leukopenia, but there are
exceptions even in these cases.
MONOTHERAPY VS COMBINATION THERAPY
 Monotherapy is preferred to combination therapy for nearly all
infections. Following are the advantages of monotherapy:
­ Cost saving
­ Monotherapy results in less chance of medication error
­ Fewer missed doses/drug interactions
 Combination therapy may be useful for drug synergy or for extending
spectrum beyond what can be obtained with a single drug. Combination
therapy is not effective in preventing antibiotic resistance, except in very
few situations.

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EXAMPLES OF ANTIBIOTIC COMBINATIONS THAT PREVENT RESISTANCE

 Anti-pseudomonal penicillin (carbenicillin) + aminoglycoside
(gentamicin, tobramycin, amikacin)
 Rifampin + other TB drugs (INH, ethambutol, pyrazinamide)
 5-flucytosine + amphotericin B
EXAMPLES OF ANTIBIOTIC COMBINATIONS THAT DO NOT PREVENT
RESISTANCE
 TMP-SMX
 Aztreonam + ceftazidime
 Cefepime + ciprofloxacin
 Aminoglycoside + imipenem
INTRAVENOUS VS ORAL SWITCH THERAPY
 Patients admitted to the hospital are usually started on IV antibiotic
therapy, then switched to equivalent oral therapy after clinical
improvement (usually within 72 hours).
 Advantages of early IV-to-PO switch programs includes:
­ Reduced cost, early hospital discharge,
­ Less need for home IV therapy, and
­ Virtual elimination of IV line infections
 Drugs well-suited for IV-to-PO switch or for treatment entirely by the
oral route includes:
­ Doxycycline, Minocycline, Clindamycin, Metronidazole,
Chloramphenicol, Amoxicillin, Trimethoprim-sulfamethoxazole,
Quinolones, and Linezolid
 Most infectious diseases should be treated orally unless patient is
critically ill, cannot take antibiotics by mouth, there is no equivalent oral
antibiotic.
 If the patient is able to take/absorb oral antibiotics, there is no
difference in clinical outcome using equivalent IV or PO antibiotics.
 It is more important to think in terms of antibiotic spectrum,
bioavailability and tissue penetration, rather than route of
administration. Nearly all non-critically ill patients should be treated in
part or entirely with oral antibiotics.
 When switching from IV to PO therapy, the oral antibiotic chosen should
have the same spectrum/degree of activity against the presumed/known

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pathogen and achieve the same blood and tissue levels as the equivalent
IV antibiotic.
OPAT (OUTPATIENT PARENTERAL ANTIBIOTIC THERAPY)
 OPAT has been used to treat infections IV on an outpatient basis or to
complete IV therapy begun during hospitalization. Preferred OPAT
antibiotics are those with few adverse effects and those with a long
serum half-life (t1/2).
 The most frequently used OPAT antibiotics are ceftriaxone and
vancomycin. Other agents with long t1/2 ideal for OPAT of Gram positive
CSSSIs (Complicated skin/skin structure infections) due to MRSA.
 The alternative to OPAT is oral antibiotic therapy, e.g. for MRSA,
minocycline or linezolid are equally efficacious as OPAT regimens
DURATION OF THERAPY
 Most bacterial infections in normal hosts are treated with antibiotics for
1–2 weeks. The duration of therapy may need to be extended in patients
with impaired immunity e.g. diabetes, SLE, alcoholic liver disease,
neutropenia, diminished splenic function.
 Chronic bacterial infections e.g. endocarditis, osteomyelitis, chronic viral
and fungal infections, or certain bacterial intracellular pathogens.

Therapy Infectious Diseases

3 weeks Lymphogranuloma venereum (LGV), syphilis (late latent), H. pylori, chronic prostatitis
Chronic otitis media, chronic sinusitis, acute osteomyelitis, chronic pyelonephritis, brain
4 weeks
abscess
4-6 weeks Acute bacterial endocarditis (S. aureus, Listeria, enterococcal), chronic osteomyelitis
3 months Lung abscess, melioidosis, bartonella
6 months Pulmonary TB, extrapulmonary TB, actinomycosis, nocardia, prosthetic-related infections
12 months Whipple's disease
> 12 months Lepromatous leprosy, HIV, Q fever (SBE/PVE)

EMPIRIC VS SPECIFIC ANTIBIOTIC THERAPY

 Always treat the usual pathogens (related to body site flora) rather than
just “covering the cultured organism” (particularly if the specimen is not
representative of the infected tissue).

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RESISTANCE POTENTIAL SELECTION OF ANTIBIOTICS

Preferred "Low Preferred "Low

Usual Organism(s)
"High Resistance Resistance Potential" Resistance Potential
Resistant for Each
Potential" Antibiotics Antibiotic Alternatives Antibiotic Alternatives
Antibiotic
in Same Class in Different Classes

Aminoglycosides
Gentamicin Or Levofloxacin Or Colistin
P. aeruginosa Amikacin
Tobramycin Or Cefepime
Cephalosporins
Ceftazidime P. aeruginosa Cefepime Levofloxacin Or Colistin
Tetracyclines
S. pneumoniae S. Doxycycline Or Levofloxacin Or
Tetracycline
aureus Minocycline Moxifloxacin
Quinolones
Levofloxacin or
Ciprofloxacin S. pneumoniae Doxycycline
Moxifloxacin
Ciprofloxacin P. aeruginosa Levofloxacin Amikacin Or Cefepime
Glycopeptides
Linezolid Or
Vancomycin MSSA MRSA None Daptomycin Or
Minocycline
Carbapenems
Meropenem Or Amikacin Or Cefepime
Imipenem P. aeruginosa
Doripenem or Colistin
Macrolides
Doxycycline Or
Azithromycin S. pneumoniae None Levofloxacin Or
Moxifloxacin
ANTIBIOTIC FAILURE
MICROBIOLOGIC FACTORS
 In vitro susceptibility but ineffective in vivo
 Antibiotic "tolerance" with gram-positive cocci
 Treating colonization (not infection)
ANTIBIOTIC FACTORS
 Inadequate coverage/spectrum
 Inadequate antibiotic blood tissue levels
 Decreased antibiotic activity in tissue
 Drug-drug interactions (inactivation/antagonism)

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ANTIBIOTIC PENETRATION PROBLEMS

 Undrained abscess
 Foreign body-related infection
 Protected focus e.g., cerebrospinal fluid
 Organ hypoperfusion/diminished blood supply
NON-INFECTIOUS DISEASES
 Medical disorders mimicking infection e.g., SLE
 Drug fever
ANTIBIOTIC-UNRESPONSIVE INFECTIOUS DISEASES
 Viral or Fungal infections

ANTIMICROBIAL STEWARDSHIP
 Antibiotic stewardship is the effort to measure and improve how
antibiotics are prescribed by clinicians and used by patients.
 Improving antibiotic prescribing and use is critical to effectively treat
infections, protect patients from harms caused by unnecessary antibiotic
use, and combat antibiotic resistance.
RATIONALE FOR STEWARDSHIP
 Antimicrobials have transformed medicine, making once lethal infections
readily curable.
 The prompt initiation of antimicrobials reduce morbidity and mortality
especially in patients with sepsis.
 Approximately 50% of all antimicrobials prescribed in acute care
hospitals are unnecessary or inappropriate—often times a direct result
of a lack of de-escalation or discontinuation when a noninfectious
source is identified.
 The result is a challenging balancing act between appropriate empiric
therapy and antimicrobial stewardship (AMS) efforts.

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RISKS OF ANTIMICROBIAL USE AND MISUSE

RISK FOR SERIOUS ADVERSE EFFECTS WITH NO CLINICAL BENEFIT
 Direct drug-related toxicity (e.g., nephrotoxicity from vancomycin or
peripheral neuropathy from metronidazole, etc.)
 Development of superinfections Clostridium difcile infection
 Patient-specific development of resistance
DEVELOPMENT OF GLOBAL RESISTANCE
 Antimicrobial resistance is increasing and has become one of the most
serious, growing threats to public health and has significant detrimental
effects on healthcare systems.
 Associated with increased risk of death, length of stay, and higher
attributable costs.
 Reduced number of antimicrobial agents approved in the past 25 years,
with no clear recovery expected in the near future.
MECHANISMS OF BACTERIAL RESISTANCE
 Initially the bacteria may acquire several genes encoding enzymes (e.g.
β-lactamases), which destroy antibacterial agent prior to having an
effect.
 Bacteria may acquire efflux pumps that remove the antibacterial agent
from the cell before they can take effect.
 Bacteria may acquire several genes to take a metabolic pathway to
produce altered bacterial cell walls without the binding sites of the
antibacterial agent.
 Bacteria may acquire mutations to limit the access of antibacterial
agents to the target site by down-regulation of porin genes:
­ Modifying or destroying the binding site, for example; change in
penicillin binding protein 2b in pneumococci, causing penicillin
resistance.
­ Up-regulation of enzyme production inactivating antimicrobials
such as; erythromycin ribosomal methylase in staphylococci.
­ Down regulation or alteration of outer membrane protein channel
that is needed by the agent for cell entering such as OmpF in E.
coli.
­ Up-regulation of pumps to expel the antimicrobial agent from the
cell (e.g. efflux of fluroquinolones in Staphylococcus aureus)

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 Acquired resistance that is developed by chromosomal mutation and

selection is couched in term known as vertical evolution.
 Horizontal evolution is also found to be responsible for acquisition of
bacterial resistance, this is due to the newly acquired genetic material
from other resistant microorganisms.
­ Genetic exchange mechanisms: conjugation, transduction and
transformation.
PURPOSE AND GOAL
 The purpose of AMS is to:
­ Optimize, safe, judicious, appropriate use of antimicrobials
­ Enhance clinical outcomes
­ Minimizing unintended consequences of antimicrobial use
­ Reduce healthcare costs without adversely affecting quality of
care.
 The primary focus of antimicrobial stewardship should be patient safety.

STAKEHOLDERS IN AMS
 The Infectious Diseases Society of America and Society for Healthcare
Epidemiology of America Guidelines for the Development of an
Institutional AMS Program recommend a
multidisciplinary group including:
­ Co-leadership by an infectious diseases
(ID) Physician and ID-trained (or
stewardship-trained) clinical pharmacist
and include representation from
hospital administration, infection
prevention, information technology,
microbiology, and front-line prescribers
to initiate, track, maintain, and improve
AMS efforts.

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GENERAL AMS STAKEHOLDER ROLES

HOSPITAL ADMINISTRATION ROLE
 Formal supportive documents for AMS efforts, FTE designation for
appropriate personnel to initiate, implement, and manage AMS efforts,
and support ID or AMS training and education
PHYSICIAN LEADER ROLE
 Responsible for AMS outcomes and assistance with
development and implementation of AMS interventions
PHARMACY ROLE
 Co-lead responsible for AMS outcomes, development, and
implementation of AMS interventions, tracking, and reporting trends
INFECTION PREVENTION ROLE
 Prevention, monitoring, and reporting hospital-acquired
infections and resistance
INFORMATION TECHNOLOGY ROLE
 Integration of electronic AMS efforts into practice
(e.g., antimicrobial order sets, physician alerting, addition of clinical
decision support tools)
MICROBIOLOGY ROLE
 Development and maintenance of hospital antibiogram, optimal
use of laboratory testing, and result reporting
PRESCRIBERS ROLE
 Engagement in and support of AMS efforts as antimicrobial prescribers
QUALITY AND PATIENT SAFETY
 Assistance with reporting and partnering with AMS team to
optimize opportunities for improvement
SPECIFIC AMS INTERVENTION
 Essential information to include on all anti-infective orders

DRUG
 Essential component of prescription

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DOSE
 Essential component of prescription
 Allows for optimization for specific situations such as renal insufficiency,
resistant pathogens, etc.
INDICATION
 Assists with dosing and therapeutic drug monitoring goals.
 Is helpful to include whether the use is for empiric coverage,
documented infection, surgical prophylaxis, or potentially medical
prophylaxis
 (e.g., Pneumocystis jiroveci pneumonia prophylaxis, spontaneous
bacterial peritonitis prophylaxis, Mycobacterium avium complex
prophylaxis, etc.).
DURATION
 If duration can be tied to the indication, it may help prevent unnecessary
prolonged duration of therapy.
 For example, the default duration for empiric orders could be 72 hours
with an alert to providers at the 48-hour time point that the patient’s
empiric therapy will be discontinued in 24 hours. Although daily
assessment of empiric therapy is recommended, this allows for a
reminder to take an antimicrobial “time-out” by reassessing the need for
medications, making necessary changes in medications (such as
increasing or decreasing the dose for renally dose-adjusted medications
as appropriate, de-escalation of therapy based on culture data, or
discontinuation of therapy based on identification of a noninfectious
source of symptoms, etc.), or continuing empiric therapy (as is often the
case for pneumonia).
 It is helpful for providers to take these actions directly through an
electronic alert.

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CLINICAL TOXICOLOGY

INTRODUCTION
”Toxicology is the branch of sciences which deals with study and treatment of
poisons”
 Earlier toxicology was an integral part of Pharmacology but with the
increase in poisoning incidents in the recent past has resulted in
emergence of Toxicology as a separate branch.
 Toxicology is the branch of science which deals with the study of
poisons, including their mechanism of action, adverse effects on the
body and treatment of the various conditions produced by the poisons.
 These poisons can be from environment, industry, home or
pharmacological substances. Branch of Toxicology is further divided into
following branches:
1. Experimental Toxicology: It is the branch of Toxicology which
studies the toxic effects of various chemicals on the biological
systems.
2. Clinical Toxicology: Clinical Toxicology involves the diagnosis and
treatment of poisoning in human beings.
3. Environmental Toxicology: This is a new branch of Toxicology and
deals with the identification and elimination of environmental
poisons.
 Poisons: Poisons are unwanted substances which produce harmful
effects on the body and sometimes can be fatal.
 Antidotes: Antidotes are the substances used to reverse the harmful
effects of the poison. Antidotes act by either by preventing absorption
or by inactivating or antagonizing the actions of poisons.

TOXICOKINETICS
ABSORPTION INTO THE BODY
 As a general rule, fat soluble liquids are readily absorbed through the
skin and fat-soluble vapors are readily absorbed through the lungs.
 Notably these routes apply to organic solvents such as hexane, toluene,
trichlorethylene and many others.

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DISTRIBUTION WITHIN THE BODY

 Many factors affect the distribution of a toxic substance but water or fat
solubility is very important. Thus for example water soluble compounds
of lead are found (amongst other places) in the red blood cells, while fat
soluble ones concentrate in the central nervous system (CNS).
 The distribution of a toxic substance determines its concentration at a
particular tissue and therefore the number and type of cells exposed to
high concentrations of it.
METABOLISM/ BIOTRANSFORMATION OF TOXIC SUBSTANCES
 Toxic substances may be converted into other substances (metabolites)
by organs such as the liver and kidneys. Water soluble metabolites are
more easily excreted by the kidney.
 Metabolism or biotransformation does not necessarily result in less toxic
compounds. For example benzene may be oxidized to an epoxide which
then inflicts damage on the DNA in genes.

TOXICODYNAMICS
 Acute effects refer to the short-term consequences of exposure. Chronic
effects relate to a much longer time scale, while sub-acute are in
between acute and chronic).
 Some effects may be dose related – the higher the exposure the worse it
gets e.g. irritant effects on the skin, asthma, asbestosis etc.
 Other effects are 'all or none' and for a given exposure there is an
element of chance (stochastic) as to whether or not the disease
develops. For example, the development of cancer (carcinogenesis) or
some forms of developmental damage to the fetus (teratogenesis).

POISON AND PRINCIPLES OF TREATMENT OF POISONING

POISON
 Poisons are substances that cause disturbances to organisms, usually by
chemical reaction or other activity on the molecular scale, when a
sufficient quantity is absorbed by an organism.
 Poison Substance which when introduced into body in relatively small
amounts causes in structural damage or functional disturbance.
REASON FOR POISONING
 Accidental  Iatrogenic
 Incidental  Intentional

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GENERAL PRINCIPLES EMPLOYED FOR THE MANAGEMENT OF POISONING

 Toxicology provides the basic guidelines to treat both acute and severe
poisoning.
 Symptoms vary, but certain common syndromes may suggest particular
classes of poisons. Diagnosis is primarily clinical, but for some
poisonings, blood and urine tests can help.
 Treatment is supportive for most poisonings; specific antidotes are
necessary for a few. Prevention includes labeling drug containers clearly
and keeping poisons out of the reach of children.
IDENTIFY THE CAUSE POISONS
 The first step of the treatment is to identify the poisons. Cause of poison
can be known from the relative of the patient or by the parent himself if
he is conscious.
 This step helps in deciding the specific treatment to the poisoning.
PREVENTING THE FURTHER ABSORPTION OF THE POISON
 This is an important step in controlling the further spread of the poison
in the body. General rules include:
1. Induction of vomiting: Syrup of Ipecac is the preferred emetic for
inducing vomiting. Dose of Ipecac syrup is 15 ml for children less
than 6 months and 30 ml for adults. Emesis is contraindicated in
the following cases:
 Vomiting should not be induced in comatose patients.
 Emesis is contraindicated in caustic poisoning and in
Petroleum distillates poisoning.
 Emetics should also be not given to those where is a risk of
convulsions in the patient.
2. Gastric lavage: Gastric lavage is an important measure to control
poisoning when it occurs due to some aromatic substances such
as perfumes. It is also helpful when emesis is contraindicated.
3. Use of activated charcoal: Activated charcoal adsorbs the poisons
and delays the gastrointestinal absorption of the poison. It is
helpful in the treatment of poisoning from aromatic and alkaloid
compounds.
HASTENING THE ELIMINATION OF POISON

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 This is also an important aspect in treating the poisoning. Following

general rules are applied for increasing the elimination of poison from
the body:
1. Altering the pH of urine: In poisoning from basic substances such
as amphetamine or quinine urine of the patient should be made
acidic to hasten the elimination of these substances. In case of
acidic substances poisoning such as salicylates or phenobarbitone,
urine should be made alkaline to speed the elimination of the
poison.
2. Dialysis: Peritoneal dialysis is used in the treatment of methanol
poisoning and in Snake bite. Hemodialysis is more superior
technique but requires highly sophisticated unit for care.
3. Cathartics: Cathartics are used to hasten the removal of a toxic
substance and are useful in ingestion of hydrocarbons and enteric
coated tablets. Sodium Sulphate is a frequently used cathartic.
4. Uses of Antidotes: There are certain specific antidotes for treating
the specific cases of poisoning.
GENERAL SUPPORTIVE MEASURES FOR IMPROVING THE CONDITION OF
PATIENT
 General supportive measures are meant to ensure the wellbeing of the
patient and for the fast recovery from the poisoning. General measures
includes following steps:
­ Use of Oxygen therapy when there is hypoxia or probability of the
same in the patient.
­ Correction of the Blood Pressure of the patient by fluid therapy; If
there is cardiac arrhythmia in the patient then safety measures
should be taken under the supervision of the expert.
­ Correction of plasma biochemistry like, acidosis or alkalosis in the
blood.
­ Airways should be cleared with the help of suction apparatus.
MONITORING OF THE PATIENT AFTER THE EPISODE OF POISONING IS OVER
 After the patient is recovered from the adverse effects it is important to
monitor the patient for some time.
 This step is necessary and performed to ensure that there are no other
complications in the case.
 After ensuring that patient is fully recovered, he is allowed to go home.

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POISON CONTROL CENTERS

 The concept of poison control center was initiated in Chicago in 1953.
After the impetus of local health officials, pediatricians, and other
interested physicians, a single center for collecting product information
was established.
 To providing a coordinating agency for these centers, the then Bureau of
Product Safety in the FDA established the National Clearinghouse for
Poison Control Centers. This clearinghouse served as a center for
collecting and standardizing product toxicology data and distributing this
data in the form of 5 by 8-inch index cards to recognized poison control
centers.
 Today, there are 57 regional poison centers certified by the American
Association of Poison Control Centers that serve the entire United States
and their territories. They are staffed primarily by pharmacist,
physicians, nurses, and scientists who have specialized expertise in the
science of toxicology. Combined, these centers answer over four million
telephone inquiries annually. Of these calls, roughly 75% of all potential
poisoning cases are managed effectively at home, based on the
information provided by poison center staff.
 The value of poison control center services goes beyond directly
impacting patient care. An often overlook benefit of poison control
center is health care cost avoidance. Interaction with poison center can
substantially reduce unnecessary emergency department visits as well as
significantly reducing poisoned patients’ hospital stays.
 In additional to providing poison treatment information once an
exposure has occurred, poison control centers play an integral role in
both public and professional poison education and prevention.
Education outreach efforts include both primary prevention education
for public and healthcare providers, as well as secondary message meant
to promote awareness of poison center services and encourage their
utilization. Additionally, poison control center are valuable tools for
training healthcare professionals in science of toxicology.

ROLE OF PHARMACIST
 There is much that a pharmacist can do to help prevent poisoning and to
improve the treatment thereof. Pharmacists direct and staff many
regional poison center. They actively provide consultation to physicians

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treating poisoned patient to assure the quality. Undoubtedly, the most

important role played by a pharmacist is in the area of prevention.
 This role, relative to poison prevention packaging of prescription drug.
However the role of the Pharmacist is particularly critical with regard to
nonprescription or OTC items. With prescription medications there is
involvement of a physician who may provide instruction and
precautionary advice. However with over-the-counter products, the
pharmacist is often the only person who is in a position to serve these
function.
 The pharmacist can and should provide, explain and amplify directions
for proper use of potentially toxic materials, bearing in mind that the
concern is for the safety of the patient and that other household
individuals. Thus, the dispensing of a toxic medication provides an
opportunity to warn the buyer about the hazards of leaving the material
within reach of unsuspecting children.
 In some instances , it is desirable to affix warning labels on the products
that a pharmacist dispense or to hand out patient information materials.
The pharmacist also has unique role to play in detecting product or
labeling defects and an obligation to call to the attention of appropriate
manufacturing or regulatory agencies potential labeling or product
defects.

ANTIDOTES
DEFINITION
“An antidote is a substance that can counteract a form of poisoning”
CLASSIFICATION
 Antidotes are classified into following classes:
1. Physical antidote
2. Chemical antidote
3. Pharmacological antidote
PHYSICAL ANTIDOTE
DEFINITION
 Agents used to prevent the absorption of poison into body.
MECHANISIM OF ACTION
 Physical antidotes act by following three mechanisms:

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1. Adsorption: This process creates a film of the adsorbate on the

surface of the adsorbent. The main example is activated charcoal.
2. Coating: A mixture of egg and milk make a coat over the mucosa.
3. Dissolving: 10% alcohol or glycine for carbolic acid antidotes.
CHEMICAL ANTIDOTEs
DEFINITION
 Agents which change the chemical nature of poison.
MECHANISM OF ACTION
 Mainly act by two mechanisms:
1. Complex formation: Antidote make complex with the toxicant
making it unavailable to cross the membrane or to interact with
receptors.
2. Metabolic conversion: Detoxification to less toxic product
PHARMACOLOGICAL ANTIDOTE
DEFINITION
 Counteract the effects of a poison by producing the opposite
pharmacological effects. Pharmacologic antidotes may neutralize or
antagonize the effects of a toxicant.
MECHANISIM OF ACTION
 Pharmacological antidotes may act by following 5 mechanisms:
1. Preventing the formation of toxic metabolites: More effective
when given immediately before toxic metabolic activation.
2. By facilitation of more rapid or complete elimination of a toxicant:
Change the physiochemical nature of toxin, allowing better
glomerular filtration and prohibit tubular reabsorption.
3. By competing with the toxicant’s action at a receptor site:
Antagonism – Competitive antagonism and Non-competitive
antagonism.
4. By blocking receptors responsible for the toxic effect: The
physiologic effect induced by a toxin is prevented by an antidote,
although the toxicant is unchanged and may still be active.
5. By aiding in the restoration of normal function: The antidote
promotes return to normal function by repairing a defect or
enhancing a function that correct the effect of poison.

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COMMON ANTIDOTES LIST

Poison indication Antidote

Acetaminophen Acetylcysteine
Crotaline snake bites Antivenin, snake
Organophosphate Atropine
Calcium channel blockers Calcium chloride
Lead Calcium disodium EDTA
Calcium channel blockers Calcium gluconate
Iron Deferoxamine
Digoxin Digoxin Immune FAB
Heavy metals Chelating agents
Methanol Folic acid
Benzodiazepines Flumazenil
Beta blockers Glucagon
Valproic acid L-Carnitine
Methotrexate Leucovorin
Opioids Naloxone
Sulfonylureas Octreotide
Anticholinergics Physostigmine
Warfarin Phytonadione (Vitamin K1)
Isoniazid Pyridoxine (Vitamin B6)
Sodium channel blockers Sodium Bicarbonate
Cyanide Sodium thiosulfate
Ethylene glycol Thiamine
Methanol Fomepizole

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SAFE INTRAVENOUS THERAPY AND

HAZARDS OF IV THERAPY

INTRODUCTION
 Intravenous (IV) is a method of administering concentrated medications
(diluted or undiluted) directly into the vein using:
­ A syringe through a needleless port on an existing IV line (Branula)
­ A saline lock.
 The direct IV route usually administers a small volume of fluid/medicine
(max 20 ml) that is pushed manually into the patient.
 Medications given by IV are usually administered intermittently to treat
emergent concerns.
 Medications administered by direct IV route are given very slowly over
at least 1 minute.

WHY IV THERAPY
 Transfusion of blood and blood products
 Replacement and/or maintenance of fluids and electrolytes
 Where the oral route is unsuitable
 Where the IM route is inappropriate.
 Where a rapid response is required
 Where there is a need to give medication as an infusion.

PURPOSES OF IV THERAPY
 To provide parenteral nutrition (TPN)
 To provide avenue for dialysis/apheresis/hemodynamic monitoring/
diagnostic testing
 IV administration eliminates:
­ Drug absorption
­ Breakdown by directly depositing it into the blood
 IV administration results in:
­ Immediate elevation of serum levels
­ High concentration in vital organs; heart, brain, and kidneys
­ Both therapeutic and adverse effects can occur quickly with direct
intravenous administration.

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SAFE INTERAVENOUS THERAPY

INTRODUCTION
 To administer IV medications safely and effectively, all health care
agencies have policies in place and the Parenteral Drug Therapy Manual
(PDTM) that identifies medications that may be given intravenously.
 Only specific medications may be administered via the direct IV route.

SAFETY CONSIDERATIONS
 Following are the safety considerations which should be employed by
Pharmacists to avoid hazards of Iv therapy:
1. Be diligent and follow all policies related to medication
calculations and preparation. Conduct thorough assessment of
patient status before and after an injection.
2. Use a blunt filter needle or blunt needle when preparing
injections. Always use a needleless system.
3. After preparing the medication, always label the IV syringe with
the patient name, date, time, medication, concentration of the
dose, dose, and your initials. Once the medication is prepared,
never leave it unattended.
4. Always administer the post-saline lock flush at the same rate as
the IV medication.
5. Always assess the patient’s symptoms and need for IV medication
prior to administration. Always assess the patient’s understanding
of the medication.
6. Review the advantages and disadvantages of IV medications. If the
medication has been diluted and there is wastage, always discard
unused diluted portion of the prepared IV medication before
going to the bedside.
7. Central venous catheters (central lines, PICC lines) may require
special pre- and post-flushing procedures and specialized training.
8. Prepare one medication for one patient at the correct time.
Review the physician’s order, MAR for the correct order and
guidelines.
9. Review the policy if a medication is a stat, given for the first time,
a loading dose, or a one-time dose.
10.Some agencies require that high-alert medications be double-
checked by a second health care provider. Always follow agency
policies.

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HAZARDS OF IV THERAPY
1. INFILTRATION
INTRODUCTION
 Leakage of fluid and accumulation in tissues. Infiltration is the diffusion or
accumulation (in a tissue or cells) of substances not normal to it or in
amounts in excess of the normal. The material collected in those tissues or
cells is called infiltrate.
ASSESSMENT
 Swelling  Discomfort
 Coolness  Sluggish flow
CAUSES
 Main cause of infiltration is the leakage of IV Fluid in the surrounding
tissue and is usually caused by the catheter becoming dislodged or by
the needle penetrating through the vein.
INTERVENTION
 Stop IV infusion immediately and remove IV Catheter
 Elevate Extremity
 If noticed within 30 minutes of onset, apply ice to the site (this will
decrease inflammation)
 If noticed later than 30 minutes of onset apply warm compress (this will
encourage absorption)
 Notify Supervisor/Physician as per individual hospital policy
 Document findings and actions
 Restart IV in an alternative location (opposite extremity if possible)
2. PHLEBITIS
INTRODUCTION
 Inflammation of walls of vein.
 Thrombophlebitis: It is an inflammation of the vein accompanied by the
formation of clot. Thrombophlebitis is the inflammation of the wall of a
vein with associated thrombosis, often occurring in the legs during
pregnancy.
 Thrombosis: Thrombosis is the formation of clot in the blood vessels
without accompanied inflammation and it is more dangerous.

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ASSESSMENT
 Redness  Pain along vein route
 Swelling  Vein is hard “cordlike”
 Warmth  IV may be sluggish
CAUSES OF PHLEBITIS
 Injury to the vein during vein puncture or from later movement
 Irritation to the vein caused by long term therapy
 Infusion of irritating or incompatible additives
 Using a vein that is too small
 Infection
CAUSES OF THROMBOPHLEBITIS
 Chemical causes: Infusate chemically erodes internal layers. Warm
compresses may help while the infusate is stopped/changed. Anti-
inflammatory and analgesic medications are often used no matter what
the cause.
 Mechanical causes: Caused by irritation to internal lumen of vein during
insertion of vascular access device and usually appears shortly after
insertion. The device may need to be removed and warm compresses
applied
 Bacterial causes: Caused by introduction of bacteria into the vein.
Remove the device immediately and treat antibiotics. The arm will be
painful, red and warm; edema may accompany.
INTERVENTIONS
 Report your observation to the senior pharmacist or trained personnel
 Trained personnel will then remove the IV and restart it in alternate
location.
PREVENTIVE MEASURES
 Keep the flow at prescribed rate
 Stabilize the catheter with correct taping
 Select a large vein
 Maintain strict aseptic techniques
 Change the catheter and tubing every 48-72 hours.

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3. NON-RUNNING IV INFUSION
INTRODUCTION
 Most common
 Also arise in very slowly running IV infusion
 Maintain drip rate
CAUSES
 IV infusion bag too close to the heart level
 Bevel of needle against wall of vein (bevel of needle facing upward)
 Tourniquet left on arm
4. CELLULITIS
INTRODUCTION
 Inflammation of loose connective tissue around insertion site.
CAUSES
 Caused by poor insertion technique
 Red swollen area spreads from insertion site outwardly in a diffuse
circular pattern.
INTERVENTIONS
 Treated with antibiotics.
5. INFECTION – LOCAL, SYSTEMIC
ASSESSMENT
 Redness, swelling, pain at site
 Pus at site
 Fever, chills
CAUSES
 Poor aseptic techniques
 Transmission from another affected part of the body to the infusion site
 Introduction of contaminants while irrigating.
INTERVENTIONS
 Prevention!! Adhere to policy for site change and site care.
 Use appropriate technique for IV starts and site care.

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 Once it occurs, involve physician, discontinue IV and Rx infection per

physician order.
6. HEMATOMA
INTRODUCTIION
 Presence of a volume of blood in area around vein / vessel causes
localized swelling and discoloration.
CAUSES
 First may develop during the attempted venipuncture if the vessel is
damaged (not preventable)
 Second cause of hematoma is usually preventable (IV procedure
completed and the needle removed from the patient)
 Improper pressure or inadequate time of pressure on the venipuncture
site can lead to a hematoma
ASSESSMENT
 Painless bluish discoloration of the skin at the site of the needle
 Develops during venipuncture attempt or at the conclusion of the IV
procedure.
PREVENTION
 Careful adherence to recommended techniques will minimize its
occurrence.
 Can be prevented by application of firm pressure for a minimum of 5 to
6 minutes.
INTERVENTION
 During venipuncture, the swelling will increase rapidly because the
tourniquet is still in place on patient’s arm.
 Immediate management:
­ Remove the tourniquet
­ Remove needle
­ Apply firm pressure with sterile gauze for 5 to 6 minutes
­ If the site is tender, ice may be applied as vasoconstrictor and as
an analgesic
7. VENOSPASM

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INTRODUCTION
 It is protective mechanism in which the vein responds to stimulation
from the needle by constricting.
 As the needle approaches the vein, the vein, it disappear or collapse.
 Occasionally accompanied by a burning sensation in the immediate
area .
 May occur before or after entry of the needle into the vein, securing the
needle and starting of the IV drip.
PREVENTION
 There is no way to prevent venospasm
ASSESSMENT
 Identified by disappearance of a vein while attempting venipuncture. A
burning sensation may or may not occur
INTERVENTION
 Do not remove from the site, pull back slightly 1-2mm, heat applied to
dilate the vessel.
8. SEPTICEMIA/PULMONARY EDEMA/ EMBOLISM
 Septicemia: Severe infection that occurs to a system or entire body.
Most often caused by poor insertion technique or poor site care.
Discontinue device immediately, culture and treat appropriately.
 Pulmonary edema: Caused by rapid infusion.
 Pulmonary embolism: Caused by any free-floating substances that
require thrombolytic therapy for several months. Increased risk w/lower
ext.
 Air embolism: Caused by air injected into IV system. Keep insertion site
below level of heart.
9. AIR EMBOLUS
INTRODUCTION
 It is an obstruction of blood vessel by air carried via the blood stream”
 An air embolism is an air bubble trapped in a blood vessel. When an air
bubble travels along an artery, it moves through a system of blood
vessels that gradually become narrower. At some point, the embolus will

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block a small artery and cut off the blood supply to a particular area of
the body. (It can be life threatening sometimes)
ASSESSMENT
 Abrupt drop in blood pressure
 Weak, rapid pulse
 Cyanosis
 Chest Pain
INTERVENTIONS
 Notify Supervisor and Physician immediately
 Immediately place patient on left side with feet elevated (this allows
pulmonary artery to absorb small air bubbles)
 Administer O2 if necessary.
PREVENTIVE MEASURES
 Clear all air from tubing before attaching it to the patient
 Monitor solution levels carefully and change bag before it becomes
empty
 Frequently check to assure that all connections are secure.
10. SPEED SHOCK
INTRODUCTION
 A sudden adverse physiologic reaction to IV medications or drugs that
are administered too quickly.
ASSESSMENT
 A flushed face, headache, a tight feeling in the chest, irregular pulse, loss
of consciousness, and cardiac arrest.
INTERVENTIONS
 Notify physician immediately
 Patent IV for fluids, reversal, emergency equipment and monitoring.
11. ALLERGIC REACTION / ANAPHYLAXIS
ASSESSMENT
 Skin ; urticaria
 Respiratory ; bronchospasm

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 Edema
 Cardiovascular ;shock. i.e. Low BP, tachycardia.
 Gastrointestinal ; cramps and diarrhea
INTERVENTIONS
 Cease treatment.
 Implement resuscitation procedures depending on severity
 Notify doctor immediately
PREVENTION
 It is the responsibility of all staff, i.e. both the person prescribing and the
person administering to be aware of previous reactions and possible
medication interactions.

ASSESSMENT OF SEVERITY OF INFILTRATION & PHLEBITIS

INFILTRATION SCALE

PHLEBITIS SCALE

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NON-COMPLIANCE

DEFINITION
“Failure or refusal to comply”
 In medicine, the term non-compliance is commonly used in regard to a
patient who does not take a prescribed medication or follow a
prescribed course of treatment.

INTRODUCTION
 Non-compliance with therapy is one of the biggest threat to successful
treatment and one of the most common problem encountered in clinical
practice.
 Reasons for patient's non-adherence to medications:
­ Language barrier
­ Low education level
­ Poor doctor - patient interaction
­ System related obstacles.

EXTENT OF COMPLIANCE
 % compliance = (NDP-NME)*100/NDP
­ NDP = number of doses prescribed
­ NME = number of medication errors
­ Any arbitrary value less than 90% indicates suboptimal use of
medication.

