ACE Inhibitors

(BANFF study)

💊 Chemical information

Angiotensin-converting Enzyme Inhibitors; Inhibidores de la ECA.
There appear to be few significant differences between ACE inhibitors. They may be distinguished from each other by the presence or absence of a sulfhydryl group, whether they are prodrugs or not, their route of elimination, and their affinity for angiotensin-converting enzyme in vascular and other tissue, although whether these characteristics modify pharmacodynamics and therefore clinical efficacy is uncertain. Differences in these characteristics do however influence onset and duration of action of ACE inhibitors.

💊 Adverse Effects and Treatment

Many of the adverse effects of ACE inhibitors relate to their pharmacological action and all therefore have a similar spectrum of adverse effects. Some effects, such as taste disturbances and skin reactions, were at one time attributed to the presence of a sulfhydryl group (as in captopril) but have now also been reported with other ACE inhibitors; however, they may be more common with captopril. The most common adverse effects are due to the vascular effects of ACE inhibitors and include hypotension, dizziness, fatigue, headache, and nausea and other gastrointestinal disturbances. Pronounced hypotension may occur at the start of therapy with ACE inhibitors, particularly in patients with heart failure and in sodium- or volume-depleted patients (for example, those given previous diuretic therapy). Myocardial infarction and stroke have been reported and may relate to severe falls in blood pressure in patients with ischaemic heart disease or cerebrovascular disease. Other cardiovascular effects that have occurred include tachycardia, palpitations, and chest pain. Deterioration in renal function, including increasing blood concentrations of urea and creatinine, may occur, and reversible acute renal failure has been reported. Renal effects are most common in patients with existing renal or renovascular dysfunction or heart failure, in whom vasodilatation reduces renal perfusion pressure; it may be aggravated by hypovolaemia. Proteinuria has also occurred and in some patients has progressed to nephrotic syndrome. Hyperkalaemia and hyponatraemia may develop due to decreased aldosterone secretion. Other adverse effects include persistent dry cough and other upper respiratory tract symptoms, and angioedema; these may be related to effects on bradykinin or prostaglandin metabolism. Skin rashes (including erythema multiforme and toxic epidermal necrolysis) may occur; photosensitivity, alopecia, and other hypersensitivity reactions have also been reported. Blood disorders have been reported with ACE inhibitors and include neutropenia and agranulocytosis (especially in patients with renal failure and in those with collagen vascular disorders such as systemic lupus erythematosus and scleroderma), thrombocytopenia, and anaemias. Other less common adverse effects reported with ACE inhibitors include stomatitis, abdominal pain, pancreatitis, hepatocellular injury or cholestatic jaundice, muscle cramps, paraesthesias, mood and sleep disturbances, and impotence. ACE inhibitors have been associated with fetal toxicity (see Pregnancy under Precautions, below). Most of the adverse effects of ACE inhibitors are reversible on withdrawing therapy. Symptomatic hypotension, including that after overdosage, generally responds to volume expansion with an intravenous infusion of sodium chloride 0.9%.
1. Parish RC, Miller LJ. Adverse effects of angiotensin converting enzyme (ACE) inhibitors: an update. Drug Safety 1992; 7: 14–31
2. Alderman CP. Adverse effects of the angiotensin-converting enzyme inhibitors. Ann Pharmacother 1996; 30: 55–61
3. Agusti A, et al. Adverse effects of ACE inhibitors in patients with chronic heart failure and/or ventricular dysfunction : metaanalysis of randomised clinical trials. Drug Safety 2003; 26: 895–908
4. Adam A, et al. Physiopathologie des effets secondaires aigus des inhibiteurs de l’enzyme de conversion de l’angiotensine. Bull Acad Natl Med 2007; 191: 1433–43.

Angioedema.

See under Hypersensitivity, below.

Cough.

