Pharmacotherapy Review: Angiotensin‐Converting Enzyme Inhibitors

Abstract

On inspection of most treatment algorithms for hypertension, it is apparent that multiple drug classes are available. In choosing a medication class for hypertension therapy, nuances of the selection process often go unappreciated. This article is the first in a series describing important pharmacotherapeutic considerations of the individual drug classes used in the treatment of hypertension.

All angiotensin‐converting enzyme (ACE)inhibitors available in the United States are approved for the treatment of hypertension. The Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), the World Health Organization/International Society of Hypertension, the European Society of Hypertension/European Society of Cardiology, and the Canadian Hypertension Education Program Evidence‐Based Recommendations Task Force currently endorse ACE inhibitors as an option for first‐line therapy in patients with essential hypertension, especially in patients with a high coronary disease risk profile, diabetes with renal disease/proteinuria, heart failure, and/or a history of myocardial infarction. ¹ , ² , ³

ACE INHIBITOR MONOTHERAPY

ACE inhibitors are considered a suitable firststep option in the treatment of hypertension in a diversity of patient types. ⁴ , ⁵ The enthusiasm for the use of ACE inhibitors extends beyond the issue of effectiveness, since they are at best comparably efficacious to most other drug classes, including diuretics, β blockers, and calcium channel blockers (CCBs) for both blood pressure (BP) control and most outcomes benefits, whether in diabetics or nondiabetics. ⁶ , ⁷ Response rates with ACE inhibitors range from 40% to 70% in stage I or II hypertension, with the level of sodium intake and ethnicity influencing the overall effect. In the interpretation of clinical trials results with ACE inhibitors, a distinction should be made between the mean reduction in BP(which is typically significant) and the percentage of individuals who are poor, average, and excellent responders (which may vary considerably in different studies).

There are no reliable predictors of the vasodepressor response to ACE inhibition. ACE gene polymorphism (and specific genotypes), amongst other genetic determinants, have been suggested to predict the antihypertensive response to an ACE inhibitor; however, routine use of genotyping as yet does not have a clear role in the treatment algorithm for hypertension. ⁸ , ⁹ There has also been an inconsistent relationship between the pre‐ and/or post‐treatment plasma renin activity values(used as markers of renin‐angiotensin axis [RAA] activity) and the decrease in BP with an ACE inhibitor; however, when hypertension is marked by significant RAA activation, such as in renal artery stenosis, the initial response to an ACE inhibitor can be quite significant.

In terms of responsiveness to ACE inhibitor monotherapy, certain patient groups are recognized as being responsive(high‐renin and young hypertensives [6‐16 years of age]) and other patient groups are typically less responsive, including low‐renin, salt‐sensitive, volume‐expanded individuals such as the diabetic and the black hypertensive. ¹⁰ , ¹¹ , ¹² However, the BP response to an ACE inhibitor can be highly variable in African Americans and diabetic patients, with some individuals in these groups experiencing significant falls in BP. ¹³ , ¹⁴ The low‐renin state characteristic of the elderly hypertensive differs from other low‐renin forms of hypertension in that it represents senescence‐related changes in the RAA axis and not volume expansion. The elderly generally respond well to ACE inhibitors at usual doses, although senescence‐related renal failure, which reduces the elimination of most ACE inhibitors, complicates analysis of dose‐specific treatment results. ¹⁵

Results from a number of head‐to‐head trials support the comparable antihypertensive efficacy (and tolerability) of the various ACE inhibitors if equivalent doses of individual ACE inhibitors are given. However, there are differences among the ACE inhibitors as to the time to onset and/or the duration of effect, which may relate to the absorption and tissue distribution characteristics of a compound. ACE inhibitors labeled as “once daily” differ in their capacity to decrease BP for a full 24 hours (as defined by a trough‐peak ratio of more than 50%), with a certain number of patients requiring a second daily ACE inhibitor dose to maintain the antihypertensive effect. Consequently, the dosing frequency for an ACE inhibitor should take place with the understanding that response patterns to these drugs are highly individualized. Also, ACE inhibitor responses are linked to a patient's volume state; thus, when intentional volume losses occur (diuretic therapy) and/or unintended changes in volume happen (sweating/exercise), major decreases in BP can occur. ¹⁶ Senescence‐related changes in renal function (which reduce ACE inhibitor clearance), and/or giving a higher‐than‐normal ACE inhibitor dose, can extend the duration of action for an ACE inhibitor such that a second dose may not be required during a 24‐hour treatment period.

A frequently asked question is what steps to take when an ACE inhibitor falls short in how well it reduces BP. This question is best answered in the context of the observed response. If there is a minimal BP reduction with an ACE inhibitor, then a switch to an alternative drug class is justified unless continuation of an ACE inhibitor is felt necessary because of a high cardiac and/or renal risk profile; however, ACE inhibitor nonresponders fairly regularly respond upon addition of a diuretic or a CCB. This latter observation suggests that very few patients should have an ACE inhibitor discontinued purely on the basis of a failure to initially respond.