CONDITIONS NECESSARY FOR PATIENT'S ADHERENCE

 Understand and believe the diagnosis
 Be interested in their health
 Correctly assess the impact of the diagnosis
 Believe in the efficacy of the prescribed treatment
 Know exactly how and how long to use their medication
 Know onset of action
 Value outcome of the treatment more than the cost
 Be ready to use the medication

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METHODS TO ASSESS PATIENT COMPLIANCE

INDIRECT METHODS
1. INTERROGATION
 Use of standard questionnaires to assess compliance level and
inconvenience of the regimen. incidence of side effects and overall level
of comprehension
 Too subjective — not always reliable
2. PILL COUNT (RESIDUAL TABLET COUNTING)
 At every visit, according to requirements, the patients received a supply
sufficient for the interval to the next appointment plus extra tablets for a
week. They were asked to return the remaining tablets at the time of the
next clinic visit. Compliance was assessed as the percentage of pills
prescribed which were taken:
o Compliance (%) = (Number of pills taken) / (Number of pills
prescribed) x 100 = (# of tabs prescribed – # of tabs returned) / (#
of tabs prescribed) x 100.
3. MEMS DEVICES
 Medication Event Monitoring System
 Standard pill containers with microprocessors to record timing and
frequency of bottle openings
 Major limitation - opening of the bottle is recorded as an event whether
or not patient actually took the drug
 At every visit, patient had a MEMS reading, data showed as a calendar
plot with information regarding no. of bottle openings each day and
exact time when the bottle was opened
 Compliance - assessed as ratio of no. of opening to no. of doses
prescribed.
DIRECT METHODS
1. DRUG ANALYSIS
 Specific and sensitive methods of analysis to detect potent agents in
body fluids
 Bioavailability (F) and clearance (CL) – assumed to remain constant,
average steady state concentration (Cpss) for a dose (D) administered at
dosage interval (T) is expressed as:
­ Cpss = (FD) / (CL*T)
 Dose input rate is calculated as:
­ FD/T = Cpss*CL

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2. URINE MARKERS
 Urine marker — Riboflavin: added to dosage regimen and its presence in
the urine is noted for more accurate assessment of compliance.

REASONS FOR NON-COMPLIANCE

1. POOR STANDARDS OF LABELING
 Labels - must be clear and specific (no ambiguity)
 Instructions such as lake as required" or use as directed" are not specific
 Poorly written labels with bad handwriting - major source of medication
errors.
2. INAPPROPRIATE PACKING
 Elderly patients - difficulty in opening container, especially if size is too
small or cap is difficult to twist
­ Blister pack - too rigid
­ Glass bottle – fragile
 Thus difficulty in handling
3. COMPLEX THERAPEUTIC REGIMEN
 Difficult to memorize and thus unintentional non-compliance
4. NATURE OF MEDICATION
 Unpleasant taste, color or odor – noncompliance within patients
(particularly children)
 Extremely small tablets – difficult to handle or identify Large tablets -
difficult to swallow
 Occurrence of irritating side effects – precipitate in noncompliance
5. DELIBERATE DEVIATION
 Some patients believe that once they begin to feel better, treatment
may be stopped
 Mental frailty – may forget to take occasional dose
 Forgetfulness – complete omission of doses or duplication of doses:
more common with socially isolated geriatric patients.
 Lack of proper physician – pharmacist – patient rapport.

STRATEGIES FOR IMPROVING NON-COMPLIANCE

1. SIMPLIFICATION OF THERAPEUTIC REGIMEN
 Minimizing the complexity – minimum number of drugs with well-
defined dosage schedule
 Use of sustained release and long-acting oral preparations

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 Single dose drugs (phenytoin, propranolol or antidepressants) promote

compliance by reducing adverse effects
 Fixed dose combinations for:
­ Synergism (Cotrimoxazole)
­ Improved efficacy (estrogen-progesterone contraceptives)
2. DEVELOPMENT OF SUITABLE MEDICATION PACKING
 Unit dose package – blister pack – encourage degree of self-monitoring –
Improved compliance in intelligent and motivated patients.
 Medication box – all the different drugs to be taken at a specific time are
grouped together in one compartment.
3. SUPPLEMENTARY LABELING
 Precautions or recommendations that enhance the advice of the
prescriber
 Based on potential clinical significance for the benefit of patients
 Should be concise, uncomplicated and foolproof:
­ Description of drug action given in lay terminology
­ Symbols and graphics to emphasize correct time of administration
­ 'Daily calendar' or 'Tablet identification card' bearing details of
administration schedule.
4. PATIENT COUNSELING AND EDUCATION
 Pharmacist should inform, educate and counsel patients about following
items about each medication in the dosage regimen:
­ Name (trade name. generic flame and common name)
­ Intended use and expected action
­ Route, dosage form, dosage and administration schedule.
­ Special directions
­ Common side effects
­ Techniques for self-monitoring
­ Proper storage
­ Drug -drug or Drug -food interactions
­ Prescription refill information
­ Action to be taken in event of a missed dose
­ Selection of OTC drugs and their uses.
 Methods for imparting patient education depend on type and extent of
advice needed:
­ Verbal counseling

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­ Printed information
 Warning cards
 Medication instruction sheet
 Leaflets and booklets describing drugs
 Patient package inserts
­ In-patient medication training programmes
­ Compliance clinics
 Routine counseling is both undesirable and impractical.
 Priority should be given to cases where:
­ Prophylactic treatment is required in absence of symptoms
(tuberculosis)
­ Drugs having low safety margin (warfarin)
­ Premature withdrawal may have serious consequences
(corticosteroids)
­ Long term therapy for chronic conditions (epilepsy).

ROLE OF PHARMACIST IN PATIENT COMPLIANCE

 Identify drug related issues, patient consultations regarding drug
therapy.
 Medication information – counseling sessions (DI, side effects,
contraindications)
 Awareness of risks of OTC drugs.

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Chapter 10.5.1 – Stroke

STROKE

“Stroke involves abrupt onset of focal neurologic deficit that lasts at least 24
hours and is presumed to be of vascular origin.”

INTRODUCTION
 A stroke occurs when the blood supply to part of brain is interrupted or
reduced, preventing brain tissue from getting oxygen and nutrients.
Brain cells begin to die in minutes.
 A stroke is a medical emergency, and prompt treatment is crucial. Early
action can reduce brain damage and other complications.
 There are two types of strokes:
­ Ischemic stroke
­ Hemorrhagic stroke

PATHOPHYSIOLOGY
 Ischemic stroke occurs in the blood vessels of the brain. Clots can form
in the brain's blood vessels, in blood vessels leading to the brain, or even
in blood vessels elsewhere in the body and then travel to the brain.
These clots block blood flow to the brain's cells. Ischemic stroke can also
occur when too much plaque (fatty deposits and cholesterol) clogs the
brain's blood vessels. About 80% of all strokes are ischemic.
 Hemorrhagic stroke occurs when a blood vessel in the brain breaks or
ruptures. The result is blood seeping into the brain tissue, causing
damage to brain cells. The most common causes of hemorrhagic stroke
are high blood pressure and brain aneurysms. An aneurysm is a
weakness or thinness in the blood vessel wall.

CLINICAL PRESENTATION
 Symptoms of stroke include:
­ Confusion, including difficulty speaking and understanding
speech.
­ A headache, possibly with altered consciousness or vomiting.
­ Numbness or an inability to move parts of the face, arm, or leg,
particularly on one side of the body
­ Vision problems in one or both eyes

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­ Difficulty walking, including dizziness and a lack of coordination

 FAST Acronym for symptoms of stroke:
­ Face drooping: If the person tries to smile, does one side of
their face droop?
­ Arm weakness: If the person tries to raise both their arms,
does one arm drift downward?
­ Speech difficulty: If the person tries to repeat a simple phrase,
is their speech slurred or unusual?
­ Time to act: If any of these symptoms are occurring, contact
the emergency services immediately.

DIAGNOSIS
 Physical examination: A physician will ask about the person’s symptoms
and medical history. They will check muscle strength, reflexes, sensation,
vision, and coordination. They may also check blood pressure, listen to
the carotid arteries in the neck, and examine the blood vessels at the
back of the eyes.
 Blood tests: A physician may perform blood tests to determine if there is
a high risk of bleeding or blood clots, measuring levels of particular
substances in the blood, including clotting factors, and checking whether
or not an infection is present.
 CT scan: A series of X-rays can show hemorrhages, strokes, tumors, and
other conditions within the brain.
 MRI scan: These use radio waves and magnets to create an image of the
brain, which a physician can use to detect damaged brain tissue.
 Carotid ultrasound: A physician may carry out an ultrasound scan to
check blood flow in the carotid arteries and to see if there is any
narrowing or plaque present.
 Cerebral angiogram: A physician may inject a dye into the brain’s blood
vessels to make them visible under X-ray or MRI. This provides a detailed
view of the blood vessels in the brain and neck.
 Echocardiogram: This creates a detailed image of the heart, which
physicians can use to check for any sources of clots that could have
traveled to the brain.

TREATMENT
ISCHEMIC STROKE AND TIA
 These stroke types are caused by a blood clot or other blockage in the

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brain. For that reason, they are largely treated with similar techniques,
which include:
 Antiplatelet and anticoagulants: Over-the-counter aspirin is often a first
line of defense against stroke damage. Anticoagulant and antiplatelet
drugs should be taken within 24 to 48 hours after stroke symptoms
begin.
 Clot-breaking drugs: Thrombolytic drugs can break up blood clots in
brain’s arteries, which still stop the stroke and reduce damage to the
brain. One such drug, tissue plasminogen activator (tPA), or Alteplase IV
r-tPA, is considered the gold standard in ischemic stroke treatment.
 Mechanical thrombectomy: During this procedure, the physician inserts
a catheter into a large blood vessel inside the head. They then use a
device to pull the clot out of the vessel. This surgery is most successful if
it is performed 6 to 24 hours after the stroke begins.
 Stents: If physician finds where artery walls have weakened, they may
perform a procedure to inflate the narrowed artery and support the
walls of the artery with a stent.
 Surgery: In the rare instances that other treatments do not work surgery
is performed.
HEMORRHAGIC STROKE
 Strokes caused by bleeds or leaks in the brain require different
treatment strategies. Treatments for hemorrhagic stroke include:
 Medications: Unlike with an ischemic stroke, if patient is having a
hemorrhagic stroke, the treatment goal is to make blood clot. Therefore,
patient may be given medication to counteract any blood thinners you
take. Patients may also be prescribed drugs that can reduce blood
pressure, lower the pressure in brain, prevent seizures, and prevent
blood vessel constriction.
 Coiling: During this procedure, physician guides a long tube to the area
of hemorrhage or weakened blood vessel. They then install a coil-like
device in the area where the artery wall is weak. This blocks blood flow
to the area, reducing bleeding.
 Clamping: This cuts off blood supply and prevents a possible broken
blood vessel or new bleeding.
 Surgery: If an aneurysm has burst, surgery is done to clip the aneurysm
and prevent additional bleeding. Likewise, a craniotomy may be needed
to relieve the pressure on the brain after a large stroke.

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Chapter 10.5.2 – Epilepsy

EPILEPSY

“Epilepsy is a chronic disorder that causes unprovoked, recurrent seizures.”

INTRODUCTION
 Epilepsy is a central nervous system (neurological) disorder in which
brain activity becomes abnormal, causing seizures or periods of unusual
behavior, sensations, and sometimes loss of awareness.
 There are two main types of seizures. Generalized seizures affect the
whole brain. Focal, or partial seizures, affect just one part of the brain.

PATHOPHYSIOLOGY
 Seizures result from excessive excitation or from disordered inhibition of
neurons. Initially, a small number of neurons fire abnormally. Normal
membrane conductance and inhibitory synaptic currents then break
down, and excitability spreads locally (focal seizure) or more widely
(generalized seizure). Epileptic seizures result only when there is also
synchronization of excessive neuronal firing.
 Mechanisms that may contribute to synchronous hyperexcitability
include:
­ Alterations of ion channels in neuronal membranes
­ Biochemical modifications of receptors
­ Modulation of second messaging systems and gene expression
­ Changes in extracellular ion concentrations.

CLINICAL PRESENTATION
 Seizures are the main symptom of epilepsy. Symptoms differ from
person to person and according to the type of seizure.
FOCAL (PARTIAL) SEIZURES
 A simple partial seizure does not involve loss of consciousness.
Symptoms include:
­ Alterations to sense of taste, smell, sight, hearing, or touch
­ Dizziness
­ Tingling and twitching of limbs.
 Complex partial seizures involve loss of awareness or consciousness.
 Other symptoms include:

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­ Staring blankly
­ Unresponsiveness
­ Performing repetitive movements.
GENERALIZED SEIZURES
 Generalized seizures involve the whole brain. There are six types:
­ Absence seizures, which used to be called “petit mal seizures,”
cause a blank stare. This type of seizure may also cause repetitive
movements like lip smacking or blinking. There is also usually a
short loss of awareness.
­ Tonic seizures cause muscle stiffness.
­ Atonic seizures lead to loss of muscle control and can make you
fall down suddenly.
­ Clonic seizures are characterized by repeated, jerky muscle
movements of the face, neck, and arms.
­ Myoclonic seizures cause spontaneous quick twitching of the arms
and legs.
­ Tonic-Clonic seizures used to be called “grand mal seizures.”
Symptoms include:
 Stiffening of the body
 Shaking
 Loss of bladder or bowel control
 Biting of the tongue
 Loss of consciousness.

DIAGNOSIS
 Blood tests may be used to look for:
­ Signs of infectious diseases
­ Liver and kidney function
­ Blood glucose levels
 Electroencephalogram (EEG) is the most common test used in
diagnosing epilepsy.
 Imaging tests can reveal tumors and other abnormalities that can cause
seizures. These tests might include:
­ CT scan
­ MRI

TREATMENT
 Anti-epileptic (anticonvulsant, antiseizure) drugs: These medications

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can reduce the number of seizures patient have. In some people, they
eliminate seizures. To be effective, the medication must be taken exactly
as prescribed.
 Vagus nerve stimulator: This device is surgically placed under the skin
on the chest and electrically stimulates the nerve that runs through your
neck. This can help prevent seizures.
 Ketogenic diet: More than half of people who do not respond to
medication benefit from this high fat, low carbohydrate diet.
 Brain surgery: The area of the brain that causes seizure activity can be
removed or altered.

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Chapter 10.5.3 – Psychosis

PSYCHOSIS

“Psychosis is characterized by an impaired relationship with reality.”

INTRODUCTION
 Psychosis involves a loss of contact with reality and can feature
hallucinations and delusions. It is a symptom of schizophrenia and
bipolar disorder, but there are many other causes.

CAUSES
 Genetics: Patients can have the genes for it, but that does not always
mean patient will get psychosis.
 Drugs: Triggers include some prescription medications and abuse of
alcohol or drugs like marijuana, LSD, and amphetamines.
 Trauma: The death of a loved one, a sexual assault, or war can lead to
psychosis. The type of trauma and the age patient when it happened
also play a role.
 Injuries and illnesses: Traumatic brain injuries, brain tumors, strokes,
Parkinson’s disease, Alzheimer’s disease, dementia, and HIV can all bring
on psychosis.

CLINICAL PRESENTATION
 Hallucinations: The person hears, sees, smells, tastes, or feels things
that do not exist.
 Delusions: The individual believes things that are false, and they may
have unfounded fears or suspicions.
 Disorganized thinking, speech, and behavior: The person may jump
between unrelated topics in speech and thought, making connections
that appear illogical to other people. Their speech may make no sense to
others.
 Catatonia: The person may become unresponsive.
 Unusual psychomotor behavior: The person makes unintentional
movements, such as pacing, tapping, and fidgeting.
 The person may also experience:
­ Mood changes ­ Sleep problems
­ Difficulty focusing

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DIAGNOSIS
 To diagnose psychosis, a physician will carry out a clinical
examination and ask various questions. They will ask about:
­ The person’s experiences, thoughts, and daily activities
­ Any family history of psychiatric illness
­ Any medical and recreational drug use
­ Any other symptoms.
 They may also do tests to rule out other factors, including:
­ The use of drugs or other substances
­ A head injury
­ Other medical conditions, such as multiple sclerosis (MS) or a
brain tumor.
 Possible tests include:
­ Blood tests
­ Urinalysis
­ An electroencephalogram (EEG), which records brain activity.

TREATMENT
 Antipsychotic drugs are the main form of treatment for people with a
psychotic illness.
 Examples of these medications include:
­ Haloperidol (Haldol)
­ Chlorpromazine (Thorazine)
­ Clozapine (Clozaril)

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Chapter 10.6.1 – Principles of Infectious Diseases

PRINCIPLES OF INFECTIOUS DISEASES

RATIONAL APPROACH
 Proper selection of antimicrobial therapy
 Before initiating therapy, first clearly establish the presence of an
infectious process because several disease states and drugs can mimic
infection (e.g., malignancy, autoimmune diseases)
 Once infection has been documented, identify most likely site.
 Signs and symptoms direct the clinician to the likely source (e.g.,
erythema associated with cellulitis)
 Certain pathogens are known to be associated with a specific site of
infection, therapy often can be directed against these organisms.
 Additional laboratory tests, including the gram stain, serology, and
antimicrobial susceptibility testing, identify the primary pathogen.

ANTIMICROBIAL CHOICE CONSIDERATION

 Spectrum of activity
 Clinical efficacy
 Adverse effect profile
 Pharmacokinetic disposition
 Cost
 Availability

EMPIRIC THERAPY PRIOR TO IDENTIFICATION OF THE ORGANISM

 Ideally, the antimicrobial agent used to treat an infection is selected
after the organism has been identified and its drug susceptibility
established. However, in the critically ill patient, such a delay could
prove fatal, and immediate empiric therapy is indicated.
TIMING
 Acutely ill patients with infections of unknown origin “For example, a
neutropenic patient (one who has a reduction in neutrophils,
predisposing the patient to infections), or a patient with severe
headache, a rigid neck, and sensitivity to bright lights (symptoms
characteristic of meningitis)” require immediate treatment.

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 Therapy is initiated after specimens for laboratory analysis have been

obtained but before the results of the culture are available.
SELECTING A DRUG
 The choice of drug in the absence of susceptibility data is influenced by
the site of infection and the patient's history (for example, whether the
infection was hospital or community-acquired, whether the patient is
immunocompromised, as well as the patient's travel record and age).
 Broad-spectrum therapy may be needed initially for serious infections
when the identity of the organism is unknown or the site makes a
polymicrobial infection likely.
 The choice of agents may also be guided by known association of
particular organisms with infection in a given clinical setting. For
example, a gram-positive coccus in the spinal fluid of a newborn infant is
unlikely to be Streptococcus pneumoniae (pneumococcus) and most
likely to be Streptococcus agalactiae (Group B), which is sensitive to
penicillin G.

ESTABLISHING SEVERITY OF INFECTION

SEPSIS
 Sepsis is when body has an unusually severe response to an infection.
It's sometimes called septicemia. During sepsis, immune system, which
defends from germs, releases a lot of chemicals into blood. This triggers
widespread inflammation that can lead to organ damage.
 Systemic infection associated with the presence of pathogenic
microorganisms or their toxins in the blood.
 A uniform system for defining the spectrum of disorders associated with
sepsis has been established.
PATHOGENESIS
 Gram-negative; endotoxin, Gram-positive; exotoxin and fungal cell wall
constituents release cytokines:
­ Tumor necrosis factor (TNF)
­ Interleukin-1 (IL-1)
­ Interleukin-6 (IL-6)
­ Platelet activating factor (PAF)
 Various other substances are also released from mononuclear
phagocytes and other cells. After release of TNF, IL-1, and PAF,

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Arachidonic acid is metabolized to form Leukotrienes, Thromboxane A 2

and Prostaglandins (prostaglandin E2 and prostaglandin I2).
 IL-1 and IL-6 activate the T-cells to produce INF, IL-2, IL-4 and
granulocyte macrophage colony-stimulating factor (GM-CSF) resulting in
enhanced endothelial permeability.
 Activation of the complement cascade (fragments C3a and C5a) causes
additional vascular abnormalities and neutrophil activation.
 Other potentially important agents include:
­ Adhesion molecules, kinins, thrombin, myocardial depressant
substance, endorphins, and heat shock protein.
 The net result of this cascade involves several hemodynamic, renal, acid
base, and other disorders.
 Uncontrolled inflammation and coagulation also have an important role
in this sepsis cascade.
1. HEMODYNAMIC CHANGES
 Systemic vascular resistance (SVR) decreases because of intense
vasodilatation resulting in increased carbon monoxide.
 Reasons of increased Carbon monoxide:
­ Increased Heart Rate
­ Stroke volume is unchanged or decreased because of
Hypovolemic state.
 Although the Heart Rate is increased on the basis of reflex tachycardia, a
chronotropic response also takes place as a result of stress-induced
catecholamine release (norepinephrine, epinephrine).
 This increase generally is insufficient to overcome the vasodilatory state
and results in hypotension.
 Some vascular beds constrict and decrease blood flow. Significant
amounts of blood are shunted away from the kidneys, mesentery, and
extremities.
OTHER ASSOCIATED CHANGES
 RENAL: Decreased blood flow to the kidney as well as mediator-induced
microvascular failure can cause acute-tubular necrosis (ATN). Decreased
renal perfusion results in Uremia where BUN and serum creatinine levels
are increased (Secondary to sepsis).
 LIVER: Decreased blood flow to the liver may result in “shock liver,” in
which liver function tests (LFT), including alanine aminotransferase

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(ALT), aspartate aminotransferase (AST), and alkaline phosphatase,

become elevated.
 COLD EXTREMITIES: Decreased blood flow to the musculature.
 CNS: Decreased blood flow to the brain can result in decreased
mentation (confusion).
2. CELLULAR CHANGES
 The sepsis syndrome is associated with significant abnormalities in
cellular metabolism.
 Glucose intolerance commonly is observed in sepsis, and patients with
previously normal blood glucose levels may experience sudden increases
in blood sugar.
 In some cases, an increase in glucose is one of the first signs of an
infectious process.
 Other sensitive indicators of sepsis-associated inflammation include the
ESR and C-reactive protein, nonspecific tests that are commonly
elevated in various inflammatory states, including infection.
3. RESPIRATORY CHANGES
 Production of organic acids (lactate)
 Increased glycolysis
 Decreased fractional extraction of oxygen, and abnormal delivery-
dependent oxygen consumption
 Increase in lactic acid results in metabolic acidosis, with accompanying
decreased serum bicarbonate levels
­ Metabolic acidosis is a condition that occurs when the body
produces excessive quantities of acid or when the kidneys are not
removing enough acid from the body.
 The lungs normally respond in a compensatory manner with an
increased respiratory rate (tachypnea), resulting in an increased
elimination of arterial CO2.
 ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS): Non-cardiogenic
pulmonary edema with severe hypoxemia caused by right-to-left
intrapulmonary shunting resulting from atelectasis and edema-filled
alveoli.
 Pathophysiology of ARDS is a breakdown in the natural integrity of the
alveolar capillary network in the lung.
­ In the early phase of ARDS, patients have severe alveolar edema
with large numbers of inflammatory cells, primarily neutrophils.

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­ The chronic phase of ARDS (10–14 days) is associated with

significant lung destruction (emphysema, pulmonary vascular
obliteration and fibrosis).
4. HEMATOLOGIC CHANGES
 Disseminated intravascular coagulation (DIC) is a well-recognized sequel
of sepsis.
 Huge quantities of clotting factors and platelets are consumed in DIC as
widespread clotting takes place throughout the circulatory system.
 As a result, the PT and the activated partial thromboplastin time (aPTT)
are prolonged and the platelet count commonly is decreased in sepsis.
5. NEUROLOGIC CHANGES
 CNS CHANGES: Lethargy, disorientation, confusion, and psychosis,
predominate in sepsis.
 Altered mental status is well recognized as a symptom associated with
infections of the CNS (meningitis and brain abscess). These changes,
however, also are common with other sites of sepsis.

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Chapter 10.6.2 – Meningitis

MENINGITIS

“Meningitis is infection of the meninges characterized by inflammation of

subarachnoid space commonly caused by hematogenous spread of an
organism.”

INTRODUCTION
 Meningitis= inflammation of leptomeninges, Encephalitis= inflammation
of the brain, Meningoencephalitis= inflammation of meninges + brain.

ANATOMY AND PHYSIOLOGY

 Brain and spinal cord are surrounded by
meninges suspended in CSF.
 Meninges have three layers:
­ Pia mater
­ Arachnoid mater
­ Dura mater
 Leptomeninges= arachnoid space + pia matter
 Subarachnoid space is present between
leptomeninges which contain CSF.
 Normal CSF volume is 50—150ml (Pressure
50—150mmH2O)
 Two barriers are present: 1Blood-CSF and 2Blood-brain barrier. Many
drugs antimicrobials pass blood-CSF barrier few pass BBB.

CAUSES OF MENINGITIS
1. BACTERIA
 NEWBORNS - Group B Streptococci, E. Coli, Listeria Monocytogenes.
 CHILDREN AND TEENS - Neisseria Meningitidis, Streptococcus
pneumoniae.
 ADULTS AND ELDERY - Streptococcus pneumoniae, Listeria
Monocytogenes.

2. VIRUS
 Enteroviruses
 Herpes Simplex

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 HIV
 Mumps
 Varicella Zoster
3. FUNGI
 Cryptococcus Genus
 Coccidioides Genus

4. TUBERCULAR MENINGITIS
 Mycobacterium Tuberculosis

5. PARASITIC MENINGITIS
 P. Falciparum

PATHOPHYSIOLOGY
 Release of inflammatory cytokines into CSF
 Adhesion of leukocytes to brain endothelium and diaphoresis into CSF
 Exudation of albumen through intracellular junctions of meningeal
venules
 Brain edema, increased intracranial pressure, altered cerebral blood
flow, cranial nerve injury, hypoxic ischemia, seizures, brain damage and
herniation.

CLINICAL PRESENTATION
SIGNS AND SYMPTOMS
 Fever  Headache
 Nuchal rigidity (stiff neck)  Photophobia
 Altered mental state  Nausea and vomiting
 Seizures  Focal neurologic deficits
 Irritability  Septic shock
 Anorexia

DIAGNOSIS
 Kernig’s sign
 Lumber puncture
 Polymerase chain reactions (PCR)
 Acid fast staining
 Culture test

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TREATMENT
OBJECTIVE
 Attainment of adequate antibiotic levels in CSF.

ROUTE OF ADMINISTRATION
 Principal route of antibiotics
­ Choroid plexus
 Alternate route
­ Via capillaries of CNS into extracellular fluid then to the ventricles
and subarachnoid space.
 Passage of antibiotics into CSF is dependent upon:
­ Degree of meningeal inflammation
­ Integrity of BBB by capillary endothelial cells
CATEGORIES OF ANTIBIOTICS
 Three categories of antibiotics:
­ Those that penetrate even when the meninges are not inflamed.
E.g., chloramphenicol, metronidazole, isoniazid, PZA.
­ Penetration only when meninges are inflamed. E.g., beta-lactams,
quinolones, rifampicin.
­ Poor penetration under all circumstances. E.g., aminoglycosides,
vancomycin, erythromycin.
BACTERIAL MENINGITIS
EMPIRIC THERAPY FOR BACTERIAL MENINGITIS

AGE GROUP RECOMMENDED THERAPY ALTERNATIVE THERAPY

Neonates (<2mo) Ampicillin & Cefotaxime Ampicillin & Gentamicin
Infants and children Cefotaxime or Ceftriaxone Cefotaxime or
(2mo—10yrs) + Vancomycin Ceftriaxone + Rifampicin
Children and adults Cefotaxime or Ceftriaxone Cefotaxime or
(10—60yrs) + Vancomycin Ceftriaxone + Rifampicin
Ampicillin, Cefotaxime & Ampicillin, Cefotaxime &
Elderly (> 60yrs)
Vancomycin Rifampicin
Nafcillin & Ceftazidime or Vancomycin &
Post-Neurosurgical
Cefepime / Gentamicin Ceftazidime or Cefepime
Vancomycin & Cefotaxime
Open head trauma Cefotaxime
or Ceftriaxone

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DEFINITIVE THERAPY FOR BACTERIAL MENINGITIS

RECOMMENDED ALTERNATIVE DURATION OF
PATHOGEN
THERAPY THERAPY THERAPY
GRAM POSITIVE ORGANISMS
Vancomycin + Cefotaxime or
Streptococcus
Cefotaxime or Ceftriaxone or 10–14 Days
Pneumoniae
Ceftriaxone Rifampicin
Staphylococcus Nafcillin or Vancomycin or
Aureus (MRSA) Vancomycin + TMP-SMX + 14–21 Days
Rifampicin Rifampicin
Listeria Ampicillin +
TMP-SMX ≥21 Days
Monocytogenes Gentamicin
GRAM NEGATIVE ORGANISMS
Ampicillin, Cefotaxime or
Haemophillus
Cefotaxime or Ceftriaxone 7 – 10 Days
Influenzae
Ceftriaxone Chloramphenicol
Cefotaxime or
Penicillin-G or
Neisseria Meningitis Ceftriaxone or 7 – 10 Days
Ampicillin
Chloramphenicol
Cefepime +
Enterobacteriaceae
Cefotaxime or Gentamicin
(E. Coli, Klebsiella, 21 Days
Ceftriaxone or Ciprofloxacin
Serratia)
or Meropenem
Cefepime +
Pseudomonas Ceftazidime + Tobramycin or
21 Days
Aeruginosa Tobramycin Ciprofloxacin,
Meropenem
STEROIDS AS ADJUNCTIVE THERAPY
 Adrenal corticosteroids regulate many components of inflammatory
response and also lower CSF hydrostatic pressure.
 By reducing inflammation may also reduce CSF penetration of
antibiotics.
 The benefits of corticosteroids in the management of meningitis are well
established in M. tuberculosis and Hib.
 Dexamethasone 0.6—1.5mg/kg/day (4 divided doses for 4 days)
significantly reduces sensorineural hearing loss.

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FUNGAL MENINGITIS
 Cryptococcus neoformans
 Cryptococcal meningitis takes 2—3 weeks for complete eradication
 Amphotericin-B  0.7—1.0mg/kg/day together with Flucytosine
100mg/kg/day (6 days)
 Fluconazole  400—800mg/day (6 weeks).

VIRAL MENINGITIS
 Fortunately, most cases of viral meningitis are self-limiting and none of
antiviral agents have useful effect.
 Usually, herpes simplex viruses tend to present as encephalitis.
 Herpes simplex meningoencephalitis is treated with high dose acyclovir
10mg/kg x 3 /day.

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Chapter 10.6.3 – Tuberculosis

TUBERCULOSIS

“Tuberculosis (TB) is a communicable infectious disease caused by

Mycobacterium tuberculosis. It can produce silent, latent infection, as well as
progressive, active disease.”

CHARACTERISTICS OF MYCOBACTERIUM TUBERCULOSIS

 Rod shaped, 0.2-0.5µ in diameter, 2-4µ in length
 Mycolic acid present in its cell wall, makes it acid fast
 It resists decolorization with acid and alcohol
 Aerobic and non-motile
 It multiplies slowly, can remain dormant for decades.

EPIDEMIOLOGY
 Globally, roughly 2 billion people are infected by M. tuberculosis, and
roughly 2 to 3 million people die from active TB each year despite the
fact that it is curable.
 The absolute number of cases is highest in Asia, with India and China
having the greatest burden of disease globally.

TRANSMISSION
 M. tuberculosis is transmitted from person to person by coughing or
other activities that cause the organism to be aerosolized. Close contacts
of TB patients are most likely to become infected.
 Human immunodeficiency virus (HIV) is the most important risk factor
for progressing to active TB, especially among people 25 to 44 years of
age. An HIV infected individual with TB infection is over 100-fold more
likely to develop active disease than an HIV-seronegative patient.

PATHOGENESIS
 Mycobacteria reach the pulmonary alveoli, where they invade and
replicate within endosomes of alveolar macrophages.
 Macrophages identify the bacterium as foreign and attempt to eliminate
it by phagocytosis. During this process, the bacterium is enveloped by
the macrophage and stored temporarily in a membrane-bound vesicle
called a phagosome. The phagosome then combines with a lysosome to
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create a phagolysosome.
 In the phagolysosome, the cell attempts to use reactive oxygen species
and acid to kill the bacterium. However, M. tuberculosis has a thick,
waxy mycolic acid capsule that protects it from these toxic substances.
M. tuberculosis is able to reproduce inside the macrophage and will
eventually kill the immune cell.
 The ensuing surviving bacteria within these phagolysosomes trigger off a
local immune reaction resulting in the formation of granulomas, which
effectively contain the spread of infection.
 Within the granuloma, which eventually becomes a calcified and fibrotic
lesion, MTC may remain dormant but viable for decades, establishing a
state of latent infection.
 When latent tuberculosis progresses into active tuberculosis, or when
primary infection cannot be controlled, MTC escapes from the
granuloma and spread within the lungs and/or to other tissues via the
blood or lymphatics.

LATENT TB VS. ACTIVE TB

 Latent Tb (LTBI) (Goal = Prevent future active disease)
­ Tb infection ­ Not sick
­ No disease ­ Not infectious
 Active Tb (Goal = Treat to cure, prevent transmission)
­ Tb infection which has progressed to tb disease
­ Sick (usually)
­ Infectious if pulmonary
­ Not infectious if not pulmonary
LATENT TUBERCULOSIS INFECTION TUBERCULOSIS DISEASE
Tubercle bacilli in the body
TST (Tuberculin skin test/Mantoux test) or QFT-Gold ® (QuantiFERON-TB
Gold) result usually positive
Chest x-ray usually normal Chest x-ray usually abnormal
Sputum smears and cultures negative Sputum smears and cultures positive
Symptoms such as cough, fever,
No symptoms
weight loss
No infectious Often infectious before treatment
Not a case of TB A case of TB

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COMMON SITES OF TB DISEASE

 Lungs  Lymphatic system
 Pleura  Genitourinary systems
 Central nervous system  Bones and joints

CLINICAL PRESENTATION
SIGNS AND SYMPTOMS
 Patients typically present with cough weight loss, fatigue, fever, and
night sweats.
 Frank hemoptysis usually occurs late in the course of disease but may
present earlier.
PHYSICAL EXAMINATION
 Dullness to chest percussion, rales, and increased vocal fremitus are
observed frequently on auscultation but a normal lung examination is
very common compared to the degree of radiological lung
involvement. Patient is usually thin with evidence of recent weight loss.
LABORATORY TESTS
 Acid-fast bacillus (AFB) smears
 Two versus three sputum samples
 Nucleic acid amplification tests (NAAT)

MDR-TB (MULTIDRUG-RESISTANT TUBERCULOSIS)

 This is defined by the presence of Mycobacterium tuberculosis isolate
demonstrating resistance to at least isoniazid and rifampicin.
 Managing patients suspected of MDR-TB will involve good infection
control measures, rapid and accurate diagnosis, appropriate drug
treatment associated with close monitoring of patients.
 The diagnosis of MDR-TB is dependent on culture and sensitivity profile
of the Mycobacterium tuberculosis isolates from the sputum, bodily
fluids or tissue specimens.
 The Xpert MTB/RIF and Genotype® MTBDR plus are two available nucleic
acid amplification tests (NAAT) which can speed up the diagnosis of drug
resistant tuberculosis.

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RISK FACTORS FOR MDR-TB

 Contact with individuals known to have MDR-TB
 Previous self-administered therapy for active tuberculosis
 Non-compliance with previous anti-tuberculosis treatment
 Individuals originating from areas where MDR-TB is common.

DIAGNOSIS
 A positive tuberculin test result signifies cell-mediated hypersensitivity
to tubercular antigens. It does not differentiate between infection and
disease.
 False-negative reactions may be produced by certain viral infections,
sarcoidosis, malnutrition, immunosuppression.
 False-positive reactions may also result from infection by atypical
mycobacteria.
CHEST RADIOGRAPH
CHEST RADIOGRAPHY IN THE CLINICAL EVALUATION OF SYMPTOMATIC
PATIENTS
 The radiographic appearance may be divided into two broad categories:
­ PRIMARY TUBERCULOSIS
 In primary tuberculosis, the predominant radiographic
feature is the presence of hilar and/or mediastinal
adenopathy in the appropriate lymph drainage pathways.
­ REACTIVATION (POSTPRIMARY) TUBERCULOSIS
 The apical/posterior segments of the upper lobes and the
superior segments of the lower lobes are most often
involved.
CHEST RADIOGRAPHIC FINDINGS THAT CAN SUGGEST ACTIVE TUBERCULOSIS
DISEASE
 A person with any of the following findings must be further evaluated
and submit sputum specimens for acid-fast bacilli (AFB) smears and
cultures:
­ Consolidation
­ Pleural effusion
­ Any cavitary lesion
­ Nodule with poorly defined margins.