Treatment with ACE inhibitors has been associated with the development of cough in up to 20% of hypertensive patients; cough may be less troublesome in those with heart failure,1 although the incidence may be higher.2 The cough is reported to be persistent, paroxysmal, and non-productive; it causes irritation of the throat, may be accompanied by voice changes (hoarseness or huskiness), and is often worse when lying down.1,3,4 It is more common in women and non-smokers, and may be delayed in onset by weeks or even months. The majority of reports of this adverse effect concern captopril and enalapril,3,4 but it has also occurred in patients receiving many of the other ACE inhibitors,5 suggesting that the effect is common to all drugs of this class. The mechanism that produces the reaction is uncertain but appears to be related to the non-specific blockade of ACE since angiotensin II receptor antagonists are associated with a much lower incidence of cough.6 The sensitivity of the cough reflex is increased.7 Prostaglandins released in the respiratory tract have been proposed as mediators,3 but other mediators such as bradykinin8 or substance P,9 both of which are substrates for ACE, have been suggested. However, attempts to show a link between the effects of ACE inhibitors on cough, and bronchial hyperreactivity of the type found in obstructive airways disease and asthma have produced conflicting evidence, with bronchial hyperreactivity being shown in some studies10 but not in others.11 Where the patient can tolerate the cough, it may be reasonable to continue treatment; in some cases reducing the dose may help. Spontaneous recovery or improvement in the cough has been reported.12 Changing to an alternative ACE inhibitor is not advised since it is rarely effective.7 Drugs that inhibit prostaglandin synthesis, including the NSAIDs sulindac13 and indometacin,14 have been reported to suppress the cough, but NSAIDs and ACE inhibitors may interact adversely (see under Interactions, below). The calcium-channel blocker nifedipine also reduced cough, although to a lesser extent than indometacin, possibly by a similar mechanism.14 Inhaled bupivacaine,15 inhaled sodium cromoglicate,16,17 oral baclofen,18 oral picotamide,19 and oral ferrous sulfate,20 have also been reported to be of help. However, in many patients there will be no alternative but to withdraw the ACE inhibitor, and this is recommended by some in all patients presenting with ACE-inhibitor induced cough.21 Angiotensin II receptor antagonists may be a suitable alternative in patients with hypertension.21
1. Anonymous. Cough caused by ACE inhibitors. Drug Ther Bull. 1994; 32: 28 and 55–6
2. Ravid D, et al. Angiotensin-converting enzyme inhibitors and cough: a prospective evaluation in hypertension and congestive heart failure. J Clin Pharmacol 1994; 34: 1116–20
3. Coulter DM, Edwards IR. Cough associated with captopril and enalapril. BMJ 1987; 294: 1521–3
4. Berkin KE, Ball SG. Cough and angiotensin converting enzyme inhibition. BMJ 1988; 296: 1279–80
5. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. Ann Intern Med 1992; 117: 234–42
6. Pylypchuk GB. ACE inhibitor- versus angiotensin II blockerinduced cough and angioedema. Ann Pharmacother 1998; 32: 1060–6
7. Overlack A. ACE inhibitor-induced cough and bronchospasm. Drug Safety 1996; 15: 72–8
8. Ferner RE, et al. Effects of intradermal bradykinin after inhibition of angiotensin converting enzyme. BMJ 1987; 294: 1119–20
9. Morice AH, et al. Angiotensin-converting enzyme and the cough reflex. Lancet 1987; ii: 1116–18
10. Bucknall CE, et al. Bronchial hyperreactivity in patients who cough after receiving angiotensin converting enzyme inhibitors. BMJ 1988; 296: 86–8
11. Boulet L-P, et al. Pulmonary function and airway responsiveness during long-term therapy with captopril. JAMA 1989; 261: 413–16
12. Reisin L, Schneeweiss A. Spontaneous disappearance of cough induced by angiotensin-converting enzyme inhibitors (captopril or enalapril). Am J Cardiol 1992; 70: 398–9
13. Nicholls MG, Gilchrist NL. Sulindac and cough induced by converting enzyme inhibitors. Lancet 1987; i: 872
14. Fogari R, et al. Effects of nifedipine and indomethacin on cough induced by angiotensin-converting enzyme inhibitors: a doubleblind, randomized, cross-over study. J Cardiovasc Pharmacol 1992; 19: 670–3
15. Brown RC, Turton CWG. Cough and angiotensin converting enzyme inhibition. BMJ 1988; 296: 1741
16. Keogh A. Sodium cromoglycate prophylaxis for angiotensinconverting enzyme inhibitor cough. Lancet 1993; 341: 560
17. Hargreaves MR, Benson MK. Inhaled sodium cromoglycate in angiotensin-converting enzyme inhibitor cough. Lancet 1995; 345: 13–16
18. Dicpinigaitis PV. Use of baclofen to suppress cough induced by angiotensin-converting enzyme inhibitors. Ann Pharmacother 1996; 30: 1242–5
19. Malini PL, et al. Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor. Lancet 1997; 350: 15–18
20. Lee S-C, et al. Iron supplementation inhibits cough associated with ACE inhibitors. Hypertension 2001; 38: 166–70
21. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. Chest 2006; 129 (suppl): 169S–173S.

Effects on the blood.

Blood disorders have occurred in patients receiving ACE inhibitors, although there have been few reports in the literature. A reduction in haemoglobin concentration and haematocrit may occur but is not usually clinically significant, although an unfavourable effect on recovery from anaemia has been reported;1 ACE inhibitors have also been used therapeutically to reduce the haematocrit (see Erythrocytosis under Uses, below). Cases of neutropenia and agranulocytosis (particularly in patients with renal or collagen vascular disorders), and thrombocytopenia have been noted. Aplastic anaemia has also occurred2,3 and may be fatal.3
1. Ripamonti V, et al. Angiotensin-converting enzyme inhibitors slow recovery from anemia following cardiac surgery. Chest 2006; 130: 79–84
2. Kim CR, et al. Captopril and aplastic anemia. Ann Intern Med 1989; 111: 187–8
3. Harrison BD, et al. Fatal aplastic anaemia associated with lisinopril. Lancet 1995; 346: 247–8.

Effects on the kidneys.

