Cardiac beta-adrenoceptor blockade: the quest for selectivity.

In the search for improved drugs much attention has been focussed on the need for greater selectivity of action. Knowing that all drugs are poisons, the pharmacologist must attempt to define the required effect more narrowly but remain aware of potential unwanted effects. These may come as a result of the primary pharmacological effect or be due to other properties of the drug molecule manifesting themselves in clinical use. This paper illustrates the process of drug discovery and development with special reference to beta-adrenoceptor antagonists. Starting from the role of noradrenaline in sympathetic transmission, many compounds have been synthesized with therapeutic aims in mind. From a series of bronchodilators, dichloro-isoprenaline emerged which unexpectedly blocked stimulation of beta-receptors. This compound proved unsatisfactory leading to the introduction of the first clinically successful beta-blocker, pronethalol. Concern about potential carcinogenic effects led to its being replaced by propanolol. Failure to recognise the full range of clinical contra-indications resulted in propranolol causing severe cardio-vascular and bronchial adverse reactions. Soon it was recognized that propranolol was a powerful local anaesthetic potentially acting as a myocardial depressant. More serious was the recognition that in certain circumstances high levels of sympathetic tone were an adaptive response to pathophysiological change and that interruption by beta-blockade was inevitably serious for the patient. Attempts to identify the properties responsible for unwanted effects directed attention to comparison with non-local anaesthetic water soluble compounds still retaining beta-blocking activity. One such compound, practolol, also proved to exhibit a higher affinity for beta-receptors in the heart than elsewhere leading to the concept of cardioselective beta-blockade. The pharmacology of this agent is reviewed but it proved to have unacceptable side effects in clinical use. The importance of practolol was to demonstrate that anginal relief was due to beta-blockade and not local anaesthetic activity. It also showed that cardiovascular adverse reactions and bronchospasm were significantly less common than with propranolol. However, in addition to being cardioselective, practolol also showed intrinsic sympathomimetic activity. This resulted in a smaller bradycardia at rest. Contrary to predictions this property did not prevent practolol becoming well accepted by both doctors and patients as an effective anti-anginal drug. It was the unrelated skin, eye and mucous membrane reactions which led to the compound being withdrawn.(ABSTRACT TRUNCATED AT 400 WORDS)