Clinical pharmacology and prescribing: Adverse drug reactions, interactions and drug allergy

🩺 Adverse drug reactions, interactions and drug allergy. Adverse drug reactions cause about 1 in 16 hospital admissions and affect many inpatients; most are predictable from a drug's known effects, and many are preventable. Drug allergy is over-labelled (especially penicillin) but true allergy can kill. Interactions are a common, avoidable cause of harm. Specialty-specific drug effects are covered in each Anatomy, Physiology and Pharmacology chapter.
Your four questions for every suspected reaction: Could this symptom be caused by a drug -which one, and when was it started? Is it dangerous (anaphylaxis, SJS/TEN, organ failure) -what must I do now? Is it an allergy, an intolerance, or a predictable side effect -and how do I record it? Is an interaction responsible?

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What Is an Adverse Drug Reaction?

• Adverse drug reaction (ADR) -a harmful, unintended response to a medicine.
• Side effect -any effect other than the intended one (may be harmless or even useful).
• Adverse drug event -any harm while taking a medicine, including errors and overdose.
• Drug allergy -an ADR caused by the immune system (hypersensitivity).
• Intolerance -a non-immune unpleasant effect (e.g. nausea with codeine, diarrhoea with metformin) -not an allergy, but should be recorded.
• Risk factors for ADRs:
  • Patient -older age, very young, female sex, frailty, multiple diseases, kidney or liver impairment, pregnancy, genetic factors, previous ADRs.
  • Drug -polypharmacy, narrow therapeutic index, high doses, new drugs, drugs needing monitoring.
  • System -poor monitoring, poor communication, errors.
• Drugs most often causing ADR admissions -NSAIDs, anticoagulants and antiplatelets, diuretics, ACE inhibitors and ARBs, opioids, beta-blockers, digoxin, insulin and sulphonylureas, antidepressants, steroids, antibiotics.

Classifying ADRs

Type	Description	Examples
A -Augmented	Predictable from the drug's known effects; dose-related; common; usually mild (about 80% of ADRs)	Bleeding with warfarin, hypoglycaemia with insulin, bradycardia with beta-blockers, constipation with opioids
B -Bizarre	Unpredictable, not dose-related, often immune or genetic; uncommon but often serious	Anaphylaxis to penicillin, SJS with carbamazepine, malignant hyperthermia
C -Chronic	Related to cumulative dose and long-term use	Osteoporosis with steroids, tardive dyskinesia, amiodarone lung fibrosis
D -Delayed	Appear long after treatment	Teratogenicity (valproate), secondary cancers after chemotherapy
E -End of use	Withdrawal effects	Adrenal crisis after steroids, benzodiazepine or alcohol withdrawal, rebound angina after beta-blockers
F -Failure	Unexpected failure of treatment, often from interactions	Contraceptive failure with enzyme inducers

• DoTS classification -describes ADRs by Dose relationship, Time course and Susceptibility factors -used in pharmacovigilance.

Recognising an ADR

• Think "could this be a drug?" for any new symptom -especially in older people (falls, confusion, constipation, incontinence).
• Clues:
  • Timing -onset after starting a drug or increasing the dose (most within weeks; some -DRESS -2–8 weeks; others years).
  • Known effect of the drug (BNF, SPC).
  • Dechallenge -improvement on stopping.
  • Rechallenge -recurrence on restarting (only if safe -never after serious reactions).
  • No other explanation.
  • Drug levels (digoxin, lithium, phenytoin) or tests (e.g. eosinophilia, LFTs).
• Causality tools -Naranjo algorithm (definite, probable, possible, doubtful).
• Management:
  • Assess severity; treat the reaction (e.g. anaphylaxis protocol).
  • Stop or reduce the suspected drug (or switch class); balance against the benefit and the risks of stopping.
  • Document clearly (drug, reaction, severity, date) in notes, allergy/ADR record and discharge letter; tell the patient.
  • Report via Yellow Card where appropriate.
• Prescribing cascades -avoid treating a side effect with another drug (see the Older Person chapter on Prescribing).