ACE inhibitors have complex effects on the kidney;1,2 they have established renoprotective effects but also cause acute deterioration in renal function in some patients. These apparently contradictory effects are related to the action of ACE inhibitors on the renin-angiotensin-aldosterone system. The renin-angiotensin-aldosterone system has an important role in maintaining normal renal blood flow and renal function. A reduction in renal perfusion, for example due to hypovolaemia, heart failure, or renal artery stenosis, leads to activation of this system and an increase in angiotensin II release. This results mainly in post-glomerular renal vasoconstriction, which maintains renal glomerular pressure and thus glomerular filtration, despite the fall in renal blood flow. In normal individuals with unrestricted sodium intake, the reninangiotensin-aldosterone system is suppressed and ACE inhibitors have little effect on renal function. In patients with essential hypertension ACE inhibitors generally increase renal blood flow despite the reduction in arterial blood pressure, since this is exceeded by the effects of renal vasodilatation. However, filtration fraction falls since the pressure within the glomerulus is reduced, and there are only minor changes in glomerular filtration rate. The increase in renal blood flow is more pronounced during sodium restriction and in younger patients. These effects are generally beneficial. However, in patients with reduced renal perfusion, glomerular filtration rate may be critically dependent on the renin-angiotensin-aldosterone system and the use of ACE inhibitors may provoke problems. Severe renal function loss or even anuria have been reported in patients with a single transplanted kidney with renal artery stenosis, or patients with bilateral renal artery disease. The stenotic kidney maintains its filtering capacity by preferential vasoconstriction of the efferent arterioles, a mechanism mainly mediated by the renin-angiotensin system; under ACE inhibition, vasodilatation of the efferent arterioles combined with the drop in arterial pressure can result in a critical decrease in filtration pressure. Hypovolaemia or sodium depletion, for example due to diuretics, also leads to activation of the renin-angiotensin-aldosterone system and predisposes patients to renal impairment. Most patients developing renal insufficiency have been using diuretics and sodium repletion can restore renal function despite continuing ACE inhibition. Patients with heart failure may also be at risk of a decline in renal function on long-term ACE inhibitor therapy. This is because in chronic heart failure, angiotensin-II mediated systemic and renal vasoconstriction is again important in the maintenance of renal perfusion pressure. The decline may be alleviated by reduction of the dosage of diuretics or liberalisation of dietary salt intake, despite continuing the ACE inhibitor. An additional risk factor in elderly patients with heart failure is the high incidence of occult renovascular disease in these patients.3 Moderate impairment of renal function either before or during use of ACE inhibitors is not necessarily an indication to stop therapy. The effects of ACE inhibitors on renal function are generally reversible, and the reduction in filtration pressure may result in renoprotection. A review4 of studies of the use of ACE inhibitors in patients with renal impairment found that those who initially lost renal function had the greatest long-term benefit. In addition to pathophysiological effects ACE inhibitors may induce membranous glomerulopathy or interstitial nephritis. The former has been associated with captopril use, particularly at high doses, but is rare, and seems less likely to occur at the lower doses favoured today. The proteinuria usually clears without appreciable renal function loss irrespective of whether or not the drug is continued, although persistent proteinuria and renal function loss have been described. Proven interstitial nephritis has also been reported rarely, and may possibly be due to an allergic mechanism.
1. Navis G, et al. ACE inhibitors and the kidney: a risk-benefit assessment. Drug Safety 1996; 15: 200–11
2. Schoolwerth AC, et al. Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Circulation 2001; 104: 1985–91
3. MacDowall P, et al. Risk of morbidity from renovascular disease in elderly patients with congestive cardiac failure. Lancet 1998; 352: 13–16
4. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitorassociated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000; 160: 685–93.

Effects on the liver.

Hepatotoxicity has been reported with ACE inhibitors, including captopril,1,2 enalapril,2 lisinopril,2 and ramipril.3 Most reports have been associated with captopril. In a report1 of 3 cases of liver disease apparently caused or aggravated by captopril, it was noted that jaundice due to captopril is usually mainly cholestatic in nature but acute hepatocellular injury has also been seen. Of 29 cases of liver dysfunction due to captopril and reported to the UK CSM, 9 had hepatocellular jaundice, with 2 deaths; 8 were cholestatic jaundice, with 1 fatality; and 3 patients had hepatorenal syndrome, all of whom died. Worldwide, excluding the UK, 164 cases of hepatic adverse reactions had been notified to the WHO by January 1989. The incidence of such reactions is estimated at 0.09 per 1000 patients but this is likely to be an underestimate. Resolution may take a long time and captopril should be withdrawn immediately at the earliest hint of liver sensitivity.
1. Bellary SV, et al. Captopril and the liver. Lancet 1989; ii: 514
2. Hagley MT, et al. Hepatotoxicity associated with angiotensinconverting enzyme inhibitors. Ann Pharmacother 1993; 27: 228–31
3. Yeung E, et al. Ramipril-associated hepatotoxicity. Arch Pathol Lab Med 2003; 127: 1493–7.

Effects on the mouth.

Aphthous and tongue ulcers may occur during treatment with ACE inhibitors. There have been a few reports of a ‘scalded mouth syndrome’, described as similar to being scalded by hot liquids, associated with captopril,1 enalapril,1 and lisinopril2 therapy.
1. Vlasses PH, et al. "Scalded mouth" caused by angiotensin-converting enzyme inhibitors. BMJ 1982; 284: 1672–3
2. Savino LB, Haushalter NM. Lisinopril-induced "scalded mouth syndrome." Ann Pharmacother 1992; 26: 1381–2.

Effects on the nervous system.

