Pharmacokinetic comparison of pindolol with other beta-adrenoceptor-blocking agents

Abstract

Many beta-adrenoceptor-blocking agents are well studied today. They differ from one another not only in their pharmacologic profiles (cardioselectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity) but also in their metabolic and pharmacokinetic profiles. The profiles of the following 10 beta blockers have been compared: acebutolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, sotalol, and timolol. Differences in the aromatic ring structure lead to differences in lipophilic characteristics. They in turn influence the pharmacokinetic parameters such as hepatic extraction ratio, protein binding, volume of distribution, and the ratio of renal versus hepatic clearance. Incomplete oral bioavailabilities are reported both for the lipophilic drugs (e.g., labetalol, oxprenolol, and propranolol) due to extensive first-pass metabolism and for the more hydrophilic drugs (e.g., atenolol, acebutalol, and nadolol) due to medium or low absorption. Low bioavailabilities (as in the case of propranolol) are the source of large biologic variations, nonlinearities, or increased plasma levels with food, with age, in nonsmokers, or in disease states (e.g., hypothermia and renal, hepatic, celiac, Crohn's, or inflammatory disease). The pharmacokinetic comparison in this series of beta blockers reveals that pindolol with its medium lipophilicity has some important advantages. A low daily dosage is possible because of the high bioavailability, the low first-pass effect, the moderate metabolism, and the potency of this drug. Due to the low first-pass effect and the low daily dosage there are no saturation effects, and a good dose linearity is observed. This, combined with moderate metabolism and low protein binding, results in small variability and a good predictability in plasma levels and drug effects. Due to the balanced renal and hepatic clearance, no relevant drug accumulation has to be expected in patients with liver or kidney impairment.