Pharmacology and Therapeutics Semi 1

UNITED REPUBLIC OF TANZANIA
Ministry of Health, Community

Development, Gender, Elderly and
Children
PST 05104
Pharmacology &
Therapeutics
NTA Level 4
Facilitator
Semester 2
Guide
PST 05104 Pharmacology & Therapeutics NTA Level 5 Semester 2 Facilitator Guide i
December 2018
PST 05104 Pharmacology & Therapeutics NTA Level 5 Semester 2 Facilitator Guide
ii
Copyright © Ministry of Health, Community Development, Gender, Elderly and Children 2018
PST 05104 Pharmacology & Therapeutics NTA Level 5 Semester 2 Facilitator Guide i
ii
Table of Contents
Background.........................................................................................................vi
Acknowledgement.............................................................................................vii
Introduction.........................................................................................................x
Abbreviations/Acronym.....................................................................................xii
Session 1: Drug Absorption.................................................................................1
Session 2: Drug Distribution..............................................................................11
Session 3: Metabolism of Drugs........................................................................18
Session 4: Drug Excretion..................................................................................25
Session 5: Drug Receptor Interaction................................................................32
Session 6: Agonists, Antagonists and Dose Response Relationship...................43
Session 7: Enzyme Inhibitors and Inducers........................................................52
Session 8: Pharmacodynamics of Drugs Acting on Endocrine System...............57
Session 9: Pharmacodynamics of Drugs Acting on Respiratory System............69
Session 10: Pharmacodynamics of Antiemetics and Drugs for Peptic Ulcer
Disease.............................................................................................................. 80
Session 11: Pharmacodynamics of Analgesics, Antipyretics and Anti-
inflammatory Drugs...........................................................................................89
Session 12: Pharmacodynamics of Drugs Acting Locally on the Skin.................96
Session 13: Pharmacodynamics of Antineoplastic Drugs................................102
Session 14: Pharmacodynamics of Immunosuppressive Agents.....................111
Session 15: Pharmacodynamics of Vitamins and Minerals..............................119
Session 16: Pharmacodynamics of Drugs Acting on Genital-Urinal System....126
Session 17: Pharmacodynamics of Antihelminthics........................................137
Session 18: Pharmacodynamics of Antimalarial Drugs....................................143
Session 19: Pharmacodynamics of Antifungal Drugs.......................................150
Session 20: Pharmacodynamics of Penicillins and Cephalosporins.................158
Session 21: Pharmacodynamics of Macrolides................................................167
Session 22: Pharmacodynamics of Fluoroquinolones.....................................172
Session 23: Pharmacodynamics of Aminoglycosides.......................................177
Session 24: Pharmacodynamics of Drugs for Amoebiasis................................182
Session 25: Pharmacodynamics of Antiviral Drugs..........................................188
Session 26: Introduction to Toxicology............................................................196
Session 27: Management of Acute Poisoning..................................................201
Session 28: Pharmacodynamics of Anticonvulsants........................................211
Session 29: Pharmacodynamics of Hypnotics and Anxiolytics.........................218
Session 30: Pharmacodynamics of Antipsychotic Drugs..................................225
Session 31: Pharmacodynamics of Drugs Used in Parkinson's Disease...........234
Session 32: Pharmacodynamics of Antidepressants........................................242
Session 33: Pharmacodynamics of Drugs for Heart Failure.............................251
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Session 34: Pharmacodynamics of Antihypertensive Drugs..........................258
Session 35: Pharmacodynamics of Anticoagulants..........................................267
Session 36: Pharmacodynamics of Antiplatelet Drugs.....................................275
Session 37: Pharmacodynamics of Local Anaesthetics....................................281
Session 38: Pharmacodynamics of General Anaesthetics................................287
Session 39: Pharmacodynamics of Antituberculosis Drugs.............................295
Session 40: Pharmacodynamics of Antiarrythmic Drugs...............................302
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Background
There is currently an ever-increasing demand for pharmaceutical personnel in Tanzania.
This is due to expanding investment in public and private pharmaceutical sector.
Shortage of trained pharmaceutical human resource contributes to poor quality of
pharmaceutical services and low access to medicines in the country (GIZ, 2012).
Through Public-Private-Partnership (PPP) the Pharmacy Council (PC) together with
Development Partners (DPs) in Germany and Pharmaceutical Training Institutions (PTIs)
worked together to address the shortage of human resource for pharmacy by designing a
project named “Supporting Training Institutions for Improved Pharmaceutical Services in
Tanzania in order to improve quality and capacity of PTIs in training, particularly of
lower cadre pharmaceutical personnel.
The Pharmacy Council formed a Steering committee that conducted a stakeholders
workshop from18th - 22ndAugust 2014 in Morogoro to initiate the implementation of the
project.
Key activities in the implementation of this project included carrying out situational
analysis, curriculum review and harmonization, development of training
manual/facilitators guide, development of assessment plan, training of trainers and
supportive supervision.
After the curricula were reviewed and harmonized, the process of developing
standardised training materials started through Writers Workshop approach. The
approach included a number of workshops for developing, reviewing, editing and
formatting the sessions of the modules.
The goals of writers workshops were to build capacity of tutors in the development of
training materials and to develop high-quality, standardized teaching materials.
The training package for pharmacy cadres includes a facilitator guide, assessment plan
and practicum. There are 11 modules for NTA level 5 making 11 facilitator guides
including one practicum guide.
v
Acknowledgement
The development of standardized training materials of a competence-based curriculum for
pharmaceutical sciences has been accomplished through involvement of different
stakeholders.
Special thanks go to the Pharmacy Council for spearheading the harmonization of training
materials in the pharmacy after noticing that training institutions in Tanzania were using
different curricula and train their students differently.
I would also like to extend my gratitude to Christian Social Service Commission (CSSC) for
their tireless efforts to mobilize funds from development partners. Special thanks to Multi
Actors Partnership (MAP) for the financial and technical support.
Particular thanks are due to those who led this important process to its completion, Centre
for Education Development in Health Arusha (CEDHA), Ms. Diana Gamuya, Mr.
Dickson Mtalitinya and Members from the secretariat of National Council for Technical
Education (NACTE) for facilitating the process.
Finally, I very much appreciate the contributions of the tutors and content experts
representing PTIs, hospitals, and other health training institutions. Their participation in
meetings and workshops, and their input in the development of this training
manual/facilitators guide have been invaluable.
These participants are listed with our gratitude below:
Ms. Elizabeth Shekalaghe Registrar, Pharmacy Council of Tanzania

Dr. Catherine Jincen Principal, CEDHA
Dr. Saitore Laizer Deputy Principal, CEDHA
Dr. Sungwa N. Kabissi Project Manager - MAP, CSSC
Ms. Diana Gamuya CEDHA
Mr. Dickson Mtalitinya SIBS
Ms. Emily Mwakibolwa Pharmacy Council
Mr. Samwel M. Zakayo Pharmacy Council
Mr. Komba NACTE
Mr. John Mmassy CSSC
Mr. Amani Phillip HKMU
Mr. Karol J. Marwa CUHAS
Mr. John M. Bitoro CUHAS
Mr. Raphael Matinde CUHAS
Mr. Rajabu I. Amiri MUHAS
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Mr. Peter Njalale MUHAS
Ms. Tumaini H. Lyombe MUHAS
Mr. Kolonjoi Olekiyapi KSP
Ms. Dilisi J. Makawia KSP
Mr. Gaspar Baltazary RuCU
Mr. Goodluck Mdugi RuCU
Mr. Joel Selestine SIBS
Mr. Jimmy M. Mutua SIBS
Mr. Nemes P. Uisso Moshi District Council
Mr. Mdoe
Dr. O. Gowele
Director of Human Resources Development
Ministry of Health, Community Development, Gender, Elderly and Children
vii
viii
Introduction
Module Overview
This module content is a guide for tutors of Pharmaceutical schools for training of
students. The session contents are based on sub-enabling outcomes and their related tasks
of the curriculum for Technician Course in Pharmaceutical Sciences. The module sub-
enabling outcomes and their related tasks are as indicated in the in the Technician
Certificate in Pharmaceutical Sciences (NTA Level 5) Curriculum
Target Audience
This module is intended for use primarily by tutors of pharmaceutical schools. The
modules sessions give guidance on the time, activities and provide information on how
to teach the session. The sessions include different activities, which focus on increasing
students knowledge, skills and attitudes.
Organization of the Module

The module consists of Forty (40) sessions; each session is divided into several parts as
indicated below:
 Session Title: The name of the session
 Total Session Time: The estimated time for teaching the session, indicated in minutes
 Pre-requisites: A module or session, which needs to be covered before teaching the
session.
 Learning Tasks: Statements which indicate what the student is expected to learn by
the end of the session
 Resources Needed: All resources needed for the session are listed including handouts
and worksheets
 Session Overview: The session overview box lists the steps, time for each step, the
activity or method used in each step and the step title
 Session Content: All the session contents are divided into steps. Each step has a
heading and an estimated time to teach that step as shown in the overview box. Also,
this section includes instructions for the tutor and activities with their instructions to
be done during teaching of the contents
 Key Points: Key messages for concluding the session contents at the end of a session
This step summarizes the main points and ideas from the session, based on the
learning tasks of the session
 Evaluation: The last section of the session consists of short questions based on the
learning tasks to check the understanding of students.
 Handouts: Additional information, which can be used in the classroom while
teaching or later for students, further learning. Handouts are used to provide extra
information related to the session topic that cannot fit into the session time. The
students to study material on their own and to refer to them after the session can use
ix
handouts. Sometimes, a handout will have questions or an exercise for the participants
including the answers to the questions.
x
Instructions for Use and Facilitators Preparation
 Tutors are expected to use the module as a guide to train students in the classroom and
skills laboratory
 The contents of the modules are the basis for teaching and learning dispensing.
 Use the session contents as a guide
 The tutors are therefore advised to read each session and the relevant handouts and
worksheets as preparation before facilitating the session
 Tutors need to prepare all the resources, as indicated in the resource section or any
other item, for an effective teaching and learning process
 Plan a schedule (timetable) of the training activities
 Facilitators are expected to be innovative to make the teaching and learning process
effective
 Read the sessions before facilitation; make sure you understand the contents in order
to clarify points during facilitation
 Time allocated is estimated, but you are advised to follow the time as much as
possible, and adjust as needed
 Use session activities and exercises suggested in the sessions as a guide
 Always involve students in their own learning. When students are involved, they learn
more effectively
 Facilitators are encouraged to use real life examples to make learning more realistic
 Make use of appropriate reference materials and teaching resources available locally
Preparation with Handouts and Worksheets

 Go through the session and identify handouts and worksheets needed for the session
 Reproduce pages of these handouts and worksheets for student use while teaching the
session. This will enable students to refer to handouts and worksheets during the
session in the class. You can reproduce enough copies for students or for sharing
 Give clear instructions to students on the student activity in order for the students to
follow the instructions of the activity
 Refer students to the specific page in the student manual as instructed in the facilitator
guide
Using Students Manual When Teaching

 The student manual is a document, which has the same content as the facilitator guide,
which excludes facilitator instructions and answers for exercises.
 The student manual is for assisting students to learn effectively and acts as a reference
document during and after teaching the session
 Some of the activities included in facilitator guide are in the student manual without
facilitator instructions
xi
Abbreviations/Acronym
AGS Gas Gangrene Antitoxin

ARS Anti Rabies Serum
ARV Anti-Retroviral
ATS Tetanus antitoxin
BCG Bacillus Calmette Guerin
CNS Central Nervous System
COCs Combined Oral Contraceptives
COPD Chronic Obstructive Pulmonary Diseases
CUHAS C atholic University of Heal and Allied sciences
DPT Diphtheria Pertussis Tetanu
E.L.C.T Evangelical Lutheran Church in Tanzania
HKMU Hurbert Kairuki Memorial University
ICP Increased Intra Cranial Pressure
IGs Immunoglobulins
ITP Idiopathic Thrombocytopenic Purpura
JSI John Snow Inc
KCMC Kilimanjaro College of Medical Sciences
LZHRC Lake zone Health Recourse Centre
MAO Mono Amine Oxidase
MMR Measles, Mumps and Rubella
MoHCGC Ministry of Health, Community development, Gender, Elderly and
children
MUHAS Muhimbili University of Health and Allied Sciences
NACTE National Council For Technical Education
NSAIDS Non-steroidal anti-inflammatory drugs
POPs Progestogen Only Pills
RuCU Ruaha Catholic University
SIBS Spring Institute of Business
SLF Saint Luke Foundation
USP United States Pharmacopoeia
xii
Session 1: Drug Absorption
Total Session Time: 120 minutes
Prerequisites
 PST04211_S1_ Introduction to Pharmacology
Learning Tasks
By the end of this session students are expected to be able to:
 Describe absorption
 Describe factors affecting/determining absorption
 Differentiate between Absolute and relative bioavailability
 Calculate bioavailability
 Explain clinical application of bioavailability
Resources Needed:
 Flip charts, marker pens, and masking tape
 Black/white board and chalk/whiteboard markers
 Computer and projector
SESSION OVERVIEW
Activity/
Step Time Content
Method
1 05 minutes Presentation Introduction, Learning tasks
Presentation/
2 10 minutes Definition of Absorption
Buzzing
Presentation/
3 45 minutes Small Group Factors Affecting Absorption
Discussion
4 20 minutes Presentation Absolute and Relative Bioavailability
Presentation/
5 20 minutes Calculation of Bioavailability
Brainstorming
6 10minutes Presentation Clinical Application of Bioavailability
7 05 minutes Presentation Key Points
8 05 minutes Presentation Evaluation
PST 05104 Pharmacology & Therapeutics NTA Level 5 Semester 2 Facilitator Guide 1
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning tasks (5 minutes)

READ or ASK students to read the learning objectives and clarify
ASK students if they have any questions before continuing.
STEP 2: Description of Absorption (10 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
 What is absorption?
 What are the processes involved in drug transport across GI tract?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
 Absorption follows administration and is the process by which a drug is made

available for use in the body.
o It is the transfer of a drug from its site of administration to the
 blood stream.
 It occurs after dissolution of a solid form of the drug or after the administration of a
liquid or parenteral drug.
 In this process the drug particles within the gastrointestinal tract are moved into the
body fluids.
 Transport of drug from the GIT involves passive diffusion, active transport and
pinocytosis.
 In active absorption a carrier molecule such as a protein or enzyme actively moves the
drug across the membrane.
 Passive absorption occurs by diffusion (movement from a higher concentration to a
lower concentration).
 In pinocytosis cells engulf the drug particle causing movement across the cell.
STEP 3: Describe Factors Affecting Absorption (45 Minutes)

2
Activity: Small Group Discussion ( 20 minutes)
DIVIDE students into small manageable groups
ASK students to discuss on the following question

 What is Absorption?
 What are factors affecting drug absorption?
ALLOW students to discuss for 15 minutes
ALLOW few groups to present and the rest to add points not mentioned
CLARIFY and SUMMARIZE by using the contents below:
Absorption
 Absorption is the movement of a drug from its site of administration into
the blood.
 Most drugs are absorbed by passive absorption but some drugs need
carrier mediated transport. Small molecules diffuse more rapidly than
large molecules.
 Lipid soluble non ionized drugs are absorbed faster.
Factors determining absorption include;

 route of administration,
 Blood flow to the absorption site
 Surface area available for drug absorption
 GI motility
 Physiochemical properties of drugs
 Particle size of the formulation
Route of administration
 Drugs are most rapidly absorbed when given by the intravenous route, followed by the
intramuscular route, the subcutaneous route, and lastly, the oral route.
 Typically, about 75% of a drug given orally is absorbed in 1-3 h, but numerous factors
alter this, some physiological and some to do with the formulation of the drug.
 The main factors are:
o gastrointestinal motility
o splanchnic blood flow
o particle size and formulation
o Physicochemical factors.
 Blood flows faster through the deltoid muscle (in the upper arm) than through the gluteal
muscle (in the buttocks).
3
o The gluteal muscle, however, can accommodate a larger volume of drug than the
deltoid muscle
Fig 1.1 Main routes of drug administration

Blood flow to the absorption site
 Blood flow to the intestine is much greater than the flow to the stomach resulting to a
favored absorption from the intestine over that from stomach.
Total surface area available for absorption
 Absorption of a drug across the GI tract is much efficient in the small intestine than
the stomach due to a higher surface area resulting from presence of microvilli:
 Other bodily conditions such as the development of lipodystrophy (atrophy of the
subcutaneous tissue) from repeated subcutaneous injections inhibit absorption of a
drug given in the site of lipodystrophy.
Enzyme activity
 Drugs such as insulin and other proteins may be degraded by gastric enzyme resulting to
poor absorption.
 The presence of food in the stomach both dilutes the drug and slows gastric emptying
thus taking a drug together with food results to a generally slow absorption.
GI tract motility
 Gastrointestinal motility has a large effect. Many disorders (e.g. migraine, diabetic
neuropathy) cause gastric stasis and slow drug absorption.
 Drug treatment can also affect motility, either reducing (e.g. drugs that block muscarinic
receptors) or increasing it (e.g. metoclopramide, which is used in migraine to facilitate
absorption of analgesic).
 Excessively rapid movement of gut contents can impair absorption.
 A drug taken after a meal is often more slowly absorbed because its progress to the small
intestine is delayed.
 There are exceptions, however, and several drugs (e.g. propranolol) reach a higher
plasma concentration if they are taken after a meal, probably because food increases
splanchnic blood flow.
Physicochemical factors
 Solubility :
4
o Some drugs are more soluble and thus are absorbed more rapidly than others
o Non-polar molecules (in which electrons are uniformly distributed) dissolve freely in
membrane lipids, and consequently diffuse readily across cell membranes.
o Consequently, there is a close correlation between lipid solubility and the
permeability of the cell membrane to different substances.
o For this reason, lipid solubility is one of the most important determinants of the
pharmacokinetic characteristics of a drug, and many properties-such as rate of
absorption from the gut, penetration into different tissues and the extent of renal
elimination-can be predicted from knowledge of a drug's lipid solubility.
 pH and ionization.
o For most drugs the mechanism of absorption is the same as for other epithelial
barriers, namely passive transfer at a rate determined by the ionisation and lipid
solubility of the drug molecules.
o Figure 1.3 below shows the absorption of various weak acids and bases as a function
of pKa.
 As expected, strong bases of pKa 10 or higher are poorly absorbed, as are strong
acids of pKa less than 3, because they are fully ionised
Fig 1.3 Absorption of drugs from the intestine, as a function of pKa, for acids and bases. Weak acids
and bases are well absorbed; strong acids and bases are poorly absorbed. (Redrawn from Schanker L S et al.
1957 J Pharmacol 120: 528.)
 Drug interaction
o Some drug interactions affect drug absorption. For example Tetracycline binds
strongly to Ca2+, and calcium-rich foods (especially milk) prevent its absorption.
o Bile acid-binding resins such as colestyramine (used to treat certain forms of hyper-
cholesterolaemia) bind several drugs, for example warfarin and thyroxine.
Particle size and formulation
 Tablets from different manufacturers may result into different plasma concentrations even
though the active ingredient content is the same because of different particle size.
 Therapeutic drugs are formulated pharmaceutically to produce desired absorption
characteristics.
 Capsules may be designed to remain intact for some hours after ingestion in order to
delay absorption, or tablets may have a resistant coating to give the same effect.
5
 In some cases, a mixture of slow- and fast-release particles is included in a capsule to
produce rapid but sustained absorption.
Fig 1.2 Variation in oral absorption among different formulations of digoxin. The four curves show the
mean plasma concentrations attained for the four preparations, each of which was given on separate
occasions to four subjects. The large variation has caused the formulation of digoxin tablets to be
standardised since this study was published. (From Lindenbaum J et al. 1971 N Engl J Med 285: 1344.)
STEP 4: Absolute and Relative Bioavailability (20minutes)

 The term bioavailability is used to indicate the proportion of drug that passes into the
systemic circulation after oral administration, taking into account both absorption and
local metabolic degradation.
 Drugs must enter the circulation if they are to exert a systemic effect.
 Unless administered intravenously, most drugs are absorbed incompletely
 There are three reasons for this:
o the drug is inactivated within the gut lumen by gastric acid, digestive enzymes or
bacteria;
o absorption is incomplete;
o presystemic (first-pass) metabolism occurs in the gut wall and liver.
 Together, these processes explain why the bioavailability of an orally administered

drug is typically less than 100%.
 Bioavailability of a drug formulation can be measured experimentally by measuring
concentration vs. time curves following administration of the preparation via its intended
route (e.g. orally) and of the same dose given intravenously
Formular: Bioavailability = AUCoral/AUCi.v. X 100%
6
Fig 1.4 Blood concentration-time curves, illustrating how changes in the rate of absorption and extent
of bioavailability caninfluence both the duration of action and the effectiveness of the same total dose
of a drug administered
Absolute Bioavailability
 Is the fraction of drug that reaches systemic circulation. I.V. is used as reference
Relative Bioavailability
 The amount of drug that reaches the system compared to the amount from another
standard formulation
Table 1.1 Routes of administration, bioavailability,and general characteristics.
7
STEP 5: Calculation of Bioavailability (20 Minute)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:

What is the bioavailability of paracetamol when 100mg is taken orally and 67mg of
the drug reaches systemic circulation?
ALLOW few students to respond?
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Bioavailability(F) = AUCoral/AUCi.v. X 100%

OR =Amount in blood /Amount administered
67/100=0.67
The bioavailability of paracetamol is 0.67
STEP 6: Clinical Application of Bioavailability (10minutes)

 Absolute Bioavailability is important in determining the amount of drug which will reach
systemic circulation hence available for distribution and consequently for action
 Difference in bioavailability between brands may lead to toxicities or reduced potency.
o For example,
 Differences in bioavailability did account for an epidemic of phenytoin
intoxication in Australia in 196869.
 Affected patients were found to be taking one brand of phenytoin in which the
excipient had been changed from calcium sulphate to lactose, increasing
phenytoin bioavailability and thereby precipitating toxicity.
o Furthermore, an apparently minor change in the manufacturing process of digoxin in
the UK resulted in reduced potency due to poor bioavailability.
 Therefore Prescribers need to be confident that different preparations (brand named or
generic) are sufficiently similar for their substitution to be unlikely to lead to clinically
important alterations in therapeutic outcome
STEP 7: Key Points (5 minutes)

 Absorption occurs through passive diffusion or active transport
 Zero per cent bioavailability implies that no drug enters the systemic circulation, whereas
100% bioavailability means that all of the dose is absorbed into the systemic circulation.
 Bioavailability may vary not only between different drugs and different pharmaceutical
formulations of the same drug, but also from one individual to another,
8
STEP 7: Evaluation (5 minutes)
 What is absorption?
 What are the factors affecting absorption of drugs?
 What is absolute bioavailability?
 Whay is the clinical use of bioavailability?
9
References
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines &
National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam,
Tanzania government printers.
Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael. (2014).
Pharmacotherapy: A Pathophysiologic Approach (9th ed.). New York, McGraw-
Hill Education.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York,
Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).

Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra
Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary
(59th ed). London, BMJ Group and RPS Publishing.
10
Session 2: Drug distribution
Prerequisites
Learning Tasks
 Describe the distribution of drugs in various compartments of the body
 Describe factors affecting/determining distribution of drugs
 Describe Volume of distribution
 Calculate Volume of distribution
 Explain clinical applications of volume of distribution
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Distribution of Drugs in Various
2 10 minutes
Buzzing Compartments of the Body
Presentation/
3 30 minutes Factors Affecting Distribution of Drugs
Brainstorming
Volume of Distribution
4 20 minutes Presentation
Presentation/
5 30 minutes Small Group Calculation of Volume of Distribution
Discussion
Clinical Application of Volume of
6 15minutes Presentation
Distribution
11
SESSION CONTENTS

STEP 2: Distribution of Drugs in various Compartments of the Body (10

minutes)
 Describe distribution process of drugs in the body?

 Once in the systemic circulation drugs will distribute into sections/units called
compartments. The following are the compartments for governing drug distribution:
o Plasma compartment (Vascular compartment)
o Drugs with very large molecular weight or those binding extensively to plasma
proteins are effectively trapped within the plasma (vascular) compartment because
such drugs are too large to move out through the endothelial slit junctions of the
capillaries.
o Extracellular fluid
o Observed in drugs with low molecular weights but also hydrophilic, such drugs can
move through the endothelial slit junctions of the capillaries into the interstitial fluid.
However, these hydrophilic drugs cannot move across the membranes of cells to enter
the water phase inside the cell.
o Total Body Water
o Observed in drugs with low molecular weight and are hydrophobic, such drugs can
not only move into the interstitium through the slit junctions, but can also
move ,through the cell membranes into the intracellular fluid.
o Other sites
12
o In pregnancy, the foetus may take up drugs and thus increase the volume of
distribution.
STEP 3: Factors Affecting Distribution of Drugs (30Minutes)

 What are the factors determining distribution of drugs?
ALLOW few students to respond

Distribution of drugs in the body is dependent on the following factors:
 Organ Blood Flow
o Organs with high blood flow will have larger amounts of drug delivered to them per unit
time.
o Organs with high blood flow will experience initial high concentrations of drug, but these
high concentrations will diminish as the drug is redistributed throughout the body to sites
with lower blood flow.
 Barriers to diffusion
o There are special barriers which restrict drug entry to some organs
o Blood Brain Barrier BBB is a special case
o In general, the BBB restricts the movement of hydrophilic drugs into brain; however, the
BBB is broken by ischemia and inflammation.
o The BBB can be exploited to develop drugs with reduced CNS adverse effects
 Adipose tissue
o Lipophilic drugs will distribute into adipose (fat) tissue.
o Distribution of lipophilic drugs into fat may necessitate a larger initial bolus of drug to
achieve the desired effect.
o Large depots of drug in fat may necessitate a longer period of time for drug to be
removed from the body.
o The distribution of lipophilic drugs will be different in thin versus obese patients
 Plasma protein Binding
o Drugs bound to protein are pharmacologically inactive.
o Only when the protein molecules release the drug can the drug diffuse into the tissues,
interact with receptors, and produce a therapeutic effect.
o Some drugs are highly bound (> 90%) to plasma proteins.
o Acid drugs bind to albumin and basic drugs bind to alpha1-acid glycoprotein.
o Binding of drugs by plasma proteins limits the distribution of drugs out of the vascular
compartment, necessitating more drug initially to achieve the desired effect
13
o Displacement of a highly plasma-protein bound drug by another drug may lead to drug-
drug interactions because of a rapid increase in the availability of free (unbound)
drug.
 Tissue protein binding
o Some drugs are highly bound to tissue proteins.
o Binding of drugs by tissue may necessitate a larger initial bolus of drug to achieve the
desired effect.
o Large depots of drug in tissue may necessitate a longer period of time for drug to be
removed from the body.
o In general Tissue bindings sites: Increase the apparent volume of distribution, represent
potential sites for drug interactions, result in sequestration of drug in the tissue, may
release the drug back into the circulation as the plasma concentration falls.
o Thus tissue binding may represent a reservoir of drug that can extend the duration of
action of the drug.
 Ion trapping
o Ion trapping can be used to distribute drugs into the urinary compartment to increase the
urinary excretion of poisons.
Example:
Alkalinisation of the urine with systemic administration of sodium bicarbonate is useful
for the treatment of overdoses of aspirin and phenobarbital.
Example:
Acidification of the urine with systemic administration of ammonium chloride is useful
for the treatment of amphetamine overdoses.
STEP 4: Volume of Distribution (20minutes)

 Volume of distribution is used to describe or predict the extent of drug distribution in the
body.
 The volume of distribution (Vd) is a hypothetical volume of fluid into which the drug is
disseminated.
o It is referred to as an apparent volume
Fig 2.1 Drugs appear to distribute in the body as if it were a single compartment.
14
 The magnitude of the drugs distribution is given by the apparent volume of distribution
(Vd)
 (Apparent) Volume of Distribution: Volume into which a drug appears to distribute with
 a concentration equal to its plasma concentration
 Vd is not a real volume with an independent existence. In this regard, the word volumeis
used in a metaphorical sense.
 However Vd is important clinically
 Values of Vd have been measured for many drugs
Volume of distribution = Dose / drug concentration
STEP 5: Calculation of Volume of Distribution (30 Minute)


 Calculate the Volume of distribution when 10mg of a drug X is administered to attain
a plasma concentration of 20mg/L?
CLARIFY and SUMMARIZE by using the contents below
 Vd = Amount of drug in body ÷ Concentration in Plasma
 =10mg/20mg/L
 The apparent Vd of the drug is 0.5L or 500ml
STEP 6: Clinical Application of Volume of Distribution (15minutes)

Volume of distribution has importance in the following situations:
 Determining the loading dose
o A delay in achieving the desired plasma levels of drug may be clinically unacceptable.
o Therefore, a "loading dose" of drug can be injected as a single dose to achieve the desired
plasma level rapidly
 LD = (VD x [C]P(target))/F
 LD = Loading dose,
15
 CP[target] is a target plasma concentration
 F=Bioavailability of the drug
From the formula above if we know the Vd and bioavailability of a drug

and predict our target plasma concentration to be obtained when a drug is
administered then we can predict the high dose (loading dose) to be
administered.
Fig 2.2 shows the effect of using loading dose for digoxin that help to achieve the required therapeutic
concentrations immediately in contract to the use of normal dosing regime which may require up to 10
dats to achieve therapeutic concentration
 Apparent volume of distribution will predict whether the drug will

reside in the blood or in the tissue.
o Water soluble drugs will reside in the blood, and fat soluble drugs
will reside in cell membranes, adipose tissue and other fat-rich
areas.
 Volume of Distribution also relates to whether a drug is Free / protein

bound
o Protein bound drugs form macromolecular complexes that cannot

cross biological membranes and remain confined to the
bloodstream.

 Various body compartments are involved in the distribution of drugs
 Distribution of drugs is affected by many factors
 The volume of distribution is a hypothetical volume but of clinical importance in the
determination of a loading dose.

16
 What is the meaning of Volume of distribution?
 What are factors affecting drug distribution?
 What is the clinical application of Volume of distribution?
 List drugs with a large volume of distribution
 What is the relationship between volume of distribution and elimination?
17
References
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National
Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania
government printers.
Pharmacotherapy: A Pathophysiologic Approach (9th ed.). New York, McGraw-Hill
Education.

18
Session 3: Metabolism of Drugs
Prerequisites
Learning Tasks
 Describe reactions involved in drug metabolism
 Describe factors affecting drug metabolism
 Describe first pass effect
 Describe kinetics of metabolism
 Explain clinical importance of drug metabolism
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 10 minutes Reactions Involved in Metabolism
Buzzing
Presentation/
3 45 minutes Small Group Factors Affecting Metabolism
Discussion
4 200 minutes Presentation First Pass Metabolism
5 20 munites Presentation Kinetics of Metabolism
6 10 minutes Presentation Clinical Importance of Metabolism
19
SESSION CONTENTS

STEP 2: Reactions Involved in Drug Metabolism (10 minutes)
 List reactions involved in drug biotransformation?
 There are several reactions involved in drug biotransformation.
 These reactions are grouped into two major groups called Phase 1 and Phase 2.
Phase 1 Reactions
 Phase 1 reactions are catabolic (e.g. oxidation, reduction or hydrolysis), and the products
are often more chemically reactive and hence, paradoxically, sometimes more toxic or
carcinogenic than the parent drug.
 Phase 1 reactions often introduce a reactive group, such as hydroxyl, into the molecule, a
process known as 'functionalisation'.
 This group then serves as the point of attack for the conjugating system to attach a
substituent such as glucuronide explaining why phase 1 reactions so often precede phase
2 reactions.
 Phase 1 reactions take place mainly in the liver whereby many hepatic drug-metabolising
enzymes, including CYP enzymes are involved.
 In general phase 1 reactions include hydroxylation, dealkylation, deamination,

desulfuration, dechlorination, hydrolysis and reductions reactions
Phase 2 reactions
20
 Most of phase 1 metabolites are more polar hence expected to be readily excreted.
 However some drugs are not eliminated rapidly require a further reaction involving an
addition of an endogenous glucuronic acid, sulfuric acid, amino acid or acetic acid to
form a highly polar conjugate for elimination.
 In general Phase 2 conjugation reactions involves glucuronidation, acetylation,

conjugation, sulphation and methylation.
STEP 3: Factors Affecting Metabolism of Drugs (45Minutes)


 What are factors affecting metabolism of drugs?
CLARIFY and SUMMARIZE by using the contents below
Drug metabolism is affected by the followings:

 Genetic factors
o Genetic factors influence enzyme levels and expression of activity. There is a great
variation in the population how individuals metabolize drugs.
o The greater part of this effect is due to Cytochrome P450 polymorphism.
o A few examples of variation on metabolism due to genetics include acetylation of
isoniazid and hydroxylation where there are slow and fast metabolizers in the population
for the drugs.
 Diet and environmental factors

21
o Cigarette smokers metabolize some drug faster than non-smokers because of enzyme
induction
o Some foods and drinks also affect drug metabolism.
 For example grape juice decrease metabolism of some drugs because of enzyme
inhibition
 Age and Sex
o A decreased metabolism of drugs is observed in clinical practice in very young patients
due to immature enzymes and very old patients due to deterioration of liver function
o A variation in metabolism basing on sex difference in human is reported for ethanol,
salicylates, some benzodiazepines, oestrogens and propranolol
 Drug drug interactions
o Drugs known to be enzyme inducers or enzyme inhibitors can affect metabolism of other
drugs when administered concomitantly
 Diseases
o Some acute or chronic diseases/conditions decrease greatly hepatic metabolism.
o Such conditions include alcoholic hepatitis, alcoholic cirrhosis and drug or viral induced
hepatitis
STEP 4: First Pass Effect (20minutes)

 Some drugs are extracted so efficiently by the liver or gut wall that the amount reaching
the systemic circulation is considerably less than the amount absorbed.
 This is known as first-pass or presystemic metabolism and reduces bioavailability even
when a drug is well absorbed.
 Presystemic metabolism is important for many therapeutic drugs and is a problem
because:
o a much larger dose of the drug is needed when it is given orally than when it is given
parenterally
o marked individual variations occur in the extent of first-pass metabolism
 Examples of drugs that undergoes first pass metabolism are as follows;
o Aspirin
o Metoprolol
o Glyceryl trinitrate
o Morphine
o Isosorbide dinitrate
o Propranolol
o Levodopa
o Salbutamol
o Lidocaine
o Verapamil
 The first pass effect can be avoided greatly by the administration of drugs through
Intraveous route, sublingual routeand the use transdermal patches.
22
STEP 5: Kinetics of Metabolism (20 Minute)
Drug metabolism involves:
 First order kinetics
 Zero order kinetics
First order kinetics (Linear Kinetics)
 Most drugs are metabolized through first order kinetics and is observed in most clinical
situations
 In the first order kinetics the rate of metabolism of a drug is directly proportional to the
concentration of free drug
 That means a constant fraction of drug is cleared per unit time
Zero order kinetics (Non Linear kinetics)

 Very few drugs exhibit this kinetics. A good examples are Aspirin, Phenytoin, Ethanol
 In general zero order kinetics is observed in drugs when doses are high thus the enzyme is
saturated with a high free drug concentration.
 In this situation the rate of metabolism is constant regardless drug concentration.
 It remains constant all the time.
 A constant amount of drug is metabolised per unit time
 Drugs like Phenytoin that follows saturable kinetics may start showing first order kinetics
initialy, but as more doses of a drug are added, the metabolising enzymes become saturated
resulting to zero order/saturable kinetics as indicated in the graph below;
23
Once the metabolising enzymes of phenytoin or any other drug with saturable kinetics are
saturated, any small increment of the dose may result into marked increase of its plasma
concentrations leading to drug toxixity
STEP 6: Clinical Importance of Drug Metabolism (10minutes)

Metabolism plays a pivotal role in the followings:
 Lipophilic drugs when metabolised are converted to a more polar form which is easily
eliminated through the kidney.
o This reduces drug accumulation and half-life.
 Pro drugs are converted to their active inorder to produce their pharmacological action.
 In some cases, metabolism of a drug may result into toxic metabolites in the body.

 Metabolism of drugs is affected by various factors
 Metabolism of drugs mainly takes pale in the liver through Phase I and Phase II reactions
 Metabolism of drugs may either follow first or zero order kinetics
 Metabolism makes a non-polar drug to be polar which will be readily excreted through
kidneys

 What are organs involved in metabolism?
 What are the factors affecting metabolism of drugs?
 List enzymes involved in phase 1 metabolism od drugs
 How can first pass effect be avoided?
24
References
Robert L. Talbert, Gary C. Yee, Gary R. Mat0pzke, Barbara G. Wells, L. Michael. (2014).
Education.

25
Session 4: Drug Excretion
Prerequisites
Learning Tasks
 Describe routes of drug elimination
 Describe factors affecting renal drug excretion
 Calculate clearance
 Describe clinical importance of elimination half life
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 10 minutes Routes of Drug Excretion
Buzzing
Presentation/
3 30 minutes Factors Affecting Renal Drug Excretion
brainstorming
5 15 minutes Presentation Calculation of Clearance
Presentation/ Description of Clinical Importance of
6 20 minutes
Brainstorming Elimination Half Life
26
SESSION CONTENTS

STEP 2:Routes of Drug Elimination (10 minutes)
 What routes are involved in the excretion of drugs?

 Removal of a drug from the body may occur via a number of routes, the most important being
through the kidney into the urine.
 Other routes include
o the bile,
o intestine,
o sweat
o lung,
o Milk in breastfeeding mothers.
Renal excretion:
 Most drugs are renally cleared and differ greatly in the rate at which they are excreted by the
kidney
 Some drugs are almost completely cleared renally such as penicillin and others are slowly
cleared, eg diazepam
 Three fundamental processes account for renal drug excretion:
o glomerular filtration
o active tubular secretion
o passive diffusion across tubular epithelium
Excretion via Breast Milk
 Breast milk is a quantitatively relatively minor route of drug excretion.

 Nevertheless, it is clinically important for breastfeeding mothers and their infants.
 The baby will ingest drugs excreted in the breast milk.
27
 Moreover, breast milk has a lower pH than plasma.
 Accordingly, basic drugs will be concentrated in the breast milk through the phenomenon of
ion (pH) trapping.
 A number of drugs can reach clinically significant concentrations in the breast milk and
thereby affect nursing babies.
Pulmonary excretion
 Is important for gaseous lipophilic substances.
 The gaseous general anaesthetics are the most common example.
 Drug diffuses from the plasma into the alveolar space and is excreted during expiration.
Biliary Excretion :
 Biliary excretion involves active secretion of drug molecules or their metabolites from
hepatocytes into the bile.
 The bile then transports the drugs to the gut, where the drugs are excreted.
 The transport process is similar to those described for renal tubular secretion.
 The efficiency of biliary excretion is quite variable.
Enterohepatic cycling.
 Although many drugs may reach the gut through Biliary Excretion, deconjugating enzymes in
the gut and the gut pH causes many drugs to assume nonpolar lipophilic forms that then are
promptly reabsorbed by diffusion into the plasma.
 Drugs that undergo extensive enterohepatic cycling generally have long durations of action
e.g Rifampicin
STEP 3: Factors Affecting Renal Drug Excretion (30 Minutes)
 What are the factors affecting renal drug clearance?


Renal excretion of a drug is affected by the following factors depending on the mechanism:
Glomerular filtration:
Molecular weight of a drug
 Glomerular capillaries allow drug molecules of molecular weight below about 20 000 to pass
into the glomerular filtrate.
 Plasma albumin (molecular weight approximately 68 000) is almost completely impermeant,
but most drugs-with the exception of macromolecules such as heparin or biological products
can cross the barrier freely.
28
Protein binding
 If a drug binds to plasma albumin, only free drug is filtered.
 If, like warfarin , a drug is approximately 98% bound to albumin, the concentration in the
filtrate is only 2% of that in plasma, and clearance by filtration is correspondingly reduced.
Disease or age.
 Glomerular filtration rate decreases approximately 1% per year and may be significantly
compromised in elderly patients.
 The decline in glomerular filtration rate is accelerated by disease states such as diabetes.
 For drugs that are eliminated by glomerular filtration, dosages are often adjusted based on the
patients glomerular filtration rate.
Tubular secretion
 Secretory mechanisms in the renal tubules actively transport endogenous substances and drug
molecules from the plasma in peritubular capillaries to the tubular lumen.
 Although quite diverse in some characteristics, the tubular transporters can be classified into
two major groups: the organic anion transporter (OAT) and the organic cation transporter
(OCT) families.
 Tubular transporters exhibit saturability.
o Transporters reach a maximum rate of excretion, after which further increases in drug
concentration do not cause further increases in secretion.
 Tubular secretion is especially important for drugs that are highly plasma protein bound,
because these drugs are not excreted effectively by glomerular filtration.
 Important in delivering some drugs, such as diuretics, to their site of action in the renal
tubule.
 Is not affected by the degree to which a drug binds to plasma proteins.
 Tubular secretion can be manipulated clinically via the use of inhibitors to extend the
duration of action and increase the plasma concentration of drugs that are rapidly excreted by
tubular secretion.
 For example, the drug probenecid blocks the OAT transporter responsible for secretion of
some penicillin and cephalosporin antibiotics into the renal tubule.
 Probenecid can be prescribed along with antibiotics in the penicillin and cephalosporin
families to prolong their duration of action.
 Reduced in neonates, infants, and the elderly.
 Affected by genetic polymorphisms in the OAT and OCT family of transporters.
Tubular reabsorption
 Once in the renal tubule, the nonionized form of the drug is able to diffuse across the tubular
membrane and re-enter the plasma.
29
 Water is reabsorbed along the renal tubule the tubular drug concentration increases, providing
a concentration gradient favouring drug reabsorption.
 Manipulation of the pH of the tubular fluid can be used to enhance or inhibit tubular
reabsorption according to the Henderson-Hasselbalch relationship.
 Acidification of urine can be used to decrease reabsorption of weak bases by increasing the
proportion of drug in the ionized form.
 Conversely, alkalinization of urine can be used to increase the renal excretion of acidic drugs
because a greater proportion of the drug is in the ionized form.
STEP 5: Calculation of Clearance (10 Minute)

 What is the clearance of drug X with a plasma concentration of 4mg/L and is eliminated
at a rate of 10mg/hr ?
 Clearance (CL) is the volume of plasma containing the total amount of drug that is removed
from the body in unit time
 Clearance: volume of plasma cleared of drug per unit time.
 Clearance = Rate of elimination ÷ plasma conc.
CL of drug X= 10mg/hr÷ 4mg/L= 2.5L/hr
 Total Clearance is obtained by adding individual clearences depending on the route of

elimination of that drug
 Therefore, for a drug that is cleared through kidneys, liver and lungs the total clearance is
obtained as follows;
Cl (Total) = Cl (Renal) + Cl(Hepatic) + Cl(Lungs)
STEP 6: Clinical importance of Elimination Half life (5minutes)
 Half-life refers to the time required for the body to eliminate 50% of the drug.
 Elimination Half-life of refer to time for plasma concentration to decrease by half.
30
 Elimination half-life (t ½) can be used to predict how long it will take from the start of dosing
to reach steady-state levels during multiple dosing or continuous intravenous (i.v.) infusion.
 Also elimination half life help in determination of dosing frequency
 Steady state is reached when rate in (input) = rate out (output).
 The time to reach steady state is dependent only on t½ of a drug , i.e. 4-5 t½
o For example, drugs with a short half-life (24 hours) need to be administered
frequently, whereas a drug with a long half-life (2124 hours) requires less frequent
dosing.
o For example, digoxin has a long half-life (36 hours) and requires once-daily dosing.
o However, aspirin has a short half-life and requires frequent dosing.
o
 Difficulty in excreting a drug increases the half-life and increases the risk of toxicity.

 The kidney cannot excrete non-polar substances efficiently, since these diffuse back into
blood as the urine is concentrated.
 Renal impairment reduces the elimination of drugs that depend on glomerular filtration
 Passive reabsorption limits the efficiency with which the kidney eliminates drugs.
 The urine may be deliberately alkalinized by infusing sodium bicarbonate intravenously in
the management of overdose with weak acids such as aspirin

 What are the factors affecting renal elimination?
 What is the clinical application of elimination half-life?
 What is the importance of acidifying or alkanizing urine?
31
References
Education.

32
Session 5: Drug Receptor Interaction
Prerequisites
Learning Tasks
 Describe of drug-receptor interaction
 Describe the types of receptors
 Explain the concept of receptor regulation
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 30 minutes Drug-Receptor Interaction
Buzzing
Presentation/
3 45 minutes Types of Receptor
brainstorming
6 30 minutes Presentation Concept of Receptor Regulation
33
SESSION CONTENTS

STEP 2: Drug-Receptor Interaction (30 minutes)
 What is a receptor?
 How do drugs interact with receptors?
 A drug receptor is a specialized target macromolecule, present on the cell surface or

intracellularly, that binds a drug and mediates its pharmacologic actions.
 It describes protein molecules whose function is to recognise and respond to endogenous
chemical signals.
 The term is most often used to describe the target molecules through which soluble
physiological mediators-hormones, neurotransmitters, inflammatory mediators, etc.-produce
their effects.
 Examples are acetylcholine receptors, cytokine receptors, steroid receptors, and growth
hormone receptors
 Pharmacological effects, therefore, require, in general, that drug molecules must be
'bound' to particular constituents of cells and tissues in order to produce an effect.
 Four main kinds of regulatory protein are commonly involved as primary drug targets,
namely:
o receptors
o enzymes
o carrier molecules (transporters)
o ion channels
 The function of a cell alters when a drug interacts with a receptor cell.
 At its most fundamental level, the interaction of drug and receptor follows the law of mass
action.
 The law of mass action dictates that:
34
o The combination of drug (also called ligand) and receptor depends on the concentrations
of each
o The amount of drug-receptor complex formed determines the magnitude of the response
o A minimum number of drug receptor complexes must be formed for a response to be
initiated (threshold)
o As drug concentration increases, the number of drug-receptor complexes increases and
drug effect increases
o A point will be reached at which all receptors are bound to drug, and therefore no further
drug-receptor complexes can be formed and the response does not increase any further
(saturation)
Law of Mass Action Applied to Drugs:
Drug +Receptor ↔ Drug-Receptor Complex →Effect
 Occupation of a receptor by a drug molecule may or may not result in activation of the
receptor.
 By activation, we mean that the receptor is affected by the bound molecule in such a way
as to elicit a tissue response
 agonists, which 'activate' the receptors
 If a drug binds to the receptor without causing activation and thereby prevents the agonist
from binding, it is termed a receptor antagonist.
 The tendency of a drug to bind to the receptors is governed by its affinity, whereas the
tendency for it, once bound, to activate the receptor is denoted by its efficacy.
35
Selectivity of Drug Responses
Drug molecules exhibit preferential affinity for receptors as follows:
 The cell will respond only to the spectrum of drugs that exhibit affinity for the receptors
expressed by the cell.
 The greater the extent to which a drug molecule exhibits high affinity for only one receptor,
the more selective will be the drugs actions, with lower potential for side effects.
 The higher the affinity and efficacy of a given drug, the smaller the amount of drug necessary
to activate a critical mass of drug receptors to effect a tissue response, and the lower the
potential for nonselective actions.
 As the concentration of a drug increases, the drug will combine with receptors for which it
has lower affinity and may generate off-target effects.
 Thus selectivity of a drug to a specific receptor is obtained at low to moderate doses.
STEP 3: Types of Receptor 45Minutes)

 What are the types of receptors?

