Unit-5 - PHARMACOLOGY III

COURSE: B.
PHARMACY SUBJECT: PHARMACOLOGY-III, CODE: BP602

PRINCIPLES OF TOXICOLOGY
UNIT: 05
 Principles of toxicology
 Definition and basic knowledge of acute, subacute and chronic toxicity.
 Definition and basic knowledge of genotoxicity, carcinogenicity,
teratogenicity and mutagenicity
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COURSE: B.PHARMACY SUBJECT: PHARMACOLOGY-III, CODE: BP602
INTRODUCTION
Toxicity testing is paramount in the screening of newly developed drugs before it
can be used on humans. Toxicity testing is the determination of potential hazards
a test substance may likely produced and the characterization of its action, most of
the toxicity testing is carried out on experimental animals.The advantages of using
animal models in toxicity testing are enormous. These advantages include the
possibility of clearly defined genetic constitution and their amenity to controlled
exposure, controlled duration of exposure, and the possibility of detailed
examination of all tissues following necropsy.. The information obtained can
serves as the basis for hazard classification and labeling of chemicals in
commerce[.The essence of toxicity testing is not just to check how safe a test
substance is; but to characterize the possible toxic effects it can produce. Toxicity
testing was given much attention following early 1960s thalidomide catastrophe;
with thousands of children born worldwide with severe birth defects2. After this
incidence many countries of the world have resolved to go for toxicity testing and
teratogenicity in both sexes so as to prevent further tragedies.
Importance of toxicity studies
afety of new chemicals for use as pesticides, drugs, or food

additives before they are registered for general use in industry or doctors clinics.
been seen in other studies.
for instance, the long investigation into the association of smoking with lung
conducted in vitro rather than in animals.
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The two basic principles guiding toxicity test in animals
toxic effect on human.
its possible
hazard on human that are exposed to much lower doses
Toxicity studies are divided into:

Acute toxicity studies
This is a short term assessment and evaluation of potential hazard test substance
or consequences of single dose of a test substance.Acute toxicity testing may be
used in risk assessments of chemicals for humans and non-target environmental
organisms. Acute toxicity study is better described as LD50, which is defined as
the dose which kills 50% of animals. LD50 is used for the estimation of the
toxicity of the chemical agents. Acute toxicity provides guidelines on the dose to
be use in more prolonged studies and it also provides the basis for which other
testing program can be design. In acute toxicity studies rodent are mostly used
because they are economical and readily available and easy to handle. This test is
carried out in each species of animal as the same route as intended to be use in
treatment
Importance of acute toxicity testing
icity.
the development and testing of test substances.
studies.
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the adverse effects of a substance on human,

animal health and environment.
transportation of chemical agents
Sub-acute toxicity studies

This study is conducted to determine organs affected by different dose levels.
This study access the nature of toxic dose under more realistic situation than the
acute toxicity studies. Three dose levels are normally used[2].
Dose that is high enough to elicit definite signs of toxicity but not to kill many
of the animals.
Doses are generally selected on the basis of information obtained in acute toxicity
studies using both LD50 and the slope of the dose response curve. The duration of
sub-acute toxicity studies depend on intended duration of the test substance.
Chronic toxicity studies
This study is basically to determine the organs affected and to check whether the
drug is potentially carcinogenic or not. This test extends over a long period of
time and it involves large groups of laboratory animals. Chronic toxicity is the
development of adverse effects as the result of long term exposure to a toxicant or
other stressor. It can manifest as direct lethality but more commonly refers to
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sublethal endpoints such as decreased growth, reduced reproduction, or

behavioral changes such as impacted swimming performance.
Common aquatic chronic toxicity tests
Chronic toxicity tests are performed to determine the long term toxicity potential
of toxicants or other stressors, commonly to aquatic organisms. Examples of
common aquatic chronic toxicity test organisms, durations, and endpoints include:
 Fathead minnow, Pimephales promelas, larval survival and growth

 Daphnia, Daphnia magna, 21-d survival and reproduction
 Green algae, Raphidocelis subcapitata, 72-h growth
 Amphipod, Hyalella azteca, 42-d survival, growth, and reproduction
GENOTOXICITY AND MUTAGENICITY- TERATOGENICITY
 – Genotoxicity covers a broader spectrum of endpoints than mutagenicity,

includes DNA damage assessments. DNA damage are not themselves
necessarily transmissible to the next generation of cells, pre-mutagenic
 – Mutagenicity refers to the production of transmissible genetic
alterations. Somatic cell genotoxicity may lead to cancer. Germ cell
genotoxicity may lead to infertility or diseased children
 TERATOGENICITY  Capacity of a drug to cause foetal abnormalitites
when administered to the pregnant mother.  Placenta does not consider a
strict barrier and any drug can cross it to a greater or lesser extent.  The
embryo is one of the most dynamic biological systems
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Genotoxicity • Genotoxicity tests can be defined as in vitro and in vivo tests

designed to detect compounds that induce genetic damage by various
mechanisms. • These tests enable hazard identification with respect to damage to
DNA and its fixation. Genotoxins can be of the following category depending on
its effects 1) Carcinogens or cancer causing agents 2)Mutagens or mutation
causing agents 3)Teratogens or birth defect causing agents. Agents that can cause
direct or indirect damage to the DNA • Reactive oxygen species. • UV and
ionizing radiations. • Nucleoside analogues . • Topoisomerase inhibitors . •
Protein synthesis inhibitors .
OECD GUIDELINES • Genetic Toxicology : was first published in 1987
.Following a global update of the Genetic Toxicology • Latest revision provides :
(1) general background and historical information on the OECD genetic
toxicology. (2) a brief overview of the important types of genetic damage
evaluated by these tests. (3) a description of the specific tests.
SCHEDULE –Y • Gene mutation in bacteria
• An in-vitro test with cytogenic evaluation of chromosomal damage
. • An in-vivo test for chromosomal damage using rodent hematopoietic cells
(chromosomal aberration , micronucleus • DNA adduct tests , DNA strands break
, DNA repair /recombination .
ICH • S2A:Guidance on Specific aspects of Regulatory Tests for Pharmaceuticals
.
• S2B: Standard Battery for Testing of Pharmaceuticals • M3:Timing of Pre-
Clinical Studies in Relation to Clinical Trials.
Importance • Genotoxicity assays have become an integral component of
regulatory requirement.
• Compounds which are positive in these tests, have the potential to be human
carcinogens and/or mutagens. so it’s used in prediction.
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Aim • To identify substances that can cause genetic alterations in somatic and/or
germ cells.
• To identify substances that causes genetic alterations and thus use this
information in regulatory decisions.
Mechanism of Genotoxicity
• The damage to the genetic material is caused by the interactions of the
genotoxic substance with the DNA structure and sequence.
• These genotoxic substance interact at a specific location or base sequence of the
DNA structure causing lesions, breakage, fusion, deletion, mis-segregation or
non- disjunction leading to damage and mutation .
Standard test battery for genotoxicity •
AMES TEST (Bacterial reverse mutation test) Bacteria : Salmonella
typhimurium or strains E.coli.
Ames test was brought forward by Bruce Ames in 1970. • He is professor in
university of California , berkely . In department of biochemistry. • He developed
this method because previous methods were expensive and time consuming.
Principle • Identifies substances that induce gene mutations by base substitutions
or frame-shifts.
• Two species of bacteria Salmonella typhimurium and Escherichia coli with
identified mutations in an amino acid i.e. His or Trp as the reporter locus.
• It detects mutations which revert mutations present in the test strains and restore
the functional capability of the bacteria to synthesize an essential amino acid
PROCEDURE • 2 methods : 1.Plate incorporation method. 2. pre-incubation
method.
STEPS OF AMES TEST: • Prepare the culture of Salmonella histidine
auxotroph's (His-). • Mix the bacterial cells and test substance in dilute molten top
agar with a small amount of histidine in one set, and control with complete
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medium plus large amount of histidine . • Pour the molten mixture on the top of
minimal agar plates and incubate at 37°C for 2-3 days. Until histidine is depleted
all the His- cells will grow in the presence of test mutagen. • When the histidine is
completely exhausted only the revertants will grow on the plate. • High number of
colonies represent the greater mutagenicity
INVITRO MAMALIAN CELL MICRONUCLEUS TEST -2010 •

