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angiotensin-converting enzyme (ACE) inhibitor

Indications: 1) heart failure - left ventricular systolic dysfunction 2) diabetes mellitus (renal protective) - better outcomes with ACE inhibitors than ARBs 3) hypertension - ACE inhibitors that cross the blood-brain barrier may be linked to less memory decline - ACE inhibitors that cross the blood-brain barrier include: - captopril, fosinopril, lisinopril, perindopril, ramipril, trandolapril [38] 4) stroke prevention [5]; atherosclerosis# in general [8,18] - no benefit for stroke prevention [26] 5) coronary artery disease (see PEACE trial, EUROPA trial) - myocardial infarction 6) migraine prophylaxis* [7] 7) chronic renal failure [13] - *up to stage 4 kidney disease [15] (GFR 15-29 mL/min/1.73 m2 & serum creatinine 3-5 mg/dL) 8) *may reduce risk of pneumonia (RR=0.7) [23] 9) treatment of cystine renal calculi [25] 10) scleroderma [25] * only lisinopril shown to have beneficial effects [7] # only ramipril (Altace) & perindopril (Aceon) shown to be of benefit [8] Contraindications: 1) pregnancy: fetal growth retardation, congenital malformation, neonatal renal failure, fetal demise, all trimesters [17,24,33] - scleroderma renal crisis is exception - generally compatible with lactation; lisinopril may be exception [4] 2) renal artery stenosis 3) hypovolemia 4) history of angioedema * inappropriate uses - ACE inhibitors as a class do not diminish risk of dementia [19] Benefit/risk: - number needed to treat - 32 hypertensive elderly for 5 years to prevent 1 additional first cardiovascular event or death [29] - 27 diabetics for 4 years to prevent 1 cardiovascular death or non-fatal myocardial infarction [30] - 16 patients with chronic heart failure to prevent 1 death (time frame not specified) Pharmacology: renin-angiotensin deactivation 1) vasodilation 2) enhanced vital organ perfusion 3) attenuation of hyponatremia 4) attenuation of hypokalemia 5) decreased fluid retention 6) decreased ventricular filling pressure 7) decreased systemic vascular resistance 8) increased cardiac output 9) little or no change in blood pressure* or heart rate 10) lower intraglomerular pressure a) diminished transglomerular capillary hydrostatic pressure b) inhibition of angiotensin II-mediated constriction of efferent glomerular arterioles c) diminished proteinuria, especially in diabetics * a small amount of diuretic is often synergistic with an ACE inhibitor for lowering blood pressure Monitor: 1) serum potassium every 6 months* 2) serum creatinine every 6 months* 3) urinalysis 4) CBC * Serum creatinine & K+ should be checked within 2-3 weeks of starting an ACE inhibitor. [4] * hold dose of ACE inhibitor if serum potassium >= 5.5 meq/L [27] * cut dose of ACE inhibitor in 1/2 or hold if serum creatinine increases by > 30% [4,27] Adverse effects: 1) cough [4] a) may occur after several weeks to 1 year b) dose reduction may alleviate cough c) switching ACE inhibitor is generally of little benefit d) risk 2.7 fold higher southeast Asians than others [16] 2) hyperkalemia & hyponatremia via inhibition of aldosterone secretion* 3) hypotension & renal insufficiency with reduced preload 4) acute renal insufficiency may develop in patients with bilateral