Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers
- Raymond R Townsend, MD
Raymond R Townsend, MD
- Professor of Medicine
- Perelman School of Medicine
- University of Pennsylvania
- Section Editors
- George L Bakris, MD
George L Bakris, MD
- Editor-in-Chief — Nephrology
- Section Editor — Hypertension
- Professor of Medicine
- The University of Chicago
- Norman M Kaplan, MD
Norman M Kaplan, MD
- Editor-in-Chief — Nephrology
- Section Editor — Hypertension
- Clinical Professor of Internal Medicine
- University of Texas Southwestern Medical Center
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are widely used in the treatment of hypertension, chronic kidney disease, and heart failure. In addition to efficacy, these agents have the additional advantage of being particularly well tolerated since they produce few idiosyncratic side effects and do not have the adverse effects on lipid and glucose metabolism seen with higher doses of diuretics or beta blockers [1,2]. (See "Antihypertensive drugs and lipids".)
The specific side effects that are observed with ACE inhibitors and ARBs will be reviewed here. The use of these drugs in disorders such as hypertension, heart failure, and proteinuric chronic kidney disease are discussed elsewhere. (See "Renin-angiotensin system inhibition in the treatment of hypertension" and "Renal effects of ACE inhibitors in hypertension" and "ACE inhibitors in heart failure with reduced ejection fraction: Therapeutic use" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of diabetic nephropathy".)
Although high-dose captopril therapy was initially associated with a variety of presumed sulfhydryl group-related complications such as rash, neutropenia, taste abnormalities, and even the nephrotic syndrome, these problems have become uncommon since the maximum dose was reduced to 100 to 150 mg/day and particularly since clinicians have begun using other angiotensin-converting enzyme (ACE) inhibitors.
The side effects that do occur are primarily related directly or indirectly to reduced angiotensin II formation. These include hypotension, acute renal failure, hyperkalemia, and problems during pregnancy . There are other complications (cough, angioedema, and anaphylactoid reactions) that are thought to be related to increased kinins since ACE is also a kininase (see 'Cough' below). This is an important distinction clinically because the side effects related to reduced angiotensin II, but not those related to kinins, are also seen with the angiotensin II receptor blockers (ARBs). (See "Renin-angiotensin system inhibition in the treatment of hypertension".)
Hypotension — Weakness, dizziness, or syncope may result from an excessive reduction in blood pressure. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), hypotensive symptoms sufficient to discontinue the drug occurred in 1.7 percent of the 8576 patients who received ramipril . First-dose hypotension, which can be marked in hypovolemic patients with high baseline renin levels, can be minimized by not beginning therapy if the patient is volume depleted and by discontinuing prior diuretic therapy for three to five days. Hypotension can also occur after the initiation of therapy in patients with congestive heart failure . The risk can be minimized by beginning with a very low dose, such as 2.5 mg BID of enalapril. (See "Treatment of hypertension in patients with heart failure".)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Izzo JL Jr, Weir MR. Angiotensin-converting enzyme inhibitors. J Clin Hypertens (Greenwich) 2011; 13:667.
- Taylor AA, Siragy H, Nesbitt S. Angiotensin receptor blockers: pharmacology, efficacy, and safety. J Clin Hypertens (Greenwich) 2011; 13:677.
- ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547.
- Kostis JB, Shelton B, Gosselin G, et al. Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators. Am Heart J 1996; 131:350.
- Toto RD, Mitchell HC, Lee HC, et al. Reversible renal insufficiency due to angiotensin converting enzyme inhibitors in hypertensive nephrosclerosis. Ann Intern Med 1991; 115:513.
- Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000; 160:685.
- Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001.
- Stirling C, Houston J, Robertson S, et al. Diarrhoea, vomiting and ACE inhibitors:--an important cause of acute renal failure. J Hum Hypertens 2003; 17:419.
- Choudhri AH, Cleland JG, Rowlands PC, et al. Unsuspected renal artery stenosis in peripheral vascular disease. BMJ 1990; 301:1197.