Common ADRs by System

Problem	Common causative drugs
GI bleeding	NSAIDs, aspirin, anticoagulants, SSRIs (with NSAIDs), steroids (with NSAIDs), clopidogrel
Constipation	Opioids, anticholinergics, iron, calcium, verapamil, ondansetron, clozapine (can be fatal)
Diarrhoea and C. difficile	Antibiotics (clindamycin, cephalosporins, co-amoxiclav, quinolones), PPIs, metformin, laxatives, colchicine, mycophenolate
Hyponatraemia	Thiazides, SSRIs, carbamazepine and oxcarbazepine, PPIs, desmopressin, MDMA, antipsychotics, cyclophosphamide
Hyperkalaemia	ACE inhibitors, ARBs, spironolactone and eplerenone, amiloride, trimethoprim, potassium supplements, heparin, NSAIDs, ciclosporin and tacrolimus
Hypokalaemia	Loop and thiazide diuretics, salbutamol (high dose), steroids, insulin, laxatives, amphotericin
AKI	NSAIDs, ACE inhibitors and ARBs (in dehydration), diuretics, aminoglycosides, vancomycin (with piperacillin–tazobactam), IV contrast, lithium, ciclosporin
Hypoglycaemia	Insulin, sulphonylureas, (quinine, beta-blockers mask symptoms)
Bradycardia	Beta-blockers, verapamil and diltiazem, digoxin, amiodarone, donepezil, ivabradine
Postural hypotension and falls	Antihypertensives, alpha-blockers, nitrates, diuretics, sedatives, antipsychotics, tricyclics, levodopa
Confusion and delirium	Anticholinergics, opioids, benzodiazepines, steroids, antiparkinsonian drugs, antiepileptics, digoxin, lithium
Gynaecomastia	Spironolactone, digoxin, anti-androgens, cimetidine, oestrogens, cannabis
Ototoxicity	Aminoglycosides, loop diuretics (high-dose IV), cisplatin, vancomycin (rare), quinine
Lung fibrosis or pneumonitis	Amiodarone, methotrexate, nitrofurantoin (long-term), bleomycin, busulfan
Photosensitivity	Amiodarone, tetracyclines (doxycycline), thiazides, quinolones, sulfonamides, NSAIDs
Weight gain	Steroids, insulin, sulphonylureas, pioglitazone, antipsychotics (olanzapine, clozapine), mirtazapine, valproate
Tendon rupture	Fluoroquinolones (with steroids)
Gingival hyperplasia	Phenytoin, ciclosporin, calcium channel blockers (nifedipine)

Drug-induced Liver, Kidney and Blood Damage

• Drug-induced liver injury (DILI):
  • Hepatocellular (high ALT) -paracetamol (overdose), isoniazid, rifampicin, pyrazinamide, statins (usually mild), methotrexate, valproate, amiodarone, NSAIDs, ketoconazole, halothane.
  • Cholestatic (high ALP, bilirubin) -co-amoxiclav (common -can appear weeks after finishing), flucloxacillin, chlorpromazine, oral contraceptives, anabolic steroids, carbamazepine, erythromycin, sulfonylureas, nitrofurantoin.
  • Fatty liver -valproate, tetracyclines, methotrexate, amiodarone, steroids.
  • Liver fibrosis -methotrexate.
  • Herbal and dietary supplements (green tea extract, turmeric, bodybuilding products) -increasingly common.
  • Stop the drug if ALT over 3–5 times normal or with jaundice (Hy's law -ALT rise plus jaundice predicts severe injury).
• Kidney damage -pre-renal (NSAIDs, ACE inhibitors, diuretics), acute tubular necrosis (aminoglycosides, contrast, amphotericin), acute interstitial nephritis (PPIs, NSAIDs, penicillins, rifampicin -fever, rash, eosinophilia, white cells in urine), crystal nephropathy (aciclovir, methotrexate), glomerular disease (gold, penicillamine, NSAIDs), nephrogenic diabetes insipidus (lithium), retroperitoneal fibrosis.
• Blood disorders:
  • Agranulocytosis -clozapine, carbimazole (warn about sore throat -urgent FBC), sulfasalazine, antithyroid drugs, chloramphenicol, mirtazapine (rare), dapsone.
  • Aplastic anaemia / pancytopenia -methotrexate (with trimethoprim), chloramphenicol, azathioprine (low TPMT), carbamazepine, chemotherapy.
  • Thrombocytopenia -heparin (HIT), quinine, valproate, linezolid, rifampicin.
  • Haemolytic anaemia -G6PD deficiency triggers (primaquine, dapsone, nitrofurantoin), methyldopa (Coombs positive), penicillins, cephalosporins.
  • Macrocytosis / megaloblastic anaemia -methotrexate, trimethoprim, phenytoin, hydroxycarbamide, metformin (B12), PPIs (B12), azathioprine.