renal artery stenosis* 5) rash 6) angioedema (1%) [6,9] a) generally occurs within 1st week b) may occur years later c) more common in blacks than whites; 1% vs 0.3% [16,28] d) probably via inhibiting breakdown of bradykinin [9] e) small intestine angioedema presenting as acute abdominal pain [20] f) 2% of patients with angioedema on an ACE inhibitor also get angioedema on an ARB [28] g) standard therapy consists of intravenous prednisolone 500 mg plus clemastine 2 mg h) icatibant 30 mg SQ is an alternative [31] i) may not respond to epinephrine [4,32] j) wait at least 4 weeks after stopping an ACE inhibitor to start an ARB [28] 7) dysgeusia 8) increased serum creatinine a) 15-20% initial increase is acceptable [4]; up to 30% acceptable (NEJM) [39] b) decline in creatinine within 1 month [4] (2 months [39]), otherwise discontinue c) increases in serum creatinine after the start of ACE inhibitor or ARB is associated with adverse cardiorenal outcomes, even below the guideline recommended threshold of a 30% increase for stopping treatment [34] d) <2% with serum creatinine increases of >=30% - these patients with increased risk for - end-stage renal disease (RR=3.4) - myocardial infarction (RR=1.5) - heart failure (RR=1.4) - all-cause mortality (RR=1.8) [34] 9) proteinuria may or may not [2] be present 10) contrast nephropathy [23] 11) leukopenia 12) vasomotor rhinitis, rhinopharyngeal inflammation 13) obstructive sleep apnea [12] 14) may exacerbate psoriasis [4] 15) increased risk of lung cancer relative to ARB (1.6 vs 1.2 per 1000 person-years) [36]* 16) increased risk of stroke 11% & stroke mortality 19% vs diuretic [40] * 22% lower risk for colorectal cancer within 3 years of negative colonoscopy (ACE inhibitor or ARB) [37] Drug interactions: 1) NSAIDs may interfere with action of ACE inhibitors a) prostaglandins act on afferent glomerular arterioles b) increased risk of hyperkalemia 2) phenothiazines may increase effect of ACE inhibitors 3) K+ & K+ sparing diuretics increase the risk of hyperkalemia 4) ACE inhibitors potientiate effect of diuretics via hypertrophy of loop of Henle Laboratory: - plasma renin should be high [4] - if not, suspect hyperaldosteronism, check plasma aldosterone/renin Mechanism of action: 1) ACE inhibitors block conversion of angiotensin 1 to angiotensin 2 by inhibiting angiotensin converting enzyme 2) angiotensin 2 is a potent vasoconstrictor & stimulates aldosterone secretion from the adrenal cortex, resulting in increased sodium & water retention 3) ACE inhibitors also inhibit degradation of bradykinin a) may account for adverse effects of cough & angioedema [6,9] b) increase in nitric oxide release & vasodilation 4) reduced antihypertensive effect in African Americans 5) ACE inhibitors decrease resistance of postglomerular efferent aterioles, decreasing glomerular filtration pressure 6) may slow progression to end-stage-renal-disease [14] 7) may slow progression of atherosclerosis [5,8] 8) may improve insulin sensitivity [11] 9) centrally-active ACE inhibitors (captopril, fosinopril, lisinopril, perindopril, ramipril, & trandolapril) cross the blood-brain barrier while benazepril, enalapril, moexipril, & quinapril do not Notes: - more effective when combined with sodium restriction

