Total and free propranolol levels in sensitive and resistant patients

The clinical effects of the beta-adrenergic inhibitor, propranolol, are believed to correlate best with circulating levels of free drug, the component of total drug concentration that is not bound to plasma proteins and is therefore free to interact with tissue beta receptors. We used the radioreceptor assay for propranolol to determine total and free propranolol levels in 32 hospitalized patients receiving a wide range of doses (40 to 1280 mg/day). Free propranolol was determined by equilibrium dialysis and by the erythrocyte drug level. Erythrocyte levels were found to correlate strongly with free drug, as determined by equilibrium dialysis. Mean percent free propranolol was 16.9 +/- 2.4 ng/ml (SEM) by equilibrium dialysis and 18.8 +/- 2.3 ng/ml (SEM) by the red cell level. Despite considerable variability in the actual level achieved at any given dose, total and free propranolol concentrations were related to dose. A weaker correlation for free drug concentration resulted from variability in free drug among responsive patients (mean +/- SD free propranolol was 13.5 +/- 8.8 ng/ml), and suggested a threshold level of free drug required to achieve clinical effects. Six patients were resistant to high doses of propranolol. Excessive protein binding was noted in four, suggesting abnormalities at the level of protein-drug interaction. Several other possible mechanisms for propranolol resistance became apparent.