Adverse drug reactions
Adverse drug reactions, interactions, teratogens and antidotes (FCPS Part 1)
ADR types, hypersensitivity, classic side effects, QT and warfarin interactions, teratogens, poisoning and antidotes for FCPS Part 1. Mechanisms are given so each side effect and antidote can be reasoned, not just memorised.
One of the most tested topics in past papers
Types of adverse drug reaction
| Type | Features | Examples |
|---|---|---|
| A (augmented) | Dose-related, predictable from the drug's action, common | Bleeding on warfarin, hypoglycaemia on insulin |
| B (bizarre) | Not dose-related, immunological or genetic, often serious | Penicillin anaphylaxis, SJS, malignant hyperthermia |
| C (chronic) | Long-term use | Steroid osteoporosis |
| D (delayed) | Appear late | Teratogenesis, cyclophosphamide bladder cancer |
| E (end of use) | Withdrawal | Rebound hypertension after clonidine, adrenal crisis after steroids |
| F (failure) | Treatment fails | Contraceptive failure with enzyme inducers |
- Report suspected reactions (yellow card), especially to new drugs.
Drug hypersensitivity
| Gell and Coombs type | Mechanism | Drug and disease examples |
|---|---|---|
| I | IgE on mast cells | Penicillin anaphylaxis, urticaria |
| II | IgG or IgM against cell-bound antigen | Drug haemolysis (methyldopa, penicillin), heparin thrombocytopenia; haemolytic disease of the newborn (Rh) |
| III | Immune complexes | Serum sickness, SLE, drug vasculitis |
| IV | T cells | Contact dermatitis, SJS/TEN (carbamazepine, allopurinol, lamotrigine, sulphonamides) |
- HLA-B*15:02 genotyping is recommended before carbamazepine in patients of Han Chinese or Thai (South-East Asian) ancestry, because carriers are at high risk of SJS/TEN. HLA-B*57:01 predicts abacavir hypersensitivity.
- Drug-induced lupus: hydralazine (slow acetylators), procainamide, isoniazid; anti-histone antibodies, rarely kidney or brain involvement.
- Anaphylactoid (direct mast cell release): vancomycin red man syndrome, opioids, contrast.
Classic adverse effects
| Drug | Characteristic toxicity and mechanism |
|---|---|
| Sodium valproate | Fulminant hepatotoxicity (young children, polytherapy), pancreatitis, weight gain, tremor, neural tube defects |
| Amiodarone | Pulmonary fibrosis, thyroid dysfunction (iodine), photosensitivity, slate-grey skin, corneal deposits, liver injury |
| Spironolactone | Gynaecomastia (anti-androgen), hyperkalaemia |
| Zidovudine (AZT) | Bone marrow suppression (anaemia, neutropenia) |
| Didanosine (and stavudine) | Painful peripheral neuropathy and pancreatitis (mitochondrial toxicity; pyridoxine does not prevent it) |
| Amphotericin B | Nephrotoxicity (dose-limiting), hypokalaemia, hypomagnesaemia, infusion fever |
| Pyrazinamide | Most hepatotoxic first-line TB drug; raises uric acid (gout) |
| Ethionamide (and PAS) | Hypothyroidism and goitre (blocks thyroid hormone synthesis) in MDR-TB |
| Streptomycin, aminoglycosides | Ototoxicity and nephrotoxicity; fetal deafness |
| Danazol | Androgenic effects; voice deepening is irreversible |
| Nicorandil | Ulcers anywhere from mouth to anus; avoid with sildenafil |
| Alosetron (5-HT3 antagonist for severe diarrhoea-predominant IBS in women) | Ischaemic colitis, severe constipation |
| Halofantrine | Highest antimalarial risk of QT prolongation and torsades; avoid after mefloquine |
| Isoniazid | Neuropathy (prevented by pyridoxine), hepatitis, lupus |
Drug interactions
- Pharmacokinetic (one drug changes another's level):
- Metronidazole (with fluconazole, clarithromycin, ciprofloxacin, amiodarone) inhibits warfarin metabolism, so the INR rises and bleeding follows.
- Allopurinol with azathioprine: azathioprine becomes 6-mercaptopurine, which xanthine oxidase normally inactivates. Blocking it lets 6-MP accumulate, causing severe marrow suppression; reduce azathioprine to a quarter or avoid.