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CHEST RADIOGRAPHIC FINDINGS THAT CAN SUGGEST INACTIVE

TUBERCULOSIS DISEASE
­ Discrete fibrotic scar or linear opacity
­ Discrete nodules without calcification.
COMPUTED TOMOGRAPHY (CT)
 Computed tomography (CT) is more sensitive than chest radiography.
 CT thorax is not utilized as a first line imaging test for screening of
pulmonary tuberculosis due to availability and cost considerations.
 A CT thorax may be performed if the chest radiograph is normal or
shows nonspecific findings in a patient suspected to have active or latent
tuberculosis on screening.
ULTRASOUND
 Ultrasound is not useful in the screening of pulmonary tuberculosis or in
the imaging of pulmonary disease.
 Ultrasound is useful in the imaging of extrapulmonary tuberculosis and
in image guided tissue sampling.
LABORATORY ASPECTS
 Various laboratory tests are being used for the diagnosis, management
and control of latent and active tuberculosis and are discussed below:
LABORATORY TESTING FOR ACTIVE TUBERCULOSIS
 The culture of Mycobacterium tuberculosis complex (MTC) from a
clinical specimen remains the gold standard test for both the diagnosis
and antimicrobial susceptibility testing for active tuberculosis.
 All clinical specimens, except blood for which special transport / culture
bottles should be used, must be collected in sterile, rigid, leak-proof,
screw-capped containers that are promptly delivered to the laboratory,
ideally within one working day.
ACID-FAST BACILLUS (AFB) SMEARS
 Direct microscopy is a relatively inexpensive and rapid test for active
tuberculosis.
TWO VERSUS THREE SPUTUM SAMPLES
 World Health Organization (WHO) recommends two, rather than three,
specimens be used for screening tuberculosis patients, but only for

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settings with a well-established laboratory network, a fully functional

External Quality Assurance program for smear microscopy including on-
site evaluation
NUCLEIC ACID AMPLIFICATION TESTS (NAAT)
 These tests detect nucleic acids and do not determine if the organism is
viable unless ribonucleic acid (RNA) is detected.
 There are several tests available including:
­ BD ProbeTec Strand Displacement Amplification DTB
­ HAIN GenoType MTBDRplus
­ GeneXpert
­ Polymerase chain reaction (PCR).
GENOTYPIC DETECTION OF DRUG-RESISTANT TUBERCULOSIS IN SPUTUM
 Some of these tests provide the additional advantage of detecting
resistance to:
­ Isoniazid and rifampicin (Genotype MTBDRplus, Hain Lifescience
GmbH)
­ Rifampicin alone (Xpert MTB/RIF, GeneXpert; INNO-LiPA Rif.TB,
Innogenetics)

MANAGEMENT OF TUBERCULOSIS
PRINCIPLES OF TUBERCULOSIS TREATMENT
 The first-line antimycobacterial agents are isoniazid, rifampicin,
ethambutol, pyrazinamide and streptomycin.
 The standard six-month tuberculosis treatment regimen comprises a 2-
month intensive phase of daily ethambutol, isoniazid, rifampicin and
pyrazinamide followed by a 4-month continuation phase of daily
rifampicin and isoniazid.
 Rifampicin and isoniazid may be dosed thrice weekly in the continuation
phase to facilitate the supervision of treatment (i.e. under directly
observed therapy (DOT)).
 The majority of the organisms are eliminated in the intensive phase.
However, to achieve cure, it is important that the entire course,
including the continuation phase, is completed.
 For patients who are unlikely to tolerate pyrazinamide (e.g. the elderly,
those with liver disease), a 9-month regimen comprising ethambutol,

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rifampicin and isoniazid for 2 months followed by rifampicin and

isoniazid for 7 months may be used.
TUBERCULOUS MENINGITIS
 Tuberculous meningitis is treated with an initial regimen of 4 drugs.
Isoniazid, rifampicin, ethambutol and pyrazinamide are the
recommended agents for initiation of treatment.
 After 2 months and adequate clinical response, ethambutol and
pyrazinamide may be stopped, and isoniazid and rifampicin continued
for 10 months.
MUSCULOSKELETAL TUBERCULOSIS
 Musculoskeletal tuberculosis includes conditions such as osteomyelitis,
arthritis as well as involvement of joint tissues alone. It can occur in any
part of the skeletal system but the spine is the most frequent site.
 A rifampicin containing regimen of 9 months duration is favored.

LYMPH NODE TUBERCULOSIS

 Tuberculosis adenitis is treated with the standard 6-month regimen. It is
to be noted that the nodes can enlarge during treatment.
 Drainage of peripheral lymph nodes that are about to rupture may be
needed but surgical excision is rarely needed unless the nodes are very
bulky.
ANTI-TUBERCULOUS DRUGS
FIRST-LINE
 Isoniazid  Ethambutol
 Rifampicin  Pyrazinamide
SECOND-LINE
 Clarithromycin  Cycloserine
 Ciprofloxacin  Amikacin
 Capreomycin  Streptomycin
I. ISONIAZID (INH)
 Acts only on mycobacteria and interferes with mycolic acid synthesis
 Passes freely to mammalian cell wall
 Effective for intracellular organism
 Bacteriostatic – to resting organism
 Bactericidal – to multiplying organism.

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PHARMACOKINETICS
 Well absorbed from GIT
 Fatty food and aluminum containing antacids may reduce absorption
 CSF penetration: 20% of plasma concentration with non-inflamed
meninges.
 Excretion – urine
 Metabolism:
­ By acetylation – genetically determined
ADVERSE EFFECT
 Hepatotoxicity  Prevented by concurrent
 Elderly, slow acetylators more pyridoxine
prone  Rashes, acne.
II. RIFAMPICIN
 Inhibits bacterial DNA-dependent RNA polymerase
 Bactericidal
 Gram positive and negative
 Kill intracellular organism
PHARMACOKINETICS
 Well absorbed from GIT  Elimination - hepatic, renal.
ADVERSE EFFECTS
 Rashes, hepatotoxicity,  Orange discoloration of urine,
thrombocytopenia sweat, tears.
III. ETHAMBUTOL
 Inhibits arabinosyl transferases involved in cell wall biosynthesis
 Bacteriostatic to M. tuberculosis
 Resistance develops rapidly if used alone.
PHARMACOKINETICS
 Well absorbed from GIT  CSF penetration - poor
 Bioavailability 80%  Elimination - renal
ADVERSE EFFECTS
 Optic retro-bulbar neuritis  Reversible
 Dose-related  May be unilateral

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IV. PYRAZINAMIDE
 Interferes with mycobacterial fatty acid synthesis
 Inactivate mycobacteria at acidic PH
 Effective against intracellular organism in macrophages – PH is low.
PHARMACOKINETICS
Well absorbed from GIT
  Hepatic metabolism
 CSF penetration: equal to  Excretion - kidney
plasma concentration
ADVERSE EFFECT
 GI disturbances  Hyperuricemia
 Hepatotoxicity  Arthralgia

V. STREPTOMYCIN
 Aminoglycoside - Inhibits protein synthesis
 Bactericidal
PHARMACOKINETICS
 Poorly absorbed from GIT -  CSF penetration: poor
given IM.  Renal elimination
ADVERSE EFFECTS
 Ototoxicity  Nephrotoxicity
USES
 Very ill patients  Not responding to treatment
 Multi- drug resistance
VI. CAPREOMYCIN
 Peptide antibiotic
 IM
 Effects 8th cranial nerve – deafness, ataxia.
VII. CYCLOSERINE
 Broad spectrum antibiotic
 Reaches the CSF well
 Causes CNS side effects
 Use in drug resistant TB

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PULMONARY TB
INTENSIVE PHASE
 INH + Pyridoxine
 Rifampicin
2 months
 Ethambutol
 Pyrazinamide
CONTINUATION PHASE
 INH + Pyridoxine
4 months
 Rifampicin
DRUG RESISTANCE
MULTIDRUG RESISTANCE (MDR)
 Resistant to at least isoniazid and rifampicin.
EXTENSIVE DRUG RESISTANCE (XDR)
 MDR strains also resistant to any fluoroquinolone and at least one
injectable second-line drugs (amikacin, capreomycin, kanamycin)
TREATMENT REGIMEN FOR MDR-TB
STEP 1
 Begin with any 1st line agents (Pyrazinamide, Ethambutol) to which the
isolate is susceptible.
 Add a fluoroquinolone (Levofloxacin, Moxifloxacin) and an injectable
drug (Amikacin, Capreomycin, Streptomycin, Kanamycin) based on
susceptibilities.
STEP 2
 Add 2nd line drugs (Cycloserine, Ethionamide, PAS) until you have 4-6
drugs to which the isolate is susceptible (and preferably which have not
been used to treat the patient previously.
STEP 3
 If there are not 4-6 drugs available in the above categories, 3rd line drugs
(Clofazimine, Linezolid, Imipenem, Macrolides, Amoxicillin/ Clavulanate,
High dose Isoniazid) in constitution with an MDR-TB expert.

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Chapter 10.6.4 – Dermatological Infections

DERMATOLOGICAL INFECTIONS

”A dermatological infection is a condition where bacteria or other germs enter

the skin through a wound and spread, causing pain, swelling and
discoloration.”

INTRODUCTION
 Natural defenses of skin are:
­ Keratin
­ Skin sloughing
­ Sebum: low pH, high lipid
­ Sweat: low pH, high salt, and Lysozyme, which digests
peptidoglycan.

CAUSES OF SKIN INFECTION

BACTERIAL
 Cellulitis, Abscess and Impetigo.

VIRAL
 Shingles, warts and herpes simplex.
FUNGAL
 Athlete’s foot and yeast infections.

PARASITAL
 Body lice and head lice.

BACTERIAL SKIN INFECTIONS

1. FOLLICULITIS
ETIOLOGY
 Inflammation of hair follicle.
 Caused by non-infectious or infectious agents.
 Moist warm environment and mechanical occlusion
contribute to condition.
SIGNS AND SYMPTOMS
 Redness around follicle that is followed by development of papule or

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pustule at the hair follicle

 Followed by development of crust that sloughs off with the hair
 Deeper infection may cause scarring and alopecia in that area.
MANAGEMENT
 Topical treatment with clindamycin 1% or erythromycin 2%, applied two
or three times a day to affected areas.
2. FURUNCULOSIS (BOILS)
ETIOLOGY
 Infection of hair follicle that results in pustule formation.
 Generally, the result of a staphylococcus infection.
SIGNS AND SYMPTOMS
 Pustule that becomes reddened and enlarged as well as hard from
internal pressure
 Pain and tenderness increase with pressure
 Most will mature and rupture.
MANAGEMENT
 Systemic Staphylococcal antibiotics (Augmentin, floxacillin, doxycycline)
3. CARBUNCLES
ETIOLOGY
 Carbuncles is a group of furuncles which can coalesce to form
larger draining nodules.
SIGNS AND SYMPTOMS
 Larger and deeper than furuncle and has several openings in the skin.
 May produce fever and elevation of WBC count.
 Starts hard and red and over a few days emerges into a lesion that
discharges yellowish pus.
MANAGEMENT
 Surgical drainage combined with the administration of antibiotics.
 Warm compress is applied to promote circulation.
4. IMPETIGO
ETIOLOGY

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 Impetigo is a common and highly contagious skin infection that mainly

affects infants and children.
SIGNS AND SYMPTOMS
 Two clinical types of impetigo exist:
­ Non-bullous: face and extremities, initially with vesicles or
pustules on reddened skin which rupture to leave the
characteristic honey- colored.
­ Bullous: flaccid bullae with clear yellow fluid that rupture and
leave a golden-yellow crust.
TREATMENT
 For most patients topical treatment is adequate, either with bacitracin
(Polysporin) or mupirocin (Bactroban), applied twice daily for 7 to 10
days.
5. ACNE VULGARIS
ETIOLOGY
 Inflammatory disease of the hair follicle and the sebaceous glands
 Sex hormones may contribute.
SIGNS AND SYMPTOMS
 Present with whiteheads, blackheads, flesh or red colored papules,
pustules or cysts.
MANAGEMENT
 Topical and systemic agents are used to treat acne
 Mild soaps are recommended.
6. ERYSIPELAS AND CELLULITIS
ETIOLOGY
 Erysipelas is a superficial cutaneous infection of the skin
involving dermal lymphatic vessels. Occurs in young children and
is a tender, well-defined, erythematous, indurated plaque on the face or
legs.
 Cellulitis is a deeper process that extends to the subcutis. Occurs as a
warm, tender, erythematous, and edematous plaque with ill-defined
borders that expands rapidly.

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SIGNS AND SYMPTOMS

 Mild itching and soreness followed by eruption of small vesicles and
pustules that rupture and crust
 Generally, develops in body folds that are subject to friction.
TREATMENT
 Penicillin (250-500 mg, qid × 7-10 days) is the treatment of choice for
erysipelas.
7. PARONYCHIA AND ONYCHIA
ETIOLOGY
 Caused by staphylococcus, streptococcus and or fungal organisms
that accompany contamination of open wounds or hangnails
 Damage to cuticle puts finger at risk
 Paronychia: inflammation / infection of the surrounding tissue.
 Onychia: infection of the nail.
SIGNS AND SYMPTOMS
 Rapid onset; painful with bright red swelling of proximal and lateral fold
of nail
 Accumulation of purulent material within nail fold.
TREATMENT
 Soak finger or toe in hot solution of Epsom salt 3 times daily
 Topical antibiotics, systemic antibiotics if severe
 May require pus removal through skin incision.

VIRAL SKIN INFECTIONS

1. HERPES SIMPLEX
INTRODUCTION
 Herpes simplex virus (HSV) infection is a painful, self-limited,
often recurrent dermatitis, characterized by small, grouped
vesicles on an erythematous base.
PATHOPHYSIOLOGY
 Disease follows implantation of the virus via direct contact at mucosal
surfaces or on sites of abraded skin.

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 After primary infection, the virus travels to the adjacent dorsal ganglia,
where it remains dormant unless it is reactivated by psychological or
physical stress, illness, trauma, menses or sunlight.
SIGNS AND SYMPTOMS
 Primary infection occurs most often in children, exhibiting vesicles and
erosions on reddened buccal mucosa, the palate, tongue, or lips (acute
herpetic gingivostomatitis).
 It is occasionally associated with fever, malaise, myalgias, and cervical
adenopathy.
 Primary genital infection is an erosive dermatitis on the external
genitalia that occurs about 7 to 10 days after exposure.
TREATMENT
 Acyclovir remains the treatment of choice for HSV infection.
 Newer antivirals, such as famciclovir and valacyclovir, are also effective.
2. CHICKEN POX
INTRODUCTION
 Chickenpox is a very contagious disease caused by the varicella-
zoster virus (VZV).
SIGNS AND SYMPTOMS
 It causes a blister-like rash, itching, tiredness and fever.
 The rash appears first on the stomach, back and face and then spreads
over the entire body causing between 250 and 500 itchy blisters.
TREATMENT
 In children: symptomatic
 In adult: antiviral therapy, within 24 to 72 hours of disease onset,
acyclovir 200mg 5x/day for 7 days.
3. HERPES ZOSTER
INTRODUCTION
 Herpes zoster (shingles) is an acute, painful dermatomal dermatitis
that affects approximately 10% to 20% of adults, often in the
presence of immunosuppression.
PATHOPHYSIOLOGY

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 During the course of varicella, the virus travels from the skin and
mucosal surfaces to the sensory ganglia, where it lies dormant for a
patient's lifetime.
 Reactivation often follows immunosuppression, emotional stress,
trauma, and irradiation or surgical manipulation of the spine, producing
a dermatomal dermatitis.
SIGNS AND SYMPTOMS
 Herpes zoster is primarily a disease of adults and typically begins with
pain and paresthesia in a dermatomal or bandlike pattern followed by
grouped vesicles within the dermatome several days.
TREATMENT
 Zoster deserves treatment with rest, analgesics, compresses applied to
affected areas and antiviral therapy, if possible, within 24 to 72 hours of
disease onset.
4. WARTS
INTRODUCTION
 Warts are common and benign epithelial growths caused by human
papillomavirus (HPV).
I. COMMON WARTS
SIGNS AND SYMPTOMS
 Small, round, elevated lesion with rough dry surfaces
 Painful, if pressure is applied.
MANAGEMENT
 If vulnerable, they should be protected until treated by a physician
 Use of electrocautery, topical salicylic acid or liquid nitrogen are
common means of managing this condition.
II. PLANTAR WARTS
ETIOLOGY
 Spread through papilloma virus.
SIGNS AND SYMPTOMS

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 Located on sole of foot, on or adjacent to areas of abnormal weight

bearing
 Areas of excessive epidermal thickening
 Discomfort, point tenderness.
MANAGEMENT
 Pair away callus and apply keratolytic
 Following season, wart can be removed by freezing it or by
electrodessication.
5. MOLLUSCUM CONTAGIOSUM
INTRODUCTION
 Molluscum contagiosum is an infectious viral disease of the skin
caused by the poxvirus.
SIGNS AND SYMPTOMS
 Molluscum are smooth pink, or flesh-colored, dome-shaped, umbilicated
papules with a central keratotic plug.
TREATMENT
 Treatment might not be necessary because the disease often resolves
spontaneously in children.
 Treatment cryosurgery and curettage are perhaps the easiest and most
definitive approaches.

PARASITAL SKIN INFECTIONS

1. SCABIES
INTRODUCTION
 Scabies is a skin infestation caused by a mite known as the
Sarcoptes scabiei.
SIGNS AND SYMPTOMS
 Discrete, small burrows, vesicles, papules, and pinpoint erosions on
fingers, finger webs, wrists, elbows, knees, groin, buttocks, penis,
scrotum, axillae, belt line, ankles and feet.
TREATMENT

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 Prescription ointments, creams and lotions that can be applied directly

to the skin E.g., Malathion lotion
 Clothing and bedding of persons with scabies should be washed in hot
water and dried in a hot dryer.
2. HEAD LICE
INTRODUCTION
 Head lice are small, wingless, blood-sucking insects. They live in
the hair on head and feed off the blood from scalp.
PATHOPHYSIOLOGY
 A person can become infected with head lice when the insects crawl
onto the head.
 Ways of transmission of head lice include:
­ Touching your head to the head of someone with head lice
­ Sharing the personal items (e.g., comb) of someone with head lice
­ Using a fabric item after a person with head lice.
SIGNS AND SYMPTOMS
 Extreme scalp itchiness, feeling like something is crawling on your scalp
 Sores and scabs on your scalp from scratching.
TREATMENT
 Wet Combing should be done every three days for two weeks.
 Delivery of hot air to kill lice by desiccation.
 Pyrethrin or Permethrin lotion, both are safe and effective to use.

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Chapter 10.6.5 – Rabies

RABIES

“Rabies is a deadly virus spread to people from the saliva of infected animals.
The rabies virus is usually transmitted through a bite.”

INTRODUCTION
 Rabies is preventable viral disease. Transmitted through rabid animal
bite (cat, bat, dog, rodents, horse, donkey, raccoons, skunks, fox etc.)

CAUSES
 Rabies infection is caused by the rabies virus. The virus is spread through
the saliva of infected animals. Infected animals can spread the virus by
biting another animal or a person.
 Replication: fusion of rabies virus envelope to the host cell membrane
(adsorption) → infection (interaction of the G protein and specific cell
surface receptors.
 After adsorption, it penetrates the host cell and enters the cytoplasm.

CLINICAL PRESENTATION
 The early symptoms of rabies in people are similar to that of many other
illnesses, including fever, headache, and general weakness or
discomfort.
 Progression of disease: more specific symptoms appear including
insomnia, anxiety, confusion, slight or partial paralysis, excitation,
hallucinations, agitation, hypersalivation (increase in saliva), difficulty
swallowing, and hydrophobia (fear of water).
 Death usually occurs within days of the onset of these symptoms.

DIAGNOSIS
 Direct fluorescent antibody (DFA) test, which looks for the presence of
rabies virus antigens in brain tissue.

TREATMENT AND PREVENTION

RABIES VACCINE (INACTIVATED RABIES VIRUS)
­ Pre- and post-exposure prophylaxis.
 PRE-EXPOSURE PROPHYLAXIS

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­ Immunization should be to high-risk exposure as in lab staff

(handling rabies virus)
­ Animal handlers
­ Travelers (where rabies is enzootic)
­ 3 doses of Rabies vaccine are given.
 POST-EXPOSURE MANAGEMENT
­ Cleansing of wound by soap and water
­ Disinfectant
­ Dressing the wound (covering).
Fully immunized individuals:
­ 2 doses of cell-derived vaccine (I.M)
­ Day 0 and day 3.
Unimmunized individuals:
­ 5 doses (over 1 month) (I.M).
­ Day 0, 3, 7, 14 and 30.
 VACCINE AVAILABLE IN PAKISTAN
­ Verorab (GSK).

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Chapter 10.6.6 – Urinary Tract Infection

URINARY TRACT INFECTION

“Presence of organisms in the urinary tract together with symptoms and

sometimes signs of inflammation.”

INTRODUCTION
 A urinary tract infection (UTI) is an infection in any part of urinary system
— kidneys, ureters, bladder and urethra. Most infections involve the
lower urinary tract — the bladder and the urethra.
TYPES OF URINARY TRACT INFECTION
I. SIGNIFICANT BACTERIURIA
 Presence of at least 1lac bacteria /ml of urine (small number of bacteria
are normally found in anterior urethra and may be washed out into
urine samples).
 Count of fewer than 1k bacteria /ml are normally considered to be
urethral contaminants that occurs in exceptional clinical circumstances
such as immunosuppressed patients.
II. ASYMPTOMATIC BACTERIURIA
 Significant bacteriuria in the absence of symptoms in the patient.
III. CYSTITIS
 A syndrome of frequency, dysuria and urgency which usually suggests
infection restricted to the lower urinary tract i.e. bladder and urethra.
IV. URETHRAL SYNDROME
 A syndrome of frequency and dysuria in the absence of significant
bacteriuria with a conventional pathogen.
V. ACUTE PYELONEPHRITIS
 An acute infection of one or both kidneys. Usually, the lower urinary
tract is also involved.
VI. CHRONIC PYELONEPHRITIS
 It can refer to continuous excretion of bacteria from the kidney to
frequent recurring infection of the renal tissue or to a particular type of
pathology of the kidney seen microscopically or by radiographic imaging,
which may or may not be due to infection. Although chronic infections
of renal tissue are relatively rare, they do occur in the presence of
kidney stones and in tuberculosis.

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VII. RELAPSE AND REINFECTION

 Recurrence of urinary infection may be due to either relapse or
reinfection.
 Relapse is recurrence caused by the same organism that caused the
original infection.
 Reinfection is recurrence caused by a different organism and is therefore
a new infection.

PATHOGENESIS
 Three possible routes (organisms might reach UT):
­ Ascending
­ Blood-borne
­ Lymphatic (little evidence)
 Blood-borne: Bacteremic illnesses (Staphylococcus aureus)
 UTI in women: Colonization of the vagina, perineum and periurethral
area by the pathogen, ascends into the bladder via the urethra.
 Uropathogens colonize the urethral opening of men and women.
 Urethra in women is shorter than in men. More chances of UTI in
females.
 Sexual intercourse (more chances in females)
 Circumcision (less chances in males).

CLINICAL MANIFESTATION
 Most UTIs are asymptomatic.
 Symptoms, when they do occur, are principally the result of irritation of
the bladder and urethral mucosa.
 Clinical features of UTI are extremely variable and to some extent
depend on the age of the patient.
BABIES AND INFANTS
 Often overlooked or misdiagnosed because the signs may not be
preferable to the urinary tract.
 Common but non-specific presenting symptoms include failure to thrive,
vomiting, fever, diarrhea and apathy.
 UTI in infancy and childhood is a major risk factor for the development
of renal scarring, which in turn is associated with future complications
such as chronic pyelonephritis in adulthood, hypertension and renal
failure.

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CHILDREN
 Above the age of 2, children with UTI: Classic symptoms such as
frequency, dysuria and hematuria.
 Children present with acute abdominal pain and vomiting, and this may
be so marked as to raise suspicions of appendicitis or other intra-
abdominal pathology.
ADULTS
 Typical symptoms of lower UTI includes:
­ Frequency, dysuria, urgency and hematuria.
 Acute pyelonephritis (upper UTI) includes:
­ Fever, rigors and loin pain in addition to lower tract symptoms.
 Untreated cystitis rarely progresses to pyelonephritis, and bacteriuria
does not seem to carry the adverse long-term consequences that it does
in children.
ELDERLY
 UTI is frequent in the elderly, great majority of cases are asymptomatic,
and even when present, symptoms are not diagnostic because
frequency, dysuria, hesitancy and incontinence are fairly common in
elderly people without infection.

DIAGNOSIS
DIPSTICKS
 Rapid near-patient for urinary blood, protein, nitrites and leukocyte
esterase. Assessment of color changes on dipstick
LEUKOCYTE ESTERASE TEST
 Enzyme released from leukocyte in urine and is 90% sensitive to detect
WBCs count of >10/mm. Presence of leukocyte is common UTI.
NITRITE TEST (GRIESS TEST)
 Urinary nitrite produced by bacteria (commonly causing UTI)

MICROSCOPY
 A drop of uncentrifuged urine is placed on a slide, covered with coverslip
and examined at 40X. Excessive WBCs indicates symptomatic UTI.
CULTURE
 Quantify the number of bacteria in urine specimen (as when urine
passes via urethra contamination occurs). True infections may be

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associated with low counts, particularly when the urine is very dilute
because of excessive fluid intake or where the pathogen is slow growing.

TREATMENT
SYMPTOMATIC UTI
 Antibiotic treatment to eradicate both symptoms and pathogen.

ASYMPTOMATIC UTI
 May or may not need treatment depending upon the circumstances of
individual case.
 Bacteriuria in children and women requires treatment (same as in the
case of surgical manipulation of UT)
NON-SPECIFIC TREATMENT
 Drink lot of fluids.
 Urinary analgesics i.e., Potassium or Sodium citrate (alkalinize urine) +
antibiotics (avoid when nitrofurantoin is used because it requires low
pH).
ANTIMICROBIAL THERAPY
 Antibiotics used for lower urinary tract infections:
­ Oral Antibiotics
 Amoxicillin  Trimethoprim
 Co-amoxiclav  Nitrofurantoin
 Cefalexin  Ciprofloxacin
­ Parenteral Antibiotics
 Cefuroxime  Gentamicin
 Ceftazidime  Ciprofloxacin
 Co-amoxiclav  Meropenem

RELAPSING UTI
 The main causes of persistent relapsing UTI are renal infection,
structural abnormalities of the urinary tract and chronic prostatitis
(men).
 Patients who fail on a 7–10-day course should be given a 2-week course,
and if that fails, a 6-week course can be considered.
 In men with prostate gland infection, it is appropriate to select
antibiotics with good tissue penetration such as trimethoprim and
fluoroquinolones.

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Chapter 10.6.7 – Malaria

MALARIA

“Malaria is a disease caused by a parasite. The parasite is transmitted to

humans through the bites of infected mosquitoes.”

INTRODUCTION
 Four species of Plasmodium are responsible for malaria:
­ P. falciparum (malignant tertian or falciparum malaria)
­ P. vivax (benign tertian or vivax malaria)
­ P. malaria (Quartan malaria)
­ P. ovale (ovale malaria)

LIFE CYCLE
 Two phase
­ Sporogony (sexual reproduction)
­ Schizogony (asexual reproduction)
I. SPOROGONY
 Sporogony is sexual phase, occurs in female anopheles mosquito. Cycle
initiates when mosquito takes blood meal from an infected individual.
 Takes RBCs that contain both male and female gametocytes of malarial
parasite, then there is formation of sporozoites that reach the salivary
glands.
 Mosquitoes injects the sporozoites into next victim and within minutes
liver cells become infected by them.
II. SCHIZOGONY
 Takes place in human host. Schizogony (nuclear division and increase in
cytoplasmic volume) occurs twice in the host.
 First phase occurs in cells of the liver. On reaching maturity, the mature
schizonts rupture and release merozoites into blood to invade
erythrocytes.
 Second phase occurs in erythrocytes. Eventually the growing parasite
occupies the entire red cell which has become spherical, depleted in
hemoglobin, and full of merozoites.
 It then ruptures so that merozoites are released destroying the RBCs.

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Chapter 10.6.7 – Malaria

 The released merozoites rapidly reinvade other red cells and start a new
asexual cycle.

PATHOGENESIS
 Infected individual experiences the outbursts of malaria in conjunction
with the synchronous release of sporozoites.
SPECIES TIME BETWEEN FEVER PAROXYSMS TERMINOLOGY
P. malariae 72 hours Quartan fever
P. vivax & ovale 48 hours Tertian fever
P. falciparum Variable 48 or 24 hours Malignant tertian fever

CLINICAL PRESENTATION
SIGNS AND SYMPTOMS
 A malaria infection is generally characterized by the following signs and
symptoms:
­ Fever ­ Nausea and vomiting
­ Chills ­ Muscle pain and
­ Headache fatigue
 Other signs and symptoms may include:
­ Sweating ­ Chest / abdominal pain
MALARIAL ATTACK
 Some people who have malaria experience cycles of malarial "attacks"
An attack usually starts with shivering and chills, followed by a high
fever, followed by sweating and a return to normal temperature.
 Exhausting episode induces sleep from which patient awakens with a
feeling of well-being.

DIAGNOSIS
 Microscopic examination
 Giemsa-stained blood smears.
 Banana shaped intra-erythrocytic gametocytes indicates P. falciparum.
 Enlarged erythrocytes with intra cellular coarse brick-red stippling
(schuffner’s dots) indicates P. vivax.
 Schuffner’s dots if oval-shaped indicates P. ovale.

TREATMENT
 Chloroquine is the drug of choice for uncomplicated malaria in areas
without resistance. Chloroquine resistant malaria is found in most areas

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of falciparum malaria, and also in many areas of vivax malaria.

 Quinine is usually the preferred alternative when Chloroquine therapy
fails. It is also the drug of choice for complicated, severe malaria and
cerebral malaria.
 Fansidar is another commonly used alternative, although a significant
number of patients experience Steven Johnson type exfoliative
dermatitis as a side effect.
 Primaquine is used for P. vivax and P. ovale infections to eradicate the
hypnozoites, as well as for treating relapses of P. vivax and P. ovale
malaria.
 Clindamycin, Trimethoprim-Sulfamethoxazole, Mefloquine,
Halofantrine, is also used in various regimens. Desferrioxamine, an iron
chelator is being investigated clinically.
 Artisunate, Artem ether are new agents in the treatment of malaria.

HOST FACTORS THAT INFLUENCE SUSCEPTIBILITY TO MALARIA

DUFFY NEGATIVE INDIVIDUALS
 Duffy negative individuals are naturally resistant to infection with P.
vivax, invasion of erythrocytes is mediated through interaction with
Duffy Fy group antigens, which are absent from the red blood cells of
many Africans and most African-Americans.
GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY
 Trophozoites do not develop effectively in red blood cells deficient in
G6PD because the parasite is unable to use the hexose mono phosphate
shunt as an energy source.
HEMOGLOBINOPATHIES
 Abnormalities of hemoglobin do not support parasite growth.

CONTROL AND PREVENTION

CONTROL
 Control entails elimination of mosquito breeding sites through residual
insecticide spraying, improvements in land drainage, and removal of
standing water, particularly in inhabited areas.
PREVENTION
 Prophylactic chemotherapy
 Vaccination

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Chapter 10.6.8 – Typhoid Fever

TYPHOID FEVER

“Typhoid fever is an acute illness associated with fever caused by the

Salmonella enterica serotype Typhi bacteria.”

INTRODUCTION
 Salmonellosis includes infection by any of approximately 2000 serotypes
of salmonellae.
 Human infections are caused almost exclusively by Salmonella enterica
subspecies enterica, of which three serotypes- typhi, typhimurium, and
choleraesuis are predominantly isolated.
 Enteric fever, the best example of which is typhoid fever, due to
serotype typhi.

PATHOGENESIS
 Infection is transmitted by consumption of contaminated food or drink.
The incubation period is 5-14 days.
 Salmonella is an intracellular pathogen. Infection begins when organisms
breach the mucosal epithelium of the intestines by transcytosis, an
organism-mediated transport process through the cell via an endocytic
vesicle.
 Having crossed the epithelial barrier, organisms invade and replicate in
macrophages in Peyer patches, mesenteric lymph nodes, and the spleen.
 Bacteremia occurs, and the infection then localizes principally in the
lymphoid tissue of the small intestine.
 Peyer patches become inflamed and may ulcerate, with involvement
greatest during the third week of disease.
 The organism may disseminate to the lungs, gallbladder, kidneys, or
central nervous system.

CLINICAL PRESENTATION
 During the prodromal stage, there is increasing malaise, headache,
cough, and sore throat, often with abdominal pain and constipation,
while the fever ascends in a stepwise fashion.
 After about 7-10 days, it reaches a plateau and the patient is much more
ill, appearing exhausted and often prostrated.

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 There may be marked constipation, especially early, or "pea soup"

diarrhea; marked abdominal distention occurs as well.
 If there are no complications, the patient's condition will gradually
improve over 7-10 days. However, relapse may occur for up to 2 weeks
after defervescence.
 The rash (rose spots) commonly appears during the second week of
disease. The individual spot, found principally on the trunk, is a pink
papule 2-3 mm in diameter that fades on pressure. It disappears in 3-4
days.

DIAGNOSIS
 Typhoid fever is best diagnosed by blood culture, which is positive in the
first week of illness in 80% of patients who have not taken
antimicrobials.
 The rate of positivity declines thereafter, but one-fourth or more of
patients still have positive blood cultures in the third week.

TREATMENT
 Because of increasing antimicrobial resistance, fluoroquinolones- such
as ciprofloxacin 750 mg orally twice daily or levofloxacin 500 mg orally
once daily, 5-7 days for uncomplicated enteric fever and 10-14 days for
severe infection have become the agents of choice for treatment of
salmonella infections.
 Ceftriaxone, 2 g intravenously for 7 days, is also effective.
 When an infection is caused by a multidrug-resistant strain, select an
antibiotic to which the isolate is susceptible in vitro.
 Alternatively, increasing the dose of ceftriaxone to 4 g/day and treating
for 10-14 days or using azithromycin 500 mg orally for 7 days in
uncomplicated cases may be effective.
 In years past, ampicillin, chloramphenicol, and trimethoprim
sulfamethoxazole had been effective treatments but resistance has
spread globally.

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Chapter 10.6.9 – Fungal Infections of Skin

FUNGAL INFECTIONS OF SKIN

“A fungal infection, also called mycosis, is a skin disease caused by a fungus”

INTRODUCTION
FUNGUS
Fungus is a colorless plant that lacks chlorophyll, Yeast like / mold like fungi
causes human infections.
FUNGAL INFECTIONS
 Fungal infections range from superficial skin infections to life-
threatening systemic infections. Systemic fungal infections are serious
that occur when fungi gain entrance into the interior of the body.

TYPES OF FUNGAL INFECTION

 Fungal infections also known as mycotic infections has two types:
1. Superficial mycotic infections
2. Deep (systemic) mycotic infections
SUPERFICIAL MYCOTIC INFECTIONS
 Superficial mycotic infections occur on the surface of, or just below, the
skin or nails.
 Superficial infections include tinea pedis (athlete’s foot), tinea cruris
(jock itch), tinea corporis (ringworm), onychomycosis /tinea unguium
(nail fungus), Yeast infections, caused by Candida albicans.
DEEP MYCOTIC INFECTIONS
 Deep mycotic infections develop inside the body, such as in the lungs.
 Treatment for deep mycotic infections is often difficult and prolonged.

ANTIFUNGALS
 Antifungals may be:
­ Fungicidal: Able to destroy fungi
­ Fungistatic: Able to slow or retard the multiplication of fungi.
 Some drugs have an effect on the cell membrane of the fungus, resulting
in a fungicidal or fungistatic effect. E.g. Amphotericin B, miconazole,
nystatin, and ketoconazole (Nizoral).

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 The fungicidal or fungistatic effect of these drugs appears to be related

to their concentration in body tissues.

SUPERFICIAL FUNGAL INFECTIONS OF SKIN

TINEA CORPORIS (RINGWORM)
CAUSES
 Fungal infection of the major skin surfaces, excluding the
feet, face, hands, groin and scalp. Often transmitted by
animals (pets or livestock) and can also be picked up from
the soil.
 Children are particularly susceptible and can easily pass it on to other
children. Adults can also become infected. Farmers and people who
work with furry animals are at increased risk.
CLINICAL PRESENTATION
 There are itchy pink or red scaly patches with a well-defined inflamed
border.
 Lesions are often paler at the center, becoming progressively inflamed
towards the outer edge.
 Lesions often occur singly but can be multiple and sometimes overlap to
form a large continuous patch.
DIFFERENTIAL DIAGNOSIS
 Discoid eczema – lesions of similar shape to ringworm, but larger and
mainly occurring on the arms, legs, hands and feet.