Encephalopathy and focal neurological signs,1 and peripheral neuropathy,2,3 including Guillain-Barré neuropathy,3 have been reported in patients receiving captopril. Some CNS effects of captopril may be attributable to alterations in cerebral blood flow. In a study in patients with severe heart failure, cerebral blood flow in patients aged under 65 was improved by a single dose of captopril 12.5 mg, but in patients aged over 70 there was a 13% reduction.4 Two patients in whom captopril 6.25 mg produced impaired consciousness and paraesthesias, and dizziness, blurred vision, and aphasia, were found to have stenosis of the carotid arteries.5 Agitation, panic, extreme depression, and insomnia was reported in a patient 4 weeks after starting treatment with enalapril; depressive episodes recurred on rechallenge.6 There have been reports of mania possibly precipitated by captopril,7 and visual hallucinations have been reported in association with captopril and enalapril therapy.8
1. Rapoport S, Zyman P. Captopril and central nervous system effects. Ann Intern Med 1983; 98: 1023
2. Samanta A, Burden AC. Peripheral neuropathy due to captopril. BMJ 1985; 291: 1172
3. Chakraborty TK, Ruddell WSJ. Guillain-Barré neuropathy during treatment with captopril. Postgrad Med J 1987; 63: 221–2
4. Britton KE, et al. Angiotensin-converting-enzyme inhibitors and treatment of heart failure. Lancet 1985; ii: 1236
5. Jensen H, et al. Carotid artery stenosis exposed by an adverse effect of captopril. BMJ 1986; 293: 1073–4
6. Ahmad S. Enalapril-induced acute psychosis. DICP Ann Pharmacother 1991; 25: 558–9
7. Peet M, Peters S. Drug-induced mania. Drug Safety 1995; 12: 146–53
8. Haffner CA, et al. Hallucinations as an adverse effect of angiotensin converting enzyme inhibition. Postgrad Med J 1993; 69: 240.

Effects on the pancreas.

The manufacturers of captopril, enalapril, and lisinopril have all been reported1 to have data on file on drug-associated pancreatitis. In 1994 the UK CSM2 noted that there had been 23 reports of pancreatitis associated with ACE inhibitors (captopril 11, enalapril 10, fosinopril 1, and quinapril 1) although whether or not this was causal was not certain.
1. Dabaghi S. ACE inhibitors and pancreatitis. Ann Intern Med 1991; 115: 330–1
2. Committee on Safety of Medicines/Medicines Control Agency. Drug-induced pancreatitis. Current Problems 1994; 20: 2–3. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ FILE&dDocName=CON2024457&RevisionSelectionMethod= LatestReleased (accessed 04/04/08)

Effects on the respiratory system.

Cough is a recognised adverse effect of ACE inhibitors but evidence for a link with bronchial hyperreactivity or airways obstruction is controversial (see Cough, above). In reports of adverse respiratory reactions to ACE inhibitors submitted to the Swedish Adverse Drug Reactions Advisory Committee and to WHO, symptoms of airway obstruction such as dyspnoea, asthma, and bronchospasm occurred rarely, usually within the first few weeks of treatment.1However, the evidence for a causal link between ACE inhibitors and these symptoms was questioned.2 Severe nasal obstruction was associated with enalapril treatment in a 45-year-old woman with a history of mild rhinorrhoea and sneezing. Symptoms cleared within 2 days of stopping enalapril and recurred on rechallenge.3 Another woman taking enalapril developed obstructive sleep apnoea,4 which improved when the enalapril was stopped. There have been case reports of pneumonitis associated with treatment with captopril5 and perindopril.6
1. Lunde H, et al. Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors. BMJ 1994; 308: 18–21
2. Inman WHW, et al. Angiotensin converting enzyme inhibitors and asthma. BMJ 1994; 308: 593–4
3. Fennerty A, et al. Enalapril-induced nasal blockage. Lancet 1986; ii: 1395–6.
4. Cicolin A, et al. Angiotensin-converting enzyme inhibitors and obstructive sleep apnea. Mayo Clin Proc 2006; 81: 53–5
5. Kidney JC, et al. Captopril and lymphocytic alveolitis. BMJ 1989; 299: 981
6. Benard A, et al. Perindopril-associated pneumonitis. Eur Respir J 1996; 9: 1314–16.

Effects on skeletal muscle.

Severe muscle pain and weakness, accompanied by morning stiffness, was reported1 in a patient taking enalapril. Symptoms resolved within a few days of stopping the drug.
1. Leloët X, et al. Pseudopolymyalgia rheumatica during treatment with enalapril. BMJ 1989; 298: 325.

Effects on the skin.

