Pharmacology chapters
Adverse drug reactions and drug interactions
How drugs cause harm: the types of adverse drug reactions (augmented, bizarre, chronic, delayed, end-of-use, failure), drug allergy, idiosyncrasy and pharmacogenetics, teratogenic drugs, drugs in the elderly and in kidney or liver disease, and the main pharmacokinetic and pharmacodynamic drug interactions.
- Adverse drug reactions are harmful, unintended responses at normal doses: type A (augmented) are dose-related, predictable extensions of the drug's action and the commonest (bleeding with warfarin, hypoglycaemia with insulin); type B (bizarre) are not dose-related, unpredictable, often allergic or idiosyncratic and more dangerous (penicillin anaphylaxis, Stevens-Johnson syndrome); then C chronic, D delayed (teratogenic, cancer), E end-of-use (withdrawal) and F failure of therapy.
- Idiosyncrasy is a genetically abnormal response: G6PD deficiency (haemolysis with primaquine, dapsone, sulphonamides, nitrofurantoin), slow acetylators (isoniazid neuropathy, hydralazine lupus), pseudocholinesterase deficiency (prolonged apnoea after suxamethonium), malignant hyperthermia (halothane and suxamethonium; treat with dantrolene).
- Key teratogens: thalidomide (phocomelia), isotretinoin, valproate and carbamazepine (neural tube defects), phenytoin (fetal hydantoin syndrome), warfarin (nasal hypoplasia, bone stippling), ACE inhibitors (fetal kidney damage), tetracyclines (teeth and bone), lithium (Ebstein anomaly).
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Definitions
- Adverse drug reaction (ADR): a harmful and unintended response to a drug at doses normally used for prevention, diagnosis or treatment.
- Side effect: an unwanted but often predictable effect at therapeutic doses, related to the drug's pharmacology (dry mouth with atropine).
- Toxic effect: harm from excessive dose or accumulation (overdose).
Classification (types A to F)
| Type | Name | Features | Examples |
|---|---|---|---|
| A | Augmented | Dose-related, predictable from the drug's pharmacology; by far the commonest; usually low mortality | Bleeding with warfarin, hypoglycaemia with insulin or sulphonylureas, bradycardia with β-blockers, digoxin toxicity |
| B | Bizarre | Not dose-related, unpredictable; allergic or idiosyncratic; uncommon but often serious | Penicillin anaphylaxis, Stevens-Johnson syndrome (sulphonamides, carbamazepine, allopurinol), malignant hyperthermia, chloramphenicol aplastic anaemia |
| C | Chronic (continuing) | Related to cumulative dose over time | Corticosteroid Cushing syndrome and adrenal suppression, analgesic nephropathy |
| D | Delayed | Appear long after use | Teratogenesis, carcinogenesis (alkylating agents → leukaemia), tardive dyskinesia |
| E | End of use (withdrawal) | On stopping the drug | Rebound hypertension (clonidine), angina (β-blockers), seizures (benzodiazepines, alcohol), adrenal crisis (steroids), opioid withdrawal |
| F | Failure of therapy | Often from interactions | Oral contraceptive failure with rifampicin |
Drug allergy
The drug (often acting as a hapten) triggers an immune response. It needs prior exposure, is not dose-related, and cross-reacts with related drugs. All four hypersensitivity types occur:
- Type I: anaphylaxis, urticaria (penicillin).
- Type II: drug-induced haemolytic anaemia (methyldopa, penicillin), thrombocytopenia (heparin, quinine).
- Type III: serum sickness, drug-induced vasculitis.
- Type IV: contact dermatitis; many drug rashes.
Severe skin reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis (sulphonamides, carbamazepine, phenytoin, lamotrigine, allopurinol, nevirapine).
Idiosyncrasy and pharmacogenetics
| Genetic variation | Drug | Effect |
|---|---|---|
| G6PD deficiency | Primaquine, dapsone, sulphonamides, nitrofurantoin, chloroquine, high-dose aspirin (and fava beans) | Haemolysis |
| Slow acetylators | Isoniazid, hydralazine, procainamide, dapsone | Peripheral neuropathy (isoniazid), drug-induced lupus |
| Pseudocholinesterase (butyrylcholinesterase) deficiency | Suxamethonium (succinylcholine) | Prolonged apnoea |
| Malignant hyperthermia (ryanodine receptor RYR1) | Halothane and other volatile anaesthetics with suxamethonium | Muscle rigidity, very high temperature, acidosis; treat with dantrolene |
| Acute intermittent porphyria | Barbiturates, sulphonamides, oral contraceptives, griseofulvin | Acute attacks (abdominal pain, neuropathy) |
| CYP2C19 poor metabolisers | Clopidogrel | Reduced antiplatelet effect |
| HLA-B*1502 | Carbamazepine | Stevens-Johnson syndrome (South and East Asian ancestry) |
| TPMT deficiency | Azathioprine, 6-mercaptopurine | Bone marrow suppression |
Drugs in pregnancy
Most drugs cross the placenta. The first trimester (especially weeks 3–8, organogenesis) carries the highest risk of structural malformations; later exposure affects growth and function.