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TREATMENT
 Clotrimazole, Econazole, Ketoconazole, Miconazole and Sulconazole
(topical cream/gel/ointment/lotion).
TINEA CRURIS (DHOBIE ITCH, JOCK ITCH)
CAUSES
 Fungal infection caused by dermatophytes of the groin,
occurring almost exclusively in young men.
CLINICAL PRESENTATION
 There is a brownish-red itchy rash, with a well-defined
border, in the groin.
 Infection often spreads to involve the lower abdomen, scrotum and
buttocks.
DIFFERENTIAL DIAGNOSIS
 Contact dermatitis, possibly caused by detergents used for washing
underwear, may be confused with tinea cruris.
 It is important to diagnose accurately, as management of the conditions
is different.
TREATMENT
 Clotrimazole, Econazole, Ketoconazole, Miconazole and Sulconazole
(topical cream/gel/ointment/lotion).
PITYRIASIS VERSICOLOR / TINEA VERSICOLOR
CAUSES
 It is caused by a type of yeast called Malassezia. The
organism is more common in hot, sunny subtropical areas.
CLINICAL PRESENTATION
 Macular (flat) patches of altered pigmentation occurring
mainly on the trunk and upper legs and arms.
 In white-skinned people patches are brownish and look as if suntanned,
whereas on darker-skinned or heavily tanned people patches are pale or
white. The affected area has an overall dappled appearance. There is a
superficial scale that can be removed by scraping with a fingernail.

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DIFFERENTIAL DIAGNOSIS
 The condition is most likely to be confused with vitiligo.
TREATMENT
 Midazole cream applied daily for 3 weeks
 ketoconazole 2% shampoo (Apply undiluted and wash off after 5
minutes). Repeat daily for 1 week, then weekly for several weeks to
prevent reinfection.
 Selenium sulfide shampoo (Selsun Blue), wash off after 4–5 hours, Use
weekly for 8 weeks.

SYSTEMIC FUNGAL INFECTIONS

 Systemic mycoses (histoplasmosis, coccidioidomycosis, cryptococcosis,
blastomycosis, para-coccidioidomycosis, and sporotrichosis), are caused
by primary or “pathogenic” fungi that can cause disease in both healthy
and immunocompromised individuals.
 Mycoses caused by opportunistic fungi such as Candida albicans,
Aspergillus spp., Trichosporon, Torulopsis (Candida) glabrata, Fusarium,
Alternaria, and Mucor are generally found only in the immune-
compromised host.
HISTOPLASMOSIS
CAUSES
 Caused by inhalation of dust-borne microconidia of the dimorphic
fungus Histoplasma capsulatum.
 Exposure to low inoculum causes mild or symptomatic pulmonary
histoplasmosis. The course of disease is generally benign, and symptoms
usually weaken within a few weeks of onset.
 Exposure to a higher inoculum during a primary infection or reinfection
may experience an acute, self-limited illness with flu-like pulmonary
symptoms, including fever, chills, headache, myalgia, and nonproductive
cough.
 Chronic pulmonary histoplasmosis involves opportunistic infection
imposed on a preexisting structural abnormality such as lesions resulting
from emphysema.
CLINICAL PRESENTATION

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 Patients demonstrate chronic pulmonary symptoms and apical lung

lesions that progress with inflammation, calcified granulomas, and
fibrosis.
DIAGNOSIS
 Progression of disease over a period of years (25% to 30% of patients)
causes cavitation, bronchopleural fistulas, extension to the other lung,
pulmonary insufficiency, and often death.
 Acute (infantile) disseminated histoplasmosis occurs in infants and
young children and (rarely) in adults with Hodgkin’s disease or other
lympho- proliferative disorders and is characterized by fever; anemia;
leukopenia or thrombocytopenia; enlargement of the liver, spleen, and
visceral lymph nodes; and GI symptoms nausea, vomiting, and diarrhea.
 In adults, disseminated histoplasmosis demonstrate a mild, chronic form
of the disease. Untreated patients are often ill for 10 to 20 years, with
long asymptomatic periods interrupted by relapses characterized by
weight loss, weakness, and fatigue.
TREATMENT
 Mild cases of histoplasmosis that are limited to the lungs will resolve
without specific treatment in about a month.
 Severe infections or disseminated cases of histoplasmosis require
treatment with antifungal medications:
­ Fluconazole
­ Itraconazole
­ Amphotericin B
BLASTOMYCOSIS
CAUSES
 Fungal infection caused by Blastomyces dermatitidis. Pulmonary disease
probably occurs by inhalation conidia, which convert to the yeast forms
in the lungs. It may be acute or chronic and can mimic infection with
tuberculosis, pyogenic bacteria, other fungi, or malignancy.
 Blastomycosis can disseminate to virtually every other body organ,
including skin, bones, and joints, or the genitourinary tract, without any
evidence of pulmonary disease.
CLINICAL PRESENTATION

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Chapter 10.6.9 – Fungal Infections of Skin

 Acute pulmonary blastomycosis is asymptomatic or self-limited disease

characterized by fever, shaking chills, and a productive, purulent cough,
with or without hemoptysis in immunocompetent individuals
 Sporadic pulmonary blastomycosis is more chronic or subacute disease,
with low-grade fever, night sweats, weight loss, and a productive cough
resembling that of tuberculosis rather than bacterial pneumonia.
 Chronic pulmonary blastomycosis involves fever, malaise, weight loss,
night sweats, and cough.
DIAGNOSIS
 The simplest and most successful method is direct microscopic
visualization of the large, multinucleated yeast with single, broad-based
buds in sputum or other respiratory specimens, following digestion of
cells and debris with 10% potassium hydroxide.
 Histopathologic examination of tissue biopsies and culture of secretions
should be used to identify B. dermatitidis.
TREATMENT
 Acute blastomycosis can resolve spontaneously without treatment;
however, antifungal treatment can hasten recovery.
 Chronic blastomycosis requires treatment with antifungal medications:
­ Fluconazole
­ Itraconazole
­ Voriconazole
­ Amphotericin B

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Chapter 10.6.10 – AIDS

AIDS

“Acquired immunodeficiency syndrome (AIDS) is a chronic, potentially life-

threatening condition caused by the human immunodeficiency virus (HIV)”

TRANSMISSION
ROUTES OF INFECTION
I. SEXUAL
 Anal
 Vaginal
 Homosexual- most common in adult males
 Heterosexual- most common in adult females
II. PERCUTANEOUS
 Transfusions
 Needle sharing
 Needle stick
III. MATERNAL-CHILD
 Transplacental
 Peripartum
 Breast milk ingestion

COURSE OF INFECTION
 Time varies by host factors and viral factors
­ Rapid progressors: AIDS in 2-3 years
­ Typical progressors: AIDS in 10 years
­ Long-term non-progressors: Low HIV levels; normal CD4+ T cells;
>10 years after HIV positive.
 Bone marrow transplant case.
­ Highly-exposed persistently seronegative patients: Infected but no
HIV antibodies or HIV-RNA detected.
 Disease progresses faster in certain subtypes of HIV.

PATHOGENESIS
 HIV destruction of CD4-T cells and macrophages causes
immunosuppression.

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Chapter 10.6.10 – AIDS

 Killing of CD4-T cells destroys ability to mount immune response to

infectious agents and to eliminate tumor cells.
 More severe the disease the lower the CD4-T cell numbers and greater
the amount of virus in blood stream.

MANIFESTATIONS
 3 different stages:
1. Primary HIV infection
2. Asymptomatic HIV infection
3. AIDS
 Many patients are asymptomatic until stage 3. Those infected with HIV
are infectious to others in all stages.
 Stage 1 ends when high titers of anti-HIV antibodies are produced.
 Detectable levels of anti-HIV antibodies are usually observed in 2-4
weeks.

DIAGNOSIS
 Usually there are no unique signs or symptoms.
 High index of suspicion- Hx high risk behaviors, unusual infections and
symptoms.
LABORATORY TESTING
SCREENING TESTS
 ELISA or EIA
 EIA- rapid testing (e.g., OraQuick)- can use whole blood, plasma, or oral
secretions.
CONFIRMATORY TESTS
 Western Blot analysis
 RT-PCR

TREATMENT
HAART THERAPY
INTRODUCTION
 HAART (Highly Active Antiretroviral Therapy)- Fewer opportunistic
infections and prolongs the life of HIV-infected patients.
 Successful HAART (available since 1996) suppresses HIV replication and
halts damage and partially restores the immune system and its function.

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Chapter 10.6.10 – AIDS

WHEN TO START HAART

 All Patients with hx of AIDS-defining condition or CD4 T-cell count of
<350 cells/mm3
 All Patients that are pregnant, HIV nephropathy, HBV co-infection when
HBV Rx is needed.
 Recommended for all Pt with 350-500 cells/mm3
 Optional for Pt with >500 cells/mm3
SELECTION OF HAART THERAPY
 Treatment for naïve HIV patients
 NNRTI OR a PI OR an integrase inhibitor PLUS 2-NRTIs.
 Four regimens are now listed as “Preferred” regimens:
1. Efavirenz + tenofovir/emtricitabine (NNRTI + NRTI/NRTI)
2. Ritonavir-boosted atazanavir + tenofovir/emtricitabine
(PI-PI + NRTI/NRTI)
3. Ritonavir-boosted darunavir + tenofovir/emtricitabine
(PI-PI + NRTI/NRTI)
4. Raltegravir + tenofovir/emtricitabine (integrase inhibitor +
NRTI/NRTI)
ADVERSE EFFECTS OF HAART THERAPY
 Four major groups:
1. MITOCHONDRIAL DYSFUNCTION: Lactic acidosis, hepatic toxicity,
pancreatitis, peripheral neuropathy
2. METABOLIC ABNORMALITIES: Fat maldistribution and change in
body habitus, dyslipidemia, hyperglycemia and insulin resistance,
bone disorders (e.g. osteopenia, osteoporosis and osteonecrosis)
3. BONE MARROW SUPPRESSION: Anemia, neutropenia and
thrombocytopenia.
4. ALLERGIC REACTIONS: Skin rashes and hypersensitivity responses
HAART THERAPY AND ANESTHETICS
 OPIOIDS:
­ Fentanyl may be enhanced by ritonavir due to both liver enzyme
inhibition and induction.
­ Methadone clearance can be affected by some HAART agents and
methadone can affect the clearance of some HAART agents.

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Chapter 10.6.10 – AIDS

 BENZODIAZEPINES: Saquinavir may inhibit midazolam metabolism.

 LOCAL ANESTHETICS: LAs such as lidocaine may have increased plasma
levels due to enzyme inhibition.
 NEUROMUSCULAR BLOCKER: Effects may be prolonged, even a single
dose of vecuronium.
 CALCIUM CHANNEL BLOCKERS: May have enhanced hypotensive effects
due to enzyme inhibition.

TESTING PATIENTS FOR HIV

 Testing for HIV is strongly encouraged by the CDC.
­ HIV screening is recommended for patients (13-64 years of age) in
all health-care settings after the patient is notified that testing will
be performed unless the patient declines (opt-out screening).
­ Annual HIV testing for individuals with high-risk behaviors.
­ HIV screening should be included in the routine panel of prenatal
screening tests for all pregnant women. Repeat screening in the
third trimester is recommended in certain jurisdictions with
elevated rates of HIV infection among pregnant women.

PREVENTION
 Adopt universal infection control precautions for all patients:
­ Especially if you practice in areas of high HIV prevalence.
­ 20% of anesthesiologists had at least one needle stick injury in the
past 3 months.
­ High prevalence area; risk acquiring HIV- 4.5% during 30yr career.
 Post-Exposure Prophylaxis- Know what to do in advance!
­ Anesthesiologists can acquire HIV during their work via sharp
injuries (risk of HIV transmission 0.3%), contamination of broken
skin with the patients’ body fluids (risk of HIV transmission <0.1%),
and splashing HIV containing body fluid in the eyes, nose or mouth
(risk of HIV transmission 0.1%).

VACCINES/RECENT PREVENTION STUDIES

 Thai vaccine study demonstrated limited success
 Male circumcision is associated with lower risk for HIV
 Tenofovir gel for prevention of HIV infection in women.

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Chapter 10.6.11 – Dengue Fever

DENGUE FEVER

“Dengue fever is a painful, debilitating mosquito-borne disease caused by any

one of four closely related dengue viruses.”

INTRODUCTON
 Dengue fever is an acute infectious viral disease, also known as
breakbone fever.
 Dengue fever virus (DENV) is an RNA virus of the family Flaviviridae;
genus Flavivirus. Most are transmitted by arthropods (mosquitoes or
ticks) and are therefore also referred to as arboviruses (arthropod-borne
viruses).

CAUSE
 Dengue fever is caused by any one of four types of dengue viruses.
Which are called serotypes, and these are referred to as DENV-1, DENV-
2, DENV-3 and DENV-4.
 All four serotypes can cause the full spectrum of disease. Infection with
one serotype is believed to produce lifelong immunity to that serotype
but only short-term protection against the others.

TRANSMISSION CYCLE OF DENGUE

 Dengue is transmitted by several species of mosquito within the genus
Aedes, principally Aedes aegypti.
 Dengue virus is primarily transmitted by Aedes mosquitoes, particularly
A. aegypti. Other Aedes species that transmit the disease include A.
albopictus, A. polynesiensis and A. scutellaris.
 Humans are the primary host of the virus, but it also circulates in non-
human primates.
 An infection can be acquired via a single bite. A female mosquito that
takes a blood meal from a person infected with dengue fever becomes
itself infected with the virus in the cells lining its gut.
 About 8–10 days later, the virus spreads to other tissues including the
mosquitos salivary glands and is subsequently released into its saliva.

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MECHANISIM
 When a mosquito carrying dengue virus bites a person, the virus enters
the skin together with the mosquitos saliva. It binds to and enters white
blood cells and reproduces inside the cells while they move throughout
the body.
 In severe infection, the virus production inside the body is greatly
increased, and many more organs (such as the liver and the bone
marrow) can be affected, and fluid from the bloodstream leaks through
the wall of small blood vessels into body cavities.
 As a result, less blood circulates in the blood vessels, and the blood
pressure becomes so low that it cannot supply sufficient blood to vital
organs. Furthermore, dysfunction of the bone marrow leads to reduced
numbers of platelets, which are necessary for effective blood clotting;
this increases the risk of bleeding, the other major complication of
dengue fever.

CLINICAL PRESENTATION
 Many people experience no signs or symptoms of a dengue infection.
When symptoms do occur, they may be mistaken for other illnesses —
such as the flu — and usually begin 4-10 days after bitten by an infected
mosquito.
 Dengue fever causes a high fever — 104°F (40°C) — and any of the
following signs and symptoms:
­ Headache
­ Muscle, bone or joint pain
­ Nausea
­ Vomiting
­ Pain behind the eyes
­ Swollen glands
­ Rash
 Most people recover within a week or so. In some cases, symptoms
worsen and can become life-threatening. This is called severe dengue,
dengue hemorrhagic fever or dengue shock syndrome.
 Severe dengue happens when blood vessels become damaged and leaky
and the number of clot-forming cells (platelets) in bloodstream drops.
This can lead to shock, internal bleeding, organ failure and even death.
 Warning signs of severe dengue fever — which is life-threatening

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Chapter 10.6.11 – Dengue Fever

emergency — can develop quickly. The warning signs usually begin the
first day or two after fever goes away, and may include:
­ Severe stomach pain
­ Persistent vomiting
­ Bleeding from gums or nose
­ Blood in urine, stools or vomit
­ Bleeding under the skin, which might look like bruising
­ Difficult or rapid breathing
­ Irritability or restlessness.

DIAGNOSIS
 Platelet count is < 1,00,000 cells/mm3 (Normal is 2-5lac cells/mm3).
 Hematocrit value is increased by 20 percent or more (due to
hemoconcentration)
 Hypoproteinemia, pleural effusion and ascites constitute the supporting
evidence of plasma leakage.
 Real time polymerase chain reaction (RT-PCR): This is done to detect
viral genome in serum. It is a primary tool to detect virus early in the
course of illness. It is a definite proof of current infection.
 NSI ELISA: Detection of nonstructural protein (NSI-Antigen) in the serum
of dengue fever patients is a useful tool for the diagnosis of acute
dengue infections.
 IgG ELISA: Samples with negative IgG in acute and a positive IgG in
convalescent phase of the infection are primary dengue infections.

TREATMENT
 No antiviral drug is available for dengue fever.
 No vaccine is available for dengue fever.
 However, following treatment is given to dengue patients:
­ Oral Rehydration Therapy
­ Intravenous fluids
­ Blood transfusion
­ Symptomatic treatment.

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Chapter 10.6.12 – Common Cold

COMMON COLD

INTRODUCTION
 The term “common cold” covers different symptoms caused by an
infection of the upper airways. It is also known as acute viral
rhinopharyngitis, or acute coryza.
 In general, the common cold is an acute, self-limiting viral infection of
the upper respiratory tract involving the nose, sinuses, pharynx and
larynx.

CAUSES
 Rhinovirus
 Adenovirus
 Coronavirus
 Parainfluenza virus
 Respiratory syncytial virus (RSV)

TRANSMISSION
 Transmission of common cold is via:
­ Direct Contact Transmission
­ Droplet Transmission/ Secondary Mechanism
I. DIRECT CONTACT TRANSMISSION
 Transmission is primarily by the virus coming into contact with the
hands, which then touch the nose, mouth and eyes.
II. DROPLET TRANSMISSION/ SECONDARY MECHANISM
 Transmission by coughing and sneezing infected mucus particles does
occur, although it is a secondary mechanism. This is why good hygiene
(washing hands frequently and using disposable tissues) remains the
cornerstone of reducing the spread of a cold.

PATHOPHYSIOLOGY
 Virus invades the nasal and bronchial epithelia, attaching to specific
receptors and causing damage to the ciliated cells and release of
inflammatory mediators, which cause inflammation of the tissues lining
the nose.

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Chapter 10.6.12 – Common Cold

 Permeability of capillary cell walls increases, resulting in oedema, which

is experienced by the patient as nasal congestion and sneezing.
 Fluid might drip down the back of the throat, spreading the virus to the
throat and upper chest causing cough and sore throat.
 Incubation period 1-3 days.

CLINICAL PRESENTATION
 Cold symptoms usually start about 2 or 3 days after coming in contact
with the virus, although it could take up to a week. Symptoms mostly
affect the nose.
 The most common cold symptoms are:
­ Sore throat and sneezing followed by profuse nasal discharge and
congestion.
 Adults and older children with colds generally have a low fever or no
fever. Young children often run a fever around 100-102°F or 38.9°C.
 Depending on which virus caused cold, also have:
­ Commonly cough and postnasal drip
­ Generally headache, muscle aches and malaise might be present.

DIAGNOSIS
 Mostly diagnosed by patient’s signs and symptoms.
 If bacterial infection or other condition is suspected, chest X-ray or other
tests are done to exclude other causes of symptoms.

TREATMENT
TRADITIONAL TREATMENT
 Drink plenty of fluids to help immune system work properly.
 Eat yogurt that contains "active cultures." These may help prevent colds.
Probiotics may help prevent colds in children.
 Chicken soup may help cold symptoms in more than one way.
 Black and green teas have the added bonus of being loaded with
disease-fighting antioxidants, which may fight colds.
PHARMACOLOGICAL TREATMENT
 Antibiotics should not be used to treat a common cold. Antibiotics are
usually not effective against colds and, because of their possible side
effects, should only be used if there are complications.

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 Many alternative treatments have been tried for colds, such as vitamin
C, zinc supplements, and echinacea.
 Products that contain zinc, vitamin C, are also commonly recommended
for the treatment of colds.
 Over-the-counter cold and cough medicines may help ease symptoms in
adults and older children. They do not make cold go away faster but can
help feel better.

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Chapter 10.6.13 – Pharyngitis & Tonsillitis

PHARYNGITIS & TONSILLITIS

UPPER RESPIRATORY TRACT INFECTIONS

PHARYNGITIS
 Pharyngitis is the inflammation of pharynx characterized by discomfort,
pain or scratchiness in the throat.
TONSILLITIS
 It is type of pharyngitis defined as inflammation of the tonsils, typically
of rapid onset.

CAUSES
 Viruses (most common)
 Bacteria (such as streptococcus)
 Fungal infections
 Parasitic infections
 Cigarette smoke
 Other causes

TYPES
 Bacterial pharyngitis
 Viral pharyngitis
BACTERIAL PHARYNGITIS
 Group A streptococcal pharyngitis:
­ Erythema, swelling, or exudates of the tonsils or pharynx
­ Temperature of 38.3°C or higher
­ Tender anterior cervical nodes (≥1 cm)
­ Absence of conjunctivitis, cough, and rhinorrhea.
VIRAL PHARYNGITIS
I. PHARYNGITIS IN THE COMMON COLD SYNDROME
 Nasal symptoms, such as sneezing, watery nasal discharge, nasal
congestion, or postnasal discharge, tend to precede throat symptoms.
 Throat symptoms can be in the form of soreness, scratchiness, or
irritation.

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 Nasal discharge may be thick and yellow. Nonproductive cough may be

present. Fever, if present, is usually low grade and is more prominent in
young children than in adults.
II. PHARYNGITIS CAUSED BY ADENOVIRUS
 Pharyngitis caused by adenovirus is common among young children and
military recruits. Patients with pharyngitis present with sore throat
(more intense than that of a common cold), high fever, dysphagia, and
red eyes. This syndrome is named pharyngoconjunctival fever.
III. PHARYNGITIS ASSOCIATED WITH EBV INFECTIOUS MONONUCLEOSIS
 EBV infectious mononucleosis is most commonly observed in
adolescents and young adults.
 Sore throat and fatigue are the most common symptoms. Pharyngeal
symptoms are usually associated with other features of the disease (e.g.
fatigue, skin rash, anorexia).
IV. PHARYNGITIS WITH INFLUENZA
 Sore throat is the chief symptom in some patients with influenza. The
onset of illness is usually abrupt, with myalgia, headache, fever, chills,
and dry cough. The pharyngitis usually resolves in 3-4 days.

SIGNS AND SYMPTOMS

 Hoarseness
 Dysphagia
 Sore throat
 Mild fever
 Irritating cough
 Difficulty speaking
 Reddening of tonsils
 Red enlarged purulent exudate
 Constant need to clear your throat.

DIAGNOSIS
 Throat swab culture
­ Beta hemolytic cocci
 Rapid antigen detection test
­ Group A streptococcus are detected if test is positive.
 Full blood count
­ Neutrophilia (bacterial)
­ Lymphocytosis (viral)

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Chapter 10.6.13 – Pharyngitis & Tonsillitis

TREATMENT
NON PHARMACOLOGICAL MANAGEMENT
 Using a humidifier
 Resting until you feel better
 Drinking plenty of fluids to prevent dehydration
 Gargling with warm salt water (1 teaspoon of salt per 8 ounces of water)

PHARMACOLOGICAL MANAGEMENT
 Penicillin
­ Amoxicillin
 Throat lozenges
 First generation cephalosporin
­ Cephalexin
­ Cefadroxil
 In resistant patients
­ Macrolides such as azithromycin, clarithromycin, and
erythromycin
 Surgery
­ Tonsillectomy

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Chapter 10.6.14 – Conjunctivitis

CONJUNCTIVITIS

INTRODUCTION
 Conjunctivitis (Pink Eye) is the inflammation of the conjunctiva, which is
the clear membrane covering the sclera and interior lining of eyelids.
 Only occurs in the eye. The inflammation of the conjunctiva cause the
eye’s blood vessels to dilate, resulting in the reddish appearance.

CAUSES
 Viral
 Bacterial
 Allergic
 Chemical splash in eye
 Foreign object in eye

VIRAL CONJUNCTIVITIS
INTRODUCTION
 Viral conjunctivitis is a highly contagious acute conjunctival infection
caused by viruses and causes watery discharge.
ETIOLOGY
 Often associated with common cold, caused by adenovirus. Occurs in
community epidemics (schools, workplaces, physicians’ offices)
CLINICAL PRESENTATION
 Acutely red eye
 Watery or mucoserous discharge
 Chemosis (swelling of conjunctiva)
 Tender preauricular node
 Burning/sanding/gritty feeling in eyes

DIAGNOSIS
 Observing signs and symptoms
 Health history
 Culture testing of discharge material
 RPS Adenodetector test to confirm adenovirus presence

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Chapter 10.6.14 – Conjunctivitis

TREATMENT
 Viral, allergic, and nonspecific conjunctivitis are self-limited
 Topical antibiotics not necessary because secondary bacterial infection is
uncommon
 Antiviral medications may be used if viral conjunctivitis is caused by the
herpes simplex virus.

BACTERIAL CONJUNCTIVITIS
INTRODUCTION
 Bacterial conjunctivitis is an infection of the eye's mucous membrane,
the conjunctiva.
ETIOLOGY
 Acute bacterial conjunctivitis is primary due to Staphylococcus aureus,
Streptococcus pneumoniae, and Haemophillus influenzae.
 Chronic conjunctivitis is primarily due to Chlamydia trachomatis.

CLINICAL PRESENTATION
 Red eyes
 Watery discharge or thick purulent discharge
 Irritation, burning, stinging, discomfort
 Tearing
 Light sensitivity
 Intolerance to contact lens
 Fluctuating or decreased vision

DIAGNOSIS
 Observing signs and symptoms
 Health history
 Culture testing of discharge material

TREATMENT
 Antibiotics:
­ Fluroquinolone
 Ciprofloxacin  Moxifloxacin
 Levofloxacin
­ Aminoglycosides
 Tobramycin  Gentamycin
­ Macrolides
 Erythromycin  Azithromycin

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Chapter 10.6.14 – Conjunctivitis

­ Other
Bacitracin
  Sulfacetamide
ointment  Fusidic acid
­ Povidone-iodine (disinfectant)

ALLERGIC CONJUNCTIVITIS
INTRODUCTION
 Most commonly seasonal allergic rhino-conjunctivitis, also called “Hay
fever rhino-conjunctivitis”
ETIOLOGY
 IgE mediated hypersensitivity reaction precipitated by small airborne
allergens which causes local mast cell degranulation resulting in release
of chemical mediators (histamine, eosinophil chemotactic factors, etc.)
CLINICAL PRESENTATION
 Bilateral, pruritus, redness, watery discharge, rhinorrhea/congestion
 Patients often have h/o atopy, seasonal allergy or specific allergy

DIAGNOSIS
 Eyes examination
 Allergy history
 Small bumps inside eyelids
 Redness in white portion of eyes

TREATMENT
 Self-limited
 Allergen avoidance
 Topical antihistamines/vasoconstrictors (do not use for greater than 2
weeks), artificial tears, topical NSAIDS (low efficacy)
 Prophylaxis: Oral antihistamines, mast cell stabilizers.

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Chapter 10.7.1 – Diabetes Mellitus

DIABETES MELLITUS

“Diabetes mellitus (DM) is a group of metabolic disorders characterized by

hyperglycemia and abnormalities in carbohydrate, fat, and protein
metabolism.”

INTRODUCTION
 Diabetes Mellitus results from defects in insulin secretion, insulin
sensitivity, or both. DM is the most common of the endocrine
disorders. Impaired insulin secretion with or without insulin
resistance.

TYPES
TYPE 1 DIABETES
 Type 1 diabetes is a disease characterized by the destruction of the
insulin-producing pancreatic β-cells, the development of which is
either autoimmune T-cell mediated destruction (type 1A) or
idiopathic (type 1B).
 In over 90% of cases, β-cell destruction is associated with
autoimmune disease. Type 1 diabetes usually develops in the young
although it can develop at any age.
TYPE 2 DIABETES
 Type 2 diabetes is more common above the age of 40, with a peak
age of onset in developed countries between 60 and 70 years.
 It is caused by a relative insulin deficiency and insulin resistance.
Type 2 diabetes may be an incidental finding.
 Type 2 disease often progresses to the extent whereby extrinsic
insulin is required to maintain blood glucose levels.
DIFFERENCE BETWEEN TYPE I AND TYPE II DIABETES
TYPE I DIABETES TYPE II DIABETES
β-cell destruction No β-cell destruction
Islet cell antibodies present No islet cell antibodies present
Strong genetic link Very strong genetic link
Age of onset usually below 30 Age of onset usually above 40
Faster onset of symptoms Slower onset of symptoms
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Diet control and oral hypoglycemic

Insulin must be administered
agents often sufficient control
Patients are usually not overweight Patients are usually overweight
Extreme hyperglycemia causes Extreme hyperglycemia causes
diabetic ketoacidosis hyperosmolar hyperglycemic state
GESTATIONAL DIABETES
 A form of glucose intolerance that is diagnosed in some women during
pregnancy. Gestational diabetes occurs more frequently among African
Americans, Hispanic/Latino Americans, and American Indians. It is also
more common among obese women and women with a family history of
diabetes.
 During pregnancy, gestational diabetes requires treatment to normalize
maternal blood glucose levels to avoid complications in the infant.
MANAGEMENT OF DIABETES IN PREGNANCY
OUTPATIENT GLUCOSE TARGETS FOR PREGNANT WOMEN
CONDITION TREATMENT GOAL
Gestational Diabetes Mellitus (GDM)
Pre-prandial glucose, mg/dL ≤95*
1-Hour PPG, mg/dL ≤140*
2-Hour PPG, mg/dL ≤120*
Preexisting Type 1 Diabetes or Type 2 Diabetes
Premeal, bedtime, and overnight
60-99*
glucose, mg/dL
Peak PPG, mg/dL 100-129*
A1c ≤6.0%*
*Provided target can be safely achieved.
FPG = fasting plasma glucose; PPG = postprandial glucose.

OTHER TYPES
 Two other varieties of non-typical diabetes that may be seen are latent
autoimmune diabetes in adults (LADA) and maturity- onset diabetes of
the young (MODY).
LATENT AUTOIMMUNE DIABETES IN ADULTS (LADA)
 Latent Autoimmune Diabetes in Adults (LADA) is a form of autoimmune
(type 1 diabetes) which is diagnosed in individuals who are older than
the usual age of onset of type 1 diabetes. Alternate terms that have

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been used for "LADA" include Late-onset Autoimmune Diabetes of

Adulthood, "Slow Onset Type 1" diabetes, and sometimes also "Type 1.5.
 Often, patients with LADA are mistakenly thought to have type 2
diabetes, based on their age at the time of diagnosis.
FEATURES OF LADA
 Patients usually aged 25 years Clinical presentation "masquerading" as
non-obese type 2 diabetes.
 Initial control achieved with diet alone or diet and oral hypoglycemic
agents.
 Insulin dependency occurs within months but can take 10 years or more.
 Other features of type 1 diabetes:
­ Low fasting and post-glucagon stimulated C-peptide
 C-peptide: To help evaluate insulin production by the beta
cells in the pancreas or to help determine the cause of
low blood glucose (hypoglycemia).
­ HLA (human leukocyte antigen) susceptibility alleles
­ ICA+ Islet cell antibody
­ GADA+ Glutamic acid decarboxylase antibody
 A GAD test is a blood test which measures whether the
body is producing a type of antibody which destroys its own
GAD cells. In type 1 diabetes, a number of autoantibodies
are thought to circulate including those which target
glutamic acid decarboxylase. Presence of these
autoantibodies suggests type 1 diabetes.
 About 80% of adults apparently with recently diagnosed Type 2 diabetes
but with GAD auto-antibodies (i.e. LADA) progress to insulin
requirement within 6 years.
 The potential value of identifying this group at high risk of progression to
insulin dependence includes:
­ The avoidance of using metformin treatment
­ The early introduction of insulin therapy
MATURITY ONSET DIABETES OF YOUNG (MODY)
 MODY is a monogenic form of diabetes with an autosomal dominant
mode of inheritance:
­ Mutations in any one of several transcription factors or in the

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enzyme glucokinase lead to insufficient insulin release from

pancreatic ß-cells, causing MODY.
­ Different subtypes of MODY are identified based on the mutated
gene.
­ Originally, diagnosis of MODY was based on presence of non-
ketotic hyperglycemia in adolescents or young adults in
conjunction with a family history of diabetes.
 However, genetic testing has shown that MODY can occur at any age
and that a family history of diabetes is not always obvious.
FEATURES SUGGESTIVE OF MONOGENIC DIABETES
 MODY (majority have HNF-1 alpha or HNF-4 alpha mutations)
­ Mutations in the HNF1A gene have been known to cause diabetes
­ (HNF= Hepatocyte nuclear factor 1 and 4)
 Young onset of diabetes (generally <25 years of age)
 Strong family history of diabetes (typically 2-3 generations affected)
 Sulfonylurea sensitivity
 Absence of insulin resistance phenotype: normal BP, TG, HDL-C
 PNDM (50% have Kir6.2 mutations): Permanent -neonatal diabetes
→ Congenital hyperinsulinism
­ Permanent neonatal diabetes mellitus (PNDM) is a monogenic
form of neonatal diabetes (NDM) characterized by persistent
hyperglycemia within the first 12 months of life in general,
requiring continuous insulin treatment.
 Diabetes onset <6 months of age
 DEND syndrome: Developmental delay-epilepsy-neonatal diabetes
 Within MODY, the different subtypes can essentially be divided into 2
distinct groups:
­ Glucokinase MODY
­ Transcription factor MODY,
 Distinguished by characteristic phenotypic features and pattern on oral
glucose tolerance testing.
 Glucokinase MODY requires no treatment, while transcription factor
MODY (i.e. Hepatocyte nuclear factor -1 alpha) requires low-dose
sulfonylurea therapy and PNDM (caused by Kir6.2 mutation) requires
high-dose sulfonylurea therapy.

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SECONDARY DIABETES MELLITUS

 Secondary causes of Diabetes mellitus include:
­ Acromegaly, GH excess – insulin resistance
­ Cushing syndrome, gluconeogenesis, insulin sensitivity
­ Thyrotoxicosis, insulin half-life reduced, gut glucose abs.
­ Pheochromocytoma, inhibition of insulin secretion by epi and nor-
epinephrine and inducing glucagon secretion via beta – 2
adrenergic receptors
­ Chronic pancreatitis
­ Cancer
DRUG INDUCED HYPER-GLYCEMIA
 Atypical Antipsychotics
­ Alter receptor binding characteristics, leading to increased insulin
resistance.
 Beta-blockers
­ Inhibit insulin secretion.
 Calcium Channel Blockers
­ Inhibits secretion of insulin by interfering with cytosolic calcium
release.
 Corticosteroids
­ Cause peripheral insulin resistance and gluconeogenesis.
 Fluoroquinolones
­ Inhibits insulin secretion by blocking ATP sensitive potassium
channels.
 Niacin
­ They cause increased insulin resistance due to increased free fatty
acid mobilization.
 Phenothiazines
­ Inhibit insulin secretion.
 Protease Inhibitors
­ Inhibit the conversion of proinsulin to insulin.
 Thiazide Diuretics
­ Inhibit insulin secretion due to hypokalemia. They also cause
increased insulin resistance due to increased free fatty acid
mobilization.

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ETIOLOGY

PATHOPHYSIOLOGY

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PRE-PROINSULIN
 Preproinsulin is the primary translational product of the INS gene. It is
a peptide that is 110 amino acids in length.
 Pre-proinsulin is a biologically inactive precursor to the biologically
active endocrine hormone insulin.
 Pre-proinsulin is converted into proinsulin by signal peptidases, which
remove its signal peptide from its N-terminus.
 Finally, proinsulin is converted into the bioactive hormone insulin by
removal of the C-peptide.
 A normal C-peptide range is 0.5 to 2.0 nanograms per milliliter.

INSULIN RELEASE
 Glucose enters the β-cells through the glucose transporters, GLUT2.
These glucose transporters have a relatively low affinity for glucose,
ensuring that the rate of glucose entry into the β-cells is proportional to
the extracellular glucose concentration (within the physiological range).
 At low blood sugar levels very little glucose enters the β-cells; at high
blood glucose concentrations large quantities of glucose enter these
cells.
 The glucose that enters the β-cell is phosphorylated to glucose-6-
phosphate (G-6-P) by glucokinase (hexokinase IV)
 Glucose-6-phosphate enters glycolytic pathway and then, via
the pyruvate dehydrogenase reaction, into the Krebs cycle, where
multiple, high-energy ATP molecules are produced by the oxidation
of acetyl CoA (the Krebs cycle substrate), leading to a rise in the ATP:ADP
ratio within the cell.
 An increased intracellular ATP:ADP ratio closes the ATP-sensitive
SUR1/Kir6.2 potassium channel. This prevents potassium ions (K +) from
leaving the cell by facilitated diffusion, leading to a buildup of
intracellular potassium ions.
 As a result, the inside of the cell becomes less negative with respect to
the outside, leading to the depolarization of the cell surface membrane.
 Upon depolarization, voltage-gated calcium ion (Ca2+) channels open,
allowing calcium ions to move into the cell by facilitated diffusion.
 The calcium ion concentration in the cytosol of the beta cells can also, or
additionally, be increased through the activation of phospholipase
C resulting from the binding of an extracellular ligand (hormone or

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neurotransmitter) to a G protein-coupled membrane receptor.

