Available ACE Inhibitors

Salient properties of the ACE inhibitors that have been described above are summarized in Table IX. 

Numerous other ACE inhibitors have been synthesized and evaluated since captopril was announced in 1977. As of 1996, 16 were in use worldwide (157), all of which are variations of the designs exemplified in Table IX. Reviews are available that describe dosage, pharmacokinetics, metabolism, and routes of elimination of many of them (111,156-159). 

In addition to those in Table IX, five additional ACE inhibitors are currently in use in the United States. Their chemical structures and generic 

Generic name Usual daily antihypertensive dose range0 Comments 

Enalaprilat 1.25 mg iv every 6 h Intravenous use only, renal excretion 

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Most of the so far available ACE-inhibitors with the exception of captopril and lisinopril are prodrugs, which are converted in the liver into an active metabolite. 

For patients with severe liver disease, captopril and lisinopril (i.e. not prodrugs, and not requiring hepatic activation and having almost solely renal elimination) are recommended. Enalaprilat (Fig. 6.18), the active metabolite of enalapril, is the only available ACE-inhibitor which is given intravenously, and can be used in patients with severe liver dysfunction. 

The CHARM-Added trial found that the addition of candesartan to ACE inhibitor and /3-blocker therapy produced incremental reductions in cardiovascular death and hospitalizations for heart failure but did not improve overall survival. In contrast, VALIANT found no benefit from the addition of valsartan to ACE inhibitor treatment in post-Ml patients, and post-hoc analysis of Val-HeET suggested potential harm in patients receiving both ACE inhibitors and p blockers. These results suggest that the addition of an ARB to optimal heart failure therapy (ACE inhibitors, 8-blockers, diuretics, etc.) offers, at best, marginal benefits with increased risk of adverse effects. Thus, until additional data are available, ACE inhibitor and -blocker therapy should be optimized first before considering the addition of an ARB. 

Table 28.4. Dosing Information for Orally Available ACE Inhibitors ...

More than 15 ACE inhibitors are presently available. They belong to three different chemical classes sul-fhydryl compounds such as captopril, carboxyl compounds such as enalapril, and phopshorus compounds... 

The combination of nitrates and hydralazine improves the composite endpoint of mortality, hospitalizations for HF, and quality of life in African Americans who receive standard therapy. A fixed-dose combination product is available that contains ISDN 20 mg and hydralazine 37.5 mg (BiDil). Practice guidelines recommend adding ISDN and hydralazine as part of standard therapy in African Americans with moderately severe to severe HF. The combination may also be reasonable for patients of other ethnicities with persistent symptoms despite optimized therapy with an ACE inhibitor (or ARB) and /Tblocker. The combination is also appropriate as first-line therapy in patients unable to tolerate ACE inhibitors or ARBs because of renal insufficiency, hyperkalemia, or possibly hypotension. 

All 10 ACE inhibitors available in the United States can be dosed once daily for hypertension except captopril, which is usually dosed two or three times daily. The absorption of captopril (but not enalapril or lisinopril) is reduced by 30% to 40% when given with food. 

For some of these diseases, such as hypertension and heart disease, drugs such as ACE inhibitors and beta-blockers are available for treatment. For some other diseases, such as Alzheimer s disease, more effective drugs have yet to be discovered. For stroke, two late stage (Phase III) trials of NXY-059 and desmoteplase failed to meet the trial criteria. Other clinical trials in progress for ischemic stroke are presented in Table 11.1. 

A rather new development is the orally available renin inhibitor aliskiren. It was approved by the U.S. Food and Drug Administration in 2007 for the treatment of hypertension. As mentioned above renin is a protease released on various stimuli from the jux-taglomerula apparatus in the kidney. Its release is the limiting step in the whole renin-angiotensin cascade. Since renin is highly substrate-specific its inhibition can be expected to have very little unspecific side effects. The result of an effective blockade of this enzyme is a reduced angiotensin I and angiotensin II formation. In contrast to ACE-inhibition or ATi-receptor blockade, the plasma concentrations of both peptides stay low. No interaction with other systems like the Kallikrenin-Bradykinin system seems to take place. 

Digoxin is indicated in patients with heart failure and atrial fibrillation. It is also most helpful in patients with a dilated heart and third heart sound. It is usually given only when diuretics and ACE inhibitors have failed to control symptoms. Only about 50% of patients with normal sinus rhythm (usually those with documented systolic dysfunction) will have relief of heart failure from digitalis. Better results are obtained in patients with atrial fibrillation. If the decision is made to use a cardiac glycoside, digoxin is the one chosen in most cases (and the only one available in the USA). When symptoms are mild, slow loading (digitalization) with 0.125-0.25 mg per day is safer and just as effective as the rapid method (0.5-0.75 mg every 8 hours for three doses, followed by 0.125-0.25 mg per day). 

An important class of orally active ACE inhibitors, directed against the active site of ACE, is now extensively used. Captopril and enalapril are examples of the many potent ACE inhibitors that are available. These drugs differ in their structure and pharmacokinetics, but in clinical use, they are interchangeable. ACE inhibitors decrease systemic vascular resistance without increasing heart rate, and they promote natriuresis. As described in Chapters 11 and 13, they are effective in the treatment of hypertension, decrease morbidity and mortality in heart failure and left ventricular dysfunction after myocardial infarction, and delay the progression of diabetic nephropathy. 

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