Safety issues associated with the use of angiotensin-converting enzyme inhibitors

In the September 2006 issue of Expert Opinion on Drug Safety, Beltrami et al. provide a timely review of safety issues associated with the use of angiotensin-converting enzyme (ACE) inhibitors, especially the occurrence of angioedema [1]. Since their introduction in the early 1980s, ACE inhibitors have become a remarkable success story, finding broad application in cardiovascular disease, including the treatment of hypertension, myocardial infarction, heart failure and certain types of nephropathy. However, the use of ACE inhibitors has been hampered by side effects, most commonly a dry cough that leads to discontinuation in up to 20% of subjects, and angioedema, which is uncommon but can be life-threatening [1].

The adverse effects of ACE inhibitors have been attributed to an accumulation of bradykinin levels, but bradykinin may also be responsible for some of the benefits. There would seem to be two approaches to this dilemma: patient prescreening or improved inhibitor design. Prescreening would involve an attempt to identify subjects at greatest risk of angioedema by the use of one or more appropriate biomarkers. Some of the risk factors are already known and more may come to light from pharmacogenomic studies. For example, ACE inhibitor-related angioedema has been associated with low plasma levels of aminopeptidase P, a protease that contributes to bradykinin metabolism [2]. Similarly, patients with C1 esterase inhibitor deficiency have a significantly increased risk of angioedema after treatment with ACE inhibitors [1].

These examples suggest that biochemical and genomic biomarkers may have utility in identifying at-risk patients before commencing ACE inhibitors. Healthcare consumers and regulatory bodies are becoming less tolerant of adverse events and drugs are expected to demonstrate ever better efficacy-risk profiles; the rofecoxib (Vioxx^®) debacle is an excellent example of this trend. Significant improvements in benefit–risk ratios can likely only be achieved through better drug targeting by use of appropriate biomarkers. Recent policy initiatives and guidance by the FDA, such as the Critical Path Initiative and guidance for drug-diagnostic co-development, are a signal of things to come.

A second approach to reducing excessive bradykinin accumulation is improved ACE inhibitor design. ACE consists of two domains, each with its own active site. The two active sites are similar but not identical and demonstrate distinct substrate preferences: most of the angiotensin I to angiotensin II conversion in vivo occurs at the C-domain site, whereas bradykinin inactivation occurs equally at the C- and N-domain sites [3]. Current-generation inhibitors, such as captopril, lisinopril and ramipril, are mixed C- and N-domain inhibitors. The crystal structures of the N- and C-domains have now been solved [4,5], opening the prospect of rational design of inhibitors with greater selectivity. A highly C-domain-selective inhibitor would shut down angiotensin conversion but allow continued bradykinin metabolism, thereby preventing excessive bradykinin build-up [3]. It may be possible to ‘dial in’ the relative N- and C-domain inhibition to achieve an optimal ratio of angiotensin suppression to bradykinin accumulation, thus maximising the benefit-risk profile.

Recent advances in our understanding of the molecular basis of disease and pharmacotherapeutics are moving us closer to an era of personalised medicine, albeit slowly. ACE inhibitors provide an interesting case study of what might be possible with well established drugs. Accumulating molecular and clinical data allow us to better define and screen patients at risk for adverse effects, while modern structure-guided drug design may lead to the development of next-generation inhibitors with superior efficacy and safety profiles.