Drug Toxicity and ADR

drug toxicity

harmful undesired effect at toxic dose (higher than therapeutic dose)

Paracelsus doctrine

all drugs are poisons, benefit depends on dosage

iatrogenic disease

drug‑induced disease (e.g., NSAIDs → peptic ulcer, antipsychotics → Parkinsonism, isoniazid → hepatitis)

adverse drug reaction (ADR)

harmful undesired effect at therapeutic dose

toxic effect

harmful undesired effect at dose higher than therapeutic dose

wrong dose overdose

common cause of toxicity

drug accumulation

toxicity due to impaired excretion or long half‑life

idiosyncrasy

hypersensitivity or unusual reaction not explained by drug action

factors influencing toxicity

age, pregnancy, ethnicity, genetics, route, environment, pathology, drug interactions

genetic predisposition example

G6PD deficiency → hemolysis with sulfonamides

route of administration example

IV drugs → higher toxicity risk

environmental factor example

smoking induces CYP1A2, diet (grapefruit juice inhibits CYP3A4)

pathological state example

liver disease → impaired metabolism, kidney disease → impaired excretion

median lethal dose (LD50)

dose lethal to 50% of animals

median toxic dose (TD50)

dose toxic to 50% of animals

median effective dose (ED50)

dose effective in 50% of population

therapeutic index (TI)

LD50/ED50 or max non‑toxic dose/min effective dose

large TI

wide safety margin (e.g., penicillin)

narrow TI

high risk (e.g., digoxin, warfarin, theophylline)

acute toxicity test

LD50 in 2 species, 2 routes, single dose

subacute toxicity test

few doses, 2 species, duration depends on clinical use

chronic toxicity test

2 species, ≥6 months, for prolonged human use

reproductive performance test

effects on mating, reproduction, birth defects, postnatal development

carcinogenic test

required for drugs intended for long‑term use

mutagenic test

Ames test in bacteria or mammalian cells for genetic mutations

ADR type A

augmented, dose‑related, predictable, common, reversible, preventable

ADR type A examples

hypotension with α1‑blockers, bleeding with anticoagulants, bradycardia with β‑blockers

ADR type B

bizarre, idiosyncratic, genetic basis, unpredictable, serious, uncommon

ADR type B examples

allergic reaction, sulfonamides → hemolysis in G6PD deficiency, aspirin → cerebral edema

ADR type C

chronic, long‑term therapy, tolerance, dependence, chronic toxicity

ADR type C examples

corticosteroids → Cushing’s syndrome, opioid dependence

ADR type D

delayed, teratogenicity, mutagenicity, carcinogenicity

ADR type D examples

thalidomide → phocomelia, anticancer drugs → mutagenicity/carcinogenicity

ADR type E

withdrawal, symptoms after sudden discontinuation

ADR type E examples

β‑blocker withdrawal → hypertensive crisis, opioid withdrawal → aches, tremors, vomiting

ADR type F

failure of therapy, expected response not achieved

serious ADR criteria

death, life‑threatening, hospitalization, disability, congenital anomaly

pharmacovigilance

WHO definition: detection, assessment, understanding, prevention of ADRs

pharmacovigilance global bodies

WHO Uppsala Monitoring Centre, US FDA

MADRAC role

collects/systematizes ADR info in Malaysia under Drug Control Authority

MADRAC reporting

via special form or website, includes patient info, reaction details, seriousness, suspected drugs, investigations, reporter details

drug interaction

modification of response to one drug by another when co‑administered

drug interaction drawbacks

increased toxicity, reduced efficacy, inconvenience, cost

drug interaction benefits

reduced toxicity, increased efficacy, convenience

pharmaceutical interaction

chemical reaction before administration (neutralization, oxidation, precipitation)

pharmaceutical interaction examples

heparin inactivated by gentamicin/penicillin/hydrocortisone; noradrenaline + sodium bicarbonate; thiopental + succinylcholine

pharmacokinetic interaction

alteration of drug concentration at site of action by another drug

absorption interaction pH

omeprazole ↓ ketoconazole absorption; vitamin C ↑ iron absorption

absorption interaction motility

metoclopramide ↑ motility ↓ absorption; opioids ↓ motility ↑ absorption

absorption interaction flora

antibiotics ↓ enterohepatic circulation of OCPs → contraceptive failure

tissue absorption interaction

adrenaline ↓ systemic absorption of local anesthetics

distribution interaction

quinidine displaces digoxin → digoxin toxicity

metabolism interaction inhibitors

CYP450 inhibitors (cimetidine, erythromycin, omeprazole, isoniazid) ↑ toxicity

metabolism interaction inducers

CYP450 inducers (rifampicin, phenobarbital, carbamazepine) ↓ efficacy

excretion interaction NSAIDs

NSAIDs ↓ lithium excretion

excretion interaction quinidine

quinidine ↓ digoxin secretion ↑ plasma level

excretion interaction urine pH

alkaline urine ↓ aspirin reabsorption (used clinically in overdose)

pharmacodynamic interaction

effect modification without concentration change

pharmacodynamic antagonism

propranolol counteracts adrenaline

pharmacodynamic summation

penicillin + ciprofloxacin (additive effect)

pharmacodynamic synergism

penicillin + gentamicin (synergistic effect)

drug‑food interaction tetracycline

Ca/Mg/iron in food ↓ tetracycline absorption

drug‑food interaction warfarin

vitamin K foods (spinach, broccoli) ↓ warfarin effect → thrombosis risk

drug‑food interaction MAO inhibitors

tyramine in cheese → hypertensive crisis (cheese syndrome)

drug‑food interaction grapefruit juice

grapefruit juice inhibits CYP3A4 → ↑ levels of statins, calcium channel blockers, amiodarone

drug‑herb interaction St John’s wort

induces CYP450 → ↓ efficacy of many drugs

drug‑herb interaction ginkgo/ginseng

↓ platelet aggregation → ↑ bleeding risk with aspirin/warfarin

pregnancy category A

no risk in human studies (magnesium sulfate, thyroxine)

pregnancy category B

animal no risk or adverse but safe in humans (penicillin, amoxicillin, paracetamol)

pregnancy category C

animal risk, no adequate human studies, benefits may outweigh (morphine, atropine, corticosteroids, adrenaline)

pregnancy category D

human fetal risk proven, benefits may outweigh (aspirin, phenytoin, carbamazepine, valproate)

pregnancy category X

fetal abnormalities proven, risks > benefits (thalidomide, ACE inhibitors, ergometrine)

withdrawal ADR β‑blocker

hypertensive crisis after sudden discontinuation

withdrawal ADR barbiturates

insomnia, anxiety, irritability after sudden discontinuation

withdrawal ADR opioids

aches, tremors, vomiting, rhinorrhea, sneezing, fever, chills after withdrawal

therapeutic index definition

ratio between max non‑toxic dose and min effective dose or LD50/ED50

therapeutic index large

wide safety margin (benzodiazepines, penicillin, cephalosporins, paracetamol)

therapeutic index narrow

high risk (barbiturates, theophylline, cardiac glycosides, warfarin)

clinical use of urine alkalinization

alkaline urine prevents aspirin reabsorption → used in overdose management

ADR reporting principle

report all suspected ADRs even if details incomplete

serious ADR reporting

mandatory reporting to MADRAC for death, hospitalization, disability, congenital anomaly

MADRAC documentation

patient info, ADR description, seriousness, suspected drug(s), concomitant drugs, investigations, reporter details