Expansion
The ratio of the toxic dose to the effective dose
Expansion
Therapeutic index = TD50 / ED50, the dose toxic to 50 per cent divided by the dose effective in 50 per cent. A high index means a wide safety margin.
Narrow therapeutic index drugs requiring monitoring:
- Digoxin: nausea, confusion, xanthopsia, arrhythmia; toxicity worsened by hypokalaemia
- Lithium: tremor, ataxia, seizures; worsened by dehydration, NSAIDs, thiazides and ACE inhibitors
- Phenytoin: zero order kinetics, so small dose increases cause large level rises
- Warfarin: monitored by effect (INR) rather than by level
- Theophylline, aminoglycosides, vancomycin, ciclosporin, methotrexate
Sampling matters: trough levels for most, and for aminoglycosides both peak (efficacy) and trough (toxicity), though once-daily regimens now rely mainly on trough or concentration-time monitoring. Digoxin must be sampled at least 6 hours post-dose to allow tissue distribution, otherwise the level is spuriously high.
The narrow index also explains why these drugs dominate the list of clinically significant drug interactions: a modest change in clearance produces a change in effect that matters.