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. 1984;18(Suppl 2):215S–229S. doi: 10.1111/j.1365-2125.1984.tb02601.x

An overview of the clinical pharmacology of enalapril

R O Davies, H J Gomez, J D Irvin, J F Walker
PMCID: PMC1463484  PMID: 6099737

Abstract

1 Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function.

2 Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics.

3 Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide.

4 Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate.

5 Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase.

Keywords: enalapril, clinical pharmacology, disposition, haemodynamics, renal function, review

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Selected References

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  1. Abe K., Ito T., Sato M., Haruyama T., Sato K., Omata K., Hiwatari M., Sakurai Y., Imai Y., Yoshinaga K. Role of prostaglandin in the antihypertensive mechanism of captopril in low renin hypertension. Clin Sci (Lond) 1980 Dec;59 (Suppl 6):141s–144s. doi: 10.1042/cs059141s. [DOI] [PubMed] [Google Scholar]
  2. Biollaz J., Brunner H. R., Gavras I., Waeber B., Gavras H. Antihypertensive therapy with MK 421: angiotensin II--renin relationships to evaluate efficacy of converting enzyme blockade. J Cardiovasc Pharmacol. 1982 Nov-Dec;4(6):966–972. [PubMed] [Google Scholar]
  3. Biollaz J., Burnier M., Turini G. A., Brunner D. B., Porchet M., Gomez H. J., Jones K. H., Ferber F., Abrams W. B., Gavras H. Three new long-acting converting-enzyme inhibitors: relationship between plasma converting-enzyme activity and response to angiotensin I. Clin Pharmacol Ther. 1981 May;29(5):665–670. doi: 10.1038/clpt.1981.92. [DOI] [PubMed] [Google Scholar]
  4. Biollaz J., Schelling J. L., Jacot Des Combes B., Brunner D. B., Desponds G., Brunner H. R., Ulm E. H., Hichens M., Gomez H. J. Enalapril maleate and a lysine analogue (MK-521) in normal volunteers; relationship between plasma drug levels and the renin angiotensin system. Br J Clin Pharmacol. 1982 Sep;14(3):363–368. doi: 10.1111/j.1365-2125.1982.tb01992.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brunner D. B., Desponds G., Biollaz J., Keller I., Ferber F., Gavras H., Brunner H. R., Schelling J. L. Effect of a new angiotensin converting enzyme inhibitor MK 421 and its lysine analogue on the components of the renin system in healthy subjects. Br J Clin Pharmacol. 1981 May;11(5):461–467. doi: 10.1111/j.1365-2125.1981.tb01151.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brunner H. R., Waeber B., Nussberger J., Schaller M. D., Gomez H. J. Long-term clinical experience with enalapril in essential hypertension. J Hypertens Suppl. 1983 Oct;1(1):103–107. [PubMed] [Google Scholar]
  7. Case D. B., Atlas S. A., Laragh J. H., Sullivan P. A., Sealey J. E. Use of first-dose response or plasma renin activity to predict the long-term effect of captopril: identification of triphasic pattern of blood pressure response. J Cardiovasc Pharmacol. 1980 Jul-Aug;2(4):339–346. doi: 10.1097/00005344-198007000-00001. [DOI] [PubMed] [Google Scholar]
  8. Chrysant S. G., Brown R. D., Kem D. C., Brown J. L. Antihypertensive and metabolic effects of a new converting enzyme inhibitor, enalapril. Clin Pharmacol Ther. 1983 Jun;33(6):741–746. doi: 10.1038/clpt.1983.101. [DOI] [PubMed] [Google Scholar]