There are four receptor types or superfamilies namely:
36
 Type 1-Ligand-gated ion channels (ionotropic receptors)
 Type 2- G-protein-coupled receptors (GPCRs) [metabotropic receptors or seven-
transmembrane-spanning (heptahelical) receptors
 Type 3-Kinase (Enzyme) linked and related receptors
 Type 4-Nuclear receptorsIntranuclear/intracellular receptors (e.g. gonadal and
glucocorticosteroids hormones)
Type 1-Ligand-gated ion channels/Trans membrane ion channel (ionotropic receptors)

 Conduct ions across membrane in response to ligand binding, voltage gradient or second
messenger; e.g., H+/K+-ATPase
 Transmembrane ion channels allow the passage of ions from one side of a membrane to
another.
 Channels can exist in the open, closed, or inactive state, which represent different
conformations of the channel protein.
 Drugs may affect the function of these channels by directly opening or closing the channel
(ligand gated channels), by influencing the voltage-dependent characteristics of the channels
(voltage gated channels) and the amount of time the channel spends in a given state, or by
generating second messengers that subsequently open or close the channel (second messenger
gated).
 Examples include the following:

o Cholinergic receptors located in skeletal muscle bind nicotine, resulting in opening of
sodium channels, initiation of an action potential in the muscle, and finally muscle
contraction.
37
o Neuromuscular (paralyzing) drugs antagonize this nicotinic receptor, thereby preventing
muscle contraction.
o Drugs that stimulate GABAA receptors open chloride channels, causing
hyperpolarization (making the cell more negative) and reducing the probability of an
action potential being produced, thereby turning off the target neuron.
o Drugs that treat anxiety and sleep disorders are clinical examples of these types of drugs.
Voltage gated ion channels.
 These ion channels change conformation (open, closed, or inactive) in response to changes in
membrane voltage.
 Drug binding to the channel alters the response of the channel to changes in membrane
voltage such that the open, closed, or inactivate state may be lengthened or shortened.
 An example is a local anesthetic agent that binds to sodium channels that are responsive to
the arrival of an action potential.
 Local anesthetics lock the channels in the inactive state, thereby rendering them temporarily
nonresponsive to future action potentials and thereby block transmission of pain signals.
Type 2: Transmembrane linked to intracellular G protein/ G-Protein Coupled

Receptor/ Metabotropic Receptors
 G-proteins consist of 3 subunits, alpha, beta and gamma. (α, β, γ)
 Guanine nucleotides bind to the α subunit, which has enzymic activity, catalysing the
conversion of GTP to GDP.
 β and γ subunits remain together as a βγ complex.
 G-proteins appear to be freely diffusible in the plane of the membranThe e, so a single pool
of G-protein in a cell can interact with several different receptors and effectors in an
essentially promiscuous fashion.
38
 In the 'resting' state, the G-protein exists as an unattached αβγ trimer, with GDP occupying
the site on the α subunit
 When a GPCR is activated by an agonist molecule, a conformational change occurs,

involving the cytoplasmic domain of the receptor , causing it to acquire high affinity for αβγ.
 Association of αβγ with the receptor occurs within about 50 ms, causing the bound GDP to
dissociate and to be replaced with GTP (GDP-GTP exchange), which in turn causes
dissociation of the G-protein trimer, releasing α-GTP and βγ subunits;
 These are the 'active' forms of the G-protein, which diffuse in the membrane and can
associate with various enzymes and ion channels, causing activation of the target as shown in
the following figure below;
 Examples include adrenergic receptors:

 In many cases the transduction or coupling mechanism is linked to the final effector system
via an intermediate cell signalling (second messenger) system which are;
o Adenylate cyclase which catalyses the conversion of ATP to cyclic AMP;
o Guanylate cyclase which catalyses the conversion of GMP to cyclic GMP (cyclic AMP
and cyclic GMP are known collectively as cyclic nucleotides)
39
o Calcium and calmodulin; phospholipase C which catalyses phosphoinositide turnover
producing inositol phosphates(IP3) and diacyl glycerol(DAG).
Type 3-Kinase (Enzyme) linked and related receptors

 There is a large and heterogenous group of membrane receptors responding to protein
mediators.
 They comprise an extracellular ligand-binding domain linked to an intracellular domain by a
single transmembrane helix.
 In many cases the intracellular domain is enzymic in nature ( with protein kinase or guanylate
cyclase activity)
 Examples include receptor tyrosine kinases

 Ligand binding stimulates the kinase enzymatic activity, which then initiates and amplifies
intracellular signals and feedback responses by changing the phosphorylation status of
cellular proteins.
Type 4-Nuclear receptorsIntranuclear/intracellular receptors (e.g. gonadal and

glucocorticosteroids hormones)
 Ligands bind to their receptor in cytoplasm and the complex then migrates to the nucleus and
binds to specific DNA sites, producing alterations in gene transcription and altered protein
synthesis. Such effects occur over a time-course of minutes to hours.
 Receptors using this coupling mechanism include: Sex hormones: estrogen, androgens,
Glucocorticoids, Mineralocorticoids, Thyroid or retinoid receptor family and Vitamin D
receptors
STEP 4: Concept of Receptor Regulation (30minutes)

Prolonged exposure of receptors to agonists, as frequently occurs in therapeutic use, can
cause
 Desensitization of receptors
 Translocation of receptors
40
Desensitization
 Desensitization mostly occurs in receptors directly coupled to ion channels.
 It can occurs at the neuromuscular junction as the result of a conformational change in the
receptor, resulting in tight binding of the agonist molecule without the opening of the ionic
channel.
 Desensitization of ion channels can also be caused by phosphorylation of intracellular regions
of the receptor protein which is a second, slower mechanism.
 Phosphorylation of the receptor interferes with its ability to activate second messenger
cascades, although it can still bind the agonist molecule.
 This type of desensitization usually takes a few minutes to develop, and recovers at a similar
rate when the agonist is removed.
Translocation of Receptors
 Prolonged exposure to agonists often results in a gradual decrease in the number of receptors
expressed on the cell surface, as a result of internalisation of the receptors.
 This is shown for β-adrenoceptors whereby the number of β-adrenoceptors can fall to about
10% of normal in 8 h in the presence of a low concentration of isoprenaline, and recovery
takes several days.
 The internalised receptors are taken into the cell by endocytosis of patches of the membrane,
a process that also depends on receptor phosphorylation.
 This type of adaptation is common for hormone receptors and has obvious relevance to the
effects produced when drugs are given for extended periods.
SUMMARY

 There are four types of drug receptors
 Prolonged use of drugs can result into up or down regulation of receptors
 Drug receptor- interaction exhibit specific properties
41
 What are receptors?
 What are the four types of receptors?
 What is desentization of receptors?
42
References
Education.

43
Session 6: Agonists, Antagonists and Dose Response
Relationship
Prerequisites
Learning Tasks
 Describe Agonist and antagonist effects
 Describe dose response relationship
 Explain on factors modifying drug response
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Description Of Agonist And Antagonist
Presentation/
4 30 minutes Effects
Brainstorming
Presentation
5 45 minutes Small Group Description of Dose Response Relationship
Discussion
Presentation/ Explanation on Factors Modifying Drug
30 minutes
Brainstorming Responses
44
SESSION CONTENTS

STEP 2: Effect of Agonist and Antagonist (30minutes)
 What are do you understand by the terms agonist and antagonist?
Drugs are categorized based on their intrinsic activity at a given receptor: :

 Agonist :
o Agonists (sometimes called full agonists) produce maximum activation of the receptor
and elicit a maximum response from the tissue.
o They are assigned an intrinsic activity of 1.
o Agonists activate receptors for endogenous mediators example salbutamol is an agonist
at β2-adrenoceptors, the consequent effect may be excitatory (e.g. increased heart rate) or
inhibitory (e.g. relaxation of airway smooth muscle).
o Agonists at nicotinic acetylcholine receptors (e.g. suxamethonium) exert an inhibitory
effect (neuromuscular blockade) by causing long-lasting depolarization at the
neuromuscular junction, and hence inactivation of the voltage- dependent sodium
channels that initiate the action potential.
 Partial Agonist
o A partial agonist is a drug that displays efficacy that is intermediate between that of an
agonist and an antagonist
o Partial agonist produces a lower response at full receptor occupancy than full agonists
o Partial agonists also produce concentration effect curves that resemble those observed
with full agonists
45
 Inverse Agonist :
o Inverse agonists inhibit rather than activate the receptor.
o This phenomenon is evident with receptors that exhibit baseline (ongoing or constitutive)
activity in the absence of agonist binding.
o In these cases, binding of the inverse agonist reduces the baseline activity of the receptor,
which in turn elicits an effect opposite that of binding of the agonist.
o Inverse agonists and antagonists will elicit similar effects because both types of drugs will
reverse the effects of endogenous ligands.
 Antagonist :
o Antagonists bind but produce no activation of the receptor and therefore block responses
from the tissue.
o They are assigned an intrinsic activity of 0.
There are two types of antagonism
Competitive antagonists
 Antagonist combines with the same receptor as an endogenous agonist (e.g. ranitidine at
histamine H2-receptors), but fail to activate it.
 When combined with the receptor, they prevent access of the endogenous mediator.
 The complex between competitive antagonist and receptor is reversible.
 Provided that the dose of agonist is increased sufficiently, a maximal effect can still be
obtained, i.e. the antagonism is surmountable.
 β-Adrenoceptor antagonists are examples of reversible competitive antagonists.
Non-competitive antagonist:
 Bind irreversibly to agonist binding site
 The effect is equivalent to removing receptors from the system
46
The effect of one drug can be reduced in the presence of another in other ways:
 Chemical antagonism
 Pharmacokinetic antagonism
 Block of receptor-effector linkage
 Physiological antagonism
Chemical antagonism
 It refers to the uncommon situation where the two substances combine in solution; as a result,
the effect of the active drug is lost.
o Eg 1→ chelating agent dimercaprol that bind to heavy metals and thus reduce their
toxicity
o Eg 2 → the neutralising antibody infliximab which has an anti-inflammatory action due
to its ability to sequester the inflammatory cytokine, tumour necrosis factor
Pharmacokinetic antagonism
 PK antagonism occurs when:
o The rate of elimination of the active drug is increased (e.g. the anticoagulant effect of
warfarin is ↓ when given together with phenobarbital,
o The rate of absorption of the active drug from the Git is reduced,
o The rate of renal excretion may be increased.
Physiological antagonism
 Physiological antagonism occurs when two drugs whose opposing actions in the body tend to
cancel each other.
 For example, histamine acts on receptors of the parietal cells of the gastric mucosa to
stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton pump;
STEP 3: Dose - Response Relationship (45minutes)

There are two types of Dose response relationships which are best represented in curves:
 Graded dose-response curve
 Quantal dose-response curve (all or none).
Graded dose-response curve

 In this type, response is gradual
 There is Gradual increase in response by increasing the dose (continuous response).
 Lowering of blood pressure, heart rate, blood glucose level, cholesterol
 Curve is usually sigmoid in shape
Graded response Curves

47
Dose -response curves- Graded are used to determine
 Maximum Efficacy (Emax): is the maximal biological response produced by a drug.
 Median Effective concentration (EC50): is the concentration of the drug that gives 50% of
the maximal response (Emax).
 Potency: the concentration of drug required to produce a specified response (50% of the
maximal response = EC50).
Quantal dose-response curve

 Relate drug concentration to % percentage of patients responding (all or none response).
 The response may be therapeutic response, adverse effect or lethal effect.
 e.g. prevention of convulsion, arrhythmias or death.
Quanta dose-response curve are Used to determine

 ED50
 TD50
 LD50
 Therapeutic index
48
A. 50% of individuals exhibit the specified therapeutic response
B. 50% of individuals exhibit the specified toxic effects
C. 50% of individuals exhibit death
STEP 3: Factors Modifying Drug Responses (30minutes)
 What are the factors modifying drug response?

Interindividual variability in responsiveness to drugs may be contributed by the following;
 Pharmacodynamic factors
 Pharmacogenetics factors
 Pharmacokinetic factors
Pharmacodynamic factors
Variation in the response to equivalent drug concentrations arises because of various factors,
such as differences in
 receptor number and structure,
 receptor-coupling mechanisms
 physiological changes in target organs resulted from differences in genetics, age and health.
Pharmacogenetics factors
49
 Some of the variation above may be influenced by genetic polymorphisms, which can result
in altered responsiveness in drug targets (e.g. receptor function) or altered drug handling (e.g.
enzyme activity).
 Polymorphisms in drug absorption, distribution, or metabolism are major causes of
interindividual variability
Pharmacokinetic factors
 It is well recognised that the clinical response to drug administration varies widely between
individuals and that most of this variability is pharmacokinetic in origin.
 In general, variability arises because of inter-individual differences in rates of drug
absorption, drug distribution and elimination, either by metabolism or excretion.
 Variability of drug response is also a consequence of a variety of drug interactions which
may influence pharmacokinetic parameters.
 Among the many factors which are responsible for the variation in human drug response, age
is relatively important.
 As a consequence of impaired metabolism and excretion the inter-individual variation in the
kinetic of many drugs is much greater in the elderly.
 Also the degree of plasma-protein binding, in turn, influences the distribution, action,
metabolism and renal excretion of drugs.
 Thus changes in plasma protein binding of drugs, e.g. in diseased states, may give rise to
altered pharmacokinetic and possibly altered drug response.

 Drugs can act as agonist, partial agonist, inverse agonist or antagonist at receptors.
 Drug response is represented as graded and quanta responses.
 Interindividual variation in drug response may be contributed by pharmacodynamics,
pharmacokinetics and pharmacogenetics factors.

 What is partial agonist?
 What is physiological antagonism?
 What are the factors which affect drug responses among individuals?
References
50
Education.

51
52
Session 7: Enzyme Inhibitors and Inducers
Prerequisites
Learning Tasks
 Describe Enzyme induction

 Describe Enzyme inhibition
 Describe role of enzyme induction and inhibition
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 300 minutes Enzyme inducers
Buzzing
Presentation/
3 45 minutes Small Group Enzyme inhibitors
Discussion
Presentation
4 30 minutes Clinical Importance of Enzyme Induction
Brainstorming
and Inhibition
53
SESSION CONTENTS

STEP 2: Description of Enzyme Induction (30 minutes)
 How does enzyme induction occur?

 List any four drugs known to induce cytochrome P450 isoenzymes
 As discussed in the earlier session on metabolism of drugs, Cytochrome P-450 Enzymes

Cytochrome (CYP450) enzymes are responsible for metabolism of endogenous or exogenous
substrates.
 There are at least 40 CYP450 enzymes but the most common isozymes are 3A4, 2D6, 2C9
and 2C19, and 1A2.
 Clinically significant drug interactions arise from either induction or inhibition of these
enzymes.
Enzyme induction:
 A number of drugs increase the activity of microsomal oxidase and conjugating systems
when administered repeatedly.
 The effect is referred to as induction and is the result of increased synthesis of microsomal
enzymes
 An inducer stimulates increased production of a CYP450 enzyme.
 Enzyme induction can increase drug toxicity and may reduce drug effectiveness (drug
interaction).
 Drugs which induce cytochrome P450 enzyme system significantly include:
o Rifampicin, ethanol and Carbamazepine
o Drinks and herbal plants may also induce the cytochrome 450 isoenzyme a good example
being St. Johns wort and nicotine (smoking).
54
STEP 3: Enzyme inhibition (45Minutes)
 How does enzyme inhibition occur?

 List any four drugs known to inhibit cytochrome P450 isoenzymes
 Inhibition of a CYP450 enzyme will result in increased levels of a substrate (drug) that is
metabolized by that enzyme.
 Inhibition may be either competitive or allosteric:
Competitive inhibition
 Two drugs are metabolized by the same enzyme system, and one of the drugs binds more
readily to the enzyme, resulting in the inhibition of metabolism of the other drug.
 Example: Erythromycin and atorvastatin are both metabolized by CYP3A4.
o Erythromycin is also a CYP3A4 inhibitor; therefore it inhibits the metabolism of
atorvastatin.
Allosteric (non-competitive) inhibition

 A drug inhibits an enzyme that it itself is not metabolized by.
 This inhibition occurs at an allosteric site (i.e., not at the site where the substrates bind).
Drugs which inhibit cytochrome P450 enzyme system significantly include:

 Cimetidine,
 Omeprazole,
 Quinolone antibiotics,
 Amiodarone,
 Antipsychotics,
 Antihistamines,
 Antifungal drugs,
 Fluvastatin,
 Isoniazid,
 Macrolide antibiotics
 Drinks and herbal plants may also inhibit the cytochrome 450 isoenzyme a good example
being grapefruit juice and red wine.
STEP 4:Clinical Importance of Enzyme Induction (30minutes)
Enzyme inhibition:
55
 It may lead to drug-drug interaction due to increased plasma concentration of active drug
(substrate) which its metabolism has been inhibited resulting in increased biologic activity (or
toxicity) of the drug.
 Prodrugs require metabolic enzymes for transformation to an active (or more active)
metabolite. Therefore enzyme inhibitor would lead to a reduction in levels of active drug, in
turn reducing the biologic activity of the drug.
Enzyme induction
 It may lead to drug-drug interaction whereby the plasma concentration of active drug
(substrate) which its metabolism has been increased will be sub-optimal, which might result
in reduced biologic activity of the drug, perhaps leading to therapeutic failure.
 However, for drugs having toxic metabolites, enzyme induction may exacerbate metabolite-
mediated toxicity because more and more toxic metabolited will be formed.
 For prodrug enzyme induction may accelerate the formation of active drug, , leading to an
exaggerated effect and toxicity

 Induction or inhibition of metabolizing enzyme has a clinical importance.
 Concomitant administration of known significant inducers or inhibitors with other drugs may
result to drug interactions
 The most common isozymes most likely to be inhibited or induced are 3A4, 2D6, 2C9
2C19 and 1A2.

 Which drugs are known to be enzyme inducers?
 What is the importance of enzyme inhibition?
 What is the consequence of enzyme induction on a pro drug?
56
References
Education.

57
Session 8: Pharmacodynamics of Drugs Acting on Endocrine
System
Prerequisites
 PST04211_S28_Description of Adrenal Hormones and Synthetic Substitutes
 PST04211_S29_ Description of Hormonal Contraceptives Methods
 PST04211_S30_ Description of Insulin and Anti Diabetic Agents
 PST04211_S31_ Description of Thyroid, Parathyroid Hormones and Their Antagonists
Learning Tasks
 Describe mechanism of action of Drugs Acting on Endocrine System
 Describe drug interactions associated with Drugs Acting on Endocrine System
 Describe side effects of Drugs Acting on Endocrine System
 Describe contraindications of Drugs Acting on Endocrine System
Resources Needed:
 Handout 8.1
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Drugs Acting on
2 45 minutes
Buzzing Endocrine System
Presentation/ Drug Interactions Associated With Drugs
3 25 minutes
brainstorming Acting on Endocrine System
Side Effects of Drugs Acting on Endocrine
System
Presentation/ Contraindications of Drugs Acting on
5 20 minutes
Brainstorming Endocrine System
58
SESSION CONTENTS

STEP 2: Mechanism of Action of Drugs Acting on Endocrine System (45

minutes)
 How do Drugs Acting on Endocrine system produce their pharmacological effects?
Drugs for Diabetes Mellitus

 Insulins
o Insulin acts by binding to transmembrane glycoprotein receptors. Receptor occupancy
results in:
1. Activation of insulin-dependent glucose transport processes (in adipose tissue and
muscle) via a transporter known as Glut-4;
2. Inhibition of adenylyl cyclase-dependent metabolism (lipolysis, proteolysis,
glycogenolysis);
3. Intracellular accumulation of potassium and phosphate, which is linked to glucose
transport in some tissues.
o Secondary effects include increased cellular amino acid uptake, increased DNA and RNA
synthesis and increased oxidative phosphorylation.
 Biguanides (Metformin)
o Mechanism remains uncertain.
o Effects of metformin include:
 Reduced glucose absorption from the gut
 Facilitation of glucose entry into muscle by a non-insulin responsive mechanism
 Inhibition of gluconeogenesis in the liver
 Suppression of oxidative glucose metabolism and enhanced anaerobic glycolysis.
59
 Sulphonylureas (tolbutamide, glibenclamide, gliclazide) and Related Drugs
o The hypoglycaemic effect of these drugs depends on the presence of functioning B cells.
o Sulphonylureas, like glucose, depolarize B cells and release insulin.
o They do this by binding to sulphonylurea receptors (SUR) and blocking ATP-dependent
potassium channels (KATP); the resulting depolarization activates voltage-sensitive Ca2+
channels, in turn causing entry of Ca2+ ions and insulin secretion.
 Thiazolidinediones (rosiglitazone and pioglitazone)
o Glitazones bind to the peroxisome-proliferating activator receptor γ (PPARγ), a nuclear
receptor found mainly in adipocytes and also in hepatocytes and myocytes.
o It works slowly, increasing the sensitivity to insulin possibly via effects of circulating
fatty acids on glucose metabolism.
 Acarbose
o Acarbose is a reversible competitive inhibitor of intestinal α-glucoside hydrolases and
delays the absorption of starch and sucrose, but does not affect the absorption of ingested
glucose.
o The postprandial glycaemic rise after a meal containing complex carbohydrates is
reduced and its peak is delayed.
 Mechanism of action of drugs for treatment of thyroid disorders and reproductive

function
 REFER Students to Handout 8.1: Pharmacodynamics of drugs for thyroid

disorders and reproductive function
STEP 3: Drug Interactions Associated With Drugs Acting on Endocrine

System (5 minutes)
 How do significant drug interactions of Drugs Acting on Endocrine system occur?
 Biguanides (Metformin etc)

o Other oral hypoglycaemic drugs are additive with metformin.
o Ethanol predisposes to metformin-related lactic acidosis.
60
 Sulphonylureas (tolbutamide, glibenclamide, gliclazide) and Related Drugs
o Monoamine oxidase inhibitors potentiate the activity of sulphonylureas by an unknown
mechanism.
o Several drugs (e.g. glucocorticosteroids, growth hormone) antagonize the hypoglycaemic
effects of sulphonylureas by virtue of their actions on insulin release or sensitivity.
 Thiazolidinediones (rosiglitazone and pioglitazone)

o Glitazones are additive with other oral hypoglycaemic drugs.
o They potentiate insulin, but this combination is contraindicated in some countries because of
concerns that it might increase the risk of heart failure.
o Pioglitazone is an inducer of CYP3A and may cause treatment failure with concomitantly
administered drugs which are CYP3A substrates (e.g. reproductive steroids).
STEP 4: Side Effects of Drugs Acting on Endocrine System (20 minutes)

The following are the dise effects of drugs for treatment of Diabetes Mellitus;
 Insulin: Hypoglycemia, Headache, Allergic reactions, Flu like symptoms, Weight gain,
Hypokalemia, Lipoatrophy, Itching, Rash , Injection site reaction
 Chlorpropamide: Has appreciably more side effects, mainly because of its very prolonged
duration of action and the consequent hazard of hypoglycaemia and it should no longer be
used. It may also cause facial flushing after drinking alcohol; this effect does not
normally occur with other drugs
 Glibenclamide: Common side effects include stomach upset and low blood sugar
(hypoglycaemia), weight gain, constipation
 Gliclazide: Hypoglycemia (low blood sugar) hyperglycemia (high blood sugar) oat,
cough back, muscle and joint pain headache high blood pressure angina (chest pain) leg
swelling diarrhea, constipation, abdominal pain, nausea dizziness skin rash/itching
depression
 Tolbutamide: Hypoglycemia, weight gain, hypersensitivity: cross allergicity with
sulfonamides
 Metformin: Anorexia, nausea, vomiting, diarrhea (usually transient), abdominal pain,
taste disturbance, lactic acidosis, decreased vitamin B12 absorption, erythema, pruritus
and urticaria. Hepatitis also reported
STEP 5: Contraindications of Drugs Acting on Endocrine System (20

minutes)
 What are the contraindications of drugs acting on endocrine system?

61
 The following are the contraindications for drugs for Diabetes Mellitus
o Insulin: Is contraindicated in persons who have Hypersensitivity to any ingredient of the
product and during episodes of hypoglycemia
o Glibenclalmide: Is contraindicated in diabetic emergencies (ketoacidosis, hyperosmolar
coma), advanced hepatic or renal insufficiencies, pregnancy and nursing period
o Gliclazide: Is contraindicated in following conditions, pregnancy, lactation,
hypersensitivity
o Tolbutamide: Is contraindicated in patients with known hypersensitivity or allergy to the
drug
o Metformin Is contraindicated in patients with any condition that could increase the risk of
lactic acidosis, including kidney disorders , lung disease and liver disease
o For other contraindications please see NTA level 4

 Drugs affecting hormonal actions have different mechanisms
 Drugs affecting hormonal actions have many adverse effects
 Drugs affecting hormonal actions exhibit many interactions with other drugs

 What is the mechanism of action of insulin?
 What are adverse effects of Sulphonylureas?
 Why is not advised to combine MAOIs and sulphonyl urea?
62
References
Education.

(59th ed). London, BMJ Group and RPS Publishing
63
Handout 8.1 Pharmacodynamics of drugs used for treatment of
thyroids disorders and reproductive function
Mechanism of actions of Drugs for Thyroid Disorders

Hypothyroidism
 Thyroxine and Tri-Iodothyronine
o Thyroxine is a prohormone.
o After entering cells it is converted to T3, which binds to the thyroid hormone nuclear
receptor and the ligandreceptor complex increases transcription of genes involved in the
following cellular functions: stimulation of metabolism raised basal metabolic rate,
promotion of normal growth and maturation ( particularly of the central nervous system
and skeleton) and sensitization to the effects of catecholamines.
Hyperthyrodism
Antithyroid drugs
 Carbimazole
o The action of carbimazole is via its active metabolite methimazole, which is a substrate-
inhibitor of peroxidase and is itself iodinated and degraded within the thyroid, diverting
oxidized iodine away from thyroglobulin and decreasing thyroid hormone biosynthesis.
 Propylthiouracil
o Propylthiouracil has similar actions, uses and toxic effects to carbimazole, but in addition
inhibits the peripheral conversion of T4 to active T3.
o It is used (by specialists) in pregnancy (see below) and has some advantages over
carbimazole in this setting.
 β-Adrenoceptor Antagonists
o Beta-blockers improve symptoms of hyperthyroidism, including anxiety, tachycardia and
tremor.
o They inhibit the conversion of T4 to T3 in the tissues.
 Radioactive Iodine
o Radioactive iodine (I131) is safe in non-pregnant adults and has largely replaced surgery in
the treatment of hyperthyroidism, except when there are local mechanical complications,
such as tracheal obstruction.
Mechanism of action for Drugs Affecting Reproductive Function

 Estrogens
Natural: estrone sulfate,17β-estradiol , estriol , sysnthetic : ethinyl estradiol, mestranol
64
o Estrogens are transcription factors; they modify messenger RNA (mRNA) synthesis
directly.
o Estrogens enter the cell passively (no receptor required) and bind to estrogen receptors in
the nucleus, which then dimerize and bind DNA directly to regions called estrogen-
responsive elements (EREs) and influence gene transcription.
Contraceptives
Combined Oral Contraceptives (COC)
The main contraceptive action of the combined oral contraceptive (COC) is to suppress
ovulation by interfering with gonadotrophin release by the pituitary via negative feedback on
the hypothalamus. This prevents the mid-cycle rise in LH which triggers ovulation.
 Progestins
Progesterone, megestrol acetate, medroxyprogesterone acetate, norethindrone, norethindrone
acetate, norgestrel, levonorgestrel, desogestrel, norgestimate, gestodene, dienogest
o Progestins are transcription factors; they modify mRNA synthesis directly.
o Progestins enter the cell passively (no receptor required) and bind to progesterone receptors
in the nucleus, which then dimerize and bind DNA directly and influence gene transcription.
Anti-progestogens
 Mifepristone
o Mifepristone is a competitive antagonist of progesterone.
o It is used as a medical alternative to surgical termination of early pregnancy (currently up
to 63 days gestation, although it is also effective during the second trimester).
o A single oral dose of mifepristone is followed by gemeprost (a prostaglandin that ripens
and softens the cervix), as a vaginal pessary unless abortion is already complete.
Reproductive hormones antagonists

 Oestrogen receptor antagonists
o Oestrogen receptor antagonists include tamoxifen which is licensed for breast cancer and
an ovulatory infertility, fulvestrant which is licensed for the treatment of oestrogen
receptor-positive metastatic or locally advanced breast cancer in post-menopausal
women, and toremifene which is licensed for hormone-dependent metastatic breast cancer
in post-menopausal women.
o Estrogens also mediate cell proliferation, in both normal and malignant cells.
o There are two estrogen receptors (ERα and ERβ), both of which either increase or
decrease transcription of target genes.
o Binding of agonist to the estrogen receptor recruits co-activators which help to stimulate
transcription. The net effect of this is to initiate transcription.
 Aromatase inhibitors
o Aromatization is the process of converting a nonaromatic ring into an aromatic ring and is
catalyzed by aromatase, a P450 enzyme.
o Aromatization converts androgens into estrogens.
65
o The aromatase inhibitors block the conversion of androgens oestrogens in the peripheral
tissues.
o They do not inhibit ovarian oestrogen synthesis and are not suitable for use in
premenopausal women who will continue to secrete ovarian oestrogens.
o Currently licensed agents include anastrozole, letrozole and exemestane.
 The gonadorelin analogues

o Goserelin is licensed for the management of advanced breast cancer in premenopausal
women.
o It acts by initially stimulating and then depressing luteinizing hormone released by the
pituitary, which in turn reduces oestrogen production.
 The inducers of gonadotrophin release

o induce gonadotrophin release by occupying oestrogen receptors in the hypothalamus,
thereby interfering with feedback mechanisms.
Drug interactions
Contraceptives
Combined Oral Contraceptives (COC)
 Oestrogens increase clotting factors and reduce the efficacy of oral anticoagulants.
o Thus a need for frequent monitoring of the international normalized ratio (INR).
 Antihypertensive therapy may be adversely affected by oral contraceptives, at least partly
because of increased circulating renin substrate.
 Enzyme inducers (e.g. rifampicin, carbamazepine, phenytoin, nelfinavir, nevirapine,
ritonavir, St Johns wort) decrease the plasma levels of contraceptive oestrogen, thus
decreasing the effectiveness of the combined contraceptive pill.
Side effects
Estrogens
 Natural: estrone sulfate ,17β-estradiol , estriol , sysnthetic : ethinyl estradiol, mestranol
o Endometrial: Some of the partial agonists have estrogen agonist effects on the
endometrium, leading to abnormal cell growth.
o This can manifest as increased endometrial thickness, endometrial polyps, leiomyomas,
and even endometrial cancer.
o Thromboembolism: Increased risk of thromboembolic events, including pulmonary
embolism, have been observed in large studies.
o Stroke: Stroke has been observed in large studies.
o Hot flashes: Hot flashes mimic the physiology of menopause.
o Nausea, vomiting
o Menstrual irregularities: Oligomenorrhea (infrequent periods) and amenorrhea (absent
periods) may occur.
66
o Cataracts
Reproductive hormones antagonists

 Aromatase inhibitors
o Reduced bone density and increased fractures
o Bone protection measures should be taken. These include bisphosphonates, vitamin D,
calcium, and exercise.
o Hot flushes from estrogen deficiency (which mimics perimenopausal symptoms)
o Nonspecific: nausea, fatigue, increased sweating, peripheral edema, and increased
appetite
Progestins
 Progesterone, megestrol acetate, medroxyprogesterone acetate, norethindrone,
o Androgenic activity: Because of the similarity of progestins to androgens and the
conversion of progestins to androgens, androgenic side effects are not uncommon.
Levonorgestrel is the most androgenic.
o Third-generation progestins are less androgenic than second-generation progestins.
o Acne and hirsutism are the most common signs.
o Increased LDL and insulin resistance are also seen.
o DVT: Third-generation progestins may be associated with a higher incidence of DVT
than second-generation progestins.
o Vaginal bleeding: The mechanism is not completely understood
Contraindications
 Estrogens
Natural: estrone sulfate ,17β-estradiol , estriol , sysnthetic : ethinyl estradiol, mestranol
o Hypercoagulable states: Estrogen is a procoagulant, and estrogen administration is a risk
factor for pathologic thromboses (deep vein thrombosis [DVT] and pulmonary embolus
[PE]).
o Cancers that could demonstrate increased growth in response to estrogen: breast, ovarian,
uterine, and endometrial.
o Strong risk factors for atherosclerosis: hypertension (HTN), diabetes, high cholesterol,
family history.
o Pregnancy: Estrogen plays an important role in maintenance of pregnancy.
o Progestins
 Progesterone, megestrol acetate, medroxyprogesterone acetate, norethindrone, norethindrone

acetate, norgestrel, levonorgestrel, desogestrel, norgestimate, gestodene,
o Risks for DVT or PE
o Severe migraine headache: There are relationships among estrogen, progesterone, and
serotonin levels. Serotonin is implicated in migraine pathophysiology; administration of
estrogen or progesterone can potentially exacerbate (or alleviate) migraines.
67
o Unexplained vaginal bleeding: Prolonged progesterone administration can cause vaginal
bleeding; it is important to diagnose any pathologic causes of bleeding before starting
treatment that could confound other bleeding.
o Breast cancer: Female sex hormones can stimulate breast tissue growth.
o Active liver disease
o Conditions of concern for hypoestrogenic effects and reduced HDL levels, theoretically
increasing cardiovascular risk:
o Current and history of ischemic heart disease
o History of stroke
o Diabetes for over 20 years or with nephropathy, retinopathy, neuropathy, or vascular
disease
Progestogen-Only Contraceptives
o Include pregnancy, undiagnosed vaginal bleeding, severe arterial disease, liver adenoma
and porphyria.
Aromatase inhibitors
o Pregnancy (which is a physiologic state requiring increased estrogen).
The inducers of gonadotrophin release

o Clomiphene is contraindicated in those with liver disease, ovarian cysts, hormone-dependent
tumours and abnormal uterine bleeding of undetermined cause.
68
69
Session 9: Pharmacodynamics of Drugs Acting on
Respiratory System
Prerequisites
 PST04211_S36_ Essential Anti-asthmatic Drugs
 PST04211_S39_ Description of Cough and Cold Preparations
Learning Tasks
 Describe mechanism of action of Drugs acting on Respiratory System
 Describe drug interactions associated with Drugs acting on Respiratory System
 Describe side effects of Drugs acting on Respiratory System
 Describe contraindications of Drugs acting on Respiratory System
Resources Needed:
 Handout 9.1
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Drugs acting on
2 45 minutes
Buzzing Respiratory System
3 25 minutes
brainstorming acting on Respiratory System
Side Effects of Drugs acting on Respiratory
System
Presentation/ Contraindications of Drugs acting on
5 20 minutes
Brainstorming Respiratory System
70
SESSION CONTENTS

STEP 2: Mechanism of Action of Drugs acting on Respiratory System (45

minutes)
 How do Drugs acting on respiratory system produce their pharmacological effects?
The following are the mechanisms of drugs used to treat Asthma and chronic obstructive
pulmonary disease (COPD);
 Beta 2 (β2)-Agonists
o β-2- Agonists (e.g. salbutamol and the long-acting β2-agonist salmeterol) are used to treat
the symptoms of bronchospasm in asthma (both in an acute attack and as maintenance
therapy) and
o Intravenous salbutamol is also used in obstetric practice to inhibit premature labour).
o Agonists occupying β2-adrenoceptors increase cyclic adenosine monophosphate (cAMP)
by stimulating adenylyl cyclase via stimulatory G-proteins.
o Cyclic AMP phosphorylates a cascade of enzymes.
o This causes a wide variety of effects including:
 Relaxation of smooth muscle including bronchial, uterine and vascular;
 inhibition of release of inflammatory mediators;
 increased mucociliary clearance;
 increase in heart rate, force of myocardial
 Muscarinic Receptor Antagonists

o There is increased parasympathetic activity in patients with reversible airways
obstruction, resulting in bronchoconstriction through the effects of acetylcholine on the
muscarinic (M2, M3) receptors in the bronchi.
71
o The final common pathway is via a membrane-bound G-protein which when stimulated
leads to a fall in cAMP and increased intracellular calcium, with consequent
bronchoconstriction.
o Antimuscarinic drugs block muscarinic receptors in the airways leading to
bronchodilation.
 Methylxanthines
o It is not clear exactly how theophylline produces bronchodilation.
o Its pharmacological actions include the following:
o Relaxation of airway smooth muscle and inhibition of mediator release (e.g. from mast
cells).
o Theophylline raises intracellular cAMP by inhibiting phosphodiesterase.
o However, phosphodiesterase inhibition is modest at therapeutic concentrations of
theophylline
o Antagonism of adenosine (a potent bronchoconstrictor) at A2-receptors;
o Anti-inflammatory activity on T-lymphocytes by reducing release of platelet-activating
factor (PAF).
 Glucocorticosteroids
o Glucocorticosteroids are used in the treatment of asthma and in severe exacerbations of
COPD because of their potent anti-inflammatory effect.
o This involves interaction with an intracellular glucocorticosteroids receptor that in turn
interacts with nuclear DNA, altering the transcription of many genes and thus the
synthesis of pro-inflammatory cytokines, β2-adrenoceptors, tachykinin-degrading
enzymes and lipocortin (an inhibitor of phospholipase A2, reducing free arachidonic acid
and thus leukotriene synthesis).
o They are used both in maintenance therapy (prophylaxis) and in the treatment of the acute
severe attack.
Mast Cell Stabilizers (Cromoglicate and Nedocromil)

o The degranulation of mast cells and eosinophils is an important step in the response to an
allergen. Degranulation leads to release of a variety of proinflammatory factors, including
histamine, leukotrienes, and various cytokines.
o These factors then act on tissues to elicit the classic signs of an allergic reaction.
o Mast cell stabilizers work by preventing this degranulation from occurring.
o The mechanism by which they accomplish this is still not confirmed.
o Mast cell stabilizers have a variety of other actions that may contribute to their efficacy.
o They suppress the actions of chemotactic factors on eosinophils, neutrophils, and
monocytes, and they may reduce movement of leukocytes in asthmatic airways.
Leukotriene Modulators
72
o Leukotriene B4 is a powerful chemo-attractant (eosinophils and neutrophils) and
increases vascular permeability producing mucosal oedema.
o Leukotrienes C4, D4 and E4 (cysteinyl leukotrienes) are potent spasmogens and pro-
inflammatory substances (SRS-A).
o Leukotriene modulators fall into two classes, namely leukotriene receptor antagonists and
5-lipoxygenase inhibitors.
o Leukotriene C4 and D4 antagonists: Montelukast is a competitive inhibitor of LTD4 and
LTC4 receptor.
5-Lipoxygenase Inhibitors: 5-Lipoxygenase is the enzyme required for the synthesis of

LTA4, which is an unstable epoxide precursor of LTB4 is which is a potent pro-inflammatory
chemo-attractant and cysteinyl leukotrienes (LTC4, LTD4 and LTE4).
o Zileuton which is a competitive inhibitor of 5-lipoxygenase enzyme results decreased
synthesis of the above leukotrienes.
Anti-IgE Monoclonal Antibody

o Omalizumab is a recombinant humanized IgG1 monoclonal anti-IgE antibody.
o It is used as additional therapy in patients with severe persistent allergic asthma due to
IgE-mediated sensitivity to inhaled allergens and inadequately controlled by
glucocorticosteroids plus long-acting β2-agonists.
o It binds to IgE at the same epitope on the Fc region that binds FcεRI, this means it cannot
react with IgE already bound to the mast cell or basophils and is not anaphylactogenic.
 For mechanism of actions of drugs for cough, cold and allergy
REFER Students to Handout 9.1: Pharmacodynamics of drugs for cough, cold

and allegy
STEP 3: Drug Interactions Associated with Drugs Acting on Respiratory

System (20 minutes)
 How do significant drug interactions of Drugs Acting on Respiratory System ?
73
The following are drug interactions for drugs used to treat Asthma and Chronic Obstructive
Pulmonary Disease
 Methylxanthines
 Although synergism between β2-adrenergic agonists and theophylline has been
demonstrated in vitro, clinically the effect of this combination is at best additive.
 Many drugs inhibit CYP1A2- mediated theophylline metabolism, e.g. erythromycin
(and other macrolides), fluoroquinolones (e.g. ciprofloxacin), interferon and
cimetidine, thus precipitating theophylline toxicity.
 Theophylline metabolism is induced in the presence of hepatic CYP450-inducing
agents, such as rifampicin.
 Mast Cell Stabilizers (Cromoglicate and Nedocromil)

o None of major significance
 Leukotriene Modulators
o No clinically important drugdrug interactions are currently recognized
STEP 4: Side Effects of Drugs acting on Respiratory System (20 minutes)
The following are the side effects of drugs used ro treat asthma
 Anticholinergic side effects (first-generation agents): dry mouth, urinary retention

o Adverse effects of muscarinic receptor antagonists include dry mouth, mydriasis
(causes blurred vision), tachycardia, hot and flushed skin, agitation, urinary retention,
constipation, and delirium.
o A mnemonic to remember these side effects is red as a beet, dry as a bone, blind as
a bat, and mad as a hatter.
o These effects are due to blockade of muscarinic receptors at different organs.
o Hyperglycemia and steroid induced diabetes
o Weight gain and severe swelling, particularly in the face; caused, in part, by the
mineralocorticoid effects
o Psychiatric symptoms including depression, mania, and psychosis; other types of
cognitive dysfunction can also occur, including euphoria, insomnia, mental confusion
o Gastric and duodenal bleeding secondary to inflammation or ulceration
o Infections resulting from immunosuppression
o Skin effects: thin skin, violaceous striae (stretch marks), acne
74
o Eyes: cataracts and glaucoma
o Muscular effects: muscle wasting, myopathy
o Adipose distribution: buffalo hump, central obesity
o Osteoporosis may occur.
o Cushings syndrome
Moon facies, buffalo hump (cervical fat pad), central obesity, supraclavicular fat
collection, acne
o Adrenal suppression: Because of negative feedback loops, exogenous glucocorticoids
will suppress CRH and ACTH.
o One significant side effect of glucocorticoids is an increased white blood count
(driven by an increase in neutrophils).
 Mast Cell Stabilizers (Cromoglicate and Nedocromil)

o Generally well tolerated
o Side effects generally related to topical application
o Cough from irritation of the throat
o Nasal irritationlocal irritation from sprays
STEP 5: Contraindications of Drugs acting on Respiratory System (10

minutes)
 What are the contraindications of Antineoplastic Drugs?

The following are the contraindications for drug used to treat asthma and COPD;

Narrow angle glaucoma, GIT &UT obstruction
o Active serious infection due to immunosuppressive effect
o Diabetic patients, refer side effects.
75
 Leukotriene antagonists (e.g. montelukast) are effective as oral maintenance therapy in
chronic persistent asthma.
 Glucocorticosteroids are associated with many adverse effects
 Some drugs like may precipitate asthma
 What are the groups of drugs used in management of asthma?
 What are contraindications of drugs for asthma?
 What is the mechanism of action of codein (antitussive)?
76
References
Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government
printers.
Education.