QT Prolongation

• Prolonged QT -risk of torsades de pointes (polymorphic VT) and sudden death; QTc over about 470 ms (men) or 480 ms (women) is prolonged; over 500 ms is high risk.
• Drugs that prolong QT:
  • Antiarrhythmics -amiodarone, sotalol, flecainide, dronedarone.
  • Antibiotics and antifungals -macrolides (clarithromycin, erythromycin, azithromycin), fluoroquinolones, fluconazole.
  • Antipsychotics -haloperidol, quetiapine, chlorpromazine, droperidol.
  • Antidepressants -citalopram and escitalopram (dose limits), tricyclics.
  • Antiemetics -ondansetron, domperidone.
  • Others -methadone, hydroxychloroquine, quinine, some antimalarials, tacrolimus.
• Risk factors -hypokalaemia, hypomagnesaemia, hypocalcaemia, bradycardia, female sex, older age, heart disease, congenital long QT, multiple QT-prolonging drugs, enzyme inhibitors raising drug levels.
• Prevention -baseline ECG for high-risk patients or drugs; correct electrolytes; avoid combinations; check the BNF and CredibleMeds.
• Torsades de pointes -IV magnesium sulfate (2 g), correct potassium, stop offending drugs, overdrive pacing or isoprenaline; DC cardioversion if pulseless or unstable.

Serotonin Syndrome and Neuroleptic Malignant Syndrome

Feature	Serotonin syndrome	Neuroleptic malignant syndrome (NMS)
Cause	Too much serotonin -combinations (SSRIs, SNRIs, MAOIs, linezolid, tramadol, fentanyl, triptans, St John's wort, lithium, MDMA, ondansetron), or overdose	Dopamine blockade -antipsychotics (also metoclopramide), or withdrawal of dopaminergic drugs (Parkinson's)
Onset	Rapid -hours	Slow -days to weeks
Neuromuscular	Clonus (inducible, ocular), hyperreflexia, tremor, myoclonus -worse in legs	"Lead-pipe" rigidity, bradyreflexia
Mental state	Agitation, confusion	Reduced consciousness, mutism, confusion
Autonomic	Fever, sweating, tachycardia, diarrhoea, dilated pupils	High fever, labile BP, sweating
Bloods	Usually non-specific	Very high CK, raised WCC, AKI (rhabdomyolysis)
Treatment	Stop serotonergic drugs, supportive care, benzodiazepines, cooling; cyproheptadine if severe	Stop the antipsychotic (or restart dopaminergic drugs), supportive care, cooling, fluids; dantrolene or bromocriptine if severe; ICU

• Malignant hyperthermia -after volatile anaesthetics or suxamethonium in susceptible people (RYR1) -rigidity, rising CO₂, hyperthermia -dantrolene.
• Anticholinergic toxidrome -hot, dry, flushed, dilated pupils, urinary retention, delirium ("hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter").

Types of Hypersensitivity

Type (Gell and Coombs)	Mechanism and timing	Drug examples
Type I -immediate	IgE-mediated mast cell degranulation; minutes to 1 hour	Anaphylaxis, urticaria and angioedema -penicillins, cephalosporins, neuromuscular blockers, chlorhexidine
Type II -cytotoxic	IgG/IgM antibodies against cells	Drug-induced haemolytic anaemia (penicillin, methyldopa), thrombocytopenia (HIT, quinine)
Type III -immune complex	Complexes deposited in tissues; 1–3 weeks	Serum sickness (fever, rash, joint pain -antivenoms, some antibiotics), drug vasculitis
Type IV -delayed	T-cell-mediated; days to weeks	Maculopapular (morbilliform) rash (commonest drug rash), SJS/TEN, DRESS, contact dermatitis

• Non-allergic (pseudo-allergic) reactions -mimic allergy without IgE:
  • Direct mast cell activation -opioids (itch, flushing), vancomycin ("red man" or vancomycin infusion reaction -slow the infusion), contrast media.
  • NSAID and aspirin sensitivity -bronchospasm in asthma with nasal polyps (COX-1 inhibition), urticaria.
  • ACE inhibitor angioedema -bradykinin-mediated (no urticaria; doesn't respond well to adrenaline or antihistamines) -can occur after years; stop permanently.
• Amoxicillin rash with EBV (glandular fever) -maculopapular rash, usually not true allergy.