  9. Cody R. J., Covit A. B., Schaer G. L., Laragh J. H. Evaluation of a long-acting converting enzyme inhibitor (enalapril) for the treatment of chronic congestive heart failure. J Am Coll Cardiol. 1983 Apr;1(4):1154–1159. doi: 10.1016/s0735-1097(83)80119-3. [DOI] [PubMed] [Google Scholar]
  10. Cody R. J., Laragh J. H., Atlas S. A., Case D. B. Converting enzyme inhibition to identify and treat renin-mediated or sodium-volume related forms of increased peripheral resistance in hypertension and in congestive heart failure. J Hypertens Suppl. 1983 Oct;1(1):77–84. [PubMed] [Google Scholar]
  11. DiCarlo L., Chatterjee K., Parmley W. W., Swedberg K., Atherton B., Curran D., Cucci M. Enalapril: a new angiotensin-converting enzyme inhibitor in chronic heart failure: acute and chronic hemodynamic evaluations. J Am Coll Cardiol. 1983 Nov;2(5):865–871. doi: 10.1016/s0735-1097(83)80233-2. [DOI] [PubMed] [Google Scholar]
  12. Dunkman W. B., Wilen M., Franciosa J. A. Enalapril (MK-421), a new angiotensin-converting enzyme inhibitor. Acute and chronic effects in heart failure. Chest. 1983 Nov;84(5):539–545. doi: 10.1378/chest.84.5.539. [DOI] [PubMed] [Google Scholar]
  13. Dunn F. G., Oigman W., Ventura H. O., Messerli F. H., Kobrin I., Frohlich E. D. Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension. Am J Cardiol. 1984 Jan 1;53(1):105–108. doi: 10.1016/0002-9149(84)90692-1. [DOI] [PubMed] [Google Scholar]
  14. Ferguson R. K., Vlasses P. H., Swanson B. N., Mojaverian P., Hichens M., Irvin J. D., Huber P. B. Effects of enalapril, a new converting enzyme inhibitor, in hypertension. Clin Pharmacol Ther. 1982 Jul;32(1):48–53. doi: 10.1038/clpt.1982.125. [DOI] [PubMed] [Google Scholar]
  15. Fitzpatrick D., Nicholls M. G., Ikram H., Espiner E. A. Haemodynamic, hormonal, and electrolyte effects of enalapril in heart failure. Br Heart J. 1983 Aug;50(2):163–169. doi: 10.1136/hrt.50.2.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fouad F. M., Tarazi R. C., Bravo E. L. Cardiac and haemodynamic effects of enalapril. J Hypertens Suppl. 1983 Oct;1(1):135–142. [PubMed] [Google Scholar]
  17. Gavras H., Biollaz J., Waeber B., Brunner H. R., Gavras I., Davies R. O. Antihypertensive effect of the new oral angiotensin converting enzyme inhibitor "MK-421". Lancet. 1981 Sep 12;2(8246):543–547. doi: 10.1016/s0140-6736(81)90937-5. [DOI] [PubMed] [Google Scholar]
  18. Gomez H. J., Cirillo V. J., Jones K. H. The clinical pharmacology of enalapril. J Hypertens Suppl. 1983 Oct;1(1):65–70. [PubMed] [Google Scholar]
  19. Griffing G. T., Melby J. C. The therapeutic use of a new potassium-sparing diuretic, amiloride, and a converting enzyme inhibitor, MK-421, in preventing hypokalemia associated with primary and secondary hyperaldosteronism. Clin Exp Hypertens A. 1983;5(6):779–801. doi: 10.3109/10641968309081808. [DOI] [PubMed] [Google Scholar]
  20. Griffing G. T., Sindler B. H., Aurecchia S. A., Melby J. C. Reversal of diuretic-induced secondary hyperaldosteronism and hypokalemia by enalapril (MK-421): a new angiotensin-converting enzyme inhibitor. Metabolism. 1983 Jul;32(7):711–716. doi: 10.1016/0026-0495(83)90129-4. [DOI] [PubMed] [Google Scholar]
