Basic principles of toxicology and about the Adverse drug events

1. BY VITHYA.S
M.PHARM I YEAR
DEPARTMENT OF
PHARMACOLOGY
MMC

2. CONTENTS
PRINCIPLES OF TOXICOLOGY

3. PRINCIPLES OF TOXICOLOGY
INTRODUCTION
TYPES OF TOXICITY
BIOACCUMULATION &
BIOMAGNIFICATION
TOXICOKINETICS
TOXICODYNAMICS

4. INTRODUCTION
Toxicology is the science of the adverse effects
of chemicals, including drugs, on living
organisms.
DESCRIPTIVE
TOXICOLOGY
to obtain information that can be used to
evaluate the risk that exposure to a chemical
poses to humans and to the environment.
REGULATORY
TOXICOLOGY
judges whether a drug or other chemical has a
low enough risk to justify making it available
for its intended purpose.

5. CONTD..
FORENSIC
TOXICOLOGY
which combines analytical chemistry and
fundamental toxicology, is concerned with the
medicolegal aspects of chemicals
MECHANISTIC
TOXICOLOGY
attempts to determine how chemicals exert
deleterious effects on living organisms. Such
studies are essential for the development of
tests for the prediction of risks, for facilitating
the search for safer chemicals, and for rational
treatment of the manifestations of toxicity.

6. TYPES OF TOXICITY
• Acute: exposure for a duration of less than 24 hr; often
a single exposure...
• Subacute: generally refers to repeated exposure for a
month or less.
• Subchronic: exposure duration from between 1-3
months.
• Chronic: exposure often greater than 3
months. Usually continual daily dietary exposure.

7. BIOACCUMULATION & BIOMAGNIFICATION
If the intake of a long lasting contaminant by an
organism exceeds the latter’s ability to
metabolize or excrete the substance, the
chemical accumulate within the tissue of the
organism- BIOACCUMULATION
Although conc. Of the contaminant is
undetectable in water, it may be magnified
hundreds or thousands as it passes the food
chain-BIOMAGNIFICATION

8. TOXICOKINETICS
There is a graded dose-response
relationship in an individual and a quantal
dose-response relationship in the
population.
Graded doses of a drug given to an
individual usually result in a greater
magnitude of response as the dose is
increased.
In a quantal dose-response relationship, the
percentage of the population affected
increases as the dose is raised; the
relationship is quantal in that the effect is
specified to be either present or absent in a
given individual
This quantal dose-response phenomenon is
extremely important in toxicology and is
used to determine the median lethal dose
(LD50) of drugs and other chemicals
DOSE-RESPONSE
RELATIONSHIP

9. TOXICODYNAMICS
NON-COVALENT INTERACTION:
Reactive metabolites of drugs can be involved in several related,
potentially cytotoxic, non-covalent interactions, including:
 lipid peroxidation
 generation of toxic reactive oxygen species
 reactions causing depletion of glutathione (GSH)
 modification of sulfhydryl groups.
COVALENT INTERACTIONS :
Targets for covalent interactions include DNA, proteins/peptides,
lipids and carbohydrates. Covalent bonding to DNA is a basic
mechanism of mutagenic chemicals.

10. Several non-mutagenic chemicals also form covalent bonds with
macromolecules, but the relationship between this and cell
damage is incompletely understood. For example, the
cholinesterase inhibitor paraoxon binds acetylcholinesterase at
the neuromuscular junction and causes necrosis of skeletal
muscle. One toxin from an exceptionally poisonous toadstool,
Amanita phalloides, binds actin, and another binds RNA
polymerase, interfering with actin depolymerisation and protein
synthesis, respectively.
Mechanisms of Toxicity
Target Organ Toxicity:
vinyl chloride: liver cancer
asbestos: mesothelioma
paraquat: lung toxicity
cadmium: kidney toxicity
NOTE:
Target organs are often not the site of
the highest concentration of a
chemical.... Lead concentrates in
bone, but its effects are mainly seen
in soft tissues, such as liver, kidney
and blood cells....

11. CONTD…
Possible mechanisms of tissue sensitivity:
preferential accumulation: toxicant may accumulate in only
certain tissues, and cause toxicity there.
Cd in kidney, paraquat in lung selective metabolic activation:
enzymes needed to convert a compound to the active form may
be present in highest quantities in a particular organ…..
CCl4, nitrosamines in liver characteristics of tissue repair: some
tissues may be protected from toxicity by actively repairing toxic
damage; some tissues may be susceptible because they lack
sufficient repair capabilities....

