5.3 Adverse Drug Reactions & Therapeutic Drug Monitoring

[!NOTE] Curriculum Focus: The MRCP(UK) Part 1 tests adverse drug reaction (ADR) classifications and practical therapeutic drug monitoring. Candidates must be fluent in the Rawlins-Thompson taxonomy, precise timing of serum sampling, reference therapeutic target windows, laboratory and electrocardiographic manifestations of toxicity, and specific rescue protocols for narrow therapeutic index medications.

An Adverse Drug Reaction (ADR) is defined by the World Health Organization as any noxious, unintended, and undesirable response to a medication occurring at doses routinely used in humans for prophylaxis, diagnosis, or therapy.

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The Rawlins-Thompson ADR Taxonomy

The Rawlins and Thompson classification system categorises adverse reactions into six distinct mechanistic groups (Type A through Type F):

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Principles of Therapeutic Drug Monitoring (TDM)

Therapeutic Drug Monitoring involves measuring serum drug concentrations at defined intervals to optimise therapeutic efficacy while avoiding concentration-dependent toxicity. TDM is indicated only when specific criteria are fulfilled:

1. Narrow Therapeutic Index: Small difference between minimum effective concentration and minimum toxic concentration.
2. Direct Correlation Between Serum Level and Effect: Established target concentration window correlating with efficacy and safety.
3. Unpredictable Dose-Concentration Relationship: Wide inter-individual pharmacokinetic variability (due to variable clearance, saturation kinetics, or polymorphic metabolism).
4. Absence of a Simple Clinical Endpoint: Unlike blood pressure (monitoring antihypertensives) or INR (monitoring warfarin), toxicity or efficacy cannot be directly observed at the bedside without laboratory assays.

Practical Timing of Serum Sampling

• Steady State Requirement: Samples must be drawn once the drug has attained steady-state equilibrium (after 4 to 5 elimination half-lives), unless acute toxicity is clinically suspected.
• Trough Concentrations: For the vast majority of drugs, serum levels are drawn immediately prior to the next scheduled dose (trough level).
• Key Exception (Digoxin): Must be sampled at least 6 to 8 hours post-dose (or immediately pre-dose). Digoxin exhibits a prolonged 6-hour distribution phase from plasma into myocardium; sampling before 6 hours yields falsely elevated plasma concentrations that do not reflect tissue receptor engagement.

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High-Yield TDM Reference Guide

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|                         High-Yield TDM Drug Summary Matrix                              |
+-----------------------------------------------------------------------------------------+
| Drug:         Target Range:     Sampling Time:    Key Toxicity Signs:                   |
| Digoxin       0.5 - 0.9 ug/L    >= 6h post-dose   Ventricular bigeminy, yellow halos    |
| Lithium       0.4 - 0.8 mmol/L  12h post-dose     Coarse tremor, ataxia, dysarthria     |
| Gentamicin    Trough < 1 mg/L   Pre-dose trough   Vestibular ataxia, ATN (rising Cr)    |
| Phenytoin     10 - 20 mg/L      Trough            Nystagmus, ataxia, cerebellar atrophy |
| Theophylline  10 - 20 mg/L      Trough            Tachyarrhythmias, refractory seizures |
+-----------------------------------------------------------------------------------------+

1. Digoxin

• Therapeutic Range: 0.5–0.9 ug/L in heart failure; 0.8–1.5 ug/L in atrial fibrillation. Toxicity incidence escalates sharply at > 2.0 ug/L.
• Mechanism: Inhibits myocardial sarcolemmal Na+/K+ ATPase, increasing intracellular sodium, which reduces calcium extrusion via the Na+/Ca2+ exchanger, enhancing cardiac inotropy.
• Precipitating Factors: Hypokalaemia (potassium competes with digoxin for binding at Na+/K+ ATPase; low serum potassium markedly enhances digoxin binding and toxicity), hypomagnesaemia, hypercalcaemia, renal failure, and interacting drugs (amiodarone, verapamil, clarithromycin, spironolactone).
• Clinical Manifestations:
  • Gastrointestinal: Anorexia, nausea, vomiting, abdominal pain (often earliest sign).
  • Neurological/Visual: Xanthopsia (yellow-green halo vision), blurred vision, confusion, delirium.
  • Cardiac Arrhythmias: Pathognomonic ventricular bigeminy, bidirectional ventricular tachycardia, paroxysmal atrial tachycardia with variable AV block, junctional escape rhythms, and severe sinus bradycardia.
• Management:
  • Correct potassium (target 4.0–5.0 mmol/L) and magnesium. Note: In acute massive overdose, digoxin causes severe hyperkalaemia by disabling the sodium-potassium pump globally; insulin/dextrose is indicated.
  • Digoxin-Specific Fab Fragments (DigiFab): Indications include life-threatening ventricular arrhythmias, refractory bradycardia unresponsive to atropine, serum potassium > 5.0 mmol/L in acute ingestion, or acute ingestion > 10 mg in adults.