Interactions

drug interactions drug adverse effects (more general classes) monitor with ACE inhibitors

Related

ACE inhibitors & dementia ACE inhibitors vs angiotensin receptor blockers (ARB) angiotensin angiotensin converting enzyme (ACE) angiotensin II receptor antagonist (ARB)

Specific

benazepril (Lotensin) captopril (Capoten) centrally-acting ACE inhibitor enalapril (Vasotec) enalaprilat (Vasotec IV) fosinopril (Monopril) lisinopril (Prinivil, Zestril) moexipril (Univasc) perindopril (Aceon, Coversyl) quinapril (Accupril) ramipril (Altace) trandolapril (Mavik, indolapril)

General

protease inhibitor renin-angiotensin-aldosterone system inhibitor (RAAS inhibitor)

Properties

INHIBITS: angiotensin converting enzyme MISC-INFO: elimination route KIDNEY

References

  1. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 117
  2. contribution from Peter Baylor, M.D. VAMC, UCSF Fresno
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018, 2021. - Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. Chest. 2006 Jan;129(1 Suppl):169S-173S. PMID: 16428706
  5. Prescriber's Letter 9(4):19 2002
  6. Prescriber's Letter 9(11):62 2002
  7. Journal Watch 23(4):34, 2003 BMJ 322:19, 2001
  8. Prescriber's Letter 10(10):59 2003
  9. Prescriber's Letter 11(7):31 2004
  10. Prescriber's Letter 9(10):41 2002 Comparison of Oral ACE Inhibitors Detail-Document#: 181023 (subscription needed) http://www.prescribersletter.com
  11. Prescriber's Letter 12(6): 2005 Comparison of Outcomes Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers Detail-Document#: 210613 (subscription needed) http://www.prescribersletter.com - Prescriber's Letter 12(7): 2005 Evidence for Preventing Type 2 Diabetes Detail-Document#: 210707 (subscription needed) http://www.prescribersletter.com
  12. Cicolin A et al Angiotensin-coverting enzyme inhibitors and obstructive sleep apnea Mayo Clin Proc 2006; 81:53
  13. Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, Jiang JP, Liang M, Wang GB, Liu ZR, Geng RW. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med. 2006 Jan 12;354(2):131-40. PMID: 16407508 - Hebert LA. Optimizing ACE-inhibitor therapy for chronic kidney disease. N Engl J Med. 2006 Jan 12;354(2):189-91. No abstract available. PMID: 16407515
  14. Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, MacAllister RJ. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005 Dec 10;366(9502):2026-33. Review. PMID: 16338452
  15. Prescriber's Letter 13(3): 2006 Angiotensin-Converting-Enzyme Inhibitors in Severe Kidney Disease Detail-Document#: 220312 (subscription needed) http://www.prescribersletter.com
  16. McDowell SE et al, Systemic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. BMJ 2006; 332:1177 PMID: 16679330 - Eliasson E, Ethnicity and adverse drug reactions: Personalized drug treatment is getting closer but will not replace good clinical judgment. BMJ 2006; 332:1163 PMID: 16709964
  17. Prescriber's Letter 13(7): 2006 ACE Inhibitors and the Risk of Birth Defects Detail-Document#: 220705 (subscription needed) http://www.prescribersletter.com
  18. Dagenais GR et al, Angiotensin-converting enzyme inhibitors in stable vascular disease without left ventricular systolice dysfunction or heart failure: A combined analysis of three trials. Lancet 2006, 368:581 PMID: 16905022 - Remuzzi G and Ruggenenti P Overview of randomized trials of ACE inhibitors. Lancet 2006, 368:555 PMID: 16905000
  19. Sink KM et al Angiotensin-Converting Enzyme Inhibitors and Cognitive Decline in Older Adults With Hypertension: Results From the Cardiovascular Health Study Arch Intern Med. 2009;169(13):1195-1202 PMID: 19597068
  20. Scheirey CD et al. Angiotensin-converting enzyme inhibitor-induced small-bowel angioedema: Clinical and imaging findings in 20 patients. AJR Am J Roentgenol 2011 Aug; 197:393. PMID: 21785085
  21. Slagman MCJ et al. Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: Randomised controlled trial. BMJ 2011 Jul 26; 343:d4366. PMID: 21791491