77
Handout 9.1 Pharmacodynamics of drugs for cough, cold and
allergy
 Antitussives
o Antitussives constitute a heterogeneous class of compounds that inhibit cough through
either a central or a peripheral mechanism, or a mixture of the two.
o Centrally acting agents such as dextromethorphan work by inhibiting the cough center in
the brain, elevating the threshold for coughing.
o The exact mechanism by which they do this is still poorly understood.
o Dextromethorphan, for example, is an N-methyl-d-aspartate (NMDA) antagonist,
although it is not known what contribution this has to its antitussive effects.
o Opiates such as codeine and hydrocodone also work through a central mechanism.
o Peripheral-acting agents work either by anesthetizing the local nerve endings or acting as
demulcents. Demulcents have a soothing effect on the throat.
o Older-generation antihistamines (dexbrompheniramine, diphenhydramine) have also been
used as antitussives with some success. The mechanism behind their use is not well
understood.
 Expectorants (guaifenesin, ammonium chloride, terpin hydrate, potassium iodide, iodinated

glycerol)
o Expectorants comprise a heterogeneous collection of compounds that facilitate the
removal of mucous from the respiratory tract.
o Mucus serves as an airway lubricant and functions as a first level of immune defense.
When mucus becomes thickened and/or dried out by infections, the functions of the
mucus, including the clearing of infections, becomes impaired.
o Expectorants typically work by increasing the amount of fluid in the respiratory tract,
which increases flow and clearance of local irritants as well as reducing the viscosity of
mucus.
o It is not clear exactly how guaifenesin increases respiratory fluid, but it may be through a
local irritant effect.
 Decongestants (phenylephrine, oxymetazoline, xylometazoline, naphazoline

pseudoephedrine, ephedrine, phenylpropanolamine )
o Nasal congestion occurs when the nasal passages become edematous, usually a result of
an inflammatory response to an upper respiratory tract infection, an allergic response, or a
response to chemical irritant
o All decongestants are vasoconstrictors.
78
o The main mechanism by which they reduce nasal congestion is by constricting
precapillary blood vessels, which reduces capillary hydrostatic pressure, blood flow, and
volume.
o Hydrostatic pressure is one of the forces that pushes plasma out of a blood vessel into the
tissues, causing edema.
o Capillary permeability and oncotic pressure are the two other factors that influence the
formation of tissue edema.
o By reducing hydrostatic pressure, the outward force that pushes fluid out of the vessel
becomes an inward force that drives fluid into the vessel.
o The net effect is to reduce leakage in blood vessels, therefore reducing congestion.
o Through reduction of blood flow and volume, a smaller amount of fluid is made available
to the leaky capillaries, and thus edema formation decreases as well.
o The vasoconstriction is mediated by stimulation of α1 receptors.
o These receptors are stimulated either by direct agonists or indirectly.
o Direct agonists tend to be analogs of norepinephrine, although with greater selectivity for
the α1 receptor.
o Indirect agonists (pseudoephedrine, ephedrine, and phenylpropanolamine) work by
increasing levels of endogenous norepinephrine.
 H1 antagonists
o H1 antagonists are agents that antagonize the allergic responses and other effects
mediated by histamine. These are also known as antihistamines.
o Histamine plays a key role in allergic reactions, also known as immunoglobulin E
(IgE)mediated hypersensitivity reactions.
o The role of histamine in the immune response is largely mediated by H1 receptors.
o H1-receptor antagonists competitively antagonize histamine at these receptors, mitigating
the immune response to an allergen.
 Mast cell stabilizers

o Mast cell stabilizers are used in conditions with an allergic component such as Asthma
(mild to moderate), Rhinitis and Conjunctivitis.
o The details on mechanism of action will be discussed in asthma
Drug interactions:
 Expectorants (guaifenesin, ammonium chloride, terpin hydrate, potassium iodide,

iodinated glycerol)
o Guaifenesin: none of major significance
None of major significance
Side effects
79
 Antitussives
Opiates main side effects are sedation and constipation at the lower doses used to
suppress cough.
 Expectorants (guaifenesin, ammonium chloride, terpin hydrate and others)

Guaifenesin: Generally well tolerated; side effects occur infrequently which include
Nausea, Drowsiness and Vomiting which are typically only seen at high doses.
o CNS stimulation: The phenylamines (phenylephrine, ephedrine, pseudoephedrine) share
common structural features with amphetamine, and therefore they also stimulate the CNS.
This manifests as: agitation, anxiety and insomnia
o Rebound congestion is typically only seen with topical agents
 H1 antagonists
o Sedation: H1 receptors in the CNS mediate wakefulness, so antagonism of these receptors
leads to drowsiness.
o Some antihistamines also antagonize serotonin receptors, and this might also contribute to
sedation.
Contraindications
 Antitussive
 Expectorants (guaifenesin, ammonium chloride, terpin hydrate, potassium iodide, iodinated

glycerol)

o Concomitant use with monoamine oxidase inhibitors (MAOIsmay lead to an increase in
norepinephrine levels which may result into hypertensive crisis..
o All Decongestants cause vasoconstriction, which may lead to rise in blood pressure in
patients with hypertension
 H1 antagonists
o Fexofenadine and hydroxyzine are contraindicated in pregnancy due to teratogenic effects
in animals
o First-generation antihistamines are contraindicated to breastfeeding mothers because they
are more likely to cross into breast milk, and this may lead to excess sedation in the
nursing infant
80
Session 10: Pharmacodynamics of Antiemetics and Drugs for
Peptic Ulcer Disease.
Prerequisites
Learning Tasks
 Describe mechanism of action of Antiemetics and Drugs for Peptic Ulcer
 Describe drug interactions associated with Antiemetics and Drugs for Peptic Ulcer
Disease
 Describe side effects of Antiemetics and Drugs for Peptic Ulcer Disease
 Describe contraindications of Antiemetics and Drugs for Peptic Ulcer Disease
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Antiemetics and
2 40 minutes
Buzzing Drugs for Peptic Ulcer Disease
Drug Interactions Associated With
Presentation/
3 20 minutes Antiemetics and Drugs for Peptic Ulcer
brainstorming
Disease
Side Effects of Antiemetics and Drugs for
Peptic Ulcer Disease
Presentation/ Contraindications of Antiemetics and Drugs
5 20 minutes
Brainstorming for Peptic Ulcer Disease
8 05 minutes Presentation Take Home Assignment
81
SESSION CONTENTS

STEP 2: Mechanism of Action of Antiemetics and Drugs for Peptic Ulcer

Disease (40 minutes)
 How do antiemetics and drugs for Peptic Ulcer Disease produce their pharmacological
effects?

The following are the mechanism of action for drugs for treating Peptic Ulceration;
 Antiacids
o Antacids have a number of actions which include neutralizing gastric acid and thus
relieving associated pain and nausea, reducing delivery of acid into the duodenum
following a meal, and inactivation of the proteolytic enzyme pepsin by raising the gastric
pH above 45.
o In addition, it is thought that antacid may increase lower oesophageal sphincter tone and
reduce oesophageal pressure.
 H2-Receptor antagonists
o H2-receptors stimulate gastric acid secretion and are also present in human heart, blood
vessels and uterus (and probably brain).
o Competitive H2-receptor antagonists when used in clinical use block/inhibit gastric acid
secretion.
 Prostaglandin Analogues
o Misoprostol is a synthetic analogue of prostaglandin E1 which inhibits gastric acid secretion,
causes vasodilatation in the submucosa and stimulates the production of protective mucus.
82
 Proton Pump Inhibitors
o The proton-pump inhibitors inhibit gastric acid by blocking the H+/K+-adenosine
triphosphatase enzyme system (the proton pump) of the gastric parietal cell. Examples are
omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.
 Bismuth chelate (a mucosal protective agent)

o Colloidal tripotassium dicitratobismuthate precipitates at acid pH to form a layer over the
mucosal surface and ulcer base, where it combines with the proteins of the ulcer exudate.
This coat is protective against acid and pepsin digestion.
o It also stimulates mucus production and may chelate with pepsin, thus speeding ulcer
healing.
o It has a direct toxic effect on H. pylori and may be used as part of triple therapy.
 Sucralfate (a mucosal protective agent)

o Sucralfate is used in the management of benign gastric and duodenal ulceration and chronic
gastritis. Its action is entirely local, with minimal if any systemic absorption.
o It is a basic aluminium salt of sucrose octasulphate which, in the presence of acid, becomes a
sticky adherent paste that retains antacid efficacy.
o This material coats the floor of ulcer craters, exerting its acid-neutralizing properties locally,
unlike conventional antacid gels which form a diffusely distributed antacid dispersion.
o In addition it binds to pepsin and bile salts and prevents their contact with the ulcer base.
 Mechanism of action of Antiemetics
 REFER Students to Handout 10.1: Pharmacodynamics of drugs for thyroid

disorders and reproductive function
STEP 3: Drug Interactions Associated with Drugs for Peptic Ulcer Disease
(20 minutes)
 How do significant drug interactions of Antiemetics and Drugs for Peptic Ulcer Disease
occur?
83
Drugs for treating Peptic Ulceration
 Antiacids
o Magnesium and aluminium salts can bind other drugs in the stomach, reducing the rate and
extent of absorption of antibacterial agents such as erythromycin, ciprofloxacin, isoniazid,
norfloxacin, ofloxacin, pivampicillin, rifampicin and most tetracyclines, as well as other
drugs such as phenytoin, itraconazole, ketoconazole, chloroquine, hydroxychloroquine,
phenothiazines, iron and penicillamine.
o They increase the excretion of aspirin (in alkaline urine).
o Absorption of ketoconazole (which requires a low pH) and itraconazole is reduced by
cimetidine.
o Metabolism of several drugs is reduced by cimetidine due to inhibition of cytochrome P450,
resulting in raised plasma drug concentrations.
o Interactions of potential clinical importance include those with warfarin, theophylline,
phenytoin, carbamazepine, pethidine and other opioid analgesics, tricyclic antidepressants,
lidocaine (cimetidine-induced reduction of hepatic blood flow is also a factor in this
interaction), terfenadine, amiodarone, flecainide, quinidine and fluorouracil.
o Cimetidine inhibits the renal excretion of metformin and procainamide, resulting in increased
plasma concentrations of these drugs.
o Ranitidine has a lower affinity for cytochrome P450 than cimetidine and does not inhibit the
metabolism of warfarin, phenytoin and theophylline to a clinically significant degree.

o Pantoprazole does not appear to have any clinically significant drug interactions, whereas
omeprazole inhibits cytochrome P450 thus affecting phenytoin and lansoprazole is a weak
inducer of cytochrome P450.
o Some drugs require an acidic environment for their proper dissolution and absorption. By
increasing gastric pH, the PPIs may therefore interfere with the absorption of vitamin B12,
ampicillin, and ketoconazole, among others.
STEP 4: Side Effects of Drugs acting on Gastrointestinal System (20

minutes)
The following are the side effects of drugs for treating Peptic Ulceration
 Antacids
o Mg2+Containing Buffers cause diarrhoea: Mg2+ salt exerts an osmotic effect on the gut.
o Ca2+ Containing Buffers cause hypercalcemia (at high doses)
o These agents may lead to formation of calculi (milk alkali syndrome).
o Calculi are solid formations, typically consisting of minerals, which precipitate in
organs such as the kidney and obstruct ducts.
84
o Bloating, flatulence, belching, and nausea are also common: These effects are caused by the
liberation of CO2 from carbonate-containing antacids. Constipation
o Al3+ Containing Buffers cause Hypophosphatemia: Al3+ can bind phosphate in the gut,
inhibiting its absorption. Constipation is also observed.
o Milk alkali syndrome is a rare disorder caused by ingestion of large amounts of calcium,
resulting in hypercalcemia and alkalosis.
o Sodium bicarbonate may cause systemic alkalosis
o Common: Diarrhoea, headache, drowsiness, fatigue, muscle pain, and constipation may
occur.
o Central nervous system (CNS) side effects(rare): Confusion, delirium, hallucinations, slurred
speech, and headache can occur and are thought to be caused by antagonism of H2 receptors
in the CNS.
o Thrombocytopenia (rare): The mechanism has not been established, but theories include bone
marrow suppression due to inhibition of DNA synthesis, and the development of platelet
antibodies against H2 antagonists.
o Cimetidine Only: Gynecomastia (breast development in men) and galactorrhoea (lactation
not associated with childbirth
o Pregnancy (or desired pregnancy) is an absolute contraindication to the use of misoprostol, as
the drug causes abortion through its effects on PG receptors.

o Hypergastrinemia, less common: Gastrin levels become elevated because of the bodys
response to chronic gastric acid suppression. This may lead to rebound hypersecretion of
gastric acid if the PPI is stopped. There is also concern over the chronic effects of
hypergastrinemia, including development of gastric tumours.
STEP 5: Contraindications of Drugs acting on Gastrointestinal System (10

minutes)
 What are the contraindications of Antiemetics and Drugs for Peptic Ulcer Disease.?
85
The contraindications of Drugs used for treating Peptic Ulceration includes;

 Antiacids
o Pregnancy (or desired pregnancy) is an absolute contraindication to the use of misoprostol, as
the drug causes abortion through its effects on PG receptors.
 Proton Pump inhibitors


 The choice of antiemetics depends on the aetiology.
 Reduction of acidity is achieved by the use of antacids; H2-blockers; proton-pump
inhibitors; and muscarinic blockers.
 Eradication of H. Pylori is important in treatment of peptic ulceration.

 What are adverse effects of cimetidine?
 What are contraindications of promethazine?
 What is eradication regime?
STEP 8: Take HomeAssignment (5 minutes)

Activity: Take Home Assignment (5 minutes)
DIVIDE students in three groups and assign one assignment for each group
ASK the students to work on the following Assignment

 Prepare a presentation on the mechanism of drugs used to treat the following conditions;
(Give examples of drugs for this pharmacplogical group)
 Antispasmodics
 Cathartics
 Drugs used for diarrhoea
ALLOCATE time for students to do the assignments and submit
REFER students to recommended reference
86
87
References
Education.

88
Handout 10.1 Pharmacodynamics of Antiemetic Drugs
Mechanism of action of Antiemetics

 Metoclopramide: Dopamine Receptor Antagonists
o It is a central dopamine antagonist and raises the threshold of the CTZ. It also decreases the
sensitivity of the visceral nerves that carry impulses from the gut to the emetic centre.
o Metoclopramide also increases the amount of acetylcholine released at post-ganglionic
terminals.
o It is relatively ineffective in motion sickness and other forms of centrally mediated vomiting.
o High doses of metoclopramide block 5HT3 receptors.
 Domperidone : Dopamine Receptor Antagonists

o Domperidone is a dopamine-receptor antagonist similar to metoclopramide. It does not
penetrate the bloodbrain barrier, however, and therefore seldom causes sedation
orextrapyramidal effects. However, the CTZ lies functionally outside the barrier and thus
domperidone is an effective antiemetic which can logically be given with centrally acting
dopamine agonists or levodopa or apomorphine to counter their emetogenic effect .
 Phenothiazines : Dopamine Receptor Antagonists

o Phenothiazines act on the CTZ and larger doses depress the vomiting centre as well.
Phenothiazines used as anti-emetics include prochlorperazine, trifluoperazine,
o perphenazine and chlorpromazine
o These act partly by their antimuscarinic action on the gut, as well as by some central action.
o Hyoscine is effective in preventing motion sickness and is useful in single doses for short
journeys, as the anticholinergic side effects make it unsuitable for chronic use.
o These are effective against opioid- and radiation-induced vomiting and are sometimes helpful
in vestibular disturbances. They are least effective in the treatment of motion sickness.
 Serotonin(5HT-3) Receptor Antagonists

o Block serotonin (5HT-3) receptors; however their exact site of action is uncertain.
o It may be peripheral at abdominal visceral afferent neurones, or central within the area
postrema of the brain, or a combination of both.
o Examples include ondansetron, granisetron, dolasetron and tropisetron
 Cannabinoids
o Cannabis and its major constituent, D-9-tetrahydrocannabinol (THC), have anti-emetic
properties and have been used to prevent vomiting caused by cytotoxic therapy. In an attempt
89
to reduce side effects and increase efficacy, a number of analogues, including nabilone, have
been synthesized.
o The site of action of nabilone is not known, but an action on cortical centres affecting
vomiting via descending pathways
seems probable.
Drug interactions
 Metoclopramide: Dopamine Receptor Antagonists
Metoclopramide potentiates the extrapyramidal effects of phenothiazines and
butyrophenones.
 Its effects on intestinal motility result in numerous alterations in drug absorption,
including increased rates of absorption of several drugs such as aspirin, tetracycline and
paracetamol
Side effects
 Side effects of antiemetic drugs are:
o Headache
o Dizziness
o Constipation
o Drowsiness
o Sedation
o Dry mouth
o Hypertension
o Hypotension
o Nasal congestion
o Diarrhea
Contraindications
 Antiemetic drugs are contraindicated in patients with known hypersensitivity to these
drugs
 Prochlorperazine is contraindicated in patients with:

o Narrow angle glaucoma
o Severe liver disease
o Cardiovascular disease
90
Session 11: Pharmacodynamics of Analgesics, Antipyretics
and Anti-inflammatory Drugs
Prerequisites
 PST04211_S7_ Description of Analgesics
 PST04211_S21_ Description of Antinflammatory and Antipruritic Drugs
Learning Tasks
 Describe mechanism of action of analgesics, antipyretics and anti-inflammatory drugs
 Describe drug interactions associated with analgesics, antipyretics and anti-inflammatory
drugs
 Describe side effects of analgesics, antipyretics and anti-inflammatory drugs
 Describe contraindications of analgesics, antipyretics and anti-inflammatory drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Analgesics,
2 45 minutes
Buzzing Antipyretics and Anti-Inflammatory Drugs
Drug Interactions Associated With
Presentation/
3 25 minutes Analgesics, Antipyretics and Anti-
brainstorming
Inflammatory Drugs
Side Effects of Analgesics, Antipyretics and
Anti-Inflammatory Drugs
Presentation/ Contraindications of Analgesics,
5 20 minutes
Brainstorming Antipyretics and Anti-Inflammatory Drugs
91
SESSION CONTENTS

STEP 2: Mechanism of Action of Analgesics, Antipyretics and Anti-

Inflammatory Drugs (45 minutes)
 How do Analgesics, Antipyretics and Anti-Inflammatory Drugs produce their

pharmacological effects?
 Anti-inflammatory, Antipyretic, Analgesics have different mechanisms of action:

 Non-Steroidal Anti-Inflammatory Drugs
o Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin biosynthesis by
inhibiting cyclo-oxygenase (COX).
o This is the basis of most of their therapeutic, as well as their undesired actions. COX is a key
enzyme in the synthesis of prostaglandins and thromboxanes, important mediators of the
erythema, oedema, pain and fever of inflammation.
o There are two main isoforms of the enzyme, namely a constitutive form (COX-1) that is
present in platelets, stomach, kidneys and other tissues, and an inducible form, (COX-2), that
is expressed in inflamed tissues as a result of stimulation by cytokines and is also present to a
lesser extent in healthy organs, including the kidneys.
Anti-inflammatory actions
 Drugs like Aspirin inhibits cyclooxygenase activity, it diminishes the formation of
prostaglandins and thus modulates those aspects of inflammation in which prostaglandins act
as mediators.
o Acetaminophen, although a useful analgesic and antipyretic, has weak anti-inflammatory
activity and is therefore not useful in the treatment of inflammation such as that seen with
rheumatoid arthritis.
92
Analgesic action
o Prostaglandin E2 (PGE2) is thought to sensitize the nerve endings to the action of bradykinin,
histamine, and other chemical mediators released locally by the inflammatory process.
o Thus, by decreasing PGE2 synthesis, aspirin and other NSAIDs repress the sensation of pain.
o NSAIDs are superior to opioids in the management of pain in which inflammation is
involved; combinations of opioids and NSAlDs are effective in, treating pain in malignancy.
Antipyretic action
o Fever occurs when the set-point of the anterior hypothalamic thermoregulatory centre is
elevated.
o This can be caused by PGE2 synthesis, stimulated when an endogenous fever-producing
agent (pyrogen) such as a cytokine is released from white cells that are activated by infection,
hypersensitivity, malignancy, or inflammation.
o The salicylates and other NSAIDs lower body temperature in patients with fever by
impeding PGE2 synthesis and release.
o They reset the "thermostat" toward normal and rapidly lower the body temperature of febrile
patients by increasing heat dissipation as a result of peripheral vasodilation and sweating.
o These drugs have no effect on normal body temperature.
Glucocorticosteroids
 Prednisolone and others
o These agents lack antipyretic and analgesic activity.
o They only have anti-inflammatory activity.
o Inhibits expression of pro-inflammatory cytokines IL-2, 3 and 6, TNF, GM-CSF and IFN-γ;
o Inhibits production of adhesion molecules – ICAM-1,E-selectin and vascortin – leading to
reduced vascular permeability.
o Reduces synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes) and reduces
histamine release.
Other (Slow Acting) Anti-Inflammatory Agents

 Gold Compounds, Chloroquine and hydroxychloroquine, penicillamine
o In contrast to the NSAlDs drugs described earlier, remittive (remission inducing) arthritis
drugs are slow-acting.
o They do not act by inhibiting cyclooxygenase and have no analgesic or primary anti-
inflammatory activity.
o These drugs are used primarily for rheumatic disorders, especially in cases where the
inflammation does not respond to cyclooxygenase inhibitors.
o They slow the course of the disease and may also induce a remission, preventing further
destruction of the joints and involved tissues.
o Gold compounds: like the other drugs in this group, cannot repair existing damage. Rather,
they can only prevent further injury.
93
o The currently available gold preparations are gold sodium thiomalate, aurothioglucose, and
auranofin.
o It is believed that gold salts are taken up by macrophages and suppress phagocytosis and
lysosomal enzyme activity.
o This mechanism retards the progression of bone and articular destruction.
o The mechanism of their anti-inflammatory activity is uncertain.
o Besides inhibiting nucleic acid synthesis, they are known to stabilize lysosomal membranes
and trap free radicals.
o In treating inflammatory disorders, they are used for rheumatoid arthritis that has been
unresponsive to NSAlDs or else they are used in conjunction with an NSAID.
STEP 3: Drug Interactions Associated With Analgesics, Antipyretics and

Anti-Inflammatory Drugs (25 minutes)
 How do significant drug interactions of Analgesics, Antipyretics and Anti-Inflammatory

Drugs occur?

Drug interactions of antipyretic, analgesics and anti-inflammatory are as follows:
o NSAIDs are associated with drug interactions but only a proportion are clinically relevant.
o Many are due to displacement of a drug from its plasma protein binding sites by NSAIDs
which are tightly protein-bound.
o They may not occur with all NSAIDs but might be selective
o Most NSAIDs do not have clinically important interactions with oral hypoglycemic agents
whereas phenylbutazone, azaprozone & aspirin prolong their half-life.
o Similarly phenylbutazone and azaprozone prolong coumadin's half-life.
o Lithium clearance may be decreased by indomethacin, piroxicam, phenylbutazone and
diclofenac. Methotrexate (MTX) may be displaced from its binding protein sites by NSAIDs.
o This is generally not clinically relevant with low doses of MTX as utilized in rheumatoid
arthritis patients with normal renal function.
o NSAIDs also may reduce renal blood flow, tubular excretion of drugs & renal prostaglandin
production and may attenuate the effect of anti-hypertensive drugs.
94
o Renal failure & hyperkalemia have been reported in patients receiving triamterene &
indomethacin.
STEP 4: Side Effects of Analgesics, Antipyretics and Anti-Inflammatory

Drugs (20 minutes)
Anti-inflammatory, Antipyretic, Analgesics:
o Non Selective: Gastrointestinal effects occur because of the inhibition of COX-1mediated
production of cytoprotective mucus in the stomach.
o Non selective: Edema: PGs inhibit the reabsorption of Na+ and the activity of ADH, so PG
inhibition leads to salt and water retention. This can lead to edema and can be problematic in
patients with conditions such as congestive heart failure.
o COX-2 Selective: Cardiovascular, cardiac failure with fluid retention and myocardial
infarction: The mechanism is not confirmed, but cardiovascular effects are thought to be a
result of disruption of the balance between the platelet-activating effects of COX-1 and the
platelet-inhibiting effects of COX-2.
o All: Central nervous system (CNS): Confusion, dizziness, depression, and hallucinations may
occur. The mechanism is not confirmed, but COX-2 is the most abundant COX isoform in the
CNS, and COX-2 may play a role in neurotransmission. The frequency of CNS side effects
appears to be higher with COX-2selective inhibitors and possibly with indomethacin.
o Actions on the kidney: Cyclooxygenase inhibitors prevent the synthesis of PGE 2 and PGl2
prostaglandins that are responsible for maintaining renal blood flow, particularly in the
presence of circulating vasoconstrictors.
o Decreased synthesis of prostaglandins can result in retention of sodium and water and may
cause edema and hyperkalaemia in some patients. Interstitial nephritis can also occur with all
of the IVSAIDs except aspirin.
o Effect on platelets: TXA2 enhances platelet aggregation, whereas PGl2 decreases it. Low
doses (60 to 80 mg daily) of aspirin can irreversibly inhibit thromboxane production in
platelets. As a result of the decrease in TXA2, platelet aggregation (the first step in thrombus
formation) is reduced, producing an anticoagulant effect with a prolonged bleeding time.
o Gastrointestinal effects: Normally, prostacyclin (PGI2) inhibits gastric acid secretion,
whereas PGE2 and PGF2 stimulate synthesis of protective mucus in both the stomach and
small intestine.
o In the presence of aspirin, these prostanoids are not formed, resulting in increased gastric acid
secretion and dirninished mucus protection. This may cause epigastric distress, ulceration,
and/or hemorrhage.
o Respiratory actions: At therapeutic doses, aspirin increases alveolar ventilation. Salicylates
uncouple oxidative phosphorylation, which leads to elevated C02 and increased
concentration.
o Adverse effects have been discussed in detail in session Pharmacodynamics of Drugs acting
on Respiratory System
95
STEP 5: Contraindications of Analgesics, Antipyretics and Anti-
Inflammatory Drugs (10 minutes)
 What are contraindications of Analgesics, Antipyretics and Anti-Inflammatory drugs?

 Anti-inflammatory, Antipyretic, Analgesics:

o Active peptic ulcer
o Acetyl salicylic acid in Asthma
o Most drugs do not exhibit significant interactions

 NSAIDs inhibit cyclo-oxygenase (COX) enzyme.
 COX-2-selective drugs may have reduced gastric toxicity, but increase cardiovascular
thrombotic events.
 What is the mechanism of action of glucocorticosteroids in the treatment of inflammation?

 What are the adverse effects of acetyl salicylic acid?
 What are the indications for Gold compounds?
 What do you understand by the term REYES syndrome?
96
References
Education.

97
Session 12: Pharmacodynamics of Drugs Acting Locally on
the Skin
Prerequisites
Learning Tasks
 Describe mechanism of action of Drugs acting locally on the skin
 Describe drug interactions associated with Drugs acting locally on the skin
 Describe side effects of Drugs acting locally on the skin
 Describe contraindications of Drugs acting locally on the skin
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Drugs Acting
2 45 minutes
Buzzing Locally on The Skin
3 20 minutes
brainstorming Acting Locally on The Skin
Side Effects of Drugs Acting Locally on The
Skin
Presentation/ Contraindications of Drugs Acting Locally
5 20 minutes
Brainstorming on the Skin
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SESSION CONTENTS

STEP 2: Mechanism of Action of Drugs Acting Locally on the Skin (45

minutes)
 How do drugs acting locally on the skin produce their pharmacological effects?
These drugs includes antibacterial/antibiotics, ant protozoans, antifungal and anti-viral

The following are the mechanism of action of Anti-infective drugs
 Antibacterial/antibiotics
o Some widely used topical antibiotics are bacitracin, neomycin, gentamycin, mupirocin and
polymyxins.
o Mechanism of action of antibacterial/antibiotics is either inhibiting bacterial growth
(bacteriostatic) or kills bacteria (bactericidal) or can have both actions depending on its
concentration (e.g Clindamycin and erythromycin in treatment of acne)
o Aminoglycosides act by interfering bacteria protein synthesis.
o Mupirocin act by inhibiting protein and RNA synthesis by binding reversibly to sub unit 50s
of bacteria ribosome or disrupt synthesis of peptidoglycan layer of bacterial cell wall. It also
inhibits bacterial isoleucyl-tRNA synthetase.
o Polymyxins binds to lipopolysaccharide on outer cell wall of GNR leading to permeability
change in cell envelope hence leakage of cell content. Polymyxins are only active against
gram negative bacteria (P. aeruginosa, E. coli, K. pneumoniae).
 Antifungal
o Antifungal drugs may be fungicidal (able to destroy fungi) or fungistatic (able to slow or
retard the multiplication of fungi)
99
o Azoles (Ketoconazole, Clotrimazole and miconazole nitrate) acts by inhibits the biosynthesis
of plasma membrane by preventing synthesis of ergosterol and other steroids which results to
damage of fungal cell wall membranes and loss of essential intracellular elements.
o Terbinafine Hydrochloride: binds with squalene epoxidase enzyme and hinders biosynthetic
pathway of ergosterone and results to growth and it is associated with high intracellular
squalene concentrations which interfere with fungal membrane function and cell wall
synthesis causes death of fungi.
 Antiviral
o Commonly agents are: acyclovir, famciclovir and valacyclovir
o Acyclovir works by lowering the ability of the herpes virus to multiply, it acts as specific
inhibitor of herpesvirus DNA polymerase (HSV), type 1 and 2 and varicella zoster virus. This
selectivity is due to the ability of these viruses to code for a viral thymidine kinase capable of
phosphorylating acyclovir to monophosphate (this capability is absent in uninfected cells)
 Ant protozoans
o Mechanism of action of ant protozoans differ significantly with drug to drug e.g
Paramomycin (antibacteria drug but also it is antiprotozoal agent) interfere with
metabolic processes (glycolysis and fatty acid oxidation) or by interfering with reproduction
and larval physiology or interfering with muscular physiology of parasites (e,g in treatment
of leishmaniasis).
 Corticosteroids:
o Used for their Antinflammatory action
o Details on glucocorticosteroids is found on pharmacology of Antinflammatory drugs
STEP 3: Drug Interactions Associated with Drugs acting locally on the skin
(20 minutes)
 What are drug interactions associated with drugs acting locally on the skin?

 Most of drugs for treating skin infection do not show significant drug interactions because of
minimal systemic absorption of these drugs hence systemic drug interactions are unlikely.
 Drug interactions can result only when the skin barrier is destroyed hence systemic
absorption.
 Antibiotics/antibacterial
100
o For example oral metronidazole has been reported to potentiate the anticoagulant effect of
warfarin and coumarin anticoagulants resulting in a prolongation of prothrombin but the
effect of topical metronidazole on prothrombin time is unknown.
 Antifungal
o Miconazole when co administered with warfarin it may increase the anticoagulant effect
of the warfarin by inhibiting hepatic microsomal cytochrome p-450 enzyme.
o Amphotericin B fungistatic activity is antagonised by azoles antifungal when applied
simultaneously
o Amphotericin B decreases the effects of miconazole.
STEP 4: Side Effects of Drugs acting locally on skin (20 minutes)

 Antibacterial/antibiotics (side effects already mentioned in NTA Level 4)
 In addition, the following are side effects which are rarely reported
o Prolonged use of mupirocin and other topical antibacterial can cause microscopic organisms,
such as bacteria or fungi, to overgrow and also they may cause diarrhoea due to infection.
They should be only used as recommended.
o Clindamycin may cause diarrhoea, dizziness, headache, contact dermatitis, maculopapular
rash, erythema, endometriosis, menstrual disorder, inflammatory swelling, abdominal cramps
and GIT disturbance
 Antifungal
o Amphotericin B is well tolerated but only occasionally causes local irritation of the skin and
it may cause temporary yellow staining of the skin especially when the cream vehicle is used
 Antiviral
o Rarely reported side effects of topical antiviral are; dry lips, desquamation, dryness of skin,
cracked lips, burning skin, flakiness of skin
STEP 5:Contraindications of Drugs acting locally on skin (10 minutes)
 What are the contraindications of Drugs acting locally on skin?

 Topical anti-infective drugs

 Antibiotics
101
o These medications should not be used if the patient is allergic to any ingredients of the
medications.
 Antifungal
o They are contraindicated in patients with known hypersensitivity to the contents of the drugs
o Miconazole cream is contraindicated during the pregnancy because small amounts of these
drugs may be absorbed from the vagina, the drug is used during the first trimester only when
essential.
 Antiviral
o Acyclovir is contraindicated in patients who have developed acyclovir hypersensitivity or
valacyclovir hypersensitivity.
o Because of similar chemical structures and possible cross-sensitivity, acyclovir should not be
used in patients with famciclovir hypersensitivity, ganciclovir hypersensitivity, penciclovir
hypersensitivity, or valganciclovir hypersensitivity.
o Pregnancy
Topical acyclovir products are classified as pregnancy risk category B. No complete or well-
controlled pregnancy studies have been performed in humans.
o Breast-feeding
Exposure of the infant after maternal use of topical administration of acyclovir is minimal,
provided the treatment area does not involve the breast. Women who have active herpetic
lesions on or near the breast should avoid nursing until the lesions have completely resolved.
o Ophthalmic administration
Acyclovir cream and ointment products are for external topical use only. Avoid ophthalmic
administration or use inside the mouth or nose.

 Clotrimazole and miconazole are common medicines in treatment of superficial fungal
infections
 Amphotericin B should not applied together with azoles
 Long term use of topical antibacterial drugs should be avoided
 Most of topical preparations do not have drug interactions due to minimal systemic
absorption
 Patient history is very important before dispensing any topical preparation to the patient

 What are the indications of acyclovir cream?
 What is the mechanism of action of topical antifungals?
 What is the mechanism of terbinafine hydrochloride?
102
References
Education.

103
Session 13: Pharmacodynamics of Antineoplastic Drugs
Prerequisites
Learning Tasks
 Describe mechanism of action of Antineoplastic Drugs
 Describe drug interactions associated with Antineoplastic Drugs
 Describe side effects of Antineoplastic Drugs
 Describe contraindications of Antineoplastic Drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Antineoplastic
2 45 minutes
Buzzing Drugs
Presentation/ Drug Interactions Associated With
3 20 minutes
brainstorming Antineoplastic Drugs
4 20 minutes Presentation Side Effects of Antineoplastic Drugs
Presentation/
5 20 minutes Contraindications of Antineoplastic Drugs
Brainstorming
104
SESSION CONTENTS

STEP 2: Mechanism of Action of Antineoplastic Drugs (45 minutes)
 How do Antineoplastic Drugs produce their pharmacological effects?
Alkylating Agents
 In general, Alkylating agents are particularly effective when cells are dividing rapidly, but are
not phase-specific.
 They combine with DNA and thus damage malignant and dividing normal cells.
 If a tumour is sensitive to one alkylating agent, it is usually sensitive to another, but cross-
resistance does not necessarily occur.
 The alkylating agents transfer alkyl (chemical) groups to DNA. DNA alkylation in the
nucleus leads to the death of the cell.
 Once in the cell, the alkylating agents undergo a structural rearrangement that results in the
formation of an unstable intermediate, an ethylene immonium ion.
 This ion either directly, or via another intermediate, a carbonium ion, transfers alkyl groups
to nucleic acids such as guanine or to other cellular constituents.
Alkylation of guanine or other bases results in abnormal base pairing

as well as the excision of these bases, which in turn leads to strand
breakage.
 The connection between DNA alkylation and death of the cancer cell has not been
established; however, one of the likely mechanisms is damage to DNA that is sufficient to
activate proapoptotic proteins such as p53, leading to cell death.
Mustine (Mechlorethamine)
105
 Mustine forms highly reactive ethyleneimine ions that alkylate and cross-link guanine bases
in DNA and alkylate other macromolecules, including proteins.
Cyclophosphamide
 It is an inactive prodrug given orally or intravenously.
Nitrosoureas:
Carmustine, lomustine, semustine, bendamustine
 Nitrosoureas have an additional mechanism of action.
 Nitrosoureas undergo another reaction, referred to as carbamoylation, with lysine residues of
proteins.
 The product of this reaction is referred to as a carbamoylated protein, and this process
appears to limit the ability of the cancer cell to repair DNA.
 This unique mechanism of action limits cross-resistance between nitrosoureas and other
members of this class.
Procarbazine
 It is an inactive prodrug given orally or intravenously
Platinum compounds
 Cisplatin, Carboplatin etc
o Platinum compound cytotoxicity results from selective inhibition of tumour DNA
synthesis by the formation of intra- and inter-strand cross-links at guanine residues in the
nucleic acid backbone.
o This unwinds and shortens the DNA helix.
Antifolate analogues antimetabolites

 Methotrexate
o Folic acid is required in the synthesis of thymidylate (a pyrimidine) and of purine
nucleotides and thus for DNA synthesis.
o Methotrexate is a very slowly reversible competitive inhibitor of dihydrofolate reductase
(DHFR).
o The affinity of DHFR for methotrexate is 100 000 times greater than that for
dihydrofolate.
o Thus, methotrexate prevents nucleic acid synthesis and causes cell death. Folinic acid
circumvents this biosynthetic block and thus non-competitively antagonizes the effect of
methotrexate.
Pyrimidine antimetabolites
106
 5-Fluorouracil
o 5-Fluorouracil is a prodrug that is activated by anabolic phosphorylation to form: 5-
fluorouridine monophosphate, which is incorporated into RNA, inhibiting its function and
its polyadenylation.
o The anabolic phosphorylation also forms 5-fluorodeoxyuridylate, which binds strongly to
thymidylate synthetase and inhibits DNA synthesis.
o Incorporation of 5-fluorouracil itself into DNA causes mismatching and faulty mRNA
transcripts.
Purine antimetabolites
 6-Mercaptopurine (6-MP)
o 6-MP requires transformation by intracellular enzymes to 6-thioguanine which inhibits
purine synthesis.
Cytotoxic Antibiotics (Anthracyclines )
 Doxorubicin
o Cytotoxic actions of anthracyclines lead to apoptosis through intercalation between
adjacent base pairs in DNA, leading, to fragmentation of DNA and inhibition of DNA
repair, enhanced by DNA topoisomerase II inhibition.
Topoisomerase Inhibitors
 Camptothecins (Topoisomerase I inhibitors)
o Camptothecins act during the S-phase of the cell cycle. DNA topoisomerase I is necessary
for unwinding DNA for replication and RNA transcription.
o Camptothecins stabilize the DNA topoisomerase IDNA complex. Cell killing is most
likely via induction of apoptosis (programmed cell death).
 Etoposide and Teniposide (Topoisomerase II inhibitors)
o DNA topoisomerase II is a nuclear enzyme that binds to and cleaves both strands of
DNA. It is necessary for DNA replication and RNA transcription. Etoposide stabilizes the
topoisomerase IIDNA complex, leading to apoptosis, as for camptotecins.
Microtubular inhibitors (Vinca Alkaloids and Taxanes)
 Vincristine and Vinblastine (Vinca alkaloids)
o Vinca alkaloids bind to β-tubulin, a protein that forms the microtubules which are
essential for the formation of the mitotic spindle.
o They prevent β-tubulin polymerizing with α-tubulin and thus inhibit mitosis. Blockade of
microtubular function involved in neuronal growth and axonal transport probably
accounts for their neurotoxicity.
 Paclitaxel (Taxanes)
o Paclitaxel binds to the β-subunit of tubulin and antagonizes the depolymerization of
microtubules, halting mitosis. Cells are blocked in the G2/M phase of the cell cycle and
undergo apoptosis.
107
STEP 3: Drug Interactions Associated with Antineoplastic Drugs (20
minutes)
 How do significant drug interactions of Antineoplastic Drugs occur?

 Alkylating Agents
 Procarbazine
o Procarbazine blocks aldehyde dehydrogenase and consequently causes flushing and
tachycardia if ethanol is taken concomitantly.
o Itis also a weak monoamine oxidase inhibitor and may precipitate a hypertensive crisis with
tyramine-containing foods
 Platinum compounds
 Cisplatin
o Additive nephrotoxicity and ototoxicity occurs with aminoglycosides or amphotericin.
 Antifolate analogues antimetabolites

 Methotrexate
o Probenecid, sulphonamides, salicylates and other NSAIDs increase methotrexate toxicity by
competing for renal tubular secretion, while simultaneously displacing it from plasma
albumin.
o Other weak acids including furosemide and high-dose vitamin C compete for renal secretion.
o Gentamicin and cisplatin increase the toxicity of methotrexate by compromising renal
excretion.
 Purine antimetabolites
 6-Mercaptopurine (6-MP)
o Allopurinol inhibits xanthine oxidase.
o The usual dose of 6-MP should be reduced by 75% to avoid toxicity in patients who are
concurrently taking allopurinol.
108
o This is important because allopurinol pre-treatment is used to reduce the risk of acute uric
acid nephropathy due to rapid tumour lysis syndrome in patients with leukaemia.
STEP 4: Side Effects of Antineoplastic Drugs (20 minutes)

 Alkylating Agents
 Cyclophosphamide and others.
o Nausea, vomiting: These are common side effects with cytotoxic agents, which tend to target
rapidly dividing cells, including those of the GI tract.
o Alopecia: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells,
such as those in hair follicles. This effect is seen most often with cyclophosphamide.
o Serious Myelosuppression: Typical of cytotoxic agents, alkylators tend to target cells that are
actively dividing, such as those found in the bone marrow.
o Pulmonary toxicity (nitrosoureas and busulfan): Interstitial lung disease may occur.
o Nephrotoxicity is seen most often with cyclophosphamide and ifosfamide.
o Bladder toxicity is seen most often with cyclophosphamide and ifosfamide.
o Haemorrhagic cystitis (cyclophosphamide and ifosfamide) is caused by acrolein, a metabolite
of cyclophosphamide and ifosfamide. This effect can be managed by increasing fluid intake
and by administering sulfhydryl donors such as N-acetylcysteine or mesna (an antioxidant).
These agents bind with acrolein and form a nontoxic compound.
o Leukemia (rare): The alkylating agents work by damaging DNA. If they damage DNA in
healthy cells, this may lead to mutations in the genome that rarely result in development of
malignancies, particularly leukemia.
 Anthracyclines:
 Doxorubicin etc
o Cytotoxic actions of anthracyclines lead to apoptosis through membrane binding alters
membrane function and contributes to cardiotoxicity
o Free-radical formation from anthracyclines also causes cardiotoxicity.
such as those in hair follicles. The hair loss is reversible.
o Mucositis or stomatitis is an inflammatory condition of the mouth. Cytotoxic chemotherapy
agents tend to target tissues with rapidly dividing cells, such as those in the oral mucosa.
o Soft tissue necrosis: If the anthracyclines become extravascular, they can damage
surrounding tissue. Infusions should be carried out slowly to reduce the risk of extravasation.
o Cardiotoxicity: The free radicals generated by the anthracyclines cause peroxidation of the
cardiac sarcoplasmic reticulum, leading to a Ca2+-dependent cardiac necrosis. The reason
this toxicity is selective for cardiac tissue is that catalase, able to neutralize these free
radicals, is not found in cardiac tissue.
o Myelosuppression: Cytotoxic chemotherapy agents tend to target tissues with rapidly
dividing cells, such as those of the bone marrow. The bone marrow suppression is reversible
but does predispose the patient to major complications such as infection while receiving
treatment.
109
 Antimetabolites:
 Methotrexate and others
o Myelosuppression: Conventional chemotherapy agents work by targeting rapidly dividing
cells.
o This nonspecific effect can also target rapidly dividing cells in other areas of the body,
including bone marrow and the GI tract.
such as those in hair follicles.
o Defective oogenesis or spermatogenesis results from targeting of rapidly dividing cells.
o Hepatotoxicity: Reversible elevations in liver enzymes may develop.
STEP 5: Contraindications of Antineoplastic Drugs (10 minutes)

 What are the contraindications of Antineoplastic Drugs?
Alkylating Agents
 Cyclophosphamide:
o Severe leukopenia, thrombocytopenia will be exacerbated (see side effects).
o Pregnancy: Like other cytotoxic agents, cyclophosphamide can cause fetal harm.
o Lactation: Cyclophosphamide is excreted in breast milk, so breastfeeding should be
avoided.
 Melphalan, Chlorambucil:
o Radiation: should not be administered with radiation therapy or within 4 weeks of
radiation therapy (chlorambucil).
o Radiation also damages DNA and may impair DNA repair mechanisms in healthy cells,
leaving them more susceptible to the DNA-damaging effects of alkylating agents.
 Lomustine:
o Severe leukopenia and/or thrombocytopenia is a contraindication.
o Lactation: It is not known whether lomustine is excreted in breast milk, but breastfeeding
is not advised during treatment
Antifolate analogues antimetabolites

 Methotrexate
o Pregnancy: Most of the antimetabolites are teratogenic in animals.
110
Anthracyclines
 Doxorubicin and others
o Severe cardiac disease: Anthracyclines should be used only with extreme caution and after a
careful risk-benefit assessment in these patients. See Side Effects.
o Lactation: Patients should not breastfeed while using these agents.

 Combination therapy is better than single drug therapy because there is improved cell
cytotoxicity; heterogeneous tumour cell populations are killed and it reduces the development
of resistance.
 Anticancer drugs have serious adverse effects
 Cytotoxic drugs are not totally selective in their toxicity to cancer cells.

 What are the indications of cyclophosphamide?
 What are the general/common adverse effects of anticancer drugs?
 How do Vinca alkaloids produce their pharmacological effects?
111
References
Education.