Anaphylaxis

• A severe, life-threatening systemic hypersensitivity reaction -sudden Airway (swelling, stridor, hoarseness) and/or Breathing (wheeze, breathlessness) and/or Circulation (hypotension, collapse) problems, usually with skin or mucosal changes (urticaria, flushing, angioedema -absent in about 20%).
• Common drug triggers -antibiotics (penicillins, cephalosporins), neuromuscular blocking drugs and chlorhexidine (anaesthesia), NSAIDs, IV contrast, biologics, blood products; also foods and insect stings.
• Treatment (Resuscitation Council UK 2021):
  • Call for help; remove the trigger (stop the infusion); lie flat (raise legs) -sit up if breathing difficulty; don't stand.
  • IM adrenaline (1 mg/mL, i.e. 1:1,000) into the anterolateral thigh -adults 500 micrograms (0.5 mL); children 6–12 years 300 micrograms; 6 months–6 years 150 micrograms; under 6 months 100–150 micrograms.
  • Repeat after 5 minutes if no improvement.
  • High-flow oxygen; IV fluid bolus (500–1,000 mL crystalloid in adults).
  • Refractory anaphylaxis (no improvement after 2 IM doses) -adrenaline infusion by experienced staff, critical care.
  • Antihistamines and steroids are not first-line -non-sedating antihistamines for skin symptoms after stabilisation; steroids no longer routinely recommended.
• After anaphylaxis -mast cell tryptase (as soon as possible after onset, ideally within 2 hours, and a baseline at least 24 hours later), observe (biphasic reactions), two adrenaline auto-injectors where appropriate with training, referral to an allergy clinic, document allergy clearly, medical alert (NICE CG134).

Severe Cutaneous Adverse Reactions

Reaction	Features	Common drugs
Stevens–Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN)	Fever and flu-like prodrome, then painful dusky red or purple macules, blisters and skin peeling (Nikolsky sign positive), mucosal involvement (mouth, eyes, genitals); SJS under 10% skin detachment, TEN over 30%; mortality up to 30% (SCORTEN); usually 4–28 days after starting the drug	Allopurinol, carbamazepine, lamotrigine (rapid dose increases, with valproate), phenytoin, phenobarbital, sulfonamides (co-trimoxazole), NSAIDs (oxicams), nevirapine
DRESS (drug reaction with eosinophilia and systemic symptoms)	2–8 weeks after starting; fever, widespread rash, facial swelling, lymphadenopathy, eosinophilia, atypical lymphocytes, organ involvement (hepatitis, nephritis, pneumonitis, myocarditis); can relapse with HHV-6 reactivation	Anticonvulsants (carbamazepine, phenytoin, lamotrigine), allopurinol, sulfonamides, minocycline, vancomycin, dapsone
AGEP (acute generalised exanthematous pustulosis)	Within days; fever and many small sterile pustules on red skin (flexures); resolves on stopping	Beta-lactams, macrolides, hydroxychloroquine, diltiazem
Fixed drug eruption	Round dusky plaque recurring at the same site each time the drug is taken	NSAIDs, tetracyclines, sulfonamides, paracetamol

• Management of SJS/TEN and DRESS -stop the culprit drug immediately; admit (burns unit or ICU for TEN); supportive care (fluids, nutrition, wound and eye care -ophthalmology, analgesia, infection control); specialist dermatology; steroids for DRESS; record as a severe allergy -never rechallenge; consider related drugs (aromatic anticonvulsants cross-react).
• Prevention -HLA testing before carbamazepine (HLA-B*15:02 in some Asian ancestries) and abacavir (HLA-B*57:01); slow lamotrigine titration.