  21. Griffing G. T., Sindler B. H., Aurecchia S. A., Melby J. C. Temporal enhancement of renin-aldosterone blockade by enalapril, an angiotensin-converting enzyme inhibitor. Clin Pharmacol Ther. 1982 Nov;32(5):592–598. doi: 10.1038/clpt.1982.208. [DOI] [PubMed] [Google Scholar]
  22. Griffing G. T., Wilson T. E., Melby J. C. Altered fractional tetrahydroaldosterone excretion during pharmacological blockade and activation of the renin-aldosterone system. J Clin Endocrinol Metab. 1982 Dec;55(6):1217–1221. doi: 10.1210/jcem-55-6-1217. [DOI] [PubMed] [Google Scholar]
  23. Gross D. M., Sweet C. S., Ulm E. H., Backlund E. P., Morris A. A., Weitz D., Bohn D. L., Wenger H. C., Vassil T. C., Stone C. A. Effect of N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro and its ethyl ester (MK-421) on angiotensin converting enzyme in vitro and angiotensin I pressor responses in vivo. J Pharmacol Exp Ther. 1981 Mar;216(3):552–557. [PubMed] [Google Scholar]
  24. Hodsman G. P., Brown J. J., Cumming A. M., Davies D. L., East B. W., Lever A. F., Morton J. J., Murray G. D., Robertson I., Robertson J. I. Enalapril in the treatment of hypertension with renal artery stenosis. Br Med J (Clin Res Ed) 1983 Nov 12;287(6403):1413–1417. doi: 10.1136/bmj.287.6403.1413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hodsman G. P., Brown J. J., Cumming A. M., Davies D. L., East B. W., Lever A. F., Morton J. J., Murray G. D., Robertson J. I. Enalapril (MK421) in the treatment of hypertension with renal artery stenosis. J Hypertens Suppl. 1983 Oct;1(1):109–117. [PubMed] [Google Scholar]
  26. Hodsman G. P., Brown J. J., Davies D. L., Fraser R., Lever A. F., Morton J. J., Murray G. D., Robertson J. I. Converting-enzyme inhibitor enalapril (MK421) in treatment of hypertension with renal artery stenosis. Br Med J (Clin Res Ed) 1982 Dec 11;285(6356):1697–1699. doi: 10.1136/bmj.285.6356.1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hodsman G. P., Zabludowski J. R., Zoccali C., Fraser R., Morton J. J., Murray G. D., Robertson J. I. Enalapril (MK421) and its lysine analogue (MK521): a comparison of acute and chronic effects on blood pressure, renin-angiotensin system and sodium excretion in normal man. Br J Clin Pharmacol. 1984 Mar;17(3):233–241. doi: 10.1111/j.1365-2125.1984.tb02337.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jackson B., McGrath B. P., Johnston C. I. Correlation between angiotensin converting enzyme inhibition and the acute hypotensive response to MK 421 in essential hypertension. Clin Exp Pharmacol Physiol Suppl. 1982;7:99–104. [PubMed] [Google Scholar]
  29. Johnston C. I., Jackson B. J., Larmour I., Cubella R., Casley D. Plasma enalapril levels and hormonal effects after short- and long-term administration in essential hypertension. Br J Clin Pharmacol. 1984;18 (Suppl 2):233S-239S, 241S. doi: 10.1111/j.1365-2125.1984.tb02602.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Johnston C. I., Jackson B., McGrath B., Matthews G., Arnolda L. Relationship of antihypertensive effect of enalapril to serum MK-422 levels and angiotensin converting enzyme inhibition. J Hypertens Suppl. 1983 Oct;1(1):71–75. [PubMed] [Google Scholar]
  31. Kono T., Oseko F., Ikeda F., Nakano R., Taniguchi A., Imura H., Endo J. Effects of a new angiotensin-converting enzyme inhibitor, MK 421, in normal men and patients. Endocrinol Jpn. 1982 Oct;29(5):615–622. doi: 10.1507/endocrj1954.29.615. [DOI] [PubMed] [Google Scholar]
