Drug Safety, Adverse Effects, and Special Populations

ADVERSE DRUG REACTION CLASSIFICATION

The Rawlins-Thompson classification system categorises adverse drug reactions (ADRs) by mechanism and predictability:

Type A (Augmented): pharmacologically predictable, dose-dependent extensions of the drug's normal therapeutic effect. Most common (~80% of ADRs). Examples: beta-blocker bradycardia, NSAID gastrointestinal ulceration, hypoglycaemia from insulin, constipation from opioids. Managed by dose reduction or drug discontinuation. Generally dose-dependent and reversible.

Type B (Bizarre): pharmacologically unpredictable, idiosyncratic reactions unrelated to dose; immune-mediated or genetic. Examples: penicillin anaphylaxis (IgE-mediated); halothane hepatitis (immune-mediated hepatotoxicity); clozapine agranulocytosis (~1% incidence, mechanism partially immune); Stevens-Johnson syndrome from carbamazepine or allopurinol (strongly associated with HLA-B*5801 in Han Chinese). Often severe, require drug withdrawal, and may be fatal.

Type C (Chronic/Continuing): related to cumulative dose over time. Examples: corticosteroid osteoporosis; analgesic nephropathy from prolonged NSAID use; tardive dyskinesia from long-term antipsychotic use.

Type D (Delayed): emerge long after drug exposure. Examples: carcinogenicity (alkylating agents → secondary leukaemia, years later); teratogenicity (thalidomide → phocomelia; valproate → neural tube defects, neurodevelopmental impairment).

Type E (End of use/Withdrawal): occur on abrupt discontinuation. Examples: opioid withdrawal (anxiety, sweating, myalgia, piloerection, vomiting, diarrhoea, tachycardia); benzodiazepine withdrawal (seizures, delirium — potentially fatal); SSRI discontinuation syndrome (not true dependence but unpleasant — dizziness, electric shock sensations).

DRUG INTERACTIONS

Pharmacokinetic interactions affect drug levels (ADME processes):

CYP450 enzyme inducers increase synthesis of CYP enzymes, accelerating metabolism of co-administered drugs and reducing their plasma levels — risk of therapeutic failure. Major inducers: rifampicin (most potent), carbamazepine, phenytoin, phenobarbital, St John's Wort. Clinical examples: rifampicin reduces warfarin effect (increase INR monitoring); oral contraceptives fail (use additional contraception during and for 4 weeks after rifampicin). P-glycoprotein induction: rifampicin also induces P-gp, reducing absorption of digoxin and other P-gp substrates.

CYP450 enzyme inhibitors reduce drug metabolism, raising plasma levels of the affected drug — risk of toxicity. Major inhibitors: azole antifungals (fluconazole, itraconazole — potent CYP3A4/2C9 inhibitors), amiodarone (potent CYP2D6/3A4 inhibitor; increases warfarin, statin levels), macrolide antibiotics (erythromycin, clarithromycin — CYP3A4), ciprofloxacin (CYP1A2 — raises theophylline, clozapine levels), grapefruit juice (irreversibly inhibits intestinal CYP3A4 — relevant for simvastatin, ciclosporin, tacrolimus, some calcium channel blockers).

Pharmacodynamic interactions affect drug effect without changing plasma levels: Additive: two CNS depressants (opioid + benzodiazepine) cause additive respiratory depression — major cause of overdose fatality. Synergistic: aminoglycoside + vancomycin → synergistic nephrotoxicity; piperacillin-tazobactam + gentamicin → synergistic killing of Gram-negative bacteria. Antagonistic: naloxone reverses opioid receptor agonism.