Skin rashes may occur during treatment with ACE inhibitors; they have been reported in 1 to 6% of patients receiving captopril. Angioedema is also an adverse effect of ACE inhibitors (see Hypersensitivity, below). There have been reports of bullous pemphigoid,1 hyperhidrosis,2 Kaposi’s sarcoma,3 lichen planus,4 onycholysis,5,6 pemphigus,7,8 and cutaneous hypersensitivity vasculitis9 associated with use of captopril. Kaposi’s sarcoma has also been reported10 with lisinopril. Onycholysis has also occurred with enalapril,11 pemphigus with enalapril12,13 and ramipril,14 and bullous pemphigoid with lisinopril.15 Lichen planus pemphigoides has been reported with ramipril.16 A severe cutaneous reaction, resembling early mycosis fungoides, and possibly allergic in nature, has been reported after use of captopril or enalapril.17 Captopril has also been reported to exacerbate psoriasis.18 Vulvovaginal pruritus with dysuria19 has been noted in a patient receiving enalapril.
1. Mallet L, et al. Bullous pemphigoid associated with captopril. DICP Ann Pharmacother 1989; 23: 63
2. Morse MH. Hyperhidrosis: a possible side effect of captopril treatment. BMJ 1984; 289: 1272
3. Puppin D, et al. Kaposi’s sarcoma associated with captopril. Lancet 1990; 336: 1251–2
4. Cox NH, et al. Lichen planus associated with captopril: a further disorder demonstrating the ‘tin-tack’ sign. Br J Dermatol 1989; 120: 319–21
5. Brueggemeyer CD, Ramirez G. Onycholysis associated with captopril. Lancet 1984; i: 1352–3
6. Borders JV. Captopril and onycholysis. Ann Intern Med 1986; 105: 305–6
7. Parfrey PS, et al. Captopril-induced pemphigus. BMJ 1980; 281: 194
8. Butt A, Burge SM. Pemphigus vulgaris induced by captopril. Br J Dermatol 1995; 132: 315–16
9. Miralles R, et al. Captopril and vasculitis. Ann Intern Med 1988; 109: 514
10. Bilen N, et al. Possible causal role of lisinopril in a case of Kaposi’s sarcoma. Br J Dermatol 2002; 147: 1042–4
11. Gupta S, et al. Nail changes with enalapril. BMJ 1986; 293: 140
12. Kuechle MK, et al. Angiotensin-converting enzyme inhibitorinduced pemphigus: three case reports and literature review. Mayo Clin Proc 1994; 69: 1166–71
13. Frangogiannis NG, et al. Pemphigus of the larynx and esophagus. Ann Intern Med 1995; 122: 803–4
14. Vignes S, et al. Ramipril-induced superficial pemphigus. Br J Dermatol 1996; 135: 657–8
15. Kalińska-Bienias A, et al. Can pemphigoid be provoked by lisinopril? Br J Dermatol 2006; 155: 854–5
16. Ogg GS, et al. Ramipril-associated lichen planus pemphigoides. Br J Dermatol 1997; 136: 412–14
17. Furness PN, et al. Severe cutaneous reactions to captopril and enalapril; histological study and comparison with early mycosis fungoides. J Clin Pathol 1986; 39: 902–7
18. Hamlet NW, et al. Does captopril exacerbate psoriasis? BMJ 1987; 295: 1352
19. Heckerling PS. Enalapril and vulvovaginal pruritus. Ann Intern Med 1990; 112: 879–80.

Gynaecomastia.

Painful unilateral gynaecomastia was reported in a patient with systemic lupus erythematosus and renal impairment who was given captopril for hypertension.1 In view of reports of breast enlargement in women given penicillamine it was suggested that the sulfhydryl structure might be responsible; however, gynaecomastia has also been reported in 2 patients receiving enalapril,2,3 which does not contain the sulfhydryl grouping.
1. Markusse HM, Meyboom RHB. Gynaecomastia associated with captopril. BMJ 1988; 296: 1262–3
2. Nakamura Y, et al. Gynaecomastia induced by angiotensin converting enzyme inhibitor. BMJ 1990; 300: 541
3. Llop R, et al. Gynecomastia associated with enalapril and diazepam. Ann Pharmacother 1994; 28: 671–2.

Hypersensitivity.

