Drugs adverse effects and toxicity

Toxic effect of drug is of clinical importance because:

• Errors in self-administration of (quite common in the
prescribed drugs elderly);

• Exaggeration of intended pharmacologic (e.g., hypotension in a pt

effect given antihypertensive drugs);

• Concomitant administration of drugs (e.g., aspirin and warfarin);

with synergistic effects

• Cytotoxic reactions (e.g., hepatic necrosis due to

acetaminophen);

• Immunologic mechanisms (e.g., quinidine-induced thrombocytopenia,

hydralazine-induced SLE);

• Genetically determined enzymatic defects (e.g., primaquine-induced

hemolytic anemia in G6PD deficiency); or

• Idiosyncratic reactions (e.g., chloramphenicol-induced aplastic

anemia).

INTRODUCTION
● Rigorous toxicity testing usually done on potential new drugs during development.
● Although under vigilant regulation, toxic effect can emerge following use, causing harm- Adverse Drug
Reaction (ADR).
● ADR is iatrogenic disease.
● Reporting using MEDWATCH scheme (US) or yellow card scheme (UK)- assist in identification of ADR

ADVERSE DRUG REACTION (ADR)

WHO DEFINITION “Any undesirable effect of a drug beyond its anticipated
therapeutic effect occurring during clinical use” - WHO
CAN CAUSE harmful effects that are related or unrelated to its pharmacological
action.
CLASSIFICATIONS Type A (‘Augmented’)
Type B (‘Bizarre’)
DoTS (Dose, time course, susceptibility)

TYPE A ADR  Related to dose and susceptibility

(‘AUGMENTED’)  E.g. bleeding following anti-coagulant therapy, or β-blockers may
cause bradycardia that results in syncope.
 Predictable- related to pharmacological action.
 2 types:
1) REVERSIBLE 2) NON-
REVERSIBLE
● Dealt with by • Drug dependence
reducing the dose. upon the use of
● Stopping the opioids.
treatment. • Intracranial bleeding
caused by
warfarin.
• Peptic ulcer caused by
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NSAIDS such as
naproxen.
● Some adverse effect is hard to detect as it works in discrete event
rather than graded symptom. e.g. Coxibs use increase risk of CVS
events.
● Adverse effect might be related to pharmacological action. E.g.
Certain diuretic can cause metabolic acidosis.
● Adverse effect might be unrelated to pharmacological action in
drugs taken in excessive dose.
○ E.g. paracetamol hepatotoxicity.
● Increased susceptibility as in pregnancy or any genetic
predisposition.

TYPE B ADR (‘BIZARRE’)  Unpredictable, dose-independent, unrelated to intended

pharmacological action.
 Can result in:

 Idiosyncratic or immunologic reactions

 Chloramphenicol and aplastic anemia.
 Methyldopa and hemolytic anemia.
 Beta lactam antibiotics and rashes.
 Affect minority of patients.
 4 types of hypersensitivity reactions
 Type I, II, III, and IV

Types of hypersensitivity reactions- Gell and Coombs classification

Type I - - immediate, anaphylactic (IgE) ; e.g. anaphylaxis with penicillins
Type II - cytotoxic antibody (IgG, IgM); e.g. methyldopa and hemolytic anemia.
Type III – immune complex (IgG, IgM) antigen-antibody complex; e.g. procainamide-
induced lupus.
Type IV - delayed hypersensitivity (T-cell); e.g. contact dermatitis topical anti histamine

Allergic reactions to drugs

● Allergen can act as hapten by interacting with protein to form stable immunogenic
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conjugate.
● Common clinical manifestations of hypersensitivity:
○ Anaphylactic shock.
○ Hematological reactions.
○ Other hypersensitivity reactions

Clinical manifestations of hypersensitivity

 Anaphylactic ○ Severe allergy reaction that can be deadly.
shock ○ Type I hypersensitivity reaction.
○ Sudden reaction- release of histamine, leukotrienes, and other mediators.
○ Feature: urticarial rash, swelling of soft tissues, bronchoconstriction,
hypotension.
○ E.g. penicillin, asparginase, corticotropin, heparin.

Hematological • Can be produced by Type II,III and IV hypersensitivity (HS).

reactions • Type II HS can destroy all blood elements (circulating or progenitor in bone
marrow).
• Antibody binds to drug-macromolecule complex  activate complement 
lysis.
• Provoke attack by killer lymphocyte and phagocytic leukocytes.
• Hemolytic anemia- common with the use of sulfonamides and methyldopa.
• Agranulocytosis- NSAIDs, phenylbutazone, sulfonamides.
• Thrombocytopenia- quinine, heparin, thiazide diuretics.
• Aplastic anemia- chloramphenicol.
Other ○ Steven-Johnson syndrome- severe generalised rash extends into alimentary tract.
hypersensitivity ○ Drug-induced systemic lupus erythematosus (Type III) – hydralazine,
reactions procainamide

Common organs involved in ADR

● Liver - Hepatoxicity
● Kidney- Nephrotoxicity
● Lung- pulmonary toxicity
● Others- eye, bone marrow toxicity, etc

Hepatoxicity ● Liver- metabolism of majority of drugs.

