Anaes · Applied cardiovascular & respiratory physiology

Plasma protein binding and drug interactions

Also known as Plasma protein binding · Protein binding · Free fraction · Drug displacement · Drug-drug interaction · Enzyme induction and inhibition

Most drugs circulate partly bound to plasma proteins and partly free, and only the free (unbound) fraction is pharmacologically active, available for distribution, metabolism and excretion. The bound fraction is a reservoir that buffers the free concentration. Understanding plasma protein binding and drug-drug interactions is essential for safe perioperative prescribing. The framework rests on six exam-critical ideas. First, only the FREE drug is active: it crosses membranes, binds receptors, is metabolised and excreted; the protein-bound drug is pharmacologically inert and acts as a slow-release reservoir. Second, different proteins bind different drugs: albumin (the major protein, concentration about 35 to 50 g per L) binds acidic and neutral drugs (warfarin, phenytoin, diazepam, thiopental), while alpha-1-acid glycoprotein (an acute-phase reactant, concentration about 0.5 to 1.2 g per L) binds basic drugs (lidocaine, bupivacaine, propranolol, opioids). Third, the free fraction matters most for drugs that are highly bound (more than 90 percent): a small change in the bound fraction produces a large change in the free concentration, so displacement or hypoalbuminaemia can double or treble the active concentration of a drug like warfarin or phenytoin. Fourth, protein binding is altered by hypoalbuminaemia (liver disease, nephrotic syndrome, critical illness, burns, the elderly and neonates), by raised alpha-1-acid glycoprotein (an acute-phase response raises it, lowering the free fraction of basic drugs in inflammation), by renal and hepatic failure (uraemic toxins and bilirubin compete for binding sites), and by displacement by a second drug. Fifth, drug-drug interactions are classified as pharmaceutical (incompatibility in the same infusion), pharmacokinetic (one drug alters the absorption, distribution, metabolism or excretion of another — chiefly through plasma protein displacement or through CYP450 enzyme induction or inhibition), and pharmacodynamic (two drugs act on the same receptor, pathway or physiological system to give additive, synergistic or antagonistic effects). Sixth, the most clinically important pharmacokinetic interactions are enzyme INHIBITION (rapid onset, raises the affected drug's concentration — ketoconazole, erythromycin, clarithromycin, fluoxetine, amiodarone and grapefruit juice inhibit CYP3A4) and enzyme INDUCTION (slow onset and slow offset over weeks, lowers the affected drug's concentration — rifampicin, phenytoin, carbamazepine, barbiturates, chronic alcohol and St John's wort induce CYP3A4 and 2C9 via the pregnane X receptor). The most dangerous pharmacodynamic interaction in anaesthesia is the serotonergic interaction culminating in serotonin syndrome. Built on the plasma-protein-binding framework study (Enlo-Scott 2026), the biomimetic-binding-to-Vd study (Valko 2026), the in vitro CYP-inhibition DDI assay study (Sensenhauser 2026), the antiseizure CYP2C9 and P-glycoprotein induction study (Cohen 2026), the pregnane-X-receptor induction study (Chen 2026), the grapefruit-juice CYP-inhibition study (Aurinsalo 2026), the serotonin-syndrome DDI detection study (Xu 2026), and the postoperative serotonin syndrome report (Aboe Aboe 2026).