112
Session 14: Pharmacodynamics of Immunosuppressive
Agents
Prerequisites
Learning Tasks
 Describe mechanism of action of Immunosuppressive agents
 Describe drug interactions associated with Immunosuppressive agents
 Describe side effects of Immunosuppressive agents
 Describe contraindications of Immunosuppressive agents
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Immunosuppressive
2 45 minutes
Buzzing Agents
Presentation/ Drug Interactions Associated with
3 20 minutes
brainstorming Immunosuppressive Agents
4 20 minutes Presentation Side Effects of Immunosuppressive Agents
Presentation/ Contraindications of Immunosuppressive
5 20 minutes
Brainstorming Agents
113
SESSION CONTENTS

STEP 2: Mechanism of Action of Immunosuppressive Agents (45 minutes)
 How do Immunosuppressive Agents produce their pharmacological effects?
Calcineurin inhibitors
 Ciclosporin
o It inhibits the production of interleukin-2 (IL-2) and other cytokines by activated
lymphocytes through its binding to a cytosolic protein cyclophilin. This conjugate
subsequently interacts with a Ca2+calmodulin dependent Calcineurin complex and inhibits
its phosphorylase activity.
o This impairs access to the nucleus of the cytosolic component of the transcription promoter
nuclear factor of activated T cells (NF-ATc), which in turn reduces the transcription of
messenger RNA for IL-2, other pro-inflammatory lymphokines and IL-2 receptors.
 Tacrolimus
o Tacrolimus (FK506) is another calcineurin inhibitor with the same mechanism of action to
ciclosporin.
o It is more potent than ciclosporin and often used in patients who are refractory to ciclosporin.
Target of Rapamycin (mTOR) Inhibitors

 Sirolimus,
o mTOR (mammalian target of rapamycin) is a serine-threonine protein kinase activated by
several growth factors after receptor binding.
o Sirolimus binds a protein called FKBP 12 (FKBP stands for FK506 binding protein) in the
cytoplasm. The drug-protein complex then binds and inhibits mTOR.
114
o Inhibition of mTOR blocks cell-cycle progression at the G1 → S phase transition.
o mTOR regulates important functions of the cell, including proliferation, angiogenesis (blood
vessel formation), cell survival, protein synthesis, and transcription. It is recognized as a key
point in many cellular functions.
o inhibits expression of pro-inflammatory cytokines IL-2, 3 and 6, TNF, GM-CSF and IFN-γ;
o inhibits production of adhesion molecules – ICAM-1,E-selectin and vascortin – leading to
reduced vascular permeability
o reduces synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes) and reduces
histamine release
Anti-Proliferative Immunosuppressants
 Azathioprine
o Azathioprine is a prodrug and is converted to 6-mercaptopurine (6-MP) by the liver.
 Mycophenolate Mofetil
o In vivo the active entity, mycophenolic acid, inhibits inosine monophosphate dehydrogenase
(a pivotal enzyme in purine synthesis). Hence, it suppresses proliferation both of T and B
lymphocytes.
o In addition, mycophenolic acid inhibits the production of pro-inflammatory cytokines.
Monoclonal Antibodies
 Anti-CD3 Antibody (Muromonab-CD3)
o Anti-CD3 antibodies bind CD3 protein, blocking antigen binding to the T-cell
antigenrecognition complex, and decreasing the number of circulating CD3-positive
lymphocytes.
o In addition, binding of anti-CD3 to its receptor causes cytokine release. The overall effect is
to reduce T-cell activation in acute solid-organ graft rejection.
Polyclonal Antibodies
 Antilymphocyte Globulin
o The major effect is probably to prevent antigen from accessing the antigen-recognition site on
the T-helper cells.
115
STEP 3: Drug Interactions Associated With Immunosuppressive Agents
(20 minutes)
 How do significant drug interactions of Immunosuppressive Agents occur?
 Ciclosporin
o These include allopurinol, cimetidine, ketoconazole (and other azoles), erythromycin,
diltiazem (and other calcium channel blockers), anabolic steroids, norethisterone and other
inhibitors of cytochrome P450 3A4, which reduce the hepatic clearance of ciclosporin
leading to increased toxicity.
o Phenytoin and rifampicin increase hepatic clearance, thus reducing plasma concentrations.
o Concomitant use of nephrotoxic agents such as aminoglycosides, vancomycin and
amphotericin increases nephrotoxicity.
o Concomitant use of ACE inhibitors increases the risk of hyperkalaemia.
 Tacrolimus
o The drugdrug interaction profile of tacrolimus is similar to that of ciclosporin, but it may
cause more neurotoxicity and nephrotoxicity.
Target of Rapamycin (mTOR) Inhibitors

 Sirolimus
o Although sirolimus is not nephrotoxic alone, coadministration with a calcineurin inhibitor
(another drug used for renal transplants) results in greater kidney damage than with a
calcineurin inhibitor alone. Therefore there is some interaction with calcineurin inhibitors that
potentiates the renal damage induced by the calcineurin inhibitor, and the two drugs should
not be coadministered.
o Details are found on pharmacodynamics of drugs acting on respiratory system .
116
STEP 4: Side Effects of Immunosuppressive Agents (20 minutes)
 Ciclosporine and others
o Increased risk of infections, especially opportunistic infections Fungal, Viral: Epstein-Barr
virus (EBV), cytomegalovirus (CMV), Atypical bacterial: Nocardia, Listeria, mycobacterial
o Increased risk of neoplasm: Cancer is often detected and eradicated by the immune system in
its very early stages.
o Nephrotoxicity: Kidney damage is a common problem with administration of cyclosporine.
This is the most important side effect. It is possibly mediated through renal arteriolar
vasoconstriction. Renal damage often limits administration of cyclosporine.
o Hypertension: The exact mechanism is unknown, but cyclosporine has been shown to
increase sympathetic nervous system activity, which would result in increased blood
pressure.
o CNS problems: Tremors and headaches may occur, usually seen with larger doses.
o Tacrolimus only: Hyperglycemia (diabetes) may occur as a result of pancreatic beta cell
inhibition.
o Cyclosporine Only: Hirsutism or hypertrichosis (hair growth): a cosmetic problem and Gum
hyperplasia
o Tacrolimus Only: Alopecia (paradoxically, the opposite of hypertrichosis)
o Details are found on pharmacodynamics of drugs acting on respiratory system
Antimetabolites
o Details are found on pharmacodynamics of anticancer drugs
Tumor Necrosis Factor (TNF)–α Inhibitors

 Infliximab, adalimumab, certolizumab
o Injection site irritation
o Acute inflammatory reaction: Because of the ability of TNF to influence the immune system,
extensive inflammatory reactions can occur within 24 hours (usually within 6 hours) after
administration.
o They are characterized by fever, hypotension, tachycardia, itching, chest pain, and shortness
of breath. These reactions are relatively common (10% of the time), but only rarely are they
severe enough to discontinue treatment.
o Delayed inflammatory reaction: Signs and symptoms that occur within 2 weeks after the
injection are probably mediated by antibodies to the drug. Symptoms of these reactions
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include fever, rash, urticaria (itching), myalgia (muscle pain), arthralgia (joint pain), jaw
tightness, and edema.
o Infection: Because of the immune suppression, common bacterial and also opportunistic
infections are more common in patients receiving TNF suppression:
o Bacterial sepsis (widespread inflammatory response caused by bacterial infection in the
blood)
o Fungal infections
o Latent TB (previous TB can be reactivated); patients must be screened for previous TB
infections before starting anti-TNF therapy
o Herpes zoster
o Severe but rare side effects include heart failure, liver failure, and demyelinating disorders of
the central nervous system (CNS).
o Cancer: Another function of the immune system is to provide surveillance of early cancer
cells and to destroy them early. A blunted immune system therefore can increase the potential
for development of cancer.
STEP 5: Contraindications of Immunosuppressive Agents (10 minutes)
 What are the contraindications of Immunosuppressive Agents?

Antimetabolites
o Details are found on pharmacodynamics of anticancer drugs (session )
o Mycophenolate is contraindicated in pregnancy, whereas azathioprine is not.
o An active, severe infection is a contraindication.
Tumor Necrosis Factor (TNF)–α Inhibitors

 Infliximab, adalimumab, certolizumab
o Latent TB: TB can be reactivated if the immune system is suppressed.
o Patients who are immunocompromised: Combination with additional immunosuppression
increases the risk of infection.
o Active infection: The immune system must remain intact to fight the current infection before
treatment with an immunosuppressant begins.
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 Tacrolimus is more potent than ciclosporin, but cause more neurotoxicity
 Various drugs are immunosuppressive through different mechanisms
 Immunosuppressants have many indications

 What are indications of immunosuppressants?
 What are the general side effects of immunosuppressants?
 What are the contraindications of immunosuppressants
119
References
Education.

120
Session 15: Pharmacodynamics of Vitamins and Minerals
Prerequisites
 PST04211_S38_ Description of Vitamins and Minerals
Learning Tasks
 Describe mechanism of action of Vitamins and Minerals Drugs
 Describe drug interactions associated with Vitamins and Minerals
 Describe side effects of Vitamins and Minerals
 Describe contraindications of Vitamins and Minerals
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Vitamins and
2 45 minutes
Buzzing Minerals Drugs
Presentation/ Drug Interactions Associated With Vitamins
3 20 minutes
brainstorming and Minerals
4 20 minutes Presentation Side Effects of Vitamins and Minerals
Presentation/
5 20 minutes Contraindications of Vitamins and Minerals
Brainstorming
121
SESSION CONTENTS

STEP 2: Mechanism of Action of Vitamins and Minerals (45 minutes)
 How do Vitamins and Minerals produce their pharmacological effects?
Vitamins and minerals have different mechanisms of action as discussed below:
 Vitamin D
o The two major forms of vitamin D replacements are vitamin D2 and vitamin D3.
o Vitamin D is an important regulator of calcium and phosphate homeostasis and bone
metabolism. It works in conjunction with PTH. The overall effect of vitamin D is to increase
serum calcium concentrations. These effects are mediated via the following:
o Increased calcium absorption from the intestine
o Regulation of bone resorption and formation. This occurs via stimulation of both osteoblastic
and osteoclastic processes. Osteoblasts form bone, and osteoclasts dissolve bone.
o Increased calcium reabsorption in the distal renal tubules
o Vitamin D results in a negative feedback loop and decreases transcription and secretion of
PTH. The overall effect of PTH is to increase serum calcium levels, so increased vitamin D
inhibits the actions of PTH so that both mechanisms do not drive up calcium levels too high.
o Vitamin D is lipophilic (it is one of the fat-soluble vitaminsA, D, E, and K) and thus freely
crosses the cytoplasmic membrane. Intracellularly, it binds vitamin D receptors (VDRs) and
binds DNA, where it regulates transcription of genes in the intestine, bone, kidney, and
parathyroid gland.
o Vitamin D also has actions in macrophages and T cells and in proliferation and differentiation
of a large number of cells, including cancer cells.
o Through these actions, it has immunomodulating and potentially, anticancer actions.
122
o Also, these actions are the basis of the mechanism whereby it is effective in psoriasis.
 Vitamin B1 (Thiamine)
o Thiamine is used in the treatment of beriberi and other states of thiamine deficiency, or in
their prevention. Such conditions include alcoholic neuritis, Wernickes encephalopathy and
the neuritis of pregnancy, as well as chronic diarrhoeal states and after intestinal resection.
o Thiamine (in the form of thiamine pyrophosphate) is required for carbohydrate metabolism,
as it is a coenzyme for decarboxylases and transketolases.
 Vitamin B6 (Pyridoxine)
o Pyridoxine hydrochloride is given to patients at risk (e.g. alcoholics) during long-term
therapy with isoniazid to prevent peripheral neuropathy, and in deficiency states. Pyridoxine
is also used to treat certain uncommon inborn errors of metabolism, including primary
hyperoxaluria.
o Vitamin B6 occurs naturally in three forms, namely pyridoxine, pyridoxal and pyridoxamine.
All three forms are converted in the body into pyridoxal phosphate, which is an essential
cofactor in several metabolic reactions, including decarboxylation, transamination and other
steps in amino acid metabolism.
 Vitamin B3 (Niacin and Nicotinic Acid)

o Niacin is used to treat and prevent pellagra. Nicotinic acid (or nicotinic acid analogues may
be used to treat dyslipidaemia, but hypolipidaemic dosing is limited by
vasodilatation/flushing.
o Niacin is vital metabolic role is as a component of nicotinamide adenine dinucleotide (NAD)
and nicotinamide adenine dinucleotide phosphate (NADP).
 Vitamin B12
o Vitamin B12 is an organic molecule with an attached cobalt atom. Linked to the cobalt atom
may be a cyanide (cyanocobalamin), hydroxyl (hydroxocobalamin) or methyl
(methylcobalamin) group. These forms are interconvertible.
o Vitamin B12 is needed for normal erythropoiesis and for neuronal integrity. It is a cofactor
needed for the isomerization of methylmalonyl coenzyme A to succinyl coenzyme A, and for
the conversion of homocysteine into methionine (which also utilizes 5-
methyltetrahydrofolate).
o Vitamin B12 is also involved in the control of folate metabolism, and B12 and folate are
required for intracellular nucleoside synthesis.
 Vitamin C (Ascorbic Acid)

o Ascorbic acid is used in the prophylaxis and treatment of scurvy. The reducing properties of
ascorbate may be used in the treatment of methaemoglobinaemia. In scorbutic patients,
wound healing is delayed and this is restored to normal by administration of ascorbic acid.
o Ascorbic acid is involved in several metabolic processes.
o It is a potent water soluble anti-oxidant.
123
 Vitamin E(Tocopherol)
o Vitamin E protects erythrocytes against haemolysis, and is a fat-soluble anti-oxidant and
detoxifies free radicals. Free radicals cause membrane and epithelial injury and have been
implicated in the pathophysiology of numerous diseases, including cancer and atheroma.
 Vitamin A (Retinoic Acid) and its derivatives

o Vitamin A is used to prevent and treat deficiency states. Regular dietary or parenteral
supplementation of vitamin A may be necessary in patients with steatorrhoea.
o Vitamin A has many physiological functions including maintenance of epithelial cell
integrity, stabilization of membranes and normal soft tissue growth. Vitamin A is also a
component of rhodopsin (essential for normal vision).
o Vitamin A is a cofactor for microsomal drug-metabolizing enzymes, cholesterol synthesis
and mucopolysaccharide synthesis.
 Vitamin K
o Vitamin K is key cofactor in the hepatic activation of four coagulation factors. The four
vitamin K-dependent clotting factors are II, VII, IX, and X. To act as a cofactor, vitamin K
must be in its reduced form, vitamin K hydroxyquinone.
o The enzyme vitamin K epoxide reductase (VKOR) converts vitamin K to its reduced form
which is the active form.
 Iron
o Iron plays a vital role in the body in many proteins including transport proteins (e.g.
haemoglobin, myoglobin) and enzymes (e.g. CYP450s, catalase, peroxidase, and
metalloflavoproteins). It is stored in the reticulo-endothelial system and bone marrow.
STEP 3: Drug Interactions Associated With Vitamins and Minerals (20

minutes)
 How do significant drug interactions of Vitamins and Minerals occur?

 Vitamins and minerals exhibit very few interactions of action as discussed below:
124
 Vitamin B6
o Isoniazid prevents the activation of pyridoxal to pyridoxal phosphate by inhibiting the
enzyme pyridoxal kinase, and slow acetylators of isoniazid are at increased risk of developing
peripheral neuropathy for this reason.
 Calcium and magnesium
o Impairs absorption of tetracyclines.
STEP 4: Side Effects of Vitamins and Minerals (20 minutes)

 Vitamin D
o Side effects are related to long-term over administration of vitamin D supplementation.
Symptoms are primarily induced by hypercalcemia, which include gastrointestinal pain, renal
stones, and psychiatric disturbances.
 Vitamin B1 (Thiamine)
o Anaphylactoid reactions following parenteral thiamine dosing have been reported, so
parenteral administration should be restricted to situations where it is essential.
 Vitamin B6
o There have been reports of ataxia and sensory neuropathy following administration of large
doses (2 g/day) of pyridoxine for more than two months.
 Vitamin B3 (Niacin and Nicotinic acid)
o In replacement therapy for pellagra, adverse effects are uncommon. High doses (as used for
hyperlipidaemia) cause the following: vasodilatation due to prostaglandin D2 (this can be
reduced by premedication with aspirin), itching, hyperglycaemia and exacerbation of
hyperuricemia.
 Vitamin C( Ascorbic Acid)
o Ascorbic acid is non-toxic in low doses. However, administration of 4 g daily raises the
urinary excretion of oxalate. Large doses of vitamin C taken chronically have resulted in
calcium oxalate urolithiasis.
 Vitamin A
o Long-term ingestion of more than double the recommended daily intake of vitamin A can
lead to toxicity and chronic hypervitaminosis. Chronic toxicity includes: anorexia and
vomiting, itching and dry skin, raised intracranial pressure (benign intracranial hypertension),
irritability and headache, tender hyperostoses in the skull and long bones, hepatotoxicity and
congenital abnormalities.
 Folic Acid
o High-dose prophylaxis (folate, 5 mg daily) is advised for women who have previously given
birth to a child with a neural-tube defect.
 Iron
o Gastro-intestinal side effects, including nausea, heartburn, constipation or diarrhoea, are
common.
o Patients with ulcerative colitis and those with colostomies suffer particularly severely from
these side effects.
125
o Accidental overdose with iron is not uncommon in young children and can be extremely
serious, with gastro-intestinal haemorrhage, cardiovascular collapse, hepatic and
neurotoxicity.
o Desferrioxamine (an iron-chelating agent) is administered to treat it.
STEP 5: Contraindications of Vitamins and Minerals (10 minutes)
 What are the contraindications of Vitamins and Minerals?

 Vitamin D
o None
 Vitamin A
o Excess vitamin A during pregnancy causes birth defects (closely related compounds are
involved in controlling morphogenesis in the foetus). Therefore pregnant women should not
take vitamin A supplements, and should also avoid liver in their diet.
o Most vitamins do not have significant contraindications

 Vitamin A toxicity is associated with gastro-intestinal upsets, headache (raised intracranial
pressure), desquamation, hepatotoxicity and teratogenicity.
 Vitamin are important for normal body function
 Some of toxicities of vitamins are detrimental

 What are the indications of vitamin B6?
 What are symptoms/signs associated with hypervitaminosis?
 How does vitamin K produce its pharmacological effects?
 What are the other forms of vitamin D?
126
References
Education.

127
Session 16: Pharmacodynamics of Drugs Acting on Genital-
Urinal System
Prerequisites
 PST04211_S_ Description of
Learning Tasks
 Describe mechanism of action of Drugs acting on Genital-Urinal System
 Describe drug interactions associated with Drugs acting on Genital-Urinal System
 Describe side effects of Drugs acting on Genital-Urinal System
 Describe contraindications of Drugs acting on Genital-Urinal System
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Drugs acting on
2 45 minutes
Buzzing Genital-Urinal System
3 20 minutes
brainstorming acting on Genital-Urinal System
Side Effects of Drugs acting on Genital-
Urinal System
Presentation/ Contraindications of Drugs acting on
5 20 minutes
Brainstorming Genital-Urinal System
128
SESSION CONTENTS

STEP 2: Mechanism of Action of Drugs Acting on Genital-Urinal System (45

minutes)
 How do drugs acting on genital-urinal system produce their pharmacological effects?

 Diuretics
 Thiazides Diuretics: (Hydrochlorothiazide, chlorothiazide, chlorthalidone)
o Thiazide diuretics are used first-line treatment for hypertension, edema and nephrogenic
diabetes insipidus (DI) (rare).
o Thiazide diuretics inhibit the Na+/Cl− co-transporter channel in the distal tubule of the
nephron leading to reduction in Na+ reabsorbed in kidney leading to rise in Na + lost in urine
hence more water lost in urine.
o Therefore Na+, Cl− (and water) remain in the lumen of the tubule hence natriuresis and
diuresis.
o In addition, the actions of the thiazides impact other ions as follows: A passive Na +/H+
exchange occurs at a distal site in the tubule. Na + gradients drive this exchange. When the
Na+/Cl− cotransporter is blocked, the Na+ concentration in the lumen of the tubule is high, this
facilitates Na+ reabsorption in exchange for excretion of H + ions at this distal site. Therefore
thiazides create alkalosis by H+ ion loss through a secondary, passive exchange.
o Similarly, Na+ is exchanged for K+ at a distal site in the tubule. By enhancing delivery of Na +
to distal sites of the nephron, Na+ is exchanged for K+, leading to enhanced K+ excretion, in a
similar manner to the K+ depletion that occurs with loop diuretics.
o Thiazides also promote Ca+2 reabsorption through a poorly understood mechanism.
o Owing to the fact they act so distally in the nephron, after much of the Na + reabsorption has
already occurred, thiazides are relatively weak diuretics when compared with loop diuretics.
129
o Thiazides are also vasodilators, an effect independent of their diuretic actions. Their
antihypertensive effect is probably related mainly to this mechanism and not the diuretic
mechanism.
o Effect on plasma ion concentrations: Decreased Na +, Cl−, K+, Mg+2, Increased Ca+2, Increased
HCO3−. (This creates a metabolic alkalosis.) This is a result of H+ ion loss. Remember that
the equation will shift left with a loss of H+:
i.e H+ + HCO3 - →H2O+CO2
 Loop Diuretics: ( furosemide, ethacrynic acid, torsemide, bumetanide )
o Loop diuretics are used in management of edema in Heart failure, Nephrotic syndrome and
Liver failure. They are also used in acute hypercalcemia.
o Loop diuretics inhibit the Na+/K+/2Cl− co-transporter channel in the thick ascending limb
(Henle’s loop) of the renal tubule. This results in less Na+ being reabsorbed back into the
body. Cl− and K+ also move in the same direction through this ion channel, as does Na +.
Therefore Na+, Cl−, and K+ are lost in the urine hence Natriuresis and diuresis.
o Blockade of the Na+/K+/2Cl− cotransporter has effects on other ions as well as follows:
o Blockade of the Na+/K+/2Cl− cotransporter interferes with the ability of K + and Cl- channels to
create the positive to negative gradient.
o Disruption of this electrochemical gradient facilitates excretion of Ca +2 and Mg+2. Normally
these divalent cations undergo paracellular reabsorption, repelled by the positively charged
tubular lumen and attracted to the negatively charged interstitium. Attenuation of the positive
to negative gradient reduces paracellular reabsorption of Ca +2 and Mg+2, and they are
excreted.
o A passive Na+/H+ exchanger is present at a distal site in the tubule. Na+ gradients drive this
exchange. When the Na+/K+/2Cl− channel is blocked, the Na+ concentration in the lumen of
the tubule is high, which facilitates the reabsorption of Na+ and excretion of H+ at this distal
site. Therefore furosemide creates alkalosis by H+ ion loss through a secondary, passive
exchange.
o Similarly, by enhancing delivery of Na+ to distal sites of the nephron, Na+ is exchanged for
K+, leading to enhanced K+ excretion, and this further depletes K+.
o Like the thiazides, the loop diuretics are also believed to act as vasodilators, an effect
independent of their diuretic actions. This may contribute to the anti-hypertensive effects of
the loop diuretics.
 Potassium-Sparing Diuretics: ( Triamterene, amiloride, Spironolactone and Eplerenone )

o Potassium-sparing diuretics are diuretics that result in increased urine production and also
lower blood pressure while increasing serum levels of potassium.
o The goal of potassium-sparing diuretics is to prevent this reabsorption of Na + and subsequent
loss of K+ in the late distal tubule or collecting duct of the nephron.
o The exchange of Na+ for K+ in the distal nephron is mediated by the actions of the epithelial
Na+ channel (ENaC) on the luminal side of the membrane and the Na+/K+-ATPase pump on
the basolateral membrane (side opposite the lumen of the tubule).
o Triamterene and Amiloride: inhibit this exchange of Na + for K+ by inhibiting ENaC alone or
both ENaC and the Na+/K+-ATPase pump.
130
o Reduced entry of Na+ into the cell reduces the amount of Na+ that can be exchanged for K+
at the ATPase pump. With the Na+/ K+-ATPase pump unable to exchange Na+ for K+, the
K+ stays in the bloodstream.
o Spironolactone and Eplerenone: These drugs directly antagonize aldosterone.
o Normally, aldosterone binds to the mineralocorticoid receptor (MR). The MR-aldosterone
complex translocates to the nucleus, where it binds to specific DNA sequences to increase the
number of ENaC channels and Na+/K+-ATPase pump. Therefore, by blocking the MR,
aldosterone antagonists inhibit the activity of ENaC and the Na+/K+-ATPase pump, reducing
Na+ reabsorption and producing mild natriuresis and diuresis.
 Carbonic anhydrase inhibitors : (Acetazolamide, Dorzolamide, methazolamide )

o Carbonic Anhydrase (CA) is classified as a diuretic, but its important clinical effects are
related to its effect on acid-base balance and on intraocular fluid formation. CA is present at
various sites throughout the nephron, but is mainly found on the luminal membrane of
proximal tubule cells.
o Carbonic anhydrase (CA) catalyses the following reaction:
o H2CO2 <--> HCO3(-) +H+ <--> CO2+ H2O
o CAIs inhibit this enzyme, which results in this reaction occurring at a much slower rate
compared with the catalysed rate, effectively stopping the reaction. The difference in reaction
speed is over 1000-fold.
o The Na+ is transported across the basolateral membrane (the side opposite the tubular lumen)
into the blood along with the HCO3−. The net effect of these movements is Na+ and HCO3−
reabsorption.
o Thus the effect of CAIs is to reduce the reabsorption of both Na+ and HCO3−. The net effect
is loss of Na+ and HCO3− in the urine.
o The effect of CAIs on the acid-base status is that loss of HCO3− lowers the pH.
 Osmotic Diuretics: ( Mannitol )

o Osmotic agents freely enter the glomerulus and Bowman’s space and enter the nephron in the
ultrafiltrate.
o Osmotic diuretics are not reabsorbed from the lumen of the nephron and create an osmotic
force, pulling more fluid into the lumen. This is then carried out as urine.
o As a second primary mechanism for a diuretic, the increased renal blood flow effectively
washes away solutes from the renal medulla, reducing tonicity in this region of the kidney.
o The hypertonicity of the medulla is a major driving force for reabsorption of fluid from the
renal tubule. Reducing this tonicity mitigates the forces that concentrate the urine in the
ascending limb of Henle.
o Lowering the concentration of Na+ in the ascending limb of Henle reduces the driving force
for Na+ reabsorption in this region, leading to diuresis.
Antidiuretic Hormone (Vasopressin) Analogues

 Vasopressin, Desmopressin and Terlipressin
131
o Vasopressin is produced in the hypothalamus and stored in the posterior pituitary gland.
Factors that stimulate its physiologic release include increased serum osmolarity and
hypotension. Its primary actions are therefore to increase body water to control osmolality
and to increase blood pressure. A third action that it exerts is to help stop bleeding through
platelet stimulation.
o Vasopressin binds two types of receptors: V1 and V2. V1 is subtyped into V1a and V1b. V1
receptors are found in many locations of the body, including endothelium and many other
sites. V2 receptors are located in the collecting ducts of the nephron.
o At very low concentrations vasopressin acts on V2 receptors. Only at higher doses are the V1
receptors activated.
o Vasoconstriction effect: V1 receptors are located on vascular smooth muscle and produce a
potent vasoconstrictor effect when stimulated. This occurs only at higher serum levels of
vasopressin. Activation of V1 receptors results in increased intracellular calcium.
o Antidiuresis action: V2 receptors are located in the collecting duct of the nephron. When
stimulated, they activate pores called aquaporins (e.g., aquaporin 2). These pores usually are
stored in intracellular vesicles and when stimulated by vasopressin will fuse with the luminal
membrane and facilitate the reabsorption of water from the nephron lumen back into the
body. In the absence of the vasopressin and the aquaporins, the collecting duct is
impermeable to water and will not absorb any water.
o Platelet Function: Factor VIII and von Willebrands factor (vWF) bind together and then
bind platelets, which causes platelet activation. A deficiency in either of these two factors
will result in decreased platelet function and bleeding disorders (hemophilia A and von
Willebrands disease). Desmopressin binds to V2 receptors, which are instrumental in
endothelial release of factor VIII.
Anticholinergics
 M3 Selective: (Darifenacin and solifenacin). Nonselective: (oxybutynin, tolterodine and
trospium)
o The human bladder contains all five subtypes (M1 to M5) of muscarinic (M) receptors.
Although M2 receptors are more abundant in this region, M3 receptors mediate contraction of
the detrusor muscle in the bladder.
o Detrusor muscle contraction facilitates emptying of the bladder (micturition). Abnormal
contractions of the detrusor, also known as hyperreflexia, can lead to incontinence,
specifically urge incontinence. Anticholinergics that antagonize the M3 receptor inhibit these
detrusor contractions, easing the symptoms of urge incontinence.
Alpha-1 (α1) Antagonists:

 Prazosin, terazosin, doxazosin and tamsulosin
o α1 Receptors are also found in the urinary sphincter (also smooth muscle) of the bladder. The
sphincter controls the flow of urine out of the bladder.
o In patients with an enlarged prostate, pressure exerted by the prostate on the sphincter can
interfere with normal urine flow. Therefore patients with an enlarged prostate experience
132
hesitancy (difficulty starting urination) and typically do not urinate much at a time but
experience urinary frequency.
o An α1 antagonist can relax the urinary sphincter, which facilitates the flow of urine.
5α-Reductase Inhibitors
 Prototype: finasteride and dutasteride
o The 5α-reductase enzyme is the last step in the synthesis of DHT, the active form of
testosterone. Prostate cells depend on stimulation by DHT for their growth. Reducing levels
of DHT will therefore slow growth of the prostate.
o The 5α-reductase type II isoform is highly expressed in prostate epithelial cells. Selective or
nonselective blockade of this enzyme results in decreased formation of DHT, inhibiting the
growth-stimulating effects of this androgen.
STEP 3: Drug Interactions Associated with Drugs acting on Genital-Urinal

System (20 minutes)
How do significant drug interactions of drugs acting on genital-urinal tract occur?
Most drugs in this group do not have significant interactions.
STEP 4: Side Effects of Drugs acting on Genital-Urinal System (20

minutes)
Diuretics
o Dehydration and decreased Na+ occur.
o Hypokalaemia or hypokalemic metabolic alkalosis: Thiazide diuretics enhance excretion
of both K+ and H+ because of increased distal tubule delivery of Na+, and hence Na+
reabsorption, in the distal nephron.
o Impaired glucose tolerance is caused by impaired insulin release and diminished use of
glucose.
133
o Hyperlipidemia: Thiazide diuretics increase cholesterol and low-density lipoprotein
(LDL); the mechanism has not been established.
o Hyperuricemia: Thiazides compete with uric acid for secretion into the PT, reducing the
excretion of uric acid. This can lead to attacks of gout.
o Impotency (rare) is likely a result of reduced volume.
o Renal dysfunction (increased serum creatinine) may occur secondary to hypovolemia and
reduced blood pressure. This is typically only seen in patients with already reduced GFR.

o Hypokalaemia is caused by Na+ reabsorption in exchange for K + excretion at the distal
tubule.
o Metabolic alkalosis (increased HCO3−)
o Increased exchange of Na+ in the lumen for H+ in the cell, resulting in H+ loss.
o Other electrolytes disturbances: Given the large number of ions (Na +, Cl−, and so on) that
are affected by these agents, electrolytes should be monitored.
o Ototoxicity: Reversible hearing loss occurs most often in those with reduced renal
function or who are receiving other ototoxic agents such as aminoglycoside antibiotics.
The mechanism has not been established, although the Na +/K+/2Cl− transporter is also
found in the inner ear. High-dose furosemide can cause permanent deafness.
o Hyperuricemia: The reduction in volume induced by the potent actions of loops elicits a
compensatory increase in uric acid reabsorption in the PT. Loop diuretics also compete
with uric acid for secretion into the PT. Increased levels of uric acid may precipitate
attacks of gout.

o Hyperkalemia can be exacerbated if the patient is taking another drug that raises
potassium or is supplementing with potassium from the diet or from supplements.
Patients with impaired renal function are also at higher risk for developing severe
hyperkalemia.
o Metabolic acidosis occurs via decreased secretion of H+ through the Na+ channel.
o Spironolactone Specific: Antiandrogenic actions mainly gynecomastia, menstrual
disorders and testicular atrophy.

o Hyperchloremic metabolic acidosis occurs because of reduction in bicarbonate stores.
o Renal stones: Renal output of phosphates and calcium increases with CAI use. Chronic
use of CAIs may also reduce excretion of solubilizing factors and, coupled with the
alkalinization of the urine (Ca+2 salts are relatively insoluble at alkaline pH), creates an
ideal environment for stone development.
o Hypokalemia: Additional NaHCO3 in the collecting tubule stimulates the secretion of K+
because of maintenance of the ion gradient.

134
o Extracellular volume expansion: Osmotic diuretics rapidly distribute to the extracellular
compartment, extracting water from cells.
 Before onset of the diuresis, this can lead to expansion of the extracellular space.
 Frank pulmonary edema can arise in patients with heart failure or pulmonary congestion.
o Dehydration and hypernatremia: Excess use without fluid replacement can lead to
dehydration. Composition of serum ions and fluid balance should be monitored.

o Vasopressin side effects: Excessive vasoconstriction. The use of vasopressin should be
restricted to physicians trained in critical care.
o Desmopressin side effects: Water intoxication (hyponatremia): This is caused by the
antidiuretic action and results in water retention leading to dilution of electrolytes,
specifically Na+. Hypotension (paradoxical to other analogues): If administered by the
intravenous route, desmopressin must be given slowly.
Anticholinergics
trospium)
o Typical anticholinergic side effects: Dry mouth, constipation, blurred vision, erythema
and pruritus.
Alpha-1 (α1) Antagonists:

 Prazosin, terazosin, doxazosin and tamsulosin
o Orthostatic hypotension is common and can be quite significant, usually occurring within
90 minutes of the first dose of the drug. It can lead to dizziness and falls.
o Headache might be caused by cerebral vasodilation.
o Somnolence may occur.
o Nasal congestion is caused by dilation of vessels in the nasal passages, causing mild
swelling.
o Palpitation is a result of reflex tachycardia.
o Cardiovascular events: Although these agents are typically well tolerated, results of a
recent study suggest that they may be associated with an increased risk, summarized in
the Antihypertensive section.
o Sexual dysfunction: Decreased libido, ejaculation disorders, and erectile dysfunction are
caused by the antiandrogenic effects.
135
STEP 5: Contraindications of Drugs acting on Genital-Urinal System (10
minutes)
What are the contraindications of drugs acting on genital-urinal system?

Diuretics
o Sulfa allergy: Thiazide diuretics should be used with extreme caution (or not at all) in
patients reporting hypersensitivity reactions to sulfa-containing drugs.

o Hypovolemia is a contraindication.
o Severe K+ abnormalities are contraindications because these drugs decrease K+ level.
o Sulfa allergy: Furosemide, bumetanide, and torsemide may be cross-reactive in those who
have an allergy to sulfonamides.

o Severe K+ abnormalities: Not used in patients with hyperkalaemia.

o No major contraindications

o Active cranial bleeding: If bleeding is occurring into the brain, then the mannitol will be
directly added to the brain and will raise the osmotic pressure in the brain and lead to
water being added to the brain, which is the opposite of what the mannitol is being given
for.
o Continuous administration of mannitol should not occur, because the drug will
accumulate in the tissues and result in osmotic-induced tissue edema, including in the
brain.
136
o Desmopressin only: patients at risk for unregulated water consumption (psychogenic
polydipsia), because they can develop hyponatremia
Anticholinergics: Bladder
trospium)
o Conditions in which cholinergic blockade would exacerbate an already serious condition,
or patients at risk for the following:
o Urinary retention
o Gastroparesis, gastric obstruction
o Narrow-angle glaucoma (uncontrolled)
o Pregnancy: Women of childbearing age should not use 5α-reductase inhibitors. They are
strictly contraindicated in pregnancy. Testosterone is essential for development of
genitalia in males; therefore these agents can lead to abnormal development. Pregnant
women are advised not only to avoid taking the medication but also to avoid even
handling the pills.

 Metronidazole and Tinidazole are common medicines in amoebiasis
 Metronidazole and Tinidazole should not given to patient who have taken alcohol
 Long term use of Metronidazole and Tinidazole need clinical and laboratory monitoring
 Long course and higher dose is required in liver abscess

 What are the indication of Metronidazole and Tinidazole
 What is the dose of Metronidazole
 Which adult dose Tinidazole
 What is the common adverse effect of Metronidazole and Tinidazole
137
References
Hill Education.

138
Session 17: Pharmacodynamics of Antihelminthics
Prerequisites
 PST04211_S10_ Description of Antihelminthes Drugs
Learning Tasks
 Describe mechanism of action of Antihelminthics
 Describe drug interactions associated with Antihelminthics
 Describe side effects of Antihelminthics
 Describe contraindications of Antihelminthics
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Mechanism of Action of Antihelminthics
Buzzing
3 20 minutes
brainstorming Antihelminthics
4 20 minutes Presentation Side Effects of Antihelminthics
Presentation/
5 20 minutes Contraindications of Antihelminthics
Brainstorming
139
SESSION CONTENTS

STEP 2: Mechanism of Action of Antihelminthics (45 minutes)
How do Antihelminthics produce their pharmacological effects?
Benzimidazoles
 Albendazole
o Albendazole like other benzimidazoles acts by binding to and interfering with the
synthesis of the parasite's microtubules and also by decreasing glucose uptake. Affected
parasites are expelled with the feces.
o Benzimidazoles have a selective inhibitory action on helminthic microtubular function,
being 250-400 times more potent in helminths than in mammalian tissue. The inhibitory
concentration is lower
 Mebendazole
Has same mechanism of action with Albendazole discussed above
 Thiabendazole
Has same mechanism of action with Albendazole discussed above
o Pyrantel pamoate
It acts as a depolarizing neuromuscular blocking agent, causing persistent activation of
the parasites nicotinic receptors. The paralysed worms are then expelled from the
intestinal tract of the host.
 Ivermectin
140
Ivermectin targets the parasite's y-aminobutyric acid (GABA) receptors. Chloride efflux
is enhanced and hyperpolarization occurs, resulting in paralysis of the worm.
 Praziquantel
Praziquantel acts by increasing membrane permeability to ca2+.This causes increased
contraction of the musculature and eventually results in paralysis and death of the worm
(SPASTIC PARALYSIS).
 It has been suggested that praziquantel (at slightly high concentrations ) modifies the
parasite so that it becomes susceptible to hosts normal immune responses by causing
tegumental damage hence worm destruction.
 It is associated with IL-4 and a type 2 (TH2) response
Piperazine
Piperazine inhibits neuromuscular transmission in the worm, probably by acting like
GABA the inhibitory neurotransmitter on GABA gated chloride channels in the nematode
muscle hence flaccid paralysis. The paralysed worms are expelled live
Niclosamide
 Act by inhibiting anaerobic phosphorylation of ADP by the mitochondria of the
parasite ,an energy producing process that is dependent on carbon dioxide (co 2 ) fixation
thus resulting into decreased glucose uptake and glycogen synthesis
 The scolex and a proximal segment are irreversibly damaged by the drug. The worm
separates from the intestinal wall and is expelled. Neither the larvae nor the ova are
affected.
 Oxamoniquine
 The drug undergoes ATP dependent enzymatic activation to unstable phosphate ester
which dissociates to yield a reactive carbocation which then alkylates DNA.
 Has some anticholinergic effects on the worm.
 Diethylcarbamazine
 Modifies parasite membrane so that it becomes susceptible to the host normal immune
response.
 Causes progressive paralysis of the worm due to decreased ATP resulting from
prevention of ADP phosphorylation.
 may also interfere with parasite arachidonate mechanism
 Levamisole
 It has nicotinic like action, stimulating and subsequently blocking the neuromuscular
junctions.
 The paralysed worms are then passed in the faeces. The ova are not killed.
141
STEP 3: Drug Interactions Associated Antihelminthics (20 minutes)
How do significant drug interactions of Antihelminthics occur?

 Antihelminthics do not have significant drug interactions.
STEP 4: Side Effects of Antihelminthics (20 minutes)
Benzimidazoles: Albendazole and others.

 Generally well tolerated. Attributing side effects to drug can be challenging, as many side
effects are consistent with the host response to dead or dying parasites rather than the
drug itself.
 GI side effects may be experienced, although in some cases these may be largely the
result of passage of the worm.
 Mebendazole only: Serious and Rare: Agranulocytosis, alopecia, and elevated hepatic
enzymes have been reported at high doses, although mechanisms have not been
established for any of these side effects.
Praziquantel
 Serious and Rare: CNS effects (seizures, changes in mental status, intracranial
hypertension) may occur in the treatment of neurocysticercosis. These effects are believed
to be caused by inflammatory reactions that occur because of the dead parasites.
Corticosteroids may be coadministered with praziquantel to reduce inflammation.
142
STEP 5: Contraindications of Antihelminthics (10 minutes)
What are the contraindications of Antihelminthic Drugs?

Benzimidazoles
 Mebendazole and albendazole
o It is contraindicated in pregnant women, because it has been shown to be embryo
toxic and teratogenic in experimental animals. However, Mebendazole and
albendazole have each demonstrated teratogenic effects in animals. They are used in
pregnancy, but only after a careful risk-benefit assessment.
 Praziquantel
 Ocular cysticercosis: The type of reaction described later in the discussion of
neurocysticercosis can be irreversible if it occurs in the eye.

 Antihelminthics have different mechanism of action
 Most antihelminthics do not exhibit significant drug interactions
 The choice of a drug is dependent on the type of the worm

 What are contraindications of antihelminthics?
 What is the mechanism of action of Ivermectin
 What are adverse effects of antihelminthics?
143
References
Hill Education.

144
Session 18: Pharmacodynamics of Antimalarial Drugs
Prerequisites
 PST04211_S11_ Description of Antimalarial Drugs
Learning Tasks
 Describe mechanism of action of antimalarial drugs
 Describe drug interactions associated with antimalarial drugs
 Describe side effects of antimalarial drugs
 Describe contraindications of antimalarial drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Mechanism of Action of Antimalarial Drugs
Buzzing
3 25 minutes
brainstorming Antimalarial Drugs
4 20 minutes Presentation Side Effects of Antimalarial Drugs
Presentation/
5 20 minutes Contraindications of Antimalarial Drugs
Brainstorming
145
SESSION CONTENTS

STEP 2: Mechanism of Action of Antimalarial Drugs (45 minutes)
How do antimalarial drugs produce their pharmacological effects?
 Drugs for Malaria include the following:
 The 4-Aminoquinolines:chloroquine
o Chloroquine is still used as antimalarial drugs world-wide, but increasing resistance
(especially P. falciparum) has reduced its efficacy.
o Its uses are now limited to malaria prophylaxis, treatment of rheumatoid arthritis or
systemic lupus erythematosis
o The erythrocyte stages of Plasmodium are sensitive to chloroquine.
o At this stage of its life cycle, the parasite digests haemoglobin in a food vacuole to
provide energy for the parasite.
o The food vacuole is acidic and the weak base chloroquine is concentrated within it by
diffusion ion-trapping.
o Chloroquine and other 4-aminoquinolines are believed to inhibit the malarial haem
polymerase within the food vacuole of the plasmodial parasite, thereby inhibiting the
conversion of toxic haemin (ferriprotoporphyrin IX) to haemozoin (a pigment which
accumulates in infected cells and is not toxic to the parasite).
o Ferriprotoporphyrin IX accumulates in the presence of chloroquine and is toxic to the
parasite, which is killed by the waste product of its own appetite (hoist with its own
petard).
o Decreased DNA synthesis: The drug can also decrease DNA synthesis in the parasite by
disrupting the tertiary structure of the nucleic acid.
146
o Mechanisms of Resistance: The actions of chloroquine and related agents on heme occur
at the food vacuole, and the main theory regarding resistance centers around the ability of
chloroquine and others to access the food vacuole.
o Malaria may limit this through various mutations that either prevent access to the vacuole
or pump drug out of the vacuole.
o One strategy being investigated to overcome resistance is to inhibit the activity of this
efflux pump using another drug
.
 Arylaminoalcohols (4-Aminoquinoline derivatives)
o Quinine is the main alkaloid of cinchona bark.
o The mechanism of its antimalarial activity remains unclear, but may be similar to that of
chloroquine
 8-Aminoquinolines (Primaquine)
o Primaquine is used to eradicate the hepatic forms of P. vivax or . malariae after standard
chloroquine therapy, provided that the risk of re-exposure is low.
o It may also be used prophylactically with chloroquine.
o It interferes with the organisms mitochondrial electron transport chain.
o Intermediates are believed to act as oxidants that are responsible for the schizonticidal
action as well as for hemolysis and methemoglobinemia encountered as toxicities.
 Artenusate and Artemether

o Artemesinins undergo haem-mediated decomposition of the endoperoxide bridge to yield
carbon-centred free radicals.
o The involvement of haem explains why they are selectively toxic to malaria parasites.
o The resulting carbon-centred free radicals alkylate haem and proteins, particularly in the
membranes of the parasites food vacuole and mitochondria, causing rapid death
 Anti-folates (Dapsone Proguanil, Pyrimethamine)

o Combinations of these drugs are taken orally in malaria prophylaxis, but their efficacy in
acute malaria treatment is limited due to resistance.
o These agents inhibit folate biosynthesis at all stages of the malaria parasites life cycle,
acting as competitive inhibitors of the malarial dihydropteroate synthase (dapsone) or the
malarial dihydrofolate reductase (proguanil or pyrimethamine).
147
STEP 3: Drug Interactions Associated With Antimalarial Drugs (20
minutes)
How do significant drug interactions of drugs acting on Antimalarial Drugs?
 Drugs for Malaria

o Retardation of absorption when quinine if taken with aluminium-containing antacids
o Potentiation of neuromuscular blocking and elevation of digoxin levels if taken
concurrently with quinine.
STEP 4: Side Effects of Antimalarial Drugs (20 minutes)

 The 4-Aminoquinolines:chloroquine
o Side effects are similar to those of quinine
o Chloroquine should be used cautiously in patients with hepatic dysfunction or severe
gastrointestinal problems, or in patients with neurologic or blood disorders.
o Retinopathy: Damage to the retina leading to deterioration of vision may occur and
typically is seen only at higher doses.
o The mechanism is still unclear, but the condition may be caused by accumulation of drug
in melanin or by degradation of photoreceptors.
o Ototoxicity occurs much less frequently than retinopathy; the mechanism may be similar.
o CNS: Seizures and psychosis may occur and typically are seen only at higher doses or
during rapid parenteral administration.
o Cardiovascular: Arrhythmia (QT prolongation) and even cardiac arrest may occur at
higher doses. Hypotension is seen with malaria but can also be exacerbated by quinolines.
Mefloquine
o Intravenous quinine can produce neurotoxicity such as tremor of the lips and limbs,
delirium, fits and coma.
o Quinine is fetotoxic
148
o Mefloquine only: Mefloquine lowers the seizure threshold.
o Hemolytic anemia is potentially fatal but typically only a concern in patients who are
glucose-6-phosphate dehydrogenase (G6PD) deficient or in patients with other risk
factors. G6PD maintains content of reduced glutathione (GSH) in erythrocytes, and
primaquine tends to reduce GSH levels.
o Methemoglobinemia may occur.
o Side effects are mild and include the following: nausea, vomiting and anorexia;
dizziness.
o Preclinical toxicology suggested neuro-, hepato- and bone marrow toxicity
STEP 5: Contraindications of Antimalarial Drugs (10 minutes)
What are the side effects and adverse effects of Antimalarial Drugs?

o Quinine should not be used for nocturnal cramps as its adverse effects outweigh any
benefit in this benign condition.
o Patients at risk for granulocytopenia, such as those with lupus and rheumatoid arthritis,
should not take primaquine.
o Myelosuppressants: Avoid concomitant administration of agents that suppress bone
marrow.
o First trimester of pregnancy as there is no evidence of safety during the first trimester of
pregnancy
 Anti-folates (Dapsone Proguanil, Pyrimethamine)
o Patients allergic to sulphur as these agents contain sulphur
149
 Drugs for malaria prophylaxis include proguanil, artovaquone etc
 Artemisinin based combination therapies are now the first line drugs world wide
 Antimalaria drugs produce their actions through different mechanisms.