  32. Kripalani K. J., McKinstry D. N., Singhvi S. M., Willard D. A., Vukovich R. A., Migdalof B. H. Disposition of captopril in normal subjects. Clin Pharmacol Ther. 1980 May;27(5):636–641. doi: 10.1038/clpt.1980.90. [DOI] [PubMed] [Google Scholar]
  33. Levine T. B., Olivari M. T., Garberg V., Sharkey S. W., Cohn J. N. Hemodynamic and clinical response to enalapril, a long-acting converting-enzyme inhibitor, in patients with congestive heart failure. Circulation. 1984 Mar;69(3):548–553. doi: 10.1161/01.cir.69.3.548. [DOI] [PubMed] [Google Scholar]
  34. MacGregor G. A., Markandu N. D., Bayliss J., Roulston J. E., Squires M., Morton J. J. Non-sulfhydryl-containing angiotensin-converting enzyme inhibitor (MK421): evidence for role of renin system in normotensive subjects. Br Med J (Clin Res Ed) 1981 Aug 8;283(6288):401–403. doi: 10.1136/bmj.283.6288.401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Millar J. A., Derkx F. H., McLean K., Reid J. L. Pharmacodynamics of converting enzyme inhibition: the cardiovascular, endocrine and autonomic effects of MK421 (enalapril) and MK521. Br J Clin Pharmacol. 1982 Sep;14(3):347–355. doi: 10.1111/j.1365-2125.1982.tb01990.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Moore T. J., Crantz F. R., Hollenberg N. K., Koletsky R. J., Leboff M. S., Swartz S. L., Levine L., Podolsky S., Dluhy R. G., Williams G. H. Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension. Hypertension. 1981 Mar-Apr;3(2):168–173. doi: 10.1161/01.hyp.3.2.168. [DOI] [PubMed] [Google Scholar]
  37. Morioka S., Simon G., Cohn J. N. Cardiac and hormonal effects of enalapril in hypertension. Clin Pharmacol Ther. 1983 Nov;34(5):583–589. doi: 10.1038/clpt.1983.219. [DOI] [PubMed] [Google Scholar]
  38. Nakashima Y., Fouad F. M., Tarazi R. C. Regression of left ventricular hypertrophy from systemic hypertension by enalapril. Am J Cardiol. 1984 Apr 1;53(8):1044–1049. doi: 10.1016/0002-9149(84)90634-9. [DOI] [PubMed] [Google Scholar]
  39. Odya C. E., Wilgis F. P., Walker J. F., Oparil S. Immunoreactive bradykinin and [des-Arg9]-bradykinin in low-renin essential hypertension--before and after treatment with enalapril (MK 421). J Lab Clin Med. 1983 Nov;102(5):714–721. [PubMed] [Google Scholar]
  40. Patchett A. A., Harris E., Tristram E. W., Wyvratt M. J., Wu M. T., Taub D., Peterson E. R., Ikeler T. J., ten Broeke J., Payne L. G. A new class of angiotensin-converting enzyme inhibitors. Nature. 1980 Nov 20;288(5788):280–283. doi: 10.1038/288280a0. [DOI] [PubMed] [Google Scholar]
  41. Reid J. L., Millar J. A., Campbell B. C. Enalapril and autonomic reflexes and exercise performance. J Hypertens Suppl. 1983 Oct;1(1):129–134. [PubMed] [Google Scholar]
  42. Shoback D. M., Williams G. H., Hollenberg N. K., Davies R. O., Moore T. J., Dluhy R. G. Endogenous angiotensin II as a determinant of sodium-modulated changes in tissue responsiveness to angiotensin II in normal man. J Clin Endocrinol Metab. 1983 Oct;57(4):764–770. doi: 10.1210/jcem-57-4-764. [DOI] [PubMed] [Google Scholar]
  43. Shoback D. M., Williams G. H., Swartz S. L., Davies R. O., Hollenberg N. K. Time course and effect of sodium intake on vascular and hormonal responses to enalapril (MK 421) in normal subjects. J Cardiovasc Pharmacol. 1983 Nov-Dec;5(6):1010–1018. doi: 10.1097/00005344-198311000-00015. [DOI] [PubMed] [Google Scholar]