  22. Caldeira D et al Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis BMJ 2012;345:e4260 PMID: 22786934 http://www.bmj.com/content/345/bmj.e4260.pdf%2Bhtml - Barnes RA Pneumonia and ACE inhibitors-and cough BMJ 2012;345:e4566 PMID: 22786936 http://www.bmj.com/content/345/bmj.e4566
  23. Rim MY et al. The effect of renin-angiotensin-aldosterone system blockade on contrast-induced acute kidney injury: A propensity-matched study. Am J Kidney Dis 2012 Oct; 60:576. PMID: 22658321
  24. Cooper WO, Hernandez-Diaz S, Arbogast PG et al Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006 Jun 8;354(23):2443-51. PMID: 16760444
  25. Deprecated Reference
  26. Cheng J, Zhang W, Zhang X et al Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on All-Cause Mortality, Cardiovascular Deaths, and Cardiovascular Events in Patients With Diabetes MellitusA Meta-analysis. JAMA Intern Med. Published online March 31, 2014 PMID: 24687000 http://archinte.jamanetwork.com/article.aspx?articleid=1847572
  27. Prescriber's Letter 21(6): 2014 Safe Use of ACE Inhibitors or ARBs Detail-Document#: 300618 (subscription needed) http://www.prescribersletter.com
  28. Prescriber's Letter 21(7): 2014 Safe Use of ARBs in Patients with ACE Inhibitor-Associated Angioedema. Detail-Document#: 300722 (subscription needed) http://www.prescribersletter.com
  29. Wing LM, Reid CM, Ryan P, et al. ACE inhibitors reduced cardiovascular events and all cause mortality in elderly people with hypertension. N Engl J Med 2003;348:583-92 http://ebm.bmj.com/content/8/5/144.full.pdf
  30. McDougall C et al Should All Diabetic Patients Receive an ACE Inhibitor? Results From Recent Trials. Br J Cardiol. 2005;12(2):130-134. http://www.medscape.com/viewarticle/504039_3
  31. Bas M et al A Randomized Trial of Icatibant in ACE-Inhibitor-Induced Angioedema. N Engl J Med 2015; 372:418-425. January 29, 2015 PMID: 25629740 http://www.nejm.org/doi/full/10.1056/NEJMoa1312524
  32. Malde B, Regalado J, Greenberger PA. Investigation of angioedema associated with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Ann Allergy Asthma Immunol. 2007 Jan;98(1):57-63. PMID: 17225721
  33. Bullo M, Tschumi S, Bucher BS et al Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review. Hypertension. 2012 Aug;60(2):444-50. Review. PMID: 22753220 Free Article
  34. Schmidt M et al Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study. BMJ 2017;356:j791 PMID: 28279964 Free full text http://www.bmj.com/content/356/bmj.j791
  35. SIGN Guideline 95: Management of chronic heart failure http://www.sign.ac.uk/guidelines/fulltext/95/section4.html (corresponding NGC guideline withdrawn Jan 2017)
  36. Hicks BM, Filion KB, Yin H et al Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ 2018;363:k4209 PMID: 30355745 Free PMC Article https://www.bmj.com/content/363/bmj.k4209 - Cronin-Fenton D Angiotensin converting enzyme inhibitors and lung cancer. BMJ 2018;363:k4337 PMID: 30355573 https://www.bmj.com/content/363/bmj.k4337
  37. Nelson R Antihypertensives Linked to Reduced Risk of Colorectal Cancer Medscape - Jul 06, 2020. https://www.medscape.com/viewarticle/933438 - Cheung KS, Chan EW, Seto WK et al ACE (Angiotensin-Converting Enzyme) Inhibitors/Angiotensin Receptor Blockers Are Associated With Lower Colorectal Cancer Risk. Hypertension. July 6, 2020 PMID: 32623923 https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.120.15317
  38. Pass W Memory benefit seen with antihypertensives crossing blood-brain barrier. Internal Medicine News. 2021. June 21. https://www.mdedge.com/internalmedicine/article/241878/neurology/memory-benefit-seen-antihypertensives-crossing-blood-brain
  39. NEJM Knowledge+ Complex Medical Care
  40. Yamal JM, Martinez J, Osani MC et al Mortality and Morbidity Among Individuals With Hypertension Receiving a Diuretic, ACE Inhibitor, or Calcium Channel Blocker. A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023;6(12):e2344998. PMID: 38048133 PMCID: PMC10696481 Free PMC article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2812523

Component-of

combination of ACE inhibitor/angiotension 2 receptor antagonist polypill (Polycap)