 Phospholipase C cleaves the membrane phospholipid, phosphatidyl
inositol 4,5-bisphosphate, into inositol 1,4,5
trisphosphate and diacylglycerol.
 Inositol 1,4,5-trisphosphate (IP3) then binds to receptor proteins in the
plasma membrane of the endoplasmic reticulum (ER).
 This allows the release of Ca2+ ions from the ER via IP3-gated channels,
which raises the cytosolic concentration of calcium ions independently
of the effects of a high blood glucose concentration.
 The significantly increased amount of calcium ions in the cells' cytoplasm
causes the release into the blood of previously synthesized insulin,
which has been stored in intracellular secretory vesicles.
PHASES OF INSULIN RELEASE
 Five different modes (or phases) of insulin secretion can be identified:
1. Basal insulin secretion is the way insulin is released in the
postabsorptive state.
2. The cephalic phase of insulin secretion is evoked by the sight,
smell, and taste of food (before any nutrient is absorbed by the
gut) and is mediated by pancreatic innervation.
3. First-phase insulin secretion is defined as the initial burst of
insulin, which is released in the first 5–10 min after the β-cell is
exposed to a rapid increase in glucose (or other secretagogues)
4. After the acute response, there is a second-phase insulin
secretion, which rises more gradually and is directly related to the
degree and duration of the stimulus.
5. Finally, a third phase of insulin secretion has been described,
albeit only in vitro.

β-CELL DYSFUNCTION
 β-Cell dysfunction is initially characterized by an impairment in the first
phase of insulin secretion during glucose stimulation.
 Initiation of the insulin response depends upon the trans-membranous
transport of glucose and coupling of glucose to the glucose sensor.
 The glucose/glucose sensor complex then induces an increase in
glucokinase.
 Glucose transporting β -cells of type 2 diabetes patients appears to be
greatly reduced, thus shifting the control point for insulin secretion from

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glucokinase to the glucose transport system. This defect is improved by

the sulfonylureas
 The second phase release of newly synthesized insulin is impaired, an
effect that can be reversed, in part at least in some patients, by restoring
strict control of glycemia.
 Secondary phenomenon, termed desensitization or β-cell glucotoxicity,
is the result of a paradoxical inhibitory effect of glucose upon insulin
release and may be attributable to the accumulation of glycogen within
the β-cell as a result of sustained hyperglycemia
 In the great majority of patients with type 2 diabetes (±80%), the delay
in immediate insulin response is accompanied by a secondary
hypersecretory phase of insulin release as a result of either an inherited
or acquired defect within the β-cell or a compensatory response to
peripheral insulin resistance.

IMPAIRED INSULIN SECRETION

 Due to glucose – probably because of defect in glucose metabolism. This
is due to reduced ATP content induced partly by high Ca2+ of islets
 The high Ca2+ in islets is due to augmented PTH-induced calcium entry
into cells and decreased calcium extrusion from the islets secondary to
reduced activity of the Ca2+ ATPase.

INSULIN RESISTANCE
 As chronic hyperinsulinemia inhibits both insulin secretion and action,
and hyperglycemia can impair both the insulin secretory response to
glucose as well as cellular insulin sensitivity, the precise relation
between glucose and insulin level as a surrogate measure of insulin
resistance has been questioned.
 Lean type 2 diabetic patients over 65 years of age have been found to be
as insulin sensitive as their age-matched nondiabetic controls.
 Moreover, in the majority of type 2 diabetic patients who are insulin
resistant, obesity is almost invariably present
 As obesity or an increase in intraabdominal adipose tissue is associated
with insulin resistance in the absence of diabetes, it is believed by some
that insulin resistance in type 2 diabetes is entirely due to the
coexistence of increased adiposity
 The increment in glucose-6-phosphate concentration was significantly
reduced in type 2 diabetics, suggesting that glucose transport or

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phosphorylation must be the rate-controlling step in insulin-

stimulated glucose disposal in skeletal muscle rather than glycogen
synthase
 Glucose transport in skeletal muscle is largely mediated by a specific
insulin-responsive transporter known as glucose transporter 4 (GLUT4),
whereas glucose phosphorylation is catalyzed by hexokinase
 According to one proposal, increased fatty acid oxidation would cause an
increase in the mitochondrial acetyl coenzyme A (CoA):CoA and
NADH:NAD+ ratios with subsequent inactivation of pyruvate
dehydrogenase.
 In turn, this would induce a rise in intracellular citrate levels, leading to
inhibition of phosphofructokinase and glucose-6-phosphate
accumulation.
 Because glucose-6-phosphate inhibits hexokinase activity, this would
result in intracellular glucose accumulation and decreased glucose
uptake.

METABOLIC SYNDROME
INTRODUCTION
 Metabolic syndrome is a collection of risk factors that increase the
chance of developing heart disease, stroke, and diabetes. Losing weight,
exercise, and dietary changes can help prevent or reverse metabolic
syndrome.
CAUSES OF METABOLIC SYNDROME
 The exact cause of metabolic syndrome is not known. Many features of
the metabolic syndrome are associated with "insulin resistance."
 Insulin resistance means that the body does not use insulin efficiently to
lower glucose and triglyceride levels.
 A combination of genetic and lifestyle factors may result in insulin
resistance. Lifestyle factors include dietary habits, activity and perhaps
interrupted sleep patterns.
DIAGNOSIS OF METABOLIC SYNDROME
 You are diagnosed with metabolic syndrome if you have three or more
of the following:
 A waistline of 40 inches or more for men and 35 inches or more for
women (measured across the belly)

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 A blood pressure of 130/85 mm Hg or higher or are taking blood

pressure medications
 A triglyceride level above 150 mg/dl
 A fasting blood glucose (sugar) level greater than 100 mg/dl or are taking
glucose-lowering medications
 A high density lipoprotein level (HDL) less than 40 mg/dl (men) or under
50 mg/dl (women)

TYPE 1 DIABETES (INSULIN-DEPENDENT)

TYPE 2 DIABETES (NON-INSULIN-DEPENDENT)

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DIAGNOSIS OF DIABETES MELLITUS

 Criteria for diagnosis of DM include any one of the following:
1. A1c of 6.5% or more.
2. Fasting (no caloric intake for at least 8 hours) plasma glucose of 126
mg/dL or more.
3. Two-hour plasma glucose of 200 mg/dL or more during an oral
glucose tolerance test (OGTT) using a glucose load containing the
equivalent of 75g anhydrous glucose dissolved in water.
4. Random plasma glucose concentration of 200 mg/dL or more with
classic symptoms of hyperglycemia or hyperglycemic crisis.
NORMAL ADULT BLOOD SUGAR LEVEL
Types of test Normal adult blood sugar level
Simple blood sugar level test 80-100 mg/dl
Fasting blood sugar level test 80-100 mg/dl
Oral glucose tolerance test <140 mg/dl
A1c test 4%-6%

BLOOD SUGAR LEVEL CHART

3 HOURS AFTER
FASTING JUST ATE
FASTING
NORMAL 80-100 mg/dl 170-200 mg/dl 120-140 mg/dl
PRE-DIABETIC 101-125 mg/dl 10-230 mg/dl 140-160 mg/dl
DIABETIC 126+ mg/dl 220-300 mg/dl 200+ mg/dl

 The fasting glucose reflects hepatic glucose production, which depends

on insulin secretory capacity of the pancreas.
 The postprandial glucose reflects uptake of glucose in peripheral tissues
(muscle and fat) and depends on insulin sensitivity of these tissues.

CLINICAL PRESENTATION
TYPE 1 DIABETES MELLITUS
 The most common initial symptoms are polyuria, polydipsia, polyphagia,
weight loss and lethargy accompanied by hyperglycemia.
 Individuals are often thin and are prone to develop diabetic ketoacidosis
if insulin is withheld or under conditions of severe stress.
 Between 20% and 40% of patients present with diabetic ketoacidosis
after several days of polyuria, polydipsia, polyphagia, and weight loss.

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TYPE 2 DIABETES MELLITUS

 Patients are often asymptomatic and may be diagnosed secondary to
unrelated blood testing.
 Lethargy, polyuria, nocturia, and polydipsia can be present. Significant
weight loss is less common; most patients are overweight or obese.

PREVENTION & DELAY OF DIABETES

Diet,
Diabetes
Life style walk –
Prevention
changes 2.5
Program
hrs/week

Reduced
Medications 25– 40 yrs & Metformin
risk up to
overweight (50 – 80 lbs) – IGT
30% over 3
group
yrs

Reduced
Acrabose – risk up to Trials ongoing for
IGT group 30% over other drugs
3 yrs

DIABETIC EMERGENCIES

2. Diabetic 3. Hyperosmolar
1. Hypoglycemia Ketoacidosis – Type Hyperglycemic state
1 diabetes - type 2 diabetes

1. HYPOGLYCEMIA
 Insulin and long acting anti-glycemic agents – chlorpropamide,
glibenclamide.
 Nocturnal Hypoglycemia – BG in the morning.

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 Counter regulatory hormones – adrenaline, nor-adrenaline –

autonomic symptoms – dizziness, sweating, fainting.
 If BG levels ~ 2mmol/L – confusion, < 0.5mmol/L – coma, seizure and
death - -cerebral malfunction – neuroglycopenia
 Asymptomatic – autonomic neuropathy, b-blockers, alcohol
intoxication.
CAUSES
 Decrease Carbohydrate Consumption, Increase Carbohydrate utilization.
TREATMENT
 Oral glucose intake – Lucozade – check 10 – 15 min.
 If < 3.5 mmol/L take more – if > 3.5mmol/L next meal - > 1 hr.
 25 g IV or glucagon IM – will not work in LD, 20% G.
2. DIABETIC KETOACIDOSIS
 Extreme Hyperglycemia – mortality 5 – 10%
 Dec. Lipolysis – Inc. non-esterified FA
 Liver > acetyl CoA – consumed by tricarboxylic acid cycle – ketone
bodies, acetoacetate, hydroxybutyrate
 Hyperglycemia – osmotic diuresis, serum volume, dizziness, weakness
– K loss, vomiting due to ketone and muscle protein catabolism.
CAUSES
 Caused by omission of insulin dose, infection, trauma or myocardial
infarction, increase dehydration, hyperosmolarity – coma in 10% cases,
patient breath fruity odor like acetone , glucosuria, ketonuria, BG >
22mmol/L.
TREATMENT
 Fluid volume expansion - 0.9% normal saline,
 Correction of hyperglycemia, and presence of ketones.
3. HYPEROSMOLAR HYPERGLYCEMIC STATE
 Associate with type 2 diabetes, mortality rate 15% - in middle aged
and elderly.
 No ketones – no acidosis Progressive hyperglycemia – osmotic
diuresis.

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 Hyperglycemia – osmotic diuresis, hyper-osmolarity – blood viscosity

– thromboembolism.
 Hyperglycemia ~ 55mmol/L, mild confusion and coma, may be
seizures.
 Increased fluid loss ~ 10 L – circulatory collapse may occur.
TREATMENT
 Fluid replacement – 0.9% or 0.45% saline
 IV insulin – not aggressive
 Prophylaxis of thromboembolism
 Incidence of macro-vascular complications at diagnosis in type 2
diabetes.

MANAGEMENT OF DIABETES
 The major components in the treatment of diabetes are:
­ Diet and Exercise
­ Oral hypoglycemic therapy
­ Insulin Therapy
1. DIET AND EXERCISE
DIET
 Diet is a basic part of management in every case. Treatment cannot be
effective unless adequate attention is given to ensuring appropriate
nutrition.
 Dietary treatment should aim at:
­ Ensuring weight control
­ Providing nutritional requirements
­ Allowing good glycemic control with blood glucose levels as close
to normal as possible
­ Correcting any associated blood lipid abnormalities.
 The following principles are recommended as dietary guidelines for
people with diabetes:
­ Dietary fat should provide 25-35% of total intake of calories but
saturated fat intake should not exceed 10% of total energy.
Cholesterol consumption should be restricted and limited to 300
mg or less daily.
­ Protein intake can range between 10-15% total energy (0.8-1 g/kg
of desirable body weight). Requirements increase for children and

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during pregnancy. Protein should be derived from both animal

and vegetable sources.
­ Carbohydrates provide 50-60% of total caloric content of the diet.
Carbohydrates should be complex and high in fiber.
­ Excessive salt intake is to be avoided. It should be particularly
restricted in people with hypertension and those with
nephropathy.
EXERCISE
 Physical activity promotes weight reduction and improves insulin
sensitivity, thus lowering blood glucose levels. Together with dietary
treatment, a program of regular physical activity and exercise should be
considered for each person. Such a program must be tailored to the
individual’s health status and fitness.
 People should, however, be educated about the potential risk of
hypoglycemia and how to avoid it.
2. ORAL ANTI-DIABETIC AGENTS
 There are currently four classes of oral anti diabetic agents:
­ Biguanides
­ Insulin Secretagogues – Sulphonylureas, Non-sulfonylureas
­ α-glucosidase inhibitors
­ Thiazolidinediones (TZDs)
2.1 ORAL AGENT MONOTHERAPY
 If glycemic control is not achieved (HbA1c > 6.5% and/or; FPG > 7.0
mmol/L or; RPG >11.0mmol/L) with lifestyle modification within 1 –3
months, oral antidiabetic agent should be initiated.
 In the presence of marked hyperglycemia in newly diagnosed
symptomatic type 2 diabetes (HbA1c > 8%, FPG > 11.1 mmol/L, or RPG >
14 mmol/L), oral anti-diabetic agents can be considered at the outset
together with lifestyle modification.
 As first line therapy:
­ Obese type 2 patients, consider use of metformin, acarbose or
TZD.
­ Non-obese type 2 patients, consider the use of metformin or
insulin secretagogues
­ Metformin is the drug of choice in overweight/obese patients.
TZDs and acarbose are acceptable alternatives in those who are
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intolerant to metformin.
­ If monotherapy fails, a combination of TZDs, acarbose and
metformin is recommended. If targets are still not achieved,
insulin secretagogues may be added.
I. SULFONYLUREAS
 Stimulating pancreatic secretion of insulin. All sulfonylureas are equally
effective in lowering blood glucose. On average, the A1C will fall by 1.5%
to 2% with FPG reductions of 60 to 70 mg/dL (3.3 to 3.9 mmol/L).
 The most common side effect is hypoglycemia, which is more
problematic with long half-life drugs.
 Individuals at high risk include the elderly, those with renal insufficiency
or advanced liver disease, and those who skip meals, exercise vigorously,
or lose a substantial amount of weight.
 Weight gain is common; less common adverse effects include skin rash,
hemolytic anemia, GI upset, and cholestasis.
 The recommended starting doses should be reduced in elderly patients
who may have compromised renal or hepatic function.
II. BIGUANIDES
 Metformin is the only biguanide available in the United States. It
enhances insulin sensitivity of both hepatic and peripheral (muscle)
tissues. Metformin consistently reduces A1C levels by 1.5% to 2%, FPG
levels by 60 to 80 mg/dL, and retains the ability to reduce FPG levels
when they are very high (>300 mg/dL).
 It reduces plasma triglycerides and low-density lipoprotein (LDL)
cholesterol by 8% to 15% and modestly increases high- density
lipoprotein (HDL) cholesterol (2%). It does not induce hypoglycemia
when used alone.
 Metformin should be included in the therapy for all type 2 DM patients
(if tolerated and not contraindicated) because it is the only oral
antihyperglycemic medication proven to reduce the risk of total
mortality and cardio- vascular death.
 The most common adverse effects are abdominal discomfort, stomach
upset, diarrhea, anorexia, and a metallic taste.
 These effects can be minimized by titrating the dose slowly and taking it
with food. Extended release metformin (Glucophage XR) may reduce
some of the GI side effects. Lactic acidosis occurs rarely and can be
minimized by avoiding its use in patients with renal insufficiency (serum

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creatinine 1.4 mg/dL or greater in women and 1.5 mg/dL or greater in

men), congestive heart failure, or conditions predisposing to hypoxemia
or inherent lactic acidosis.
 Metformin should be discontinued 2 to 3 days prior to IV radiographic
dye studies and withheld until normal renal function has been
documented poststudy.
 Metformin immediate-release is usually initiated at 500 mg twice daily
with the largest meals and increased by 500 mg weekly until glycemic
goals or 2,000 mg/day is achieved. Metformin 850 mg can be dosed
once daily and then increased every 1 to 2 weeks to a maximum of 850
mg three times daily (2,550 mg/day).
 Metformin extended-release (Glucophage XR) can be initiated with 500
mg with the evening meal and increased by 500 mg weekly to a
maximum dose of 2,000 mg/day. Administration two to three times a
day may help minimize GI side effects and improve glycemic control. The
750-mg tablets can be titrated weekly to the maximum dose of 2,250
mg/day.
III. THIAZOLIDINEDIONES (GLITAZONES)
 These agents activate PPAR-γ. PPAR-γ agonists enhance insulin
sensitivity in muscle, liver, and fat tissues indirectly. Insulin must be
present in significant quantities for these actions to occur.
 When given for about 6 months, pioglitazone and rosiglitazone reduce
A1C values by about 1.5% and FPG levels by about 60 to 70 mg/dL at
maximal doses. Maximal glycemic-lowering effects may not be seen until
3 to 4 months of therapy. Monotherapy is often ineffective unless the
drugs are given early in the disease course when sufficient β-cell
function and hyperinsulinemia are present.
ROSIGLITAZONE VS PIOGLITAZONE ADVERSITY PROFILE
 Pioglitazone (Actos) is started at 15 mg once daily. The maximum dose is
45 mg/day. More evidence of vascular endothelial improvement with
Pioglitazone.
 Rosiglitazone (Avandia) is initiated with 2 to 4 mg once daily. The
maximum dose is 8 mg/day. A dose of 4 mg twice daily can reduce A1c
by 0.2% to 0.3% more than a dose of 8 mg taken once daily. A slightly
higher prevalence of volume overload incidents with Rosiglitazone.
IV. α-GLUCOSIDASE INHIBITORS

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 These agents prevent the breakdown of sucrose and complex

carbohydrates in the small intestine, thereby prolonging the absorption
of carbohydrates. The net effect is a reduction in the postprandial
glucose concentrations (40 to 50 mg/dL) while fasting glucose levels are
relatively unchanged (about 10% reduction). Efficacy on glycemic control
is modest, with average reductions in A1c of 0.3% to 1%. Good
candidates for these drugs are patients who are near target A1C levels
with near-normal FPG levels but high postprandial levels.
 The most common side effects are flatulence, bloating, abdominal
discomfort, and diarrhea, which can be minimized by slow dosage
titration. If hypoglycemia occurs when used in combination with a
hypoglycemic agent (sulfonylurea or insulin), oral or parenteral glucose
(dextrose) products or glucagon must be given because the drug will
inhibit the breakdown and absorption of more complex sugar molecules
(e.g., sucrose).
 Acarbose (Precose) and miglitol (Glyset) are dosed similarly. Therapy is
initiated with a very low dose (25 mg with one meal a day) and increased
very gradually (over several months) to a maximum of 50 mg three times
daily for patients weighing 60 kg or more, or 100 mg three times daily
for patients above 60 kg. The drugs should be taken with the first bite of
the meal so that the drug is present to inhibit enzyme activity.
V. DIPEPTIDYL PEPTIDASE-IV (DPP-IV) INHIBITORS
 Dipeptidyl peptidase-IV inhibitors prolong the half-life of an
endogenously produced glucagon-like peptide-1. These agents partially
reduce the inappropriately elevated glucagon postprandially and
stimulate glucose- dependent insulin secretion. The average reduction in
A1c is approximately 0.7% to 1% at a dose of 100 mg/day.
Sitagliptin (Januvia)
Overview
 1st approved member of a new class of OAHA - DPP-4 inhibitor
 Potent, highly selective, reversible, and competitive inhibitor of DPP-4
enzyme
 Approved by the FDA on October 17, 2006. EU approval March 2007
Mechanism of action

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 Acts through inhibition of dipeptidyl peptidase-4 (DPP-4), an enzyme

that acts to degrade and inactivate glucagon-like peptide-1 (GLP-1).
Clinical Pharmacology of Sitagliptin: Pharmacokinetics and Drug Interactions
 Pharmacokinetics
­ Tmax (median): 1 to 4 hours post dose.
­ Apparent t½ (mean): 12.4 hours
­ Metabolism: approximately 79% excreted unchanged
in urine
 Drug Interactions
­ Based on in vitro data, sitagliptin does not inhibit CYP isozymes
CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6 or induce CYP3A4.
Dosing
 Sitagliptin is usually dosed at 100 mg orally once daily. In patients with
renal impairment, the daily dose should be reduced to 50 mg (creatinine
clearance 30–50 mL/min) or 25 mg (creatinine clearance <30 mL/min).
INCRETINS
 Incretins are a group of metabolic hormones that stimulate a decrease in
blood glucose levels. Incretins are released after eating and augment the
secretion of insulin released from pancreatic beta cells of the islets of
Langerhans by a blood glucose-dependent mechanism.
 GIP: Glucose-dependent insulinotropic polypeptide. Small effect in Type
2 diabetes.
 GLP-1 (glucagon-like peptide 1) augmented in the presence of
hyperglycaemia. Action less at euglycemia and in normal subjects.
2.2 COMBINATION ORAL AGENTS
 Combination of oral agents is indicated in: Newly diagnosed
symptomatic patients with HbA1c >10. Patients who are not reaching
targets after 3 months on monotherapy.
2.3 COMBINATION ORAL AGENTS AND INSULIN
 If targets have not been reached after optimal dose of combination
therapy for 3 months, consider adding intermediate-acting/long-acting
insulin (BIDS).
 Combination of insulin+ oral anti-diabetic agents (BIDS = Bedtime Insulin
Daytime Sulfonylurea) has been shown to improve glycemic control in

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those not achieving target despite maximal combination oral anti-

diabetic agents.
 Combining insulin and the following oral anti-diabetic agents has been
shown to be effective in people with type 2 diabetes:
­ Biguanide (metformin)
­ Insulin secretagogues (sulfonylureas)
­ Insulin sensitizers (TZDs)(the combination of a TZD plus insulin is
not an approved indication)
­ α-glucosidase inhibitor (acarbose)
GENERAL GUIDELINES FOR USE OF ORAL ANTI-DIABETIC AGENT IN DIABETES
 In elderly non-obese patients, short acting insulin secretagogues can be
started but long acting Sulphonylureas are to be avoided. Renal function
should be monitored.
 Oral anti-diabetic agents are not recommended for diabetes in
pregnancy.
 Oral anti-diabetic agents are usually not the first line therapy in diabetes
diagnosed during stress, such as infections. Insulin therapy is
recommended for both the above.
 Targets for control are applicable for all age groups. However, in patients
with comorbidities, targets are individualized.
 When indicated, start with a minimal dose of oral anti-diabetic agent,
while reemphasizing diet and physical activity. An appropriate duration
of time (2-16 weeks depending on agents used) between increments
should be given to allow achievement of steady state blood glucose
control.
3. INSULIN THERAPY
SHORT-TERM USE
 Acute illness, surgery, stress and emergencies
 Pregnancy
 Breast-feeding
 Insulin may be used as initial therapy in type 2 diabetes in marked
hyperglycemia.
 Severe metabolic decompensation (diabetic ketoacidosis, hyperosmolar
non-ketotic coma, lactic acidosis, severe hypertriglyceridemia)
LONG-TERM USE

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 If targets have not been reached after optimal dose of combination

therapy or BIDS (Bedtime Insulin Daytime Sulfonylurea), consider change
to multi-dose insulin therapy. When initiating this, insulin secretagogues
should be stopped and insulin sensitizers e.g. Metformin or TZDs, can be
continued.
INSULIN REGIMENS
 The majority of patients will require more than one daily injection if
good glycemic control is to be achieved. However, a once-daily injection
of an intermediate acting preparation may be effectively used in some
patients.
 Twice-daily mixtures of short- and intermediate-acting insulin is a
commonly used regimen.
 In some cases, a mixture of short- and intermediate-acting insulin may
be given in the morning. Further doses of short-acting insulin are given
before lunch and the evening meal and an evening dose of intermediate-
acting insulin is given at bedtime.
 Other regimens based on the same principles may be used.
 A regimen of multiple injections of short-acting insulin before the main
meals, with an appropriate dose of an intermediate-acting insulin given
at bedtime, may be used, particularly when strict glycemic control is
mandatory.
 Regular insulin - slow onset of action when given subcutaneously,
injection 30 minutes prior to meals to achieve optimal postprandial
glucose control and to prevent delayed post meal hypoglycemia.
 Lispro, aspart, and glulisine insulins are analogs that are more rapidly
absorbed, peak faster, and have shorter durations of action – permitting
more convenient dosing within 10 minutes of meals (rather than 30
minutes prior), produces better efficacy in lowering postprandial blood
glucose than regular insulin in type 1 DM, and minimizes delayed post
meal hypoglycemia.
 Neutral protamine Hagedorn (NPH) is intermediate-acting. Variation in
absorption, inconsistent preparation by the patient, and inherent
pharmacokinetic differences a labile glucose response, nocturnal
hypoglycemia, and fasting hyperglycemia.
 Glargine and detemir are long-acting “peak less” human insulin analogs
- less nocturnal hypoglycemia than NPH insulin when given at bedtime.

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­ In type 1 DM, the average daily requirement is 0.5 to 0.6 units/kg.

Higher doses (0.5 to 1 unit/kg) are warranted during acute illness
or ketosis.
­ In type 2 DM, a dosage range of 0.7 to 2.5 units/kg is often
required for patients with significant insulin resistance.
 Hypoglycemia and weight gain are the most common adverse effects of
insulin. Treatment of hypoglycemia is as follows:
­ Glucose (10 to 15 g) given orally is the recommended treatment in
conscious patients.
­ Dextrose IV may be required in individuals who have lost
consciousness.
­ Glucagon, 1 g intramuscular, is the treatment of choice in
unconscious patients when IV access cannot be established.
OTHERS
EXENATIDE
 Exenatide is a synthetic analog of exendin-4, a 39-amino acid peptide
isolated from the saliva of the Gila monster that enhances glucose-
dependent insulin secretion and reduces hepatic glucose production.
 It also decreases appetite and slows gastric emptying, which may reduce
caloric intake and cause weight loss. It significantly decreases
postprandial glucose excursions but has only a modest effect on FPG
values.
 The average A1c reduction is approximately 0.9%. The initial dose is 5
mcg subcutaneously twice daily, titrated to 10 mcg twice daily in 1
month. It should be injected 0 to 60 minutes before the morning and
evening meals.
 Exenatide should be used as adjunctive therapy in patients who have not
achieved adequate glycemic control despite treatment with metformin,
a sulfonylurea, and/or a thiazolidinedione.
PRAMLINTIDE
 Pramlintide is a synthetic analog of amylin, a neurohormone co-secreted
from β-cells with insulin. Pramlintide suppresses inappropriately high
postprandial glucagon secretion, reduces food intake (which can cause
weight loss), and slows gastric emptying.
 The average A1C reduction is approximately 0.6%, Pramlintide decreases
prandial glucose excursions but has little effect on FPG concentrations.
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Its main advantage is in type 1 DM, where it helps stabilize wide,

postprandial glycemic swings. It does not cause hypoglycemia when
used alone, but it is indicated only in patients receiving insulin, so
hypoglycemia can occur. If a prandial insulin dose is used, it should be
reduced by 30% to 50% when pramlintide is started to minimize severe
hypoglycemic reactions.
 In type 2 DM, the starting dose is 60 mcg subcutaneously prior to major
meals; the dose is titrated up to 120 mcg per dose as tolerated and as
warranted based on postprandial plasma glucose levels.
 In type 1 DM, dosing starts at 15 mcg prior to each meal, titrated up to a
maximum of 60 mcg prior to each meal if tolerated and warranted.

INSULIN DOSE CALCULATIONS

 Approximately 40-50% of the total daily insulin dose is to replace insulin
overnight, when you are fasting and between meals. This is called
background or basal insulin replacement.
 The basal or background insulin dose usually is constant from day to day.
 The other 50-60% of the total daily insulin dose is for carbohydrate
coverage (food) and high blood sugar correction. This is called the bolus
insulin replacement.
 The bolus dose for food coverage is prescribed as an insulin to
carbohydrate ratio. The insulin to carbohydrate ratio represents how
many grams of carbohydrate are covered or disposed of by 1 unit of
insulin.
­ Generally, one unit of rapid-acting insulin will dispose of 12-15
grams of carbohydrate. This range can vary from 4-30 grams or
more of carbohydrate depending on an individual’s sensitivity to
insulin. Insulin sensitivity can vary according to the time of day,
from person to person, and is affected by physical activity and
stress.
 The bolus dose for high blood sugar correction is defined as how much
one unit of rapid-acting insulin will drop the blood sugar.
­ Generally, to correct a high blood sugar, one unit of insulin is
needed to drop the blood glucose by 50 mg/dl. This drop in blood
sugar can range from 15-100 mg/dl or more, depending on
individual insulin sensitivities, and other circumstances.

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INSULIN DOSE BASED ON CHO COVERAGE

 CHO insulin dose = Total grams of CHO in the meal ÷ grams of CHO
disposed by 1 unit of insulin (the grams of CHO disposed of by 1 unit of
insulin is the bottom number or denominator of the Insulin : CHO ratio).
 For Example #1, assume:
­ You are going to eat 60 grams of carbohydrate for lunch
­ Your Insulin: CHO ratio is 1:10
 To get the CHO insulin dose, plug the numbers into the formula:
­ CHO insulin dose = Total grams of CHO in the meal (60 g) ÷ grams
of CHO disposed by 1 unit of insulin (10) = 6 units
­ You will need 6 units of rapid acting insulin to cover the
carbohydrate.
HIGH BLOOD GLUCOSE DOSE CORRECTION
 High blood sugar correction dose = Difference between actual blood
sugar and target blood sugar ÷ correction factor.
 For Example #2, assume:
­ 1 unit will drop your blood sugar 50 points (mg/dl) and the high
blood sugar correction factor is 50.
­ Pre-meal blood sugar target is 120 mg/dl.
­ Your actual blood sugar before lunch is 220 mg/dl.
­ Now, calculate the difference between your actual blood sugar
and target blood sugar:
 220 minus 120 mg/dl = 100 mg/dl
 To get the high blood sugar correction insulin dose, plug the numbers
into this formula:
­ Correction dose = Difference between actual and target blood
glucose (100mg/dl) ÷ correction factor (50) = 2 units of rapid
acting insulin
­ So, you will need an additional 2 units of rapid acting insulin to
“correct” the blood sugar down to a target of 120 mg/dl.
MEALTIME DOSE
 Finally, to get the total mealtime insulin dose, add the CHO insulin dose
together with the high blood sugar correction insulin dose:
­ CHO Insulin Dose + High Blood Sugar Correction Dose = Total Meal
Insulin Dose
 For Example #3, assume:

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­ The carbohydrate coverage dose is 6 units of rapid acting insulin.

The high blood sugar correction dose is 2 units of rapid acting
insulin.
­ Now, add the two doses together to calculate your total meal
dose.
­ Carbohydrate coverage dose (6 units) + high sugar correction dose
(2 units) = 8 units total meal dose!
­ The total lunch insulin dose is 8 units of rapid acting insulin.
TOTAL DAILY INSULIN REQUIREMENT
 The general calculation for the body’s daily insulin requirement is:
­ Total Daily Insulin Requirement (in units of insulin) = Weight in
Pounds ÷ 4.
 Alternatively, if you measure your body weight in kilograms:
­ Total Daily Insulin Requirement (in units of insulin) = 0.55 X Total
Weight in Kilograms.
 Example 1:
­ If you are measuring your body weight in pounds:
­ Assume you weigh 160 lbs.
­ In this example: TOTAL DAILY INSULIN DOSE = 160 lb ÷ 4 = 40 units
of insulin/day.
 Example 2:
­ If you are measuring your body weight in kilograms:
­ Assume your weight is 70Kg
­ In this example: TOTAL DAILY INSULIN DOSE = 0.55 x 70 Kg = 38.5
units of insulin/day.
 If your body is very resistant to insulin, you may require a higher dose. If
your body is sensitive to insulin, you may require a lower insulin dose.
HBA1C CONVERSION INTO MG/DL AND MMOL/L
 Avg. Plasma Blood Glucose (mg/dl) = (HbA1c * 35.6) - 77.3
 Avg. Plasma Blood Glucose (mmol/L) = (HbA1c * 1.98) - 4.29
 Avg. whole blood glucose = Plasma Blood Glucose / 1.12

COMMON THERAPEUTIC PROBLEMS IN DIABETES

 Achieving normoglycemia or HbA1c targets
 Achieving an acceptable balance between improving glycemic control
and minimizing episodes of hypoglycemia

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 Achieving adequate control in type 2 diabetes with diet alone, especially

in patients who are overweight
 Drug-related weight gain, notably with insulin and sulfonylureas
 Achieving blood pressure targets in patients with co-existing
hypertension
 Ensuring adherence as drug regimens become complex, requiring
multiple drug therapies
 Making insulin therapy acceptable to patients with type 2 diabetes,
inadequately controlled with oral therapies.

SELF-CARE
 Patients should be educated to practice self-care. This allows the patient
to assume responsibility and control of his / her own diabetes
management.
 Self-care should include:
­ Blood glucose monitoring
­ Body weight monitoring
­ Foot-care
­ Personal hygiene
­ Healthy lifestyle/diet or physical activity
­ Identify targets for control
­ Stop smoking

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DIABETES MANAGEMENT ALGORITHM

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Chapter 10.7.2 – Thyroid Disorders

THYROID DISORDERS

“Thyroid disorders involve thyroid hormone production or secretion and result

in alterations in metabolic stability.”

THYROID HORMONE PHYSIOLOGY

 Thyroid hormones: thyroxine (T4) and triiodothyronine (T3) are formed
on thyroglobulin, a large glycoprotein synthesized within the thyroid cell.
Inorganic iodide enters the thyroid follicular cell and is oxidized by
thyroid peroxidase and covalently bound (organified) to tyrosine
residues of thyroglobulin.
 Iodinated tyrosine residues monoiodotyrosine (MIT) and diiodotyrosine
(DIT) combine (couple) to form iodothyronines in reactions catalyzed by
thyroid peroxidase. Thus, two molecules of DIT combine to form T4, and
MIT and DIT join to form T3.
 Proteolysis within thyroid cells releases thyroid hormone into the
bloodstream. T4 and T3 are transported by thyroid-binding globulin
(TBG), transthyretin, and albumin. Only the unbound (free) thyroid
hormone can diffuse into cells, elicit biologic effects, and regulate
thyroid-stimulating hormone (TSH) secretion from the pituitary.
 T4 is secreted solely from the thyroid, but less than 20% of T3 is
produced there; most T3 is formed from breakdown of T4 catalyzed by
the enzyme 5′- monodeiodinase in peripheral tissues.
 Thyroid hormone production is regulated by TSH secreted by the
anterior pituitary, which in turn is under negative feedback control by
the circulating level of free thyroid hormone and the positive influence
of hypothalamic thyrotropin-releasing hormone (TRH).
 Thyroid hormone production is also regulated by extrathyroidal
deiodination of T4 to T3, which can be affected by nutrition, nonthyroidal
hormones, drugs, and illness.

