11.3 Adverse Drug Reactions & Drug Safety

Adverse Drug Reactions & Drug Safety

An Adverse Drug Reaction (ADR) is defined by the World Health Organization (WHO) as any response to a drug that is noxious and unintended, occurring at doses normally used in humans for prophylaxis, diagnosis, or therapy. In hospital medicine, ADRs account for $6.5%$ of all acute medical admissions and complicate up to $15%$ of inpatient stays.

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Rawlins-Thompson Classification of Adverse Drug Reactions

The standard clinical taxonomy divides ADRs into six distinct categories (Types A through F).

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Severe Cutaneous Adverse Reactions (SCAR)

Severe Cutaneous Adverse Reactions represent life-threatening Type B hypersensitivity reactions requiring immediate emergency recognition and drug discontinuation.

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

• Spectrum: Mucocutaneous reactions characterized by extensive keratinocyte apoptosis, epidermal detachment, and painful mucosal erosions (oral, ocular, genital).
  • SJS: $< 10%$ Body Surface Area (BSA) epidermal detachment.
  • SJS/TEN Overlap: $10-30%$ BSA detachment.
  • TEN: $> 30%$ BSA epidermal detachment.
• Clinical Signs: Targetoid purpuric macules, positive Nikolsky sign (slippage of normal-appearing epidermis under gentle pressure).
• High-Risk Culprit Drugs: Allopurinol, Sulfonamides (Co-trimoxazole), Antiepileptics (Carbamazepine, Phenytoin, Lamotrigine), NSAIDs (Oxicam class).
• Management: Immediate withdrawal of suspect drug, transfer to Burn Intensive Care Unit, supportive fluid/electrolyte balance, cyclosporine or IVIG.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome)

• Latency: $2 \text{ to } 8 \text{ weeks}$ after drug initiation (characteristically longer onset than SJS/TEN).
• Clinical Triad:
  1. High fever ($>38.5^\circ\text{C}$) and extensive morbilliform facial edema/rash.
  2. Hematological abnormalities: Eosinophilia ($\ge 1.5 \times 10^9\text{/L}$) or circulating atypical lymphocytes.
  3. Systemic organ involvement: Hepatitis ($>50%$ of cases), interstitial nephritis, pneumonitis, or myocarditis.
• Pathophysiology: T-cell mediated reaction frequently associated with reactivation of latent human herpesviruses (HHV-6, HHV-7, EBV).
• Culprit Drugs: Allopurinol, Carbamazepine, Phenytoin, Vancomycin, Minocycline, Sulfasalazine.

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Organ-Specific Drug Toxicities

1. Drug-Induced Liver Injury (DILI)

DILI is categorized into three patterns based on the R-ratio, calculated from initial liver biochemistry:

[ R = \frac{\text{Patient ALT} / \text{Upper Limit of Normal (ULN) for ALT}}{\text{Patient ALP} / \text{Upper Limit of Normal (ULN) for ALP}} ]

• Hepatocellular Pattern ($R \ge 5$): Marked elevation in ALT/AST. Triggers: Paracetamol, Isoniazid, Rifampicin, Methotrexate, Statins.
  • Hy’s Law: Hepatocellular DILI with ALT/AST $>3\times \text{ULN}$ combined with Total Bilirubin $>2\times \text{ULN}$ (in the absence of biliary obstruction or hemolysis) carries a $10%$ to $50%$ mortality rate from acute liver failure.
• Cholestatic Pattern ($R \le 2$): Predominant elevation in ALP and Gamma-GT. Triggers: Amoxicillin-clavulanate (most common cause of DILI in Western countries), Flucloxacillin, Chlorpromazine, Combined Oral Contraceptives.
• Mixed Pattern ($R = 2 \text{ to } 5$): Concurrent ALT and ALP elevations. Triggers: Phenytoin, Carbamazepine, Azathioprine.