Assessing and Documenting Drug Allergy

• Ask every patient about drug allergies before prescribing -and record "no known drug allergies" if none (NICE CG183).
• Document:
  • The drug (generic and brand).
  • The reaction -what happened (e.g. "urticaria and wheeze" vs "nausea").
  • Severity and treatment needed.
  • When it happened and how soon after the drug.
  • Whether it is an allergy or a non-allergic intolerance or side effect.
  • The source of the information.
• Communicate -drug chart, records, GP (discharge letter), patient (written information, alert bracelet for severe reactions).
• Refer to specialist allergy services -anaphylaxis or severe reactions, suspected allergy to drugs essential for future care (e.g. penicillin, NSAIDs in cardiovascular disease, general anaesthesia drugs, local anaesthetics), and for penicillin allergy delabelling where appropriate.
• Skin tests and drug challenges -specialist only.
• Cross-reactivity -related drugs may react (penicillins with each other; aromatic anticonvulsants; sulfonamide antibiotics -but not usually other sulfonamide-containing drugs like furosemide).

Penicillin Allergy

• About 10% of people have a penicillin allergy label, but over 90% are not truly allergic when tested (many were rashes in childhood viral illness, or side effects like diarrhoea).
• Harms of a false label -use of broader-spectrum or less effective antibiotics, more C. difficile and MRSA, more treatment failure, longer stays, higher costs.
• Penicillin-containing antibiotics (all avoided in true allergy) -benzylpenicillin, phenoxymethylpenicillin, amoxicillin, co-amoxiclav, flucloxacillin, piperacillin–tazobactam, temocillin, pivmecillinam, ampicillin.
• Cephalosporins and carbapenems -cross-reactivity is low (about 1–2% for most cephalosporins; less for third generation; carbapenems under 1%) -avoid in anaphylaxis or severe reactions unless specialist advice; often usable after non-severe reactions (follow local policy).
• Severe delayed reactions (SJS/TEN, DRESS) to penicillin -avoid all beta-lactams unless specialist advice.
• Delabelling -low-risk histories (e.g. GI side effects, family history only, non-itchy rash over 10 years ago) -direct oral amoxicillin challenge in some services (penicillin allergy delabelling pathways); specialist assessment for higher-risk histories.
• Alternatives in penicillin allergy (follow local guidance) -macrolides (clarithromycin), doxycycline, vancomycin or teicoplanin, co-trimoxazole, clindamycin, quinolones (with cautions), aztreonam.

Pharmacokinetic Interactions

• One drug changes the absorption, distribution, metabolism or excretion of another.
• Absorption -chelation (calcium, iron, magnesium, antacids with tetracyclines, quinolones, bisphosphonates, levothyroxine); colestyramine binding; PPIs reduce absorption of itraconazole and some antiretrovirals.
• Metabolism -enzyme inhibition (raises levels -quick onset):
  • Clarithromycin / erythromycin + simvastatin or atorvastatin → myopathy and rhabdomyolysis (suspend statin).
  • Clarithromycin + colchicine → colchicine toxicity; + DOACs → bleeding.
  • Fluconazole, metronidazole, ciprofloxacin, clarithromycin, amiodarone + warfarin → raised INR and bleeding.
  • Diltiazem, verapamil + simvastatin; ritonavir (HIV, Paxlovid) + many drugs.
  • Allopurinol + azathioprine → marrow toxicity (xanthine oxidase inhibition).
  • Valproate + lamotrigine → raised lamotrigine (rash, SJS).
  • Grapefruit juice + simvastatin, ciclosporin, calcium channel blockers.
• Metabolism -enzyme induction (lowers levels -slow onset, 1–2 weeks; slow offset):
  • Rifampicin, carbamazepine, phenytoin, St John's wort + combined contraceptives (failure), warfarin (low INR), DOACs, ciclosporin and tacrolimus (rejection), steroids, antiretrovirals, methadone (withdrawal).
  • Smoking induces CYP1A2 -stopping smoking (e.g. on admission) raises clozapine and theophylline levels → toxicity.
• Excretion:
  • Lithium + NSAIDs, ACE inhibitors, ARBs, thiazides → reduced lithium clearance → toxicity.
  • Methotrexate + NSAIDs, PPIs (high-dose), penicillins → reduced clearance.
  • Digoxin + amiodarone, verapamil, clarithromycin (P-glycoprotein) → toxicity.
  • Probenecid reduces penicillin excretion (used deliberately).