| Drug | Effect on the fetus |
|---|---|
| Thalidomide | Phocomelia (limb defects) |
| Isotretinoin (retinoids) | Severe craniofacial, heart and CNS defects |
| Sodium valproate | Neural tube defects (spina bifida), developmental delay; carbamazepine also raises NTD risk |
| Phenytoin | Fetal hydantoin syndrome (cleft lip and palate, nail hypoplasia, growth delay) |
| Warfarin | Nasal hypoplasia, stippled epiphyses (first trimester); fetal bleeding later; heparin is used instead |
| ACE inhibitors, ARBs | Fetal kidney damage, oligohydramnios, skull defects (second and third trimesters) |
| Tetracyclines | Discoloured teeth, impaired bone growth |
| Aminoglycosides (streptomycin) | Deafness (eighth nerve damage) |
| Lithium | Ebstein anomaly (tricuspid valve) |
| Methotrexate | Abortion, skull and limb defects |
| Diethylstilboestrol | Vaginal clear cell adenocarcinoma in daughters |
| Alcohol | Fetal alcohol syndrome |
| Androgens, danazol | Masculinisation of a female fetus |
| Chloramphenicol (near term or in neonates) | Grey baby syndrome |
| Sulphonamides (near term) | Kernicterus (displace bilirubin) |
| NSAIDs (third trimester) | Premature closure of the ductus arteriosus |
Generally considered safer choices include paracetamol (pain), penicillins and cephalosporins (infection), insulin (diabetes), methyldopa, labetalol and nifedipine (hypertension), heparin (anticoagulation) and folic acid supplements; always check current national guidance.
Special groups
- Elderly: reduced renal clearance, altered body composition and more sensitive receptors; more falls and confusion with sedatives; polypharmacy.
- Neonates: immature liver (glucuronidation) and kidneys.
- Renal disease: reduce doses of renally cleared drugs (aminoglycosides, digoxin, lithium, metformin); avoid nephrotoxic drugs.
- Liver disease: caution with drugs that are heavily metabolised by the liver, sedatives (can precipitate encephalopathy) and drugs causing bleeding.
Drug interactions
Pharmacokinetic interactions
| Mechanism | Example |
|---|---|
| Absorption | Tetracyclines and fluoroquinolones bind calcium, iron, magnesium and antacids |
| Protein-binding displacement | Sulphonamides displace bilirubin (neonates); usually minor in adults unless combined with reduced elimination |
| Enzyme induction (lower levels) | Rifampicin reduces oral contraceptives, warfarin, steroids, antiretrovirals; carbamazepine, phenytoin |
| Enzyme inhibition (higher levels) | Erythromycin, ketoconazole or cimetidine with warfarin, theophylline or statins; allopurinol with azathioprine (xanthine oxidase) |
| Excretion | Probenecid blocks tubular secretion of penicillin (useful); thiazides and NSAIDs raise lithium levels |
Pharmacodynamic interactions
- Additive (summation): the combined effect equals the sum (two NSAIDs → more stomach injury).
- Synergism (potentiation): the combined effect is greater than the sum (trimethoprim + sulphamethoxazole; alcohol + benzodiazepines → respiratory depression; levodopa + carbidopa).
- Antagonism: effects oppose (β-blocker with salbutamol; naloxone with morphine).
Dangerous combinations to remember
- Warfarin with aspirin or NSAIDs, macrolides, azoles, metronidazole → bleeding.
- MAO inhibitors with tyramine-rich foods (cheese) → hypertensive crisis ("cheese reaction"); with SSRIs, pethidine or tramadol → serotonin syndrome.
- Digoxin with diuretics (low potassium) → toxicity; with verapamil, amiodarone → higher digoxin levels.
- Lithium with thiazides, ACE inhibitors or NSAIDs → lithium toxicity.
- ACE inhibitors with potassium-sparing diuretics → hyperkalaemia.
- Alcohol with metronidazole → disulfiram-like reaction.
- Sildenafil with nitrates → severe hypotension.
- Aminoglycosides with loop diuretics → ototoxicity and nephrotoxicity.
Pharmacovigilance is the monitoring of drug safety after marketing; doctors report suspected adverse reactions to the national regulator (in Pakistan, the Drug Regulatory Authority of Pakistan).
Expect: type A vs type B reactions with examples and the remaining types C to F, drug allergy and Stevens-Johnson causes, G6PD drugs, slow acetylators, suxamethonium apnoea, malignant hyperthermia and dantrolene, teratogens matched to defects, grey baby and kernicterus, interaction mechanisms with classic examples (rifampicin and the pill, probenecid and penicillin, MAOI and cheese, sildenafil and nitrates).
Quick revision
- A: augmented, dose-related, commonest. B: bizarre, unpredictable.
- C chronic, D delayed, E end-of-use (withdrawal), F failure.
- G6PD: primaquine, dapsone, sulphonamides, nitrofurantoin.
- Malignant hyperthermia: halothane + suxamethonium; dantrolene.
- Thalidomide phocomelia; valproate NTD; lithium Ebstein; warfarin nasal hypoplasia; ACE inhibitor fetal kidney; tetracycline teeth.
- Inducer rifampicin → contraceptive failure. Probenecid ↑ penicillin. MAOI + cheese → hypertensive crisis.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
What is the difference between type A and type B adverse drug reactions?
Type A reactions are dose-related and predictable from the drug's actions (the commonest); type B reactions are not dose-related, are unpredictable and are usually allergic or idiosyncratic.
Which drug causes phocomelia?
Thalidomide.
Which drugs cause haemolysis in G6PD deficiency?
Primaquine, dapsone, sulphonamides and nitrofurantoin, among others; fava beans can also trigger it.
How is malignant hyperthermia treated?
By stopping the trigger anaesthetic, giving dantrolene and cooling and supporting the patient.