If the BP response is modest, one can increase the daily dose (this can occur by shifting to twice‐daily drug administration), understanding that the dose‐response curve for ACE inhibitors, like many antihypertensive agents, is relatively steep at beginning low doses and thereafter levels out. ¹⁷ Increasing the dose of an ACE inhibitor typically does not increase the peak effect; rather, it prolongs the response. In fact, several of the shorter‐acting ACE inhibitors, such as enalapril, can function as “true” once‐a‐day medications if high‐enough doses are given. A final consideration with ACE inhibitor therapy is that of an ever‐increasing BP benefit (over several weeks) relating to factors such as vascular remodeling and/or improvement in endothelial function. ¹⁸

ACE INHIBITOR COMBINATION THERAPY

The BP‐lowering ability of an ACE inhibitor is enhanced by the administration of a diuretic, particularly in patients with a salt‐sensitive form of hypertension. This type of response has been the basis for the development of fixed‐dose combination products consisting of an ACE inhibitor and a thiazide‐type diuretic. The underlying principle for combining these two drug classes is that diureticinduced sodium depletion activates the RAA and moves BP to an angiotensin‐II‐dependent mode. Of note, even minimally natriuretic doses (12.5 mg/d) of thiazide‐type diuretics further reduce BP when combined with an ACE inhibitor. ¹⁹ , ²⁰

A β blocker can be given together with an ACE inhibitor, although the incremental effect on BP lowering is rather minor. A presumed physiologic basis exists for this combination in that β blockade blunts the reactive rise in plasma renin activity level that follows from ACE inhibition. ¹⁹ If BP falls when a β blocker is added to an ACE inhibitor, typically it is in tandem with a significant β‐blocker‐related decrease in heart rate. Alternatively, the combination of a β blocker and an ACE inhibitor can be used in the setting of coronary artery disease, with any BP decrease being a secondary benefit. ²¹

In the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial(ALLHAT), the β blocker atenolol was a permissible second‐step treatment choice(other options were clonidine and reserpine). As it turned out, the β blocker atenolol was the most commonly added second medication in ALLHAT, which allowed the interplay between the first‐step therapy lisinopril and atenolol to be judged. ⁵ BP was further reduced when atenolol was added to lisinopril treatment in ALLHAT; however, the additional reduction in BP in the African‐American cohort was less so. ²² Moreover, it can be further inferred that BP was less effectively brought to treatment goal with lisinopril and atenolol, since step 3 therapy with hydralazine was more often required than in either the diuretic or the CCB treatment arms of ALLHAT.

Adding a peripheral a antagonist, such as doxazosin, to an ACE inhibitor can further reduce BP, albeit with an uncertain mechanistic basis. ²³ The BP‐lowering effect of an ACE inhibitor is also enhanced with the addition of either a dihydropyridine or a nondihydropyridine‐type CCB. Several fixed‐dose combination products comprised of both drug classes are currently available. ²⁴ , ²⁵ Of note, combined ACE inhibitor and CCB treatment(benazepril and amlodipine) has also been proven more effective than high doses of either individual agent (at similarly reduced BP levels) in improving arterial compliance and regressing left ventricular mass. ²⁶ In addition, a verapamil‐trandolaprilbased treatment strategy was clinically as effective as an atenolol‐hydrochlorothiazide strategy in hypertensive patients with coronary artery disease. ²⁷ The addition of an ACE inhibitor to a CCB can also reduce CCB‐related peripheral edema. ²⁸ In addition, preliminary findings suggest a CCB can attenuate the drop in glomerular filtration rate that may come with ACE inhibitor therapy. ²⁹ This has some bearing on ACE inhibitor use in the elderly, since one reason for underuse of these compounds is concern for a further decline in renal function on top of existing age‐related renal disease.

The efficacy of both ACE inhibitors and angiotensin receptor blockers(ARBs) as individual antihypertensive classes is well established. The observation that angiotensin II escape occurs with prolonged ACE inhibitor therapy has provided the theoretic basis for the addition of an ARB to an ACE inhibitor. It is presumed that an incremental reduction in BP occurs from blocking the effect of angiotensin II made during the process of ACE inhibitor “escape”; however, there is insufficient evidence to support a broad recommendation for the combination of these two drug classes in BP management. ³⁰

Finally, studies have established the usefulness of ACE inhibitors in regressing left ventricular hypertrophy induced by the potent vasodilator minoxidil, as it may be used in complex medical regimens. In addition, if an acute reduction in BP is needed, oral or sublingual captopril (onset of action as soon as 15 minutes) can be administered. An additional option for the management of hypertensive emergencies is IV enalaprilat(the lone ACE inhibitor available in an IV form ¹² ), with a dose of 0.625 mg representing a maximum‐effect dose(higher doses may only extend the duration of action). ACE inhibitors should be used with care in patients with obvious(or suspected) activation of the RAA(e.g., prior effective treatment with diuretics and/or in the borderline hypotensive state immediately post‐myocardial infarction). In such subjects, sudden and sometimes extreme drops in BP have been observed following the first dose of an ACE inhibitor. ³¹

CONCLUSIONS

ACE inhibitor therapy has an important role in the management of hypertension—either as monotherapy or in combination with any of a range of other drug classes (Table). However, as is the case with all other antihypertensive drug classes, there are both issues of class effect and how best to combine a chosen ACE inhibitor with other medication classes. Fortunately, the lengthy treatment experience with ACE inhibitors as a class provides meaningful direction in the choice of coadministered antihypertensive medications.