● Cytochrome P450 enzymes.
● Drug-induced liver damage
○ Fatty liver.
○ Necrosis.
○ Apoptosis.
○ Cholestasis.
○ Hepatitis.
○ Cancer.
● Liver damage (hepatitis, laboratory abnormalities such as ↑
aspartate transaminase).
● E.g., Paracetamol, iproniazid, halothane.
● Isoniazid, phenytoin- genetic difference in drug
metabolism.
● Triglitazone- withdrawn from the market due to cases of
fatal hepatic failure.

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Paracetamol metabolism

Nephrotoxicity ● NSAIDs and ACE inhibitors- common inducers of

nephrotoxicity.
○ NSAIDs inhibit prostaglandin. Therefore, reduce renal
perfusion in patients with heart/liver disease.
○ ACE inhibitor inhibit angiotensin II therefore affect GFR in
patients with renal artery stenosis.
● Captopril can cause proteinuria- glomerular injury.
● Reduce drug clearance, elevate the concentration of plasma
drug, therefore increase toxicity. E.g. cisplatin, cyclosporine,
amphotericin B.

Pulmonary toxicity  Lung is susceptible- nature of being in direct contact with

drugs.
 Therefore, possibility of damage is enormous.
 Opioid analgesic can cause respiratory depression.
 Bleomycin and amiodarone can result in pulmonary fibrosis.
 Toxicity
 Irritation
 Cell necrosis
 Fibrosis
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 Emphysema
 Allergic responses

Other organ toxicity ● Eye: Toxic cataract- chloroquine, adrenal steroids,

phenothiazines
● Uterus: endometrial cancer after postmenopausal estrogen
therapy
● Skin: phototoxicity-sulfonamides
ADR risk factors ● Age (children and elderly).
● Multiple medications (Drug-drug interactions).
● Multiple co-morbid conditions (co-medications).
● Inappropriate medication prescribing, use, or monitoring.
● End-organ dysfunction.
● Altered physiology.
● Prior history of ADRs .
● Extent (dose) and duration of exposure.
● Genetic predisposition.
Drug interactions

● Change in the pharmacological effects of a drug that

results from the concurrent administration with other
xenobiotic (drug/ food/ etc).
● Can result in the change in the pharmaceutical interaction,
pharmacodynamic & pharmacokinetic properties of the drug

1) Pharmaceutical ● Chemical interaction

interactions between drugs prior to their
administration and
absorption.
● Occur most frequently when
there are combined and given
IV.
● E.g. penicillin and
aminoglycosides- inactivate
each other (chemical

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Pharmacokinetic interactions
Therapeutic window
Therapeutic window
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Drugs adverse effects and toxicity
antagonist)
2)Pharmacodynamic ● Occur when 2 drugs have
interactions additive, antagonistic, or
synergistic effects.
● Additive effect: effect
equivalent to 1 individual
drug. (1+1=2)
● Antagonistic effect: drug
with opposite mechanism of
action. (1+1=0)
● Synergistic effect: drug that
can result greater effect that
one individual drug.
(1+1=10)
3)Pharmacokinetic ● Drug alter A.D.M.E.
interactions ● Alter Absorption
○ Binding to other drug
(cholestryamine vs digoxin).
● Alter Distribution
○ Wide-spectrum antibiotic
and OCP containing estrogen,
reduce plasma
conc of estrogen and cause
contraceptive failures
● Alter Metabolism
○ Inducer P450 enzyme- barbiturate, carbamazepine, rifampin
○ Inhibitor of drug metabolism- cimetidine vs warfarin.
● Alter Elimination
○ Drugs like carbonic anhydrase inhibitor can alter renal pH.
○ Probenicid compete with penicillin for active transport in
renal system.
○ Verapamil decrease biliary clearance of digoxin.
● A range of dose/ concentration of drugs
that provides safe effective therapy without
toxic
effects.
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Therapeutic index (TI) ● Measure of a margin of safety of a drug.

● Can foresee the relationship between
dose needed for desired effect, and dose
causing harmful, unwanted effect.
● The narrower the margin, the less safe
the drug
● High TI  penicilin; low TI  warfarin
● Measured in animals

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Effective dose ● Dose of drug that will produce desired

therapeutic effect in 50% of the population.
● ED50.
● Smaller the ED50, the more potent the
drug is.

Lethal dose ● Dose or concentration of drug that will

cause death in 50% of
the population (LD50).
● Expressed in the form of mg/kg.
● General indicator of acute toxicity.
● The lower the LD50, more toxic the drug
is.

~End😊

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