- Sulphonamides in a jaundiced newborn displace bilirubin from albumin; free unconjugated bilirubin crosses the immature blood–brain barrier, causing kernicterus.
- Chelation: tetracyclines and quinolones with antacids, iron, calcium. NSAIDs and thiazides raise lithium.
- Pharmacodynamic (effects add or oppose):
- QT prolongation is dangerous when two QT drugs combine, for example erythromycin with haloperidol (also methadone, antipsychotics, macrolides, quinolones, class Ia and III antiarrhythmics), worse with hypokalaemia.
- Digoxin with loop or thiazide diuretics: hypokalaemia leaves more Na+/K+ ATPase sites free for digoxin to bind, causing nausea, yellow vision and arrhythmias. Hypercalcaemia and hypomagnesaemia also increase toxicity.
- ACE inhibitor with potassium-sparing diuretic (hyperkalaemia); verapamil with beta-blocker (heart block); SSRI with tramadol or MAOI (serotonin syndrome); MAOI with tyramine (hypertensive crisis); sildenafil with nitrates or nicorandil (hypotension); ACE inhibitor, diuretic and NSAID together (acute kidney injury).
Teratogens and pregnancy prescribing
- Organogenesis (weeks 3–8) is the most sensitive period; before that exposure is "all or none". The neural tube closes by day 28, often before pregnancy is recognised.
| Drug | Fetal effect |
|---|---|
| Thalidomide | Phocomelia |
| Valproate | Neural tube defects (highest antiepileptic risk), developmental delay |
| Carbamazepine, phenytoin | NTDs, cleft lip, digit hypoplasia |
| Warfarin | Nasal hypoplasia, stippled epiphyses |
| ACE inhibitors, ARBs | Fetal renal failure, oligohydramnios |
| Lithium | Ebstein anomaly |
| Isotretinoin | Craniofacial, cardiac, CNS defects |
| Tetracyclines | Tooth staining, bone growth |
| Streptomycin, aminoglycosides | Permanent fetal deafness |
| Diethylstilboestrol | Vaginal clear cell adenocarcinoma in daughters |
| Danazol | Virilisation |
| NSAIDs near term | Premature closure of the ductus |
- Epilepsy planning pregnancy: valproate is avoided because it is teratogenic; lamotrigine (or levetiracetam) is safer. Women on antiepileptics take folic acid 5 mg daily from before conception through the first trimester (0.4 mg for low-risk women).
- DVT in pregnancy: low molecular weight heparin, because large, charged heparin molecules do not cross the placenta; warfarin does.
- UTI in the first trimester: nitrofurantoin is safest (avoid at term because of neonatal haemolysis); amoxicillin and cephalexin are alternatives. Avoid trimethoprim in the first trimester (folate antagonist).
- Mitral stenosis with tachycardia in pregnancy: a beta-blocker such as metoprolol, because slowing the rate lengthens diastolic filling across the stenotic valve.
- Generally safe: penicillins, cephalosporins, heparin, insulin, methyldopa, labetalol, nifedipine, paracetamol, levothyroxine. Untreated TB is more dangerous than first-line treatment (avoid streptomycin).
Poisoning management
- ABCDE, glucose, and paracetamol and salicylate levels in every overdose.
- Activated charcoal within 1 hour; it does not bind iron, lithium, alcohols, acids, alkalis or metals. Avoid inducing vomiting with kerosene (aspiration).
- Aspirin: sodium bicarbonate alkalinises urine, ionising salicylic acid (a weak acid). Ionised drug cannot diffuse back across the tubule, so it is trapped in urine and excreted (ion trapping). Salicylate first stimulates breathing (respiratory alkalosis) then causes metabolic acidosis. Dialyse severe cases.
- Haemodialysis removes small-Vd, water-soluble toxins: salicylate, lithium, methanol, ethylene glycol, theophylline, metformin.
- Benzodiazepine overdose: if breathing is adequate, give supportive care only. Flumazenil can precipitate seizures, especially in benzodiazepine-dependent patients, those with epilepsy, or mixed overdoses with tricyclics.
- Organophosphates: muscarinic excess (miosis, secretions, bradycardia) plus nicotinic weakness. Death is usually respiratory failure from bronchorrhoea, bronchospasm and respiratory muscle paralysis. Give atropine until the chest is dry, plus pralidoxime.
