Pharmacokinetic Properties of the Beta-Receptor Antagonists
Most of the drugs in this class are well absorbed after oral admin-istration; peak concentrations occur 1–3 hours after ingestion. Sustained-release preparations of propranolol and metoprolol are available.
Propranolol undergoes extensive hepatic (first-pass) metabolism; its bioavailability is relatively low (Table 10–2). The proportion of drug reaching the systemic circulation increases as the dose is increased, suggesting that hepatic extraction mechanisms may become saturated. A major consequence of the low bioavailability of propranolol is that oral administration of the drug leads to much lower drug concentrations than are achieved after intrave-nous injection of the same dose. Because the first-pass effect varies among individuals, there is great individual variability in the plasma concentrations achieved after oral propranolol. For the same reason, bioavailability is limited to varying degrees for most antagonists with the exception of betaxolol, penbutolol, pin-dolol, and sotalol.
The β antagonists are rapidly distributed and have large volumes of distribution. Propranolol and penbutolol are quite lipophilic and readily cross the blood-brain barrier (Table 10–2). Most β antago-nists have half-lives in the range of 3–10 hours. A major exception is esmolol, which is rapidly hydrolyzed and has a half-life of approximately 10 minutes. Propranolol and metoprolol are exten-sively metabolized in the liver, with little unchanged drug appear-ing in the urine. The cytochrome P450 2D6 (CYP2D6) genotype is a major determinant of interindividual differences in metoprolol plasma clearance . Poor metabolizers exhibit three-fold to tenfold higher plasma concentrations after administration of metoprolol than extensive metabolizers. Atenolol, celiprolol, and pindolol are less completely metabolized. Nadolol is excreted unchanged in the urine and has the longest half-life of any available antagonist (up to 24 hours). The half-life of nadolol is prolonged in renal failure. The elimination of drugs such as propranolol may be prolonged in the presence of liver disease, diminished hepatic blood flow, or hepatic enzyme inhibition. It is notable that the pharmacodynamic effects of these drugs are sometimes prolonged well beyond the time predicted from half-life data.