Clinical Pharmacology and Therapeutics
This section tests prescribing safety rather than drug lists: kinetics, interactions, monitoring, dose adjustment in renal and hepatic impairment, and recognition of drug-induced syndromes. Egyptian board questions frequently use a single prescription scenario and ask what to change.
Kinetics you must apply
- Steady state is reached after about five half-lives; a loading dose fills the volume of distribution faster.
- Zero-order kinetics (phenytoin, ethanol, salicylate at high dose, high-dose theophylline) means a small dose increase can cause a disproportionate rise in level. Phenytoin also shows saturable protein binding, so interpret the free level.
- Cytochrome P450 3A4 inhibitors include macrolides, azole antifungals, and grapefruit; inducers include rifampicin, carbamazepine, phenytoin, and St John's wort. Warfarin, statins, and calcineurin inhibitors are classic victims.
Monitoring and toxicity
- Digoxin: nausea, visual disturbance, confusion, and any arrhythmia; risk rises with hypokalaemia and renal impairment. Treat severe toxicity with digoxin-specific antibody fragments.
- Lithium: narrow index, toxicity with dehydration, non-steroidal anti-inflammatory drugs, thiazides, and ACE inhibitors; severe toxicity needs haemodialysis.
- Vancomycin: monitor area under the curve or trough; aminoglycosides: monitor trough to limit nephrotoxicity and ototoxicity.
- Renal dose adjustment is needed for most renally cleared drugs; in hepatic impairment avoid paracetamol overdose, reduce sedatives, and monitor international normalised ratio closely.
Drug-induced syndromes
- Drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis: stop the culprit drug immediately and support the patient.
- Angioedema from ACE inhibitors does not respond to antihistamines; stop the drug and secure the airway.
- Serotonin syndrome (clonus, hyperthermia, agitation) versus neuroleptic malignant syndrome (rigidity, slow onset, raised creatine kinase).
Worked example
An 80-year-old on warfarin for atrial fibrillation is prescribed clarithromycin for pneumonia. Two days later the international normalised ratio is 6.5 with gum bleeding. Clarithromycin inhibits CYP3A4 and displaces warfarin from protein. Stop warfarin and clarithromycin, give vitamin K, switch the antibiotic to one with less interaction, and recheck the ratio in 24 hours; restart warfarin at a lower dose once bleeding resolves.
Traps
Ignoring renal function when prescribing; attributing digoxin toxicity to the drug alone while missing hypokalaemia; and forgetting that enzyme inducers reduce the effect of warfarin and oral contraceptives.