SPECIAL POPULATIONS

Pregnancy: Teratogenicity — critical period is organogenesis (weeks 3–8). Known teratogens: thalidomide (limb reduction defects); valproate (neural tube defects, cardiac defects, neurodevelopmental impairment — use only if no alternatives); ACE inhibitors (second/third trimester: renal agenesis, oligohydramnios, neonatal hypotension); warfarin (first trimester: warfarin embryopathy — nasal hypoplasia, stippled epiphyses; third trimester: fetal haemorrhage); methotrexate (abortion, multiple congenital anomalies); isotretinoin (cardiac and CNS defects). Folic acid 5 mg pre-conception in women on valproate or with prior neural tube defect pregnancy. Physiological pharmacokinetic changes in pregnancy: increased GFR (increases clearance of renally excreted drugs — gentamicin, digoxin); increased volume of distribution (decreased peak plasma concentrations); decreased albumin (increased free fraction of highly protein-bound drugs); increased hepatic blood flow (alters first-pass); gastric motility changes. Gestational diabetes: metformin crosses the placenta but is widely used; insulin has no placental transfer and remains gold standard.

Paediatrics: Neonates have immature CYP450 enzymes (CYP3A4, CYP1A2 develop slowly over weeks to months) and reduced glucuronidation (UGT1A1) — Gray Baby Syndrome: chloramphenicol accumulates because neonates cannot glucuronidate it, causing cardiovascular collapse. Weight-based dosing is essential; mg/kg dosing is the standard with age-specific dose limits. Appropriate formulations: liquid preparations for neonates and infants; dispersible tablets; age-appropriate flavouring. Off-label prescribing is common in paediatrics due to historical lack of clinical trials in children.

Elderly: Polypharmacy (≥5 medications) is common; the Beer's Criteria (American Geriatrics Society) identify drugs potentially inappropriate in older adults (e.g., benzodiazepines, first-generation antihistamines, NSAIDs, TCAs). Anticholinergic burden scale: cumulative anticholinergic load (from multiple drugs) contributes to cognitive impairment, falls, urinary retention, and constipation. Pharmacokinetic changes: reduced renal function (use Cockcroft-Gault equation to estimate CrCl for renal drug dosing; GFR-based adjustment for many drugs including metformin, DOACs, antibiotics); reduced hepatic blood flow and enzyme activity; increased volume of distribution for fat-soluble drugs (prolonged half-life); decreased albumin (increased free drug). Pharmacodynamic changes: increased sensitivity to CNS depressants, anticoagulants (increased bleeding risk), and antihypertensives (orthostatic hypotension, falls risk).

PHARMACOVIGILANCE

Post-marketing surveillance identifies rare adverse effects not detected in pre-registration trials (which typically enrol thousands, insufficient to detect reactions occurring in 1:10,000). Yellow Card Scheme (MHRA, UK): spontaneous reporting of suspected ADRs by healthcare professionals and patients. MARC (Medicines Adverse Reactions Committee, New Zealand Pharmacovigilance Centre at University of Otago). Signal detection uses disproportionality analysis (PRR, reporting odds ratio) to identify drug-event pairs occurring more frequently than background. Signal detection led to withdrawal of rofecoxib (Vioxx — CV risk) and association of SSRIs with suicidality in adolescents.

THERAPEUTIC DRUG MONITORING (TDM)

TDM is indicated for drugs with narrow therapeutic index where plasma levels correlate well with efficacy and toxicity. Drugs requiring TDM: lithium (therapeutic range 0.6–1.0 mmol/L; toxicity: coarse tremor, confusion, cardiac arrhythmias above 1.5 mmol/L; 12-hour post-dose trough level); digoxin (0.5–2.0 nanomol/L; toxicity: nausea, visual disturbances, bradyarrhythmias); phenytoin (40–80 micromol/L; non-linear kinetics, protein binding-dependent — measure free phenytoin in hypoalbuminaemia); aminoglycosides (peak and trough, or AUC-guided); vancomycin (AUC/MIC-guided). Timing of sampling matters: trough levels (pre-dose) for most; post-dose peak for aminoglycosides.

SAFE PRESCRIBING

The five rights: right drug, right dose, right route, right frequency, right duration. Medication reconciliation at admission, transfers, and discharge. Allergy documentation and verification. Renal dose adjustment using Cockcroft-Gault CrCl. Hepatic dose adjustment using Child-Pugh score (class A — mild impairment; class B — moderate; class C — severe; most drug metabolism studies use this). Check for interactions using resources such as BNF Appendix 1 or Lexicomp.