Micronuclei is the small nucleus that forms whenever a chromosome or its
fragment is incorporated with daughter nuclei during cell division.
principle • Micronuclei are the product of fragmented chromosomes or mitotic
spindle failure in a cell. Micronuclei are formed by condensation of acentric
chromosomes that are not included in the main nuclei following the anaphase. •
Micronuclei are formed in the cytoplasm through the following events: • In
anaphase, a chromatid and chromosomal fragments lag behind when the centric
elements move towards the spindle poles. Micronucleus arises from chromosomal
fragments or acentric chromosomes that are not incorporated into daughter nuclei
at mitosis because they lack a centromere.
Mammalian Erythrocyte Micronucleus Test • Animals are exposed to the test

substance by an appropriate route • If bone marrow > the animals are sacrificed,
bone marrow extracted, and preparations made and stained • If peripheral blood >
the blood is collected at appropriate times after treatment and smear preparations
are made and stained. • Preparations are analysed for the presence of micronuclei
Principle • For the detection of damage induced by the test substance to the
chromosomes or the mitotic apparatus of erythroblasts (rodents) • Identifies
micronuclei containing lagging chromosome fragments or whole chromosomes. •
An increase in the frequency of micronucleated polychromatic erythrocytes in
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treated animals is an indication of induced chromosome damage because they

lack main nucleus
INVITRO MAMMALIAN CHROMASOMALABBERATION TEST
PRINCIPLE • After exposure of cell cultures , treated with a metaphase-
arresting substance colchicine . with and without metabolic activation • harvested,
stained and metaphase cells are analysed microscopically for the presence of
chromosome aberrations .
Cell lines: CHO, CHL, V79, TK6. • Structural aberrations may be of two types:
chromosome or chromatid.
MAMMALIAN BONE MARROW CHROMOSOME ABERRATION TEST

principle • For the detection of structural chromosome aberrations induced by test
compounds only in bone marrow cells of animals (rodents). • Animals are
exposed to the test substance , metaphase-arresting agent , sacrificed at
appropriate times after treatment.
Bone marrow cells are usually obtained from the femurs or tibias immediately
after sacrifice , and stained using established methods. • Blood :tail vein or other
appropriate blood vessel , smear preparations are made and then stained • DNA
specific stain [e.g acridine orange or Hoechst 33258 plus pyronin-Y]
Prior to sacrifice, animals are injected i.p with an appropriate dose of a metaphase
arresting agent , sampled thereafter. Cells are harvested from the bone marrow
and analysed from chromosome aberrations. • Chromosome preparation: bone
marrow in hypotonic solution , spread on slides and stained
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General Principles In Treatment of Poisoning

 GENERAL PRINCIPLES OF TREATMENT OF POISONING,
 CLINICAL SYMPTOMS AND MANAGEMENT OF BARBITURATES,
 MORPHINE,
 ORGANOPHOSPHOSPHORUS COMPOUND
 LEAD, MERCURY AND ARSENIC POISONING.
General Principles of Poisoning

Poisoning is contact with a substance that results in toxicity. Symptoms vary, but
certain common syndromes may suggest particular classes of poisons. Diagnosis
is primarily clinical, but for some poisonings, blood and urine tests can help.
Treatment is supportive for most poisonings; specific antidotes are necessary for a
few. Prevention includes labeling drug containers clearly and keeping poisons out
of the reach of children.
Most poisonings are dose-related. Dose is determined by concentration over time.

Toxicity may result from exposure to excess amounts of normally nontoxic
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substances. Some poisonings result from exposure to substances that are

poisonous at all doses. Poisoning is distinguished from hypersensitivity and
idiosyncratic reactions, which are unpredictable and not dose-related, and from
intolerance, which is a toxic reaction to a usually nontoxic dose of a substance.
Poisoning is commonly due to ingestion but can result from injection, inhalation,
or exposure of body surfaces (eg, skin, eye, mucous membranes). Many
commonly ingested nonfood substances are generally nontoxic (see Table:
Substances Usually Not Dangerous When Ingested*); however, almost any
substance can be toxic if ingested in excessive amounts.
Accidental poisoning is common among young children, who are curious and
ingest items indiscriminately despite noxious tastes and odors; usually, only a
single substance is involved. Poisoning is also common among older children,
adolescents, and adults attempting suicide; multiple drugs, including alcohol,
acetaminophen, and other OTC drugs, may be involved. Accidental poisoning
may occur in the elderly because of confusion, poor eyesight, mental impairment,
or multiple prescriptions of the same drug by different physicians (see also
After exposure or ingestion and absorption, most poisons are metabolized, pass
through the GI tract, or are excreted. Occasionally, tablets (eg, aspirin, iron,
enteric-coated drugs) form large concretions (bezoars) in the GI tract, where they
tend to remain, continuing to be absorbed and causing toxicity.
Symptoms and Signs
Symptoms and signs of poisoning vary depending on the substance (see Table:
Symptoms and Treatment of Specific Poisons ). Also, different patients poisoned
with the same substance may present with very different symptoms. However, 6
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clusters of symptoms (toxic syndromes, or toxidromes) occur commonly and may

suggest particular classes of substances (see Table: Common Toxic Syndromes
(Toxidromes)). Patients who ingest multiple substances are less likely to have
symptoms characteristic of a single substance.
Symptoms typically begin soon after contact but, with certain poisons, are
delayed. The delay may occur because only a metabolite is toxic rather than the
parent substance (eg, methanol, ethylene glycol, hepatotoxins). Ingestion of
hepatotoxins (eg, acetaminophen, iron, Amanita phalloides mushrooms) may
cause acute liver failure that occurs one to a few days later. With metals or
hydrocarbon solvents, symptoms typically occur only after chronic exposure to
the toxin.
Ingested and absorbed toxins generally cause systemic symptoms. Caustics and
corrosive liquids damage mainly the mucous membranes of the GI tract, causing
stomatitis, enteritis, or perforation. Some toxins (eg, alcohol, hydrocarbons) cause
characteristic breath odors. Skin contact with toxins can cause various acute
cutaneous symptoms (eg, rashes, pain, blistering); chronic exposure may cause
dermatitis.
Inhaled toxins are likely to cause symptoms of upper airway injury if they are
water-soluble (eg, chlorine, ammonia) and symptoms of lower airway injury and
noncardiogenic pulmonary edema if they are less water-soluble (eg, phosgene).
Inhalation of carbon monoxide, cyanide, or hydrogen sulfide gas can cause organ
ischemia or cardiac or respiratory arrest. Eye contact with toxins (solid, liquid, or
vapor) may damage the cornea, sclera, and lens, causing eye pain, redness, and
loss of vision.
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Some substances (eg, cocaine, phencyclidine, amphetamine) can cause severe