 What are the contraindications of primaquine
 What is the mechanism of action of quinine?
 What are adverse effects of quinine?
150
References
Hill Education.

151
Session 19: Pharmacodynamics of Antifungal Drugs
Prerequisites
 PST04211_S14_ Description of Antifungal Drugs
Learning Tasks
 Describe mechanism of action of antifungal drugs
 Describe drug interactions associated with antifungal drugs
 Describe side effects of antifungal drugs
 Describe contraindications of antifungal drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Mechanism of Action of Antifungal Drugs
Buzzing
3 20 minutes
brainstorming Antifungal Drugs
4 20 minutes Presentation Side Effects of Antifungal Drugs
Presentation/
5 20 minutes Contraindications of Antifungal Drugs
Brainstorming
152
SESSION CONTENTS

STEP 2: Mechanism of Action of Antifungal Drugs (45 minutes)
How do antifungal drugs produce their pharmacological effects?
Polyenes
 Amphotericin B
o Is a polyene macrolide with a hydroxylated hydrophilic surface on one side of the
molecule and an unsaturated conjugated lipophilic surface on the other side.
o The lipophilic surface has a higher affinity for fungal sterols than for cholesterol in
mammalian cell membranes and increases membrane permeability by creating a
membrane pore with a hydrophilic centre which causes leakage of small molecules,
e.g. glucose and potassium ions.
 Nystatin
o Nystatin works in the same way as amphotericin B, but its greater toxicity precludes
systemic use.
Azoles (imidazoles and Triazoles)

 Fluconazole (a triazole)
o Imidazoles and Triazoles competitively inhibit lanosterol 14-α-demethylase (a fungal
cytochrome-haem P450 enzyme), which is a major enzyme in the pathway that
synthesizes ergosterol from squalene. This disrupts the acyl chains of fungal membrane
phospholipids, increasing membrane fluidity and causing membrane leakage and
dysfunction of membrane-bound enzymes.
153
o Triazole drugs work by the same mechanism as imidazoles but have a wider antifungal
spectrum and are more specific for fungal CYP450.
o The imidazoles have considerable specificity/affinity for fungal cytochrome-haem P450
enzymes.
 Ketoconazole (an imidazole)

o Mechanism of action is as discussed above
o Imidazoles are fungistatic at low concentrations and fungicidal at higher concentrations.
o The imidazoles have considerable specificity/affinity for fungal cytochrome-haem P450
enzymes but less specific when compared to Triazoles.
 Itraconazole and Voriconazole ( Triazoles)
o Have a similar mechanism of action to fluconazole
Echinocandins
 Caspofungin and micafungin
o Echinocandins are non-competitive inhibitors of 1, 3-β-D glucan synthase, an enzyme
necessary for synthesis of a glucose polymer crucial to the structure and integrity of the
cell walls of some fungi.
o Fungal cells unable to synthesize this polysaccharide cannot maintain their shape and lack
adequate rigidity to resist osmotic pressure, which results in fungal cell lysis.
Allylamines
 Terbinafine
o Terbinafine acts by inhibiting the enzyme squalene epoxidase, which is involved in
fungal ergosterol biosynthesis.
Other antifungals
 Griseofluvin
o This drug is concentrated in fungi and binds to tubulin, blocking polymerization of the
microtubule, disrupting the mitotic spindle.
 Flucytosine (5-Fluorocytosine)
o This drug is deaminated to 5-fluorouracil in the fungus and converted to an antimetabolite
5-FdUMP. This inhibits thymidylate synthetase, impairing fungal DNA synthesis.
154
STEP 3: Drug Interactions Associated With Antifungal Drugs (20
minutes)
How do significant drug interactions of antifungal drugs occur?

o Fluconazole reduces the metabolism of several drugs by inhibiting CYP3A, including
benzodiazepines, calcium channel blockers, ciclosporin, docetaxel and, importantly,
warfarin.
o The plasma concentrations and toxicity of these drugs will increase during concomitant
treatment with fluconazole.
o Rifampicin enhances the metabolism of fluconazole.
 Itraconazole and Voriconazole ( Triazoles)

o Drugs which decrease gastric acid (e.g. proton pump inhibitors) reduce the bioavailablity
of both agents and drugs that induce hepatic CYP3A decrease systemic drug
concentrations.
Echinocandins
o These are minimal compared to the azoles. Ciclosporin increases Caspofungin AUC by
35% and micafungin increases the bioavailability of sirolimus and nifedipine.
o The pharmacokinetics of micafungin do not appear to be affected by other drugs;
however, micafungin has been shown to increase levels of amphotericin B.
o Because of their complementary MOA, these two antifungal agents might be combined.
Other antifungals
 Griseofluvin
o Griseofluvin induces hepatic CYP450s and consequently can interact with many drugs.
155
STEP 4:Adverse Effects of Antifungal Drugs (20 minutes)
Polyenes
 Amphotericin B
o Nephrotoxicity: Reversible kidney dysfunction, sometimes leading to chronic kidney
dysfunction, can result. The mechanism is incompletely understood but thought to be
mediated in part by both renal tubular injury and renal vasoconstriction.
o Infusion reactions: Fever, chills, hypotension, vomiting, dyspnoea, and headaches
may occur. The mechanism of these reactions is unknown.
o Electrolyte abnormalities: Because of increases in the distal tubular permeability,
potassium and magnesium wasting, leading to Hypokalemia and hypomagnesemia,
can occur.
Nystatin
o Nystatin is not administered systemically because of high toxicity

 Ketoconazole (imidazole)
o Hepatotoxicity (has occurred rarely)
Echinocandins
o Infusion reactions: Swelling and rash occur and may be an allergic-type reaction mediated
by histamine
o Elevated liver enzymes: This side effect occurs mainly in patients receiving both
cyclosporine and caspofungin. Cyclosporine is an immunosuppressant, and patients who
are immunosuppressed are more likely to develop fungal infections and therefore are
more likely to be treated with antifungals.
Allylamines
 Terbinafine
o Stevens-Johnson syndrome is a life-threatening condition whereby the dermis and
epidermis separate. It is commonly caused by drugs (there is a long list). It is mediated by
a hypersensitivity reaction. It occurs in about 2 to 3 per million people per year.
o Toxic epidermal necrolysis is a less severe form of Stevens-Johnson syndrome.
o Liver failure: Liver enzymes must be measured before patients start terbinafine.
o Neutropenia and lymphopenia: Neutrophil and lymphocyte counts can be severely
decreased. The drug should be discontinued if the counts are very low. The effect is
reversible.
156
Other antifungals
 Griseofluvin
o The drug potentiates the intoxicating effects of alcohol. Griseofluvin is teratogenic in
laboratory animals
o Headache: can sometimes be very severe and force discontinuation of the drug
o Peripheral neuropathy: tingling of the hands and feet
o Sleep disturbances and fatigue
o Dermatologic: Skin rashes: Remember that the drug is in high concentrations in the
keratin. Different rash types can include the following: Urticaria (hives) ,Erythema (red
rash)
o There is a risk of infection. Avoid treating patients with nonfungal infections.
o Liver damage can rarely occur. Liver enzymes should be routinely measured.
o Bone marrow suppression: Anemia, low WBC count, and low platelet counts can occur.
This is due to inhibition of rapidly dividing cells, as 5-DUMP can inhibit DNA synthesis
o Toxic epidermal necrolysis is a severe skin reaction with a mortality rate around 30%.
STEP 5: Contraindications of Antifungal Drugs (10 minutes)
What are the contraindications of antifungal drugs?

Polyenes
 Amphotericin B
o Amphotericin B
o Renal dysfunction, because amphotericin B is nephrotoxic
 Nystatin
o None of significance

157
o Fluconazole is contraindicated in pregnancy because of fetal defects in rodents and
humans.
o Breast milk concentrations are similar to those in plasma and fluconazole should not be
used by nursing mothers.
 Ketoconazole (imidazole)
o Ketoconazole and amphotericin B should not be used together
Echinocandins
Other antifungals
 Griseofluvin
o Griseofulvin may cause hepatotoxicity and is contraindicated in patients with acute
intermittent porphyria.
o Pregnancy: Griseofulvin is a potential teratogen.
o Pregnancy is a contraindication because of the conversion to 5-FU, which is an
antimetabolite for human DNA and a potential teratogen.

 Systemic toxicity (especially nephrotoxicity) of amphotericin is reduced by using the
liposomal/ lipid/micellar formulations.
 Antifungals may be used for topical or systemic conditions
 Some antifungals like amphotericin B have some toxicities

 What are the common adverse effects of ketoconazole?
 What is the mechanism of action of Echinocandins?
 What are advantages of using fluconazole versus fluconazole in systemic conditions?
158
References
Hill Education.

159
Session 20: Pharmacodynamics of Penicillins and
Cephalosporins
Prerequisites
 PST04211_S44_ Description of Penicillins and Cephalosporins
Learning Tasks
 Describe mechanism of action of Penicillins and Cephalosporins
 Describe drug interactions associated with Penicillins and Cephalosporins
 Describe side effects of Penicillins and Cephalosporins
 Describe contraindications of Penicillins and Cephalosporins
Resources Needed:
 Handout 20.1 Important Information on Mechanism of Actions of Penicillins and
Cephalosporins
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Penicillins and
2 45 minutes
Buzzing Cephalosporins
3 20 minutes
brainstorming Penicillins and Cephalosporins
Side Effects of Penicillins and
Cephalosporins
Presentation/ Contraindications of Penicillins and
5 20 minutes
Brainstorming Cephalosporins
160
SESSION CONTENTS

STEP 2: Mechanism of Action of Penicillins and Cephalosporins (45

minutes)
How do Penicillins and Cephalosporins produce their pharmacological effects?
 B-lactams
 Penicillins
o The penicillins interfere with the last step of bacterial cell wall synthesis
(transpeptidation or cross-linkage thus exposing the osmotically less stable membrane.
o Cell lysis can then occur, and these drugs are therefore bactericidal.
o The efficacy of penicillin antibiotic in causing cell death is related to its size, charge,
and hydrophobicity.
o These drugs are only effective against rapidly growing organisms that synthesize a
peptidoglycan cell wall.
o Therefore, Penicillins are inactive against organisms devoid of this structure, such as
mycobacteria, protozoa, fungi, and viruses.
 Cephalosporins
o These drugs have the same mode of action as Penicillins.
General information for cephalosporins and penicillins:

 In general two major components are required for β-lactam activity
 The first is the binding to penicillin-binding proteins.
 The second is the destruction of the bacterial cell wall.
161
 All β-lactams (penicillins, carbapenems, and cephalosporins) act through this
common sequence of events.
o Virtually all bacteria contain penicillin-binding proteins.
REFER Students to Handout 20.1: Important Information on Mechanism of

Actions of Penicillins and Cephalosporins
STEP 3: Drug Interactions Associated With Penicillins and

Cephalosporins (20 minutes)
How do significant drug interactions of Penicillins and Cephalosporins occur?

 B-lactams
 Penicillins
o Probenecid, a uricosuric, competes with penicillin in the organic acid transporter in
the kidney and therefore decreases renal clearance of penicillin, thereby prolonging
high tissue concentrations and a longer half life. It is coadministered with penicillin.
STEP 4: Description of Side Effects of Penicillins and Cephalosporins

(20 minutes)
 B-lactams
 Penicillins
o Hypersensitivity: most commonly only a rash, but can include anaphylaxis
o Nausea and vomiting if given orally
o Diarrhoea
o Stinging in the vein if given intravenously (IV)
 Cephalosporins
o Hematologic: rare cases of bone marrow suppression resulting in a low white blood cell
(WBC) count (aka neutropenia or granulocytopenia)
o Nephrotoxicity: occasional interstitial nephritis and tubular necrosis
162
o Pseudomembranous colitis: many antibiotics, including cephalosporins, can wipe out gut
flora and permit the bacterium C. difficile to colonize, which causes this condition.
STEP 5: Description of Contraindications of Penicillins and

Cephalosporins (10 minutes)
What are the contraindications of Penicillins and Cephalosporins?


 B-lactams
 Penicillins
o Hypersensitivity (allergy)
o Incidence is as high as 10%.
o Anaphylaxis
o Cross-reactivity between penicillin allergy and other β-lactam antibiotics (cephalosporins
and carbapenems) is around 1% to 10%.
o Anaphylaxis to penicillins is an absolute contraindication.
o Nonanaphylactic allergy to penicillins is a relative contraindication; however, the cross-
reactivity is reported to be 2% to 10%, and cephalosporins have been used frequently in
patients with a penicillin allergy.
o Side effects (GI upset, nausea) are sometimes called allergies by patients when in fact
they are not allergies. Always ask what reaction the patient experienced. Side effects are
not a contraindication.
 Cephalosporins
o Anaphylaxis to penicillins is an absolute contraindication.
o Nonanaphylactic allergy to penicillins is a relative contraindication; however, the cross-
reactivity is reported to be 2% to 10%, and cephalosporins have been used frequently in
patients with a penicillin allergy.
o Maculopapular rash (flat confluent red rash)
o Urticaria (itchy hives)
o Eosinophilia (which is common to allergic reactions)
163
 Penicillin and cephalosporins have similar structure and mechanism of action
 The four generations of cephalosporins have different spectrum against bacteria
 Anaphylactic shock is a serious adverse effect of penicillins

 What are adverse effects of penicillins?
 What is the mechanism of action of cephalosporins?
 What contraindications of penicillins?
164
References
Hill Education.

165
Handout 20.1 Important Information on Mechanism of Action of
Penicillins and Cephalosporins
o Different bacteria have different amounts and different types of penicillin-binding
proteins.
o For example, Escherichia coli has seven types, and Staph. aureus has four.
o Different penicillin-binding proteins have different affinities for β-lactams, and therefore
different bacteria will demonstrate different sensitivities to β-lactams.
o Gram-positive bacteria have a thick peptidoglycan layer.
o They are therefore sensitive to β-lactams.
o Gram-negative bacteria have a thinner peptidoglycan layer, but external to this layer is a
lipopolysaccharide layer.
o This lipopolysaccharide layer protects the peptidoglycan layer from β-lactam activity, and
therefore gram-negative bacteria are significantly more resistant to β-lactams.
o β-Lactamase inhibitors are added to some β-lactam antibiotics to overcome resistance
caused by β-lactamase.
o Although β-lactamase inhibitors do contain a β-lactam, they are not toxic to the bacteria;
they merely bind to β-lactamase.
o Examples of β-lactamase inhibitors include : Clavulanic acid (added to amoxicillin) and
Tazobactam (added to piperacillin)
o Narrow-spectrum penicillins contain a larger molecule on the penicillin molecule side
chain that confers steric hindrance: the inability to twist the molecule into other
stereoisomers.
o This results in these penicillins being resistant to β-lactamase but at the same time
restricts their spectrum of activity (thus they are said to be narrow-spectrum agents).
o Aminopenicillins have an added amino group (NH2) that makes the molecule more
hydrophilic and thus able to cross the lipopolysaccharide layer more easily.
o Therefore aminopenicillins have greater activity against gram-negative bacteria.
o Broad-spectrum penicillins are modifications of aminopenicillins: nitrogen and carbon
atoms are added to the molecule.
o This increases the range of bacteria that are sensitive to the antibiotic. These penicillins
are usually coadministered with a β-lactamase inhibitor because they are β-lactamase
sensitive (a common example is “Pip/Tazo,” which is piperacillin and tazobactam).
o The main mechanisms of resistance to β-lactams include the following:
o Variation of the penicillin-binding protein leading to decreased binding of the β-lactam
o Production of β-lactamase, which enzymatically destroys the four-carbon β-lactam ring
o Changes in membrane channels called porins that are important in allowing influx of the
antibiotic
o Efflux pump mechanisms, which pump the drug out of the bacteria
o The four generations of cephalosporins have different indications:
166
o First-generation cephalosporins are:
o Good for skin infections (which are commonly Streptococcus or Staphylococcus) .
Commonly used as prophylactic antibiotics (preventative) given before surgery to
prevent wound infections
o Second-generation cephalosporins are: Good for Bacteroides infection (anaerobic),
which can occur with intraabdominal infections. Used less commonly for severe
infections because third-generation cephalosporins are more efficacious. Second-
generation cephalosporins can be used for mild infections in which gram-negative
organisms are predicted or known
o Third-generation cephalosporins are: Commonly used for severe infections in
combination with another drug of a different class (different MOA)
o Fourth-generation cephalosporins are: Reserved for severe nosocomial (hospital-
acquired) infections, which have a tendency to be: Resistant to multiple other
antibiotics. More severe infections and commonly caused by gram-negative
organisms.
167
168
Session 21: Pharmacodynamics of Macrolides
Prerequisites
 PST04211_S45_ Description of Macrolides
Learning Tasks
 Describe mechanism of action of Macrolide
 Describe drug interactions associated with Macrolides
 Describe side effects of Macrolides
 Describe contraindications of Macrolides
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Mechanism of Action of Macrolides
Buzzing
3 20 minutes
brainstorming Macrolides
4 20 minutes Presentation Side Effects of Macrolides
Presentation/
5 20 minutes Contraindications of Macrolides
Brainstorming
169
SESSION CONTENTS

STEP 2: Mechanism of Action of Macrolides (45 minutes)
How do Macrolides produce their pharmacological effects?
Macrolides
 The macrolides bind irreversibly to a site on the 50s subunit of the bacterial ribosome,
thus inhibiting the translocation steps of protein synthesis.
 The binding site is either identical to or in close proximity to that for lincomycin,
clindamycin, and chloramphenicol. Inhibition of protein synthesis does not typically kill
bacteria cells, so these agents are generally bacteriostatic, but in high concentrations they
can be bactericidal.
 Macrolides are phagocytosed by macrophages, which is a benefit because WBCs
preferentially travel to sites of infection, thereby theoretically delivering the drug to the
site at which it is needed.
 Mechanisms of Resistance:
o Modification of the RSU binding site either by chromosomal mutation or through
methylation via methylase greatly decreases the efficacy of macrolides; bacterial
methylase can be produced constitutively (all the time) or can be induced.
o Reduced intracellular concentrations are found within the bacterium, through either
reduced permeability of cell membrane to macrolides or, probably more important,
increased efflux of macrolides via active pumps.
o A third, and maybe least prominent, method of resistance is through the production of
esterases that hydrolyze macrolides; this is more common with gram-negative enteric
bacteria (bacteria that colonize the GI tract).
 Cross-resistance is complete among all macrolides; if a bacterium is resistant to one, it
will be resistant to all others in this class.
170
STEP 3: Drug Interactions Associated With Macrolides (20 minutes)
How do significant drug interactions of Macrolides occur?

Macrolides
 Erythromycin
o Erythromycin metabolites inhibit cytochrome P450 enzymes and, thus, increase the serum
concentrations of numerous drugs, including theophylline, warfarin, cyclosporine, and
methylprednisolone.
o Erythromycin also increases serum concentrations of oral digoxin by increasing its
bioavailability.
o Erythromycin and some antibiotics eliminate a species of intestinal flora that ordinarily
inactivates digoxin, thus leading to a greater reabsorption of digoxin from the
enterohepatic circulation.
o Erythromycin and clarithromycin are significant CYP450 enzyme inhibitors and are
metabolized by the liver. Drug interactions with other CYP450 inhibitors should be
monitored.
 Azithromycin
o Because it has a 15-member (not 14-member) lactone ring, azithromycin does not
inactivate cytochrome P450 enzymes and, therefore, is free of the drug interactions that
occur with erythromycin and clarithromycin.
o Erythromycin is unstable in gastric acid and therefore must be administered with salts or
esters or via enteric-coated tablets when administered orally.
o The addition of a methyl group to erythromycin creates clarithromycin, and the addition
of methylated nitrogen to erythromycin creates azithromycin; both are stable in gastric
acid and very well absorbed orally.
o Because of the long duration of action of azithromycin, a 5-day, oral, once-a-day course
for most sensitive infections is considered a treatment of adequate duration.
STEP 4: Side Effects of Macrolides (20 minutes)

Macrolides
171
 Erythromycin
o GI: Significant GI upset because of increased gut motility
o Acute cholestatic hepatitis: Likely hypersensitivity-related, this side effect can lead to
fever, jaundice, and impaired liver function. Abdominal pain, especially right upper
quadrant pain, should lead to the suspicion of liver involvement.
 Azithromycin
o These agents are better tolerated but can also cause liver impairment.
STEP 5: Contraindications of Macrolides (10 minutes)
 What are the contraindications of Macrolides?

Macrolides
 Previous liver complications with a macrolide are likely to recur and therefore should be
considered a contraindication to macrolide use.

 Macrolides target protein synthesis in bacteria
 Newer macrolides are devoid of disadvantages of erythromycin
 Erythromycin is a potent enzyme inhibitor

 What is the mechanism of action of macrolides?
 How does resistance to macrolides develop?
 What are drug interactions associated with erythromycin?
172
References
Hill Education.

173
Session 22: Pharmacodynamics of Fluoroquinolones
Prerequisites
 PST04211_S42_ Description of Fluoroquinolones
Learning Tasks
 Describe mechanism of action of Fluoroquinolones
 Describe drug interactions associated with Fluoroquinolones
 Describe side effects of Fluoroquinolones
 Describe contraindications of Fluoroquinolones
Resources Needed:
SESSION OVERVIEW
Ste Activity/
Time Content
p Method
05
1 Presentation Introduction, Learning tasks
minutes
45 Presentation/ Mechanism of Action of
2
minutes Buzzing Fluoroquinolones
20 Presentation/ Drug Interactions Associated With
3
minutes brainstorming Fluoroquinolones
20
4 Presentation Side Effects of Fluoroquinolones
minutes
Presentation/
20
5 Brainstormin Contraindications of Fluoroquinolones
minutes
g
05
6 Presentation Key Points
minutes
05
7 Presentation Evaluation
minutes
174
SESSION CONTENTS

STEP 2: Mechanism of Action of Fluoroquinolones (45 minutes)
 How do Fluoroquinolones produce their pharmacological effects?
Fluoroquinolones
 DNA is normally supercoiled. Supercoiled DNA is under too much tension to be
separated, so an extra step is required before replication and transcription can occur. DNA
gyrase relaxes supercoiled DNA by cutting it, allowing rotation to occur, and then
reattaching it.
 Fluoroquinolones bind to and inhibit DNA gyrase (also called topoisomerase II) and
topoisomerase IV. Fluoroquinolones inhibit DNA gyrase in gram-negative organisms and
topoisomerase IV in gram-positive organisms.
 The fluoroquinolones inhibit DNA gyrase after the cutting step, preventing reattachment
from occurring.
o At high doses this leads to the release of these broken segments of DNA.
o It is thought that the accumulation of these DNA fragments leads to cell death,
accounting for the bactericidal action of fluoroquinolones.
 Fluoroquinolones can enter human cells easily and therefore are often used to treat
intracellular pathogens.
 Originally, quinolones were mainly effective against gram-negative bacteria, but newer
agents are useful against gram-positive cocci as well.
 Mechanism of resistance:
o Mutations in the genes that encode type II topoisomerase result in the enzyme not being
inhibited by the fluoroquinolone.
175
o Alterations in membrane porins or efflux pumps that actively pump the drug out of the
bacterial cell result in lower drug levels inside the bacteria.
STEP 3: Drug Interactions Associated With Fluoroquinolones (20
minutes)
 How do significant drug interactions of Fluoroquinolones occur?
The following are drug interaction associated with Fluoroquinolones;

 With NSAIDS, fluoroquinolones may potentiate CNS toxicity and cause seizures.
 With theophylline, they will increase theophylline levels and increase risk of theophylline
toxicity.
STEP 4: Side Effects of Fluoroquinolones(20 minutes)

Fluoroquinolones have the following side effects:
 Most fluoroquinolones are cleared renally, and dose adjustment may be required in
patients with renal impairment.
 Tendon ruptures (Achilles, shoulder); occur rarely. The mechanism of this complication
is not well understood.
 Gatifloxacin: hyperglycemia
 Trovafloxacin: acute liver failure and death
 Temafloxacin: hemolytic anemia
 Grepafloxacin: long QT syndrome and sudden death
 Fleroxacin: phototoxicity
176
STEP 5: Contraindications of Fluoroquinolones (10 minutes)

 What are the contraindications of Fluoroquinolones?
Fluoroquinolones have the following contraindications:

 Moxifloxacin: is cleared by the liver and therefore contraindicated in patients with hepatic
failure.
 Pregnancy
 Children: Joint pain (arthralgia) and swelling has occurred, and therefore administration
to children is not common.

 More than 30 different fluoroquinolones exist. Some are used for veterinary purposes
only.
 Newer fluoroquinolones have extended spectrum against gram-positive cocci as well.
 Fluoroquinolones have some significant drug interactions

 What is the mechanism of action of fluoroquinolones?
 What are contraindications of ciprofloxacin?
 What are the side effects of gatifloxacin?
177
References
Education.

178
Session 23: Pharmacodynamics of Aminoglycosides
Prerequisites
 PST04211_S42_ Description of Fluoroquinolones
Learning Tasks
 Describe mechanism of action of Aminoglycosides
 Describe drug interactions associated with Aminoglycosides
 Describe side effects of Aminoglycosides
 Describe contraindications of Aminoglycosides
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Mechanism of Action of Aminoglycosides
Buzzing
3 20 minutes
brainstorming Aminoglycosides
4 20 minutes Presentation Side Effects of Aminoglycosides
Presentation/
5 20 minutes Contraindications of Aminoglycosides
Brainstorming
179
SESSION CONTENTS

STEP 2: Mechanism of Action of Aminoglycosides (45 minutes)
How do Aminoglycosides produce their pharmacological effects?
Aminoglycosides include Tobramycin, amikacin, neomycin, streptomycin, kanamycin and

Paromomycin.
 Aminoglycosides are protein synthesis inhibitors.
 They irreversibly bind the 30S ribosomal subunit (RSU).
 At low concentrations they cause misreading of the mRNA by ribosomes, leading to
synthesis of proteins with incorrect amino acid sequences.
 Recent experimental studies show that the initial site of action is the outer bacterial
membrane.
 The cationic antibiotic molecules create fissures and pores in the outer cell membrane,
resulting in leakage of intracellular contents and enhanced antibiotic uptake.
 Aminoglycosides are particularly effective against gram-negative bacteria.
 Many other protein synthesis inhibitors are bacteriostatic (only inhibit replication of bacteria
versus killing bacteria).
 The action of aminoglycosides on the outer bacterial membrane, in addition to its protein
synthesis inhibition, is thought to be the reason that aminoglycosides are bactericidal.
 Mechanisms of Resistance: Three mechanisms of resistance have been recognized:
Ribosome alteration, Decreased permeability and inactivation by aminoglycoside modifying
enzymes.
 The third mechanism is of most clinical importance, because the genes encoding
aminoglycoside-modifying enzymes can be disseminated by plasmids, which are segments of
DNA that are outside of the chromosome.
180
 Amikacin is particularly effective when used against bacteria that are resistant to other
aminoglycosides, because its chemical structure makes it less susceptible to inactivating
enzymes.
STEP 3: Drug Interactions Associated With Aminoglycosides (20 minutes)
How do significant drug interactions of Aminoglycosides occur?
STEP 4: Side Effects of Aminoglycosides (20 minutes)
Aminoglycosides have the following side effects;

 Ototoxicity (damage to the inner ear): Occurs in about 10% of patients.
Is caused by inhibition of human mitochondrial ribosomes, damaging the hair cells of the
inner ear. Symptoms can include the following:
 Decreased hearing,
 tinnitus (ringing in the ear)
 vertigo (a spinning type of dizziness)
 Nephrotoxicity: Occurs in up to 10% of patients and in up to 25% of patients who are
critically ill.
 Drug accumulates in proximal tubule cells, leading to mitochondrial poisoning and cell
membrane disruptions.
 If the serum creatinine starts to rise during administration, then there must be a very high
suspicion that kidney damage secondary to the aminoglycoside is occurring.
 The aminoglycoside should be immediately stopped. Nephrotoxicity is usually mild and
reversible if the drug is stopped.
 Neuromuscular blockade: occurs because of a reduction in acetylcholine release.
 These drugs do not paralyze patients, but under anesthesia in patients who are already
receiving a neuromuscular blocking drug (such as rocuronium or vecuronium), the duration
of blockade can be longer than normal.
181
 Hypersensitivity reactions: skin rash, fever, eosinophilia and anaphylactic shock can be seen
though infrequently.
 The special attention should be paid to the anaphylactic shock caused by streptomycin.
STEP 5: Contraindications of Aminoglycosides (10 minutes)
What are the contraindications of Aminoglycosides?

The following are the contraindications of Aminoglycosides;

 Renal dysfunction: Patients starting with poor functioning kidneys can experience a further
decline in kidney function if exposed to aminoglycosides.
 Serum levels of aminoglycosides must be monitored.
 Peak and trough levels help determine required doses.
 Doses must be adjusted according to the patients renal function (creatinine clearance).

 Aminoglycosides have some serious adverse effects
 Aminoglycosides are water soluble.

 What is the mechanism of action of aminoglycosides?
 What are contraindications of aminoglycosides?
 How does bacterial resistance to aminoglycosides develop?
182
References
Education.

183
Session 24: Pharmacodynamics of Drugs for Amoebiasis
Prerequisites
 PST04211_S9_ Description of Amoebiasis
Learning Tasks
 Describe mechanism of action of Drugs for Amoebiasis
 Describe drug interactions associated with Drugs for Amoebiasis
 Describe side effects of Drugs for Amoebiasis
 Describe contraindications of Drugs for Amoebiasis
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Drugs for
2 45 minutes
Buzzing Amoebiasis
Presentation/ Drug Interactions Associated With Drugs for
3 20 minutes
brainstorming Amoebiasis
4 20 minutes Presentation Side Effects of Drugs for Amoebiasis
Presentation/
5 20 minutes Contraindications of Drugs for Amoebiasis
Brainstorming
184
SESSION CONTENTS

STEP 2: Mechanism of Action of Drugs for Amoebiasis (45 minutes)
How do Drugs for Amoebiasis produce their pharmacological effects?
Tissue Amoebicides
 Nitroimidazoles amoebicides (Metronidazole, tinidazole and ornidazole).
o Nitroimidazoles are chemically reduced by ferredoxin and the reduction products are
responsible for killing the parasite.
o Entamoeba lacks a functional Krebs cycle and oxidative phosphorylation
o Metronidazole is a prodrug. The nitrogen group must be reduced (addition of electron) before
the chemical obtains its anti-infective function.
 It is reduced by a nitro reductase enzyme called a ferredoxin (an iron- and sulfur-containing
enzyme).
 The extra nitrogen side chain is reduced in this reaction.
o With aerobic bacteria the electron transport chain does not require these special enzymes
because oxygen is the terminal electron acceptor; therefore the prodrug is not converted to the
active form of the drug.
o However, with anaerobic bacteria, with which oxygen is absent, these special enzymes are
present.
o Therefore metronidazole is not activated with aerobic bacteria but is particularly effective
against anaerobic bacteria.
o Reduction of the prodrug metronidazole results in the production of toxic products
(hydroxylamine) and other free radicals that damage DNA.
185
o Their bactericidal, activity is limited to anaerobic bacteria and protozoa. Metronidazole kills
trophozoites of E. histolytica in intestine and tissue but does not eradicate cysts from
intestines.
 Emetines (Emetine and dihydroemetine).

o The drugs cause an irreversible block of protein synthesis by inhibiting movement of the
ribosome along messenger RNA.
o They have a direct lethal action to trophozoites.
 Chloroquine
o Is active principally against amoeba in the liver
Luminal Amoebicides
 Dichloracetamides (Diloxanide furoate, clefamide, teclozan, etofanide)
o Mechanism is still unknown
 Halogenated hydroxyquinolines ( Iodoquinol, Clioquinol)

o Mechanism is unknown
o Luminal amoebicide; acts primarily in bowel lumen since it is poorly absorbed.
o Since active only against intraluminal form of amoebiasis, used to eradicate cysts of E.
histolytica after treatment of invasive disease.
 Antibiotics
o Tetracyclines these affect luminal amoebae indirectly- tetracyclines inhibit the bacterial
associates of amoebae (E.histolytica).
o Paromomycin- an effective directly acting amoebicide
o Erythromycin has direct amoebicidal action but cannot be used alone.
STEP 3: Drug Interactions Associated With Drugs for Amoebiasis (20

minutes)

How do significant drug interactions of Drugs for Amoebiasis occur?
186
 Nitroimidazoles amoebicides (Metronidazole, tinidazole and ornidazole).
o Metronidazole elimination is accelerated by simultaneous use of phenytoin and phenobarbital
which are CYP450 enzyme inducers.
o Metronidazole clearance is decreased by cimetidine which is an enzyme inhibitor.
o Metronidazole potentiates coumarin type of anticoagulants.
o Metronidazole can have a disulfuram-like effect: ingestion with alcohol can lead to severe
nausea and vomiting.
 This results from inhibition of the enzyme acetaldehyde dehydrogenase, leading to
increased levels of acetaldehyde, which are toxic.
STEP 4: Side Effects of Drugs for Amoebiasis (20 minutes)

The following areSide and adverse effects;
 Metronidazole
o Metallic taste: common, harmless
o CNS toxicity: rare, manifests as ataxia, encephalopathy, or seizure.
STEP 5: Contraindications of Drugs for Amoebiasis (10 minutes)
What are the contraindications of Drugs for Amoebiasis?


Contraindications include;
 Metronidazole
o Ethanol: Metronidazole can have a disulfuram-like effect: ingestion with alcohol can lead to
severe nausea and vomiting.
o This results from inhibition of the enzyme acetaldehyde dehydrogenase, leading to increased
levels of acetaldehyde, which are toxic.
o Pregnancy (first trimester in particular): Metronidazole causes tumour growth in laboratory
rats and readily crosses the placenta.
o It should be used only in extreme situations in pregnancy, after risks have been weighed
against benefits.
187
 Metronidazole is not recommended during pregnancy
 Tinidazole have similar mechanism to metronidazole

 Mention drugs used in treatment of amoebiasis
 What is the mechanism of action for metronidazole?
 How does bacterial resistance to metronidazole develop?
188
References
Education.

189
Session 25: Pharmacodynamics of Antiviral Drugs
Prerequisites
Learning Tasks
 Describe mechanism of action of Antiviral Drugs
 Describe drug interactions associated with Antiviral Drugs
 Describe side effects of Antiviral Drugs
 Describe contraindications of Antiviral Drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Mechanism of Action of Antiviral Drugs
Buzzing
Presentation/ Drug Interactions Associated With Antiviral
3 20 minutes
brainstorming Drugs
4 20 minutes Presentation Side Effects of Drugs for Antiviral Drugs
Presentation/
5 20 minutes Contraindications of Antiviral Drugs
Brainstorming
190
SESSION CONTENTS

STEP 2: Mechanism of Action of Antiviral Drugs (45 minutes)
How do Antiviral Drugs produce their pharmacological effects?
Anti-HIV Drugs
 Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs): Zidovudine(ZDV),
lamivudine (3-TC), stavudine (d4T), didanosine(ddI), emtricitabine (FTC) and abacavir
(ABC).
o Anti retroviral drugs targets several steps which are involved in the replication of HIV.
o The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase,
become incorporated into the host genome, and be transcribed to viral RNA, which is then
translated into polyproteins.
o Reverse transcriptase is an enzyme that transcribes viral RNA into viral DNA (hence the term
reverse).
o The parent drug, ZDV, enters virally infected cells by diffusion and undergoes
phosphorylation first to its monophosphate (ZDV-MP) then to the diphosphate (ZDV-DP),
the rate-limiting step, and finally to the triphosphate (ZDV-TP).
o ZDV-TP is a competitive inhibitor of the HIV-1 reverse transcriptase and when incorporated
into nascent viral DNA causes chain termination.
o Human cells lack reverse transcriptase and human nuclear DNA polymerases are much less
sensitive (by at least 100-fold) to inhibition by ZDV-TP, thus producing a selective effect on
viral replication.
o This mechanism of action is common to all anti-HIV nucleoside analogues.
191
 Non -Nucleoside Analogue Reverse Transcriptase Inhibitors (nNRTIs): nevirapine,
delavirdine, efavirenz and Second-generation: etravirine
o Reverse transcriptase is an enzyme that transcribes viral RNA into viral DNA (hence the term
reverse).
o The nNRTIs bind to a site distant from the active site of the reverse transcriptase, and induce
a conformational change in the enzyme.
o This conformational change greatly reduces the activity of the enzyme.
o Unlike the NRTIs, the nNRTIs have no activity against DNA polymerase.
o Also, because the binding of nNRTIs to the reverse transcriptase is very specific, nNRTIs act
specifically on the HIV-1 strain and lack activity against HIV-2.
o Conversely, the NRTIs indirectly inhibit reverse transcriptase and are therefore not specific
for HIV-1.
 Protease Inhibitors: Saquinavir, indinavir, nelfinavir, ritonavir, atazanavir, fosamprenavir,

amprenavir, lopinavir and darunavir
o Several steps are involved in the replication of HIV. The virus must fuse to the host cell,
uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host
genome, and be transcribed to viral RNA, which is then translated into polyproteins.
o These polyproteins are then cleaved into smaller viral proteins by proteases as they are
released from the cell.
o This process is called viral maturation.
o These smaller viral proteins perform important functions, either structural or acting as
enzymes such as reverse transcriptase, integrase, or protease itself.
o Protease inhibitors bind to these proteases and prevent them from performing this important
step in viral maturation.
o This results in the production of immature, non-infectious virus particles.
o The selective toxicity of the protease inhibitors is based on structural differences between
human proteases and viral proteases.
 Integrase Inhibitors:
o Integrase inhibitors are a newer class of drugs for HIV infection that inhibit HIV by
preventing the virus from incorporating its DNA into the host genome.
o The integrase enzyme incorporates viral DNA into the host genome.
o Specifically, integrase binds to viral DNA and joins it with host DNA. The divalent cations in
the catalytic core of integrase enable it to form covalent bonds with DNA.
o This is followed by cellular repair activities that seal the viral DNA into the chromosome.
o Integrase inhibitors prevent the formation of covalent bonds with host DNA. This prevents
incorporation of HIV into the host genome.
 Fusion Inhibitors: enfuvirtide ibalizumab
192
o Enfuvirtide mimics the HIV machinery required to fuse to the CD4 cell. It competes with the
HIV proteins and prevents entry of the virus into the CD4 cell:
o Glycoprotein gp120 binds HIV and activates gp41.
o Glycoprotein gp41 changes conformation and creates an entry channel (pore) into the cell.
o Specifically, enfuvirtide binds gp41 and prevents conformation change.
STEP 3: Drug Interactions Associated With Antiviral Drugs (20 minutes)

How do significant drug interactions of Antiviral Drugs occur?
The following are the drug interactions of Anti-HIV Drugs

 Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs).
o Didanosine is easily degraded in an acidic environment and is therefore formulated with
buffers such as calcium carbonate and magnesium hydroxide.
o Agents that bind to divalent cations (e.g., calcium and magnesium) should be administered
separately from didanosine.
o Examples of these agents include fluoroquinolones such as ciprofloxacin.
o The same is true for agents whose dissolution is pH dependent, such as itraconazole.
o Stavudine and zidovudine compete for intracellular phosphorylation and should not be used
in combination with each other
 Non- Nucleoside Analogue Reverse Transcriptase Inhibitors (nNRTIs).
o Many of the nNRTIs are CYP3A4 substrates (nevirapine, delavirdine, efavirenz, and
etravirine). Given the number of CYP3A4 inducers and inhibitors, these drugs might be more
likely to have their metabolism inhibited or induced by other drugs.
o CYP450 inducers: Efavirenz, nevirapine, and etravirine are moderate inducers of CYP3A4.
o CYP450 inhibitors: Delavirdine (CYP3A4) Etravirine (CYP2C9 and CYP2C19)
 Protease Inhibitors:
o Ritonavir is by far the most potent CYP3A4 inhibitor and is purposely combined with other
protease inhibitors that are substrates of CYP3A4 in order to prolong the half-life of these
agents.
o As potent CYP3A4 inhibitors, PIs will affect plasma concentrations of many drugs when
administered together.
193
o Indinavir absorption is also affected by pH; therefore agents that raise pH such as antacids
should not be administered simultaneously.
o Raltegravir is not a substrate for CYP450 enzymes. It also does not inhibit or induce CYP450
enzymes. It is primarily metabolized by glucuronidation (UGT1A1), and it is a Pgp substrate.
o Atazanavir is a UGT1A1 inhibitor, and concomitant administration of raltegravir and
atazanavir has been shown to elevate raltegravir levels.
o Rifampin is a strong inducer of UGT1A1; therefore concomitant administration of these two
agents can significantly reduce raltegravir levels.
STEP 4: Side Effects of Antiviral Drugs (20 minutes)

The following are the side effects of Anti-HIV Drugs;
o NRTIs also inhibit host cell DNA polymerase, although this likely contributes more to their
toxic effects than their efficacy.
o Inhibition of DNA polymerase in mitochondria leads to depletion of mitochondrial DNA and
subsequent depletion of mitochondrial RNA and peptides involved in oxidative
phosphorylation.
o This leads to mitochondrial dysfunction, and this is believed to be the cause of several of the
important toxicities associated with drugs of this class.
o Myalgia: One of the most common and earliest side effects associated with NRTIs, myalgia
was also the first indication of the mitochondrial toxicity that has become associated with
these agents.
o The mitochondrial toxicity is believed to be caused by the inhibition of DNA polymerase by
the NRTI.
o Diarrhoea is most associated with didanosine, likely as a result of the buffers used in oral
formulations, some of which contain magnesium, a known laxative.
o Lactic acidosis: The impairment of mitochondrial function leads to a reliance on anaerobic
metabolism, which produces excessive amounts of lactate.
o Lipodystrophy is most associated with stavudine.
o Peripheral neuropathy (didanosine, stavudine, zalcitabine) is likely caused by mitochondrial
toxicity. Typically this effect will improve or resolve completely as long as the drug is
stopped as soon as the symptoms appear.
o Pancreatitis (didanosine, stavudine, zalcitabine) is a rare but potentially fatal adverse effect,
likely caused by mitochondrial toxicity. It is more common with didanosine and particularly
common when two of these agents are combined.
o Hepatotoxicity (didanosine, zidovudine) is rare but potentially fatal.
o Bone marrow suppression is likely the result of toxic effects on erythroid stem cells.
o Special for Abacavir: Hypersensitivity, characterized by fever, GI problems including
abdominal pain, rash, malaise, and fatigue may occur.
194
o If fever, abdominal pain, and rash occur within 6 weeks of initiation of therapy, the drug
should be discontinued.
o Special for Tenofovir: Acute renal failure is a rare side effect, and although tenofovir is an
antiviral nucleotide like cidofovir and adefovir, it is not believed to share their nephrotoxic
effects.
o Stomatitis and oral ulcers (zalcitabine): Zalcitabine may be toxic to rapidly dividing cells,
but the mechanism is unclear.
 Non- Nucleoside Analogue Reverse Transcriptase Inhibitors (nNRTIs).
o Rash: Macular or papular rash, often pruritic and also self-limiting, may occur with continued
drug administration. In a minority of individuals, rash can progress to more serious Stevens-
Johnson syndrome.
o Hepatitis can be severe and fatal; it is more common in female patients, especially during
pregnancy. Most cases are the result of a hypersensitivity reaction. Delavirdine has not been
associated with fatal hepatitis.
o Neutropenia is a rare effect.
o Efavirenz only: CNS effects: The mechanism has not been established. These side effects are
typically transient, resolving after a few hours or up to several weeks. These include
dizziness, impaired concentration, dysphoria, vivid dreams, psychosis and insomnia
o Note: The nNRTIs do not inhibit DNA polymerase and therefore do not exhibit the same
mitochondrial toxicities as the
o GI (nausea, vomiting, diarrhea): Diarrhea in particular is a common and troublesome adverse
effect of protease inhibitor therapy. The mechanism is not established and is complicated by
the fact that diarrhea is a complication of HIV infection.
o Hyperlipidemia: A side effect common to all protease inhibitors, hyperlipidemia might occur
less frequently with atazanavir. Protease inhibitors appear to stimulate lipogenesis in
hepatocytes.
o Lipodystrophy: Fat redistribution is a problem in HIV that appears to be exacerbated with the
use of protease inhibitors.
o The nature of the fat redistribution may depend to an extent on the total body fat at baseline
as well as energy balance.
o Hyperglycemia, insulin resistance: Protease inhibitors appear to inhibit the activity of the
glucose transporter (GLUT-4), inhibiting insulin-stimulated glucose uptake by cells.
o Atazanavir may be less likely to cause this side effect compared with other protease
inhibitors.
o Crystalluria, nephrolithiasis (Indinavir only): Indinavir has poor solubility and precipitates
easily.
o Patients are advised to increase fluid intake while on indinavir.
o Hyperbilirubinemia (atazanavir only) is not considered to be a serious side effect or sign of
hepatotoxicity.
195
o Because the antiretroviral are typically administered in combination regimens, it is difficult
to determine the side effects that are associated with a specific class or drug within that class.
o Generally well-tolerated: In controlled trials, raltegravir did not elicit more adverse effects
than placebo.
o As with most antiretrovirals, the safety of integrase inhibitors in pregnancy has not been
established.
 Fusion Inhibitors:
o Injection site irritation
o Peripheral neuropathy (can cause pain, numbness, or weakness in extremities)
STEP 5: Contraindications of Antiviral Drugs (10 minutes)
What are the contraindications of Antiviral Drugs ?

