Clinical pharmacokinetics of beta-adrenoreceptors blockers

Abstract

beta-blockers are completely and rapidly absorbed from the gastro-intestinal tract. In their first passage through the liver they are metabolised to a varying extent - the so-called first-pass effect. For propranolol and alprenolol this degradation is partly compensated for by the formation of active metabolites, the 4-OH derivatives. The beta-blocking effect is linearly correlated with the log plasma concentration of the drugs. Although there is also a relationship between the antihypertensive effect of the drugs and their log plasma concentration, it seems to be of limited value to determine the plasma levels of the drugs in order to adjust the therapeutic dose. This is due to the great inter-individual differences of the plasma concentration-antihypertensive effect relationship. It is essential to investigate whether pharmacologically active metabolites are formed. These may not only influence the relationship between plasma concentration and therapeutic effect but may also modify the pharmacological profile of the drug. The plasma levels, and thereby the effects of the drugs, can be modified by other drugs and diseases. Thus practolol, which is mainly eliminated via the kidneys, has a longer plasma half-life in patients with renal failure. The plasma of propranolol, which is eliminated from the body by bio-transformation in the liver, is not prolonged in patients with renal failure, but its metabolites are excreted at a lower rate in such patients. Although most beta-blockers have a relatively short plasma half-life (2 to 5 hours), the drugs can be administered twice daily in clinical practice. This due to the fact that the effect declines according to zero-order kinetics while the elimination of the drug follows first-order kinetics. It is desirable that all these factors are clarified before a drug is used in clinical practice as they all will have an influence on its dose regimen. The responsibility for this must be on the drug company, which must be able to inform physicians not only about the standard dosage of the drug but also how other drugs and diseases can change the individual responses to the drug.