agitation, which can result in hyperthermia, acidosis, and rhabdomyolysis.
Diagnosis
 Consideration of poisoning in patients with altered consciousness or

unexplained symptoms
 History from all available sources
 Selective, directed testing
The first step of diagnosis of poisoning is to assess the overall status of the
patient. Severe poisoning may require rapid intervention to treat airway
compromise or cardiopulmonary collapse.
Poisoning may be known at presentation. It should be suspected if patients have

unexplained symptoms, especially altered consciousness (which can range from
agitation to somnolence to coma). If purposeful self-poisoning occurs in adults,
multiple substances should be suspected.
History is often the most valuable tool. Because many patients (eg, preverbal
children, suicidal or psychotic adults, patients with altered consciousness) cannot
provide reliable information, friends, relatives, and rescue personnel should be
questioned. Even seemingly reliable patients may incorrectly report the amount or
time of ingestion. When possible, the patient’s living quarters should be inspected
for clues (eg, partially empty pill containers, a suicide note, evidence of
recreational drug use). Pharmacy and medical records may provide useful
information. In potential workplace poisonings, coworkers and supervisors should
be questioned. All industrial chemicals must have a material safety data sheet
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(MSDS) readily available at the workplace; the MSDS provides detailed

information about toxicity and any specific treatment.
Testing
In most cases, laboratory testing provides limited help. Standard, readily available
tests to identify common drugs of abuse (often called toxic screens) are
qualitative, not quantitative. These tests may provide false-positive or false-
negative results, and they check for only a limited number of substances. Also, the
presence of a drug of abuse does not necessarily indicate that the drug caused the
patient’s symptoms or signs. Urine drug screening is used most often but has
limited value and usually detects classes of drugs or metabolites rather than
specific drugs. For example, an opioid urine immunoassay test does not detect
fentanyl or methadone but does react with very small amounts of morphine or
codeine analogues. The test used to identify cocaine detects a metabolite rather
than cocaine itself.
For most substances, blood levels cannot be easily determined or do not help
guide treatment. For a few substances (eg, acetaminophen, aspirin, carbon
monoxide, digoxin, ethylene glycol, iron, lithium, methanol, phenobarbital,
phenytoin, theophylline), blood levels may help guide treatment. Many authorities
recommend measuring acetaminophen levels in all patients with mixed ingestions
because acetaminophen ingestion is common, is often asymptomatic during the
early stages, and can cause serious delayed toxicity that can be prevented by an
antidote. For some substances, other blood tests (eg, PT for warfarin overdose,
methemoglobin levels for certain substances) help guide treatment. For patients
who have altered consciousness or abnormal vital signs or who have ingested
certain substances, tests should include serum electrolytes, BUN, creatinine,
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serum osmolality, glucose, coagulation studies, and ABGs. Other tests (eg,
methemoglobin level, carbon monoxide level, brain CT) may be indicated for
certain suspected poisons or in certain clinical situations.
For certain poisonings (eg, due to iron, lead, arsenic, other metals, or to packets of
cocaine or other illicit drugs ingested by so-called body packers), plain abdominal
x-rays may show the presence and location of ingested substances.
For poisonings with drugs that have cardiovascular effects or with an unknown
substance, ECG and cardiac monitoring are indicated.
If blood levels of a substance or symptoms of toxicity increase after initially

decreasing or persist for an unusually long time, a bezoar, a sustained-release
preparation, or reexposure (ie, repeated covert exposure to a recreationally used
drug) should be suspected.
Treatment
 Supportive care
 Activated charcoal for serious oral poisonings
 Occasional use of specific antidotes or dialysis
 Only rare use of gastric emptying
Seriously poisoned patients may require assisted ventilation or treatment of

cardiovascular collapse. Patients with impaired consciousness may require
continuous monitoring or restraints. The discussion of treatment for specific
poisonings, below and in see Table: Common Specific Antidotes, see Table:
Guidelines for Chelation Therapy, and see Table: Symptoms and Treatment of
Specific Poisons , is general and does not include specific complexities and
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details. Consultation with a poison control center is recommended for any

poisonings except the mildest and most routine.
Initial stabilization
 Maintain airway, breathing, and circulation

 IV naloxone
 IV dextrose and thiamine
 IV fluids, sometimes vasopressors
Airway, breathing, and circulation must be maintained in patients suspected of

a systemic poisoning. Patients without a pulse or BP require emergency
cardiopulmonary resuscitation.
If patients have apnea or compromised airways (eg, foreign material in the

oropharynx, decreased gag reflex), an endotracheal tube should be inserted (see
Tracheal Intubation). If patients have respiratory depression or hypoxia,
supplemental oxygen or mechanical ventilation should be provided as needed.
IV naloxone (2 mg in adults; 0.1 mg/kg in children; doses as high as 10 mg may

be necessary in some cases) should be tried in patients with apnea or severe
respiratory depression while maintaining airway support. In opioid addicts,
naloxone may precipitate withdrawal, but withdrawal is preferable to severe
respiratory depression. If respiratory depression persists despite use of naloxone,
endotracheal intubation and continuous mechanical ventilation are required. If
naloxone relieves respiratory depression, patients are monitored; if respiratory
depression recurs, patients should be treated with another bolus of IV naloxone or
endotracheal intubation and mechanical ventilation. Using a low-dose continuous
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naloxone infusion to maintain respiratory drive without precipitating withdrawal

has been suggested but in reality can be very difficult to accomplish.
IV dextrose (50 mL of a 50% solution for adults; 2 to 4 mL/kg of a 25% solution

for children) should be given to patients with altered consciousness or CNS
depression, unless hypoglycemia has been ruled out by immediate bedside
determination of blood glucose.
Thiamine (100 mg IV) is given with or before glucose to adults with suspected
thiamine deficiency (eg, alcoholics, undernourished patients).
IV fluids are given for hypotension. If fluids are ineffective, invasive

hemodynamic monitoring may be necessary to guide fluid and vasopressor
therapy. The first-choice vasopressor for most poison-induced hypotension is
norepinephrine 0.5 to 1 mg/min IV infusion, but treatment should not be delayed
if another vasopressor is more immediately available.
Topical decontamination
Any body surface (including the eyes) exposed to a toxin is flushed with large
amounts of water or saline. Contaminated clothing, including shoes and socks,
and jewelry should be removed. Topical patches and transdermal delivery systems
are removed.
Activated charcoal
Charcoal is usually given, particularly when multiple or unknown substances have

been ingested. Use of charcoal adds little risk (unless patients are at risk of
vomiting and aspiration) but has not been proved to reduce overall morbidity or
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mortality. When used, charcoal is given as soon as possible. Activated charcoal

adsorbs most toxins because of its molecular configuration and large surface area.
Multiple doses of activated charcoal may be effective for substances that undergo
enterohepatic recirculation (eg, phenobarbital, theophylline) and for sustained-
release preparations. Charcoal may be given at 4- to 6-h intervals for serious
poisoning with such substances unless bowel sounds are hypoactive. Charcoal is
ineffective for caustics, alcohols, and simple ions (eg, cyanide, iron, other metals,
lithium).
The recommended dose is 5 to 10 times that of the suspected toxin ingested.