- Hannedouche T, Godin M, Fries D, Fillastre JP. Acute renal thrombosis induced by angiotensin-converting enzyme inhibitors in patients with renovascular hypertension. Nephron 1991; 57:230.
- Kifor I, Moore TJ, Fallo F, et al. Potassium-stimulated angiotensin release from superfused adrenal capsules and enzymatically dispersed cells of the zona glomerulosa. Endocrinology 1991; 129:823.
- Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. How much should we worry? Arch Intern Med 1998; 158:26.
- Desai AS, Swedberg K, McMurray JJ, et al. Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program. J Am Coll Cardiol 2007; 50:1959.
- Phillips CO, Kashani A, Ko DK, et al. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials. Arch Intern Med 2007; 167:1930.
- Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351:543.
- Knoll GA, Sahgal A, Nair RC, et al. Renin-angiotensin system blockade and the risk of hyperkalemia in chronic hemodialysis patients. Am J Med 2002; 112:110.
- Han SW, Won YW, Yi JH, Kim HJ. No impact of hyperkalaemia with renin-angiotensin system blockades in maintenance haemodialysis patients. Nephrol Dial Transplant 2007; 22:1150.
- Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney Dis 2004; 44:738.
- Panese S, Mártin RS, Virginillo M, et al. Mechanism of enhanced transcellular potassium-secretion in man with chronic renal failure. Kidney Int 1987; 31:1377.
- Hörl MP, Hörl WH. Drug therapy for hypertension in hemodialysis patients. Semin Dial 2004; 17:288.
- Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992; 117:234.
- Wood R. Bronchospasm and cough as adverse reactions to the ACE inhibitors captopril, enalapril and lisinopril. A controlled retrospective cohort study. Br J Clin Pharmacol 1995; 39:265.
- Bangalore S, Kumar S, Messerli FH. Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians' Desk Reference. Am J Med 2010; 123:1016.
- Woo KS, Nicholls MG. High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese. Br J Clin Pharmacol 1995; 40:141.
- Yeo WW, Chadwick IG, Kraskiewicz M, et al. Resolution of ACE inhibitor cough: changes in subjective cough and responses to inhaled capsaicin, intradermal bradykinin and substance-P. Br J Clin Pharmacol 1995; 40:423.
- Lunde H, Hedner T, Samuelsson O, et al. Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors. BMJ 1994; 308:18.
- Malini PL, Strocchi E, Zanardi M, et al. Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor. Lancet 1997; 350:15.
- Gilchrist NL, Richards AM, March R, Nicholls MG. Effect of sulindac on angiotensin converting enzyme inhibitor-induced cough: randomised placebo-controlled double-blind cross-over study. J Hum Hypertens 1989; 3:451.
- Dicpinigaitis PV. Use of baclofen to suppress cough induced by angiotensin-converting enzyme inhibitors. Ann Pharmacother 1996; 30:1242.
- Tenenbaum A, Grossman E, Shemesh J, et al. Intermediate but not low doses of aspirin can suppress angiotensin-converting enzyme inhibitor-induced cough. Am J Hypertens 2000; 13:776.
- Dykewicz MS. Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management. Curr Opin Allergy Clin Immunol 2004; 4:267.
- Fogari R, Zoppi A, Tettamanti F, et al. Effects of nifedipine and indomethacin on cough induced by angiotensin-converting enzyme inhibitors: a double-blind, randomized, cross-over study. J Cardiovasc Pharmacol 1992; 19:670.
- Goldberg AI, Dunlay MC, Sweet CS. Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension. Am J Cardiol 1995; 75:793.
- Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med 2008; 148:16.
- Sica DA. Angiotensin-converting enzyme inhibitors side effects--physiologic and non-physiologic considerations. J Clin Hypertens (Greenwich) 2004; 6:410.
- Rasoul S, Carretero OA, Peng H, et al. Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension. J Hypertens 2004; 22:593.
- Mulhern JG, Lipkowitz GS, Braden GL, et al. Association of post-renal transplant erythrocytosis and microalbuminuria: response to angiotensin-converting enzyme inhibition. Am J Nephrol 1995; 15:318.