Some of the adverse effects of ACE inhibitors might be mediated by the immune system, but evidence of specific hypersensitivity reactions seems to be limited. The presence of an IgG antibody to captopril was demonstrated in the serum of 2 of 45 patients taking the drug but the clinical significance was unclear.1 A reaction resembling serum sickness was reported in a patient given captopril, with deposition of immune complexes in the glomerular basement membrane, and symptoms of rash, arthralgia, epidermolysis, fever, and lymphadenopathy.2 Eosinophilia has also been reported in a number of patients.3 The formation of antinuclear antibodies and lupus-like reactions have been described.4,5 Treatment with ACE inhibitors (enalapril, captopril, or lisinopril) has been associated with the development of anaphylactoid reactions in patients undergoing high-flux haemodialysis using polyacrylonitrile membrane (AN69).6,7 The UK CSM has advised that the combined use of ACE inhibitors and such membranes should be avoided.8 Similar anaphylactoid reactions have occurred in patients taking ACE inhibitors while being treated for severe hypercholesterolaemia by extracorporeal removal of low-density lipoproteins (LDL-apheresis) with dextran sulfate columns.9 These reactions are thought to be bradykinin-mediated. Prolonging the interval between the last dose of ACE inhibitor and dextran sulfate apheresis has averted the reaction;10 successful prevention has also been reported with the bradykinin receptor antagonist icatibant acetate.11 Hypotensive reactions associated with blood transfusion through bedside leucoreduction filters in patients taking ACE inhibitors have also been attributed to bradykinin.12 There have also been rare reports of severe allergic reactions, including anaphylaxis, occurring in patients taking ACE inhibitors who were stung by insects or during desensitisation with Hymenoptera venom (e.g. bee or wasp venom).13 Angioedema, a known adverse effect of ACE inhibitors,14-17 is reported to occur in 0.1 to 0.2% of patients.16,17 The incidence may be higher in black American18 or Afro-Caribbean19 patients. There is no evidence that it results from an immunological mechanism in these patients and it has been suggested that the effect is due to impaired kinin degradation. However, angioedema has been reported with lisinopril in a patient who had previously tolerated captopril.20 The onset of angioedema has usually been within hours or at most a week of starting treatment with the ACE inhibitor,16 but can occur after prolonged therapy for several months or years.21-24 It may also occur episodically with long symptom-free intervals.24 Visceral angioedema presenting as abdominal pain with diarrhoea, nausea, and vomiting, has also been reported.25,26 If angioedema occurs the ACE inhibitor should be withdrawn and if there is swelling affecting the tongue, glottis, or larynx likely to cause airway obstruction, adrenaline should be given. Fatalities have occurred.27 Angiotensin II receptor antagonists have been suggested as an alternative in patients unable to tolerate ACE inhibitors, but there have also been reports of angioedema associated with their use. For a report of angioedema occurring after use of alteplase for stroke in patients taking ACE inhibitors, see under Interactions of Alteplase.
1. Coleman JW, et al. Drug-specific antibodies in patients receiving captopril. Br J Clin Pharmacol 1986; 22: 161–5
2. Hoorntje SJ, et al. Serum-sickness-like syndrome with membranous glomerulopathy in patient on captopril. Lancet 1979; ii: 1297
3. Kayanakis JG, et al. Eosinophilia during captopril treatment. Lancet 1980; ii: 923
4. Schwartz D, et al. Enalapril-induced antinuclear antibodies. Lancet 1990; 336: 187
5. Pelayo M, et al. Drug-induced lupus-like reaction and captopril. Ann Pharmacother 1993; 27: 1541–2
6. Verresen L, et al. Angiotensin-converting-enzyme inhibitors and anaphylactoid reactions to high-flux membrane dialysis. Lancet 1990; 336: 1360–2
7. Tielmans C, et al. ACE inhibitors and anaphylactoid reactions to high-flux membrane dialysis. Lancet 1991; 337: 370–1
8. Committee on Safety of Medicines. Anaphylactoid reactions to high-flux polyacrylonitrile membranes in combination with ACE inhibitors. Current Problems 33 1992. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_ FILE&dDocName=CON2024451&RevisionSelectionMethod= LatestReleased (accessed 04/04/08
9. Olbricht CJ, et al. Anaphylactoid reactions, LDL apheresis with dextran sulphate, and ACE inhibitors. Lancet 1992; 340: 908–9
10. Keller C, et al. LDL-apheresis with dextran sulphate and anaphylactoid reactions to ACE inhibitors. Lancet 1993; 341: 60–1
11. Davidson DC, et al. Prevention with icatibant of anaphylactoid reactions to ACE inhibitor during LDL apheresis. Lancet 1994; 343: 1575
12. Quillen K. Hypotensive transfusion reactions in patients taking angiotensin-converting-enzyme inhibitors. N Engl J Med 2000; 343: 1422–3
13. Stumpf JL, et al. Safety of angiotensin-converting enzyme inhibitors in patients with insect venom allergies. Ann Pharmacother 2006; 40: 699–703
14. Wood SM, et al. Angio-oedema and urticaria associated with angiotensin converting enzyme inhibitors. BMJ 1987; 294: 91–2
15. Hedner T, et al. Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors. BMJ 1992; 304: 941–6
16. 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: 234–42
17. Vleeming W, et al. ACE inhibitor-induced angioedema. Drug Safety 1998; 18: 171–88
18. Brown NJ, et al. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther 1996; 60: 8–13
19. Gibbs CR, et al. Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol 1999; 48: 861–5
20. McElligott S, et al. Angioedema after substituting lisinopril for captopril. Ann Intern Med 1992; 116: 426–7
21. Chin HL, Buchan DA. Severe angioedema after long-term use of an angiotensin-converting enzyme inhibitor. Ann Intern Med 1990; 112: 312–13
22. Edwards TB. Adverse effects of ACE inhibitors. Ann Intern Med 1993; 118: 314
23. Chu TJ, Chow N. Adverse effects of ACE inhibitors. Ann Intern Med 1993; 118: 314
24. Adverse Drug Reactions Advisory Committee (ADRAC). Angioedema – still a problem with ACE inhibitors. Aust Adverse Drug React Bull 2005; 24: 7. Also available at: http:// www.tga.gov.au/adr/aadrb/aadr0504.htm (accessed 06/11/06
25. Mullins RJ, et al. Visceral angioedema related to treatment with an ACE inhibitor. Med J Aust 1996; 165: 319–21
26. Byrne TJ, et al. Isolated visceral angioedema: an underdiagnosed complication of ACE inhibitors? Mayo Clin Proc 2000; 75: 1201–4
27. Cupido C, Rayner B. Life-threatening angio-oedema and death associated with the ACE inhibitor enalapril. S Afr Med J 2007; 97: 244–5.

Overdosage.