12. CONTD…
nitrosamines in liver specific receptors and/or functions:
toxicant may interact with receptors in a given tissue.
curare:
a receptor-specific neuromuscular blocker used in dart poisons
Physiological sensitivity: the nervous system is extremely
sensitive to agents that block utilization of oxygen....
nitrite: oxidizes hemoglobin (methemoglobinemia)
cyanide: inhibits cytochrome oxidase (cells not able to utilize
oxygen)

13. EFFECTS
the toxic effects observed following single or repeated
exposure to a chemical are often quite different.
.
Acute Effects: rapidly developing, reaching a maximum
with severe symptoms.
(exposure to high doses of CN- will kill within a
few minutes.)
Subacute Effects: symptoms generally not as severe,
but toxic effects often same as acute.
Chronic Effects: progresses at a slow and varying rate;
may be mistaken for other diseases. Often difficult to
determine cause-and-effect unless in laboratory

14. CONTD…
asbestos-caused cancer may be delayed 20-30 years....
Accumulative Effects: occurs two ways...
accumulation of toxin: exposure to heavy metals (lead,
mercury) that have long half-lives result in disease due to metal
accumulation....
accumulation of effect: low level exposure to organophosphate
pesticides depresses acetylcholine esterases to a point where
symptoms occur.
Delayed Effects: effect may occur only after long exposure;
agent cannot be found in blood or tissues. Damage to system
already done.... radiation sickness

15. MANAGEMENT OF POSIONING
Emesis: Vomiting can be induced mechanically by stroking the
posterior pharynx. However, this technique is not as effective as
the administration of ipecac or apomorphine.
Gastric Lavage. Gastric lavage is accomplished by inserting a
tube into the stomach and washing the stomach with water,
normal saline, or one-half normal saline to remove the
unabsorbed poison.
Chemical Adsorption. Activated charcoal avidly adsorbs drugs
and chemicals on the surfaces of the charcoal particles, thereby
preventing absorption and toxicity

16. Chemical Inactivation. Antidotes can change the chemical
nature of a poison by rendering it less toxic or preventing its
absorption. Formaldehyde poisoning can be treated with
ammonia to form hexamethylenetetramine.
Purgation. The rationale for using an osmotic cathartic is to
minimize absorption by hastening the passage of the toxicant
through the gastrointestinal tract
Sorbitol is the most effective, but sodium sulfate and magnesium
sulfate also are used

17. YELLOW CARD SYSTEM

18. INTRODUCTION
Any undesirable or unintended consequences of drug
administration .
DEFINITION
Any noxious change which is suspected to be due to a drug
occurs at doses normally used in man, requires treatment or
decrease in dose or indication caution in the future use of the
same drug.
CLASSIFICATION
Type A- predictable ( side effects, toxic effects, etc.)
Type B- unpredictable(allergy & idiosyncracy)

19. TOLERANCE
When a large dose of drug is required to elicit
pharmacological response ordinarily produced
by its therapeutic dose, the phenomenon is
called tolerance.
Classification:
It is of two types,
True tolerance
Apparent or pseudo tolerance

20. CLASSIFICATION
Tolerance
True tolerance
Apparent or pseudo
tolerance
Natural tolerance Acquired tolerance
Species
tolerance
Racial
tolerance
Tissue
tolerance
Cross
tolerance
Tolerance to one drug produce tolerance to that group of drug
eg. Alcohol and general anesthetics
Some doses of morphine may produce pinpoint pupil and constipation but
not euphoria
A solution of ephedrine instilled into the conjuctival sac of the caucasians
produces prompt dilatation of pupil but in black it may not produce any
dilatation.
Some Rabbit species can tolerate large doses of belladona which are lethal to
human. This is due to atropine esterase present in the plasma and liver which
detoxify the belladona

21. MECHANISM
Due to changes in pharmacokinetics leading to decreased intensity
and duration of contact between a given drug and target tissue
DISPOSITIONAL TOLERANCE
E.g. Repeated administration of barbiturates enhance their own degradation by
enhancing microsomal enzymes.
In many tumours p-glycoprotein pump out the anticancer drugs
Due to changes in pharmacodynamics leading to changes in
properties and functions of target tissue- less sensitive to the given
dose of drug FUNCTIONAL TOLERANCE
E.g. Repeated administration of Morphine, alcohol and barbiturates has
demonstrated that the cells of the CNS, which usually develop tolerance to
these drugs become capable of normal physiological functions in the presence
of high concentration of these drugs. The adaptive mechanism involved are not
clearly understood

22. HABITUATION/DEPENDENCE & ADDICTION
WHO defined drug dependence as-
A state , psychic and sometimes also physical, resulting from the
interaction between the living organism and a drug, characterized
by behavioural and other responses that always include a
compulsion to take the drug on a continuous or periodic basis in
order to experience its psychic effects and sometimes to avoid the
discomfort of its absence. Tolerance may or may not be present. A
person may be dependent on more than one drug.
TYPES
 Psychic,
 Physical ,
 Combined.

