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