However, because the amount of toxin ingested is usually unknown, the usual
dose is 1 to 2 g/kg, which is about 10 to 25 g for children < 5 yr and 50 to 100 g
for older children and adults. Charcoal is given as a slurry in water or soft drinks.
It may be unpalatable and results in vomiting in 30% of patients. Administration
via a gastric tube may be considered, but caution should be used to prevent
trauma caused by tube insertion or aspiration of charcoal; potential benefits must
outweigh risks. Activated charcoal should probably be used without sorbitol or
other cathartics, which have no clear benefit and can cause dehydration and
electrolyte abnormalities.
Gastric emptying
Gastric emptying, which used to be well-accepted and seems intuitively

beneficial, should not be routinely done. It does not clearly reduce overall
morbidity or mortality and has risks. Gastric emptying is considered if it can be
done within 1 h of a life-threatening ingestion. However, many poisonings
manifest too late, and whether a poisoning is life threatening is not always clear.
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Thus, gastric emptying is seldom indicated and, if a caustic substance has been
ingested, is contraindicated (see Caustic Ingestion).
If gastric emptying is used, gastric lavage is the preferred method. Gastric lavage
may cause complications such as epistaxis, aspiration, or, rarely, oropharyngeal or
esophageal injury. Syrup of ipecac has unpredictable effects, often causes
prolonged vomiting, and may not remove substantial amounts of poison from the
stomach. Syrup of ipecac may be warranted if the ingested agent is highly toxic
and transport time to the emergency department is unusually long, but this is
uncommon in the US.
For gastric lavage, tap water is instilled and withdrawn from the stomach via a
tube. The largest tube possible (usually > 36 French for adults or 24 French for
children) is used so that tablet fragments can be retrieved. If patients have altered
consciousness or a weak gag reflex, endotracheal intubation should be done
before lavage to prevent aspiration. Patients are placed in the left lateral decubitus
position to prevent aspiration, and the tube is inserted orally. Because lavage
sometimes forces substances farther into the GI tract, stomach contents should be
aspirated and a 25-g dose of charcoal should be instilled through the tube
immediately after insertion. Then aliquots (about 3 mL/kg) of tap water are
instilled, and the gastric contents are withdrawn by gravity or syringe. Lavage
continues until the withdrawn fluids appear free of the substance; usually, 500 to
3000 mL of fluid must be instilled. After lavage, a 2nd 25-g dose of charcoal is
instilled.
Whole-bowel irrigation
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This procedure flushes the GI tract and theoretically decreases GI transit time for
pills and tablets. Irrigation has not been proved to reduce morbidity or mortality.
Irrigation is indicated for any of the following:
 Some serious poisonings due to sustained-release preparations or

substances that are not adsorbed by charcoal (eg, heavy metals)
 Drug packets (eg, latex-coated packets of heroin or cocaine ingested by
body packers)
 A suspected bezoar
A commercially prepared solution of polyethylene glycol (which is

nonabsorbable) and electrolytes is given at a rate of 1 to 2 L/h for adults or at 25
to 40 mL/kg/h for children until the rectal effluent is clear; this process may
require many hours or even days. The solution is usually given via a gastric tube,
although some motivated patients can drink these large volumes.
Alkaline diuresis
Alkaline diuresis enhances elimination of weak acids (eg, salicylates,

phenobarbital). A solution made by combining 1 L of 5% D/W with 3 50-mEq
ampules of NaHCO3 and 20 to 40 mEq of K can be given at a rate of 250 mL/h in
adults and 2 to 3 mL/kg/h in children. Urine pH is kept at > 8, and K must be
repleted. Hypernatremia, alkalemia, and fluid overload may occur but are usually
not serious. However, alkaline diuresis is contraindicated in patients with renal
insufficiency.
Dialysis
Common toxins that may require dialysis or hemoperfusion include
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 Ethylene glycol
 Lithium
 Methanol
 Salicylates
 Theophylline
These therapies are less useful if the poison is a large or charged (polar) molecule,
has a large volume of distribution (ie, if it is stored in fatty tissue), or is
extensively bound to tissue protein (as with digoxin, phencyclidine,
phenothiazines, or tricyclic antidepressants). The need for dialysis is usually
determined by both laboratory values and clinical status. Methods of dialysis
include hemodialysis, peritoneal dialysis, and lipid dialysis (which removes lipid-
soluble substances from the blood), as well as hemoperfusion (which more rapidly
and efficiently clears specific poisons—see Overview of Renal Replacement
Therapy).
Specific antidotes
For the most commonly used antidotes, see Table: Common Specific Antidotes.
Chelating drugs are used for poisoning with heavy metals and occasionally with
other drugs (see Table: Guidelines for Chelation Therapy). IV fat emulsions in
10% and 20% concentrations and high-dose insulin therapy have been used to
successfully treat several different cardiac toxins (eg, bupivacaine, verapamil).
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Antidote therapy N-acetylcysteine (NAC): gives maximum protection against

hepatotoxicity when administered within 10 hours of paracetamol overdose, but can be
given with (lesser) benefit upto 36 hours Indications 1. Paracetamol ingested is more than
100 mg/kg. 2. Likelihood exists of paracetamol-induced hepatic failure General
Principles in Rx of Poisoning & common drug poisoning
Salicylates Acute Poisoning: a. Early : Nausea, vomiting, sweating,tinnitus, vertigo &

hyperventilation due to respiratory alkalosis. disorientation,hyperactivity, slurred speech,
ataxia, and restlessness may be early findings in patients with severe toxicity b. Late—
Deafness, hyperactivity, agitation, delirium, convulsions, hallucinations, hyperpyrexia.
Coma is unusual c. Complications—Metabolic acidosis, pulmonary oedema,
rhabdomyolysis, cardiac depression, thrombocytopenic purpura General Principles in Rx
of Poisoning & common drug poisoning
Chronic Poisoning (Salicylism):  This is characterised by slow onset of confusion,

agitation, lethargy, disorientation, slurred speech, hallucinations, convulsions, and coma
 Sometimes “salicylism” presents as pseudosepsis syndrome characterised by fever,
leukocytosis, hypotension, and multi-organ system failure: ARDS, acute renal failure and
coagulopathy (DIC) General Principles in Rx of Poisoning & common drug poisoning
Salicylates must not be therapeutically administered to children under 15 years of age,
especially if they are suffering from chicken pox or influenza. There is a serious risk of
precipitating Reye’s syndrome which can be fatal  Main feature: onset of hepatic failure
& encephalopathy General Principles in Rx of Poisoning & common drug poisoning
Treatment • Patients with major signs or symptoms (metabolic acidosis,dehydration,

