Only the free fraction is active, and only the free fraction is cleared
Expansion
Only unbound (free) drug is active, and only free drug can be metabolised, filtered or reach its receptor.
- Acidic drugs bind albumin: warfarin, phenytoin, aspirin, sulphonylureas, NSAIDs
- Basic drugs bind alpha-1 acid glycoprotein: lidocaine, propranolol, tricyclics
It matters most for highly bound drugs with a narrow therapeutic index: warfarin (99 per cent), phenytoin (90 per cent) and sulphonylureas.
Hypoalbuminaemia raises the free fraction. In nephrotic syndrome, liver disease, malnutrition, burns, pregnancy and critical illness, a total phenytoin level underestimates the free level, so the report looks subtherapeutic while the patient is toxic. Measure the free level or apply a correction.
Displacement interactions are usually overstated: displacing a drug from albumin raises the free fraction transiently, but clearance rises too and a new steady state is reached quickly. The important interactions are almost always metabolic, which is why the warfarin and NSAID problem is mainly bleeding risk and enzyme inhibition rather than displacement.
Uraemia reduces binding by competing for albumin sites, a further reason total levels mislead in renal failure.