Pharmacodynamic Interactions

• Drugs with similar or opposing effects act together at their targets.
• Additive or synergistic effects:
  • Bleeding -anticoagulants + antiplatelets + NSAIDs + SSRIs.
  • Sedation and respiratory depression -opioids + benzodiazepines + gabapentinoids + alcohol + antihistamines.
  • Hyperkalaemia -ACE inhibitor/ARB + spironolactone + trimethoprim + potassium supplements.
  • AKI -"triple whammy" -ACE inhibitor/ARB + diuretic + NSAID.
  • QT prolongation -two or more QT-prolonging drugs.
  • Serotonin syndrome -SSRIs + tramadol, linezolid, triptans, MAOIs, St John's wort.
  • Bradycardia and heart block -beta-blocker + verapamil (asystole risk -especially IV verapamil), digoxin + beta-blocker, amiodarone + beta-blocker.
  • Hypotension -PDE5 inhibitors (sildenafil) + nitrates (contraindicated -severe hypotension), alpha-blockers + antihypertensives.
  • Anticholinergic burden -several anticholinergic drugs.
  • Hypoglycaemia -insulin + sulphonylurea; beta-blockers mask warning symptoms.
  • Ototoxicity and nephrotoxicity -aminoglycoside + loop diuretic or vancomycin.
• Opposing effects:
  • NSAIDs reduce the effect of antihypertensives and diuretics.
  • Beta-blockers (non-selective) block salbutamol -avoid in asthma.
  • Anticholinergics cancel acetylcholinesterase inhibitors (donepezil).
  • Dopamine antagonists (metoclopramide, antipsychotics) worsen Parkinson's disease and block levodopa.
  • Vitamin K (diet, supplements) opposes warfarin.
  • Steroids and thiazides raise glucose, opposing diabetes treatment.

Dangerous Interactions to Know

Combination	Result	Action
Methotrexate + trimethoprim / co-trimoxazole	Bone marrow suppression	Avoid; use another antibiotic
Simvastatin + clarithromycin	Rhabdomyolysis	Suspend statin during course
Warfarin + antibiotics, azoles, amiodarone	Raised INR, bleeding	Check INR within days; adjust
Warfarin + NSAID or aspirin	GI bleeding	Avoid; paracetamol
Allopurinol + azathioprine	Marrow failure	Avoid or reduce azathioprine to a quarter (specialist)
Lithium + NSAID, ACE inhibitor, thiazide	Lithium toxicity	Avoid; monitor levels
Sildenafil + nitrates	Severe hypotension	Contraindicated
Beta-blocker + verapamil	Bradycardia, heart block, asystole	Avoid
ACE inhibitor + spironolactone (+ trimethoprim)	Hyperkalaemia	Monitor potassium
ACE inhibitor + diuretic + NSAID	AKI	Avoid NSAID; sick day rules
SSRI + tramadol, linezolid, triptan, MAOI	Serotonin syndrome	Avoid; washout before MAOIs
Opioid + benzodiazepine or gabapentinoid	Respiratory depression	Avoid or lowest doses
Rifampicin / carbamazepine + COC, warfarin, DOAC, ciclosporin	Treatment failure	Alternative contraception; monitor; avoid DOAC
Clozapine + stopping smoking	Clozapine toxicity (seizures)	Check levels; reduce dose
Gentamicin + furosemide or vancomycin	Ototoxicity, nephrotoxicity	Monitor levels and kidneys
Digoxin + amiodarone	Digoxin toxicity	Halve digoxin dose; monitor
Macrolide or quinolone + QT drugs	Torsades de pointes	Avoid; check ECG and electrolytes
Metformin + IV contrast (with AKI risk)	Lactic acidosis (rare)	Withhold per local policy if eGFR low

