Makindo Medical Notes

Adverse drug effects are unintended, harmful reactions to medications that occur at normal therapeutic doses. They are a major cause of morbidity and mortality, contributing to ~6–7% of hospital admissions in the UK. A systematic approach is crucial for recognising, classifying, and preventing ADEs.

📖 Introduction

• Defined by WHO as: "a response to a drug which is noxious, unintended, and occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy."
• Affect up to 1 in 10 inpatients, with elderly and polypharmacy patients at greatest risk.
• Different from medication errors (wrong drug/dose) but may overlap.

🧬 Pathophysiology

• Pharmacological effects (dose-related toxicity, predictable).
• Immune-mediated hypersensitivity (allergic reactions, unpredictable).
• Idiosyncratic reactions (unusual, genetic or metabolic basis).
• Drug–drug and drug–disease interactions (e.g. NSAIDs + CKD → AKI).

⚖️ Classification (Rawlins & Thompson)

Type	Features	Examples
Type A ("Augmented") 📈	Predictable, dose-dependent, related to pharmacology. Common.	Hypoglycaemia with insulin, bleeding with warfarin, hypotension with beta-blockers.
Type B ("Bizarre") ⚡	Unpredictable, not dose-dependent, often immune or genetic. Rare but serious.	Anaphylaxis with penicillin, agranulocytosis with clozapine, SJS/TEN with carbamazepine.
Type C ("Chronic") ⏳	Due to prolonged treatment or cumulative dose.	Steroid-induced osteoporosis, analgesic nephropathy.
Type D ("Delayed") ⌛	Appear long after exposure.	Cancer after chemotherapy, teratogenesis with thalidomide.
Type E ("End of use") 🚫	Withdrawal effects after drug stopped.	Seizures after stopping benzodiazepines, adrenal insufficiency after steroids.
Type F ("Failure") ❌	Therapeutic failure, often due to drug interactions or resistance.	Contraceptive failure with enzyme-inducing antibiotics, antibiotic resistance.

🩺 Clinical Assessment

• 📝 History: Timeline of drug exposure, dose, indication, and onset of symptoms.
• 📋 Drug list: Include prescriptions, OTC, herbal supplements.
• 🔎 Exam: Rash, jaundice, bleeding, confusion, renal/hepatic signs.
• 🧪 Investigations: FBC (agranulocytosis), U&E (renal toxicity), LFTs (hepatotoxicity), INR (warfarin control).
• 📈 Causality tools: Naranjo algorithm (probable vs possible ADR).

⚠️ Risk Factors

• 👴 Elderly age.
• 💊 Polypharmacy (>5 drugs).
• 🧬 Genetic factors (slow acetylators, HLA types).
• 🩺 Comorbidities: renal, liver, cardiac disease.
• 🚺 Pregnancy, paediatrics (altered pharmacokinetics).

📊 Comprehensive Summary Table — Adverse Drug Effects

💊 Drug / Class	⚙️ Mechanism	🩺 Adverse Effect	⚕️ Management
ACE inhibitors (Ramipril, Lisinopril)	↑ Bradykinin	Dry cough, angioedema	Stop drug 🚫, switch to ARB or CCB, airway support if angioedema
NSAIDs (Ibuprofen, Naproxen, Diclofenac)	COX inhibition → ↓ prostaglandins	GI bleed/ulcer, AKI, fluid retention, asthma exacerbation	Stop NSAID 🚫, IV PPI for bleed, fluids, OGD, use alternative analgesia
Amiodarone	Iodine effect + cytotoxicity	Thyroid disease (hypo/hyper), pulmonary fibrosis, corneal deposits, skin photosensitivity	Stop drug 🚫 if possible, manage thyroid/lung complications, regular TFTs & CXR
Statins (Simvastatin, Atorvastatin)	↓ Cholesterol synthesis, ↑ muscle breakdown risk	Myopathy, rhabdomyolysis, deranged LFTs	Stop statin 🚫, check CK & LFTs, consider lower dose or switch to ezetimibe
Metformin	↑ Lactate due to mitochondrial inhibition	Lactic acidosis (esp. in CKD/AKI), GI upset	Stop drug 🚫 if renal impairment, treat acidosis, use insulin if diabetes uncontrolled
Sulfonylureas (Gliclazide, Glibenclamide)	↑ Insulin secretion	Hypoglycaemia	Give glucose/IV dextrose, review regimen
Isoniazid (TB treatment)	Pyridoxine deficiency	Peripheral neuropathy, hepatitis	Pyridoxine (B6) supplementation, monitor LFTs
Rifampicin	Hepatic enzyme induction	Hepatitis, orange urine/tears, drug interactions	Monitor LFTs, counsel on harmless discoloration
Carbamazepine	Sodium channel blocker	Agranulocytosis, hyponatraemia (SIADH), rash (SJS)	Stop drug 🚫, monitor FBC/U&E, supportive care
Valproate	↑ GABA levels	Hepatotoxicity, pancreatitis, teratogenic (NTDs)	Avoid in pregnancy, monitor LFTs, stop if hepatitis
Clozapine	Dopamine D2 antagonist	Agranulocytosis, myocarditis, seizures, constipation	Mandatory FBC monitoring, stop if neutropenia
SSRIs (Sertraline, Fluoxetine)	↑ Serotonin	GI upset, hyponatraemia (elderly), serotonin syndrome	Stop drug 🚫, supportive care, manage electrolytes
Opiates (Morphine, Codeine)	μ-receptor agonist	Constipation, respiratory depression, nausea	Laxatives, naloxone for overdose
Warfarin	Vitamin K antagonist	Bleeding, skin necrosis (rare)	Stop drug 🚫, vitamin K, PCC/FFP if severe bleed
DOACs (Apixaban, Rivaroxaban)	Direct factor Xa inhibitors	Bleeding	Andexanet alfa (Xa reversal), PCC if unavailable
Digoxin	Na⁺/K⁺ ATPase inhibition	Nausea, vomiting, visual disturbance (yellow halos), arrhythmias	Stop drug 🚫, digoxin-specific antibody fragments if severe
Lithium	Alters neuronal ion transport	Nephrogenic diabetes insipidus, hypothyroidism, tremor, toxicity	Stop drug 🚫, monitor TFTs/U&E, haemodialysis in toxicity

