Mechanism of Drug Toxicity

On-Target and off-target Adverse Drug Effects

Alterations in exposure to Unintended targets.
the drug
Exaggeration of the desired
pharmacologic action
 Mechanism of Drug Toxicity
On-target adverse effects in the intended tissue/receptor
Exaggeration of the desired action due to alterations in exposure to the drug
Alteration in exposure can be due to :
Dosing error: (overdose) deliberate or accidental
Alterations in the pharmacokinetics of the drug
liver or kidney disease or to interactions with other drugs
enzyme induction or inhibition
Alteration in drug distribution
Change in the clearance profile
Changes in absorption profile
Changes in the pharmacodynamics of the drug-receptor interaction
Changes in receptor number (Up or down regulation)
All such changes can lead to an increased biological response. increase in the effective
concentration of the drug
 Mechanism of Drug Toxicity
On-Target Effects Examples
Appropriate receptor but in the incorrect tissue.
Diphenhydramine : Antihistaminic
H1 receptor antagonist
Treatment of allergic conditions.
Diphenhydramine crosses the B.B.B
H1 receptors in the CNS
Toxicity: somnolence.
Statins: Tx ↓ cholesterol levels (atorvastatin, lovastatin)
HMG CoA reductase inhibitors.
Target tissue the liver.
Adverse effect : Muscle toxicity: rhabdomyolysis and myositis
Inhibitions of muscular HMG CoA reductase
HMG-CoA: regulate the post-translational modification of muscle proteins

HMG CoA: hydroxymethylglutaryl coenzyme A

 Mechanism of Drug Toxicity
Off-Target Effects: Examples
Incorrect receptor is activated or inhibited.
Thalidomide (racemic mixture of [R] and [S]-enantiomers):
Treatment: Morning sickness in pregnant women.
(R)-enantiomer effective sedative
(S)-enantiomer potent teratogen.
β-blockers: Propranolol
Target: to the β1 receptor in Heart
Treatment: To control HR and decrease myocardial oxygen demand in patients with
angina or heart failure.
Propranol: β adrenergic non-selective antagonist (β1 and β2 receptor)
Contraindicated in patients with asthma
↑ bronchoconstriction by antagonizing β2 receptors
 Mechanism of Drug Toxicity
Hypersensitivity & immunological reactions

Drugs can be recognized by the immune system as immunogens

Small molecule drugs act as haptens
The two principal immune mechanisms are:
hypersensitivity responses (allergic responses)
Ester-Local anesthetics: meablotes realted to p-aminobenzoic acid
autoimmune reactions : the organism's immune system attacks its own cells (IDRs ??)
Methyldopa: hemolytic anemia by eliciting an autoimmune Rx against Rhesus
antigens (Rh factor)
Drugs can cause Lupus-like syndrome by inducing antibodies to myeloperoxidase
(Hydralazine, isoniazid) or DNA (procainamide)
 Mechanism of Drug Toxicity
4-Production of Toxic Metabolites (Cytotoxic Reaction)
Bioactivation to toxic reactive intermediates
Acetaminophen Tx: analgesic and antipyretic
acetaminophen to N-acetyl-benzoquinoneimine
 Idiosyncratic Drug Reaction (IDR)
Type B reactions
Rare adverse effects for which no obvious mechanism is apparent.
It occur in a small proportion of patient; Predisposing factors are unknown.
The reaction can occur the first time you are exposed to a medication.
It occurs only in susceptible individuals: genetic susceptibility; immune mediate reaction
IDRs are difficult to explain and often difficult to study in animal models
IDRs are not detected during clinical trials
Most comon targets: Skin, liver, blood cells,
Skin: rash, urticaria, eruption, epidermal necrolysis
Liver: Heptocellular injury, cholestatic liver injury
Blood: agranulocytosis, thrombocytopenia, anemias,
Some drugs cause IDRs limit to one organ, whereas other affect several organs
Common characteristic of IDRs :
delay onset (exceptions)
the risk often does not appear to increase with dose
The MOA of IDRs do not involve the therapeutic effect of the drug