ADRs and Interactions at a Glance

Topic	Key facts
Type A ADRs	Predictable, dose-related, common (bleeding on warfarin)
Type B ADRs	Unpredictable, immune or genetic (anaphylaxis, SJS)
Anaphylaxis	IM adrenaline 500 micrograms (1 mg/mL) adults; repeat at 5 minutes; tryptase; allergy referral
SJS/TEN	Blisters, skin peeling, mucosal involvement, 4–28 days; allopurinol, carbamazepine, lamotrigine, sulfonamides
DRESS	2–8 weeks; rash, facial swelling, eosinophilia, organ involvement
ACE inhibitor angioedema	Bradykinin; no urticaria; stop permanently
Penicillin label	Over 90% not truly allergic; delabel where appropriate
Co-amoxiclav	Contains penicillin; cholestatic jaundice
Serotonin syndrome	Rapid onset, clonus, hyperreflexia, dilated pupils
NMS	Slow onset, lead-pipe rigidity, very high CK
QT	Macrolides, quinolones, antipsychotics, citalopram, ondansetron; low K and Mg; IV magnesium for torsades
Enzyme inducers	Lower levels slowly -rifampicin, carbamazepine, phenytoin, St John's wort
Enzyme inhibitors	Raise levels quickly -clarithromycin, azoles, ritonavir, amiodarone, grapefruit

Spot the Diagnosis

Clue	Diagnosis
Wheeze, hypotension and urticaria minutes after IV co-amoxiclav	Anaphylaxis -IM adrenaline
Swollen lips and tongue without rash in a man on ramipril for 3 years	ACE inhibitor angioedema
Flushing and itch over the upper body during a fast vancomycin infusion	Vancomycin infusion reaction -slow the rate
Rash after amoxicillin in a teenager with sore throat and lymphadenopathy	Amoxicillin rash with EBV
Blistering, skin peeling and sore eyes 2 weeks after starting allopurinol	SJS/TEN -stop immediately
Fever, facial swelling, eosinophilia and hepatitis 5 weeks after carbamazepine	DRESS
Recurring dark patch on the same spot of the lip after ibuprofen	Fixed drug eruption
Jaundice 3 weeks after finishing co-amoxiclav	Cholestatic DILI
AKI, fever, rash and eosinophils in urine on omeprazole	Acute interstitial nephritis
Sore throat and neutrophils 0.2 on carbimazole	Agranulocytosis
Platelets fall by half 7 days after starting heparin	Heparin-induced thrombocytopenia
Agitation, clonus, dilated pupils and fever after tramadol in a patient on sertraline	Serotonin syndrome
Rigidity, fever and CK 40,000 a week after starting haloperidol	Neuroleptic malignant syndrome
Hot, dry, flushed, confused with urinary retention after promethazine	Anticholinergic toxidrome
Torsades de pointes on clarithromycin and citalopram with low potassium	Drug-induced long QT
Muscle pain and CK 15,000 on simvastatin after clarithromycin	Rhabdomyolysis -CYP3A4 interaction
Unplanned pregnancy in a woman on the COC and carbamazepine	Enzyme induction
INR 9 after a course of metronidazole	Warfarin interaction
Tremor, diarrhoea and confusion after ibuprofen in a patient on lithium	Lithium toxicity
Collapse after sildenafil in a man taking isosorbide mononitrate	Severe hypotension -nitrate interaction
Seizure in a man on clozapine admitted to a no-smoking ward	Clozapine toxicity after stopping smoking

Exam-style Scenarios

1. A 55-year-old woman develops wheeze, facial swelling and a BP of 70/40 within 5 minutes of starting IV piperacillin–tazobactam. She has urticaria over her chest.
Answer: Anaphylaxis to a penicillin.

• Stop the infusion; call for help; lie flat with legs raised (sit up if breathing is difficult).
• IM adrenaline 500 micrograms (0.5 mL of 1 mg/mL) into the anterolateral thigh; repeat after 5 minutes if needed; high-flow oxygen; IV fluid bolus; refractory -adrenaline infusion with critical care.
• Mast cell tryptase (early and 24 hours later); document "penicillin -anaphylaxis"; refer to allergy services; choose a non-beta-lactam antibiotic per local guidance.

2. A 62-year-old man started allopurinol 300 mg daily 3 weeks ago for gout. He now has fever, sore red eyes, painful mouth ulcers and dusky skin lesions that are starting to blister on his trunk.
Answer: Stevens–Johnson syndrome / toxic epidermal necrolysis.

• Stop allopurinol immediately; urgent dermatology; admit (burns unit or ICU if extensive); ophthalmology review.
• Supportive care -fluids, nutrition, analgesia, wound care, infection prevention; calculate SCORTEN.
• Record as a severe allergy -never rechallenge; note that starting at high dose (especially with CKD) increases risk.