mental status changes, seizures, pulmonary oedema) should be admitted to the Intensive
Care Unit regardless of serum salicylate level • Minor symptoms only (i.e. nausea,
tinnitus) following acute overdose may be managed in the emergency department with
decontamination and alkaline diuresis if the salicylate level is shown to be declining
General Principles in Rx of Poisoning & common drug poisoning
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Stomach wash may be beneficial upto 12 hours after ingestion, since toxic doses of salicylates
often cause pylorospasm and delayed gastric emptying. • Activated charcoal (AC): It is said to be
very efficacious in the treatment of salicylate poisoning since each gram of AC can adsorb 550
mg of the drug. A 10:1 ratio of AC to salicylate ingested appears to result in maximum
efficiency. The initial dose of AC can be combined with a cathartic to enhance elimination.
General Principles in Rx of Poisoning & common drug poisoning
OP Poisoning 1. Acute Poisoning: a. Cholinergic Excess: • Muscarinic effects:

bronchoconstriction with wheezing and dyspnoea,cough, pulmonary oedema, vomiting,
diarrhoea,abdominal cramps, increased salivation, lacrimation, sweating, bradycardia,
hypotension,miosis, & urinary incontinence • Nicotinic effects: Muscle weakness, fatiguability,
and fasciculations are very common. General Principles in Rx of Poisoning & common drug
poisoning
CNS Effects—Restlessness, headache, tremor, drowsiness, delirium, slurred speech, ataxia &
convulsions.Coma supervenes in the later stages  Death usually results from respiratory failure
due to weakness of respiratory muscles, as well as depression of central respiratory drive. 
Chronic Poisoning: Those who are engaged in pesticide spraying of crops. The following are the
main features— a. Polyneuropathy: paraesthesias, muscle cramps, weakness, gait disorders. b.
CNS Effects : drowsiness, confusion, irritability, anxiety General Principles in Rx of Poisoning
& common drug poisoning
Acute Poisoning: a. Decontamination:  If skin spillage has occurred, it is imperative that the
patient should be undressed & washed thoroughly with soap & water  If ocular exposure has
occurred, copious eye irrigation should be done with normal saline or Ringer’s solution. If these
are not immediately available, tap water can be used General Principles in Rx of Poisoning &
common drug poisoning Treatment
Antidotes:  Atropine—It is a competitive antagonist of acetylcholine at the muscarinic

postsynaptic membrane & in the CNS & blocks the muscarinic manifestations of
organophosphate poisoning  Oximes—The commonest is pralidoxime, which is a nucleophilic
Page 23
oxime that helps to regenerate acetylcholinesterase at muscarinic, nicotinic, & CNS sites General
Principles in Rx of Poisoning & common drug poisoning
Supportive Measures:  Administer IV fluids to replace losses  Maintain airway patency and
oxygenation. Suction secretions. Endotracheal intubation and mechanical ventilation may be
necessary. Monitor pulse oximetry or arterial blood gases to determine need for supplemental
oxygen  The following drugs are contraindicated: parasympathomimetics, phenothiazines,
antihistamines General Principles in Rx of Poisoning & common drug poisoning
Barbiturates Poisoning is mostly suicidal,rarely accidental  Characterized by respiratory

failure,cardiovascular collapse,coma & renal failure  Treatment : Gastric lavage,artificial
respiration & forced alkaline diuresis with mannitol & sodium bicarbonate General Principles in
Rx of Poisoning & common drug poisoning
Atropine • Belladonna poisoning may occur due to drug overdose or consumption of seeds &
berries of belladonna/datura plant • Dry mouth, difficulty in swallowing & talking Dilated pupil,
photophobia, blurring of near vision, palpitation, psychotic behaviour, ataxia, delirium, visual
hallucinations,Hypotension, weak & rapid pulse, cardiovascular collapse with respiratory
depression • Convulsions & coma occur only in severe poisoning General Principles in Rx of
Poisoning & common drug poisoning
Iron • Has a direct corrosive action on the stomach & proximal small bowel • Once absorbed,
produces shock, metabolic acidosis, liver failure& death • Initially, GI symptoms prevail with
persistent vomiting, abdominal pain& hemorrhage • A quiescent phase may be observed,
followed by shock, coma, metabolic acidosis& liver failure General Principles in Rx of
Poisoning & common drug poisoning
Treatment • Management of iron poisoning includes gastric lavage with normal saline • The
treatment of choice is the antidote desferrioxamine, which chelates free serum iron in the plasma
to form ferrioxamine • Indications :  All critical patients who present with coma, shock, or
hemorrhage  All patients with a serum iron level higher than 500 mg/dL  Patients who are
Page 24
symptomatic with a serum iron > 300 mg/dL General Principles in Rx of Poisoning & common
drug poisoning 53
Morphine • It may be accidental, suicidal or seen in drug abusers. The human lethal dose is
estimated to be about 250 mg • Stupor or coma, flaccidity, shallow & occasional breathing,
cyanosis, pinpoint pupil,fall in BP & shock; convulsions may be seen in few, pulmonary edema
occurs at terminal stages, death is due to respiratory failure General Principles in Rx of
Poisoning & common drug poisoning 54
Treatment • Consists of respiratory support & maintenance of BP (i.v.fluids, vasoconstrictors) •

Gastric lavage should be done with pot. permanganate to remove unabsorbed drug • Specific
antidote: Naloxone 0.4–0.8 mg i.v. repeated every 2–3 min till respiration picks up, is the
specific antagonist of choice  Due to short duration of action, naloxone should be repeated
every 1–4 hours, according to the response.
Page 25
CHRONOPHARMACOLOGY
INTRODUCTION
Many functions of the human body vary day by day and these types of variations cause the
changes in both in disease state and in normal state. Cardiovascular functions such as heart rate
and blood pressure show 24 hours variation. The incidence of cardiovascular disease such as
acute myocardial infarction, strokes and arrhythmia also exhibits clear diurnal oscillation since
most of these disorders can induce fatal or severe outcomes. It is important to elucidate the
precise mechanism of the onset of these diseases. The dependence of our body functions in the
certain diseased state depends on the circadian rhythm. The science dealing with the
phenomenon of biological rhythmicity in living organism is called chronobiology.
Circadian rhythm - The phase of circadian rhythm is defined with respect to an easily
identifiable reference point of the endogenous circadian oscillation such as through of the body
temperature rhythm or the onset of metabolism rhythm. Thus circadian phase shift can be
determined by measuring the change in timing of the chosen phase maker from one cycle to the
next. During ambulatory conditions, changes in environmental stimuli and behaviour (e.g. -
Light/dark, rest/ activity and temperature) often obscure the endogenous component of the
underlying circadian oscillation that is being measured.The amplitude of circadian rhythm refers
to the half distance from the maximum to the minimum of the observed rhythm.4 Circadian
clocks regulate a number of key behaviours in a wide variety of organisms. It also helps
organism to restrict their activity to species – specific times of the day, which enable them to find
food escape predators & avoid undue competition between sympatric species e.g. - in drosophila
parasitism activity peaks of different species occurs at different times of the day, which
significantly reduces intrinsic competitive disadvantage for the inferior competitor and such
temporal portioning is achieved at least partly with the help of circadian clocks.5In the evening,
when less light enters in the eyes, the master clock triggers production of a hormone called
melatonin which makes feel drowsy and helps stay in asleep. Circadian rhythm and their
sensitivity to time may change as the age of the individual person increase.
The Chronopharmacology is useful to solve problems of drugs optimization means to enhance
the desired efficiency or to reduce its undesired effects. The chronopharmacologic approach
involves a lesser risk of errors or false information than the conventional homeostatic approach.
Page 26
Many seasonal psychopharmacological drugs are useful in seasonal affective disorders though
diazepam has fewer adverse effects and other selected drugs like phenobarbitone and
chlorpromazine also have many adverse effects because of which they are leaving the market
even though their pharmacological actions are potent. The need of this is to design strategies to
ameliorate the side effects which make them more acceptable if the pharmacology and adverse
effects of these drugs is circadian time dependant, it can be modulated by altering the time of
administration of drugs. Any dependence of these drugs on the circadian time may provide a clue
to ameliorate the major drawback of drugs.
Chronotherapeutics: - Chronotherapeutics refers to a treatment method in which drug
availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and
minimize side effects. It is based on the observation that there is an interdependent relationship
Page 27
between the peak-to through rhythmic activity in disease symptoms and risk factors,
pharmacologic sensitivity, and pharmacokinetics of many drugs takes into account predictable
administration time dependent variation in the pharmacokinetics of drugs as well as the
susceptibility due to temporal organization of physiochemical process and function of body as
circadian and others rhythms. One approach to increase the efficiency of pharmacotherapy is the
administration of drugs at times at which they are most effective and best tolerated.Advantages
of Chronopharmacotherapy: –
1. It prevents an overdosing of any class of drug.
2. It makes the utilization of the drug more appropriate and thus the value of a drug is increased.
3. It reduces the unnecessary side effects of a drug and helps in caring out the treatment for only
a particular or limited period of time.7
Reason for Chronopharmacology