There have been reports of overdosage with captopril,1,2 enalapril,3-6 and lisinopril.7,8 The main adverse effect is hypotension which usually responds to supportive treatment and volume expansion. Activated charcoal may be given in severe overdosage if the patient presents within 1 hour of ingestion. If hypotension persists, sympathomimetics may be given, although they are not usually required. Specific therapy with angiotensinamide may be considered if conventional therapy is ineffective,5,6,8 but it is not widely available. There has also been a report9 of the successful use of naloxone after captopril overdosage.
1. Augenstein WL, et al. Captopril overdose resulting in hypotension. JAMA 1988; 259: 3302–5
2. Graham SR, et al. Captopril overdose. Med J Aust 1989; 151: 111
3. Waeber B, et al. Self poisoning with enalapril. BMJ 1984; 288: 287–8
4. Lau CP. Attempted suicide with enalapril. N Engl J Med 1986; 315: 197
5. Jackson T, et al. Enalapril overdose treated with angiotensin infusion. Lancet 1993; 341: 703
6. Newby DE, et al. Enalapril overdose and the corrective effect of intravenous angiotensin II. Br J Clin Pharmacol 1995; 40: 103–4
7. Dawson AH, et al. Lisinopril overdose. Lancet 1990; 335: 487–8
8. Trilli LE, Johnson KA. Lisinopril overdose and management with intravenous angiotensin II. Ann Pharmacother 1994; 28: 1165–8
9. Varon J, Duncan SR. Naloxone reversal of hypotension due to captopril overdose. Ann Emerg Med 1991; 20: 1125–7.

💊 Precautions

ACE inhibitors are usually contra-indicated in patients with aortic stenosis or outflow tract obstruction (but see below). They should not generally be used in patients with renovascular disease or suspected renovascular disease, but are occasionally necessary for severe resistant hypertension in such patients, when they should only be given with great caution and under close specialist supervision. The elderly, or patients with peripheral vascular diseases or generalised atherosclerosis, may be at high risk because they may have clinically silent renovascular disease. Renal function should be assessed in all patients before use of ACE inhibitors and should be monitored during therapy. Patients with existing renal disease or taking high doses should be monitored regularly for proteinuria. Regular white blood cell counts may be necessary in patients with collagen vascular disorders, such as systemic lupus erythematosus and scleroderma, or in patients receiving immunosuppressive therapy, especially when they also have impaired renal function. ACE inhibitors should be used with caution in patients with a history of idiopathic or hereditary angioedema. Patients with heart failure and patients who are likely to be sodium or water depleted (for example, those receiving treatment with diuretics or dialysis) may experience symptomatic hypotension during the initial stages of ACE inhibitor therapy. Treatment should therefore be started under close medical supervision, using a low dose and with the patient in a recumbent position to minimise this effect. Anaphylactoid reactions have occurred in patients taking ACE inhibitors during haemodialysis using high-flux polyacrylonitrile membranes, during LDLapheresis with dextran sulfate columns, and during desensitisation with wasp or bee venom (see Hypersensitivity under Adverse Effects, above). ACE inhibitors have been associated with fetal toxicity and should not be used during pregnancy (see below).

Aortic stenosis.

Vasodilators, including ACE inhibitors, are usually contra-indicated in obstructive cardiac disorders such as aortic stenosis since cardiac output cannot increase to compensate for systemic vasodilatation and there is a risk of severe hypotension. However, a study1 in patients with symptomatic aortic stenosis found that enalapril was well-tolerated and improved symptoms, and a drug withdrawal study2 in hypertensive patients with asymptomatic aortic stenosis suggested that ACE inhibitors had beneficial haemodynamic effects. Another study3 in patients with heart failure and perceived contra-indications to ACE inhibitors (including 17.3% with aortic stenosis) found that survival was improved in those given ACE inhibitors. There is also some evidence that ACE inhibitors may slow the progression of calcific aortic stenosis, but this remains to be confirmed.4
1. Chockalingam A, et al. Safety and efficacy of angiotensin-converting enzyme inhibitors in symptomatic severe aortic stenosis: Symptomatic Cardiac Obstruction-Pilot study of Enalapril in Aortic Stenosis (SCOPE-AS). Am Heart J 2004; 147: E19.
2. Jiménez-Candil J, et al. Effects of angiotensin converting enzyme inhibitors in hypertensive patients with aortic valve stenosis: a drug withdrawal study. Heart 2005; 91: 1311–18
3. Ahmed A, et al. A propensity score analysis of the impact of angiotensin-converting enzyme inhibitors on long-term survival of older adults with heart failure and perceived contraindications. Am Heart J 2005; 149: 737–43
4. Newby DE, et al. Emerging medical treatments for aortic stenosis: statins, angiotensin converting enzyme inhibitors, or both? Heart 2006; 92: 729–34.

Diarrhoea.

Several reports have indicated that life-threatening hypotension and signs of renal failure may develop in patients receiving captopril1-3 or enalapril3 after volume depletion due to diarrhoea.
1. McMurray J, Matthews DM. Effect of diarrhoea on a patient taking captopril. Lancet 1985; i: 581
2. Benett PR, Cairns SA. Captopril, diarrhoea, and hypotension. Lancet 1985; i: 1105
3. McMurray J, Matthews DM. Consequences of fluid loss in patients treated with ACE inhibitors. Postgrad Med J 1987; 63: 385–7.

Ethnicity.

ACE inhibitors are less effective as antihypertensives in Afro-Caribbean black patients than in white patients. A similar difference has been reported in heart failure; in a pooled analysis1of the Studies of Left Ventricular Dysfunction (SOLVD) treatment and prevention trials, treatment with enalapril significantly reduced the risk of hospitalisation for heart failure in white patients with left ventricular dysfunction, but not in similar black patients. However, analysis2 of the prevention arm alone showed that enalapril reduced the relative risk of disease progression to a similar extent in black and white patients.
1. Exner DV, et al. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 2001; 344: 1351–7
2. Dries DL, et al. Efficacy of angiotensin-converting enzyme inhibition in reducing progression from asymptomatic left ventricular dysfunction to symptomatic heart failure in black and white patients. J Am Coll Cardiol 2002; 40: 311–17. Correction. ibid.; 1019.

