Elsevier

Progress in Cardiovascular Diseases

Volume 47, Issue 2, September–October 2004, Pages 116-130
Progress in Cardiovascular Diseases

The clinical use of angiotensin-converting enzyme inhibitors

https://doi.org/10.1016/j.pcad.2004.04.003Get rights and content

Abstract

Through an integrative understanding of cardiovascular pathophysiologic characteristics at the multiorgan level, significant achievements in cardiovascular therapeutics have been achieved and enabled the rationale design and development of drugs such as the angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). In this article, we present a detailed review of the physiologic features of the renin-angiotensin-aldosterone system (RAAS), ACE inhibitors and ARB clinical pharmacologic characteristics, and specific diseases in which they are considered to be the standard of the care as supported by important clinical trial data. It is envisioned that an updated and detailed understanding of ACE inhibitors and ARBs will facilitate their successful use in the treatment of heart failure, myocardial infarction, hypertension, renal failure, and diabetic nephropathy.

Section snippets

Physiology of the RAAS

The RAAS has two components—circulating and tissue. Whereas the former component participates acutely in maintaining adequate systemic hemoperfusion, the latter component is chronically operative at the local tissue level. Despite these differences, both components share pathways for synthesis and degradation.1 Upon initial RAAS activation, renin synthesized from both renal and extra-renal tissues is released in response to stimuli such as glomerular hypoperfusion, sympathetic stimulation, and

ACE inhibitor pharmacology

From an understanding of the physiology of the RAAS, the pharmacodynamic response of ACE antagonism may be predicted: a short-term dose-dependent decrease in AG-II levels, preload and afterload reduction, lowering of both the systolic and diastolic pressure with little or no change in the cardiac output, reduction of proteinuric nephropathy, and inhibition of bradykinin degradation. More exclusive effects of certain ACE inhibitors such as ramipril and quinapril, perhaps mediated through AT1

Clinical applications of ACE inhibitors

The following is a discussion of disease entities in which ACE inhibitors have been proven to be efficacious. These include hypertension, symptomatic or asymptomatic left ventricular systolic dysfunction, post-myocardial infarction, renal failure, and diabetic nephropathy.

Side effects and contraindications

The use of ACE inhibitors in clinically indicated conditions at recommended doses has been established as safe and effective. As with all drugs, recognition and management of drug side effects and toxicity is critical. Provided in Table 5 is a review of the major ACE inhibitor side effects listed by organ system.

ACE inhibitors are generally safe and well-tolerated in patients with advanced compensated heart failure with poor left ventricular systolic function. It is important to ensure that

ACE inhibitors and ARBs

The major use of ARBs in addition to or in substitution of ACE inhibitors may be appreciated through an understanding of the ACE escape concept, which is a decrease in the efficacy of ACE inhibitors secondary to an increase in circulating AG-II levels from chronic ACE inhibition. To overcome this excess AG-II concentration, ARBs, which competitively block AG-II receptor binding, may be used. And although AG-II receptor upregulation may occur, experimental data suggest that there is insufficient

Conclusions

The RAAS is an important neurohormonal pathway that can be targeted by ACE inhibition in the successful management of cardiovascular diseases. Thus, whenever possible, ACE inhibitors should be used in the treatment of patients with acute MI, asymptomatic or symptomatic left ventricular dysfunction, diabetic nephropathy, renal failure, and hypertension. Furthermore, this therapy should generally be implemented taking into consideration a patient’s hemodynamic profile, race, renal function,

Selected clinical pearls

  • 1.

    Captopril requires tid dosing, enalapril bid, all the others qd, based on their pharmacokinetic profiles, making captopril useful when an initial challenge is needed and making enalapril a less reasonable choice than when it was first introduced.

  • 2.

    Trandolapril, quinapril, benazapril, and ramapril (in that order) have greater lipophilicity (and thereby presumed tissue ACE inhibition) than the other ACE inhibitors. Inhibition of tissue ACE likely has clinical relevance regarding the following:

    • a

References (63)

  • H. Yoshida et al.

    Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy

    J Clin Invest

    (1995)
  • K.F. Adams

    Angiotensin-converting enzyme inhibition and vascular remodeling in coronary artery disease

    Coron Artery Dis

    (1998)
  • L.A. Scharschmidt et al.

    Prostaglandin synthesis by rat glomerular mesangial cells in culture. Effects of angiotensin II and arginine vasopressin

    J Clin Invest

    (1983)
  • B. Hornig et al.

    Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure

    Circulation

    (1998)
  • T. Unger

    Neurohormonal modulation in cardiovascular disease

    Am Heart J

    (2000)
  • J. Sadoshima

    Cytokine actions of angiotensin II

    Circ Res

    (2000)
  • M. Nakajima et al.

    The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptorGain-of-function study using gene transfer

    Proc Natl Acad Sci U S A

    (1995)
  • S. Keidar et al.

    Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized LDLA possible role for interleukin-6

    Arterioscler Thromb Vasc Biol

    (2001)
  • B.M. Massie et al.

    Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failureResults From the ATLAS trial

    Arch Intern Med

    (2001)
  • L. Hennig

    Clinical studies on the therapy of heart failure using ACE-inhibitors and AT1-receptor blockers—Does combination treatment make sense?

    Clin Nephrol

    (2002)
  • J. Nussberger et al.

    Plasma angiotensins under sustained converting enzyme inhibition with enalapril in normal humans

    J Hypertens

    (1985)
  • B.M. Massie et al.

    Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: Results from the ATLAS trial. The Assessment of Treatment with Lisinopril and Survival

    Arch Intern Med

    (2001)
  • S. Lewington et al.

    Age-specific prevalence usual blood pressure to vascular mortality

    Lancet

    (2002)
  • B. Neal et al.

    Effects of ACE inhibitors, calcium antagonists and other blood pressure lowering drugs

    Lancet

    (2000)
  • A.V. Chobanian et al.

    The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

    JAMA

    (2003)
  • S. Yusuf et al.

    Ramipril and the development of diabetes

    JAMA

    (2001)
  • C.J. Pepine et al.

    A calcium antagonist versus a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial

    JAMA

    (2003)
  • Diuretic versus [alpha]-blocker as first-step antihypertensive therapyFinal results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

    Hypertension

    (2003)
  • Effects on enalapril on mortality in sever congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)

    N Engl J Med

    (1987)
  • Effect of enalapril n survival in patients with reduced left ventricular ejection fractions and congestive heart failure

    N Engl J Med

    (1991)
  • J.N. Cohn et al.

    A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure

    N Engl J Med

    (1991)
  • Cited by (86)

    • Orthostatic Hypotension

      2016, Life-Threatening Effects of Antipsychotic Drugs
    • Diabetic cardiomyopathy: Mechanisms and new treatment strategies targeting antioxidant signaling pathways

      2014, Pharmacology and Therapeutics
      Citation Excerpt :

      ACE inhibition hence elicits dose-dependent reduction in Ang II levels, with concomitant inhibition of bradykinin degradation and lowering of systolic and diastolic pressure (Dunn et al., 1984; Erdos et al., 1999; Wong et al., 2004). The pharmacokinetic profiles of different ACE-Is are distinguished by their biochemical structure and bioavailability, plasma half-life, elimination profile and their distribution and affinity for tissue-bound ACE (Brown & Vaughan, 1998; Wong et al., 2004). As reviewed by Wong et al., ACE-Is can be divided into 3 subgroups, based on the molecular structure of their active moieties; sulfydryl-containing, dicarboxyl-containing and phosphorus-containing (Wong et al., 2004).

    View all citing articles on Scopus
    View full text