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HYPERTHYROIDISM
 A hyper metabolic biochemical state. It is a multi-system disease with
elevated levels of T4 or T3 or both.
PATHOPHYSIOLOGY
1. Graves Disease – Diffuse Toxic Goiter
2. Plummer’s Disease – Toxic MNG
3. Toxic phase of Sub Acute Thyroiditis - SAT
4. Toxic Single Adenoma – TSA
5. Pituitary Tumors – excess TSH
6. Molar pregnancy and Choriocarcinoma (↑↑ βHCG)
7. Metastatic thyroid cancers (functioning)
8. Struma Ovaria (Dermoid and Ovarian tumors)
9. Thyrotoxicosis Factitia ; INF, Amiodarone, SSRIs
GRAVES DISEASE
 Grave disease is organ specific auto-immune disease, the most common
cause of thyrotoxicosis (50-60%).
 The most important autoantibodies are:
­ Thyroid Stimulating Immunoglobulin (TSI) or TSA.
 TSI acts as proxy to TSH and stimulates T 4 and T3.
­ Anti thyro peroxidase (anti-TPO) antibodies
­ Anti thyro globulin (anti-TG), Anti Microsomal and other.
TOXIC MULTINODULAR GOITER (TMG)
 TMG is the next most common hyperthyroidism - 20%
 More common in elderly individuals – long standing goiter
 Lumpy bumpy thyroid gland
 Milder manifestations (apathetic hyperthyroidism)
 Mild elevation of T4 and T3
 Progresses slowly over time
 Clinically multiple firm nodules (called Plummer’s disease)
 Scintigraphy shows - hot and normal areas
SUB ACUTE THYROIDITIS (SAT)
 SAT is the next most common hyperthyroidism – 15%
 T4 and T3 are extremely elevated in this condition
 Immune destruction of thyroid due to viral infection

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 Destructive release of preformed thyroid hormone

 Thyroid gland is painful and tender on palpation
 Nuclear Scintigraphy scan - no RIU in the gland
 Treatment is NSAIDs and Corticosteroids.
TOXIC SINGLE ADENOMA (TSA)
 TSA is a single hyper functioning follicular thyroid adenoma
 Benign monoclonal tumor that usually is larger than 2.5 cm
 It is the cause in 5% of patients who are thyrotoxic
 Nuclear Scintigraphy scan shows only a single hot nodule
 TSH is suppressed by excess of thyroxines. So, the rest of the thyroid
gland is suppressed.
AGE AND SEX
AGE
Graves disease 20 to 40 years
Toxic MNG > 50 years
Toxic Single Adenoma 35 to 50 years
Sub-Acute Thyroiditis Any age
SEX (M : F)
Graves Disease 1: 5 to 1:10
Toxic MNG 1: 2 to 1: 4

RADIO-NUCLEOTIDE SCINTIGRAPHY

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CLINICAL PRESENTATION
 Symptoms include:
­ Anxiety, Bulging eyes, Chest pain
­ Difficulty sleeping and/or insomnia
­ Irregular menstrual periods, Irritability or nervousness
­ Muscle weakness, Rapid or irregular heartbeat, Restlessness
­ Sensitivity to heat, Shortness of breath and/or difficulty breathing
­ Unexplained weight loss (typically despite an increase in appetite)
­ More frequent stools and/or diarrhea, Vision problems or changes
­ Elevated blood pressure, Hand tremors, Increased sweating.
 Physical signs include:
­ Warm, smooth, moist skin, and unusually fine hair
­ Separation of the ends of the fingernails from the nail beds
(onycholysis)
­ Retraction of the eyelids and lagging of the upper lid behind the
globe upon downward gaze (lid lag)
­ Tachycardia at rest, widened pulse pressure, and systolic ejection
murmur, Occasional gynecomastia in men
­ Fine tremor of the protruded tongue and outstretched hands
­ Hyperactive deep tendon reflexes. Thyromegaly is usually present.
 Graves’ disease is manifested by hyperthyroidism, diffuse thyroid
enlargement, and extrathyroidal findings of exophthalmos, pretibial
myxedema, and thyroid acropachy. In severe disease, a thrill may be felt
and a systolic bruit may be heard over the gland.
 In subacute thyroiditis, patients have severe pain in the thyroid region,
which often extends to the ear.
 Painless thyroiditis has a triphasic course that mimics painful subacute
thyroiditis.
 Thyroid storm is a life-threatening medical emergency characterized by
decompensated thyrotoxicosis, high fever (often >39.4°C), tachycardia,
tachypnea, dehydration, delirium, coma, nausea, vomiting, and diarrhea.
DIAGNOSIS
 Typical clinical presentation
 Markedly suppressed TSH (<0.05 µIU/mL)
 Elevated FT4 and FT3 (Markedly in Graves)
 Thyroid antibodies – by Elisa – anti-TPO (thyro-peroxidase), TSI
 ECG to demonstrate cardiac manifestations

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 Ultrasonography
 Thyroid Scan (radio-nucleotide scintigraphy)
 Biopsy - find needle aspiration (FNA)
TREATMENT
1. Symptom relief medications 4. Thyroidectomy – Subtotal or
2. Anti-Thyroid Drugs – ATD Total
3. Radioactive Iodine treatment 5. NSAIDs and Corticosteroids –
– RAI Rx. for SAT
I. SYMPTOM RELIEF MEDICATIONS
 Rehydration is the first step
 β – blockers to decrease the sympathetic excess
­ Propranolol, Atenolol and Metoprolol
 Rate limiting CCBs if β`1 – blockers contraindicated
 Treatment of CHF, Arrhythmias
 Calcium supplementation
 SSKI or Lugol solution for ↓ vascularity of the gland.
II. ANTI THYROID DRUGS (ATD)

Imp. Considerations Methimazole Propylthiouracil

Efficacy Very potent Potent
Duration of action Long acting BID/OD Short acting QID/TID
In pregnancy Contraindicated Safely can be given
Mechanism of action Iodination, Coupling Iodination, Coupling
Conversion of T4 to T3 No action Inhibits conversion
Adverse reactions Rashes, Neutropenia Rashes, ↑ Neutropenia
Dosage 20 to 40 mg/ OD PO 100 to 150mg qid PO

III. RADIOACTIVE IODINE (RAI RX.)

 In women who are not pregnant, In cases of Toxic MNG and TSA
 Graves disease not remitting with ATD.
 RAI Rx is the best treatment of hyperthyroidism in adults.
 The effect is less rapid than ATD or Thyroidectomy. It is effective, safe,
and does not require hospitalization.
 Given orally as a single dose in a capsule or liquid form. Very few adverse
effects as no other tissue absorbs RAI.
 I123 is used for Nuclear Scintigraphy (Dx.), I131 is given for RAI Rx. (6 to 8
milli Curies).

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 Goal is to make the patient hypothyroid. No effects such as Thyroid Ca

or other malignancies. Never given for children and pregnant/ lactating
women. Not recommended with patients of severe Ophthalmopathy.
IV. SURGICAL TREATMENT
 Subtotal Thyroidectomy, Total Thyroidectomy
 Hemi Thyroidectomy with contra-lateral subtotal
 ATD and RAI Rx are very efficacious and easy – so Surgical treatment is
reserved for MNG with:
­ Severe hyperthyroidism in children
­ Pregnant women who cannot tolerate ATD
­ Large goiters with severe Ophthalmopathy
­ Large MNGs with pressure symptoms
­ Who require quick normalization of thyroid function.
DIETARY ADVICE
 Avoid Iodized salt, Sea foods
­ Excess amounts of iodide in some expectorants, x-ray contrast
dyes, Seaweed tablets, and health food supplements
 These should be avoided because the iodide interferes with or
complicates the management of both ATD and RAI Rx.
ALGORITHM FOR HYPERTHYROIDISM

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HYPOTHYROIDISM
 Hypothyroidism is an underactive thyroid gland. Hypothyroidism means
that the thyroid gland cannot make enough thyroid hormone to keep
the body running normally.
 People are hypothyroid if they have too little thyroid hormone in the
blood.
CLASSIFICATION OF HYPOTHYROIDISM
I. PRIMARY HYPOTHYROIDISM
 Primary hypothyroidism (90%) is characterized by a high serum
thyrotropin (TSH) concentration and a low serum free thyroxine (T4)
concentration.
­ Iodine deficiency – most common cause
­ Hashimoto’s thyroiditis – where iodine is sufficient
­ Diagnosis based on measurement of TSH and fT4.
II. SUBCLINICAL HYPOTHYROIDISM
 Subclinical hypothyroidism is defined biochemically as a normal free T 4
concentration in the presence of an elevated TSH concentration. Other
terms for this condition are mild hypothyroidism, early thyroid failure,
preclinical hypothyroidism, and decreased thyroid reserve.
III. SECONDARY (CENTRAL) HYPOTHYROIDISM
 Secondary (central) hypothyroidism is characterized by a low serum T 4
concentration and a serum TSH concentration that is not appropriately
elevated.
IV. TRANSIENT OR TEMPORARY HYPOTHYROIDISM
 Transient or temporary hypothyroidism can be observed as a phase of
subacute thyroiditis.
V. CONSUMPTIVE HYPOTHYROIDISM
 Consumptive hypothyroidism, identified in an increasing number of
clinical settings, is the result of accelerated inactivation of thyroid
hormone by the type 3 iodothyronine deiodinase (D3).
PATHOPHYSIOLOGY
 The vast majority of patients have primary hypothyroidism due to
thyroid gland failure from chronic autoimmune thyroiditis.
 Defects in suppressor T lymphocyte function lead to survival of a
randomly mutating clone of helper T lymphocytes directed against

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antigens on the thyroid membrane. The resulting interaction stimulates

β lymphocytes to produce thyroid antibodies.
CLINICAL PRESENTATION
 Symptoms of hypothyroidism include:
­ Dry skin, cold intolerance, weight gain, constipation, weakness,
lethargy, fatigue, muscle cramps, myalgia, stiffness, and loss of
ambition or energy. In children, thyroid hormone deficiency may
manifest as growth or intellectual retardation.
 Physical signs include:
­ Coarse skin and hair, cold or dry skin, periorbital puffiness,
bradycardia, and slowed or hoarse speech. Reversible neurologic
syndromes such as carpal tunnel syndrome, polyneuropathy, and
cerebellar dysfunction may also occur.
 Most patients with secondary hypothyroidism due to inadequate TSH
production have clinical signs of generalized pituitary insufficiency, such
as abnormal periods and decreased libido, or evidence of a pituitary
adenoma, such as visual field defects, galactorrhea, or acromegaloid
features.
 Myxedema coma is a rare consequence of decompensated
hypothyroidism manifested by hypothermia, advanced stages of
hypothyroid symptoms, and altered sensorium ranging from delirium to
coma.
DIAGNOSIS
 A rise in TSH level is the first evidence of primary hypothyroidism. Many
patients have a free T4 level within the normal range (compensated
hypothyroidism) and few, if any, symptoms of hypothyroidism. As the
disease progresses, the free T4 drops below normal.
 The T3 concentration is often maintained in the normal range despite
low T4. Antithyroid peroxidase antibodies and antithyroglobulin
antibodies are usually elevated.
TREATMENT
I. LEVOTHYROXINE
 Levothyroxine (L-thyroxine, T4) is the drug of choice for thyroid
hormone replacement and suppressive therapy because it is
chemically stable, relatively inexpensive, active when given orally,
free of antigenicity, and has uniform potency.

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 Because T3 (and not T4) is the biologically active form, levothyroxine

administration results in a pool of thyroid hormone that is readily and
consistently converted to T3.
 In patients with long-standing disease and older individuals without
known cardiac disease, start therapy with levothyroxine 50 mcg daily
and increase after 1 month.
 The recommended initial dose for older patients with known cardiac
disease is 25 mcg/day titrated upward in increments of 25 mcg at
monthly intervals to prevent stress on the cardiovascular system.
II. THYROID USP
 Thyroid USP (or desiccated thyroid) is usually derived from pig
thyroid gland. It may be antigenic in allergic or sensitive patients.
III. LIOTHYRONINE
 Liothyronine (synthetic T3) has uniform potency but has a higher
incidence of cardiac adverse effects, higher cost, and difficulty in
monitoring with conventional laboratory tests.
IV. LIOTRIX
 Liotrix (synthetic T4:T3 in a 4:1 ratio) is chemically stable, pure, and
has a predictable potency but is expensive.

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Chapter 10.7.3 Pituitary Gland Non-Malignant Disorders

PITUITARY GLAND NON-MALIGNANT

DISORDERS

INTRODUCTION
 The pituitary gland is located in the brain and is an endocrine gland. This
means that it produces chemicals called hormones. Hormones are
chemical messengers, help different organs in the body communicate
with each other.
 The pituitary gland is one part of a messenger system. The pituitary
gland helps to control body's functions by releasing hormones into
bloodstream. These hormones are transported in your blood to their
target. Here they usually cause the release of a second hormone. The
target can either be specialized endocrine glands or other types of body
tissue such as groups of cells.

ANATOMY
 About the size of a pea, the pituitary gland is found
at the base of the brain, behind the bridge of nose.
The pituitary gland is very close to another part of
the brain, called the hypothalamus.
 The pituitary gland has two main parts:
­ The part of the pituitary gland at the front,
called the anterior pituitary.
­ The part of the pituitary gland at the back,
called the posterior pituitary.
 These two parts release different hormones which are aimed at different
parts of the body.
 There is also a section between the two main parts, called the
intermediate part, which releases a single hormone. The final part of the
pituitary gland is the stalk, which connects the posterior pituitary to the
hypothalamus.

FUNCTION OF PITUITARY GLAND

 Pituitary gland releases hormones which control so many different
processes in the body. It senses the body's needs and sends signals to
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different organs and glands throughout the body to regulate their

function and maintain an appropriate environment.
PITUITARY HORMONES
THE ANTERIOR PITUITARY HORMONES
Hormone released Main target Function
Adrenocorticotrophic Stimulates the adrenal glands to produce
Adrenal glands
hormone (ACTH) cortisol.
Stimulates the ovaries to produce an egg
Ovaries -women (ovum) for fertilization. Also causes an
Follicle-stimulating
Testicles (testes) increase in the hormone estrogen.
hormone (FSH)
– men Stimulates the testicles to produce
sperm.

Many different In adults and children, it helps to control

Growth hormone (GH)
cells of the body the amount of muscle and fat in the body

Triggers ovulation - the release of an egg

Ovaries - women
Luteinizing hormone (ovum) ready for fertilization.
(LH) Stimulates cells in the testes to produce
Testicles – men
testosterone.

Together with other hormones, prolactin

Prolactin Breasts
stimulates the breasts to produce milk.

TSH stimulates the thyroid gland to

Thyroid-stimulating
Thyroid gland produce its own hormones,
hormone (TSH)
triiodothyronine (T3) and thyroxine (T4).
THE POSTERIOR PITUITARY HORMONES
Hormone released Main target Function
Antidiuretic hormone Kidneys Decreases urine production. (It causes
(ADH) more water filtered by the kidneys to be
returned to the blood. This reduces the
amount of urine.)
ADH also causes a rise in blood pressure

Oxytocin Breasts and Stimulates contraction of the womb

womb (uterus) during childbirth. Helps breasts to
release milk.

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PATHOPHYSIOLOGY
 There are mainly 2 reasons for disorders of pituitary glands:
­ Hyperactivity
­ Hypoactivity
DISORDERS OF PITUITARY GLANDS
PARTS INVOLVED HYPER-ACTIVITY HYPO-ACTIVITY
Anterior Pituitary 1. Gigantism 1. Dwarfism
2. Acromegaly 2. Acromicria
3. Acromegalic gigantism 3. Simmond’s disease
4. Cushing’s disease 4. Addison’s disease
5. Prolactinoma
Posterior Pituitary Syndrome of inappropriate
hypersecretion of ADH (SIADH) Diabetes insipidus

Anterior and Posterior _______

Dystrophia adiposogenitalis
Pituitary

ANTERIOR PITUITARY DISORDERS

DISORDERS DUE TO HYPER-ACTIVITY
1. GIGANTISM
INTRODUCTION
 Gigantism is a rare condition that causes abnormal growth in children. It
occurs when children pituitary gland makes too much growth hormone.
 A pituitary gland benign tumor is almost always the cause of gigantism.
 Certain rare tumors of the pancreas and lungs also can produce
hormones that stimulate the pituitary to produce excessive amounts of
growth hormone with similar consequences.
 Other rare causes: ↑ GHRH (problems in hypothalamus)
CLINICAL PRESENTATION
SIGNS
 Very large hands and feet
 Thick toes and fingers
 Prominent jaw and forehead coarse facial features.
SYMPTOMS
 Excessive sweating, severe or recurrent headaches

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 Weakness, insomnia and other sleep disorders

 Delayed puberty in both boys and girls
 Irregular menstrual periods in girls
 Deafness
 Vision problems
 Hypertension and heart failure
 Sleep apnea
DIAGNOSIS
 Blood tests:
­ Growth hormone
­ Insulin-like growth factor 1 (IGF-1)
­ Fasting blood glucose
­ HB A1c
­ Oral glucose tolerance test : Blood samples will be taken before
and after child drinks the beverage. In a normal body, growth
hormone levels will drop after eating or drinking glucose. If child
levels remain the same, it means their body is producing too much
growth hormone.
 CT or MRI scan
 X-ray of the skull
TREATMENT
NON-PHARMACOLOGICAL
 SURGERY
­ Removing the tumor is the preferred treatment for gigantism if it
is the underlying cause.
 RADIATION THERAPY
­ The "gamma knife" is a collection of highly focused radiation
beams. These beams do not harm the surrounding tissue, but they
are able to deliver a powerful dose of radiation at the point where
they combine and hit the tumor. This dose is enough to destroy
the tumor.
­ Gamma knife treatment takes years to be fully effective and to
return the levels of growth hormone to normal.

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PHARMACOLOGICAL TREATMENT
 DRUG THERAPY
­ Octreotide is being a somatostatin analog, inhibits the release of
GH from the pituitary gland through a process normally involved
in negative feedback. Octreotide is used to prevent the growth
hormone's release and stops growth hormone production. They
are usually given as an injection about once a month.
­ Bromocriptine is a semisynthetic ergot alkaloid derivative with
potent dopaminergic activity. Bromocriptine also inhibits prolactin
secretion and may be used to treat dysfunctions associated with
hyperprolactinemia. It also causes sustained suppression of
somatotropin (growth hormone) secretion in some patients with
acromegaly.
­ Daily shots of pegvisomant might be used as well. Pegvisomant is
a drug that blocks the effects of growth hormones. This lowers the
levels of IGF-1 in child body.
2. ACROMEGALY
INTRODUCTION
 Anterior pituitary disorder characterized by:
­ Enlargement, thickening and broadening of bones
­ Particularly extremities of the body
ETIOLOGY
 Hypersecretion of GH after fusion of epiphysis with shaft of bone
 Adenomatous tumor of anterior pituitary involving the acidophilic cells.
CLINICAL PRESENTATION
 Striking features are protrusion of:
­ Supraorbital ridges
­ Broadening of nose
­ Thickening of lips
­ Thickening and wrinkles formation on forehead
­ Lower jaw prognathism
 Kyphosis: enlargement of hands and feet with bowing spine
 Scalp is thickened and thrown into folds
 Overgrowth of body hair

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 Visceral organs are enlarged

 Thyroid, parathyroid and adrenal glands shows hyperactivity
 Hyperglycemia and glucosuria
 Hypertension, Headache
 Visual disturbance — Bitemporal hemianopia
TREATMENT
NON-PHARMACOLOGICAL
 Surgery
 Radiotherapy
PHARMACOLOGICAL
 Somatostatin analogues
 Dopamine analogues
 GH receptor antagonists
3. ACROMEGALIC GIGANTISM
 Rare disorder
 Due to hypersecretion of GH in children before fusion of epiphysis
with the shaft of bone results in Gigantism.
 If hypersecretion of GH is continued after the fusion of epiphysis, the
symptoms of acromegaly also appears.
4. CUSHING DISEASE
INTRODUCTION
 Rare disease caused by obesity.
ETIOLOGY
 Hypersecretion of glucocorticoids mainly cortisol.
 Either pituitary origin (Cushing’s disease) or adrenal origin (Cushing’s
syndrome)
CLINICAL PRESENTATION
 Myopathies
 Muscular weakness
 Fat accumulation
TREATMENT

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NON-PHARMACOLOGICAL
 Surgery
PHARMACOLOGICAL
 Steroidogenesis inhibitors
 Adrenolytic agents
 Neuromodulators of ACTH release
 Glucocorticoid receptor blocking agents
5. PROLACTINOMA
INTRODUCTION
 A prolactinoma is a non-cancerous growth (benign tumor) in the
pituitary gland that makes a hormone called prolactin.
ETIOLOGY
 A prolactinoma occurs when some of the cells in the pituitary gland
(the ones producing prolactin) multiply more than usual to form a
small growth (tumor) in the pituitary gland.
 The prolactinoma makes too much prolactin and this can cause
symptoms.
CLINICAL PRESENTATION
 Female: Oligomenorrhoea, infertility, hirsutism
 Male: Decrease libido, erectile dysfunction, infertility
DIAGNOSIS
 Prolactin serum concentration
­ Females: >20mcg/L
­ Males: >25mcg/L
 MRI Scan
TREATMENT
NON-PHARMACOLOGICAL
 Transsphenoidal surgical removal of tumor
 Radiation therapy
PHARMACOLOGICAL

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 Dopamine agonists
 Bromocriptine
 Cabergoline
DISORDERS DUE TO HYPO-ACTIVITY
1. DWARFISM
INTRODUCTION
 Dwarfism is a condition of short stature but mentally and sexually
normal.
TYPES OF DWARFISM
PROPORTIONATE DWARFISM
 When the head, trunk, and limbs are all proportionate to each other.
DISPROPORTIONATE DWARFISM
 This is the most common kind of dwarfism. It is characterized by
having body parts that are disproportionate to each other.
ETIOLOGY
 Achondroplasia
 Growth hormone deficiency
 Turner syndrome
 Hypothyroidism
 Intrauterine growth retardation
DIAGNOSIS
 Physical examination: Weight, height and body proportions.
 Hand x rays: A trident hand in which fingers are of nearly equal length
and deflected at the first interphalangeal joint, so as to give a forklike
shape consisting of separation of the first and second as well as the third
and fourth digits.
 Thyroid function (T4, TSH) to exclude primary hypothyroidism.
 Karyotyping: To rule out turner syndrome.
 Growth hormone levels.
 Insulin-like growth factor 1 (IGF-1)
 MRI
TREATMENT

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HORMONE THERAPY
 Treatment with growth hormone supplements (Somatropin)
­ Injections of synthetic human growth hormone may be helpful.
­ Injection of Synthetic GHRH (Sermorelin)
­ Girls with Turner's syndrome need estrogen therapy and other
hormones to help trigger puberty and appropriate female
development.
 Cortisol and thyroid hormone replacement.
 Treatment with gonadal sex steroids
PHYSICAL THERAPY AND ORTHOTICS
 Physical therapy and orthotics are non-invasive solutions to some
complications of dwarfism.
 Orthotics are custom-made devices that fit into your shoes to help
improve your foot health and function.
2. ACROMICRIA
INTRODUCTION
 Rare disease in adults characterized by the atrophy of the extremities
of the body.
ETIOLOGY
 Deficiency of GH in adults
 Secretion of GH decreases in the following conditions:
­ Deficiency of GH releasing hormone
­ Atrophy of acidophilic cells in the anterior pituitary.
CLINICAL PRESENTATION
 Atrophy and thinning of extremities (major symptoms)
 Hyposecretion of adrenocortical hormone
 Person becomes lethargic and obese.
TREATMENT
NON-PHARMACOLOGICAL
 Surgery
 Radiation

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PHARMACOLOGICAL
 Somatostatin analogue
 Dopamine agonists
 Growth hormone antagonists.
3. SIMMOND'S DISEASE
INTRODUCTION
 Rare pituitary disease, also called as pituitary cachexia.
 Occurs mostly in panhypopituitarism.
ETIOLOGY
 Damage of pituitary by Ischemia and Tumors
 Postpartum hemorrhage
 Pituitary necrosis (Sheehan's Syndrome).
CLINICAL PRESENTATION
 Developing senile decay
 Senile decay is due to deficiency of hormone from target glands of
anterior pituitary e.g. thyroid gland, adrenal cortex and the gonads.
 Loss of hair and loss of teeth
 The skin on face becomes dry and wrinkled. (most common).
TREATMENT
 The ideal treatment of Simmonds' disease would be replacement of the
anterior pituitary hormones by synthetic or natural products. As yet this
is not practicable.
 Recently, fairly pure adreno-corticotropic hormone and thyrotrophic
hormone preparations have been made available (Cortrophin and
Ambinon, Organon, Ltd.).
 Muscular strength and energy are increased and cold sensitivity
becomes less marked.
4. ADDISON’S DISEASE
INTRODUCTION
 Addison's disease, also called adrenal insufficiency, is an uncommon
disorder that occurs when your body does not produce enough of
certain hormones.

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 In Addison's disease, adrenal glands, located just above kidneys,

produce too little cortisol and, often, too little aldosterone.
EETIOLOGY
 Acquired immunodeficiency syndrome
 Metastatic neoplasia
 Hemochromatosis
CLINICAL PRESENTATION
 Weight loss
 Increase pigmentation
 Fever
DIAGNOSIS
 Insulin hypoglycemic test
 Metyrapone test
TREATMENT
 Parenteral hydrocortisone
 Correction of fluid and electrolyte abnormalities.

POSTERIOR PITUITARY DISORDERS

1. SYNDROME OF INAPPROPRIATE HYPERSECRETION OF ANTIDIURETIC
HORMONE (SIADH)
INTRODUCTION
 SIADH disease is characterized by loss of sodium through urine due to
hypersecretion of ADH.
ETIOLOGY
 Due to cerebral tumors, lung tumors and lung cancers because the
tumor cells secrete ADH.
 Normal secretion of ADH makes the plasma hypotonic.
 Hypotonic solution inhibits the ADH secretion and restoration of
plasma osmolarity takes place.
 But in SIADH, secretion of ADH from tumor is not inhibited by
hypotonic plasma.

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CLINICAL PRESENTATION
 Hypo-osmolality is associated primarily with a broad spectrum of
neurologic manifestations termed hyponatremic encephalopathy,
ranging from mild to severe.
­ Mild nonspecific symptoms (e.g., headache, nausea, lethargy, poor
concentration, depressed mood, impaired memory, muscle
cramps)
­ More significant disorders (e.g., disorientation, confusion,
obtundation, focal neurologic deficits, and seizures. Hallucination,
vomiting, limb weakness)
DIAGNOSIS
 Laboratory findings that are suggestive of SIADH include a low serum
sodium level (usually below 130mmol/L), dilutional hypokalemia, and
hypocalcemia. The urine is concentrated in comparison with the plasma
and urine sodium level is inappropriately increased compared coexisting
low serum sodium level
­ Normal ECF v (or slightly increased)- Euvolemic
­ ↓ serum Na/OSM (< 275 mM) - Hypo-osmolar (285-295)
­ Urine OSM > 100 mosm/kg, (100-900)
­ Urine Na > 40 mEq/L (40 to 220)
­ Low plasma uric acid (< 238 umol/L)
­ Low- BU/Creatinine
TREATMENT
 3% hypertonic saline (513 mEq/L)
 Loop diuretics with saline.
 Vasopressin-2 receptor antagonists (aquaretic, such as conivaptan or
tolvaptan)
 Water restriction.
2. DIABETES INSPIDUS
INTRODUCTION
 Posterior Pituitary disorder characterized by excess excretion of water
through urine.
 Central diabetes insipidus (DI): associated with brain tumors, head injury,
neurosurgery, or central nervous system (CNS) infections

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 Nephrogenic DI: caused by drug therapy (lithium) or kidney disease

ETIOLOGY
 Develops due to the deficiency of ADH which occurs in the following
conditions:
­ Lesion (injury) or degradation of supraoptic and paraventricular
nuclei of hypothalamus.
­ Inability of renal tubules to give response to ADH hormone.
CLINICAL PRESENTATION
 Polyuria
 Polydipsia
 Dehydration
DIAGNOSIS
 Diagnosis begins with a patient who has polyuria, polydipsia, serum
hyper-osmolality, and urine hypo-osmolality.
 In patient with apparent idiopathic DI, additional testing is needed.
 The dehydration test is used to determine if patient responds to
hyperosmotic stimulus with increasing ADH release.
 The patient with nephrogenic DI does not respond to presence of
vasopressin so urine remains high and is dilute in concentration.
TREATMENT
 Desmopressin is preferred agent for ADH replacement. It has a high
antidiuretic effect and decreased vasopressor effect. Has a quick onset
of action (within 1 hr) and long duration of action (6 to 24 hours) which
makes it ideal for treatment. Usually given in alert patients in form of
nasal spray. Can be administered on the buccal mucosa.
 Other agents available for treating patients with DI include
chlorpropamide and carbamazepine which will enhance the release of
ADH or augment its effect on renal tubules. These drugs are not quite
effective in the patient with central DI.
 Paradoxically, Thiazide Diuretics may reduce polyuria in nephrogenic
and central DI by reducing urine output by causing sodium depletion.
 They works most effectively in conjunction with dietary salt restriction.
 In severe DI, the patient requires large amounts of IV fluids
replacement. The IV fluid intake requirement usually is titrated to hourly

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urine output. Hypotonic saline solutions usually are used because these
solutions are hypotonic with patients hyperosmolar state.
 The use of aqueous vasopressin is recommended when a short acting
agent (duration of 4 to 6 hours) that allows considerable flexibility is
needed.
3. DISORDERS OF OXYTOCIN
INTRODUCTION
 Disorders of Oxytocin includes Autism, Anxiety, Schizophrenia And
Depression.
CLINICAL PRESENTATION
 Obstructive Symptoms:
­ Hesitancy
­ Weak stream
­ Urinary retention
­ Prolonged micturition
­ Straining to pass urine
­ Feeling of incomplete bladder emptying.
TREATMENT
WATCHFUL WAITING
 Regular follow ups
 In patients with mild symptoms
 Patients with moderate symptoms who are not bothered by their
symptoms.
PHARMACOLOGICAL TREATMENT
 Non-selective alpha 1 antagonists
­ Short acting: Prazosin, Alfuzosin
­ Long acting: Terazosin, Doxazosin
 Selective alpha 1A antagonists
­ Tamsulosin, Silodosin
 5- alpha reductase inhibitors
­ Finasteride, Dutasteride
 Miscellaneous PDE 5 inhibitor
­ Naferelin acetate, Leuprolide

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ANTERIOR AND POSTERIOR PITUITARY DISORDERS

DYSTROPHIA ADIPOSOGENITALIS
INTRODUCTION
 Characterized by obesity and hypogonadism affecting mainly adolescent
boys. Also known as Frohlich syndrome or hypothalamic eunuchism.
ETIOLOGY
 Hypoactivity of both anterior and posterior pituitary
 Tumor in pituitary gland and hypothalamic regions concerned with food
intake and gonadal development
 Injury or atrophy of pituitary gland
 Genetic inability of hypothalamus to secrete luteinizing hormone.
CLINICAL PRESENTATION
 Obesity (common feature)
 Sexual infantilism (failure to develop secondary sexual characters)
 Dwarfism occurs if disease starts in growing age
 Called as infantile or prepubertal type of Frohlich syndrome (in children)
and adult type of Frohlich's syndrome (in adults)
TREATMENT
 Surgery
 Pituitary extracts

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PROSTATE CANCER

“Prostate cancer is a malignant neoplasm that arises from the prostate gland.”

PATHOPHYSIOLOGY
 In prostate cancer, the cells of these prostate glands mutate into cancer
cells. Mutation is majorly in p53 gene, BCL2 and ERK5 or alteration in Akt
kinase signaling contribute toward the development of prostate cancer.
 The prostate glands require hormones, known as androgens, that are
involved in cell survival and apoptosis. Androgens include testosterone,
dehydroepiandrosterone and dihydrotestosterone.
 Initially, small clumps of cancer cells remain confined to prostate glands,
a condition known as carcinoma in situ or prostatic intraepithelial
neoplasia (PIN). Over time, these cancer cells begin to multiply and
spread to the surrounding prostate tissue forming a tumor.
 Eventually, the tumor may grow large enough to invade nearby organs
such as the nearby lymph nodes or the rectum, or metastasize to bone,
lymphatic system and bladder.

CLINICAL MANIFESTATION
EARLY STAGE
 Asymptomatic
 Cancer is in the peripheral zone

LOCALLY ADVANCED DISEASE

 Obstructive / irritative voiding
­ Retention of urine
­ Hesitancy
­ Intermittent urinary stream
­ Decreased force of stream
 May have growth into the urethra or bladder neck
 Pelvic pain

ADVANCED DISEASE (SPREAD TO THE REGIONAL PELVIC LYMPH NODES)

 Edema of the lower extremities
 Pelvic and perineal discomfort

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METASTATIC DISEASE
 Bone pain
 Spinal cord compression symptoms
 Hematuria- prostatic urethra/ trigone involvement
 Extra prostatic spread- often asymptomatic/ extensive dis.
 Constipation
 Intermittent diarrhea
 Abdomino-pelvic pain
 Renal impairment due to prolonged bladder outlet obstruction.

SIGNS AND SYMPTOMS

 Blood in urine or semen
 Trouble urinating
 Discomfort in pelvic area
 Painful sensation during urination
 Difficulty with passing urine
 Impotence

DIAGNOSIS
LABORATORY
 Complete blood cell count, blood biochemistry
 Serum PSA (total, free, percentage free) – prostate specific antigen
 Plasma acid phosphatases (prostatic/total)

DIAGNOSTIC TESTS
 Transrectal ultrasonography (for biopsy guidance)
 Biopsy/Needle biopsy of prostate (transrectal, transperineal)
 Chest radiograph (high risk for metastatic disease)
 Computed tomography of pelvis
 Radioisotope bone scan
 Magnetic resonance imaging
 PET CT Scan for metastasis

SCREENING FOR PROSTATE CANCER

DIGITAL RECTAL EXAM (DRE)
 During a DRE, doctor inserts a gloved, lubricated finger into rectum to
examine prostate, which is adjacent to the rectum. If doctor finds any
abnormalities in the texture, shape or size of the gland, you may need
further tests.

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PROSTATE-SPECIFIC ANTIGEN (PSA) TEST

 A blood sample is drawn from a vein in arm and analyzed for PSA, a
substance that is naturally produced by prostate gland. It is normal for a
small amount of PSA to be in bloodstream. However, if a higher than
normal level is found, it may indicate prostate infection, inflammation,
enlargement or cancer.
TRUS GUIDED BIOPSY
 Trans-rectal ultrasonography (TRUS)
­ To establish the diagnosis.
­ To report extent and grade of cancer in each core.
­ To document presence of PNI (perineural invasion) or ECE (extra
prostatic extension).
DETERMINING HOW FAR THE CANCER HAS SPREAD
 When a biopsy confirms the presence of cancer, the next step is to
determine the level of aggressiveness (grade) of the cancer cells
 The most common scale used to evaluate the grade of prostate cancer
cells is called:
­ Gleason scores
­ TNM staging
GLEASON SCORES
 Typical Gleason Scores range from 6-10. The higher the Gleason Score,
the more likely that the cancer will grow and spread quickly.
 It is recommended that the primary and secondary pattern as well as the
score be reported, e.g. Gleason score 3+4=7.
 If the tumor only has one pattern, Gleason score is obtained by doubling
that pattern, e.g. Gleason score 3+3=6.
 Scores of 6 or less describe cancer cells that look similar to normal cells
and suggest that the cancer is likely to grow slowly.
 A score of 7 suggests an intermediate risk for aggressive cancer.
 Scoring a 7 means that the primary score (largest section of the tumor)
scored a 3 or 4.
 Tumors with a primary score of 3 and a secondary score of 4 have a fairly
good outlook, whereas cancers with a primary Gleason Score of 4 and a
secondary score of 3, are more likely to grow and spread.

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 Scores of 8 or higher describe cancers that are likely to spread more

rapidly, these cancers are often referred to as poorly differentiated or
high grade.

GRADING
• Gleason X: The Gleason score cannot be determined.
• Gleason 6 or lower: The cells are well differentiated, meaning they look
similar to healthy cells.
• Gleason 7: The cells are moderately differentiated, meaning they look
somewhat similar to healthy cells.
• Gleason 8, 9, or 10: The cells are poorly differentiated or
undifferentiated, meaning they look very different from healthy cells.
• Gleason scores are often grouped into simplified Grade Groups:
­ Grade Group 1 = Gleason 6
­ Grade Group 2 = Gleason (3 + 4) = 7
­ Grade Group 3 = Gleason (4 + 3 ) = 7
­ Grade Group 4 = Gleason 8
­ Grade Group 5 = Gleason 9 or 10

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CANCER STAGE GROUPING

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MANAGEMENT
1. PROSTATECTOMY
 Removal of Prostate gland surgically.