The following are the contraindications of Anti-HIV Drugs;

o Avoid in patients with history of pancreatitis or neuropathy: particularly true with didanosine,
stavudine, and zalcitabine .See adverse/side effects above
 Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (nNRTIs).
o Pregnancy (efavirenz): Of all the antiretrovirals, efavirenz carries the clearest risk in
pregnancy, as it has demonstrated teratogenicity in primates.
o Drug interactions (CYP3A4): Ritonavir is such a potent CYP3A4 inhibitor that its use is
contraindicated with drugs that are highly dependent on CYP3A4 for their elimination, and
where elevated plasma levels of these agents would lead to unacceptable toxicity.

 Drugs active against HIV have different mechanisms of Action
 Antiretroviral drugs show serious drug interactions
 Resistance to antiretroviral drugs has developed
196
 What is the mechanism of action of Zidovudine?
 What are adverse effects of efavirenz?
 Why do NRTIs cause lactic acidosis?
197
References
Education.

198
Session 26: Introduction to Toxicology
Prerequisites
Learning Tasks
 Define terms used in toxicology
 Describe broad areas/branches of toxicology
 Describe mechanisms of toxicology
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Definition of Terms Used in Toxicology
Buzzing
Presentation/ Description of Broad Areas/Branches of
3 20 minutes
brainstorming Toxicology
4 20 minutes Presentation Description of Mechanisms of Toxicology
199
SESSION CONTENTS

STEP 2: Definition of Terms Used in Toxicology (45 minutes)
What do you understand by the term toxicology?
The followings are common terms/definitions used in toxicology

 Toxicology:
o The science that investigates the adverse effects of chemicals on health.
o The field of toxicology is a broad-based multidisciplinary science that examines the harmful
effects of substances on living organisms, including humans.
 Poison:
o Is any substance that may disrupt biologic function and potentially kill an organism.
 Toxin:
o Toxin, by strict definition, is a poison of biologic origin that does not have the ability to
replicate.
o However, the term toxin has been used more loosely.
o For example, environmental toxin has been used to describe toxic substances of nonbiologic
origin.
 Venom:
o Is a toxin that is injected into the victim by some means (e.g., bee sting, snake bite).
 Toxicant:
o Is a general term that refers to any harmful substance and is generally interchangeable with
poison.
 Toxicodynamics:
o Refers to the general concepts of pharmacodynamics (interaction with molecular targets and
mechanisms of effects) as applied to interactions and mechanisms that generate toxic effects.
200
 Toxicokinetics:
o Refers to the general concepts of pharmacokinetics (absorption, distribution,
biotransformation, and elimination) as applied to toxic substances.
 Toxicity:
o Is the ability of a chemical to damage an organ system, to disrupt a biochemical process, or to
disturb an enzyme system.
 Paracelsus theory:
o All things are toxic and there is nothing without poisonous qualities: it is only the dose
which makes something a poison .
STEP 3: Broad Areas/Branches of Toxicology (20 minutes)
What are branches of toxicology?

The field of toxicology is a broad-based multidisciplinary science that examines the harmful
effects of substances on living organisms, including humans and have several major
subdivisions as listed below:
 Descriptive toxicology:
o Focuses on toxicity testing with the intent of defining the degree of risk associated with
substances.
 Environmental toxicology:
o Involves the detection and understanding of environmental pollutants and their effects on
humans and other organisms.
 Forensic toxicology:
o Is primarily concerned with detection and quantification of toxic substances for legal
purposes.
 Mechanistic toxicology:
o Is focused on determining the mechanisms by which substances exert toxic effects.
 Regulatory toxicology:
o Uses toxicologic data to establish policies regarding exposure limits for toxic substances.
 Medical or clinical toxicology:
o Focuses on the diagnosis and treatment of toxic effects in humans.
201
STEP 4: Mechanisms of Toxicology (20 minutes)
 Mechanisms of toxicity can be classified as follows:
 Physical:
o The physical presence of the toxicant triggers reactions that are harmful (e.g., asbestos fibers
in the lung).
 Chemical:
o Toxicants react chemically with the tissues or body fluids such as blood to produce harmful
effects (e.g., strong acids or bases cause burns).
 Pharmacologic:
o Toxicants interact with endogenous pharmacologic pathways, resulting in inhibition or
overstimulation (e.g., botulinum toxin inhibits release of acetylcholine to cause paralysis).
 Biochemical:
o Toxicant reacts biochemically with cellular constituents to produce cellular damage (e.g.,
venom of many snakes contains phospholipases that destroy cell membranes).
 Genomic (genotoxic):
o Toxicant alters the genetic material of the cell, resulting in disruption of function. Genotoxic
substances may be mutagenic or carcinogenic.
 Mutagenic (carcinogenic):
o Toxicants alter DNA structure or function sufficiently to cause mutations (benzene) or initiate
and promote the development of cancers (polycyclic aromatic hydrocarbons such as
benzo[a]pyrene, found in cigarette smoke).
 Immunologic:
o Toxicant may trigger an immune response that leads to cellular damage (e.g., penicillin-
induced hemolytic anemia) or conversely suppresses the immune system, causing an
increased susceptibility to infection (e.g., procainamide-induced agranulocytosis).
 Teratogenic:
o Toxicant alters foetal development, resulting in birth defects (e.g., phenytoin is associated
with development of cleft lip).

 Drugs and chemicals produce toxicity by different mechanisms
 There are different branches of toxicology resulted from different causes and mechanisms by
which these toxicities occurs

 What is a toxicant?
 What are branches of toxicology?
 What are mechanisms by chemicals/drugs produce toxicity?
202
References
Education.

203
Session 27: Management of Acute Poisoning
Prerequisites
Learning Tasks
 Describe approaches/measures in management of acute poisoning
 Describe management of specific drug overdoses/poisoning of clinical importance
 Describe management of overdoses/poisoning of other chemicals of clinical
importance
Resources Needed:
 Handout 27.1: Management of Specific Drug Overdoses/Poisoning of Clinical
Importance
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Approaches/Measures in Management of
2 45 minutes
Buzzing Acute Poisoning
Presentation/ Management of Specific Drug
3 20 minutes
brainstorming Overdoses/Poisoning of Clinical Importance
Management of Overdoses/Poisoning of
Other Chemicals of Clinical Importance
204
SESSION CONTENTS

STEP 2: Approaches/Measures in Management of Acute Poisoning (45

minutes)
 What are approaches in management of poisoned/overdosed patients?

Supportive Therapy
 In general involves maintaining of the airways flow, proper breathing, adequate circulation.
 After an initial assessment of vital signs and instigation of appropriate resuscitation, repeated
observations are necessary, as drugs may continue to be absorbed with a subsequent increase
in plasma concentration.
 In the unconscious patient, repeated measurements of cardiovascular function, including
blood pressure, urine output and (if possible) continuous electrocardiographic (ECG)
monitoring should be performed.
 Plasma electrolytes and acid-base balance should be measured.
 Hypotension is the most common cardiovascular complication of poisoning.
o Hypotension can usually be managed with intravenous colloid.
o If this is inadequate, positive inotropic agents (e.g. dobutamine) may be considered.
o If dysrhythmias occur any hypoxia or hypokalaemia should be corrected, but anti-
dysrhythmic drugs should only be administered in life-threatening situations.
Prevention of Further Absorption

 Emesis:
o Replaced by lavage/charcoal
o Syrup of ipecacuanha is no longer recommended in the management of poisoning.
o Contraindicated in corrosive poisonings/aspiration risk.
205
 Gastric Lavage:
o Technique involves placing of patient in left lateral head down position if not intubated.
o Then Insertion of a soft lubricated tube through mouth or nose into stomach.
o Aspirate and save contents and then lavage repeatedly with 50-100ml of fluid until
returns are clear .
o Use luke warm water or saline.
o Gastric aspiration and lavage should only be performed if the patient presents within one
hour of ingestion of a potentially fatal overdose.
o If there is any suppression of the gag reflex, a cuffed endotracheal tube is mandatory.
o Gastric lavage is unpleasant and is potentially hazardous.
o Indications: Removal of gastric contents (within the first hour). Examination of gastric
contents is important.
o Contraindications: Do not do if patient comatose unless intubated. Also do not use if
corrosives are ingested
 Activated Charcoal:
o Adsorbs almost all drugs and poisons. Poorly adsorbed substances are Lithium,
Potassium, alcohol, iron, cyanide. Metal salts, alcohols and solvents are not adsorbed by
activated charcoal.
o To be effective, large amounts of charcoal are required, typically ten times the amount of
poison ingested, and again timing is critical, with maximum effectiveness being obtained
soon after ingestion. Its effectiveness is due to its large surface area (1000m2/g). Binding
of charcoal to the drug is by non-specific adsorption.
o The use of repeated doses of activated charcoal may be indicated after ingestion of
sustained-release medications or drugs with a relatively small volume of distribution, and
prolonged elimination half-life (e.g. salicylates, quinine, dapsone, carbamazepine,
barbiturates or theophylline).
o The rationale is that these drugs will diffuse passively from the bloodstream if charcoal is
present in sufficient amounts in the gut or to trap drug that has been eliminated in bile
from being re-absorbed.
o Whole bowel irrigation using non-absorbable polyethylene
o Contraindications: Comatose or obtunded unless given by gastric tube or intubated as
drinking charcoal can cause emesis. Ileus or intestinal obstruction (delays expulsion of
charcoal). Corrosive poisonings where endoscopy is planned. Oral charcoal may also
inactivate any oral antidote (e.g. methionine).
 Whole Bowel Irrigation :
o Cleanses the GI tract
o Indications: Whole bowel irrigation using non-absorbable polyethylene glycol solution
may be useful when large amounts of sustained-release preparations, iron or lithium
tablets or packets of smuggled narcotics have been taken by body stuffers/packers
(People who swallow packets of drugs for smuggling.)
o Contraindication: Paralytic ileus
206
 Decontamination
o Sometimes it may be necessary to wash the skin or remove clothes and other coverings to
minimize contact with the source of allergy /poison.
 Enhanced Elimination
 Urine manipulation:
o Alkaline diuresis (urinary alkalinization) should be considered in cases of salicylate,
chlorpropramide, phenoxyacetate herbicides and phenobarbital poisoning, and may be
combined with repeated doses of oral activated charcoal.
o Acid diuresis may theoretically accelerate drug elimination in phencyclidine and
amphetamine/ ecstasy poisoning.
 Haemodialysis and charcoal haemoperfusion:
o Not all drugs or poisons can be cleared by this method.
o Hepatic or renal failure where excretion of the drug may be compromised.
Administration of Antidote
 Antidotes are available for a small number of poisons and the most important of these,
including chelating agents have been discussed in the previous sessions.
Table 27.1 Drugs and their antidotes

Drug Antidote
1 Acetaminophen N-Acetylcysteine i.v. ,Methionine
2 Organophosphates Atropine/Pralidoxime
4 Opioids Naloxone
4 Benzodiazepines Flumazanil
5 Ethylene Glycol Fomepizol
6 Methanol Fomepizol
7 Beta-blockers Atropine, Glucagon, Isoprenaline
8 Carbon monoxide Oxygen,Hyperbaric oxygen
9 Iron Desferrioxamine
10 Cyanide Oxygen, dicobalt edetate i.v. or sodium nitrite i.v. followed
by sodium thiosulphate i.v.
11 Lead (inorganic) Sodium EDTA i.v., Penicillamine p.o., Dimercaptosuccinic
acid (DMSA)
Mercury Dimercaptopropane sulphonate(DMPS),
12 Dimercaptosuccinic acid (DMSA),
Dimercaprol,
Penicillamine
13 Organophosphorus Atropine, pralidoxime
insecticide
14 Digoxin Digoxin-specific fab antibody fragments
15 Calcium-channel blockers Calcium chloride or gluconate i.v.
16 Insulin 20% dextrose i.v., Glucagon i.v. or i.m.
207
STEP 3: Management of Specific Drug Overdoses/Poisoning of Clinical
Importance (20 minutes)
 What is the management of poisoned/overdosed patients?
Paracetamol poisoning/overdose
 Treatment
o Acetaminophen is metabolized by the cytochrome P450 pathway to a toxic intermediate
that is detoxified by glutathione.
o With acute acetaminophen overdose hepatocellular glutathione is depleted allowing the
toxic intermediate (NAPQI) N-acetyl-p-benzoquinoneimine) to attack cell proteins and
cause cell necrosis.
o Patients with enhanced cytochrome P450 activity like alcoholics and anticonvulsant users
are at greater risk of hepatotoxicity.
o If a potentially toxic overdose is suspected, the stomach should be emptied if within one
hour of ingestion. The antidote should be administered and blood taken for determination
of paracetamol concentration, prothrombin time (INR), creatinine and liver enzymes.
o Rumack-Matthew Nomogram utilized to decide whether treatment with N-acetylcysteine
is required.
o Intravenous acetylcysteine and/or oral methionine are potentially life-saving antidotes and
are most effective if given within eight hours of ingestion; benefit is obtained up to 24
hours after ingestion.
o For serious paracetamol overdoses seen greater than 24 hours after ingestion, advice
should be sought from poisons or liver specialists.
o Acetylcysteine is administered as an intravenous infusion.
o Methionine is an effective oral antidote in paracetamol poisoning. It may be useful in
remote areas where there will be a delay in reaching hospital or when acetylcysteine is
contraindicated.
208
Salicylate poisoning/overdose
 Treatment
o Respiratory alkalosis frequently predominates and is due to direct stimulation of the
respiratory centre.
o The metabolic acidosis is due to uncoupling of oxidative phosphorylation and consequent
lactic acidosis.
o If acidosis predominates, the prognosis is poor.
o The typical presentation includes nausea, tinnitus and hyperventilation and the patient is
hot and sweating.
o Immediate management includes estimation of arterial blood gases, electrolytes, renal
function, blood glucose (hypoglycaemia is particularly common in children) and plasma
salicylate concentration.
o The patient is usually dehydrated and requires intravenous fluids.
o A stomach washout is performed, if within one hour of ingestion.
o Activated charcoal should be administered. Multiple dose activated charcoal is advised
until the salicylate level has peaked.
o Depending on the salicylate concentration and the patients clinical condition,
o an alkaline diuresis should be commenced using intravenous sodium bicarbonate.
 However, this is potentially hazardous, especially in the elderly.
 Children metabolize aspirin less effectively than adults and are more likely to
develop a metabolic acidosis and consequently are at higher risk of death.
o Plasma electrolytes, salicylate and arterial blood gases and pH must be measured
regularly.Frequent monitoring of serum electrolytes is essential.
o If the salicylate concentration reaches 8001000 mg/L, haemodialysis is likely to be
necessary.
 Haemodialysis may also be life-saving at lower salicylate concentrations if the
patients metabolic and clinical condition deteriorates.
REFER Students to Handout 27.1: Management of Specific Drug

Overdoses/Poisoning of Clinical Importance
STEP 4: Management of Overdoses/Poisoning of other Chemicals of

Clinical Importance (20 minutes)
Ethylene Glycol/Methanol
 Treatment
o Ethanol loading dose: Traditionally been used as antidote for Methanol and Ethylene
Glycol
209
o Mechanism: Preferred substrate of alcohol dehydrogenase therefore inhibits formation
of NEW toxic substrate. Systemic alcohol is used in poisoning by methanol or
ethylene glycol, since it competes with these for oxidation by alcohol dehydrogenase,
slowing the production of toxic metabolites (e.g. formaldehyde, oxalic acid).
o Fomepizole (4-methypyrazole): Competitive Inhibitor of Alcohol dehydrogenase
(in vitro: 80,000 times affinity for ADH than methanol).
Ethanol
 Treatment
o Disulfiram and other Alcohol-sensitizing drugs: These produce an unpleasant reaction
when taken with alcohol.
 The only drug of this type used to treat alcoholics is disulfiram, which inhibits
aldehyde dehydrogenase, leading to acetaldehyde accumulation if alcohol is
taken, causing flushing, sweating, nausea, headache, tachycardia and
hypotension.
 Cardiac dysrhythmias may occur if large amounts of alcohol are consumed.
o Disulfiram also inhibits phenytoin metabolism and can lead to phenytoin intoxication.
 Unfortunately, there is only weak evidence that disulfiram has any benefit in
the treatment of alcoholism.
 Its use should be limited to highly selected individuals in specialist clinics.
o Acamprosate: The structure of acamprosate resembles that of GABA and glutamate.
 It appears to reduce the effects of excitatory amino acids and, combined with
counselling, it may help to maintain abstinence after alcohol withdrawal.
 Acamprosate-inhibt NMDA receptor prolongs abstinence.

 Management of poisoned patients involve different approaches
 There are specific antidotes for some chemicals/drugs poisoning

 What are approaches in management of poisoned patients?
 What are antidotes for ethanol poisoning?
 What is the treatment for isoniazid poisoning?
210
References
Education.

211
Handout 27.1 Management of Specific Drug Overdoses/Poisoning
of Clinical Importance
Tricyclic Antidepressants poisoning/overdose
 Treatment
o Tricyclic antidepressants cause death by dysrhythmias, myocardial depression,
convulsions or asphyxia.
 If the patient reaches hospital alive they may be conscious, confused,
aggressive or, in deep coma.
 Clinical signs include dilated pupils, hyperreflexia and tachycardia
o Gastric lavage may be performed up to one hour after ingestion if the patient is fully
conscious.
o Occasionally, assisted ventilation is necessary.
o The most common dysrhythmia is sinus tachycardia, predominantly due to
anticholinergic effects and does not require any intervention. Broadening of the QRS
complex can result from a quinidine-like (sodium ion blocking) effect and is associated
with a poor prognosis.
o Anti-dysrhythmic prophylaxis should be limited to correction of any metabolic
abnormalities, especially hypokalaemia, hypoxia and acidosis. Intravenous sodium
bicarbonate (12 mmol/kg body weight) is the most effective treatment for the severely
ill patient and its mode action may involve a redistribution of the drug within the tissues.
o If resistant ventricular tachycardia occurs, intravenous magnesium or overdrive pacing
have been advocated.
o Convulsions should be treated with intravenous benzodiazepines. Oral benzodiazepines
may be used to control agitation.
Selective Serotonin Reuptake Inhibitors (SSRIs) poisoning/overdose

 Treatment
o SSRIs do not have anticholinergic actions and are much less cardiotoxic unlike TCAs
o Nausea and diarrhoea are common.
 Seizures may occur and are associated with venlafaxine (which blocks
noradrenaline, as well as serotonin reuptake).
o Supportive and symptomatic measures are usually sufficient.
o Oral activated charcoal is recommended following the ingestion of more than ten tablets
within one hour.
Ca Channel Blockers poisoning/overdose

 Treatment
o Symptoms of the poisoning include bradycardia, conduction delays, impaired contractility
and hypotension.
o Gastric lavage and activated charcoal are usually employed
212
o Patients may respond to atropine and isoproterenol.
o If no response IV calcium chloride or calcium gluconate are used to treat hypotension and
conduction defects.
o Glucagon is occasionally beneficial in severe toxicity
Atropine & Anticholinergics poisoning/overdose

 Treatment
o Symptoms: Dry mouth, thirst, blurring of vision, constipation.
o Signs: Psychosis, dilated pupils, fever, ileus, urinary retention.
o Activated charcoal is beneficial as there is delayed gut emptying
o Physostigmine is administered (with ECG monitoring).
Beta Blockers poisoning/overdose

 Treatment
o Management of Bradycardia: Breathing and circulatory support is necessary.
o Management of hypotension: fluids administration and dopamine are preferred
o Bradycardia management: atropine, pacers, dopamine are employed
o Catecholamines (epi, dobutamine, dopamine) often are ineffective in treating beta -
blocker effect because they act on the same beta receptor which is blocked therefore
action requires free receptors or replacement of the drug (beta blocker at the receptor).
 Affinity to the receptor could be a major determinant. Dopamine is only 25%
effective while Epinephrine is 67% effective.
o Glucagon: Drug of choice for beta blockers & calcium channel blockers
poisoning/overdose. Glucagon is secreted by pancreas secondary to hypoglycaemia.
o Glucagon Receptors are found in heart muscle. The drug acts by stimulating adenylate
cyclase independent of beta receptor resulting to positive chronotropic and inotropic
effects despite beta adrenergic receptor blockade.
Isoniazid (INH) poisoning/overdose

 Treatment
o Isoniazid enhances elimination of pyridoxine leading to pyridoxine deficiency. Isoniazid
also inactivates the conversion of pyridoxine to pyridoxal 5 phosphate resulting to GABA
deficiency hence seizures develop due to lack of inhibitory activity of GABA.
o As with all seizing patients, ABCs (airway protection, IV fluids) is important.
o Benzodiazepines (Valium, 5-10 mg iv) are used in initial approach. However
Benzodiazepines may not be effective because their action requires the presence of
GABA which is depleted by Isoniazid.
o Pyridoxine (Vit B6) is the only antidote available for INH toxicity
213
Session 28: Pharmacodynamics of Anticonvulsants
Prerequisites
 PST04211_S_ Description of
Learning Tasks
 Describe mechanism of action of Anticonvulsants
 Describe drug interactions associated with Anticonvulsants
 Describe side effects of Anticonvulsants
 Describe contraindications of Anticonvulsants
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Mechanism of Action of Anticonvulsants
Buzzing
3 20 minutes
brainstorming Anticonvulsants
4 20 minutes Presentation Adverse Effects of Anticonvulsants
Presentation/
5 20 minutes Contraindications of Anticonvulsants
Brainstorming
214
SESSION CONTENTS

STEP 2: Mechanism of Action of Anticonvulsants Drugs (45 minutes)
 How do Drugs acting on the CNS produce their pharmacological effects?

Anticonvulsants
 Sodium channel blockers (Phenytoin, Carbamazepine,)
o Carbamazepine stabilizes the inactive form of the Na+ channel, which slows the rate of
channel recovery from the inactivated state. This increases the threshold for action potentials
and prevents repetitive firing.
o Carbamazepine and other Na+ channel blockers bind to the Na+ channel when it is open.
Because rapidly firing neurons, such as those found in seizure disorders are open a greater
percentage of the time, these drugs tend to be selective for abnormal electrical activity found
in a seizure focus and do not suppress normal neuronal activity. This is referred to as use-
dependent blockade and is essential for limiting the toxicity of these agents.
o Valproic acid may also reduce reduces the propagation of abnormal electrical discharge in the
brain. It may enhance GABA action at inhibitory synapses.
 Calcium channel blockers (Ethosuximide)
o Ethosuximide is used clinically for its selective effect on absence seizures. The mechanism of
action is due to inhibition of T-type calcium channels, which may play a role in generating
the 3/second firing rhythm in thalamic relay neurons that is characteristic of absence seizures
 Barbiturates: (Phenobarbital, Secobarbital, pentobarbital, mephobarbital, butabarbital,
amobarbital)
o Binding of GABA to GABA A receptors leads to the opening of the chloride (Cl−) channel,
facilitating Cl− influx and cellular hyperpolarization (making the inside more negative).
o Hyperpolarization of a cell decreases the probability that the cell can be subsequently
depolarized by other incoming excitatory signals; this will have a net inhibitory effect.
215
o Barbiturates increase the binding of GABA to GABA A receptors and increase the influx of
Cl− into the neuron, resulting in hyperpolarization and decreased neuronal activity.
Barbiturates also potentiate the binding of benzodiazepines to GABAA receptors. The overall
net effect of this binding is a global reduction in CNS activity; barbiturates are CNS
depressants.
 GABA-transaminase inhibition (vigabatrin )

o Vigabatrin inhibit transaminase enzyme thus preventing the metabolism of GABA to its
metabolites resulting to an increase in GABA concentration.
 GABA-reuptake inhibitors (Tiagabine )
o Tiagabine Inhibits GABA transporter (GAT-1) hence reducing reuptake of GABA by
neurons and glial cells.
 γ-Aminobutyric acid (GABA) Analogues (Gabapentin, Pregabalin)
o GABA analogues are primarily used in the treatment of seizures and management of
neuropathic pain.
o The structure of gabapentin is derived from GABA; therefore it has long been thought of as
simply a GABA agonist. However, gabapentin does not appear to bind to GABA receptors.
Instead, it may promote the release of GABA.
 Benzodiazepines
o BDZ like Diazepam (Valium), lorazepam, clonazepam, clorazepate have anticonvulsant
activity. Not all BDZ are used as anticonvulsants.
o These drugs increases the frequency of GABAA-activated Cl- channel opening as discussed
in Pharmacodynamics of Hypnotics and Anxiolytics
STEP 3: Drug Interactions Associated with Anticonvulsants (20 minutes)
 How do significant drug interactions of anticonvulsants occur?

The following are drug interactions of Anticonvulsants
 Sodium channel blockers (Phenytoin, Carbamazepine, Valproate )
o Carbamazepine: should not be combined with monoamine oxidase inhibitors. It is a potent
enzyme inducer and, in particular, it accelerates the metabolism of warfarin, theophylline and
the oral contraceptive.
216
o Carbamazepine: The hepatic metabolism of carbamazepine is inhibited by cimetidine,
isoniazid, diltiazem and erythromycin. Toxic symptoms may arise if the dose is not adjusted.
o Phenytoin:
1. Inhibition of phenytoin metabolism: Inhibition of microsomal metabolism of phenytoin in
the liver is caused by chloramphenicol, dicumarol, cimetidine, sulfonarnides, and isoniazid.
When used chronically, these drugs increase the concentration of phenytoin in plasma by
preventing its metabolism.
2. A decrease in the plasma concentration of phenytoin is caused by carbamazepine, which
enhances phenytoin metabolism
3. Increase in metabolism of other drugs by phenytoin: Phenytoin induces the P-450 system
which leads to an increase in the metabolism of other antiepileptics, anticoagulants, oral
contraceptives, quinidine, doxycycline, cyclosporine, mexiletine, methadone, and levodopa.
o Valproic acid: Valproate is a CYP2C9 enzyme inhibitor and can interfere with the
metabolism of other antiseizure medications such as phenytoin and phenobarbital.
 Barbiturates
o All barbiturates are liver enzyme inducers; they increase the activity of CYP2A and CYP3A
enzymes, which results in faster metabolism (and thus reduced effect of) other,
coadministered drugs that are also hepatically metabolized.
o Barbiturates are an example of autoinducers: a drug that induces the same enzymes that
metabolize it. This results in increased dose requirements over time, compared with initial
dose requirements.
STEP 4:Adverse Effects of Anticonvulsants (20 minutes)

The following are adverse effects of Anticonvulsants;
 Sodium channel blockers (Phenytoin, Carbamazepine, Valproate, Lamotrigine)
o Lamotrigine: Rash: Rashes can range from mild to severe, including Stevens-Johnson
syndrome and toxic epidermal necrolysis.
 These rashes can be fatal in patients who are otherwise compromised, or if treatment is
not discontinued and/or if the rash is not treated.
 The exact mechanism behind these severe reactions is not known.
o Carbamazepine: Dermatologic reactions may occur, including Stevens-Johnson syndrome
and toxic epidermal necrolysis, which are both very severe reactions with possible fatal
outcomes.
o Valproic acid: Hepatotoxicity: Elevations in liver enzymes and bilirubin are relatively
common; however, severe hepatotoxicity leading to liver failure and death is rare.
 Infants are at highest risk of developing severe hepatotoxicity.
 The mechanism has not been established; however, depletion of carnitine is believed to
play a key role.
 Barbiturates
o Sedation: Anti-seizure effects occur at a lower dose than sedation; however, some patients
will need higher doses of treatment to suppress seizure activity, and the dose can approach a
sedating dose.
217
 Therefore the therapeutic index between the anti-seizure dose and the sedating
dose is small.
o Addiction: Barbiturates are highly addictive.
o Hypotension may occur when barbiturates are given intravenously for anesthesia, especially
in patients at risk (cardiac disease or trauma).
o CNS: Barbiturates cause drowsiness, impaired concentration, and mental and physical
sluggishness.
o Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well after the
patient awakes.
 This drug hangover leads to impaired ability to function normally for many hours after
waking.
 Occasionally, nausea and dizziness occur.
o Addiction: Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness,
restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest.
 Withdrawal is much more severe than that associated with opiates and can result in death.
o Poisoning: Barbiturate poisoning has been a leading cause of death among drug overdoses for
many decades.
 Severe depression of respiration is coupled with central cardiovascular depression, and
results in a shock-like condition with shallow, infrequent breathing.
 Treatment includes artificial respiration and purging the stomach of its contents if the
drug has been recently taken.
 Haemodialysis may be necessary if large quantities have been taken.
 Alkalinization of the urine often aids in the elimination of phenobarbital.
STEP 5: Contraindications of Anticonvulsants (10 minutes)
 What are the contraindications of Drugs acting on the CNS?

 Anticonvulsants
 Sodium channel blockers (Phenytoin, Carbamazepine, Valproate, Lamotrigine)
o Valproic acid: Pregnancy: As is the case with a number of other antiseizure drugs, valproate
is teratogenic, and its use in pregnancy should be considered only after a careful risk-benefit
assessment.
218
o Valproic acid is contraindicated in significant hepatic disease or dysfunction.
 Barbiturates
o Porphyria is a rare group of diseases caused by enzyme deficiencies resulting in accumulation
of porphyrins, which are precursors to heme.
 Barbiturates can increase activity through these biochemical pathways and exacerbate
accumulation of porphyrins.
o Significant hepatic disease or dysfunction.
o Pregnancy: As is the case with a number of other antiseizure drugs, valproate is teratogenic,
and its use in pregnancy should be considered only after a careful risk-benefit assessment.

 The choice of antiepileptic drugs depends on the type of seizures
 Anticonvulsants exhibit different mechanisms of action
 Anticonvulsants use is associated with a lot of significant drug interactions
 Anticonvulsants have serious adverse effect when used

 What is the mechanism of action of phenytoin?
 Anticonvulsants are contraindicated in which conditions?
 Which drugs should be avoided to be co-administered with carbamazepine ?
219
References
Education.

220
Session 29: Pharmacodynamics of Hypnotics and Anxiolytics
Prerequisites
Learning Tasks
 Describe mechanism of action of Hypnotics and Anxiolytics
 Describe drug interactions associated with Hypnotics and Anxiolytics
 Describe side effects of Hypnotics and Anxiolytics
 Describe contraindications of Hypnotics and Anxiolytics
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Hypnotics and
2 45 minutes
Buzzing Anxiolytics
3 25 minutes
brainstorming Hypnotics and Anxiolytics
4 20 minutes Presentation Side Effects of Hypnotics and Anxiolytics
Presentation/ Contraindications of Hypnotics and
5 20 minutes
Brainstorming Anxiolytics
221
SESSION CONTENTS

STEP 2: Mechanism of Action of Hypnotics and Anxiolytics (45 minutes)
 How do Hypnotics and Anxiolytics produce their pharmacological effects?

Hypnotics and Anxiolytics
 The distinction between hypnotics and anxiolytics is rather arbitrary, and the same classes of
drugs are used for both purposes.
 Compounds with a short half-life tend to be used as hypnotics, because they cause less
hangover effects; longer half-life drugs tend to be used as anxiolytics, since a longer
duration of action is generally desirable in this setting.
 Benzodiazepines
o These drugs are anxiolytic, anticonvulsant muscle relaxants that induce sleepiness; they
remain drugs of choice for the pharmacological treatment of insomnia and anxiety.
o Clonazepam is believed to be more anticonvulsant than other members of the group at equi-
sedating doses.
o Benzodiazepines target the GABA receptors (GABA is the major inhibitory neurotransmitter
in the CNS). Binding of BZDs to this BZD binding site at GABA enhances the effects of
GABA at the GABAA receptor.
o Binding of GABA triggers the opening the Cl- channel resulting in hyperpolarization
pushing the postsynaptic neuron further from the threshold. This result to an increase in
suppressing action potential generation thus increased hyperpolarization-induced neuronal
inhibition.
o The clinical effects of BZDs correlate well with GABA receptor binding affinity.
o BZDs are unable to activate the GABAA receptor on their own; therefore BZDs have no
pharmacologic effects on the Cl− channel when GABA is absent.
222
The Actions of BDZ are:
o Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic. They are thought to
reduce anxiety by selectively inhibiting neuronal circuits in the limbic system of the brain.
o Sedative and hypnotic actions: All of the benzodiazepines used to treat anxiety have some
sedative properties. At higher doses, certain benzodiazepines produce hypnosis (artificially-
produced sleep).
o 3Anticonvulsant action: Several of the benzodiazepines have anticonvulsant activity and are
used to treat epilepsy and other seizure disorders.
o Muscle relaxant effect: The benzodiazepines relax the spasticity of skeletal muscle, probably
by increasing presynaptic inhibition in the spinal cord.
 Zolpidem
o Although the hypnotic zolpidem is not a benzodiazepine, it acts on a subset of the
benzodiazepine receptor family.
o The difference with BDZ: Zolpidem has no anticonvulsant or muscle relaxing properties. It
shows no withdrawal effects, exhibits minimal rebound insomnia and little or no tolerance
occurs with prolonged use.
o These
 Buspirone
o Buspirone is useful in the treatment of generalized anxiety disorders and has an efficacy
comparable to the benzodiazepines.
o The actions of buspirone appear to be mediated by serotonin (5-HT lA) receptors, although
other receptors could be involved, since buspirone displays some affinity for DA 2 doparnine
receptors and 5-HT2 serotonin receptors. The mode of action thus differs from that of the
benzodiazepines.
o Difference with BDZ: Buspirone lacks anticonvulsant and muscle-relaxant properties of the
benzodiazepines and causes only minimal sedation. Dependence is unlikely. Buspirone has
the disadvantage of a slow onset of action.
 Hydroxyzine
o Hydroxyzine is an antihistamine with antiemetic activity.
o It has a low tendency for habituation; thus it is useful for patients with anxiety, who have a
history of drug abuse. It is also often used for sedation prior to dental procedures or surgery.
 Barbiturates
o Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and
insomnia. Most have been replaced by the benzodiazepines.
o Details on mechanism of action, side effects, drug interactions and contraindications of
barbiturates are shown in Session 34(Pharmacodynamics of Anticonvulsants).
223
STEP 3: Drug Interactions Associated with Hypnotics and Anxiolytics (20
minutes)
 How do significant drug interactions of Hypnotics and Anxiolytics occur?

The drug interaction of Hypnotics and Anxiolytics include;
 Benzodiazepines
o Pharmacodynamic interactions with other centrally acting drugs are common, whereas
pharmacokinetic interactions are not.
o Pharmacodynamic interactions include potentiation of the sedative actions of alcohol,
histamine (H1) antagonists and other hypnotics.
o SSRIs and oral contraceptives decrease metabolism of BDZs.
STEP 4: Side Effects of Hypnotics and Anxiolytic (20 minutes)

The side effects of Hypnotics and Anxiolytics include;
 Benzodiazepines
o Psychological and physical-dependence-on benzodiazepines can develop if high doses of the
drug are given over a prolonged period. Abrupt discontinuation of-the benzodiazepines
results in withdraw symptoms, including confusion, anxiety, agitation, restlessness, insomnia,
and tension.
o Because of the long half-lives of some of the benzodiazepines, withdrawal symptoms may
not occur until a number of days after discontinuation of therapy.
o Benzodiazepines with a short elimination half-life, such as triazolam, induce more abrupt and
severe withdrawal reactions than those seen with drugs that are slowly eliminated, such as
flurazepam.
o In general, Benzodiazepines short half-life like lorazepam short-term use is associated with
intense withdrawal phenomena and dependence than those with long half-life.
o Flumazenil is a benzodiazepine antagonist. It can be used to reverse benzodiazepine sedation.
o It is short acting, so sedation may return. It can cause nausea, flushing, anxiety and fits, so is
not routinely used in benzodiazepine overdose which seldom causes severe adverse outcome.
o Amnesiathe impaired ability to remembermay be a desired effect for medical procedures.
o Respiratory depression may be seen at higher doses and can lead to respiratory acidosis,
particularly in those with chronic obstructive pulmonary disease (COPD).
224
o Decreased blood pressure, increased heart rate: These cardiovascular effects are seen at
higher doses and are likely mediated by a decrease in vascular resistance (midazolam) or
cardiac output (diazepam).
o Daytime sedation: This is a continuation of the intended therapeutic effect of BZDs. The
extent of sedation is largely a function of the half-life and frequency of use.
o Disinhibition may occur.
o Drowsiness and confusion: These effects are the two most common side effects of the
benzodiazepines; Ataxia occurs at high doses and precludes activities that require fine motor
coordination, such as driving an automobile.
o Cognitive impairment (decreased long-term recall and acquisition of new knowledge) can
occur with use of benzodiazepines.
o Triazolam, the benzodiazepine with the most rapid elimination, often shows a rapid
development of tolerance, early morning insomnia and daytime anxiety, along with amnesia
and confusion.
 Zolpidem
o Adverse effects of zolpidem include nightmares, agitation, headache, gastrointestinal upset,
dizziness, and daytime drowsiness.
 Buspirone
o The frequency of adverse effects is low, the most common effects being headaches, dizziness,
nervousness, and lightheadness.
o Sedation and psychomotor and cognitive dysfunction are minimal, and dependence is
unlikely.
STEP 5: Contraindications of Hypnotics and Anxiolytics (10 minutes)
 What are the contraindications of Hypnotics and Anxiolytics Drugs?

Contraindications of Hypnotics and Anxiolytics include;

 Benzodiazepines
o Addiction to other drugs or past history of BZD addiction is a contraindication.
o Sleep apnea: Patients with central or obstructive sleep apnea have abnormal respiratory
centers and may be at risk for exacerbations of sleep apnea if given sedatives of any type.
225
 Flumazenil is a benzodiazepine antagonist. It can be used to reverse benzodiazepine sedation.
 It is a dose which determines the anxiolytic and sedative hypnotic effect of drugs used.
 Benzodiazepines have other indications than anxiolytic effects.

 What is the mechanism of action of benzodiazepines in controlling anxiety
 What are adverse effects of benzodiazepines?
 What is the mechanism of action of Buspirone
226
References
Education.

(59th ed). London, BMJ Group and RPS Publishing
227
Session 30: Pharmacodynamics of Antipsychotic Drugs
Prerequisites
 PST04211_S43_ Description of Antipsychotic Drugs
Learning Tasks
 Describe mechanism of action of Antipsychotic Drugs
 Explain the dopamine theory of schizophrenia
 Describe drug interactions associated with Antipsychotic Drugs
 Describe side effects of Antipsychotic Drugs
 Describe contraindications of Antipsychotic Drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 15 minutes Dopamine Theory of Schizophrenia
Buzzing
Mechanism of Action of Antipsychotic
Drugs
4 20 minutes
brainstorming Antipsychotic Drugs
5 20 minutes Presentation Side Effects of Antipsychotic Drugs
Presentation/
6 20 minutes Contraindications of Antipsychotic Drugs
Brainstorming
228
SESSION CONTENTS

STEP 2: Dopamine Theory of Schizophrenia (20 minutes)

Pathophysiology of Schizophrenia
 Dopamine theory
o Schizophrenia is due to neurochemical disorder, this concept is advanced by the dopamine
theory of schizophrenia which gives evidence that schizophrenia is mainly due to excess
levels of dopamine in the CNS.
o Evidence supporting dopamine theory is shown below:
o There is excess dopamine activity in the mesolimbic system in schizophrenia.
o Antipsychotic potency is often proportional to D2-blocking potency.
o Amphetamine (which increases dopamine release) can produce acute psychosis that is
indistinguishable from acute schizophrenia (positive symptoms).
o D2 agonists (bromocriptine and apomorphine) aggravate schizophrenia in schizophrenic
patients.
o There is an increase in D2 and D4 receptors on PET in schizophrenic patients.
o L-Dopa can cause hallucinations and acute psychotic reactions and paranoia, but does not
cause all the features of these conditions.
o The majority of antipsychotics block dopamine receptors in the forebrain.
o However, about 30% of patients with schizophrenia respond inadequately to conventional
dopamine D2 receptor antagonists.
o This indicates that there are other neurotransmitters involved apart from dopamine.
o 5-Hydroxytryptamine is also implicated in schizophrenia.
o Glutamine hypoactivity, GABA hypoactivity and α-adrenergic hyperactivity are also
potential neurochemical targets.
STEP 3: Mechanism of Action of Antipsychotic Drugs (45 minutes)

 How do antipsychotics produce their pharmacological effects?

229
Conventional/Typical Antipsychotic drugs (First generation antipsychotics)
 Phenothiazine:
o Include chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine,
pipotiazine, pericyazine, prochlorperazine
o Conventional antipsychotics are antagonists at dopamine D2 receptors. It is the antagonism of
D2 receptors in the mesolimbic pathway that is thought to alleviate the positive symptoms of
schizophrenia.
o Blockade of D2 receptors in other pathways is believed to result in many of the side effects of
typical antipsychotics.
o The effect on D1 receptors is variable. Blockade of the D2 receptors induces extrapyramidal
effects.
o Repeated administration causes an increase in D2-receptor sensitivity due to an increase in
abundance of these receptors.
o This appears to underlie the tardive dyskinesias that are caused by prolonged use of the
conventional antipsychotic drugs.
o The choice of conventional drugs is largely determined by the demands of the clinical
situation, in particular the degree of sedation needed and the patients susceptibility to
extrapyramidal toxicity and hypotension.
o First-generation antipsychotics antagonize numerous other receptors, including adrenergic
and cholinergic as well as histamine H1 receptors.
o Although it is still unclear to what extent, if any, antagonism of these receptors contributes to
the efficacy of antipsychotics, they have a clear role in mediating many of the side effects
associated with these agents.
 Butyrophenones :
o Include Haloperidol, droperidol
o Butyrophenones are antagonists at dopamine D2 receptors. It is the antagonism of D2
receptors in the mesolimbic pathway that is thought to alleviate the positive symptoms of
schizophrenia. Blockade of D2 receptors in other pathways is believed to result in many of
the side effects of typical antipsychotics.
o Other actions are similar to phenothiazines.
 Thioxanthenes:
o Include Flupenthixol, thiothixene, zuclopenthixol
o Thioxanthenes are antagonists at dopamine D2 receptors. It is the antagonism of D2 receptors
in the mesolimbic pathway that is thought to alleviate the positive symptoms of
schizophrenia. Blockade of D2 receptors in other pathways is believed to result in many of
the side effects of typical antipsychotics.
o Other actions are similar to phenothiazines.
Atypical/Newer/ Antipsychotic drugs (Second generation antipsychotics)

 Clozapine, olanzapine, quetiapine, risperidone, paliperidone, ziprasidone and aripiprazole.
o In comparison to the conventional antipsychotics where potency is closely related to D2
receptor blockade, atypical antipsychotics bind less tightly to D2 receptors and have
additional pharmacological activity which varies with the drug. Efficacy against negative
230
symptoms, as well as less extrapyramidal side effects, are characteristic. These may be the
result of the transient (hit and run) binding to D2 receptors.
o The second-generation antipsychotics are believed to antagonize several different
receptors, primarily dopamine and serotonin (5-HT).
o Clozapine is the original atypical antipsychotic and is described below. Its use is
limited to resistant patients due to the risk of agranulocytosis.
o Features of clozapine are: D4 +5HT2 blockade; D1 >D2 blockade; α-adrenoceptor
blockade; effective in resistant patients; effective against negative and positive symptoms;
virtually free from extrapyramidal effects; agranulocytosis (3%) and severe postural
hypotension – initiate therapy under supervision.
STEP 4: Drug Interactions Associated with Antipsychotic Drugs (20

minutes)
 How do significant drug interactions of antopsychotics occur?