Auto induction:- A repetitive dose of a drug induces or increases enzymes responsible for its
elimination, thereby increasing its clearance. This is called as auto induction. It is dependent on
dose and concentration of the drug. It has a number of therapeutic consequences. It affects the
time to achieve steady state and limits one’s ability to use information from a single dose to
predict kinetics after repeated dose or continuous administration. Carbamazepine shows time
dependence in its disposition. The decrease in its peak concentration on repetitive oral
administration that either oral bioavailability decreases or clearance increases with time.
Auto inhibition:- It may occur during the metabolism of certain drugs. The metabolites formed
from drug firstly increase in concentration and further inhibit metabolism of the parent drug.
This phenomenon is called as product inhibition or allosteric inhibition or feedback inhibition.
Need for Chronopharmacotherapy
It is required to monitor therapy so as to limit the duration of therapy especially in cases where
patients are already having compromised renal, cardiac and hepatic or any other function of the
body. Any type of accumulation of drugs in these organs causes greater toxicity which may led
to diminished function of the organ. Thus the chronopharmacotherapy becomes a very important
part of treatment of several diseases particularly those effecting targeted body parts. According
to the 1996 American medical association review, more consideration of chronotherapy in
clinical trials is highly welcomed by the whole medical community. The result of the survey
Page 28
showed that 75 percent of the doctors are in favour of patient’s circadian or daily rhythm
oriented treatment.
Biological Rhythms and Rhythmic Components
Circadian implies approximately a day, major periodic components of biological rhythms are
found around 24 hours (circadian) and 30 days (Circamensual) and one year (Circannual).
Circadian rhythms are found in all the organisms, infact the existence of circadian rhythms in
living organisms was first established during a detailed study of leaf movement in plants more
than 200 year ago. Biological rhythms posses both an internal as well as external components.
Rhythmicity has been detected for a numbers of physiological variables like pulse, temperature,
blood pressure, hormonal secretion via diurnal variation in effects of insulin on blood glucose.
Page 29
Human Circadian Time Structure

release should also vary over time. Chronopharmaceutical drug delivery system are gaining
importance in the field of pharmaceutical technology as these system deliver right dose at
specific time at a specific site. Various technologies such as time- controlled, pulsed, triggered
and programmed drug delivery devices have been developed and extensively studied in recent
years for Chronopharmaceutical drug delivery.Many functions of the human body vary
considerably in a day. These variations cause changes both in disease state and in plasma drug
concentrations. Human circadian rhythm is based on sleep-activity cycle, is influenced by our
genetic makeup and hence, affects the body’s functions day and night (24- hours period.
Research in the chronopharmacological field has demonstrated the importance of biological
rhythms in drug therapy and this brought a new approach to the development of drug delivery
systems.
Page 30
Circadian rhythm in the pathogenesis of diseases- From the various studies, it is formed that
the many cardiovascular events including myocardial infarction, stroke and sudden death occur
during the initial hours of morning activity between 6 A.M. and 12 noon. And this is much
higher during this period that other timing during the day. BP rises rapidly in the early morning
hours, the time when most individuals wake and begin their day. This rise in BP corresponds to
increased secretion of catecholamine’s and increased plasma rennin activity. Thus, vascular tone
and total peripheral resistance increase in the morning hours, and rises as a result. At the same
time, heart rate increases in the late morning or early afternoon.
Chronotherapy of cardiovascular diseases -
The differences in patterns of illness between day and night for cardiovascular disorders such as
hypertension, angina, heart attack, sudden cardiac death and stroke have been documented.
Chronotherapeutics approach gives more accurate determination of the time when patients are at
highest risk and in greatest need of therapy. For example – it has often been found that the blood
pressure of hypertensive patient increases rapidly in the morning after awakening, typically
peaks in the middle to late time of the day, decreases in the evening and is lowest while the
patient sleeps at night. It may also be important to recognize that the risk of heart attack appears
to be greatest during the early morning hours after awakening. For instance, capillary resistance
and vascular reactivity are higher in the morning and decreases later in the day. Platelet
agreeability is increased and fibrnolytic activity is deceased in the morning, leading to a state of
relative hyper coagulability of the blood. Blood Pressure is at its lowest during sleeping period
and rises steeply during the early morning period. Many anti- hypertensive drugs do not control
the early morning blood pressure, when given once daily early in the morning.
VARIOUS CARDIOVASCULAR DISEASES
Page 31
Blood pressure (B.P) / Hypertension Blood Pressure is well known to exhibit 24 h variation
with a peak in the morning. A number of factors influence diurnal variation of blood pressure
which is internal factors such as the autonomic nervous system, vasoactive intestinal peptide,
plasma cortisol, plasma rennin activity, aldosterone, plasma atrial natriuretic peptide. Both
sympathetic activity and the rennin-angiotensin–aldosterone access peak in the early morning
hours. In addition, b.p is affected by a variety of external factors including physical activity,
emotional state, meal and sleep/wake routine. These extrinsic stimuli alsoaffect the autonomic
nervous system thus the 24 h variation in the B.P is representative of both endogenous diurnal
rhythms and exogenous factors. Blood pressure is characterized by a circadian rhythm, both in
hypertensive and in normotensive subjects; this pattern is associates with lower B.P values
during sleeping time and periods of minimal activity and higher B.P levels during wakefulness
and mental and physical activity. Various, researchers reported that blood pressure changed
depending on whether the subjects was sleeping, resting or working. Blood pressure fluctuates
throughout the day and night. The duration of the fluctuations may be short, from seconds to
minutes, or long from day to night and season to season. The most easily noted and significant
blood pressure variations are the diurnal changes related to the sleep-wake cycle. The pattern of
blood pressure values obtained during the sleep-wake cycle from characteristic circadian rhythm.
The Continuous monitoring of blood pressure throughout the day and night reveals a pattern with
minimum values of systolic & diastolic pressure between midnight & 4 am. The pressure
increases during waking hours remaining at a plateau for several hours & then reaching a
maximum values early in the morning. This diurnal blood pressure fluctuation is altered in
certain disease states, such as preeclampsia & chronic hypertension. Changing paradigm for
targeting blood pressure control Multiple daily dosing of medication Once daily dosing of
long acting medication Evening dosing of long acting chronotherapeutics medication
Acute myocardial infraction (AMI) / pulmonary embolism(PE)-