💉 Management

• ⛔ Stop the suspected drug if safe to do so.
• 🔄 Switch to alternative if therapy essential.
• 🛡️ Supportive treatment: fluids, oxygen, antihistamines, steroids, adrenaline in anaphylaxis.
• 📊 Monitor organ function (renal, hepatic, haematological).
• 📢 Report ADRs via MHRA Yellow Card Scheme (UK requirement).
• 👨‍👩‍👧 Patient education: carry allergy cards, warn about recurrence risk.

📌 Prevention

• 💊 Prescribe lowest effective dose.
• 🔎 Regular medication review (esp. elderly, polypharmacy).
• 🧬 Pharmacogenomic testing where appropriate (e.g. HLA-B*57:01 before abacavir).
• 📚 Use BNF & NICE guidelines for safe prescribing.
• 🤝 Multidisciplinary working with pharmacists.

📚 Key References

• BNF – British National Formulary (latest edition).
• NICE Guidance: Medicines optimisation (NG5).
• MHRA Yellow Card Scheme: Report an ADR.

💡 Summary: Adverse drug effects are common and preventable. Always think: Is this symptom due to a drug? Early recognition, withdrawal of culprit, supportive treatment, and reporting are the pillars of safe practice.

Cases — Adverse Drug Effects (ADEs)

• Case 1 (ACE inhibitor → angioedema): 💊😮 A 63-year-old man started on ramipril for hypertension presents 3 weeks later with facial swelling, lip oedema, and difficulty speaking. No rash or pruritus.
  Management: Ramipril stopped immediately. Treated with IV steroids and antihistamines; monitored in hospital.
  Outcome: Swelling subsided within 24 hours. Switched to amlodipine for blood pressure control. Counselled to avoid ACE inhibitors in future.
• Case 2 (NSAID → AKI + GI bleed): 💊🩸 A 70-year-old woman with osteoarthritis has been taking ibuprofen daily for several months. She presents with melaena, dizziness, and reduced urine output. Bloods: Hb 85 g/L, creatinine 250 µmol/L.
  Management: IV fluids, PPI infusion, blood transfusion, and urgent OGD which identifies and clips a bleeding gastric ulcer. NSAIDs discontinued.
  Outcome: Renal function gradually recovered. Pain managed with paracetamol and topical agents instead.
• Case 3 (Amiodarone → thyroid dysfunction): 💊🦋 A 58-year-old man on amiodarone for atrial fibrillation presents with weight loss, tremor, and palpitations. TFTs show suppressed TSH and elevated free T4 = amiodarone-induced thyrotoxicosis.
  Management: Amiodarone stopped after cardiology review. Treated with carbimazole and steroids. Endocrinology follow-up arranged.
  Outcome: Thyroid function normalised after 6 months. Patient later switched to alternative rhythm-control therapy.

🧑‍⚕️ Teaching Commentary

Adverse drug effects can occur via several mechanisms: • Idiosyncratic (ACE inhibitor angioedema). • Predictable dose-related (NSAID-induced AKI and GI bleed). • Metabolic/endocrine (amiodarone-induced thyroid disease). 🔑 Always review drug history in any acute presentation, and consider: stop the offending drug, treat the complication, and find a safer alternative. Documenting ADEs clearly prevents recurrence and improves patient safety.