23. CONTD…
Most of the drugs used by addicts have predominantly CNS Effects.
Drugs like opiates, barbiturates, alcohol and cocaine produce sense of
well being in the user-EUPHORIA
Habituation- Less intensive involvement with the drug, so that it
withdrawal produce only mild discomfort.
E.g. drinking tea , coffee, etc.
PRINCIPLES OF TREATMENT OF DRUG DEPENDENCE:
 Hospitalization
 Gradual or sudden withdrawal of the drug
 Substitution therapy
 Psychotherapy and occupational therapy
 Correction of nutritional deficiency
 Community treatment and rehabilitation.

24. IDIOSYNCRACY
Abnormal reactivity to a chemical that is
peculiar to a given individual. It may also result
due to genetic polymorphism
SENSTIVITY TO
LOW DOSES
INSENSTIVITY
TO HIGH DOSES
GENETIC
POLYMORPHISM

25. EXAMPLES
Inherited
deficiency
in
acetylation
I
N
H
INCREASED
RISK OF
PERIPHERAL
NEUROPATHY
PRIMAQUINEDeficiency of
glucose-6
phosphate
dehydrogenase
HEMOLYTIC
ANAEMIA

26. ALLERGY & HYPERSENSTIVITY
Chemical allergy is an adverse reaction that
results from previous sensitization to a
particular chemical or to one that is structurally
similar. Such reactions are mediated by the
immune system. The terms hypersensitivity and
drug allergy often are used to describe the
allergic state.

29. TACHYPHYLAXIS
Certain drugs like ephedrine, tyramine, amphetamine and 5-
hydroxytryptamine, tolerance may appear within few minutes in
isolated preparations
If any of these drug is administered repeatedly at very short
intervals, the pharmacological response elicited decreases
progressively. This phenomenon is called Tachyphylaxis
E.g. Repeated dose of ephedrine at short intervals in bronchial
asthma may produce diminishing response

30. EFFECTS OF DRUGS

31. ANTAGONISM
Antagonism is the interference of one chemical with the action
of another. An antagonistic agent is often desirable as an
antidote.
Functional or physiological antagonism occurs when two
chemicals produce opposite effects on the same physiological
function.
For example, this principle is applied to the use of intravenous
infusion of dopamine to maintain perfusion of vital organs
during certain severe intoxications characterized by marked
hypotension.

32. CONTD…
Chemical antagonism or inactivation is a reaction between two
chemicals to neutralize their effects.
For example, dimercaprol chelates various metals to decrease
their toxicity
Dispositional antagonism is the alteration of the disposition of a
substance (its absorption, biotransformation, distribution, or
excretion) so that less of the agent reaches the target organ or
its persistence there is reduced (see below). Antagonism at the
receptor for the chemical entails the blockade of the effect of an
agonist with an appropriate antagonist that competes for the
same site.
For example, the antagonist naloxone is used to treat respiratory
depression produced by opioids

33. Contd…
COMPETITIVE ANTAGONISM
It binds with the same receptor as the agonist
E.g. Ach-Atropine
Morphine-Naloxone
 Equilibrium type:
The drug competes with normal substrate or coenzyme so that
new equilibrium is achieved.
E.g. Allopurinol competes with hypoxanthine for xanthine oxidase.
Carbidopa and methyl dopa compete with levodopa for dopa
decarboxylasee

34.  Non-equilibrium type:
Drug react with the same catylatic site of the enzyme either
form covalent bond or high affinity towards the receptor.
E.g. organophosphates react with esteric site of the enzyme
cholinesterase.
NON-COMPETITIVE ANTAGONISM
It binds to another site of receptor
E.g. Diazepam-Bicuculline

35. SYNERGISM
synergistic effect is one in which the combined
effect of two chemicals exceeds the sum of the
effects of each agent given alone.
E.g. carbon tetrachloride and ethanol are
hepatotoxins, but together they produce much
more injury to the liver than expected from the
sum of their individual effects.

36. POTENTIATION
Potentiation is the increased effect of a toxic
agent acting simultaneously with a nontoxic
one.
Isopropanol alone, for example, is not
hepatotoxic; however, it greatly increases the
hepatotoxicity of carbon tetrachloride

37. REFERENCE
 ESSENTIALS OF MEDICAL PHARMACOLOGY BY K.D TRIPATHI 6TH EDITION
 BASICS AND CLINICAL PHARMACOLOGY BY KATZUNG 12TH EDITION
 PHARMACOLOGY AND PHARMACOTHERAPEUTICS BY SATOSKAR 22ND EDITION
 GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS - 11th Ed. (2006)