, Volume 1, Issue 4, pp 233-263
Date: 15 Dec 2012

Clinical Pharmacokinetics of β-Adrenoceptor Blocking Drugs

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Summary

All β-adrenoreceptor blocking drugs seem to be fairly rapidly and completely absorbed from the gastro-intestinal tract. The rate of absorption, however, appears to be lower in elderly patients and possibly also in patients with renal failure than in younger patients.

The extent of bioavailability varies considerably between different β-blockers. Some of these drugs (e.g. alprenolol and propranolol) have a low extent of bioavailability due to a high first-pass elimination effect, while pindolol and practolol for example are influenced very little by this effect. However, as some β-blockers form active metabolites, the bioavailability calculated as the ratio between the area under the plasma concentration time curve of unchanged drug after oral and intravenous administration does not give an accurate estimation of the fraction of the biologically active dose reaching the systemic circulation.

The β-blockers so far studied are rapidly distributed in the body. The t½ of distribution ranges between 5 to 30 minutes. The apparent volume of distribution varies 3-to 4-fold between the compounds but in all cases the apparent volume of distribution exceeds the physiological body space. In patients with impaired liver function an increase of the volume of distribution of propranolol has been found.

The β-blockers are relatively rapidly eliminated from the body and most of them have an elimination half-life between 2 to 4 hours. For atenolol, practolol and Sotalol higher values have been reported. The most lipophilic β-blockers are almost completely metabolised in the liver, whereas those of lower lipophilicity are mainly excreted via the kidneys. Impaired liver and kidney function have been found to significantly influence the rate of elimination of those β-blockers eliminated via the insufficient organ of elimination.

Numerous investigators have shown that the β-blocking effect is linearly related to the logarithm of the plasma concentration. In spite of this relationship, it is difficult from mean data to predict the individual plasma concentration which is necessary for a certain degree of β-blockade. This might be due to variations in the quantitative formation of active metabolites, individual differences in the plasma protein binding and rather flat plasma level-response curves.

Also with respect to the therapeutic effect, the plasma levels vary considerably between individuals. This limits the value of determination of plasma concentrations in order to adjust the therapeutic dose. Our recommendation is that these facilities should be utilised in selected patient groups, e.g. those who have a poor therapeutic response to a β-blocker although the dose is high, and those patients with impaired renal or liver function.

The duration of β-blockade is dose-dependent since the pharmacological effect declines with a constant rate (zero-order kinetics) within relatively wide dosage intervals. The rate of decline is a function of the plasma half-life and the slope of the regression line for the effect versus plasma concentration. This implies that most of the β-blockers can be administered at substantially longer intervals than indicated by their half-lives.