- Snake venom: phospholipase A2 is the main enzyme causing tissue destruction, haemolysis and myotoxicity; give antivenom.
| Poison | Antidote |
|---|---|
| Paracetamol | N-acetylcysteine (restores glutathione) |
| Opioids | Naloxone |
| Benzodiazepines | Flumazenil (rarely) |
| Organophosphates | Atropine and pralidoxime |
| Digoxin | Digoxin-specific Fab fragments |
| Warfarin; heparin; dabigatran | Vitamin K and PCC; protamine; idarucizumab |
| Beta-blockers | Glucagon, high-dose insulin |
| Iron | Desferrioxamine |
| Lead | Succimer (DMSA), EDTA, dimercaprol |
| Methanol, ethylene glycol | Fomepizole or ethanol; dialysis |
| Cyanide | Hydroxocobalamin |
| Carbon monoxide | 100% oxygen |
| Methaemoglobinaemia | Methylene blue |
| Tricyclics | Sodium bicarbonate (wide QRS) |
| Local anaesthetics | IV lipid emulsion |
| Malignant hyperthermia | Dantrolene |
| Isoniazid; methotrexate | Pyridoxine; folinic acid |
Remember Charcoal cannot bind iron, lithium, alcohols or metals; dialysis removes small-volume, water-soluble poisons.
Exam trap Hypokalaemia from diuretics makes digoxin more toxic.
Exam trap Allopurinol with azathioprine causes marrow failure unless the azathioprine dose is cut.
How FCPS asks about this
- Serious adverse effect of valproate: fulminant hepatotoxicity; in pregnancy planning switch to lamotrigine with folic acid 5 mg.
- Digoxin toxicity after starting a loop diuretic: hypokalaemia.
- Warfarin patient given metronidazole: INR rises; QT danger with erythromycin plus haloperidol.
- Classic drug side effects: amiodarone pulmonary fibrosis, spironolactone gynaecomastia, AZT marrow suppression, amphotericin nephrotoxicity, pyrazinamide hepatotoxicity and hyperuricaemia, ethionamide hypothyroidism.
- Kernicterus from sulphonamides: displaced bilirubin from albumin; LMWH in pregnancy because heparin does not cross the placenta.
- Why bicarbonate in aspirin poisoning: ion trapping in alkaline urine; flumazenil is avoided because it can cause seizures.
- Hypersensitivity types: erythroblastosis fetalis type II; SLE type III; HLA-B*15:02 testing before carbamazepine in Han Chinese or Thai patients.
Test yourself on this topic
5 of the 147 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A woman with a mechanical heart valve on warfarin becomes pregnant. Which fetal abnormality is she at risk of if warfarin continues in weeks 6–12?
Answer: Nasal hypoplasia, stippled epiphyses
Warfarin crosses the placenta. In weeks 6–12 it can cause warfarin embryopathy (nasal hypoplasia, stippled epiphyses, short limbs); later it causes fetal bleeding including intracranial haemorrhage. Most women switch to LMWH in the first trimester and near delivery, but in mechanical valves the choice balances maternal valve thrombosis against fetal risk, with specialist advice. Heparins do not cross the placenta.
Warfarin in pregnancy
- Weeks 6–12: embryopathy
- Nasal hypoplasia, stippled epiphyses
- Later: fetal bleeding
- Heparins: do not cross placenta
Remember Warfarin flattens the nose of the fetus.
Exam trap Warfarin is safe in breastfeeding.
Why the other options are wrong
- Phocomelia of all four limbs Thalidomide.
- Open neural tube defect Valproate, carbamazepine.
- Cleft lip and palate Phenytoin, steroids.
- Congenital complete heart block Maternal anti-Ro antibodies.
A 24-year-old woman with generalised epilepsy wants to start a family. Why is sodium valproate avoided, and what is a safer option?
Answer: Teratogenic; use lamotrigine
Sodium valproate exposure in pregnancy causes major congenital malformations in about 10% (neural tube defects such as spina bifida, cardiac defects, cleft palate, hypospadias) and neurodevelopmental problems including lower IQ and autism in up to 30–40%. It must not be used in women of childbearing potential unless other treatments are ineffective and a pregnancy prevention programme is in place. Lamotrigine and levetiracetam have the lowest known risks; carbamazepine and phenytoin carry intermediate risks. Women on antiepileptics should take high-dose folic acid (5 mg daily) before conception and in the first trimester. Seizure control should not be stopped abruptly, as uncontrolled seizures also harm mother and fetus.
