Most orally effective inhibitors of peptidyl dipeptide hydrolase are prodrug ester compounds that must be hydrolyzed in plasma to the active moiety before becoming effective. These drugs include benazepril (Lotensin), enalapril (Vasotec), fosinopril (Monopril), moexipril (Univasc), quinapril (Accupril), perindopril (Aceon), and ramipril (Altace). The ester group promotes absorption of the compound from the gastrointestinal tract. In contrast to captopril, the recommended dosing interval for these prodrug compounds is once to twice daily. These compounds are otherwise generally similar to captopril in their mechanism of action and indicated uses.
All prodrug ACE inhibitors are indicated for use as first-choice agents in the treatment of hypertension and congestive heart failure. In addition, results from clinical trials demonstrate that ramipril, a prodrug ACE inhibitor, can reduce the rate of death, myocardial infarction, and stroke in a broad range of high-risk patients who did not have heart failure. These results suggest that ACE inhibitors may be useful in the management of ischemia and atherosclerosis.
While essentially all ACE inhibitors have a similar mechanism of action and therefore exhibit similar efficacy in the treatment of hypertension and congestive heart failure, these drugs differ slightly in their phar-macokinetic profiles. Enalapril, lisinopril, and quinapril are excreted primarily by the kidney, with minimal liver metabolism, while the other prodrug compounds are metabolized by the liver and renally excreted. Thus, in patients with renal insufficiency, the half-life of renally excreted ACE inhibitors is prolonged. In addition, patients with impaired liver func tion may have a compromised ability to convert pro-drug to the active drug moiety, so the efficacy of the compounds may be reduced. In addition, compounds dependent on liver metabolism for elimination may exhibit an increase in plasma half-life. An additional property that distinguishes among these prodrugs is their individual abilities to bind tightly to tissue ACE, as opposed to the circulating form of the enzyme. Of the prodrug inhibitors, quinapril and perindopril bind most tightly.
All ACE inhibitors are contraindicated during pregnancy. Their administration to pregnant women during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including fetal death. A summary of the ACE inhibitors and their properties is provided in Table 18.1.
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