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

• Adverse drug reactions: What Is an Adverse Drug Reaction? | Classifying ADRs | Recognising an ADR | Common ADRs by System | Drug-induced Liver, Kidney and Blood Damage | QT Prolongation | Serotonin Syndrome and Neuroleptic Malignant Syndrome
• Drug allergy: Types of Hypersensitivity | Anaphylaxis | Severe Cutaneous Adverse Reactions | Assessing and Documenting Drug Allergy | Penicillin Allergy
• Interactions: Pharmacokinetic Interactions | Pharmacodynamic Interactions | Dangerous Interactions to Know
• Revision: ADRs and Interactions at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🩺 Adverse drug reactions, interactions and drug allergy -page 3 of the Clinical Pharmacology and Prescribing chapter. 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?

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

• 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

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

• 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

• 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

• 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