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DRUG TOXICITYBy Imad Nmeir

Supervised by Dr. Rita Mouawad

HOLY-SPIRIT UNIVERSITY OF KASLIKFaculty of sciences Department of pharmacology and cosmetology

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TABLE CONTENTIntroduction

• Toxicology and pharmacology• Drug toxicity• Adverse effects of drugs

Mechanism• Introduction

• Factors affecting drug toxicity• Classification

• On-target adverse effect• Causes• Miscellaneous

• Off-target adverse effect• Reason as drug causing it• Reason as body causing it

• Production of toxic metabolism• Drug metabolism

Acetaminophen toxicity• Biotransformation in normal dose levels• Biotransformation with large doses

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INTRODUCTIONDrug toxicity and its science

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TOXICOLOGY AND PHARMACOLOGY

ToxicologyPharmacolog

y

Kinetic

Dynamic

Dose-response

Receptors

Common fields of study

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DRUGS

Therapeutic

• Used correctly

Toxic

• Supratherapeutic-doses

• Genetic predispositions

• Inappropriate use

• Non-selective actions

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ADVERSE EFFECTS OF DRUGS

All drugs have

adverse effects

Most are undesirable

From nuisance to

life threatening

Subject of focus of drug

toxicology

Inappropriate drug

behavior

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MECHANISM OF DRUG TOXICITYIntroduction

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FACTORS AFFECTING DRUG TOXICITY

Patient’s Age

Geneticfactors

Pathological conditionsDose

Drug-drug interaction

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EXAMPLES

The very young and the very old may be more susceptible to the toxic effects of a drug because of age-dependent differences in pharmacokinetic profiles or in drug metabolizing enzymes.

Liver or kidney dysfunction will affect drug pharmacokinetics

Genetic difference may yield difference in drug metabolism or in receptor activity, as well differences in activities of repair mechanism

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CLINICAL DETERMINATION IS NOT STRAIGHT FORWARD

a patient treated with antibiotic may develop skin rash, high fever, and other morbidities for several reasons: Allergic reactions to antibiotics Recurrence of infection

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DRUG TOXICITY CLASSIFICATION

“On Target” adverse effect

Drug binding in its intended

receptor

Inappropriate posology or Inadequate kinetics or

Incorrect tissue

“Off Target” adverse effect

Binding to a receptor that it

was not intended

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OTHER CLASSIFICATIONS

Prod

uction

of to

xic

met

aboli

tes

Harmful immune response Idiosyncrati

c response

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MECHANISM OF DRUG TOXICITYOn-Target adverse effect

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CAUSES OF ON-TARGET EFFECTS

Exaggeration in pharmacologic

action

Alteration in the

pharmacodynamics

Alteration of the pharmacokinetics

Dosing error

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SUBCLASS AND IMPORTANT DETAILS OF ON-TARGET EFFECTS

May expose unknown

functions of the biological target

Drug action on the same receptor but on different tissue

than the target one

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EXAMPLE: HMG COA REDUCTASE INHIBITOR

Used to decrease blood cholesterol levels Target organ: liver Inhibition of HMG CoA reductase Rate limiting step in isoprenoid synthesis Have muscle toxicity as side effect HMG CoA reductase is important for muscle

protein posttranslational modification regulation

Lipidation through geranyl-geranylation

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EXAMPLE: ANTIHISTAMINE DIPHENHYDRAMINE

Used to reduce allergic reaction Minimize histamine release by interacting

with H1 receptors. Pass the blood-brain barrier Causes drowsiness by interacting with H1

receptor in the brain.

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MECHANISM OF DRUG TOXICITYOff-Target adverse effect

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REASONS FOR OFF-TARGET ADVERSE EFFECT FROM DRUGS PERSPECTIVE

Rare are the rugs with a single molecular targets.

The presence of enantiomers

Each enantiomer is treated as a compound

Different enantiomers have different affinities which give different functions

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EXAMPLE: ANTIHISTAMINE TERFENADINE

Inhibits histamine release in the blood Also inhibits cardiac potassium channels Causes fatal cardiac arrhythmias Withdrawn from the market Now usage of fexofenadine Have affinity to cardiac potassium channels

but to a much lesser degree than terfenadine

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EXAMPLE: R AND S THALIDOMIDE

Effective sedative S-thalidomide is a potent teratogen Cause of this is: anti-angiogenic property of

S-thalidomide

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REASONS FOR OFF-TARGET ADVERSE EFFECTS FROM BODY PERSPECTIVE

Unintentional activation of a different receptor other than the target one.

Usage of genetically modified animals which lack the target receptor.

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EXAMPLE: BETA-BLOCKERS

Beta1 receptors: causes increase in heart rate and myocardium contractility

Beta2 receptors: smooth muscle relaxation and dilatation of these tissues

Some Beta1 antagonist exert activity on beta 2 receptors

May cause airway constriction with asthma patients

Non-selective Beta blockers are not given to these patients then

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MECHANISM OF DRUG TOXICITY Production of toxic metabolites

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DRUG METABOLISM

Metabolized in the

liver

Gives active

compound

Undesired actions

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EXAMPLE: LOSARTAN AND EBASTIN

Losartan is converted to the active E3174 Ebastin is converted to carebastine Both are active inside the body and may

cause damage.

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ACETAMINOPHEN Mechanism of Acetaminophen toxicity

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WITH NORMAL DOSES

Acetaminophen enter through the digestive

tract

Heavily metabolized by

the liver by Liver enzymes

P450 will metabolize it into intermediate “N-

acetyl-p-benzoquinoneimi

ne (NAPQI)”

NAPQI is then immediately conjugated

with glutathione

Then it is further

conjugated with

glucuronate and sulfate

Finally it is excreted from

the body

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WITH HIGH DOSE ADMINISTERED

The high levels of acetaminophen will saturate the

conjugation enzymes

First the glucuronate

transferase and the sulfate transferase will be saturated

This will eventually

saturate the glutathione transferase

When that happens high

levels of NAPQI will accumulate inside the cell

NAPQI will react with other

hepatic proteins giving other toxic

compounds

This will cause hepatotoxicity and will cause

death

This is solved by giving the patient N-

acetylcysteine