 Phenothiazine, Butyrophenones and Thioxanthenes
o Chlorpromazine and haloperidol are metabolized through CYP2D6 and CYP3A4,
fluphenazine through CYP2D6, and trifluoperazine through CYP1A2; therefore caution
should be exercised when using known inducers or inhibitors of these isozymes.
o Haloperidol is an inhibitor of CYP3A4. Fluphenazine inhibits CYP2D6.
o Conventional antipsychotics interacts with drugs below and the effect of interaction is as
shown:
o alcohol and other CNS depressants enhanced sedation; hypotensive drugs and anaesthetics
enhanced hypotension; increased risk of cardiac arrhythmias with drugs that prolong the
QT interval (e.g. amiodarone, sotalol); tricyclic antidepressants increased antimuscarinic
actions; metoclopramide increased extrapyramidal effects and akathisia; antagonism of
anti-Parkinsonian dopamine agonists (e.g. L-dopa) (these are in any case contraindicated in
schizophrenia).
231
Newer/Atypical Antipsychotic drugs (Second generation antipsychotics)
 Clozapine:
o Clozapine is metabolized by CYP450 enzyme system and its metabolism is affected by
notable inducers or inhibitors of the specific isozymes, such as the following:
o Inhibitors: erythromycin, cimetidine, azole antifungals, protease inhibitors, SSRIs
o Inducers: carbamazepine, phenytoin, rifampin, omeprazole, cigarette smoking
 Olanzapine:
o Olanzapine itself a weak CYP450 enzyme inhibitor, but it has not been shown to have
significant effects on other drugs.
o The metabolism of olanzapine has been affected by fluvoxamine which is an enzyme
inhibitor.
 Quetiapine:
o Inhibitors of quetiapine metabolism include: azole antifungals, macrolide antibiotics
o Inducers of quetiapine metabolism include: carbamazepine, phenytoin
 Risperidone:
o Inhibitors of risperidone metabolism include: fluoxetine, paroxetine
o Inducers of risperidone metabolism include: carbamazepine
STEP 5: Side Effects of Antipsychotic Drugs (20 minutes)

 Phenothiazine, Butyrophenones and Thioxanthenes
o Anticholinergic effects: include dry mouth, constipation, difficulty urinating, and loss of
accommodation.
o α-Antagonism: Orthostatic hypotension and ejaculatory failure may occur.
o H1 receptor blockade: Sedation is probably due to H1 receptor antagonism, and is more
common with the phenothiazines.
o Extrapyramidal syndrome (EPS): Blockade of dopamine receptors in the basal ganglia
leads to Parkinson-like symptoms such as slow movement (bradykinesia), stiffness, and
tremor.
o Tardive dyskinesia: Slow-developing, often permanent dyskinesia typically appears well
after initiation of therapy (months to years).
o This effect is characterized by repetitive, involuntary movements of the face, arms, and trunk.
o One theory is that D2 receptors become hypersensitive after prolonged blockade. It can be
very resistant to treatment.
o Hyperprolactinemia: Dopamine inhibits prolactin secretion.
o Antidopaminergic drugs will therefore have the potential to increase prolactin secretion,
resulting in the following: Amenorrhea (loss of menstrual period), galactorrhoea (production
of breast milk in women only, not in association with pregnancy), gynecomastia
(feminization of men) and decreased libido (sex drive).
232
o Neuroleptic malignant syndrome (NMS): Is a rare but life-threatening side effect. The
mechanism is not fully understood, but it is thought to be a result of inhibition of dopamine in
the hypothalamus, an area responsible for temperature regulation.
o The condition is characterized by: decreased or altered level of consciousness, increased
muscle tone (rigidity), fever, myoglobinemia and death, which occur in about 10% of these
cases and autonomic instability (variable heart rates and blood pressures).
o NMS responds to treatment with dantrolene (a ryanodine receptor antagonist that blocks
intracellular Ca2+ mobilization).
o Agranulocytosis: A decreased white blood cell count can occur as a result of antipsychotics.
o This will result in undesired immunosuppression and requires discontinuation of the drug.
o This effect is observed with chlorpromazine and other phenothiazines (<0.1% of patients).
o Cardiac conduction abnormalities: Such as long QT (thioridazine, droperidol) are a rare
but serious side effect that has led to the market withdrawal of these agents in some
jurisdictions.
o Antipsychotics appear to affect cardiac potassium channels, and these two agents are likely to
have a greater impact on these channels than other agents.
Newer/Atypical Antipsychotic drugs (Second generation antipsychotics)

 Clozapine, risperidone and all other second generation antipsychotics
o Increased mortality in elderly patients: These agents are associated with increased risk of
death in elderly patients with dementia, from a variety of causes, largely cardiovascular or
infectious. The mechanism is still unclear at this time.
o Endocrine:
o Weight gain occurs because of suppression of satiety and other factors. The receptor
responsible has not been established, although the focus is currently on H1.
o Exacerbation of diabetes, hyperglycemia: Diabetes (type 2) may simply be secondary to
weight gain, but these agents might also affect glucose transporters.
o Dyslipidemia is probably secondary to weight gain.
o Dopamine inhibits prolactin release, so dopamine blockade leads to increased prolactin
release.
o Neuroleptic malignant syndrome (NMS) is a rare but critically life-threatening effect seen
with both first- and second-generation antipsychotics. The mechanism is not fully
understood, but it is thought to be caused by inhibition of dopamine in the hypothalamus, an
area responsible for temperature regulation.
 Clozapine only:
o Agranulocytosis can be fatal and necessitates weekly or biweekly blood monitoring of all
patients taking clozapine.
o The risk is about 1% in the first 3 months and then decreases to about 0.01% after 1 year.
o Although agranulocytosis is a risk with all antipsychotics, it is much more common with
clozapine compared to other agents.
o Seizures may occur.
 Ziprasidone only:
233
o QT interval prolongation: As a class, the second-generation agents are considered to
prolong the QT interval; however, ziprasidone is the only member of this class in which
this adverse effect has led to consistent clinically relevant events.
STEP 6: Contraindications of Antipsychotic Drugs (10 minutes)
 What are the contraindications of Drugs acting on the CNS?


 Phenothiazine, Butyrophenones and Thioxanthenes :
o Severe CNS depression: Typical antipsychotics tend to have CNS depressant effects and
should be avoided in conditions of decreased level of consciousness.
Atypical/Newer/ Antipsychotic drugs (Second generation antipsychotics)

 Clozapine, olanzapine, quetiapine, risperidone, paliperidone, ziprasidone (All):
o History of neuroleptic malignant syndrome (see Side Effects)
 Clozapine:
o Myeloproliferative disorders are a contraindication because of the risk of agranulocytosis
with clozapine
o Liver disease or failure is a contraindication.
o Severe renal or cardiac disease:
o Paralytic ileus is a contraindication because of significant anticholinergic effects.
o Seizure disorders: Clozapine appears to lower the seizure threshold, thus promoting seizures.
 Ziprasidone:
o QT prolongation: Ziprasidone may prolong the QT interval and therefore should be avoided
in patients with a history of QT prolongation (see Side Effects).
o Ziprasidone should also be avoided in patients with recent significant cardiac events for this
reason.

 Conventional antipsychotics (e.g. chlorpromazine, haloperidol, fluphenazine), act
predominantly by D2 blockade.
234
 Atypical antipsychotics (e.g. clozapine, risperidone, olanzapine) are less likely to cause
extrapyramidal side effects.
 Although there may be a rapid behavioural benefit when antipsychotics are used, a delay
(usually of the order of weeks) in reduction of many symptoms implies secondary effects
(e.g. receptor up/downregulation).

 Why do first generation antipsychotics produce extra pyramidal symptoms?
 What are advantages of second generation compared to the first generation
antipsychotics?
 What are contraindications of phenothiazines?
235
References
Education.

236
Session 31: Pharmacodynamics of Drugs Used in Parkinson's
Disease
Prerequisites
Learning Tasks
 Describe mechanism of action of Drugs Used in Parkinson's Disease
 Describe drug interactions associated with Drugs Used in Parkinson's Disease
 Describe side effects of Drugs Used in Parkinson's Disease
 Describe contraindications of Drugs Used in Parkinson's Disease
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Drugs Used in
2 45 minutes
Buzzing Parkinson's Disease
3 20 minutes
brainstorming Used in Parkinson's Disease
Adverse Effects of Drugs Used in
Parkinson's Disease
Presentation/ Contraindications of Drugs Used in
5 20 minutes
Brainstorming Parkinson's Disease
237
SESSION CONTENTS

STEP 2: Mechanism of Action of Drugs Used in Parkinson's Disease (45

minutes)
 How do drugs Used in Parkinson's Disease produce their pharmacological effects?
 Parkinsonism is a progressive neurologic disorder of muscle movement, characterized by

tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary
movements), and postural and gait abnormalities.
 The cause of Parkinson's disease is unknown for most patients.
 The disease is correlated with a reduction in the activity of inhibitory dopaminergic
neurons in the substantia nigra and corpus striatum parts-of the brain's basal ganglia
system that are responsible for motor control.
Mechanisms of drugs used for treatement of Parkinsonism are:

Dopamine Precussors;
 Levodopa
o Levodopa is a metabolic precursor of dopamine.
o Cross blood brain barrier as it is readily taken up by the amino transport systems.
o It restores dopamine levels in the extrapyramidal centers (substantia nigra) that atrophy in
parkinsonism.
o Required in high doses because the drug is decarboxylated to dopamine in the periphery
by L-aromatic amino acid decarboxylase enzyme.
o Since Parkinsonism results from insufficient dopamine in specific regions of the brain,
attempts have been made to replenish the dopamine deficiency. Dopamine itself does not
238
cross the blood-brain barrier, but its immediate precursor levodopa is readily transported
into the CNS and is converted to dopamine in the brain
o Actions: Levodopa decreases rigidity, tremors and other symptoms of parkinsonism.
 Carbidopa
o The effects of levodopa on the CNS can be greatly enhanced by coadministering
carbidopa, a dopamine decarboxylase inhibitor that does not cross the blood-brain barrier.
o Carbidopa diminishes the metabolism of levodopa in the GI tract and peripheral tissues;
thus, it increases the availability of levodopa to the CNS.
o The addition of carbidopa lowers the dose of levodopa needed by 4- to 5- fold and,
consequently, decreases the severity of the side effects of peripherally formed dopamine.
Catechol-O-Methyl Transferase (COMT) Inhibitors:

 Entacapone and tolcapone
o COMT inhibitors increase the amount of dopamine available to the CNS. COMT is one
of the two major enzymes involved in the metabolism of catecholamines (epinephrine,
norepinephrine, and dopamine).
o Thus one of the ways COMT inhibitors increase dopamine is by inhibiting its breakdown.
Monoamine oxidase B inhibitors (MAO B) Inhibitors:

 Selegiline and Rasagiline
o Selectively inhibit MAO-B which metabolizes dopamine more efficiently than NE and 5-
HT. The net effect is an increase in brain dopamine levels. These drugs can be used in
conjunction with L-dopa.
o Because selegiline and rasagiline selectively inhibit MAO-B, they are much less likely to
produce a hypertensive reaction with cheese or other sources of tyramine than non-
selective MAOIs, such as phenelzine.
Dopamine Agonists:
 Bromocriptine
o The absorption and extent of first-pass metabolism of bromocriptine is highly variable,
leading to wide fluctuations in plasma concentrations and variability in dose response.
o Dopamine agonists bind to dopamine receptors to produce actions similar to dopamine.
o The dopamine agonists used in Parkinsons disease have longer durations of action than
L-dopa. Cabergoline, an agent not used for Parkinsons disease, has an exceptionally
long elimination half-life (approximately 100 hours).
o Other dopamine agonist include cabergoline, pergolide, pramipexole, ropinirole
Drugs that increase dopamine release:

 Amantadine
o A tricyclic amine used in prophylaxis of Influenza A virus.
o Increase the release of dopamine from surviving neurons
o It may also reduce dopamine reuptake
o Have anticholinergic effects too
239
o Use with L-dopa in patients who cant tolorate L-dopa or who dont respond to L-dopa
therapy well.
Antimuscarinics:
 Trihexyphenidyl, benzatropine, orphenadrine, procyclidine
o Non-selective muscarinic receptor antagonism is believed to restore, in part, the balance
between dopaminergic/cholinergic pathways in the striatum.
o Muscarinic antagonists are effective in the treatment of parkinsonian tremor and to a
lesser extent rigidity, but produce only a slight improvement in bradykinesia.
STEP 3: Drug Interactions Associated with Drugs Used in Parkinson's

Disease (20 minutes)
 How do significant drug interactions of Drugs used in Parkinson's disease occur?
Dopamine precursors :
 Levodopa
o The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and
diminishes its effectiveness.
o Concomitant administration of levodopa and monoamine oxidase (MAO) inhibitors, such
as phenelzine can produce a hypertensive crisis caused by enhanced catecholamine
production; therefore, caution is required when they are used simultaneously.
o In many psychotic patients, levodopa exacerbates symptoms, possibly through the
buildup of central amines (an increase in dopamine levels).
o In patients with glaucoma, the drug can cause an increase in intraocular pressure.
o Cardiac patients should be carefully monitored because of the possible development of
cardiac arrhythmias.
240
Monoamine oxidase B inhibitors (MAO B) Inhibitors:
 Selegiline and Rasagiline
o At very high doses (six times the therapeutic dose), MAO-B selectivity is lost and pressor
responses to tyramine are potentiated. Hypertensive reactions to tyramine-containing
products (e.g. cheese or yeast extract) have been described, but are rare.
o Amantadine and centrally active antimuscarinic agents potentiate the anti-parkinsonian
effects of selegiline.
STEP 4: Adverse Effects of Drugs Used in Parkinson's Disease (20

minutes)
Dopamine precursors :
 Levodopa
o Large doses of levodopa are required because much of the drug is decarboxylated to
dopamine in the periphery resulting in peripheral side effects (nausea, vomiting, cardiac
arrhythmias, hypotension).

o Dopamine-related effects include dyskinesia (peak dose), vivid dreams, hallucinations,
nausea, hypotension.
o Abdominal pain may occur.
o Diarrhea may occur.
o Discoloration of urine is caused by the chemical structure of the drug and occurs only in
alkaline urine.
o The side effect is harmless, but patients should be warned of the dark yellow or reddish
brown tinge.
o Hepatotoxicity: observed only with tolcapone so far
Dopamine Agonists:
 Bromocriptine and others
o Ropinirole and pramipexole: Sudden sleep onset occurs without warning and poses a
potential risk for activities requiring attention, such as driving. This may be a class effect
but has been confirmed with ropinirole and pramipexole.
241
STEP 5: Contraindications of Drugs Used in Parkinson's Disease (10
minutes)
 What are the contraindications of Drugs used in Parkinson's disease?


o Concomitant use with nonselective MAOIs: This includes the use of an MAO-A and an
MAO-B inhibitor in combination.
o The MAO pathway becomes the key metabolic route for epinephrine and norepinephrine
in the presence of COMT blockade.
o There should be at least a 2-week washout before initiation of treatment with a COMT
inhibitor.
o Caution should also be exercised in patients on MAO-B selective inhibitors, as these
become nonselective at higher doses.
o History of neuroleptic malignant syndrome and/or non-traumatic rhabdomyolysis is a
contraindication.
o Liver impairment is a contraindication because of hepatotoxicity seen with tolcapone.
o Pheochromocytoma is a contraindication because of increased risk of hypertensive crisis.
Dopamine Agonists:
 Bromocriptine and others
o Pramipexole, Ropinirole: Caution should be exercised when driving or engaging in other
activities that require alertness, because of the potential for sudden onset of sleep (see
Side Effects).

 Drugs for parkinsonism aim at ensuring proper action of dopamine in the CNS
 Drugs for parkinsonism are associated with adverse events
 Non pharmacological approaches are also important in parkinsonism
242
 What is the mechanism of action of levodopa?
 What are contraindications of Entacapone?
 What are adverse effects of bromocriptine?
243
References
Education.

244
Session 32: Pharmacodynamics of Antidepressants
Prerequisites
Learning Tasks
 Explain pathophysiology of depression
 Describe mechanism of action of Antidepressants
 Describe drug interactions associated with Antidepressants
 Describe side effects of Antidepressants
 Describe contraindications of Antidepressants
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
15minutes Presentation Pathophysiology of depression

Presentation/
2 45 minutes Mechanism of Action of Antidepressants
Buzzing
3 20 minutes
brainstorming Antidepressants
4 20 minutes Presentation Side Effects of Antidepressants
Presentation/
5 20 minutes Contraindications of Antidepressants
Brainstorming
245
SESSION CONTENTS

STEP 2: Pathophysiology of Depression (20 minutes)
 Monoamine theory of depression suggest that depression is due to a cerebral deficiency of

monoamines particularly noradrenaline (NA), 5-hydroxytryptamine (5HT) and
methyltyrosine.
 The following actions of drugs support the above theory: Reserpine -depletes neuronal
stores of noradrenaline (NA) and 5-hydroxytryptamine (5HT) and α-methyltyrosine,
which inhibits NA synthesis causing depression, Tricyclic antidepressants (TCA) of the
amitriptyline type (which raise the synaptic concentration of NA and 5HT) are
antidepressant and Monoamine oxidase inhibitors (MAOIs, which increase total brain NA
and 5HT) are antidepressant.
 Another theory of depression is the serotonin-only hypothesis.
o This theory emphasizes the role of 5HT and downplays that of NA in the
causation of depression, and is backed by the effectiveness of the selective
serotonin reuptake inhibitors, or SSRI class of drugs, in the treatment of
depression.
STEP 3: Mechanism of Action of Antidepressants (45 minutes)
 How do antidepressants produce their pharmacological effects?
 Tricyclic Antidepressants (TCAs)

Examples include amitriptyline, desipramine, imipramine, nortriptyline, clomipramine,
trimipramine, doxepin, maprotiline
246
o The monoamine hypothesis suggests that depression is caused by a deficiency of synaptic
neurotransmitters such as serotonin (5-HT), NA, and dopamine. Serotonin, in particular,
is associated with mood.
o Normally, 5-HT and NA are released from presynaptic vesicles into the synaptic cleft,
where they travel to postsynaptic receptors.
o Once released from these postsynaptic receptors, 5-HT and NA are removed from the
synaptic cleft by reuptake transporters located on the presynapse.
o The TCAs inhibit the reuptake of serotonin (5-HT) and NA into the presynaptic cell body,
increasing the amount of 5-HT and NA available to bind to postsynaptic receptors.
o TCAs antagonize other receptors: muscarinic, histamine (H1), adrenergic (α1) receptors.
This accounts for their extensive list of side effects.
 Selective Serotonin Reuptake Inhibitors (SSRIs)

Examples include fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and
escitalopram.
o The monoamine hypothesis suggests that depression is caused by a deficiency of synaptic
neurotransmitters such as serotonin (5-HT), norepinephrine, and dopamine. Serotonin, in
particular, is associated with mood.
o Normally, 5-HT is released from presynaptic vesicles into the synaptic cleft, where it
travels to postsynaptic receptors.
o Once released from these postsynaptic receptors, 5-HT is removed from the synaptic cleft
by reuptake transporters located on the presynapse. Once it is taken up presynaptically, it
is degraded.
o SSRIs bind to this reuptake transporter, preventing the removal of 5-HT and leading to
increased 5-HT available to bind to postsynaptic receptors.
 Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)

Examples include venlafaxine, desvenlafaxine, duloxetine and milnacipran
o Once released from these postsynaptic receptors, 5-HT and NA are removed from the
synaptic cleft by reuptake transporters located on the presynapse. Once they are taken up
presynaptically, they are degraded.
o SNRIs bind to these reuptake transporters, preventing the removal of 5-HT and NA and
leading to increased availability to bind to postsynaptic receptors.
o Venlafaxine has much higher affinity for the serotonin reuptake transporter, and at low
doses acts more like an SSRI. It is not until higher doses are used that it also blocks
noradrenaline reuptake.
o Conversely, milnacipran blocks serotonin and noradrenaline reuptake equally, whereas
the other agents in this class fall somewhere between these two.
 Monoamine oxidase Inhibitors (MAOIs)

Examples include :Selective to MAO-B: Selegiline, rasagiline, Selective to MAO-A:
Moclobemide and Nonselective inhibitors: phenelzine and tranylcypromine
247
o MAO degrades catecholamines, serotonin, and other endogenous amines in the CNS
as well as in the periphery.
o There are two key isoenzymes: MAO-A which degrades epinephrine,
norepinephrine, and serotonin and MAO-B which degrades phenylethylamine. Both
degrade dopamine.
o The purpose of MAO inhibition is therefore to increase levels of these substances
within the body, specifically the CNS. The efficacy of these agents is a result of their
actions within the CNS, whereas the side effects are largely mediated by their actions
outside of the CNS.
 Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs)

Examples include: Mirtazapine
o Mirtazapine increases noradrenergic and serotonergic neurotransmission via central
α2 adrenoceptors.
o The increased release of 5HT stimulates 5HT1 receptors, whilst 5HT2 and 5HT3
receptors are blocked. H1 receptors are also blocked.
o This combination of actions appears to be associated with antidepressant activity,
anxiolytic and sedative effects.
STEP 4: Drug Interactions Associated with Antidepressants (20 minutes)
 How do significant drug interactions of antidepressants occur?

Examples include amitriptyline, desipramine, imipramine, nortriptyline and others.
o Most TCAs exhibit some degree of CP450 enzyme inhibition.
o The most prominent inhibitors are amitriptyline, imipramine, clomipramine, and doxepin,
mainly at CYP2C19.
Examples include fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and others.
o The SSRIs inhibit multiple CYP450 isozymes.
248
o Fluoxetine and paroxetine inhibit the CYP2D6 isoenzyme, and this can lead to clinically
important drug interactions with drugs such as tricyclic antidepressants (TCAs),
carbamazepine, or vinblastine.
o There is also a very serious interaction with thioridazine (see Contraindications).
Examples include: venlafaxine, desvenlafaxine, duloxetine, milnacipran
o Duloxetine and (to a lesser extent) venlafaxine are inhibitors of CYP2D6.
o Hypertensive crisis occurs because of a drug-drug or drug-food interaction, leading to
increased levels of norepinephrine and subsequent rapid elevation in blood pressure.
Before the triggering factors (tyramine-rich foods) were identified, this interaction limited
the utility of these agents.
STEP 5: Side Effects of Antidepressants (20 minutes)

Examples include amitriptyline, desipramine, imipramine, nortriptyline and others.
o Anticholinergic: Dry mouth, Confusion, Urinary retention, Constipation, Blurred vision
and increased intraocular pressure (IOP).
o Sedation: via blockade of histamine (H1) receptors.
o Serious Cardiovascular toxicities: are typically only seen when high doses are
administered (see Important Notes). In high doses TCAs impair cardiac conduction,
leading to a widening of the QRS complex and heart block, often accompanied by
hypotension.
o Orthostatic hypotension: related to blockade of α1 receptors.

Examples include fluoxetine, fluvoxamine, paroxetine, sertraline and others.
o Serotonin syndrome (SS) is a rare but potentially life-threatening elevation in serotonin,
most commonly caused by concomitant use of SSRIs and MAOIs.
o Symptoms include: Hyperthermia, muscle rigidity, myoclonus, rapid fluctuations in vital
signs (because of autonomic instability) and rapid fluctuations in mental status
(confusion, irritability, extreme agitation, delirium, and coma).
o Sexual dysfunction may be both mechanical, as serotonin inhibits functions such as
erections, ejaculation, lubrication, and orgasm, and central, as serotonin has an inhibitory
effect on dopamine, a neurotransmitter believed to play an important role in arousal.
Note: sexual dysfunction can also accompany depression.
o Gastrointestinal (GI) distress: Serotonin receptors are also found in the gut, and serotonin
appears to have an effect on GI motility (cramping, diarrhoea, nausea) that becomes
intolerable in some patients. Nausea and vomiting are also likely mediated by activation
of serotonin receptors in the CNS.
249
o Agitation, insomnia: These effects are likely via stimulation of central serotonin
receptors.
o The intensity of this side effect can vary among the SSRI. In some cases, these side
effects can be somewhat beneficial in patients who have fatigue or apathy and
hypersomnia.
 Examples include: venlafaxine, desvenlafaxine, duloxetine, milnacipran
o Gastrointestinal (GI) distress, attributed to inhibition of serotonin reuptake, appears to be
most common with venlafaxine.
o Stimulation of serotonin receptors in the brain likely mediates nausea. Serotonin receptors
are also found in the gut, and serotonin appears to have an effect on GI motility that
becomes intolerable in some patients, leading to cramping and diarrhoea.
o Dizziness may occur although the mechanism is unknown.
o Somnolence may be secondary to sleep disturbances, although the mechanism is
unknown.
o Insomnia may occur due to stimulation of 5-HT receptors in the CNS. Both the length and
quality of sleep may be impaired.
o Sexual dysfunction, attributed to inhibition of serotonin reuptake, appears to be most
common with venlafaxine.
o It may be both mechanical, as serotonin inhibits functions such as erections, ejaculation,
lubrication, and orgasm, and central, as serotonin has an inhibitory effect on dopamine, a
neurotransmitter believed to play an important role in arousal.
o Sweating: The mechanism for this effect has not been established.
o Dry mouth is likely caused by NA.
o Sustained hypertension is dose related. The elevation in blood pressure is likely caused by
the pressor effects of increased NA. Patients should have blood pressure monitored.
o Sleep disturbances include insomnia.
o The insomnia is likely a central stimulatory effect from the increased monoamines,
although a mechanism has not been established. Moclobemide, a reversible and selective
MAO-A inhibitor, may cause fewer problems with sleep.
o Weight gain is a common side effect of antidepressants; likely, increased monoamines
play a role, but the mechanism has not been established.
o Postural hypotension: The mechanism has not been established. This can be problematic
in elderly patients, leading to falls.
o Sexual disturbances: Might be due to enhanced serotonin activity resulting to sexual
dysfunction with these agents.
250
 Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs)
Examples include: Mirtazapine
o Sedation occurs because of blockade of histamine receptors. It tends to predominate at
lower doses, as increasing NA at higher doses counteracts this effect.
o Increased appetite may be due to H1 antagonism, although the mechanism is unclear.
Weight gain may be due to H1 antagonism
STEP 6: Contraindications of Antidepressants (10 minutes)
 What are the contraindications of antidepressants?


o Avoid concomitant use of TCAs and MAOIs: TCAs increase serotonin concentrations in
the synapse, whereas MAOIs inhibit the breakdown of serotonin.
o Concomitant use can therefore lead to excessive serotonin.
o When switching from a TCA to an MAOI, or vice versa, allow for a washout period of at
least 2 weeks.

o SSRIs and monoamine oxidase inhibitors (MAOIs): SSRIs increase serotonin
concentrations in the synapse, whereas MAOIs inhibit the breakdown of serotonin.
Concomitant use can therefore lead to excessive serotonin (see details in Side Effects).
When switching from an SSRI to an MAOI, or vice versa, allow for a washout period of
at least 1 to 2 weeks.
o SSRIs and thioridazine (an antipsychotic): Thioridazine elicits QT interval
prolongation, and fluoxetine in particular enhances this effect by inhibiting the
metabolism of thioridazine.
o A washout period of at least 5 weeks should elapse before someone who was on
fluoxetine should be started on thioridazine, and fluoxetine should not be initiated for at
least 2 weeks after discontinuation of thioridazine.
o The seriousness of these drug interactions has led to the withdrawal of thioridazine in
many markets.
251
o Citalopram and pimozide: The combination of these two agents is associated with a
greater risk of QT interval prolongation, although the mechanism is unknown.
 Examples include: venlafaxine, desvenlafaxine, duloxetine, milnacipran
o SNRIs and MAOIs: MAOIs inhibit the breakdown of serotonin. Concomitant use can
therefore lead to excessive serotonin. When switching from an SNRI to an MAOI, or vice
versa, allow for a washout period of at least 1 to 2 weeks.
 Examples include :Selective to MAO-B: Selegiline, rasagiline, Selective to MAO-A:
o MAOI with sympathomimetics: nonselective MAOIs may potentiate the hypertensive
effects of sympathomimetics, leading to a hypertensive crisis that can be fatal.
Methylphenidate, dopamine, epinephrine, norepinephrine, and similar agents
(methyldopa, l-dopa, l-tryptophan, l-tyrosine, and phenylalanine) should be avoided.
o Foods with tyramine: See interactions of MAOIs

 The choice is usually related to the side-effect profile of relevance to the particular
patient.
 Tricyclic antidepressants commonly cause antimuscarinic and cardiac effects.
 Tricyclic antidepressants tend to increase appetite and weight, whereas SSRIs more
commonly reduce appetite and weight.
 SSRIs are associated with nausea, sexual dysfunction and sleep disturbance.

 What are the contraindications of TCAs?
 What are side effects of MAOIs?
 Why are MAOIs not preferred in patients consuming tyramine containing foods?What are
the main catecholamines deficient in depression?
252
References
Education.

253
Session 33: Pharmacodynamics of Drugs for Heart Failure
Prerequisites
Learning Tasks
 Describe mechanism of action of drugs for heart failure
 Describe drug interactions associated with drugs for heart failure
 Describe side effects of drugs for heart failure
 Describe contraindications of drugs for heart failure
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Drugs for Heart
2 45 minutes
Buzzing Failure
Presentation/ Drug Interactions Associated Drugs for Heart
3 20 minutes
brainstorming Failure
4 20 minutes Presentation Side Effects of Drugs for Heart Failure
Presentation/
5 20 minutes Contraindications of Drugs for Heart Failure
Brainstorming
254
SESSION CONTENTS

STEP 2: Mechanism of Action of Drugs for Heart Failure (45 minutes)
 How do Drugs for Heart Failure produce their pharmacological effects?
 Drugs For Heart Failure

 Diuretics
o For more information on adverse effects, interactions , contraindications and mechanism
refer a session on Pharmacodynamics of drugs acting on urinal genital system
o In Chronic heart failure: a diuretic is used to control symptomatic oedema and dyspnoea
in patients with heart failure.
o Spironolactone improves survival in patients with cardiac failure and counters diuretic-
induced hypokalaemia.
o Diuretic-induced hypokalaemia increases the toxicity of digoxin. Conversely,
spironolactone and other K+-retaining diuretics (e.g. amiloride, triamterene) can cause
severe hyperkalaemia, especially if given with ACEI or sartans to patients with renal
impairment.
o It is therefore important to monitor plasma K+ during treatment with all diuretic therapy.
 Angiotensin-Converting Enzyme Inhibitors
refer a session on Pharmacodynamics of drugs acting on urinal genital system (session )
and Pharmacodynamics of Antihypertensive drugs(session )
o When symptoms are mild, diuretics can be temporarily discontinued a day or two before
starting an ACEI, reducing the likelihood of first-dose hypotension.
 Angiotensin Receptor Antagonists, Sartans
255
o For more information on adverse effects, interactions, contraindications and mechanism
refer a session on Pharmacodynamics of Pharmacodynamics of Antihypertensive drugs
(session).
o As in hypertension, the pharmacodynamics of sartans are similar to those of ACEI apart
from a lower incidence of some adverse effects, including, particularly, dry cough.
 Beta blockers
refer a session on Pharmacodynamics of Antihypertensives
o Beta-blockers are negative inotropes and so intuitively would be expected to worsen heart
failure.
o There is, however, a rationale for their use in terms of antagonizing counter regulatory
sympathetic activation and several randomized controlled trials have demonstrated
improved survival when a β-adrenoceptor antagonist is added to other drugs, including an
ACEI.
 Digoxin
o Inotropic action: Through the action of Na/K/ATP ion pump blockade, the following
sequence of ionic events occurs:
o ↓ Na exits the cell
o ↑ Intracellular Na
o ↓ Na electrochemical gradient for Na-Ca exchanger
o ↓ Ca exits the cell
o ↑ Intracellular Ca
o The increase in intracellular calcium results in increased contractility, SV, and CO.
o In heart failure, sympathetic tone is increased as a compensatory mechanism to increase
CO.
o Digoxin increases contractility and hence SV and CO, therefore reducing the need for
sympathetic compensation; thus digoxin reduces the sympathetic tone in heart failure.
 Beta1-Adrenergic Agonists: Dobutamine ,Dopamine, Amrinone and Milrinone
o Improves cardiac performance by their positive inotropic effects and vasodilatation ((β-
2), minimum effects on HR by dobutamine)
o Increase in intracellular cAMP → results in the entry of Ca2+ into the myocardial cells
increases, thus enhancing contraction
o Diminished effects after long-time infusions and possible worsening upon withdrawal
o Ibopamine which is a pro-drug and has actions at β-1, β-2, D1 and D2 is not preferred
because of the non-selectivity hence increased toxicity.
 Glucagon
o Glucagon increases cyclic AMP thus increasing myocardial contraction hence used in
acute cardiac dysfunction due to overdose of β-blockers
 Inhibitors of Phosphodiesterase III
o Inhibitors of phosphodiesterase III which is specific to the heart and responsible for
degradation of cyclic AMP thus increase myocardial contractility are also used.
256
STEP 3: Drug Interactions Associated With Drugs for Heart Failure (20
minutes)
 How do significant drug interactions of Drugs for Heart Failure occur?

o Important drugdrug interactions can occur with NSAIDs, which may cause renal failure
and severe hyperkalaemia, especially in heart failure patients treated with ACEI.
 Digoxin
o Certain drug interactions increase digoxin levels. These include; diuretics such as
spironolactone, amiloride and triamterene, antiarrhythmics mainly quinidine and
amiodarone, calcium antagonists verapamil only and HMG-CoA reductase inhibitors
mainly atorvastatin at high doses (80 mg daily).
o Corticosteroids thiazide diuretics and loop diuretics increase digoxin toxicity because
they decreased blood levels of potassium.
o Calcium channel blockers, Beta blockers and class 1A antidsyrhythmics increase
cardiotoxicity caused by digoxin because these drugs also have positive ionotropic effect.
o Amiodarone, Erythromycin, Quinidine, Tetracycline and Verapamil which inhibit
cytochrome P450 isoenzymes may increase digoxin concentration during concurrent
therapy
STEP 4: Adverse Effects of Drugs for Heart Failure (20 minutes)

o Hypotension is more of a problem when starting treatment in heart failure patients
than when treating hypertension, especially with short-acting drugs (e.g. captopril).
o Not only is the blood pressure lower to start with, but concentrations of circulating
renin are high and increased further by diuretics. ACEI cause first-dose
hypotension most severely in patients with the greatest activation of the
reninangiotensin system.
257
o These are consequently those most likely to benefit from an ACEI in the long term.
Long-acting drugs (e.g. ramipril, trandolapril) cause less first-dose hypotension and
can be given once daily.
o ACEI are usually well tolerated during chronic treatment, although dry cough is
common and occasionally unacceptable apart from a lower incidence of some adverse
effects, including, particularly, dry cough.
 Beta blockers
o Intolerance Fatigue and cold extremities are common and dose related.
o Erectile dysfunction occurs, but is less common than with thiazide diuretics.
o Central nervous system (CNS) effects (e.g. vivid dreams) can occur.
o Airways obstruction β-adrenoceptor antagonists predispose to severe airways
obstruction in patients with pre-existing obstructive airways disease, especially
asthma.
o Peripheral vascular disease and vasospasm β-adrenoceptor antagonists worsen
claudication in patients with symptomatic atheromatous peripheral vascular disease
and worsen Raynaud’s phenomenon.
o Hypoglycaemia β-adrenoceptor antagonists mask symptoms of hypoglycaemia, and
slow the rate of recovery from it, because adrenaline stimulates gluconeogenesis via
β2-adrenoceptors.
o Heart block
 Digoxin
o The therapeutic index is very low.
o The therapeutic range for digoxin is 0.5 to 2.5 nmol/L (in the blood). The probability
of toxicity is significant when the level is > 2.6.
o Children experience less toxicity than adults and have a higher therapeutic range (2.5
to 3.5).
o It is estimated that 20% of patients taking digoxin will experience toxicity.
o Clearance is via the kidneys.
o Renal dysfunction increases the elimination half-time, which increases digoxin levels
and increases the risk of toxicity. The dose must be reduced accordingly.
o Factors that increase digoxin sensitivity (and thus increase toxicity risk) include
Hypokalemia (most common cause), Hypercalcemia (less common),
Hypomagnesemia (less common), Hypothyroidism and Hypoxia or acidosis.
o Adverse effects (Toxicity) sign and symptoms include:
o GI: Nausea, vomiting, diarrhoea, abdominal pain and anorexia (loss of appetite)
o CNS: Confusion, dizziness, and agitation
o Cardiovascular: Arrhythmias and heart block
o Visual: Orange tinted vision, visual disturbances
o Increased automaticity occurs.
o Atrial or ventricular dysrhythmias such as premature atrial contractions (PACs),
premature ventricular contractions (PVCs), atrial or ventricular tachycardia can
occur.
258
o Treatment is to stop giving the drug for a short period, or, if there are severe
cardiac arrhythmias, an antibody called Digibind can be given; Digibind binds
digoxin and increases the rate of clearance
STEP 5: Contraindications of Drugs for Heart Failure (10 minutes)
 What are the contraindications of an Drugs for Heart Failure ?


 Diuretics
o Refer lecture on Pharmacodynamics of Drugs acting on Genital urinal system and
Pharmacodynamics of Antihypertensive drugs
o Refer lecture on Pharmacodynamics of Drugs acting on Genital urinal system and
Pharmacodynamics of Antihypertensive drugs
 Digoxin
o Care must be exercised when prescribing to patients at risk for toxicity

 Treatment of heart failure involves also non pharmacological approaches
 drugs used in heart failure act through different mechanisms
 Significant drug interactions occur when drugs for heart failure are used concomitantly
with other drugs

 What are the adverse effects of digoxin?
 How is digoxin toxicity treated/ controlled?
 What is the mechanism of action of digoxin?
259
References
Education.

260
Session 34: Pharmacodynamics of Antihypertensive Drugs
Prerequisites
 PST04211_S17_ Description of Antihypertensive Drugs
Learning Tasks
 Describe mechanism of action of Antihypertensive Drugs
 Describe drug interactions associated with Antihypertensive Drugs
 Describe side effects of Antihypertensive Drugs
 Describe contraindications of Antihypertensive Drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/ Mechanism of Action of Antihypertensive
2 45 minutes
Buzzing Drugs
3 20 minutes
brainstorming Antihypertensive Drugs
4 20 minutes Presentation Side Effects of Antihypertensive Drugs
Presentation/ Contraindications of Antihypertensive
5 20 minutes
Brainstorming Drugs
261
SESSION CONTENTS

STEP 2: Mechanism of Action of Antihypertensive Drugs (45 minutes)
 How do antihypertensive drugs produce their pharmacological effects?
 Antihypertensives
 Angiotensin-Converting Enzyme Inhibitors(ACEI)
o These drugs block the enzyme that cleaves angiotensin I to form the potent
vasoconstrictor, angiotensin II.
o ACEI lower blood pressure by reducing angiotensin II and perhaps also by increasing
vasodilator peptides, such as bradykinin by diminishing their inactivation.
o Angiotensin II causes aldosterone secretion from the zona glomerulosa of the adrenal
cortex and inhibition of this contributes to the antihypertensive effect of ACE inhibitors
because of decreased sodium and water retention.
 Beta blockers
o Β-Adrenoceptor antagonists reduce cardiac output (via negative chronotropic and
negative inotropic effects on the heart).
o These drugs also inhibit renin secretion and some have additional central actions reducing
sympathetic outflow from the central nervous system (CNS).
 Angiotensin receptor blockers
o Most of the effects of angiotensin II, including vasoconstriction and aldosterone release,
are mediated by the angiotensin II subtype 1 (AT1) receptor.
o These drugs block the AT1 receptors thus blocking Angiotensin II actions/effects.
 Calcium Channel blockers
262
o Calcium-channel blockers inhibit Ca2+ influx through voltage-dependent L-type calcium
channels. Cytoplasmic Ca2+ concentrations control the contractile state of actomyosin.
o Calcium-channel blockers therefore relax arteriolar smooth muscle, reduce peripheral
vascular resistance and lower arterial blood pressure.
 Diuretics
o Thiazide Diuretics: Thiazide diuretics inhibit reabsorption of sodium and chloride ions in
the proximal part of the distal convoluted tubule.
o Excessive salt intake or a low glomerular filtration rate interferes with their
antihypertensive effect. Natriuresis is therefore probably important in determining their
hypotensive action.
 α-Adrenoceptor antagonists
o There are two main types of α-adrenoceptor, α1- and α2.
o Noradrenaline activates α1-receptors on vascular smooth muscle, causing tonic
vasoconstriction. α1-Antagonists cause vasodilatation by blocking this tonic action of
noradrenaline hence α1-Adrenoceptor antagonists lower blood pressure.
o Prazosin, doxazosin and other alpha 1 receptor blockers decrease peripheral vascular
resistance and lower arterial blood pressure by causing the relaxation of both arterial and
venous smooth muscle.
o These drugs cause only minimal changes in cardiac output, renal blood flow, and
glomerular filtration rate.
 Centrally acting drugs
o Methyldopa: after uptake into central neurones and methyldopa is metabolised to a false
transmitter (α-methylnoradrenaline) which is an α2-adrenoceptor agonist.
o Activating central α2-adrenoceptors by the false transmitter inhibits sympathetic outflow
from the CNS.
o Moxonidine is another centrally acting drug: it acts on imidazoline receptors and is said to
be better tolerated than methyldopa.
 Other vasodilators
o Minoxidil: works via a sulphate metabolite which activates potassium channels. This
relaxes vascular smooth muscle, reducing peripheral vascular resistance and lowering
blood pressure.
o Nitroprusside: It is a rapid acting inorganic nitrate which degrades to NO relaxes blood
vessels hence reduced blood pressure.
STEP 3: Drug Interactions Associated With Antihypertensive Drugs (20

minutes)
 How do significant drug interactions of antihypertensives occur?

263
 Angiotensin Converting Enzyme Inhibitors
o ACEI interaction with Diuretics:
o Diuretic treatment increases plasma renin activity and the consequent activation of
angiotensin II and aldosterone thus limiting efficacy of ACEIs.
o ACE inhibition interrupts the loop and thus enhances the hypotensive efficacy of
diuretics, as well as reducing thiazide-induced hypokalaemia.
o Conversely, ACEI have a potentially adverse interaction with potassium-sparing
diuretics and potassium supplements, leading to hyperkalaemia, especially in patients
with renal impairment.
o As with other antihypertensive drugs, NSAIDs increase blood pressure in patients
treated with ACE inhibitors.
 Beta Blockers
o Pharmacokinetic interactions:
o β-adrenoceptor antagonists inhibit drug metabolism indirectly by decreasing hepatic
blood flow secondary to decreased cardiac output.
o This causes accumulation of drugs such as lidocaine that have such a high hepatic
extraction ratio that their clearance reflects hepatic blood flow.
o Pharmacodynamic interactions:
o Increased negative inotropic and atrioventricular (AV) nodal effects occur with
verapamil (giving both intravenously can be fatal), lidocaine and other negative
inotropes.
 Calcium channel blockers
o Intravenous verapamil can cause circulatory collapse in patients treated concomitantly
with β-adrenoceptor antagonists.
 Diuretics
o Diuretics exhibit a non-specific adverse interaction with NSAIDs,
o All diuretics interact with lithium. Li + is similar to Na+ in many respects, and is
reabsorbed mainly in the proximal convoluted tubule.
o Diuretics indirectly increase Lireabsorption in the proximal tubule, by causing volume
contraction.
o This results in an increased plasma concentration of Liand increased toxicity.
o Diuretic-induced hypokalaemia and hypomagnesaemia increase the toxicity of
digoxin.
264
o Combinations of a thiazide with a potassium-sparing diuretic, such as amiloride,
triamterene or spironolactone can prevent undue hypokalaemia, and are especially
useful in patients who require simultaneous treatment with digoxin, sotalol or other
drugs that prolong the electrocardiographic QT-interval.
STEP 4: Side Effects of Antihypertensive Drugs (20 minutes)

 Angiotensin Converting Enzyme Inhibitors :
o ACE inhibitors are generally well tolerated. Adverse effects include:
o First-dose hypotension.
o Dry cough this is the most frequent symptom (530% of cases) during chronic
dosing.
o It is often mild, but can be troublesome.
o The cause is unknown, but it may be due to kinin accumulation stimulating cough
afferents.
o Sartans do not inhibit the metabolism of bradykinin and do not cause cough.
o Functional renal failure this occurs predictably in patients with haemodynamically
significant bilateral renal artery stenosis, and in patients with renal artery stenosis in
the vessel supplying a single functional kidney.
o Hyperkalaemia is potentially hazardous in patients with renal impairment and great
caution must be exercised in this setting.
o This is even more important when such
patients are also prescribed potassium supplements and/or potassium-sparing
diuretics.
o Fetal injury ACEI cause renal agenesis/failure in the foetus, resulting in
oligohydramnios. ACEI are therefore contraindicated in pregnancy and other drugs
are usually preferred in women who may want to start a family.
o Urticaria and angio-oedema increased kinin concentration may explain the
urticarial reactions and angioneurotic oedema sometimes caused by ACEI.
o Sulphhydryl group-related effects high-dose captopril causes heavy proteinuria,
neutropenia, rash and taste disturbance, attributable to its sulfhydryl group.
 Beta Blockers :
o Hypotension: β-Blockers are negative chronotropes and inotropes.
o CHF: β-Blockers are negative inotropes.
o Asthma and bronchoconstriction: Nonselective β-blockers block β2 receptors in the
airways.
o Bradycardia and heart block: The SA and AV nodes are under adrenergic influence.
o Raynaud’s phenomenon: Cold extremities (fingers in particular) may result from
antagonism of β2 receptors, leading to vasoconstriction in the periphery.
o Impotence: Erectile function is dependent on changes in blood flow and vasodilation
in the corpora cavernosa, and these mechanisms can be blocked by β-blockers.
265
o Fatigue: This is likely a result of the reduction in CO.
o Hypoglycemia: Nonselective β-blockers may interfere with recovery from
hypoglycemia in type 1 (insulin-dependent) diabetes, as they antagonize the ability of
catecholamines to promote glycogenolysis and mobilize glucose.
o Also, in diabetics, the β-blockade prevents symptoms caused by hypoglycemia and so
masks early mild hypoglycemia, which can then deteriorate.
o CNS effects: Insomnia, nightmares, and depression are side effects.
o The mechanism is not well understood, but in theory these effects should occur more
frequently with lipophilic drugs that cross the blood-brain barrier, such as propranolol
and metoprolol.
o Lipid profiles: β-Blockers (except partial agonists) increase triglyceride levels and
reduce high-density lipoprotein (HDL), without changing total cholesterol.
o The long-term effects of these changes are not known.
 Angiotensin receptor blockers:
o Adverse effects on renal function in patients with bilateral renal artery stenosis are
similar to an ACEI, as is hyperkalaemia and fetal renal toxicity.
o Angio-oedema is much less common than with ACEI, but can occur.
o First-dose hypotension can occur and it is sensible to apply similar precautions as
when starting an ACEI (first dose at night, avoid starting if volume contracted).
o Nondihydropyridines:
o Bradycardia: caused by SA node or AV node suppression
o Heart failure and hypotension: secondary to reduced contractility
o Dihydropyridines:
o Vasodilation-related symptoms: Flushing: Caused by cutaneous vasodilation,
Dizziness: Caused by decreased cerebral perfusion from low BP, Headache: Caused
by cerebral vasodilation, Tachycardia: A baroreceptor reflex response to decreased
BP
 Diuretics :
o Refer session on drugs acting on genital urinary system.
STEP 5: Contraindications of Antihypertensive Drugs (10 minutes)
 What are the side effects and adverse effects of antihypertensive drugs?
266
 Angiotensin Converting Enzyme Inhibitors are contraindicated in the followings:
o Pregnant women: ACE inhibitors are fetotoxic and should not be used in pregnant
women.
 Beta Blockers are contraindicated in the followings:
o Airways obstruction: asthmatics sometimes tolerate a small dose of a selective drug
when first prescribed, only to suffer an exceptionally severe attack subsequently, and
β-adrenoceptor antagonists should ideally be avoided altogether in asthmatics and
used only with caution in COPD patients, many of whom have a reversible
component.
o Decompensated heart failure – β-adrenoceptor antagonists are contraindicated (in
contrast to stable heart failure) because of decreased contractility of heart muscles
through blockade of B1-receptors.
o Peripheral vascular disease and vasospasm – β-adrenoceptor antagonists
worseclaudication and Raynaud’s phenomenon.
o Hypoglycaemia – β-adrenoceptor antagonists can mask symptoms of hypoglycaemia
and the rate of recovery is slowed, because adrenaline stimulates gluconeogenesis.
This effect is inhibited by these drugs.
o Heart block – β-adrenoceptor antagonists can precipitate or worsen heart block.
o Metabolic disturbance – β-adrenoreceptor antagonists worsen glycaemic control in
type 2 diabetes mellitus.
 Angiotensin receptor blockers are contraindicated in the followings:
o Pregnant women: These drugs are fetotoxic and should not be used in pregnant
women.
o Verapamil should be avoided in treating patients with congestive heart failure due to
its negative inotropic effects
o Nondihydropyridines: Wolff-Parkinson-White (WPW) syndrome: In WPW the
accessory pathway (bundle of Kent) is not blocked by Ca+2 channel blockers, but the
AV node is. Therefore the use of Ca+2 channel blockers will promote conduction
through the accessory pathway. Because the accessory pathway does not have a
conduction delay as the AV node does, conduction through the accessory pathway can
result in very high ventricular rates in the presence of atrial fibrillation or atrial flutter.
o Nondihydropyridines: Hypotension: Ca+2 channel blockers lower BP and should
not be used in patients who already have low BP.
o Nondihydropyridines: Acute CHF: Non-DHPs have a depressant effect on the heart
and must be avoided in acute CHF.
o Nondihydropyridines: AV blocks: Ca+2 channel blockers can make an AV block
more severe.
o Dihydropyridines: Pregnancyteratogenic effects seen in animals
267
o Dihydropyridines: Conditions in which tachycardia is harmful such as Coronary
artery disease, Aortic stenosis and Mitral stenosis
 Diuretics are contraindicated in the followings:
o Patients with Gout: most diuretics reduce uric acid clearance, increase plasma uric
acid and can precipitate gout.
o Diabetic patients: thiazides reduce glucose tolerance thus high doses cause
hyperglycaemia in type 2 diabetes.
o Patients with severe renal impairment because the effects of diuretics depend on renal
function.
o Diuretics should not be used in pre-eclampsia, which is associated with a contracted
intravascular volume.
o Diuretics should be avoided in men with prostatic symptoms.
o It is prudent to discontinue diuretics temporarily in patients who develop intercurrent
diarrhoea and/or vomiting, to avoid exacerbating fluid depletion.

