Key Points

  • ADRs are unintended, harmful events caused by medicines and contribute to many unscheduled hospital admissions.
  • A careful medication history helps identify previous ADRs that could preclude re-exposure.
  • Prevention depends on avoiding treatment in susceptible patients and using therapeutic plans that reduce risk.
  • Spontaneous reporting (e.g., Yellow Card Scheme) is crucial but underused. Always report if in doubt.

Introduction

An Adverse Drug Reaction (ADR) is defined as "a response to a medicinal product that is noxious and unintended". ADRs range from minor symptoms to life-altering events, often leading to hospital admission, prolonged stay, morbidity, and increased costs. Diagnosis is challenging as ADRs can mimic underlying diseases or go unrecognized.

Studies in Europe show ADRs cause 0.5–12.8% of acute hospital admissions, with 1.7–50.9% of inpatients experiencing an ADR during admission.

Classification of Adverse Drug Reactions

Traditionally, ADRs are classified as:

  • Type A (Augmented): Predictable based on drug pharmacology.
  • Type B (Bizarre): Unpredictable, often idiosyncratic.

An alternative classification is DoTS (Dose-relatedness, Time course, Susceptibility).

Dose-relatedness

All pharmacological effects are dose-related. Subclasses include:

  • Hypersusceptibility reactions: Occur at very low doses in susceptible individuals (e.g., anaphylaxis).
  • Collateral effects: Occur at standard therapeutic doses.
  • Toxic effects: Occur with high doses, reduced elimination, or drug interactions.

Time Course

ADRs can be:

  • Time-independent: Can occur anytime during treatment (e.g., bleeding with warfarin).
  • Time-dependent: Occur at characteristic times (e.g., anaphylaxis shortly after first dose, delayed hypersensitivity after 10 days–10 weeks).
  • Delayed reactions: Occur long after treatment ends (e.g., second cancers years after alkylating agents).

Susceptibility

Risk varies with age, renal function, genetics, ethnicity, pregnancy, comorbidities, and concomitant drugs. Pharmacogenetics (drug–gene interactions) helps predict susceptibility (e.g., CYP2D6 poor metabolizers, HLA-B*57:01 with abacavir).

Detection and Diagnosis

Causality is often assessed via temporal relationship, de-challenge (resolution on stopping), and re-challenge (recurrence on restarting). Tools like the Naranjo algorithm exist but are more useful in research than individual cases.

Post-marketing surveillance systems (e.g., Yellow Card Scheme, prescription-event monitoring) are vital for detecting ADRs not seen in clinical trials.

Preventing Adverse Drug Reactions

Many ADRs are preventable through:

  • Identifying susceptible subgroups (using pharmacogenetics, patient history).
  • Modifying treatment plans to mitigate risks (e.g., co-prescribing folic acid with methotrexate, monitoring electrolytes with diuretics).
  • Safe prescribing and patient-centred communication about risks and monitoring.

Common and Important ADRs (Examples)

Drug-induced Disorder Examples of Causative Drugs Mechanism
Oxidative haemolysis Primaquine, dapsone G6PD deficiency
Myopathy Statins (simvastatin, atorvastatin) SLCO1B1 polymorphism increases muscle uptake
Stevens–Johnson syndrome / Toxic epidermal necrolysis Abacavir, allopurinol, carbamazepine Associated with HLA genotypes (e.g., HLA-B*57:01, HLA-B*15:02)
QT prolongation / Torsade de pointes Amiodarone, erythromycin, citalopram, haloperidol Drug-induced repolarization abnormality; risk increased with hypomagnesemia/hypokalemia
Serotonin syndrome SSRIs, linezolid, tramadol Excessive serotonin activity
Ketoacidosis (euglycaemic) SGLT2 inhibitors (canagliflozin, dapagliflozin) Increased lipolysis and ketogenesis despite normal glucose

Drug Interactions

Interactions can occur between drugs, herbs, and foods, leading to altered efficacy or toxicity. Categories include:

  • Pharmaceutical (in vitro): Outside the body (e.g., IV incompatibility).
  • Pharmacokinetic (in vivo): Affect absorption, distribution, metabolism, elimination.
  • Pharmacodynamic (in vivo): Additive/synergistic or antagonistic effects.

Food–Drug & Drug–Herb Interactions

Type Substance Drug/Class Effect
Food–Drug Food (any) Rifampicin, iron, penicillin Reduced absorption
Food–Drug Leafy vegetables (high vitamin K) Warfarin Diminished anticoagulant effect
Drug–Herb St John’s wort Ciclosporin, warfarin, antidepressants Induces CYP enzymes → reduced drug levels
Drug–Herb Ginkgo, garlic, ginger Warfarin Increased anticoagulant effect (bleeding risk)

Clinical Cases for Self-Assessment

Question 1: A 68-year-old Chinese man with previous stent placement presents with stent thrombosis despite being on clopidogrel. What is the most likely pharmacological reason?
Answer: B. Clopidogrel resistance due to pharmacogenomic variation (CYP2C19 poor metabolizer status).
Question 2: A 54-year-old on warfarin with prosthetic valve develops intracerebral bleed with INR 8.2 after starting amoxicillin and clarithromycin for pneumonia. What is the most likely cause?
Answer: B. Metabolic drug–drug interaction between clarithromycin (CYP3A4 inhibitor) and warfarin, increasing warfarin levels.
Question 3: A 58-year-old diabetic on empagliflozin presents with vomiting, fever, ketosis, and normal glucose. What is the most likely cause?
Answer: B. Ketoacidosis due to a sodium-glucose co-transporter 2 (SGLT2) inhibitor (euglycaemic diabetic ketoacidosis).