drug toxicity
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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