2. Drug-Induced QT Prolongation & Torsades de Pointes (TdP)

Acquired Long QT Syndrome occurs when drugs block the delayed rectifier potassium current ($I_{Kr}$ / HERG channel), prolonging ventricular repolarization ($QTc > 470 \text{ ms}$ in men, $> 480 \text{ ms}$ in women). A $QTc > 500 \text{ ms}$ or an absolute increase of $>60 \text{ ms}$ confers high risk for Torsades de Pointes (TdP), a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation.

• High-Risk Offending Drug Classes:
  • Antiarrhythmics: Class IA (Quinidine, Procainamide), Class IC (Flecainide), Class III (Amiodarone, Sotalol).
  • Psychotropics: Haloperidol, Chlorpromazine, Quetiapine, Citalopram, Escitalopram, Methadone, TCAs.
  • Antimicrobials: Macrolides (Erythromycin, Clarithromycin), Fluoroquinolones (Ciprofloxacin, Levofloxacin), Azole antifungals (Fluconazole).
  • Antiemetics: Ondansetron, Domperidone.
• Acute Management of Torsades de Pointes:
  1. Hemodynamically unstable $\rightarrow$ Immediate unsynchronized DC cardioversion.
  2. Hemodynamically stable polymorphic VT $\rightarrow$ Intravenous Magnesium Sulfate 2 g bolus over 10–15 minutes (regardless of baseline serum magnesium level).
  3. Correct hypokalemia (target $K^+ \ge 4.5 \text{ mmol/L}$) and hypomagnesemia.
  4. Refractory cases $\rightarrow$ Overdrive atrial/ventricular pacing or Isoprenaline infusion (to increase heart rate and shorten QTc).

3. Drug-Induced Nephrotoxicity

• Acute Tubular Necrosion (ATN): Aminoglycosides, Cisplatin, Amphotericin B, Radiocontrast media.
• Acute Interstitial Nephritis (AIN): Classic triad of fever, maculopapular rash, and eosinophilia/eosinophiluria. Triggers: NSAIDs, Proton Pump Inhibitors (Omeprazole), Penicillins, Cephalosporins, Loop diuretics.
• Hemodynamic AKI: ACE inhibitors/ARBs (reduce efferent arteriolar tone) combined with NSAIDs (inhibit prostaglandin-mediated afferent arteriolar vasodilation) and diuretics ("Triple Whammy").

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Pharmacogenomics & Pre-Prescribing Safety Screening

Pharmacogenomic testing identifies genetic variations that alter drug metabolism or trigger severe hypersensitivity reactions.

Clinical Table: Essential Pharmacogenomic Screening Markers

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Pharmacovigilance & Causality Assessment

• Naranjo Causality Scale: Evaluates the probability of an ADR based on 10 standardized questions (dose-response, re-challenge, alternative causes). Score $\ge 9$ = Definite ADR; $5-8$ = Probable ADR; $1-4$ = Possible ADR; $\le 0$ = Doubtful.
• Yellow Card Scheme (MHRA / HPRA): National reporting system for adverse drug reactions.
  • Black Triangle ($\blacktriangledown$) Symbols: Signifies newly licensed drugs or vaccines subject to intensive surveillance. Clinicians MUST report all suspected adverse reactions (both minor and severe) for black triangle medications.
  • For established medicines, clinicians should report all serious suspected ADRs (fatal, life-threatening, disabling, or resulting in hospitalization).

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Exam Pearls

MRCPI Exam Pearl: Screening for HLA-B*5701 is mandatory prior to initiating Abacavir. If positive, abacavir must NEVER be prescribed; rechallenging a sensitized patient causes fatal anaphylactoid cardiovascular collapse.

MRCPI Exam Pearl: In suspected Drug-Induced Liver Injury (DILI), Hy's Law specifies that jaundice (Total Bilirubin $> 2\times \text{ULN}$) accompanying hepatocellular injury (ALT $> 3\times \text{ULN}$) carries a $10-50%$ mortality rate from acute liver failure. Immediate drug cessation is paramount.