Beta-adrenoceptor-blocking agents: are pharmacologic differences relevant?

Abstract

beta-Adrenoceptor-blocking agents constitute a heterogeneous group of compounds. Membrane- stabilizing (quinidine-like) effects can be demonstrated pharmacologically with most compounds, but only at relatively high concentrations. There is no evidence to suggest that this property is of clinical relevance. Some compounds have a certain selectivity for receptors of the beta 1-type, whereas others possess beta-adrenoceptor stimulant activity (partial agonism). The clinical importance of these latter properties remains controversial. The selectivity for beta 1-adrenoceptors, which can be demonstrated pharmacologically for atenolol, metoprolol, and practolol, appears quite broad. Nevertheless a clear advantage over nonselective compounds with respect to their effects on lung function and vascular resistance in patients has not been established. There are two possible explanations. The first is that the doses used therapeutically may lie outside the selective range; the second is that most tissues appear to possess and mixed population of beta 1- and beta 2-adrenoceptors. According to our present understanding, even absolute specificity for a given subtype cannot provide organ or tissue specificity. Partial agonists provide a constant stimulation of beta-adrenoceptors while at the same time preventing access of catecholamines to the receptor they occupy. With some compounds (e.g., pindolol), stimulant activity may be sufficient to counterbalance the myocardial depression normally resulting from blockade of basal sympathetic tone. Heart rate and cardiac output are thus maintained within normal limits and compensatory increases in vasomotor tone (seen with antagonists lacking intrinsic activity) do not occur. Pindolol has been shown to dilate blood vessels at very low doses and to produce significant relaxation of isolated tracheal smooth muscle at concentrations within the range of therapeutic plasma levels found in humans. These effects may underly the relatively low incidence of bronchopulmonary and vascular side effects reported for this compound.