2. Lithium

• Therapeutic Range: 0.4–0.8 mmol/L for maintenance therapy; 0.8–1.0 mmol/L for acute mania. Monitored exactly 12 hours post-evening dose.
• Toxicity Stages:
  • Mild (1.5–2.0 mmol/L): Nausea, diarrhoea, polyuria, polydipsia, fine resting tremor converting into a coarse tremor, hyperreflexia.
  • Moderate (2.0–2.5 mmol/L): Cerebellar ataxia, dysarthria, coarse myoclonus, nystagmus, fasciculations.
  • Severe (> 2.5 mmol/L): Generalised tonic-clonic seizures, encephalopathy, coma, cardiovascular collapse, and the irreversible SILENT syndrome (Syndrome of Irreversible Lithium-Effectuated Neurotoxicity: permanent cerebellar ataxia and cognitive impairment).
• Precipitating Drug Interactions (Mnemonic: "NSA"):
  • NSAIDs: Inhibit renal prostaglandins, reducing renal medullary blood flow and GFR.
  • Spironolactone / Thiazide diuretics: Induce natriuresis in the distal tubule; the compensatory proximal tubular sodium reabsorption causes equimolar reabsorption of lithium (handled identically to sodium).
  • ACE Inhibitors / ARBs: Dilate efferent arterioles, reducing GFR and lithium filtration.
  • Dehydration, vomiting, diarrhoea, and sodium restriction similarly trigger toxicity.
• Long-Term Complications: Nephrogenic diabetes insipidus (lithium enters principal cells via ENaC and decouples vasopressin V2 receptor adenylate cyclase, downregulating aquaporin-2 channels), chronic tubulointerstitial nephritis, primary hypothyroidism, and hyperparathyroidism with hypercalcaemia.
• Management: Volume expansion with IV 0.9% sodium chloride to promote renal excretion. Haemodialysis is indicated if lithium > 4.0 mmol/L regardless of symptoms, > 2.5 mmol/L with severe neurological manifestations or renal failure, or if clinical deterioration continues despite IV saline.

3. Gentamicin & Aminoglycosides

• Pharmacodynamic Target: Concentration-dependent bactericidal killing. Governed by the Cmax : MIC ratio (optimal target >= 10:1) and a prolonged post-antibiotic effect (PAE).
• Extended-Interval Dosing (Hartford Nomogram): Administering a large single daily dose (5–7 mg/kg) achieves an intense bactericidal peak while allowing serum concentrations to decline to negligible levels before the next dose.
• Trough Target: < 1.0 mg/L (pre-dose). Elevated trough concentrations reflect tissue accumulation in renal cortical cells and endolymph/perilymph, directly driving toxicity.
• Toxicities:
  • Nephrotoxicity: Non-oliguric acute tubular necrosis (ATN) caused by pinocytosis of aminoglycoside molecules into proximal tubular brush-border lysosomes. Typically manifests as a rising serum creatinine 5 to 7 days into therapy. Reversible upon cessation.
  • Ototoxicity: Destruction of sensory hair cells in the cochlea and vestibular apparatus. Cochlear injury causes bilateral high-frequency sensorineural hearing loss and tinnitus; vestibular toxicity causes severe oscillopsia (inability to fixate vision during head movement) and dynamic ataxia. Ototoxicity is frequently permanent and irreversible. Exacerbated by loop diuretics (furosemide) and vancomycin; patients with the mitochondrial 1555A>G mutation in the 12S rRNA gene are exquisitely susceptible to profound deafness after a single dose.

4. Phenytoin

• Therapeutic Range: 10–20 mg/L (40–80 umol/L). Governed by saturable zero-order kinetics.
• Protein Binding & The Sheiner-Tozer Equation: Phenytoin is 90% bound to plasma albumin. In states of hypoalbuminaemia (cirrhosis, nephrotic syndrome, sepsis) or end-stage renal disease (where uremic toxins displace phenytoin from albumin), the measured total serum phenytoin is falsely depressed. Clinicians must calculate the adjusted concentration:

Adjusted Phenytoin (mg/L) = Measured Total Phenytoin / [(0.2 x Serum Albumin [g/dL]) + 0.1]

• Dose-Dependent Toxicity Spectrum:
  • > 20 mg/L (80 umol/L): Far-lateral horizontal gaze nystagmus (earliest sign).
  • > 30 mg/L (120 umol/L): Marked cerebellar ataxia, dysarthria, nausea, diplopia.
  • > 40 mg/L (160 umol/L): Severe lethargy, stupor, encephalopathy, and paradoxical increase in seizure frequency.
• Idiosyncratic and Chronic Manifestations: Gingival hyperplasia (platelet-derived growth factor upregulation), hirsutism, coarsening of facial features, peripheral sensorimotor neuropathy, osteomalacia (accelerated vitamin D catabolism), megaloblastic anaemia (folate deficiency), cerebellar atrophy, and Dupuytren's contracture.

5. Theophylline

• Therapeutic Range: 10–20 mg/L (55–110 umol/L). Non-selective phosphodiesterase inhibitor and adenosine receptor antagonist.
• Toxicity: Concentrations > 20 mg/L cause nausea, intractable vomiting, sinus tachycardia, hypokalaemia, and metabolic acidosis. Concentrations > 30 mg/L precipitate life-threatening atrial and ventricular tachyarrhythmias and intractable status epilepticus resistant to conventional antiepileptic therapy.
• Critical Interactions: CYP1A2 inhibitors (ciprofloxacin, erythromycin, cimetidine) cause dramatic spikes in theophylline levels.
• Management: Multiple-dose activated charcoal (enhances gastrointestinal dialysis), IV beta-blockers (e.g., esmolol) for ventricular tachydysrhythmias, and urgent charcoal haemoperfusion or haemodialysis for levels > 550 umol/L (> 100 mg/L) in acute ingestion.