1. DRUG TOXICITY
By Imad Nmeir
Supervised by Dr. Rita Mouawad
HOLY-SPIRIT UNIVERSITY OF KASLIK
Faculty of sciences
Department of pharmacology and cosmetology
1

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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3. INTRODUCTION
Drug toxicity and its science3

4. TOXICOLOGY AND PHARMACOLOGY
ToxicologyPharmacology
Kinetic
Dynamic
Dose-
response
Receptors
Common
fields of
study
4

5. DRUGS
Therapeutic
• Used correctly
Toxic
• Supratherapeutic-
doses
• Genetic
predispositions
• Inappropriate use
• Non-selective
actions
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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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7. MECHANISM OF DRUG TOXICITY
Introduction7

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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12. OTHER CLASSIFICATIONS
Harmful
immune
response
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13. MECHANISM OF DRUG TOXICITY
On-Target adverse effect13

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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18. MECHANISM OF DRUG TOXICITY
Off-Target adverse effect18

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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24. MECHANISM OF DRUG TOXICITY
Production of toxic metabolites24

25. DRUG METABOLISM
Metabolized
in the liver
Gives
active
compound
Undesired
actions
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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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27. ACETAMINOPHEN
Mechanism of Acetaminophen toxicity27

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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