3. A 40-year-old woman on sertraline 100 mg takes tramadol for back pain. Twelve hours later she is agitated, sweaty and tremulous, with temperature 38.6°C, HR 120, dilated pupils, hyperreflexia and inducible ankle clonus.
Answer: Serotonin syndrome.

• Stop sertraline and tramadol; supportive care -IV fluids, cooling, cardiac monitoring.
• Benzodiazepines for agitation and muscle activity; cyproheptadine if moderate to severe; ICU if temperature over 41°C (sedation, paralysis).
• Avoid serotonergic analgesics in future (use paracetamol, NSAIDs or non-serotonergic opioids).

4. A 75-year-old man on warfarin for AF (stable INR 2.5) is prescribed clarithromycin for a chest infection. Five days later he has haematuria; INR is 8.2. No major bleeding.
Answer: Warfarin interaction (enzyme inhibition) with high INR and minor bleeding.

• Withhold warfarin; give IV vitamin K 1–3 mg (INR over 8 with minor bleeding, per BNF); recheck INR daily.
• Restart warfarin when INR is under 5; review the antibiotic (an alternative with less interaction if possible).
• Future -check INR within 3–5 days of starting any interacting drug.

5. A 30-year-old woman says she is "allergic to penicillin" because she had diarrhoea with amoxicillin as a teenager. She now has a dental abscess.
Answer: Penicillin intolerance, not allergy.

• Diarrhoea is a side effect, not an allergy -explain this, and update the record ("intolerance -diarrhoea").
• Amoxicillin or phenoxymethylpenicillin can be used (with consent); dental drainage is the main treatment.
• Refer for formal delabelling if there's any doubt; correct labels improve future antibiotic choices.

Key Points

• Any new symptom could be an ADR -check timing, known effects, dechallenge.
• Type A -predictable and dose-related; type B -unpredictable (immune or genetic).
• Commonest culprits -NSAIDs, anticoagulants, diuretics, ACE inhibitors, opioids, insulin, digoxin.
• Anaphylaxis -IM adrenaline 500 micrograms (1 mg/mL) in adults, repeat after 5 minutes; tryptase; allergy referral.
• Antihistamines and steroids are not first-line in anaphylaxis.
• ACE inhibitor angioedema is bradykinin-mediated -stop permanently.
• SJS/TEN and DRESS -stop the drug at once; never rechallenge; allopurinol, anticonvulsants and sulfonamides are common causes.
• Document allergies with the drug, reaction, severity and date; record "no known drug allergies" when none.
• Most penicillin labels are wrong -delabel where appropriate; co-amoxiclav and piperacillin–tazobactam contain penicillin.
• Co-amoxiclav and flucloxacillin cause cholestatic jaundice; PPIs cause interstitial nephritis.
• Carbimazole and clozapine -agranulocytosis; heparin -HIT.
• Serotonin syndrome -fast, clonus, hyperreflexia; NMS -slow, rigidity, high CK.
• QT prolongation -avoid combinations; correct potassium and magnesium; IV magnesium for torsades.
• Enzyme inhibitors raise levels quickly; inducers lower them slowly.
• Know the dangerous pairs -methotrexate + trimethoprim, statin + clarithromycin, warfarin + antibiotics, sildenafil + nitrates, beta-blocker + verapamil, lithium + NSAIDs, "triple whammy".

Guidelines and Further Reading

• NICE CG183: Drug allergy -diagnosis and management
• Resuscitation Council UK: Emergency treatment of anaphylaxis (2021)
• NICE CG134: Anaphylaxis -assessment and referral after emergency treatment
• British Society for Allergy and Clinical Immunology (BSACI): Management of allergy to penicillins and other beta-lactams; penicillin allergy delabelling
• British Association of Dermatologists: Guidelines for SJS/TEN
• BNF Appendix: Interactions; MHRA Drug Safety Updates
• CredibleMeds: QT drug lists
• Pirmohamed M et al.: Adverse drug reactions as cause of admission to hospital (BMJ)
• Edwards IR and Aronson JK: Adverse drug reactions -definitions, diagnosis and management (Lancet)
• BNF -for current doses