- Yildiz A, Cine N, Akkaya V, et al. Comparison of the effects of enalapril and losartan on posttransplantation erythrocytosis in renal transplant recipients: prospective randomized study. Transplantation 2001; 72:542.
- Plata R, Cornejo A, Arratia C, et al. Angiotensin-converting-enzyme inhibition therapy in altitude polycythaemia: a prospective randomised trial. Lancet 2002; 359:663.
- Beltrami L, Zanichelli A, Zingale L, et al. Long-term follow-up of 111 patients with angiotensin-converting enzyme inhibitor-related angioedema. J Hypertens 2011; 29:2273.
- Lip GY, Ferner RE. Poisoning with anti-hypertensive drugs: angiotensin converting enzyme inhibitors. J Hum Hypertens 1995; 9:711.
- Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet 2000; 355:637.
- Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004; 351:585.
- Lee HY, Kim CH. Acute oliguric renal failure associated with angiotensin II receptor antagonists. Am J Med 2001; 111:162.
- Lacourcière Y, Brunner H, Irwin R, et al. Effects of modulators of the renin-angiotensin-aldosterone system on cough. Losartan Cough Study Group. J Hypertens 1994; 12:1387.
- van Rijnsoever EW, Kwee-Zuiderwijk WJ, Feenstra J. Angioneurotic edema attributed to the use of losartan. Arch Intern Med 1998; 158:2063.
- Irons BK, Kumar A. Valsartan-induced angioedema. Ann Pharmacother 2003; 37:1024.
- Tanaka H, Teramoto S, Oashi K, et al. Effects of candesartan on cough and bronchial hyperresponsiveness in mildly to moderately hypertensive patients with symptomatic asthma. Circulation 2001; 104:281.
- Saji H, Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic effects. Lancet 2001; 357:363.
- Serreau R, Luton D, Macher MA, et al. Developmental toxicity of the angiotensin II type 1 receptor antagonists during human pregnancy: a report of 10 cases. BJOG 2005; 112:710.
- FDA Drug Safety Communication: FDA approves label changes to include intestinal problems (sprue-like enteropathy) linked to blood pressure medicine olmesartan medoxomil. http://www.fda.gov/Drugs/DrugSafety/ucm359477.htm (Accessed on July 09, 2013).
- Ianiro G, Bibbò S, Montalto M, et al. Systematic review: Sprue-like enteropathy associated with olmesartan. Aliment Pharmacol Ther 2014; 40:16.
- Basson M, Mezzarobba M, Weill A, et al. Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study. Gut 2016; 65:1664.
- Talley NJ. Use of olmesartan for ≥ 1 year was associated with hospitalization for intestinal malabsorption. Ann Intern Med 2015; 163:JC13.
- Sipahi I, Debanne SM, Rowland DY, et al. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 2010; 11:627.
- Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol 2011; 12:65.
- ARB Trialists Collaboration. Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138,769 individuals. J Hypertens 2011; 29:623.
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm257670.htm (Accessed on June 15, 2011).
- Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ 2004; 329:1248.
- Bangalore S, Kumar S, Wetterslev J, Messerli FH. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials. BMJ 2011; 342:d2234.
- Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372:547.
- Holdiness A, Monahan K, Minor D, de Shazo RD. Renin Angiotensin Aldosterone System Blockade: Little to No Rationale for ACE Inhibitor and ARB Combinations. Am J Med 2011; 124:15.
- ACE INHIBITORS
- Reduction in GFR
- - Treatment
- Angioedema and anaphylactoid reactions
- Contraindication in pregnancy
- Incidence of cough with ARBs
- Avoid in pregnancy
- Enteropathy with olmesartan
- Lack of cancer and myocardial infarction risk
- ACE INHIBITORS VERSUS ARBS
- COMBINATION OF ACE INHIBITORS AND ARBS
- Increased adverse effects
- - Possible increased risk of cancer
- INFORMATION FOR PATIENTS