  44. Simon A. C., Levenson J. A., Bouthier J. D., Benetos A., Achimastos A., Fouchard M., Maarek B. C., Safar M. E. Comparison of oral MK 421 and propranolol in mild to moderate essential hypertension and their effects on arterial and venous vessels of the forearm. Am J Cardiol. 1984 Mar 1;53(6):781–785. doi: 10.1016/0002-9149(84)90403-x. [DOI] [PubMed] [Google Scholar]
  45. Simon G., Morioka S., Snyder D. K., Cohn J. N. Increased renal plasma flow in long-term enalapril treatment of hypertension. Clin Pharmacol Ther. 1983 Oct;34(4):459–465. doi: 10.1038/clpt.1983.198. [DOI] [PubMed] [Google Scholar]
  46. Sweet C. S., Arbegast P. T., Gaul S. L., Blaine E. H., Gross D. M. Relationship between angiotensin I blockade and antihypertensive properties of single doses of MK-421 and captopril in spontaneous and renal hypertensive rats. Eur J Pharmacol. 1981 Dec 3;76(2-3):167–176. doi: 10.1016/0014-2999(81)90498-2. [DOI] [PubMed] [Google Scholar]
  47. Sweet C. S., Gross D. M., Arbegast P. T., Gaul S. L., Britt P. M., Ludden C. T., Weitz D., Stone C. A. Antihypertensive activity of N-[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-Ala-L-Pro (MK-421), an orally active converting enzyme inhibitor. J Pharmacol Exp Ther. 1981 Mar;216(3):558–566. [PubMed] [Google Scholar]
  48. Tocco D. J., deLuna F. A., Duncan A. E., Vassil T. C., Ulm E. H. The physiological disposition and metabolism of enalapril maleate in laboratory animals. Drug Metab Dispos. 1982 Jan-Feb;10(1):15–19. [PubMed] [Google Scholar]
  49. Turini G. A., Waeber B., Brunner H. R. The renin-angiotensin system in refractory heart failure: clinical, hemodynamic and hormonal effects of captopril and enalapril. Eur Heart J. 1983 Jan;4 (Suppl A):189–197. doi: 10.1093/eurheartj/4.suppl_a.189. [DOI] [PubMed] [Google Scholar]
  50. Ulm E. H. Enalapril maleate (MK-421), a potent, nonsulfhydryl angiotensin-converting enzyme inhibitor: absorption, disposition, and metabolism in man. Drug Metab Rev. 1983;14(1):99–110. doi: 10.3109/03602538308991383. [DOI] [PubMed] [Google Scholar]
  51. Ulm E. H., Hichens M., Gomez H. J., Till A. E., Hand E., Vassil T. C., Biollaz J., Brunner H. R., Schelling J. L. Enalapril maleate and a lysine analogue (MK-521): disposition in man. Br J Clin Pharmacol. 1982 Sep;14(3):357–362. doi: 10.1111/j.1365-2125.1982.tb01991.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Vlasses P. H., Rotmensch H. H., Swanson B. N., Irvin J. D., Lee R. B., Koplin J. R., Ferguson R. K. Comparative antihypertensive effects of enalapril maleate and hydrochlorothiazide, alone and in combination. J Clin Pharmacol. 1983 May-Jun;23(5-6):227–233. doi: 10.1002/j.1552-4604.1983.tb02729.x. [DOI] [PubMed] [Google Scholar]
  53. Wilkins L. H., Dustan H. P., Walker J. F., Oparil S. Enalapril in low-renin essential hypertension. Clin Pharmacol Ther. 1983 Sep;34(3):297–302. doi: 10.1038/clpt.1983.171. [DOI] [PubMed] [Google Scholar]
  54. de Leeuw P. W., Hoogma R. P., van Soest G. A., Tchang P. T., Birkenhäger W. H. Humoral and renal effects of MK-421 (enalapril) in hypertensive subjects. J Cardiovasc Pharmacol. 1983 Sep-Oct;5(5):731–736. doi: 10.1097/00005344-198309000-00005. [DOI] [PubMed] [Google Scholar]

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