It is well known that AMI or PE frequently occurs in the early morning. A number of
physiological functions exhibit diurnal variation including BP, heart rate, coronary blood flow,
platelet function, blood coagulability and fibrnolytic activity. In the early morning, systemic BP
& heart rate increases and augment the oxygen demand of the heart. In addition, the vascular
tone of the coronary artery rises and coronary blood flow decreases in the morning. This
Page 32
increases in oxygen demand & decreases in oxygen supply exaggerate a mismatch of oxygen
demand and supply in the morning. In addition, platelet function & blood coagulability also
increases in the morning. A reduction in fibrnolytic activity resulting in a hypercoagulable state
that could elicit the morning onset of thromboimbolic events. Accumulating evidences suggests
that the autonomic nervous system plays a major role in the circadian variation of the onset of
AMI. A morning increase in the frequency of ischemic episodes is absent in diabetic patients
with autonomic nervous dysfunction. Patients receiving beta-blocker do not show morning
increase in the incidence of angina, AMI & sudden death. Heart rate variability which reflects
sympathetic/vagal balance is also associated with the onset of ischemic episode in the chronic
stable angina. Platelets are not involved in the variation of AMI or thromboimbolic numbers &
their aggregation activity possess circadian oscillation. Platelet activation in vivo is induced by
catecholamine secreted from the sympathetic nervous system in a circadian fashion. However
studies regarding platelet activation do not show
clear circadian expression of any surface marker characteristic of platelet activation, therefore it
is unclear whether the internal clock system directly affects the circadian functions of platelets.2
Arrhythmia
A number of reports demonstrated the presence of circadian variation of cardiac arrhythmia.
Evidences suggest that basic electrophysiological parameters have circadian variations. Atrial &
ventricular refractory periods are strongly affected by the autonomic nervous system, in which
sympathetic activity shortens it and parasympathetic activity elongates the period. Therefore
fluctuations in the activity of autonomic nervous system within a day can be a major trigger of
circadian onset of cardiac arrhythmia. Each parameter of ECG was analyzed as to whether it has
diurnal variations. ECG, AV nodal function, QT interval, R&T wave voltage & QT interval have
been shown to exhibit circadian variations. BIOLOGICAL RHYTHMS OBSERVED IN
VARIOUS BIOLOGICAL SYSTEMS
Page 33
The basic physiological process governing the drug action the absorption the distribution the
metabolism and the excretion are controlled by the following systems of the body. Hence it is
important to know the circadian rhythms in these systems and their effect on drug action.
Urinary system- The urinary system which plays a pivotal role in the elimination of a drug has
many instances of circadian rhythms altering either the clearance or the urinary flow causing
nephrotoxicity. Amino glycosides can produce renal toxicity with chronic administration.
Because these antibiotics are primarily eliminated by renal excretion, diminishing renal function
with time may cause greater drug accumulation and more toxicity. There is clearly a need to
monitor therapy to limit the duration of therapy, especially in patients who already have
compromised renal function. Theophylline causes increase in the renal flow by increasing the
clearance levels and thereby increase in the urine flow and renal excretion. Carbamazepine
shows time dependence in its disposition.
Gastrointestinal system- The gastrointestinal motility, the intraluminal pH, blood flow to
stomach and enzymatic action are not the only factors that influence the gastro intestinal
absorption of the drug. It even depends on the circadian rhythms and all the above mentioned
factors are also influenced by the time of the day. Most of the drugs we generally take are
lipophilic and they are found to have more rate of absorption in early mornings rather than any
hour of the day.
Hepatic system- The anti-depressant nartryptalline which is injected to significant presystemic
hepatic metabolism accumulates in a highly predictable manner on multiple oral dosing. The
clearance levels of acetaminophen are decreased due to the effect of circadian rhythms and thus
resulting in the hepatotoxicity.
Diseases Showing Dependence on Biological Rhythms Asthma-
Chronic airway inflammation and limitation of airflow in the airways characterize bronchial
asthma, and attacks begin with paroxysms of coughing, wheezing, and dyspnoea.
Chronopharmacological studies statistically show that the development of asthma symptoms and
many types of bronchospastic attacks is clearly more common from midnight to early morning
from 2 A.M. and 6am every day. Chronopharmacotherapy for asthma is aimed at getting
maximal effect from bronchodilator medications during the early morning hours. Several drugs
for asthma have beendeveloped based on chronopharmacology. One example is the
bronchodilator uniphyl, a long-acting theophylline taken once a day in the evening causes
Page 34
theophylline blood levels to reach their peak and improve lung function during the difficult early
morning hours. Some studies have even proved that a single dose administered in those early
hours is equally effective as four doses given in a day. In addition to bronchodilators, the inhaled
glucocorticosteroid ciclesonide is now available with once-daily dosing, which also improves
patient’s compliance. Numerous investigations have demonstrated the usefulness of
chronotherapy for asthma, especially for patients with nocturnal asthma.
Diabetes- Biologists have found that a key protein that regulates the biological clocks of
mammals also regulates glucose production in the liver and altering the levels of this protein can
improve the health of diabetic mice. The additional function of the cytochrome is the regulation
of gluconeogenesis according to the diurnal activity and feeding levels. So modulating
cytochrome levels can also help decrease the diabetic effect on the patients.
Arthritis- Chronobiological patterns have been observed with arthritis pain. The symptoms of
rheumatoid arthritis are always worse in the morning. Taking long-acting NSAIDs like
flubiprofen, ketoprofen and indomethacin at bedtime optimizes their therapeutic effect and
minimizes or averts their side effects. People with osteoarthritis, the most common form of the
Page 35
disease, tend to have less pain in the morning and more at night. For osteoarthritis sufferers, the
optimal time for a non-steroidal anti-inflammatory drug such as ibuprofen would be around noon
or mid-afternoon. Ankylosing spondylitis is characterized by swelling and discomfort of the
joints of the back. The overall, back stiffness and pain were a problem throughout the 24 hours,
but pain intensity was rated 2 to 3 times higher and stiffness about 8 times greater between 06:00
and 09:00 than between noon and 15:00.10
Cancer- The tumour cells and the normal cells differ in their Chronobiological cycles. This fact
is the basis for the chronopharmacotherapy of cancer. Based on study which suggested that the
DNA synthesis in the normal human bone marrow cells has a peak around noon while the peak
of DNA synthesis in lymphoma cells is near midnight, a s-phase active cytotoxic therapy at late
nights was administered and it was found that there is a decrease in the tumour cell count with a
little effect on normal cells.
Allergy- The allergic reactions both local and systemic are mediated through interactions of
immune and inflammatory responses. Such responses during the day are usually coordinated by
adrenocortical function and steroid release with high amplitude daily rhythms. Scientists now
believe that the symptoms of allergic rhinitis, and even the skin testing results, can vary
according to the time of day.
New Techniques of Time Controlled Pulsatile Technology Currently pharmaceutical
companies have been focused on developing and commercializing PDDS that fulfil unmet
medical needs in the treatment of various diseases. Recently developed technologies are SODAS
® technology, IPDAS ® technology, CODAS technology, CONTINR, OROSR, CEFORMR,
DIFFUCAPSR, chronomodulating infusion pumps, TIMERx R and physic-chemical
modification of API.
Spheroidal Oral Drug Absorption System (SODAS)- This technology is based on the
production of controlled release beads and it is characterised by its inherent flexibility, enabling
the production of customized dosage forms that respond directly to individual drug candidate
needs. SODAS can provide a number of tailored drug release profiles, including immediate
release of drug followed by sustained release to give to a fast onset of action, which is
maintained for 24 hrs. An additional option is pulsatile release, where a once daily dosage form
can resemble multiple daily doses by releasing drug in discrete bursts throughout the day.
Chronotherapeutics Oral Drug Absorption System (CODAS)-
Page 36
The Chronotherapeutics oral drug absorption system (CODAS) is a multiparticular system which
is designed for bedtime drug dosing, incorporating a 4-5 hrs delay in drug delivery. This delay is
introduced by the level of non enteric release – controlling polymer applied to drug loaded beads.
This technology was designed to release its drug component after a prolonged period of time
when administered. A good example is Verelan PM, which was designed to release verapamil
approximately four to five hours after ingestion. This delay is introduced by the level of release –
controlling polymer applied to the drug –loaded beads. The release controlling polymer is a
combination of water-soluble and water –insoluble polymers. When fluid from the
gastrointestinal tract contacts the polymer coat beads, the water-soluble polymer slowly dissolves
and the drug diffuses through the resulting pores in the coating. The water- insoluble polymer
continues to act as a barrier, maintaining the controlled-release of the drug. controlled onset
extended release delivery system enables a maximum Plasma concentration of verapamil in the
morning hours, when blood pressure normally is high.
Continr Technology- In this technology, molecular coordination complexes are formed between
a cellulose polymer & a non polar aliphatic alcohol optionally substituted with a aliphatic group
by solvating the polymer with a volatile polar solvent & reacting the solvated cellulose polymer
directly with the aliphatic alcohol . This constitutes the complex having utility as matrix in
controlled release formulations since it has a uniform porosity (Semi permeable matrix).
Chronomodulating Infusion Pumps- Externally and internally controlled systems across a
range of technologies including pre-programmed systems, as well as systems that are sensitive to
modulated enzymatic or hydrolytic degradation , ph, magnetic fields, ultrasound, electronic field,
temperature, light, & mechanical stimulation have been developed .
TIMERx Technology- The TIMERx Technology (hydrophilic system) combines primarily