 ACE inhibitors are particularly useful as an addition to a thiazide in moderately severe
disease. The main adverse effect on chronic use is cough.
 Calcium-channel antagonists are useful, especially in moderately severe disease.
 α-Methyldopa is useful in patients with hypertension during pregnancy.

 What are the contraindications of Beta blockers
 What are the adverse effects of calcium channel blockers?
 What are drug interactions associated with beta blockers?
268
References
Education.

269
Session 35: Pharmacodynamics of Anticoagulants
Prerequisites
Learning Tasks
 Describe mechanism of action of Anticoagulants
 Describe drug interactions associated with Anticoagulants
 Describe side effects of Anticoagulants
 Describe contraindications of Anticoagulants
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Mechanism of Action of Anticoagulants
Buzzing
3 20 minutes
brainstorming Anticoagulants
4 20 minutes Presentation Side Effects of Anticoagulants
Presentation/
5 20 minutes Contraindications of Anticoagulants
Brainstorming
270
SESSION CONTENTS

STEP 2: Mechanism of Action of Anticoagulants(45 minutes)
 How do Anticoagulants produce their pharmacological effects?
 Anticoagulants
 Heparins:
 Heparin is a sulphated acidic mucopolysaccharide that is widely distributed in the body.
 The unfractionated preparation is extracted from the lung or intestine of ox or pig, and is
a mixture of polymers of varying molecular weights.
 Since the structure is variable, the dosage is expressed in terms of units of biological
activity.
 Low-molecular-weight heparins (LMWH) are fragments or short synthetic sequences of
heparin with much more predictable pharmacological effects, and monitoring of their
anticoagulant effect is seldom needed.
 They have largely replaced unfractionated heparin in therapy.
 Unfractionated Heparin(UFH)
o Unfractionated heparin has been replaced by LMWH for most indications, but remains
important for patients with impaired or rapidly changing renal function.
o Treatment is monitored by measuring the activated partial thromboplastin time (APTT)
four to six hours after starting treatment and then every six hours, until two consecutive
readings are within the target range, and thereafter at least daily.
o Dose adjustments are made to keep the APTT ratio (i.e. the ratio between the value for
the patient and the value of a control) in the range 1.52.5.
o Mechanism:
271
o The main action of heparin is on the coagulation cascade. It works by binding to
antithrombin III, a naturally occurring inhibitor of thrombin and other serine proteases
(factors IXa, Xa, XIa and XIIa), and enormously potentiating its inhibitory action.
o A lower concentration is required to inhibit factor Xa and the other factors early in the
cascade than is needed to antagonize the action of thrombin, providing the rationale for
low-dose heparin in prophylaxis.
o As an antithrombin drug, it inhibits platelet activation by thrombin
 Low Molecular Weight Heparins (LMWH)
Advantages/difference with UFH include:
o Low-molecular-weight heparins (LMWH) preferentially inhibit factor Xa.
o They do not prolong the APTT, and monitoring (which requires sophisticated factor Xa
assays) is not needed in routine clinical practice, because their pharmacokinetics are more
predictable(less protein binding and first-order kinetics) than those of unfractionated.
o LMWH (e.g. enoxaparin and dalteparin) are at least as safe and effective as
unfractionated products, except in patients with renal impairment.
o Thrombocytopenia and related thrombotic events and antiheparin antibodies are less
common than with unfractionated preparations.
o Once-daily dosage makes them convenient, and patients can administer them at home,
reducing hospitalization.
o However, LMWH are eliminated solely by renal excretion, unlike unfractionated heparin;
as a consequence, unfractionated heparin should be used rather than low-molecular-
weight preparations in patients with significant renal dysfunction.
o Mechanism: as discussed on UFH
 Direct Factor Xa Inhibitors: Rivaroxaban:
o Direct factor Xa inhibitors are agents that inhibit clotting by inhibiting a specific
component of the coagulation cascade.
o Factor Xa converts prothrombin to thrombin (factor IIa). Thrombin is an enzyme that
catalyses the final step in the coagulation cascade, the conversion of fibrinogen to fibrin.
o Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The
mesh is created by the cross-linking of fibrin, and this cross-linking step is facilitated by
factor XIII.
o In addition to converting fibrinogen to fibrin, thrombin also activates factor XIII; thus
thrombin not only catalyses the creation of the key component of the clot, it also
facilitates the provision of structural rigidity to the clot.
o Thrombin also activates factors V, VIII, and XI, therefore amplifying the coagulation
cascade. In addition, thrombin activates platelets, leading to their aggregation.
o Direct factor Xa inhibitors directly inhibit the conversion of prothrombin to thrombin
without using antithrombin III as an intermediary.
o The direct inhibition of thrombin formation results in an anticoagulant effect.
 Direct Factor Xa Inhibitors: Rivaroxaban::
o Direct factor Xa inhibitors are agents that inhibit clotting by inhibiting a specific
component of the coagulation cascade.
272
 Direct Thrombin Inhibitors: Parenteral: Hirudin, Bivalirudin and Desirudin Oral:
Dabigatran, Ximelagatran and Argatroban
o Thrombin (factor IIa) is an enzyme that catalyses the final step in the coagulation
cascade, the conversion of fibrinogen to fibrin.
o Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The
mesh is created by the cross-linking of fibrin, and this cross-linking step is facilitated by
factor XIII.
o Thrombin also activates factors V, VIII, and XI, therefore amplifying the coagulation
cascade. Thrombin also has antiplatelet effects.
o Thrombin has an active site as well as two other sites, referred to as exosite 1, which
binds fibrin, and exosite 2, which binds heparin.
o Direct thrombin inhibitors all bind to thrombin directly at its active site. The bivalent
inhibitors (-irudins) also bind at exosite 1 (hence the term bivalent, indicating two
binding sites), while the univalent inhibitors only bind at the active site.
o The univalent thrombin inhibitors (e.g., argatroban and dabigatran) and bivalirudin all
bind reversibly, whereas the other bivalent inhibitors bind thrombin irreversibly.
o The net result of this binding is that the effects of thrombin are inhibited. The inhibition
of thrombin results in an anticoagulant effect.
 Vitamin K Antagonists: Warfarin
o Vitamin K antagonists are a family of naturally derived anticoagulants, which are also
known as coumarins.
o Vitamin K is key cofactor in the hepatic activation of four coagulation factors. The four
vitamin K-dependent clotting factors are II, VII, IX, and X (Figure 16-4).
o To act as a cofactor, vitamin K must be in its reduced form, vitamin K hydroxyquinone.
The enzyme vitamin K epoxide reductase (VKOR) converts vitamin K to its reduced
form.
o Warfarin inhibits the enzyme VKOR. Blocking formation of the reduced form of vitamin
K inhibits the activation of these four clotting factors.
o These clotting factors vary in their half-lives (6 to 50 hours), with factor II having the
longest half-life and factor VII having the shortest. This delays the onset of action of
warfarin, as one must wait until these clotting factors have been mostly depleted before
the full anticoagulant effects have been achieved.
o There is significant genetic variability in responses to warfarin owing to variants in 2C9
that metabolize the drug less efficiently and to variants in VKOR.
273
STEP 3: Drug Interactions Associated With Anticoagulants (20 minutes)
 How do significant drug interactions of Anticoagulants occur?

o Potentially important pharmacodynamic interactions with warfarin include those with
antiplatelet drugs.
o Aspirin not only influences haemostasis by its effect on platelet function, but also
increases the likelihood of peptic ulceration, displaces warfarin from plasma albumin, and
in high doses decreases prothrombin synthesis.
o Broad-spectrum antibiotics potentiate warfarin by suppressing the synthesis of vitamin
K1 by gut flora.
o Several pharmacokinetic interactions with warfarin are of clinical importance. Several
non-steroidal anti-inflammatory drugs (NSAIDs) and dextropropoxyphene inhibit
warfarin metabolism.
o The gastrotoxic and platelet-inhibitory actions of the NSAIDs further increase the risk of
serious haemorrhage.
o Cimetidine (but not ranitidine) and amiodarone also potently inhibit warfarin metabolism
and potentiate its effect, as do other inhibitors of hepatic cytochrome P450, such as
erythromycin, ciprofloxacin and omeprazole.
o Drugs that induce hepatic microsomal enzymes, including rifampicin, carbamazepine and
phenobarbital, increase warfarin metabolism and increase the dose required to produce a
therapeutic effect; furthermore, if the dose is not reduced when such concurrent therapy is
discontinued, catastrophic over-anticoagulation and haemorrhage may ensue.
STEP 4: Adverse Effects of Anticoagulants (20 minutes)
 Anticoagulants
 Heparin
o Heparin Induced Thrombocytopenia Syndrome (HITS): Antibodies against platelet factor
4 are produced and bind to platelets. Platelets get activated and sticky, and this causes:
Thromboses (multiple),Platelet consumption resulting in thrombocytopenia and bleeding
as a result of thrombocytopenia
o Hemorrhage can be reversed with protamine.
274
o Osteoporosis occurs with long-term therapy; the cause is unknown.
o Hyperkalemia: Although not a common occurrence, heparin can cause increased serum
potassium; it is more likely to occur in patients with diabetes or renal disease.
o In this regard the action of heparin is similar to that of spironolactone, which is an
aldosterone blocker classified as a K-sparing diuretic.
o Fever: Rarely, heparin can cause a drug fever.
o Heparins provide a safe and important alternative to teratogenic warfarin in pregnancy.
o For cases of heparin overdose, protamine sulphate is a strongly basic protein that forms a
complex with heparin, acting as a chemical antagonist. LMWH does not have an antidote.
o Danaparoid works by the same mechanism as the heparins, but it is not structurally
related to the heparins; it is therefore considered a heparinoid. Therefore it can be used in
the management of patients with heparin-induced thrombocytopenia (HIT) too.
o Bleeding: As with all anticoagulants, bleeding is the major side effect
 Direct Thrombin Inhibitors:
o Bleeding: As with all anticoagulants, bleeding is the major side effect
o Hemorrhage:Minor: Small cuts, nosebleeds, easy bruising, hematuria (blood in urine),
and bleeding gums may occur.
o Major: Intracranial bleeding is often catastrophic.
o Warfarin therapy is monitored using the International Normalized Ratio (INR),
STEP 5: Description of Contraindications of Anticoagulants (10 minutes)
 What are the contraindications of Anticoagulants?


 Anticoagulants
 Heparin
o Previous heparin-induced thrombocytopenia syndrome (HITS) (see Side Effects)
o Coagulopathies: hemophilia, thrombocytopenia (low platelet count)
o Active bleeding: intracranial hemorrhage, gastrointestinal (GI) ulcers, certain cancers
o Active bleeding
o Pregnancy
275
o Patients at increased risk of bleeding: clotting disorders, history of recent hemorrhagic
stroke
 Direct Thrombin Inhibitors:
o Patients who are at high risk of bleeding, such as those with the following conditions:
Uncontrolled active bleeding, major bleeding (coagulopathy) disorders
o Pregnancy: Warfarin is teratogenic and can also cause fetal bleeding.
o Recent events that predispose to bleeding include the following: Surgery and stroke
o Platelet disorders (If you have dysfunctional clotting cells and dysfunctional clotting
proteins, there really is not much left to form a clot if you should need it.)
o The anticoagulant effects of warfarin can be reversed by administration of vitamin K. The
time required for vitamin K to work is dependent on the time the liver requires to generate
more proteins (many hours).

 Anticoagulants produce effects through different mechanisms
 Most anticoagulants cause bleeding as their main side effect
 LMWH have advantages over UFH

 What are the adverse effects of Heparins?
 What is the mechanism of action of UFH?
 What are contraindications of warfarin?

DIVIDE students in groups or individuals

 Prepare a presentation on the mechanism of thrombolytc drugs (Give examples of drugs
for this pharmacplogical group)
276
References
Education.

277
Session 36: Pharmacodynamics of Antiplatelet Drugs
Prerequisites
Learning Tasks
 Describe mechanism of action of Antiplatelet Drugs
 Describe drug interactions associated with Antiplatelet Drugs
 Describe side effects of Antiplatelet Drugs
 Describe contraindications of Antiplatelet Drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Presentation/
2 45 minutes Mechanism of Action of Antiplatelet Drugs
Buzzing
3 20 minutes
brainstorming Antiplatelet Drugs
4 20 minutes Presentation Side Effects of Antiplatelet Drugs
Presentation/
5 20 minutes Contraindications of Antiplatelet Drugs
Brainstorming
278
SESSION CONTENTS

STEP 2: Mechanism of Action of Antiplatelet Drugs (45 minutes)
 How do Antiplatelet Drugs produce their pharmacological effects?
 Antiplatelet Drugs
 Salicylates: acetylsalicylic acid (ASA)
o ASA works by irreversibly inhibiting COX-1, an enzyme that catalyses the formation of
cyclic endoperoxide, which in turn is then converted to Thromboxane A2 (TXA2) in
platelets. TXA2 is a potent inducer of platelet aggregation and release.
o Inhibition of TXA2 leads to the antiplatelet effects of ASA.
 Adenosine Diphosphate (ADP) Blockers
o Platelets are activated by adhering to damaged endothelium by linking of glycoprotein Ia
(GPIa) receptors with collagen and GPIb receptors with von Willebrand factor (vWF).
The activation of platelets leads to aggregation and clot formation.
o Platelet activation leads to synthesis and release of mediators involved in platelet
aggregation: TXA2, Serotonin (5-HT) and ADP.
o Mediators such as ADP promote platelet aggregation by increasing GP receptor
expression and promoting binding of fibrinogen to GPIIIa/IIb receptors.
o Ticlopidine, prasugrel, and clopidogrel inhibit the ADP-dependent pathway of platelet
activation and subsequent aggregation.
 Antiplatelet IIb/IIIa Inhibitors
o IIb/IIIa receptors are located on the outside of platelets, in very high numbers (50,000 to
80,000 per cell); in the resting platelet they are inactive.
o Fibrinogen and vWF bind to IIb/IIIa receptors; once bound, they bind to foreign surfaces
and also bridge other platelets to induce platelet aggregation.
279
o These drugs bind to the IIb/IIIa receptor complex on the platelet and prevent binding of
endogenous ligands including fibrinogen and vWF, thus inhibiting aggregation of the
platelet
 Dipyridamole
o Dipyridamole was introduced as a vasodilator, but provokes rather than prevents angina
(via a steal mechanism).
o It is used acutely as in stress tests for ischaemic heart disease (e.g. combined with nuclear
medicine myocardial perfusion scanning).
o It is also used chronically, combined with aspirin, for its antiplatelet effect in patients
with cerebrovascular disease.
o Dipyridamole inhibits phosphodiesterase which leads to reduced breakdown of cAMP,
and inhibits adenosine uptake with consequent enhancement of the actions of this
mediator on platelets and vascular smooth muscle..
STEP 3: Drug Interactions Associated With Antiplatelet Drugs (20

minutes)
 How do significant drug interactions of Antiplatelet Drugs occur?

o Aspirin not only influences haemostasis when co-administered with warfarin by its
effect on platelet function, but also increases the likelihood of peptic ulceration, displaces
warfarin from plasma albumin, and in high doses decreases prothrombin synthesis. When
low doses of aspirin are taken regularly with warfarin may be more than offset by clinical
benefits to patients at high risk of thromboembolism following cardiac valve replacement.
o For details refer session on Pharmacodynamics of Antinflammatory drugs
 Dipyridamole
o Dipyridamole increases the potency and duration of action of adenosine.
o This may be clinically important in patients receiving dipyridamole in whom adenosine is
considered for treatment of dysrhythmia.
280
STEP 4: Adverse Effects of Antiplatelet Drugs (20 minutes)
o GI: GI effects are caused by reduced levels of a PG (produced by COX-1) that protects
the lining of the stomach. They can range in severity from upset stomach to GI bleeds and
ulcers.
o Bleeding is caused by the antiplatelet effect.
o Tinnitus: Ringing of the ears is typically only seen at higher doses.
o For details refer Pharmacodynamics of Antinflammatory drugs
o Bleeding
o Rash, diarrhea: mechanism not known
o Severe neutropenia is a rare side effect associated with ticlopidine but not with
clopidogrel.
o It necessitates discontinuation of the drug.
o Thrombotic thrombocytopenic purpura (TTP): has been associated with ticlopidine and
less commonly with clopidogrel.
o Bleeding
o Thrombocytopenia is the most serious complication. Thrombocytopenia is immune-
mediated and occurs in 5% of patients but is severe in 1%.
STEP 5: Contraindications of Antiplatelet Drugs (10 minutes)
 What are the contraindications of Antiplatelet Drugs ?


o Hypersensitivity (allergy) to ASA. Can be fatal.
o Not for use in children. Causes Reyes syndrome, an often fatal encephalopathy in
children that has been associated with the use of ASA during viral infection.
o Active bleeding: These agents impair clotting and prolong bleeding.
281
o Significant hepatic impairment: Clopidogrel and ticlopidine agents need a functioning
liver in order to be converted to their active metabolites. Hepatic complications have also
been reported with both agents but are extremely rare.
o High risk of bleeding, including but not limited to the following: Recent surgery, recent
stroke, thrombocytopenia (low platelet count) and recent GI bleed.

 Hemorrhage is a particular problem with agents displaying less specificity for newly
formed thrombi (streptokinase and urokinase).

 What are the adverse effects of ASA?
 What is the mechanism of action of clopidogrel?
 What are contraindications of antiplatelet Drugs?
282
References
Education.

283
Session 37: Pharmacodynamics of Local Anaesthetics
Prerequisites
Learning Tasks
 Describe mechanism of action of Local Anaesthetics
 Describe drug interactions associated with Local Anaesthetics
 Describe side effects of Local Anaesthetics
 Describe contraindications of Local Anaesthetics
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
2 45 minutes Presentation Mechanism of Action of Local Anaesthetics

Presentation/ Drug Interactions Associated With Local
3 20 minutes
brainstorming Anaesthetics
4 20 minutes Presentation Side Effects of Local Anaesthetics
Presentation/
5 20 minutes Contraindications of Local Anaesthetics
Brainstorming
284
SESSION CONTENTS

STEP 2: Mechanism of Action of Local Anaesthetics (45 minutes)

 How do local anaesthetics produce their pharmacological effects?
 Local anaesthetics are drugs which upon topical application or local injection cause
reversible loss of sensory perception, especially of pain in a localized area of the body.
 They block generation and conduction of nerve impulses at a localized site of contact
without structural damage to neurons.
 Clinically they are used to block pain sensation from or sympathetic vasoconstrictor
impulses to specific areas of the body
 Local Anaesthetics are classified as follows;

o Injectable anaesthetic:
 Low potency, short duration Procaine and Chlorprocaine
 Intermediate potency Lidocaine (Lignocaine) and Prilocaine
 High potency and long duration Tetracaine, Bupivacaine, Ropivacaine, Etidocaine,
Mepivacaine and Dibucaine (Cinchocaine)
o Surface anaesthetic:
 Soluble Cocaine, Lidocaine, Tetracaine and Benoxinate
 Insoluble Benzocaine, Butylaminobenzoate and Oxethazine
o Miscellaneous drugs:
Clove oil, phenol, chlorpromazine and diphenhydramine etc.
The mechanism of action of Local Anaesthetics is as follows;

 All local anesthetics are membrane stabilizing drugs
 They slows down speed of Action Potential (AP) ultimately stoping AP generation
 They reversibly decrease the rate of depolarization and repolarization of excitable
membranes
285
 They inhibiting sodium influx through sodium-specific ion channels in the neuronal cell -
voltage-gated sodium channels
 When the influx of sodium is interrupted - action potential cannot rise and signal
conduction is inhibited
 Local anesthetic s bind (located at inner surface) more readily to sodium channels in
activated state and slows its reversion to the resting state refractory period is
increased - state dependent blockade - no action on resting nerve.
STEP 3: Drug Interactions Associated with Local Anaesthetics (20

minutes)
 How do significant drug interactions of Local Anaesthetics occur?
 Anti-arrhythmics: increased myocardial depression when anti-arrhythmics given with

Bupivacaine, Levobupivacaine, Prilocaine or Ropivacaine
 Beta-Blockers: Increased risk of bupivacaine toxicity when given with Propranolol
STEP 4: Side Effects of Local Anaesthetics (20 minutes)

CNS Stimulation:
o It is dose-related spectrum of effects and All effects are due to depression of neurons
o First an apparent CNS stimulation (convulsions most serious) followed by CNS
depression (death due to respiratory depression)
o Premonitory signs include: ringing in ears, metallic taste, and numbness around lips
o Cocaine causes euphoria (unique in its ability to stimulate CNS)
o Lidocaine causes sedation even at non-toxic doses.
Cardiocascular system
 Arrhythmias:
o The adverse cardiovascular effects of local anaesthetics are due mainly to myocardial
depression, conduction block and vasodilatation.
o Reduction of myocardial contractility probably results indirectly from an inhibition of the
Na+ current in cardiac muscle
286
o The resulting decrease of [Na+]i in turn reduces intracellular Ca2+ stores and this reduces
the force of contraction.
o Interference with atrioventricular conduction can result in partial or complete heart block,
as well as other types of dysrhythmia
 Hypotension
o Vasodilatation, mainly affecting arterioles, is due partly to a direct effect on vascular
smooth muscle, and partly to inhibition of the sympathetic nervous system.
o This leads to a fall in blood pressure, which may be sudden and life-threatening.
o Cocaine is an exception in respect of its cardiovascular effects, because of its ability to
inhibit noradrenaline reuptake
STEP 5: Contraindications of Local Anaesthetics (10 minutes)
 What are the contraindications of Local Anaesthetics?

 Local anaesthetics should not be injected into inflamed or infected tissues nor should they
be applied to damaged skin.
o Increased absorption into the blood increases the possibility of systemic side-
effects, and the local anaesthetic effect may also be reduced by altered local pH.
 Patients with Heart block, second or third degree (without pacemaker)
 Patients with Severe sinoatrial block (without pacemaker).
 Concurrent treatment with quinidine, flecainide, disopyramide, procainamide (class 1
antiarrhythmic agents) should be avoided.

 Local anaesthetic drugs act by causing a reversible block to conduction along nerve
fibres.
 They are administered by injection or by application to mucous membranes to produce
local analgesia.
 They vary widely in their potency, toxicity, duration of action, stability, solubility in
water, and ability to penetrate mucous membranes
287
 What are local Anaesthetics?
 What is the mechanism of action of local anaesthetics?
 What are the side effects of local anaesthetics?
 What are contraindications of local anaesthetics?
288
References
Education.

289
Session 38: Pharmacodynamics of General Anaesthetics
Prerequisites
Learning Tasks
 Describe mechanism of action of General Anaesthetics
 Describe drug interactions associated with General Anaesthetics
 Describe side effects of General Anaesthetics
 Describe contraindications of General Anaesthetics
Resources Needed:
 Handout 38.1. Side Effects of Inhalation Anaesthetics
SESSION OVERVIEW
Activity/
Step Time Content
Method
Mechanism of Action of General
Anaesthetics
Presentation/ Drug Interactions Associated With General
3 20 minutes
brainstorming Anaesthetics
4 20 minutes Presentation Side Effects of General Anaesthetics
Presentation/
5 20 minutes Contraindications of General Anaesthetics
Brainstorming
290
SESSION CONTENTS

STEP 2: Mechanism of Action of General Anaesthetics (45 minutes)

 How do general anaesthetics produce their pharmacological effects?
 General Anaesthetics are the drugs which produce reversible loss of all sensation and
consciousness, or simply, a drug that brings about a reversible loss of consciousness
 General Anaesthetics are generally administered by an anesthesiologist in order to induce
or maintain general anesthesia to facilitate surgery
 General anaesthetics are mainly inhalation or intravenous as shown in the table below;
Inhalation: Intravenous:
Gas: Inducing agents:
e.g Nitrous Oxide  Thiopentone,
 Methohexitone sodium,
 propofol
 etomidate
Volatile liquids: Benzodiazepines (slower acting):
 Ether  Diazepam
 Halothane  Lorazepam
 Enflurane  Midazolam
 Isoflurane
 Desflurane
 Sevoflurane
Dissociative anaesthesia:
e.g Ketamine
Neurolept analgesia:
e.g. Fentanyl
291
 Major targets of General Anaesthetics is ligand gated ion channels GABA-A, Cl¯
channel receptors which are found throughout the CNS
 Normally, GABA-A receptor mediates the effects of gamma-amino butyric acid (GABA),
the major inhibitory neurotransmitter in the brain
 When a general anaesthetic binds to this receptor, it causes conformational changes

leading to opening of central pore and passing down of Cl- along concentration gradient
 The result is inhibitory effect which reduces the activity of neurones
 Therefore, General Anaesthetics bind with these channels and cause opening and
potentiation of these inhibitory channels leading to inhibition and anaesthesia
Fig 38. 2 Structure of GABAA receptor
STEP 3: Drug Interactions Associated with General Anaesthetics (20

minutes)
 How do significant drug interactions of General Anaesthetics occur?
292
 Adrenergic Neurone Blockers: enhanced hypotensive effect when general anaesthetics
given with Adrenergic Neurone Blockers
 Alpha-blockers: enhanced hypotensive effect when general anaesthetics given with
Alpha-Blockers
 Aminophylline: increased risk of convulsions when Ketamine given with Aminophylline
 Analgesics: metabolism of etomidate inhibited by Fentanyl (consider reducing dose of
etomidate);
 effects of thiopental possibly enhanced by Aspirin;
 effects of intravenous general anaesthetics and volatile liquid general anaesthetics
possibly enhanced by Opioid Analgesics
 Angiotensin-II Receptor Antagonists: enhanced hypotensive effect when general
anaesthetics given with Angiotensin-II Receptor Antagonists
STEP 4: Side Effects of Local Anaesthetics (20 minutes)

The side effects of General Anaesthetics are as indicated in the tables below;
Table 28.1; Intravenous Anaesthetic Agents
Drug Speed of induction and Main unwanted effect(s) Notes
recovery
Propofol Fast onset, very fast Cardiovascular and  Rapidly metabolized
recovery respiratory depression  Possible to use as
continuous infusion
 Causes pain at
injection site
Thiopental Fast (accumulation Cardiovascular and  Largely replaced by
occurs, giving slow respiratory depression propofol
recovery)  Causes pain at
'Hangover' injection site
 Risk of precipitating
porphyria in
susceptible patients
Etomidate Fast onset, fairly fast Excitatory effects during  Less cardiovascular
recovery induction and recovery and respiratory
Adrenocortical depression than with
suppression thiopental
 Causes pain at
injection site
Ketamine Slow onset, after effects  Psychotomimetic Produces good analgesia
common during recovery effects following and amnesia
recovery
 Postoperative nausea,
vomiting and
salivation
 Raised intracranial
pressure
Midazolam Slower than other agents - Little respiratory or
cardiovascular depression
 For side effects of inhalation Anaesthetics;
REFER Students to Handout 38.1: Side Effects of Inhalation Anaesthetics

293
STEP 5: Contraindications of general Anaesthetics (10 minutes)
 What are the contraindications of Local Anaesthetics?

General Anaesthetics are contraindicated in patients with;

 Family history of malignant hyperthermia.
 Hyperkalaemia
 Low plasma-cholinesterase activity (including severe liver disease) .
 Major trauma .
 Neurological disease involving acute wasting of major muscle .
 Personal or family history of congenital myotonic disease .
 Prolonged immobilisation (risk of hyperkalaemia) .

 Anaesthesia is induced with either a volatile drug given by inhalation or with an
intravenously administered drug;
 Propofol is the most widely used intravenous anaesthetic, and can be used for induction
or maintenance of anaesthesia in adults and children

 What are General Anaesthetics?
 What is the mechanism of action of general anaesthetics?
 What are the side effects of general anaesthetics?
 What are contraindications of general anaesthetics?
294

 Prepare a presentation on the mechanism of action of opioid analgesics (Give
examples of drugs in this pharmacological group)
295
References
Education.

296
Handout 20.1 Side Effects of Inhalation Anaesthetics
Table 28.2 Inhalation Anaesthetics
Drug Speed of Main unwanted Notes
induction and effect(s)
recovery
Nitrous Fast Few adverse effects Good analgesic effect
oxide Risk of anaemia (with Low potency precludes
prolonged or repeated use as sole anaesthetic
use) agent-normally combined
Accumulation in with other inhalation
gaseous cavities agents
lsoflurane Medium Few adverse effects Widely used
Possible risk of coronary Has replaced halothane
ischemia in susceptible
patients
Sevoflurane Fast Few reported Similar to desflurane
Theoretical risk of renal
toxicity owing to
fluoride
Desflurane Fast Respiratory tract Used for day-case surgery
irritation, cough, because of fast onset and
bronchospasm recovery (comparable
with nitrous oxide)
Halothane Medium Hypotension Little used nowadays
Cardiac arrhythmias Significant metabolism to
Hepatotoxicity (with trifluoracetate
repeated use)
Malignant hyperthermia
(rare)
Enflurane Medium Risk of convulsions Has declined in use
(slight) May induce seizures
Malignant hyperthermia
(rare)
Ether Slow Respiratory irritation Now obsolete, except
Nausea and vomiting where modern facilities
Explosion risk are lacking
297
Session 39: Pharmacodynamics of Antituberculosis Drugs
Prerequisites
 PST04211_S13_ Description of Antituberculosis Drugs
Learning Tasks
 Describe mechanism of action of Antituberculosis Drugs
 Describe drug interactions associated with Antituberculosis Drugs
 Describe side effects of Antituberculosis Drugs
 Describe contraindications of Antituberculosis Drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Mechanism of Action of Antituberculosis
Drugs
3 20 minutes
brainstorming Antituberculosis Drugs
4 20 minutes Presentation Side Effects of Antituberculosis Drugs
Presentation/
5 20 minutes Contraindications of Antituberculosis Drugs
Brainstorming
298
SESSION CONTENTS

STEP 2: Mechanism of Action of Antituberculosis Drugs (45 minutes)

 How do Antituberculosis Drugs produce their pharmacological effects?
Isoniazid
 Isoniazid inhibits synthesis of mycolic acids, which are essential components of
mycobacterial cell walls.
 Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.
 The activated form of isoniazid forms a covalent complex with an acyl carrier protein
(AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid
synthesis and kills the cell.
Rifampin
 Rifampin binds to the β subunit of bacterial DNA-dependent RNA polymerase and
thereby inhibits RNA synthesis
 Human RNA polymerase does not bind rifampin and is not inhibited by it.
 Rifampin is bactericidal for mycobacteria.
 It can kill organisms that are poorly accessible to many other drugs, such as intracellular
organisms and those sequestered in abscesses and lung cavities
Ethambutol
 Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the
embCAB operon.
 Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wall.
299
Pyrazinamide
 Pyrazinamide is converted to pyrazinoic acidthe active form of the drugby
mycobacterial pyrazinamidase, which is encoded by pncA .
 The specific drug target is unknown, but pyrazinoic acid disrupts mycobacterial cell
membrane metabolism and transport functions.
STEP 3: Drug Interactions Associated with Antituberculosis Drugs (20

minutes)
 How do significant drug interactions of Antituberculosis Drugs occur?
 There is no serious interaction between ant tuberculosis drugs and other drugs except that
rifampicin reduces plasma concentration of digoxin
 Absorption of isoniazid is reduced by antacids,
 Hepatotoxic of isoniazid is potentiated by general anaesthesia and its CNS toxicity is
increased by cycloserine
 Pyrazinamide antagonizes effect of probenecid
STEP 4: Side Effects of Antituberculosis Drugs (20 minutes)

Side effects and adverse effects of antituberculosis drugs include:
 Rifampicin
o Occasional adverse effects include rashes, thrombocytopenia, and nephritis. It may
cause cholestatic jaundice and occasionally hepatitis
o Rifampin commonly causes light-chain proteinuria
 Isoniazid side effects are dose related
o They occur in high dose and may include nausea, vomiting, constipation, dry mouth;
peripheral neuritis with high doses (pyridoxine prophylaxis, see notes above), optic
neuritis, convulsions, psychotic episodes and vertigo
 Pyrazinamide
o Major adverse effects of pyrazinamide include hepatotoxicity, nausea, vomiting, drug
fever, and hyperuricemia
o Hyperuricemia may provoke acute gouty arthritis
300
 Ethambutol; the most common serious adverse event is retro bulbar neuritis, resulting in
loss of visual acuity and red-green color blindness
 Streptomycin is ototoxic and nephrotoxic
o Vertigo and hearing loss are the most common side effects and may be permanent.
o Toxicity is dose-related, and the risk is increased in the elderly
o Toxicity can be reduced by limiting therapy to no more than 6 months whenever
possible
STEP 5: Contraindications of Antituberculosis Drugs (10 minutes)
Activity: Brainstforming (5 minutes)
 What are the contraindications of Antituberculosis Drugs?

 Rifampicin is contraindicated to patient with jaundice

 Isoniazid is contraindicated to patient with drug induced liver disease
 Pyrazinamide is contraindicated to patient with Hepatic disorders
o Patients or their careers should be told how to recognize signs of liver disorder,
and advised to discontinue treatment and seek immediate medical attention if
symptoms such as persistent nausea, vomiting, malaise or jaundice develop
 Ethambutol is contraindicated in optic neuritis and poor vision
 Streptomycin is contraindicated to patient with mythenia gravis
 Cycloserine is contraindicated to patient with epilepsy, depression, severe anxiety,
psychotic states, alcohol dependence and acute porphyria

 Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide and ethambutol are the four
first-line agents for treatment of tuberculosis
 In practice, therapy is initiated with a four-drug regimen of isoniazid, rifampin, and
pyrazinamide plus ethambutol
 The incidence and severity of untoward reactions to isoniazid are related to dosage and
duration of administration.
301
 What are the mechanisms of antituberculosis drugs?
 What are the drug interactions of action of antituberculosis drugs?
 What are the side effects of antituberculosis drugs?
 What are contraindications of antituberculosis drugs?
302
References
Education.

303
304
Session 40: Pharmacodynamics of Antiarrythmic Drugs
Prerequisites
Learning Tasks
 Describe mechanism of action of Antiarrythmic Drugs
 Describe drug interactions associated with Antiarrythmic Drugs
 Describe side effects of Antiarrythmic Drugs
 Describe contraindications of Antiarrythmic Drugs
Resources Needed:
SESSION OVERVIEW
Activity/
Step Time Content
Method
Mechanism of Action of Antiarrythmic
Drugs
3 20 minutes
brainstorming Antiarrythmic Drugs
4 20 minutes Presentation Side Effects of Antiarrythmic Drugs
Presentation/
5 20 minutes Contraindications of Antiarrythmic Drugs
Brainstorming
305
SESSION CONTENTS

STEP 2: Mechanism of Action of Antiarrythmic Drugs (40 minutes)

 How do Antiarrythmic Drugs produce their pharmacological effects?
 Arrhythmias are caused by abnormal pacemaker activity or abnormal impulse

propagation.
 Thus, the aim of therapy of the arrhythmias is to reduce ectopic pacemaker activity and
modify conduction or refractoriness in reentry circuits to disable circus movement.
 Drugs used for treatment of Arrhythmias are classified into four classes according to the
SinghVaughanWilliams classification (classesIIV) as shown in the table 40.1;
 Thus, the aim of therapy of the arrhythmias is to reduce ectopic pacemaker activity and
modify conduction or refractoriness in reentry circuits to disable circus movement.
 The major pharmacologic mechanisms currently available for accomplishing these goals
are;
o sodium channel blockade,
o blockade of sympathetic autonomic effects in the heart,
o prolongation of the effective refractory period
o calcium channel blockade
 Antiarrhythmic drugs decrease the automaticity of ectopic pacemakers more than that of
the SA node.
 They also reduce conduction and excitability and increase the refractory period to a
greater extent in depolarized tissue than in normally polarized tissue
 This is accomplished chiefly by selectively blocking the sodium or calcium channels of
depolarized cells
306
Table 40.1 Anti-dysrhythmic drugs: the VaughanWilliams/Singh classification
STEP 3: Drug Interactions Associated with Antiarrythmic Drugs (20

minutes)
 How do significant drug interactions of Antiarrythmic Drugs occur?
Signifi cant interactions with Antiarrhythmics are as follows;

 Quinidine
o Quinidine may increase serum levels of digoxin and increase the effects of digitalis on
the heart, with a resultant increase in toxicity.
o Severe orthostatic hypotension may occur with concomitant administration of
vasodilators (e.g., nitroglycerin).
o Phenytoin, rifampin, and barbiturates may antagonize quinidine activity and reduce its
therapeutic effi cacy.
 Amiodarone and cimetidine may increase plasma procainamide levels, possibly leading to
drug toxicity.
 Phenytoin accelerates disopyramide metabolism, possibly reducing its therapeutic effi
cacy.
307
 Lidocaine
o Phenytoin may increase the cardiodepressant eff ects of lidocaine.
o Beta Blockers (class II antiarrhythmics) may reduce lidocaine metabolism, possibly
leading to drug toxicity.
 Amiodarone
o Amiodarone may increase the plasma levels of quinidine, procainamide, diltiazem,
digitalis, and flecainide.
o It may increase the pharmacological effect of beta-blockers, calcium-channel
blockers, and warfarin.
.
STEP 4: Side Effects of Antiarrythmic Drugs (20 minutes)
Amiodarone
 Life-threatening pulmonary toxicity may occur during amiodarone therapy, especially
in patients receiving 400 mg/day. Baseline as well as routine pulmonary function tests
reveal relevant pulmonary changes.
 Most patients develop corneal microdeposits 1 to 4 months aft er amiodarone therapy
begins. However, this reaction rarely causes visual disturbance, but the patient should be
monitored with routine ophthalmological examinations.
 Blood pressure and heart rate and rhythm should be monitored for hypotension and
bradyarrhythmias.
 Patients should be monitored routinely for the possible development of hepatic
dysfunction, thyroid disorders (e.g., hyperthyroidism, hypothyroidism), and
photosensitivity.
Quinidine
 Cardiotoxicity effects, such as pronounced slowing of conduction in all heart regions
which may lead to SA block or arrest, ventricular tachycardia, or asystole may occur.
Procainamide
 Toxicity may cause acute cardiac effects (e.g., pronounced slowing of conduction in all
heart regions), which, in turn, may lead to SA block or arrest,ventricular tachycardia, or
asystole.
 High serum procainamide levels may induce ventricular arrhythmias (e.g., PVCs,
ventricular tachycardia, or fibrillation).
 Hypotension may occur with rapid intravenous administration.
 GI effects are less common than with quinidine therapy.
 Hypersensitivity reactions are the most severe adverse eff ects of procainamide. These
reactions include drug fever, agranulocytosis, and an SLE-like syndrome.
308
STEP 5: Contraindications of Antiarrythmic Drugs (10 minutes)
 What are the contraindications of Antiarrythmic Drugs?

Quinidine
This drug is contraindicated in patients with;
 Complete AV block unless a ventricular pacemaker is in place.
 Marked prolongation of the QT interval or prolonged QT syndrome because ventricular
tachyarrhythmia may arise, resulting in quinidine syncope (i.e.,syncope or sudden death).
Procainamide
 This drug is contraindicated in patients with hypersensitivity to procaine and related
drugs, myasthenia gravis, second- or third-degree AV block with no pacemaker, a
history of procainamide-induced systemic lupus erythematosus (SLE), or prolonged QT
syndrome
Disopyramide
 This drug may cause marked hemodynamic compromise and ventricular dysfunction. It
is contraindicated in patients with cardiogenic shock or second- or third-degree AV block
with no pacemaker.
 Disopyramide should be avoided in patients with heart failure (HF).
 It should also be used cautiously in patients with urinary tract disorders, myasthenia
gravis, and renal or hepatic dysfunction.
Mexiletine
 This drug is contraindicated in patients with cardiogenic shock or second- or third- degree
AV block with no pacemaker

 Antiarrhymic drugs block electrical activity when there is a fast tachycardia (many
channel activations and inactivations per unit time) or when there is significant loss of
resting potential (many inactivated channels during rest)
309
 In cells with abnormal automaticity, most of these drugs reduce the phase 4 slope by
blocking either sodium or calcium channels, thereby reducing the ratio of sodium (or
calcium) permeability to potassium permeability

 What are the mechanisms of antiarrhythmic drugs?
 What are the drug interactions of action of amiodarone?
 What are the side effects of proicanamide?
 What are contraindications of quinidine?


 Prepare a presentation on the mechanism of essential drugs used to treat hyperlipidemia
(Give examples of drugs from this pharmacological group)
310
References
Education.

311

Pharmacology and Therapeutics Semi 1

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UNITED REPUBLIC OF TANZANIA

Ministry of Health, Community

These participants are listed with our gratitude below:

Ms. Elizabeth Shekalaghe Registrar, Pharmacy Council of Tanzania

Organization of the Module

Preparation with Handouts and Worksheets

Using Students Manual When Teaching

AGS Gas Gangrene Antitoxin

Total Session Time: 120 minutes

7 05 minutes Presentation Key Points

8 05 minutes Presentation Evaluation

STEP 1: Presentation of Session Title and Learning tasks (5 minutes)

ASK students if they have any questions before continuing.

STEP 2: Description of Absorption (10 minutes)

Activity: Buzzing (5 minutes)

WRITE their response on the flip chart/board

CLARIFY and SUMMARIZE by using the content below

 Absorption follows administration and is the process by which a drug is made

STEP 3: Describe Factors Affecting Absorption (45 Minutes)

DIVIDE students into small manageable groups

ASK students to discuss on the following question

ALLOW students to discuss for 15 minutes

CLARIFY and SUMMARIZE by using the contents below:

Factors determining absorption include;

Fig 1.1 Main routes of drug administration

STEP 4: Absolute and Relative Bioavailability (20minutes)

 Together, these processes explain why the bioavailability of an orally administered

Formular: Bioavailability = AUCoral/AUCi.v. X 100%

Table 1.1 Routes of administration, bioavailability,and general characteristics.

Ask students to brainstorm on the following question:

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

Bioavailability(F) = AUCoral/AUCi.v. X 100%

STEP 6: Clinical Application of Bioavailability (10minutes)

STEP 7: Key Points (5 minutes)

School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).

Total Session Time: 120 minutes

8 05 minutes Presentation Evaluation

STEP 1: Presentation of Session Title and Learning tasks (5 minutes)

ASK students if they have any questions before continuing.

STEP 2: Distribution of Drugs in various Compartments of the Body (10

Activity: Buzzing (5 minutes)

 Describe distribution process of drugs in the body?

WRITE their response on the flip chart/board

CLARIFY and SUMMARIZE by using the content below

o Plasma compartment (Vascular compartment)

o Total Body Water

STEP 3: Factors Affecting Distribution of Drugs (30Minutes)

Ask students to brainstorm on the following question:

 What are the factors determining distribution of drugs?

ALLOW few students to respond

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

STEP 4: Volume of Distribution (20minutes)

Volume of distribution = Dose / drug concentration

STEP 5: Calculation of Volume of Distribution (30 Minute)

DIVIDE students into small manageable groups

ASK students to discuss on the following question

CLARIFY and SUMMARIZE by using the contents below

 Vd = Amount of drug in body ÷ Concentration in Plasma