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New Drugs: Angiotensin converting enzyme inhibitors

The development of angiotensin converting enzyme inhibitors is often cited as a prime example of task oriented research. The truth is far from this, and, as so often, chance played a large part in the development of this group of drugs. Some 25 years ago a group of Brazilian pharmacologists was searching for substances that would block the inactivation of bradykinin, a process subsequently shown to take place in man in the pulmonary vascular bed. It was shown that this was also the site for the conversion of angiotensin I to the potent vasoconstrictor angiotensin II, and the two processes were controlled by enzymes that, if not the same, were very similar. It has been appreciated for many years that the renin-angiotensin aldosterone system is important in the control of blood pressure. Most early stratagems to lower blood pressure clinically, however, were based on manipulating the sympathetic nervous system, and attempts to perturb the renin-angiotensin-aldosterone system came much later. The use of effective orally active angiotensin converting enzyme inhibitors depended on translating the experiences of pharmacologists, who were interested primarily in the breakdown of bradykinin, to physiologists, who were interested in the mechanisms of controlling blood pressure, and then using the skills of medicinal chemists and clinical pharmacologists to design and test suitable compounds. A recent review by Ferreira, an important figure in the early development of this subject, details this interesting story.1 There are currently two orally active angiotensin converting enzyme inhibitors available in the United Kingdom, captopril and enalapril. Some 20 compounds that have a similar pharmacological activity are in, various stages of development, several of them having been already given to volunteers and patients. This review will concentrate on the two marketed products because, as will be seen below, a risk-benefit analysis for angiotensin converting enzyme inhibitors can be made only after extensive exposure of patients, and any assessment of new members of the group is difficult. I will therefore compare captopril and enalapril with respect to their pharmacology, relative efficacy, and relative toxicity.