Xanthan & Locust bean gums mixed with dextrose .The physical interaction between these
components works to form a strong binding gel in the presence of water. Drug release is
controlled by the rate of water penetration from the gastrointestinal tract into the timer x gum
matrix which expands to form a gel & subsequently releases the active drug Substances.
CONCLUSION
The major objective of this article is to inform biologists, clinicians, pharmaceutical scientists
and other professional about the importance of biological clocks & Chronopharmacology to
Page 37
human health and disease also motivate the investigator to develop new tools for the treatment of
cardiovascular diseases such as cardiac arrhythmia, myocardial infarction etc. this article also
provide a new ideas to use of older or already well-established active pharmaceutical ingredients
for the treatment of various diseases.
Page 38

Unit-5 - PHARMACOLOGY III

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COURSE: B.

PHARMACY SUBJECT: PHARMACOLOGY-III, CODE: BP602

afety of new chemicals for use as pesticides, drugs, or food

been seen in other studies.

conducted in vitro rather than in animals.

The two basic principles guiding toxicity test in animals

toxic effect on human.

Toxicity studies are divided into:

the development and testing of test substances.

the adverse effects of a substance on human,

transportation of chemical agents

Sub-acute toxicity studies

sublethal endpoints such as decreased growth, reduced reproduction, or

Common aquatic chronic toxicity tests

 Fathead minnow, Pimephales promelas, larval survival and growth

GENOTOXICITY AND MUTAGENICITY- TERATOGENICITY

 – Genotoxicity covers a broader spectrum of endpoints than mutagenicity,

Genotoxicity • Genotoxicity tests can be defined as in vitro and in vivo tests

INVITRO MAMALIAN CELL MICRONUCLEUS TEST -2010 •

Mammalian Erythrocyte Micronucleus Test • Animals are exposed to the test

treated animals is an indication of induced chromosome damage because they

MAMMALIAN BONE MARROW CHROMOSOME ABERRATION TEST

General Principles In Treatment of Poisoning

General Principles of Poisoning

Most poisonings are dose-related. Dose is determined by concentration over time.

substances. Some poisonings result from exposure to substances that are

Symptoms and Signs

clusters of symptoms (toxic syndromes, or toxidromes) occur commonly and may

Some substances (eg, cocaine, phencyclidine, amphetamine) can cause severe

 Consideration of poisoning in patients with altered consciousness or

Poisoning may be known at presentation. It should be suspected if patients have

(MSDS) readily available at the workplace; the MSDS provides detailed

If blood levels of a substance or symptoms of toxicity increase after initially

Seriously poisoned patients may require assisted ventilation or treatment of

details. Consultation with a poison control center is recommended for any

 Maintain airway, breathing, and circulation

Airway, breathing, and circulation must be maintained in patients suspected of

If patients have apnea or compromised airways (eg, foreign material in the

IV naloxone (2 mg in adults; 0.1 mg/kg in children; doses as high as 10 mg may

naloxone infusion to maintain respiratory drive without precipitating withdrawal

IV dextrose (50 mL of a 50% solution for adults; 2 to 4 mL/kg of a 25% solution

IV fluids are given for hypotension. If fluids are ineffective, invasive

Charcoal is usually given, particularly when multiple or unknown substances have

mortality. When used, charcoal is given as soon as possible. Activated charcoal

The recommended dose is 5 to 10 times that of the suspected toxin ingested.

Gastric emptying, which used to be well-accepted and seems intuitively

 Some serious poisonings due to sustained-release preparations or

A commercially prepared solution of polyethylene glycol (which is

Alkaline diuresis enhances elimination of weak acids (eg, salicylates,

Common toxins that may require dialysis or hemoperfusion include

Antidote therapy N-acetylcysteine (NAC): gives maximum protection against

Salicylates Acute Poisoning: a. Early : Nausea, vomiting, sweating,tinnitus, vertigo &

Chronic Poisoning (Salicylism):  This is characterised by slow onset of confusion,

Treatment • Patients with major signs or symptoms (metabolic acidosis,dehydration,

OP Poisoning 1. Acute Poisoning: a. Cholinergic Excess: • Muscarinic effects:

Antidotes:  Atropine—It is a competitive antagonist of acetylcholine at the muscarinic

Barbiturates Poisoning is mostly suicidal,rarely accidental  Characterized by respiratory

Treatment • Consists of respiratory support & maintenance of BP (i.v.fluids, vasoconstrictors) •

Reason for Chronopharmacology