2. RADIOTHERAPY
A. EXTERNAL BEAM RADIOTHERAPY
 External beam radiation therapy (RT) is one of the principle treatment
options for clinically localized prostate cancer.
 A dose of 75.6-79 Gy into the prostate (with or without seminal
vesicles) is appropriate for patients with low-risk cancers.
 Intermediate-risk and high-risk patients should receive doses between
75 and 80 Gy.
 For higher doses (above 75 Gy), daily prostate localization using daily
image-guided radiation therapy (IGRT) is essential for target margin
reduction and treatment accuracy.
B. BRACHYTHERAPY
 Brachytherapy involves placing radioactive sources into the prostate
tissue.
 Most centers use permanent implants, where the sources are
implanted into the prostate and gradually lose their radioactivity.
 Prostate brachytherapy as monotherapy has become a popular
treatment option for early, clinically organ-confined prostate cancer
(cT1c-T2a, Gleason grade 2-6, PSA < 10 ng/mL).
C. PROTON THERAPY
 Proton beams can be used as an alternative radiation source.
 Theoretically, protons may reach deeply-located tumors with less
damage to surrounding tissues.
D. PALLIATIVE RADIATION
 Palliative radiation is an effective means of palliating bone metastases
from prostate cancer.
 A short course of 800 cGy x 1 is as effective and less costly than 3000
cGy in 10 fractions.
 Most patients should be managed with a single fraction of 800 cGy for
non-vertebral metastases based on therapeutic guidelines from the
American College of Radiology
3. HORMONE THERAPY
 The goal is to reduce levels of hormones, called androgens, in the

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body, or to prevent them from reaching prostate cancer cells. There

are different types of drugs that lower testosterone levels.
A. LUTEINISING HORMONE (LH) BLOCKERS
 Luteinizing hormone blockers stop the pituitary gland making the
hormone. So, the testicles do not receive the message telling them to
make testosterone.
B. ANTI-ANDROGENS
 Medications known as anti-androgens prevent testosterone from
reaching your cancer cells. Examples include bicalutamide (Casodex),
nilutamide (Nilandron) and flutamide. The drug enzalutamide
(Xtandi) may be an option when other hormone therapies are no
longer effective.
4. CHEMOTHERAPY
 Chemotherapy is sometimes used if prostate cancer has spread
outside the prostate gland and hormone therapy is not working. For
prostate cancer, chemo drugs are typically used one at a time. Some
of the chemo drugs used to treat prostate cancer include:
­ Docetaxel ­ Vinblastine
­ Cabazitaxel ­ Paclitaxel
­ Doxorubicin ­ Carboplatin
 In most cases, the first chemo drug given is docetaxel, combined with
the steroid drug prednisone.
 If this drug does not work (or stops working), a newer drug called
Cabazitaxel is given specially in cases when cancer has stopped
responding to hormone therapy and chemotherapy.
5. BIOLOGICAL THERAPY
 Also known as immunotherapy.
 Biological therapy uses body's immune system to fight cancer cells.
 One type of biological therapy called SIPULEUCEL-T (Provenge) has
been developed to treat advanced, recurrent prostate cancer.
 This treatment takes some own immune cells, genetically engineers
them in a laboratory to fight prostate cancer, then injects the cells
back into body through a vein.
 SIPULEUCEL-T (Provenge) is also known as cancer vaccine for treating
prostate cancer.

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Chapter 10.8.2 – Breast Cancer

BREAST CANCER

“Breast cancer is a malignancy originating from breast tissue. It is found

mostly in women, but men can get breast cancer, too.”

GROSS ANATOMY

LYMPHATIC SYSTEM
 Consists of vessels and organs, plays two vital roles in our lives:
1. The vessels essentially maintain interstitial fluid levels by carrying
excess fluids as well as any plasma proteins, back into the CVS.
2. The organs, house critical immune cells such as lymphocytes which
carry out our body defense against infection.
 Most of the lymph vessels of the
breast drain into:
­ Lymph nodes under the
arm (auxiliary nodes).
­ Lymph nodes around the
collar bone (supraclavicular
and infraclavicular lymph
nodes)
­ Lymph nodes inside the
chest near the breastbone
(internal mammary lymph
nodes)

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BREAST TUMORS
 Benign – non-cancerous, non-invasive
­ Benign breast tumors are
abnormal growths, but they do not
spread outside of the breast and
they are not life threatening.
­ Most lumps are caused by the
combination of cysts and fibrosis
 Cysts are fluid-filled sacs.
 Fibrosis is the formation of
scar - like tissue.
­ These changes can cause breast
swelling and pain.
 Malignant – cancerous, invasive.

TYPES OF BREAST CANCER (PATHOPHYSIOLOGY)

1. DUCTAL CARCINOMA
­ Inner linings of milk duct.
a) Invasive Ductal carcinoma
b) Ductal Carcinoma In situ (DCIS)
­ Non – invasive, contained within the milk
ducts
­ May become invasive (pre cancer)
­ Most common breast cancer
­ Invasive ductal carcinoma - accounts for about
8 out of 10 invasive breast cancers
­ Lining of the ducts Grows /invades the breast
tissues
­ Spreads to lymph nodes and other organs.
2. LOBULAR CARCINOMA
­ The lobules – the milk producing glands.
a) Invasive Lobular carcinoma
b) Lobular Carcinoma In situ (LCIS)
­ Non – Invasive
­ Contained in the lobules and does not spread to the tissues of the
breast

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­ May become malignant

­ Invasive Lobular Carcinoma
­ About 1 in 10 Invasive breast cancers are
Invasive lobular cancer
­ Formed in the lobules, Grows through the
wall of the lobules and spreads.
3. INFLAMMATORY BREAST CANCER
­ Uncommon (1% to 3% of all breast cancers)
­ Invasive Brest Cancer
­ No lump or tumor
­ Mistaken for infection in its early stages
­ IBC makes the skin of the breast look red and
feel warm
­ It also may make the skin look thick and
pitted and may have an orange peel feel
­ The breast may get bigger, hard, tender, or
itchy.

CONTRIBUTING FACTORS
RISK FACTORS
MODIFIABLE
 Alcohol  Certain kinds of birth control
 Physical activity  Using hormone therapy after
 Tobacco smoking menopause
 Not breastfeeding  Not having children or having
 Being overweight or obese them later in life
NON-MODIFIABLE, UN-CONTROLLED
 Age  Reproductive history
 Gender  Personal history of breast
 Family history cancer
 Genetic risk factors  Having dense breasts
 Race ethnic background
FACTORS NOT LINKED TO BREAST CANCER
 Bras  Breast implants
 Antiperspirant  Induced abortion

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PREVENTION
 Diet  Alcohol consumption
 Bodyweight  Breast cancer screening
 Breastfeeding  Postmenopausal hormone
 Physical exercise therapy

SIGNS AND SYMPTOMS

 A lump in a breast
 A pain in the armpits or breast that does not seem to be related to the
woman's menstrual period
 Pitting or redness of the skin of the breast; like the skin of an orange
 A rash around (or on) one of the nipples
 A swelling (lump) in one of the armpits
 An area of thickened tissue in a breast
 One of the nipples has a discharge; sometimes it may contain blood
 The nipple changes in appearance; it may become sunken or inverted
 The size or the shape of the breast changes
 The nipple-skin or breast-skin may have started to peel, scale or flake.

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DIAGNOSIS
 Breast exam
 Mammograms
 Breast ultrasound Imaging tests Imaging
 Breast MRI scan
 Biopsy

CLINICAL BREAST EXAM

 Women in their 20s and 30s should have a clinical breast exam every 3
years.
 After age 40, women should have a breast exam every year.

BREAST SELF EXAM

 BSE is an option for women starting in their 20s.
 Any changes detected should be reported to a medical expert.
 BSE: Conducted standing or reclining and followed following steps
­ Step 1: Start by looking for differences between your breasts.
­ Step 2: Put your hands on your hips, pull your elbows forward.
­ Step 3: Use 3 fingers when examining your breasts.
­ Step 4: Examine the areas surrounding the breast.
­ Step 5: Perform the test at the same time each month.
BREAST IMAGING TECHNIQUES
MAMMOGRAMS
 An x-ray of the breast.
 It uses a very small amount of radiation.
 Types of Mammograms
­ Screening mammogram
­ Diagnostic mammogram

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 A technologist will position your breast for

the test
 The breast is pressed between 2 plates to
flatten and spread the tissue
 The pressure lasts only a few seconds while
the picture is taken
 The breast and plates are repositioned and
then another picture is taken
 The whole process takes about 20 minutes.
BREAST ULTRASOUND
 Breast Ultrasound uses sound waves to outline a part of the body.
 The sound wave echoes are picked up by a computer to create a picture
on a computer screen.
 Used to investigate areas of concerns found by a mammogram.

MAGNETIC RESONANCE IMAGING

 Use magnets and radio waves.
 Cross-sectional images of the body.
 MRI scans can take a long time.
 Used if view areas of concern found on a mammogram.
 Patients must lie inside a narrow tube, face down on a special platform.
 The platform has openings for each breast that allow the image to be
taken without pressing on the breast.
 Contrast material may be injected into a vein to help the MRI show more
details.
BIOPSY
 A biopsy is done when other tests show that you might have breast
cancer. It confirms if a mass is cancerous or not.
 Mass is removed and studied.

TYPES OF BIOPSIES
I. FINE NEEDLE ASPIRATION (FNA) BIOPSY
 Very fine needle is used.
 Extracts fluid from the lump.
 Guided by ultrasound.
 Simple but is not 100% accurate.
II. CORE NEEDLE BIOPSY

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 Needle is larger than in fine needle biopsy.

 Removes more tissues.
 Clearer results.
III. VACUUM-ASSISTED BIOPSY
 Done with systems such as ATEC® (Automated Tissue Excision and
Collection)
 Guided by MRI
 First the skin is numbed and a small cut (incision) is made.
 A hollow probe is put through the cut into the breast tissue.
 A piece of tissue is sucked out.
IV. SURGICAL (OPEN) BIOPSY
 Anesthesia is administered.
 Incision is made.
 Part or whole lump is extracted and studied.
V. LYMPH NODE BIOPSY
 Removal of fluids – needle biopsy
 Removal of lymph nodes – surgical biopsy

EXAMINATION
Malignant or Benign

­ Size ­ Is the lymph nodes
­ Type affected?
­ Invasive or Non – ­ Has it metastasized?
invasive
FACTORS CONSIDERED DURING EXAMINATION
I. BREAST CANCER GRADE
 If a biopsy sample is cancer, it is then graded.
 A lower grade number means a slower-growing cancer, while a higher
number means a faster growing cancer. The grade helps predict the
outcome.
II. HORMONE RECEPTOR STATUS
 Hormone receptors are proteins in cells that can attach to hormones.
 Estrogen and progesterone are hormones that fuel breast cancer
growth.
 Breast cancers are tested for hormone receptors, If the tumor has them,
it is often called ER positive, PR positive.
 About 2 out of 3 breast cancers have at least one of these.

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III. HER2/NEU STATUS

 About 1 out of 5 breast cancers have too much of a protein called
HER2/neu.
 Tumors with increased levels of HER2/neu are called HER2-positive.
These cancers tend to grow and spread faster than other breast cancers.

TESTS FOR DISTANT METASTASIS

 Chest x-ray: the lungs.
 Bone scan: the bones.
 CT scan (computed tomography): the chest and/or abdomen.
 MRI: brain and spinal cord.
 Ultrasound: other parts

STAGING OF BREAST CANCER

 The TNM staging system
 This system takes into account:
­ the tumor size and spread (T),
­ whether the cancer has spread to lymph nodes (N) and
­ whether it has spread to distant organs (M) for metastasis.
STAGING
 STAGE 0
­ Non – Invasive breast cancer. Has not spread to breast tissues.
 STAGE I
­ ≤ 2cm and has not spread to lymph nodes.
 STAGE ll
­ Stage llA: ≤ 2 cm and has spread to lymph nodes or 2-5 cm and
has spread to lymph nodes.
­ Stage llB: 2-5 cm and has spread to lymph nodes or > 5 cm and
has not spread to lymph nodes.
 STAGE lll
­ Stage lllA: ≤ 5cm and spread to lymph nodes forming clumps or >5
cm and spread to lymph nodes without forming clumps.
­ Stage lllB: Any size and spread to the skin or chest wall. Swelling.
­ Stage lllC: Any size, spread to lymph nodes, skin and chest wall.
 Stage lV
­ Metastasized.

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SURVIVAL

Stage 5 Year Relative Survival Rate

0 100%

I 100%

II 93%

III 72%

IV 22%

TREATMENT
CONSIDERATION
 The type of breast cancer
 The stage and grade of the breast cancer - how large the tumor is,
whether or not it has spread, and if so, how far?
 Whether or not the cancer cells are sensitive to hormones
 The patient's overall health
 The age of the patient
 The patient's own preferences

MAIN TREATMENTS
 Surgery
 Radiation therapy
 Chemotherapy
 Biological therapy (targeted drug therapy)
 Endocrine therapy

1. SURGERY
 Surgery for breast cancer:
­ Lumpectomy
­ Mastectomy
 Lymph node surgery:
­ Sentinel node biopsy
­ Axillary lymph node dissection
 Breast reconstruction surgery

LUMPECTOMY
 Breast-conserving surgery (BCS) or partial/segmented mastectomy.

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 Breast-conserving surgery (BCS) is a good option for many women with

early-stage cancers.
 Surgically removing the tumor and a small margin of healthy tissue
around it. Followed by radiation therapy.
 The main advantage is that a woman keeps most of her breast.
However, she will in most cases also need radiation therapy, given by a
radiation oncologist.
 Women who have their entire breast removed (mastectomy) for early
stage cancers are less likely to need radiation.
MASTECTOMY
 Surgically removing the breast and other infected components. A simple
mastectomy, the surgeon removes the entire breast, including the
nipple, areola, and skin. Some underarm lymph nodes may or may
not be removed depending on the situation.
SKIN-SPARING MASTECTOMY
 Most of the skin over the breast is left intact. Only the breast tissue,
nipple and areola are removed. The amount of breast tissue removed is
the same as with a simple mastectomy.
MODIFIED RADICAL MASTECTOMY
 A modified radical mastectomy combines a simple mastectomy with the
removal of the lymph nodes under the arm (called an axillary lymph
node dissection)
NIPPLE-SPARING MASTECTOMY
 A variation of the skin-sparing mastectomy
 Breast tissue is removed, but the breast skin and nipple are left in place.
A RADICAL MASTECTOMY
 Extensive operation, the surgeon removes the entire breast, axillary
(underarm) lymph nodes, and the pectoral (chest wall) muscles under
the breast.
SIDE EFFECTS
 Pain after the surgery and the change in the shape of the breast.

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 Wound infection, build-up of blood and buildup of clear fluid in the

wound.
 If axillary lymph nodes are removed swelling of the arm and chest may
occur (Lymphedema).
BREAST RE-CONSTRUCTIVE SURGERY
TISSUE FLAP PROCEDURES
 These techniques use muscle and tissue from elsewhere in the body to
reshape the breast. Tissue flap surgery may be done with a “pedicle
flap,” which means tissue from the back or belly is moved to the chest
without cutting the blood vessels.
 A “free flap” means the blood vessels are cut and the surgeon needs to
attach the moved tissue to new blood vessels in the chest. There are
several flap procedures:
­ Transverse rectus abdominis muscle (TRAM) flap
 This method, which can be done as a pedicle flap or free
flap, uses muscle and tissue from the lower stomach wall.
­ Latissimus dorsi flap
 This pedicle flap method uses muscle and tissue from the
upper back.
­ Deep inferior epigastric artery perforator (DIEP) flap
 The DIEP free flap takes tissue from the abdomen and the
surgeon attaches the blood vessels to the chest wall.
­ Gluteal free flap
 The gluteal free flap uses tissue and muscle from the
buttocks to create the breast, and the surgeon also attaches
the blood vessels.
ADJUVANT THERAPY
 Adjuvant treatment is an addition, designed to help reach the ultimate
goal. Adjuvant therapy for cancer usually refers to surgery followed by
chemo- or radiotherapy to help decrease the risk of the cancer recurring
(coming back).
NEO-ADJUVANT THERAPY
 Neo-adjuvant therapy is defined as the treatment given before the
primary therapy, as opposed to adjuvant treatment which is given after

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the primary therapy, and it is generally used to downstage the tumors

(i.e., lower the stage of tumor) and improve surgical options.
2. RADIATION THERAPY
 Radiation therapy is treatment with high energy rays (such as x-rays)
or particles to kill cancer cells.
 The patient may require three to five sessions per week for three to
six weeks.
 The type of breast cancer will determine the type of radiation
therapy used.
TYPES OF RADIATION THERAPY
 BREAST RADIATION THERAPY
­ Applied after a lumpectomy
 CHEST WALL RADIATION THERAPY
­ Applied after a mastectomy
 BREAST BOOST
­ A high-dose of radiation therapy is applied to where the tumor
was surgically removed
 LYMPH NODES RADIATION THERAPY
­ Aimed at the axilla and surrounding area to destroy cancer cells
that have reached the lymph nodes
RADIATION THERAPY SCHEDULE
 Radiation therapy is usually given daily for a set number of weeks.
 AFTER A LUMPECTOMY
­ Radiation therapy after a lumpectomy is external-beam radiation
therapy given Monday through Friday for 3 to 4 weeks if the
cancer is not in the lymph nodes. If the cancer is in the lymph
nodes, radiation therapy is given for 5 to 6 weeks. This often starts
with radiation therapy to the whole breast, followed by a more
focused treatment to where the tumor was located in the breast
for the remaining treatments.
­ This focused part of the treatment, called a boost, is standard for
women with invasive breast cancer to reduce the risk of a
recurrence in the breast. Women with DCIS may also receive the
boost.
 AFTER A MASTECTOMY

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­ For those who need radiation therapy after a mastectomy, it is

usually given 5 days a week for 5 to 6 weeks. Radiation therapy
can be given before or after reconstructive surgery.
­ Even shorter schedules have been studied and are in use in some
centers, including accelerated partial breast radiation therapy for
5 days.
BRACHYTHERAPY
 Radiation to the breast by placing radioactive seeds (pellets) into the
breast tissue.
 The most common type of brachytherapy used to treat breast cancer is
called intracavitary brachytherapy.
 A device is put into the space left from breast conserving surgery, a
source of radiation is then placed in the device for a short time and then
removed.
PROTON THERAPY
 Standard radiation therapy for breast cancer uses x-rays, also called
photon therapy, to kill cancer cells.
 Proton therapy is a type of external-beam radiation therapy that uses
protons rather than x-rays. At high energy, protons can destroy cancer
cells.
 Protons have different physical properties that may allow the radiation
therapy to be more targeted than photon therapy and potentially
reduce the radiation dose.
 The therapy may also reduce the amount of radiation that goes near the
heart. Researchers are studying the benefits of proton therapy versus
photon therapy in a national clinical trial.
SIDE EFFECTS OF RADIATION THERAPY
 Weakness
 Swelling and heaviness in the breast
 Sunburn-like changes in the skin and feeling very tired
 Radiation to lymph nodes causes Lymphedema
 Damage some of the nerves to the arm. This can lead to numbness, pain,
and weakness in the shoulder, arm and hand.

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3. CHEMOTHERAPY
 Chemotherapy (chemo) is the use of cancer-killing drugs.
Intravenously, given as a shot, or taken as a pill or liquid. They enter
the bloodstream and reach most parts of the body. Combats
metastasis. Damage some normal cells.
 To prevent cancer from coming back after surgery and radiation.
When chemotherapy is used this way, it is called adjuvant therapy.
 To shrink a tumor before surgery to make it easier to remove. This is
called neo-adjuvant therapy.
 Chemotherapy destroys cancer cells and is used to treat most triple
negative, HER2 positive and luminal B-like breast cancers.
Chemotherapy is usually given every 1–3 weeks as intravenous
infusions. Some patients may also be offered additional oral
chemotherapy following completion of standard intravenous
chemotherapy.
ADJUVANT AND NEOADJUVANT CHEMOTHERAPY
 Anthracyclines, such as doxorubicin (Adriamycin) and epirubicin (Ellence)
 Taxanes, such as paclitaxel (Taxol) and docetaxel (Taxotere)
 5-fluorouracil (5-FU)
 Cyclophosphamide (Cytoxan)
 Carboplatin (Paraplatin)
 Most often, combinations of 2 or 3 of these drugs are used.
CHEMOTHERAPY FOR ADVANCED BREAST CANCER
 Taxanes, such as paclitaxel (Taxol), docetaxel (Taxotere), and albumin-
bound paclitaxel (Abraxane)
 Anthracyclines (Doxorubicin, pegylated liposomal doxorubicin, and
Epirubicin)
 Platinum agents (cisplatin, carboplatin)
 Vinorelbine (Navelbine)
 Capecitabine (Xeloda)
 Gemcitabine (Gemzar)
 Ixabepilone (Ixempra) Albumin-bound paclitaxel (nab-paclitaxel or
Abraxane)
SIDE EFFECTS OF CHEMOTHERAPY FOR BREAST CANCER

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 Chemo drugs can cause side effects. These depend on the type and dose
of drugs given, and the length of treatment. Some of the most common
possible side effects include:
­ Hair loss
­ Nail changes
­ Mouth sores
­ Loss of appetite or weight changes
­ Nausea and vomiting
­ Diarrhea
4. TARGETED THERAPY
 Targeted therapies are drugs that block specific signaling pathways in
cancer cells that encourage them to grow. A number of targeted
therapies are used in the treatment of breast cancer:
­ Anti-HER2 agents - Anti-HER2 agents act on the HER2 receptor to
block signaling and reduce cell proliferation in HER2 positive
breast cancers.
 Trastuzumab, lapatinib, pertuzumab and trastuzumab
emtansine (TDM-1) are all currently-used anti-HER2 agents.
Neratinib is a new anti-HER2 agent that may also be used to
treat HER2 positive disease.
­ CDK4/6 inhibitors - Inhibitors of cyclin-dependent kinases 4/6
(CDK4/6) reduce cellular proliferation in tumors.
 Palbociclib, ribociclib and abemaciclib are CDK4/6 inhibitors
used in the treatment of breast cancer.
­ mTOR inhibitors - Inhibitors of mechanistic target of rapamycin
(mTOR), such as everolimus, reduce the growth and proliferation
of tumor cells stimulated by mTOR signaling.
­ PARP inhibitors - Inhibitors of poly ADP-ribose polymerase (PARP)
make it difficult for cancer cells to fix damaged DNA, which can
cause cancer cells to die.
 Olaparib and talazoparib are new PARP inhibitors that may
be used to treat some patients with a BRCA mutation.
­ VEGF inhibitors - Vascular endothelial growth factor (VEGF)
inhibitors, such as bevacizumab, stop tumors from stimulating

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blood vessel growth within the tumor, thereby starving them of

the oxygen and nutrients they need to continue growing.
5. ENDOCRINE THERAPIES / HORMONAL THERAPIES
 Endocrine therapies aim to reduce the effects of estrogen in ER
positive breast cancers. This is the most important type of systemic
treatment for ER positive tumors, also called hormone-dependent
tumors.
 There are a number of types of endocrine therapy available, which
are taken orally or administered as an injection:
­ SERM
 Selective estrogen receptor modulators (SERMs) block
ER on breast cells to prevent estrogen attaching to the
receptors. Tamoxifen is a type of SERM.
­ SERD
 Selective estrogen receptor down regulators (SERDs),
such as fulvestrant, work in a similar way to SERMs, but
also reduce the number of ERs.
­ OVARIAN FUNCTION SUPPRESSORS
 Ovarian function suppression by gonadotropin-releasing
hormone analogues or by surgery may be offered to pre-
and perimenopausal women to reduce the supply of
estrogen from the ovaries to the tumor.
­ AROMATASE INHIBITORS
 Aromatase inhibitors reduce the production of estrogen
in tissues and organs other than the ovaries, and is
therefore effective only in postmenopausal women,
unless the function of the ovaries is suppressed in
premenopausal women. Anastrozole, letrozole and
exemestane are all aromatase inhibitors.
6. OTHER TREATMENTS
 Patients with bone metastases should be treated with bone-
modifying drugs such as bisphosphonates or denosumab, in
combination with calcium and vitamin D supplements.
 These agents strengthen the bone, reducing bone pain and the risk of
fractures. Bisphosphonates are also used in the postoperative
treatment of early breast cancer, as they may reduce the risk of
recurrence.
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MALE BREAST CANCER

 90% are invasive at time of diagnosis
 80% ER+, 75% PR+, 30% HER2/neu
 More invade into pectoralis
 Treatment same as for female breast cancer

ALGORITHIM OF BREAST CANCER TREATMENT

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LUNG CANCER

“Lung cancer is a solid tumor originating from the bronchial epithelial cells.”

PATHOPHYSIOLOGY
 Lung carcinomas arise from normal bronchial epithelial cells that have
acquired multiple genetic lesions and are capable of expressing a variety
of phenotypes.
 Activation of proto-oncogenes, inhibition or mutation of tumor
suppressor genes, and production of autocrine growth factors contribute
to cellular proliferation and malignant transformation. Molecular
changes, such as overexpression of c-KIT in Small Cell Lung Cancer (SCLC)
and epidermal growth factor receptor (EGFR) in Non-Small Cell Lung
Cancer (NSCLC), also affect disease prognosis and response to therapy.
 The major cell types are SCLC, adenocarcinoma, squamous cell
carcinoma, and large cell carcinoma.

RISK FACTORS
1. SMOKING
 The incidence of lung cancer is strongly correlated with cigarette
smoking, with about 90% of lung cancers arising as a result of tobacco
use.
2. PASSIVE SMOKING
 Passive smoking or the inhalation of tobacco smoke by nonsmokers
who share living or working quarters with smokers, also is an
established risk factor for the development of lung cancer.
3. EXPOSURE TO ASBESTOS FIBERS
 Asbestos fibers are silicate fibers that can persist for a lifetime in lung
tissue following exposure to asbestos.
4. EXPOSURE TO RADON GAS
 Radon gas is a natural radioactive gas that is a natural decay product
of uranium that emits a type of ionizing radiation. Radon gas is a
known cause of lung cancer, with an estimated 12% of lung cancer
deaths attributable to radon gas.

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5. FAMILIAL PREDISPOSITION
 Individual genetic susceptibility, may play a role in the causation of
lung cancer.
 People who inherit certain genes, like genes that interfere with DNA
repair, may be at greater risk for several types of cancer.
6. LUNG DISEASES
 The presence of certain diseases of the lung, notably chronic
obstructive pulmonary disease (COPD), is associated with an
increased risk (four- to six-fold the risk of a nonsmoker) for the
development of lung cancer. Pulmonary fibrosis (scarring of the lung)
appears to increase the risk about seven-fold, and this risk does not
appear to be related to smoking.
7. AIR POLLUTION
 Air pollution from vehicles, industry, and power plants can raise the
likelihood of developing lung cancer in exposed individuals.
8. PREVIOUS HISTORY OF LUNG CANCER
 Survivors of lung cancer have a greater risk of developing a second
lung cancer than the general population has of developing a first lung
cancer.

CLINICAL PRESENTATION
 Fatigue
 Chest pain
 Weight loss
 Cough (chronic, recurrent)
 Shortness of breath or wheezing
 Coughing up phlegm that contains blood

DIAGNOSIS
 Chest X-ray
 Bone scans
 Blood tests
 Bronchoscopy
 Sputum cytology
 Molecular testing
 CT (computerized tomography) scans
 Magnetic resonance imaging (MRI) scans
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 Positron emission tomography (PET) scans

 Needle biopsy: Fine-needle aspiration (FNA)

TYPES OF LUNG CANCER

 There are only two major types of lung cancers:
­ Small cell lung cancer (SCLC)
­ Non-small cell lung cancers (NSCLC).
NON-SMALL CELL LUNG CANCER
 Non-small cell lung cancers are the most common type of lung cancer.
These cancers account for about 90% of all lung cancers and are less
aggressive than small cell lung cancers, meaning they spread to other
tissues and organs more slowly.
SMALL CELL LUNG CANCER
 Small cell lung cancer, also called oat cell lung cancer, accounts for about
10% of all lung cancers. This form of cancer tends to spread quickly.

STAGING OF LUNG CANCER

 After the type of lung cancer is determined, the type is then assigned a
lung cancer stage. The stage indicates how much the cancer has spread
in the body (for example, to the lymph nodes or to distant organs like
the brain). - Stage 0 through stage 4.
SMALL CELL LUNG CANCER STAGES
 A two-stage classification is widely used for SCLC.
I. LIMITED STAGE
 In this form, small cell lung cancer is limited to one side of the chest,
typically in the lungs and lymph nodes.
 About one in three people with small cell lung cancer have limited stage
cancer upon the first diagnosis.
II. EXTENSIVE STAGE
 This refers to small cell lung cancer that has spread throughout one lung,
spread into both lungs, to lymph nodes on the other side of the chest or
to other body parts.
 About two in three people with small cell lung cancer have extensive
stage cancer upon first diagnosis.

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Chapter 10.8.3 – Lung Cancer

NON-SMALL CELL LUNG CANCER STAGES

 OCCULT (HIDDEN) STAGE
­ In this stage, cancer cells appear in a sputum cytology exam or
other test, though no tumor location can be found.
 STAGE 0 (CARCINOMA IN SITU)
­ In this lung cancer stage, cancer cells are only found in the top
layer of cells lining air passages and has not crept deeper into the
lungs or spread beyond the air passages.
 STAGE I
­ A small lung cancer tumor (less than 3 centimeters across) is
discovered, but has not spread to surrounding lung membranes,
lymph nodes, or the main bronchial branches of the lungs.
 STAGE II
­ There are several ways that stage II lung cancer may be diagnosed.
One is that the lung cancer has spread to lymph nodes near the
lungs.
 STAGE III
­ As in stage II lung cancer, stage III has several definitions. One is
that the lung cancer is found in both the lung and lymph nodes in
the middle of the chest. Stage III lung cancer is divided into two
subsets.
 Stage III a
 Stage III b
 STAGE IV
­ This is the most advanced stage of lung cancer. The cancer can be
any size, but two of these three things have happened:
 The cancer has spread to the opposite lung from where it
began.
 Cancer cells have been discovered in the fluid surrounding
the lung.
 Cancer cells have been discovered in the fluid surrounding
the heart.

MANAGEMENT
1. EARLY-STAGE LUNG CANCER TREATMENT
SURGERY
 Part or all of a lung segment that contains the cancer may be removed;

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in some individuals, this may result in a cure. However, many patients

still undergo chemotherapy, radiation therapy or both to kill any cancer
cells not removed by surgery.
TYPES OF SURGERY
A. LIMITED RESECTION
­ An operation to remove only a small portion of the lung is called a
segmental or wedge resection.
B. LOBECTOMY
­ Removal of large section of the lung, (there are three lobes of the
lung on the right and two on the left), is called a lobectomy. This is
the most common surgery performed for lung cancer.
C. PNEUMONECTOMY
­ The removal of an entire lung is called a pneumonectomy.
2. ADVANCED LUNG CANCER TREATMENT
 Most small cell and non-small-cell lung cancers are treated with
chemotherapy; they may also be treated with radiation therapy and
surgery. In many patients with advanced disease, these methods may
be used together, depending on the patient's condition and
recommendations by their cancer doctors.
CHEMOTHERAPY
 Chemotherapy is the use of drugs that are designed to kill rapidly
growing cells, such as cancer cells.
 Chemotherapy may be injected directly into a vein (by IV, or
intravenously) or given through a catheter, which is a thin tube placed
into a large vein and kept there until it is no longer needed.
 Some chemotherapy drugs are taken by pill.

SIDE EFFECTS
 The side effects of chemo depend on the type and dose of drugs given
and how long they are taken, given following:
­ Fatigue
­ Hair loss
­ Mouth sores
­ Loss of appetite
­ Nausea and vomiting
­ Diarrhea or constipation

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­ Easy bruising or bleeding

­ Increased chance of infections.
DRUGS USED IN CHEMOTHERAPY
 The chemotherapy treatment plan for lung cancer often consists of a
combination of drugs. Among the drugs most commonly used are:
­ Cisplatin (Platinol) or Carboplatin (Paraplatin) plus
­ Docetaxel (Taxotere)
­ Gemcitabine (Gemzar)
­ Paclitaxel (Taxol and others)
­ Vinorelbine (Navelbine and others)
­ Pemetrexed (Alimta).
DRUGS USED TO TREAT NSCLC
 Generally used drugs are:
­ Cisplatin ­ Vinorelbine
­ Carboplatin ­ Irinotecan
­ Paclitaxel ­ Etoposide
­ Docetaxel ­ Vinblastine
­ Gemcitabine ­ Pemetrexed
TREATMENT PROTOCOLS FOR NSCLC
 Concurrent chemotherapy drugs:
­ Cisplatin plus etoposide
­ Cisplatin plus vinblastine
­ Cisplatin plus pemetrexed
­ Carboplatin plus paclitaxel
­ Carboplatin plus pemetrexed
 Sequential chemotherapy drugs:
­ Cisplatin plus vinblastine
­ Carboplatin plus paclitaxel
DRUGS USED IN TREATMENT OF SCLC
TREATMENT PROTOCOLS FOR SCLC
 1st line drugs
­ Cisplatin plus etoposide
­ Carboplatin plus etoposide
­ Cisplatin plus Irinotecan
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­ Carboplatin plus Irinotecan

­ Cyclophosphamide plus doxorubicin plus vincristine
nd
 2 line drugs: (refractory disease)
­ Etoposide ­ Cisplatin plus
­ Topotecan Irinotecan
­ Paclitaxel ­ Carboplatin plus
Irinotecan
rd
 3 line drugs: (relapsed or refractory disease)
­ Nivolumab ­ Paclitaxel
­ Cisplatin plus ­ Carboplatin plus
Irinotecan Irinotecan
­ Topotecan
RADIATION THERAPY
 Radiation therapy is a form of high energy X-ray that kills cancer cells. It
can be used as a primary treatment, or in combination with
chemotherapy (with or without surgery).
 Radiation therapy is a “focused” treatment, meaning it is designed to
maximize its effect on the cancer cells while minimizing any injury to
normal cells.
3. TARGETED LUNG CANCER THERAPIES
 New therapeutic treatments are being tried; for example:
­ Some therapies termed targeted therapies are designed to
prevent or stop lung cancer cells from growing by targeting the
new blood vessels that are needed to allow the cancer cells to
survive and grow; other treatments target growth and
multiplication of lung cancer cells by interfering with chemical
signals required by growing or multiplying cancer cells.

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Chapter 10.9.1 – Renal Failure

RENAL FAILURE

“Renal failure is defined as a significant loss of renal function in both kidneys to

the point where less than 10 to 20% of normal GFR remains.”

INTRODUCTION
 Renal failure may occur as an acute and rapidly progressing process or
may present as a chronic form in which there is a progressive loss of
renal function over a number of years.
 Acute renal failure has an abrupt onset and is potentially reversible.
 Chronic failure progresses slowly over at least three months and can
lead to permanent renal failure.

PATHOPHYSIOLOGY OF RENAL FAILURE

 In renal failure there is either glomerular or tubular dysfunction.
 Glomerular dysfunction: As the main function of glomeruli is filtration,
glomerular dysfunction leads to fall in GFR with retention of those
substances usually cleared by filtration, including water.
 Tubular Dysfunction: As the main function of tubules is reabsorption,
tubular failure results in the voiding of large volumes of dilute urine
(polyuria) of low specific gravity, along with electrolytes and nutrients.

ACUTE RENAL FAILURE

INTRODUCTION
 Sudden decrease in renal function. Acute renal failure may be pre-renal,
intra-renal or post-renal in nature. Acute renal failure is often reversible
so long as permanent injury to the kidney has not occurred.
CLASSIFICATION OF ARF
 There are three criteria-based classification systems developed to define
and stage Acute kidney injuries (AKI):
 RIFLE (Risk, Injury, Failure, Loss of Kidney Function, and End-Stage
Renal Disease)
 AKIN (Acute Kidney Injury Network)
 KDIGO (Kidney Disease: Improving Global Outcomes).

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CATEGORY CRITERIA FOR STAGING ACUTE KIDNEY FAILURE (ARF)

RIFLE CRITERIA
Risk (R) Increased serum creatinine level by 1.5 times or GFR decrease by >25%
Injury (I) Increased serum creatinine level by 2.0 times or GFR decrease by >50%
Failure (F) Increased serum creatinine level by 3.0 times or GFR decrease by >75%
Loss (L) Persistent acute renal failure or complete loss of function for >4 weeks
End-SKD (E) End-stage kidney disease for >3 months
AKIN CRITERIA
Stage 1 Serum creatinine increase 1.5- to 2-fold from baseline
Stage 2 Serum creatinine increase >2- to 3-fold from baseline
Stage 3 Serum creatinine increase >3-fold from baseline
KDIGO CRITERIA
Stage 1 Serum creatinine increase 1.5 to1.9 times from baseline
Stage 2 Serum creatinine increase 2 to 2.9 times from baseline
Stage 3 Serum creatinine increase 3 times from baseline
PATHOPHYSIOLOGY OF ARF
 Causes of Acute Renal Failure:
 Myocardial infarction, rhabdomyolysis, decreased blood flow,
renal obstruction, hemolytic uremic syndrome, glomerulonephritis
are common causes of acute renal failure.
 Acute Renal Failure classified as pre-renal failure, intra-renal failure and
post-renal failure
 Pre-renal failure: Results from impaired or reduced blood flow to
the kidney.
Possible causes:
 Shock, hypotension, anaphylaxis, ischemic formation.
 Intra-renal failure: Results from acute damage to renal structures.
Possible causes:
 Acute glomerulonephritis, pyelonephritis
 May also result from acute tubular necrosis (ATN)
 Damage of kidney structure from exposure to toxins, drugs
and heavy metals; ATN is the most common cause of ARF.
 Post-renal failure: Results from conditions block urine outflow.
Possible causes:
 Obstruction of urine outflow by calculi, tumors, prostatic
hypertrophy.