Antiepileptics in pregnancy
- Valproate: ~10% malformations (NTD), neurodevelopmental harm
- Avoid in women of childbearing potential (pregnancy prevention programme)
- Safer: lamotrigine, levetiracetam
- Folic acid 5 mg preconception
- Don't stop abruptly
Remember Valproate and pregnancy don't mix.
Why the other options are wrong
- Reduces fertility only Main concern is the fetus.
- Safe in pregnancy Not safe.
- Avoid folic acid with it Folic acid is recommended.
- All carry identical risks Risks differ markedly.
In severe aspirin poisoning, why is sodium bicarbonate given to alkalinise the urine?
Answer: Ion trapping in alkaline urine
Ion trapping: only the un-ionised form of a drug crosses tubular membranes and is reabsorbed. A weak acid (salicylate, phenobarbital, methotrexate) becomes more ionised in alkaline urine and is trapped and excreted. Bicarbonate also reduces entry of salicylate into the brain by raising blood pH. Weak bases (amphetamine) are excreted faster in acidic urine, though urinary acidification is rarely used now. Haemodialysis is used for very high levels or severe toxicity.
Ion trapping
- Weak acid + alkaline urine → ionised → excreted
- Examples: salicylate, phenobarbital, methotrexate
- Weak bases: acidic urine
- Severe: haemodialysis
Remember Like dissolves like; opposite gets trapped.
Why the other options are wrong
- Binds salicylate in the gut Activated charcoal binds in the gut.
- Speeds hepatic metabolism Not the mechanism.
- Blocks aspirin absorption Not the mechanism.
- Reverses COX inhibition Aspirin's COX inhibition is irreversible.
A woman who took a large aspirin overdose has tinnitus and rapid breathing. Early ABG shows a high pH and low PaCO₂; later a low bicarbonate appears. What is the pattern?
Answer: Resp. alkalosis, then HAGMA
Salicylates stimulate the respiratory centre directly, causing hyperventilation and early respiratory alkalosis (more marked in adults). They also uncouple oxidative phosphorylation and interfere with metabolism, causing lactic and ketoacid accumulation and a high anion gap metabolic acidosis (dominant in children and severe poisoning). Features: tinnitus, vomiting, sweating, hyperthermia, hypoglycaemia, non-cardiogenic pulmonary oedema. Treatment: activated charcoal, IV sodium bicarbonate to alkalinise urine, haemodialysis for severe cases.
Salicylate poisoning
- Early: respiratory alkalosis (centre stimulated)
- Later: high AG metabolic acidosis (uncoupling)
- Tinnitus, sweating, hyperthermia
- Treat: bicarbonate (alkaline urine), dialysis
Remember Aspirin: breathe fast first, then acid builds.
Why the other options are wrong
- Pure metabolic alkalosis Not the pattern.
- Resp. acidosis, met. alkalosis Breathing is fast, not slow.
- Normal anion gap acidosis The gap is raised.
- No acid–base change Salicylates disturb acid-base markedly.
A kidney transplant patient on azathioprine is started on allopurinol for gout and develops severe bone marrow suppression. Why?
Answer: Xanthine oxidase block raises 6-MP
Azathioprine is converted to 6-mercaptopurine, which is inactivated mainly by xanthine oxidase (and by TPMT). Allopurinol and febuxostat inhibit xanthine oxidase, so 6-MP accumulates, causing life-threatening myelosuppression; the azathioprine dose must be reduced to about a quarter or an alternative used. People with low TPMT activity are also at risk, so TPMT is checked before starting azathioprine. Allopurinol lowers uric acid production and is started after an acute attack settles (with colchicine or NSAID cover); it can cause rash, including severe hypersensitivity (HLA-B*5801), and needs dose adjustment in renal impairment.
Allopurinol–azathioprine interaction
- Azathioprine → 6-MP → inactivated by xanthine oxidase
- Allopurinol blocks XO → 6-MP↑ → myelosuppression
- Reduce azathioprine to ~25%
- Check TPMT before azathioprine
- Allopurinol rash: HLA-B*5801
Remember Block the drain and 6-MP floods the marrow.
Why the other options are wrong
- Direct marrow suppression The interaction is the cause.
- Azathioprine raises allopurinol Reversed.
- Allopurinol induces CYP450 It is not an inducer.
- Gout causes marrow failure Not correct.
Where this sits in the CPSP syllabus
- Paper 1: General pharmacology, Adverse drug reactions, interactions, teratogens and poisoning
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