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Drug toxicity
1. DRUG TOXICITY
By Imad Nmeir
Supervised by Dr. Rita Mouawad
HOLY-SPIRIT UNIVERSITY OF KASLIK
Faculty of sciences
Department of pharmacology and cosmetology
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2. TABLE CONTENT
Introduction
• 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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6. 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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8. FACTORS AFFECTING DRUG TOXICITY
Patient’s Age
Genetic
factors
Pathological
conditions
Dose
Drug-drug
interaction
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9. 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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10. 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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11. 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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14. CAUSES OF ON-TARGET EFFECTS
Exaggeration in
pharmacologic action
Alteration
in the
pharmacod
ynamics
Alteration
of the
pharmaco
kinetics
Dosing
error
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15. 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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16. 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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17. 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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19. 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 19
20. 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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21. 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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22. 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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23. 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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26. 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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28. 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-
benzoquinoneimine
(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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29. 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
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