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CLINICAL MANIFESTATIONS OF ARF

 Oliguria (reduced urine output)
 Possible edema and fluid retention
 Elevated blood urea nitrogen levels (BUN) and serum creatinine
 Alterations in serum electrolytes.

SYMPTOMS OF ARF
 Decreased kidney function (electrolyte imbalance)
 Obstruction in the urinary tract
 Blood in urine
 Reduced urine output
 Dehydration
 Detectable abnormal mass
 Pale skin, Poor appetite.

DIAGNOSIS OF ARF
 Routine laboratory test (creatinine and blood urea nitrogen)
 Ultrasound of the kidney helps to determine whether kidney problem is
acute or chronic.
 Kidney biopsy
 Computed tomography scan.

TREATMENT OF ARF
I. PHARMACOLOGICAL THERAPY
 Hyperkalemia the elevated K levels may be reduced by administering
cation-exchange resins (sodium polystyrene sulfonate [Kayexalate])
orally or by retention enema. It works by exchanging sodium ions for
potassium ions in the intestinal tract.
 Sorbitol may be administered in combination with Kayexalate to induce
diarrhea type effect (induce water loss in the GIT)
 If hemodynamically unstable, IV dextrose 50%, insulin and calcium
replacement may be administered to shift potassium back into the cells.
 Diuretics are often administered to control fluid volume, but they have
not been shown to hasten the recovery form ARF.
II. NUTRITIONAL THERAPY
 Dietary proteins are individualized to provide the maximum benefit.
Caloric requirements are met with high-carbohydrate meals because
carbohydrates have a protein sparing effect.
 Foods and fluids containing potassium or phosphorous such as banana.

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Chapter 10.9.1 – Renal Failure

CHRONIC RENAL FAILURE

INTRODUCTION
 Chronic renal failure is the end result of progressive kidney damage and
loss of function.
CLASSIFICATION OF CRF
 Chronic renal failure is often classified into four progressive stages based
on the loss of GFR.
CATEGORY GFR
Stage 1: Diminished Renal Reserve GFR decreased to 35 to 50% of normal
Stage 2: Renal Insufficiency GFR decreased to 20 to 35% of normal
Stage 3: Renal Failure GFR decreased to less than 20% of normal
Stage 4: End-Stage Renal Disease GFR decreased to less than 5% of normal
CAUSES OF CRF
 Chronic glomerulonephritis, chronic infections, renal obstruction
(prolonged)
 Exposure to toxic chemicals, toxins or drugs (aminoglycoside antibiotics
and nephrotoxicity)
 Diabetes, Hypertension, Nephrosclerosis (atherosclerosis of the renal
artery), Diabetic nephropathy
 Polycystic kidney disease, Interstitial nephritis or pyelonephritis.

PATHOPHYSIOLOGY OF CRF
 As renal function declines, the end products of Protein (CHON)
metabolism (which are normally excreted in urine) accumulate in the
blood.
 Uremia develops and adversely affects every system in the body.

CLINICAL MANIFESTATIONS OF CRF

CV MANIFESTATIONS
 Hypertension – due to Na and H2O retention or from R-A-A activation
 Heart failure and edema - due to fluid overload
 Pericarditis - due to irritation of pericardial lining by uremic toxins.
DERMATOLOGIC MANIFESTATIONS
 Severe pruritus is common
 Uremic frost, the deposit of urea crystals on the skin.

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GI MANIFESTATIONS
 Anorexia, nausea, vomiting and hiccups
 The patient’s breath may have the odor of urine (uremic fetor); this may
be associated with inadequate dialysis.
NEUROLOGIC MANIFESTATIONS
 Inability to concentrate, muscle twitching, agitation, confusion and
seizures.
SYMPTOMS OF CRF
 Malaise  Bone pain
 Dry skin  Metallic taste in mouth
 Poor appetite  Detectable abdominal mass
 Vomiting  Anemia
DIAGNOSIS OF CRF
 GFR
 Anemia
 Sodium and water retention
 Acidosis – due to inability of kidneys to excrete increased load of acid
 Calcium and phosphorous imbalance – hypocalcemia and increase in
phosphorous.
TREATMENT OF CRF
I. PHARMACOLOGIC THERAPY
 Calcium carbonate (Os-cal) or calcium acetate (Phoslo) are prescribed
to treat hyperphosphatemia and hypocalcemia
 Antiseizure agents – diazepam (Valium) or phenytoin (Dilantin)
 Antihypertensive and CV drugs - digoxin (Lanoxin) and dobutamine
(Dobutrex)
 Erythropoietin (Epogen) to treat anemia. It is initiated to reach a
hematocrit of 33% - 385 and a target hemoglobin of 12g/dl.
II. NUTRITIONAL THERAPY
 Low sodium, low CHON and low K diet.
III. DIALYSIS
 Peritoneal dialysis
 Hemodialysis.
IV. KIDNEY TRANSPLANT
 Indicated for ESRD – End Stage Renal Disease.

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Chapter 10.9.2 – Nephrotic Syndrome

NEPHROTIC SYNDROME

“Nephrotic syndrome is a clinical disorder characterized by marked increase of

protein in the urine (proteinuria), decrease in albumin in the blood
(hypoalbuminemia), edema and excess lipids in the blood (hyperlipidemia).”

INTRODUCTION
 Nephrotic syndrome is characterized by the loss of plasma protein,
particularly albumin, in the urine.
 Nephrotic syndrome is a primary glomerular disease characterized by
the following:
­ Marked increase in protein in the urine (proteinuria)
­ Decrease in albumin in the blood (hypoalbuminemia)
­ Edema - The swelling can be most noticeable on the face, around
the eyes, around the feet and ankles, and in the belly area (or the
abdomen).
­ High serum cholesterol and low-density lipoproteins
(hyperlipidemia).

PATHOPHYSIOLOGY
 Nephrotic syndrome is usually caused by damage to the clusters of tiny
blood vessels (glomeruli) of kidneys.
 Many diseases and conditions can cause glomerular damage and lead to
nephrotic syndrome, including:
­ Diabetic kidney disease. Diabetes can lead to kidney damage
(diabetic nephropathy) that affects the glomeruli.
­ Minimal change disease. This is the most common cause of
nephrotic syndrome in children.
­ Focal segmental glomerulosclerosis. Characterized by scarring of
some of the glomeruli, this condition can result from another
disease, a genetic defect or certain medications or occur for no
known reason.
­ Membranous nephropathy. This kidney disorder is the result of
thickening membranes within the glomeruli. The thickening is due
to deposits made by the immune system.

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Chapter 10.9.2 – Nephrotic Syndrome

­ Systemic lupus erythematosus. This chronic inflammatory disease

can lead to serious kidney damage.
­ Amyloidosis. This disorder occurs when amyloid proteins
accumulate in your organs. Amyloid buildup often damages the
kidneys filtering system.

CLINICAL MANIFESTATIONS
 The major manifestation of nephrotic syndrome is edema. It is usually
soft and pitting and most commonly occurs around the eyes
(periorbital), in dependent areas (sacrum, ankles and hands) and in the
abdomen (ascites).
 Other symptoms, including malaise, foamy urine, headache, irritability,
weight gain and fatigue are common.

DIAGNOSIS
URINE TESTS
 A urinalysis can reveal abnormalities in urine, such as large amounts of
protein.
BLOOD TESTS
 A blood test can show low levels of the protein albumin and often
decreased levels of blood protein overall. Loss of albumin is often
associated with an increase in blood cholesterol and blood triglycerides.
 The creatinine and urea nitrogen levels in blood also might be measured
to assess overall kidney function.
KIDNEY BIOPSY
 A small sample of kidney tissue is removed for testing. During a kidney
biopsy, a needle is inserted through skin and into kidney.
 Kidney tissue is collected and sent to lab for testing.

TREATMENT
BLOOD PRESSURE MEDICATIONS
 Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure
and the amount of protein released in urine. E.g., lisinopril, captopril and
enalapril.
 Angiotensin II receptor blockers (ARBs) reduce blood pressure and
protein in urine. E.g., losartan and valsartan.
 Other medications, such as renin inhibitors, also might be used,

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though ACE inhibitors and ARBs are generally used first.

WATER PILLS (DIURETICS)
 These help control swelling by increasing kidneys fluid output. Diuretic
medications typically include furosemide (Lasix). Others include
spironolactone (Aldactone) and thiazides, such as hydrochlorothiazide or
metolazone.
CHOLESTEROL-REDUCING MEDICATIONS
 Statins can help lower cholesterol levels. However, it is not clear
whether cholesterol-lowering medications can improve the outcomes
for people with nephrotic syndrome, such as avoiding heart attacks or
decreasing the risk of early death.
 Statins include atorvastatin, fluvastatin, lovastatin, pravastatin,
rosuvastatin and simvastatin.
BLOOD THINNERS (ANTICOAGULANTS)
 These might be prescribed to decrease blood ability to clot, especially if
patient have had a blood clot.
 Anticoagulants include heparin, warfarin, dabigatran, apixaban and
rivaroxaban.
IMMUNE SYSTEM-SUPPRESSING MEDICATIONS
 Medications to control the immune system, such as corticosteroids, can
decrease the inflammation that accompanies some of the conditions
that can cause nephrotic syndrome.
 Medications include rituximab, cyclosporine and cyclophosphamide.

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Chapter 10.10.1 - Thrombocytopenia

THROMBOCYTOPENIA

“The term thrombocytopenia refers to a relative decrease of platelets in the

blood. Also called low platelet count.”

INTRODUCTION
 When blood has too few platelets, mild to serious bleeding can occur.
Bleeding can occur inside the body (internal bleeding) or underneath
skin or from the surface of the skin (external bleeding).
 A normal platelet count in adults ranges from 150,000 to 450,000
platelets per microliter of blood.
 If blood platelet count falls below normal, thrombocytopenia occurs.
However, the risk for serious bleeding does not occur until the count
becomes very low—less than 10,000 or 20,000 platelets per microliter.
Mild bleeding sometimes occurs when the count is less than 50,000
platelets per microliter.

CAUSES
 Sometimes the cause of thrombocytopenia is not known. In general, a
low platelet count occurs because:
I. BONE MARROW DOES NOT MAKE ENOUGH PLATELETS
 Bone marrow is the sponge-like tissue inside the bones. It contains stem
cells that develop into red blood cells, white blood cells, and platelets.
When stem cells are damaged, they do not grow into healthy blood cells.
II. CANCER
 Cancer, such as leukemia or lymphoma, can damage the bone marrow
and destroy blood stem cells. Cancer treatments, such as radiation and
chemotherapy, also destroy the stem cells.
III. APLASTIC ANEMIA
 Aplastic anemia is a rare, serious blood disorder in which the bone
marrow stops making enough new blood cells. This lowers the number
of platelets in blood.

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Chapter 10.10.1 - Thrombocytopenia

IV. TOXIC CHEMICALS

 Exposure to toxic chemicals—such as pesticides, arsenic, and benzene
can slow the production of platelets.
V. MEDICINES
 Some medicines, such as diuretics and chloramphenicol can slow the
production of platelets.
 Common over-the-counter medicines, such as aspirin or ibuprofen also
can affect platelets.
VI. ALCOHOL
 Alcohol also slows the production of platelets. A temporary drop in the
platelet count is common among heavy drinkers, especially if they are
eating foods that are low in iron, vitamin B12, or folate.
VII. VIRUSES
 Chickenpox, mumps, rubella, or parvovirus can decrease platelet count
for a while.
VIII. BODY DESTROYS ITS OWN PLATELETS
 A low platelet count can occur even if the bone marrow makes enough
platelets. The body may destroy its own platelets due to autoimmune
diseases, certain medicines, infections, surgery, pregnancy, and some
conditions that cause too much blood clotting.
IX. AUTOIMMUNE DISEASES
 Autoimmune diseases occur if the body’s immune system mistakenly
attacks healthy cells in the body. If an autoimmune disease destroys the
body’s platelets, thrombocytopenia can occur. One example of this type
of auto-immune disease is immune thrombocytopenia (ITP).
 ITP is a bleeding disorder in which the blood does not clot as it should.
An autoimmune response is thought to cause most cases of ITP.
X. THE SPLEEN HOLDS ON TO TOO MANY PLATELETS
 Usually, one-third of the body’s platelets are held in the spleen. If the
spleen is enlarged, it will hold on to too many platelets. This means that
not enough platelets will circulate in the blood.
 An enlarged spleen often is due to cancer or severe liver disease.

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SIGNS AND SYMPTOMS

 Occasionally, there may be bruising, particularly purpura in the
forearms, petechia (pinpoint hemorrhages on skin and mucous
membranes), nose bleeds and/or bleeding gums.
 A person with this disease may also complain of malaise, fatigue, and
general weakness (with or without accompanying blood loss).

DIAGNOSIS
 Laboratory tests might include:
­ Full blood count
­ Liver enzymes
­ Renal function
­ Vitamin B12 levels
­ Folic acid levels
­ Erythrocyte sedimentation rate
­ Peripheral blood smear.

TREATMENT
 Thrombocytopenia can last for days or years. Patients with mild
thrombocytopenia might not need treatment. For Patients who do need
treatment for thrombocytopenia, treatment depends on its cause and
how severe it is.
BLOOD OR PLATELET TRANSFUSIONS
 If platelet level becomes too low, doctor can replace lost blood with
transfusions of packed red blood cells or platelets.
MEDICATIONS
 If patient’s condition is related to an immune system problem, doctor
might prescribe drugs to boost platelet count. The first-choice drug
might be a corticosteroid. If that does not work, stronger medications
can be used to suppress immune system.
SURGERY
 If other treatments do not help, doctor might recommend surgery to
remove spleen (splenectomy).
PLASMA EXCHANGE
 Thrombotic thrombocytopenic purpura can result in a medical
emergency requiring plasma exchange.

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Chapter 10.10.2

HEMOPHILIA

“Hemophilia is an inherited bleeding disorder in which a person lacks or has low

levels of certain proteins called “clotting factors” and the blood doesn’t clot
properly as a result.”

INTRODUCTION
BLOOD CLOTTING FACTORS
 There are 13 types of clotting factors, and these work with platelets to
help the blood clot.
1. Foolish (Fibrinogen) 9. Christmas (Antihemophilic
2. People (Prothrombin) factor b/Christmas factor/
3. Try (Thromboplastin/tissue plasma thromboplastin
factor) component ptc)
4. Climbing (Calcium ions) 10.Some (Stuart prower factor)
5. Long (Labile factor) 11.People (Plasma thromboplastin
6. No longer used antecedent pta/ ahf c)
7. Slopes (Stable factor) 12.Have (Hageman factor)
8. After (Antihemophilic factor a) 13.Fallen (Fibrin stabilizing factor).

CAUSES
 A process in body that is known as “the coagulation cascade” normally
stops bleeding. Blood platelets coagulate, or gather together at the
wound site, to form a clot.
 Then the body’s clotting factors work together to create a more
permanent plug in the wound. A low level of these clotting factors or the
absence of them causes bleeding to continue.
FORMS OF HEMOPHILIA
 The three forms of hemophilia are hemophilia A, B, and C.
­ Hemophilia A is the most common type of hemophilia, and it is
caused by a deficiency in factor VIII.
­ Hemophilia B, which is also called Christmas disease, is caused by
a deficiency of factor IX.
­ Hemophilia C is a mild form of the disease that is caused by a
deficiency of factor XI.

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Chapter 10.10.2

HEMOPHILIA AND GENETICS

 Hemophilia is an inherited genetic condition. It is caused by a defect in
the gene that determines how the body makes factors VIII, IX, or XI.
These genes are located on the X chromosome, making hemophilia an X-
linked recessive disease.
 Each person inherits two sex chromosomes from their parents. Females
have two X chromosomes. Males have one X and one Y chromosome.
 Males inherit an X chromosome from their mother and a Y chromosome
from their father. Females receive an X chromosome from each parent.
Because the genetic defect that causes hemophilia is located on the X
chromosome, fathers cannot pass the disease to their sons. This also
means that if a male gets the X chromosome with the altered gene from
his mother, he will have hemophilia.
 A female who has the altered gene on one of her X chromosomes is
typically called a “carrier.” Males with an X chromosome that has the
altered gene may pass it on to their daughters, making them carriers. A
female must have this altered gene on both of her X chromosomes to
have hemophilia. However, this is very rare.

SIGNS AND SYMPTOMS

 Perpetuated oozing after injuries
 Repeated bleeding after first bleeding
 Easy or spontaneous bruising
 Prolonged bleeding
 The most frequent symptom for Hemophilia’s types A & B is
spontaneous joint bleeding.

DIAGNOSIS
 Hemophilia A & B are diagnosed by measuring factor clotting activity.
Individuals who have Hemophilia A have low factor VIII clotting activity.
Individuals who have hemophilia B have low factor IX clotting activity.
 Genetic testing is also available for the factor VIII gene and the factor IX
gene.
 Laboratory tests include:
­ Platelet count: Normal
­ Bleeding time: Normal
­ PT: Normal
­ Clotting time & PTT: Prolonged

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Chapter 10.10.2

­ Factor VIII or Factor IX assay: Decreased Normal values for FVIII

assays are 50-150%.

TREATMENT
 Several different types of clotting factors are associated with different
varieties of hemophilia. The main treatment for severe hemophilia
involves receiving replacement of the specific clotting factor that is
needed through a tube placed in a vein.
 Replacement clotting factor can be made from donated blood. Similar
products, called recombinant clotting factors, are manufactured in a
laboratory.
 Other therapies may include:
­ Desmopressin. In some forms of mild hemophilia, this hormone
can stimulate body to release more clotting factor. It can be
injected slowly into a vein or provided as a nasal spray.
­ Clot-preserving medications. These medications help prevent
clots from breaking down.
­ Fibrin sealants. These medications can be applied directly to
wound sites to promote clotting and healing. Fibrin sealants are
especially useful in dental therapy.
­ Physical therapy. It can ease signs and symptoms if internal
bleeding has damaged your joints. If internal bleeding has caused
severe damage, surgery may be needed.
­ First aid for minor cuts. Using pressure and a bandage will
generally take care of the bleeding. For small areas of bleeding
beneath the skin, use an ice pack. Ice pops can be used to slow
down minor bleeding in the mouth.
­ Vaccinations. Although blood products are screened, it is still
possible for people who rely on them to contract diseases.

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Chapter 10.10.3 – Vitamin K Deficiency

VITAMIN K DEFICIENCY

“Vitamin K deficiency is a disease that occurs due to insufficient vitamin K in

body which results in bleeding and easy bruising.”

INTRODUCTION
 Vitamin K is a nutrient that the body requires in small, regular amounts.
It is essential for the formation of several substances called coagulation
factors that work together to clot the blood when injuries to blood
vessels occur.
 Vitamin k is a fat-soluble vitamin necessary for the synthesis (activation)
of clotting factors:
­ Clotting factor II (Prothrombin)
­ Clotting factor VII (Proconvertin)
­ Clotting factor IX (Thromboplastin)
­ Clotting factor X (Stuart factor)

TYPES OF VITAMIN K
 Types of vitamin k are:
­ Vitamin K1 (phylloquinone or phytomenadione)
­ Vitamin K2 (menaquinones)
­ Vitamin k3 (Menadione)
VITAMIN K1
 Vitamin K1 (phylloquinone or phytomenadione) is the natural from of
vitamin K that comes from foods, especially green leafy vegetables but
also dairy products and vegetable oils.
 K1 is considered as the "plant form" of vitamin K, but it is also produced
commercially to treat some conditions associated with excess bleeding.
VITAMIN K2
 Vitamin K2 (menaquinones) is made by bacteria, the normal flora in the
intestines. Bacteria in the intestines can also convert K1 into K2.
 Vitamin K2 supplements K1 from the diet to meet the body's
requirements.
 Menaquinone is also present in animal origin foods like:

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Chapter 10.10.3 – Vitamin K Deficiency

­ Meat especially liver Cheese.

VITAMIN K3
 Menadione is a non-natural, man-made chemical compound that is used
in some countries as a nutritional supplement because of its vitamin K
activity. It is sometimes called K3.

CAUSES
 The most common causes of vitamin K deficiency are insufficient dietary
intake, inadequate absorption, and decreased storage of the vitamin due
to liver disease, but it may also be caused by decreased production in
the intestines.
 Although vitamin K deficiency is uncommon in adults, certain people are
at increased risk if they:
­ Take coumarin anticoagulants such as warfarin, which thins the
blood
­ Are taking antibiotics
­ Have a condition that causes the body to not absorb fat properly
(fat malabsorption)
­ Have a diet that is extremely lacking in vitamin K.
 Some antibiotics cause the body to produce less of its own vitamin K.
Other antibiotics may cause vitamin K to become less effective in the
body.
 Fat malabsorption leading to vitamin K deficiency may occur in people
with:
­ Celiac disease
­ Cystic fibrosis
­ A disorder in the intestines or biliary tract (liver, gallbladder, and
bile ducts)
­ Part of their intestine removed.
 Newborn infants are at increased risk for vitamin K deficiency for a
variety of reasons:
­ Breast milk is very low in vitamin K
­ Vitamin K does not transfer well from a mother’s placenta to her
baby
­ The liver of a newborn infant does not use the vitamin efficiently
­ Newborns do not produce vitamin K2 on their own in the first few
days of life.

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Chapter 10.10.3 – Vitamin K Deficiency

SIGNS AND SYMPTOMS

 The signs and symptoms associated with vitamin K deficiency may
include:
­ Easy bruising
­ Oozing from nose or gums
­ Excessive bleeding from wounds, and injection or surgical sites
­ Heavy menstrual periods
­ Bleeding from the gastrointestinal (GI) tract
­ Blood in the urine and/or stool
­ Increased prothrombin time (PT)

DIAGNOSIS
PHYSICAL EXAM
 The exam is often unremarkable. In severe cases, the individual may be
weak and pale due to loss of blood.
 Physical findings may reveal small hemorrhagic spots in the skin
(petechial), a localized collection of blood (hematoma), or oozing of
blood from a puncture site.
 Bruising is common. Infants may have an underdeveloped face, nose, or
bones.
LABORATORY TESTS
 Prothrombin time
 Thrombin time
 Platelet count
 Platelet function tests
 Coagulation factor tests
 Fibrinogen

TREATMENT
 Short-term treatment for vitamin K deficiency usually involves either
oral supplementation or injections.
 Long-term or lifetime supplementation may be necessary for those with
underlying chronic conditions.
 In life-threatening bleeds, fresh frozen plasma should be administered
prior to VK.
 The treatment for vitamin K is the drug phytonadione which is vitamin
K1 .

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Chapter 10.10.4 – Anemia

ANEMIA

“Anemia is a group of diseases characterized by a decrease in either

hemoglobin (Hb) or the volume of red blood cells (RBCs), resulting in decreased
oxygen-carrying capacity of blood.”

INTRODUCTION
 Anemia is a condition in which body lack enough healthy red blood cells
to carry adequate oxygen to the tissues.
 There are many forms of anemia, each with its own cause. Anemia can
be temporary or long term, and it can range from mild to severe.

TYPES
 Aplastic anemia
 Iron deficiency anemia
 Sickle cell anemia
 Thalassemia
 Vitamin deficiency anemia.

CAUSES
 Different types of anemia have different causes. They include:
IRON DEFICIENCY ANEMIA
 This most common type of anemia is caused by a shortage of iron in
body. Bone marrow needs iron to make hemoglobin. Without adequate
iron, body cannot produce enough hemoglobin for red blood cells.
 Without iron supplementation, this type of anemia occurs in many
pregnant women. It is also caused by blood loss, such as from heavy
menstrual bleeding, an ulcer, cancer and regular use of some over-the-
counter pain relievers, especially aspirin, which can cause inflammation
of the stomach lining resulting in blood loss.
VITAMIN DEFICIENCY ANEMIA
 Besides iron, body needs folate and vitamin B-12 to produce enough
healthy red blood cells. A diet lacking in these and other key nutrients
can cause decreased red blood cell production.
 Also, some people who consume enough B-12 are not able to absorb the

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Chapter 10.10.4 – Anemia

vitamin. This can lead to vitamin deficiency anemia, also known as

pernicious anemia.
ANEMIA OF INFLAMMATION
 Certain diseases — such as cancer, HIV/AIDS, rheumatoid arthritis,
kidney disease, Crohn's disease and other acute or chronic inflammatory
diseases — can interfere with the production of red blood cells.
APLASTIC ANEMIA
 This rare, life-threatening anemia occurs when body does not produce
enough red blood cells. Causes of aplastic anemia include infections,
certain medicines, autoimmune diseases and exposure to toxic
chemicals.
ANEMIAS ASSOCIATED WITH BONE MARROW DISEASE
 A variety of diseases, such as leukemia and myelofibrosis, can cause
anemia by affecting blood production in bone marrow. The effects of
these types of cancer and cancer-like disorders vary from mild to life-
threatening.
HEMOLYTIC ANEMIAS
 This group of anemias develops when red blood cells are destroyed
faster than bone marrow can replace them. Certain blood diseases
increase red blood cell destruction.
SICKLE CELL ANEMIA
 This inherited and sometimes serious condition is a hemolytic anemia. It
is caused by a defective form of hemoglobin that forces red blood cells
to assume an abnormal crescent (sickle) shape. These irregular blood
cells die prematurely, resulting in a chronic shortage of red blood cells.

CLINICAL PRESENTATION
 Signs and symptoms depend on rate of development and age and
cardiovascular status of the patient.
 Acute-onset anemia is characterized by cardiorespiratory symptoms
such as palpitations, angina, orthostatic light-headedness, and
breathlessness.
 Chronic anemia is characterized by weakness, fatigue, headache,
orthopnea, dyspnea on exertion, vertigo, faintness, cold sensitivity,
pallor, and loss of skin tone.

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Chapter 10.10.4 – Anemia

DIAGNOSIS
COMPLETE BLOOD COUNT (CBC)
 A CBC is used to count the number of blood cells in a sample of blood.
For anemia, the levels of the red blood cells contained in blood
(hematocrit) and the hemoglobin in blood are measured.
 Normal adult hematocrit values vary among medical practices but are
generally between 40% and 52% for men and 35% and 47% for women.
Normal adult hemoglobin values are generally 14 to 18 grams per
deciliter for men and 12 to 16 grams per deciliter for women.
TEST TO DETERMINE THE SIZE AND SHAPE OF RED BLOOD CELLS
 Some of red blood cells might also be examined for unusual size, shape
and color.

TREATMENT
IRON DEFICIENCY ANEMIA
 Treatment for this form of anemia usually involves taking iron
supplements and changing diet.
 If the cause of iron deficiency is loss of blood — other than from
menstruation — the source of the bleeding must be located and the
bleeding stopped. This might involve surgery.
VITAMIN DEFICIENCY ANEMIAS
 Treatment for folic acid and vitamin C deficiency involves dietary
supplements and increasing these nutrients in diet.
ANEMIA OF CHRONIC DISEASE
 There is no specific treatment for this type of anemia. If symptoms
become severe, a blood transfusion or injections of a synthetic hormone
normally produced by kidneys (erythropoietin) might help stimulate red
blood cell production and ease fatigue.
APLASTIC ANEMIA
 Treatment for this anemia can include blood transfusions to boost levels
of red blood cells.
ANEMIAS ASSOCIATED WITH BONE MARROW DISEASE
 Treatment of these various diseases can include medication,
chemotherapy or bone marrow transplantation.

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Chapter 10.10.4 – Anemia

HEMOLYTIC ANEMIAS
 Managing hemolytic anemias includes avoiding suspect medications,
treating infections and taking drugs that suppress immune system,
which could be attacking red blood cells.
SICKLE CELL ANEMIA
 Treatment might include oxygen, pain relievers, and oral and
intravenous fluids to reduce pain and prevent complications.
 Blood transfusions, folic acid supplements and antibiotics might also be
recommended.
 A cancer drug called hydroxyurea (Droxia, Hydrea, Siklos) is also used to
treat sickle cell anemia.
THALASSEMIA
 Most forms of thalassemia are mild and require no treatment. More
severe forms of thalassemia generally require blood transfusions, folic
acid supplements, medication, removal of the spleen, or a blood and
bone marrow stem cell transplant.

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Topic Viz Past Papers Clinical Pharmacy

CLINICAL PHARMACY PAST PAPERS

01: RATIONAL USE OF DRUGS

Q: Discuss problems with irrational use of drugs related to patient diagnosis (8)
Annual 2015, 2nd Annual 2016
Q: Briefly explain the following: (2 each) Annual 2016, 2017
i. Multi-stage sampling
ii. Stratified sampling
iii. Systematic sampling with probability proportional to size
iv. Components to learn drug use problems
v. Sampling unit
Q: Enlist Qualitative methods to study drug use indicators (3) Annual 2016
Q: Describe the factors contributing towards irrational use of drugs (6) Annual
2016, Annual 2019
Q: Write a brief note on Non-probability sampling methods (3) 2nd Annual 2016
Q: Briefly explain health facility indicators (5) 2nd Annual 2016, Annual 2017
Q: What are the managerial, educational and regulatory interventional strategies
in ensuring rational use of drugs (7) 2nd Annual 2018, Annual 2020

02: INTRODUCTION TO ESSENTIAL DRUGS

Q: Discuss benefits of Essential Drugs List (5) Annual 2015
Q: Discuss underlying principle and criteria of selecting Essential Drugs List (7)
Annual 2015, Annual 2019
Q: Discuss benefits of Essential Drugs List (5) Annual 2015
Q: What is the basic concept behind essential drug list (EDL), also give brief
account of essential Drug List Pakistan (7) Annual 2017

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Topic Viz Past Papers Clinical Pharmacy

Q: What are WHO core drug use indicators, and describe Patient related
indicators in detail (7) 2nd Annual 2017, 2nd Annual 2018
Q: What are the managerial, educational and regulatory interventional strategies
in ensuring rational use of drugs (8) Annual 2017

03: DUE / DUR

Q: What are the distinct types of DUR? Discuss the importance of each type. (20)
Annual 2015
Q: Describe Drug Utilization Review Categories and process of establishing review
criteria and thresholds. (7) 2nd Annual 2016
Q: Role of a Pharmacist in Drug Utilization Review Process (4) 2 nd Annual 2016
Q: Formulate drug utilization evaluation criteria of Cimetidine (7) Annual 2017, 2 nd
Annual 2018, Annual 2020
Q: Define Drug Utilization Review (DUR) and various categories of DUR in detail
(7) 2nd Annual 2017

04: CLINICAL PHARMACOKINETICS

Q: Write a note on Therapeutic Drug Monitoring (TDM) process? (07) Annual 2015
Q: What are the pre-requisites of TDM (3) 2nd Annual 2017, 2nd Annual 2018
Q: Write down the factors affecting TDM? (05) Annual 2015, 2 nd Annual 2016, 2nd
Annual 2017, Annual 2019
Q: Write a detailed note on TDM of Gentamicin (08) Annual 2015, 2 nd Annual
2016
Q: Describe Therapeutic Monitoring of Single dose and once daily Gentamicin
regimen with and without Renal Impairment (07) 2nd Annual 2017, Annual 2018,
Annual 2019, Annual 2020
Q: Write a detailed note on Therapeutic Drug Monitoring of Phenytoin (08)
Annual 2016
Q: Write a detailed note on Therapeutic Drug Monitoring of Digoxin (08) 2 nd
Annual 2016, Annual 2017, 2nd Annual 2018

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Topic Viz Past Papers Clinical Pharmacy

Q: Write a detail note on therapeutic drug monitoring of Lithium (10) Annual

2016, 2nd Annual 2017, Annual 2018

05: PHARMACEUTICAL CARE

Q: Write a detailed note on SOAP and CORE pharmacotherapy plan (20) Annual
2017
Q: Write a note on Pharmacist work-up of drug therapy (PWDT) (20) Annual 2018,
Annual 2019
Q: Annual 2019
a) Define Pharmaceutical care (4)
b) Discuss standards of care for pharmaceutical care practitioners with respect
to assessment, care plan development and follow up evaluation. (8)
c) Discuss design of an optimal individualized pharmaco-therapeutic plan and
SMART approach. (8)
Q: Discuss drug therapy problems and its components. (8) Annual 2019
Q: Write in detail application of pharmaceutical care plan and how pharmacist can
utilize it for improved patient outcomes (8) Annual 2019

06: CLINICAL THERAPEUTICS

No Question in Past Papers.

07: CLINICAL TOXICOLOGY

No Question in Past Papers.

08: SAFE IV THERAPY AND HAZARDS OF IV THERAPY

Q: Explain hazards of I/v infusions? (20) Annual 2015
Q: Describe the hazards of intravenous (iv) therapy and explain the role of
Pharmacist to avoid hazards of IV therapy ? (10) Annual 2020

09: NON-COMPLIANCE
No Question in Past Papers.

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Topic Viz Past Papers Clinical Pharmacy

10: DISEASE MANAGEMENT

CHAPTER 5
No Question in Past Papers.
CHAPTER 6
Q: Annual 2018, Annual 2019, Annual 2020
a) What is the rational approach in the selection of antibiotics for treatment
(4)
b) What hemodynamic changes occur in the body alter the invasion of
infectious agent (8)
c) Write About the respiratory changes during infection. (8)
Q: What is the etiology and clinical presentation of patient afflicted with
meningitis (7) Annual 2016
Q: What are the therapeutic options for the most common pathogens of
meningitis (15) Annual 2017
Q: Briefly discuss treatment plan for meningitis (6) 2nd Annual 2018
Q: Enlist the sign and symptoms and pathophysiology of Tuberculosis (10) Annual
2016
Q: Write a detailed note on the clinical diagnosis and principles of Multi-drug
resistant TB treatment (10) Annual 2017, 2nd Annual 2018
Q: How Tuberculosis is diagnosed (6) Annual 2019
Q: Annual 2019
a) Define superficial and systemic fungal infections (4)
b) What is Blastomycosis? discuss clinical presentation and treatment, (8)
c) What are common skin fungal infections? Discuss causes, signs and
symptoms, diagnosis and treatment. (8)
Q: Discuss causes, signs and symptoms, diagnosis and treatment of Tinea cruris
and Pityriasis versicolor. (10) Annual 2020

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Topic Viz Past Papers Clinical Pharmacy

Q: Enlist the sign and symptoms and mode of transmission of HIV/AIDS and
Hepatitis in detail (10 marks) 2nd Annual 2016
Q: Write names of ANY THREE Antiretroviral drugs for the treatment of AIDS (3)
Annual 2017
Q: Write down the etiology of common cold (10) Annual 2016
Q: Write a note on conjunctivitis (7) 2nd Annual 2018
CHAPTER 7
Q: Discuss in detail the diabetic emergencies and their management (8) 2 nd
Annual 2016, 2nd Annual 2018
Q: Write a note on the diabetes management algorithm for type II diabetes with
more emphasis on the role of various Insulin regimens in the management of
type-Il diabetes (10) 2nd Annual 2017
Q: Write a detailed note on the non-Pharmacological management of Diabetes
and role of Pharmacist in its management (10) Annual 2018
Q: Write a note on type I diabetic complication and its management (7) Annual
2019
Q: How diabetic ketoacidosis (DKA) is diagnosed and draw management
algorithm of DKA (10) Annual 2020
Q: Draw algorithm for adding and intensifying Insulin, basal (long acting) and
post-prandial control (10) Annual 2020
Q: Draw hyperthyroid management algorithm (5) Annual 2019, Annual 2020
Q: Name Posterior pituitary hormones and briefly discuss the diagnosis and
management of disorder of posterior pituitary hormones (10) Annual 2019
CHAPTER 8
Q: Write a note on main treatment options available for Breast cancer patients (8)
Annual 2019
Q: Discuss in detail treatment considerations in Breast cancer (10) Annual 2020

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Topic Viz Past Papers Clinical Pharmacy

CHAPTER 9
Q: Write a detailed note on angiotensin converting enzyme inhibitors/angiotensin
receptor blockers-induced acute kidney failure (8) Annual 2016, 2nd Annual 2016
Q: 2nd Annual 2016
a) Define chronic kidney disease and describe its stages (5 Marks)
b) write a detailed note on analgesics-induced chronic kidney disease (8)
Q: Define acute kidney injury and describe its stages (3) Annual 2016
CHAPTER 10
Q: 2nd Annual 2018
a) Pharmacological Treatment of Iron deficiency anemia (7)
b) Pharmacological Treatment of vitamin B12 deficiency anemia (6)
Q: Classify anemia based on the etiologies and red blood cells morphology (10)
2nd Annual 2017

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References

References for Clinical Pharmacy Notes

1. Dr Hamid lectures
2. Dr Furqan lectures
3. Roger Walker Clinical Pharmacy and Therapeutics
4. Dipiro - Pharmacotherapy Handbook
5. Pharmacotherapy- A Pathophysiologic Approach

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