Hepatic cirrhosis.

It has been suggested that in patients with cirrhosis, captopril could cause a marked reduction in arterial pressure and severely compromise renal function, since maintenance of glomerular filtration rate might be mediated by angiotensin II in these patients.1 This theory was supported by a report of a reduction in glomerular filtration rate in response to a fall in mean arterial pressure in 4 patients with resistant ascites secondary to hepatic cirrhosis.2 The fall in mean arterial pressure was associated with orthostatic hypotension and increasing encephalopathy. Severe confusion has also been reported in 2 patients with cirrhosis during treatment with captopril 6.25 to 12.5 mg three times daily.3
1. Ring T. Captopril and resistant ascites: a word of caution. Lancet 1983; ii: 165
2. Wood LJ, et al. Adverse effects of captopril in treatment of resistant ascites, a state of functional bilateral renal artery stenosis. Lancet 1985; ii: 1008–9
3. Jørgensen F, et al. Captopril and resistant ascites. Lancet 1983; ii: 405.

Huntington’s disease.

The condition of a woman with Huntington’s disease deteriorated dramatically during treatment with captopril and improved on withdrawal of the drug.1
1. Goldblatt J, Bryer A. Huntington’s disease: deterioration in clinical state during treatment with angiotensin converting enzyme inhibitor. BMJ 1987; 294: 1659–60.

Peripheral vascular disease.

Patients with peripheral vascular disease may have a high incidence of renal artery stenosis and are therefore at high risk of renal failure with ACE inhibitor therapy (see Effects on the Kidneys, above). Mild renal artery stenosis was found in 64 of 374 patients (17%) with peripheral vascular disease, and severe renal artery stenosis in 52 (14%); the stenosis was bilateral in 43 (12%).1 Renal function should be carefully monitored in any patient with peripheral vascular disease who receives ACE inhibitors.
1. Salmon P, Brown MA. Renal artery stenosis and peripheral vascular disease: implications for ACE inhibitor therapy. Lancet 1990; 336: 321.

Pregnancy.

There is evidence from animal studies that use of ACE inhibitors during pregnancy is associated with fetal toxicity and an increase in still-births.1 In humans, the main effect of ACE inhibitors is on the kidneys. Several case reports have described the development of fetal renal failure, with oligohydramnios or neonatal anuria, in the offspring of mothers receiving captopril2-4 or enalapril;5 there have been fetal4 and neonatal3deaths. A literature search up to the end of 1989 indicated that the use of ACE inhibitors during pregnancy can cause severe disturbances of fetal and neonatal renal function, long-lasting neonatal anuria, and pulmonary hypoplasia.6 There are also 2 case reports in which maternal captopril7 or enalapril8 therapy, in association with other drugs, was associated with birth defects including defective ossification of the skull. A registry study9 found that 2 of 19 infants exposed to ACE inhibitors during pregnancy had serious life-threatening conditions: one had prolonged anuria requiring dialysis; the other had microcephaly and a large occipital encephalocele. The FDA has re-emphasised that ACE inhibitors can cause injury and even death to the developing fetus in the second and third trimester.10 Although use of ACE inhibitors in the first trimester had been thought to carry a lesser risk,11-13 a review of the available experimental and clinical data concluded that the use of ACE inhibitors should be avoided throughout pregnancy.14 Also, a later cohort study15 of 29 507 infants found a significantly increased risk of major congenital malformations in 209 who had been exposed to ACE inhibitors alone in the first trimester and concluded that such use should be avoided.
1. Broughton Pipkin F, et al. Possible risk with captopril in pregnancy: some animal data. Lancet 1980; i: 1256
2. Boutroy M-J, et al. Captopril administration in pregnancy impairs fetal angiotensin converting enzyme activity and neonatal adaptation. Lancet 1984; ii: 935–6
3. Guignard JP, et al. Persistent anuria in a neonate: a side effect of captopril? Int J Pediatr Nephrol 1981; 2: 133
4. Knott PD, et al. Congenital renal dysgenesis possibly due to captopril. Lancet 1989; i: 451
5. Schubiger G, et al. Enalapril for pregnancy-induced hypertension: acute renal failure in a neonate. Ann Intern Med 1988; 108: 215–16. Correction. ibid.: 777
6. Hanssens M, et al. Fetal and neonatal effects of treatment with angiotensin-converting enzyme inhibitors in pregnancy. Obstet Gynecol 1991; 78: 128–35
7. Duminy PC, Burger P du T. Fetal abnormality associated with use of captopril during pregnancy. S Afr Med J 1981; 60: 805
8. Mehta N, Modi N. ACE inhibitors in pregnancy. Lancet 1989; ii: 96
9. Piper JM, et al. Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors. Obstet Gynecol 1992; 80: 429–32
10. Nightingale SL. Warnings on use of ACE inhibitors in second and third trimester of pregnancy. JAMA 1992; 267: 2445
11. CDC. Postmarketing surveillance for angiotensin-converting enzyme inhibitor use during the first trimester of pregnancy— United States, Canada, and Israel, 1987-1995. JAMA 1997; 277: 1193–4
12. Lip GYH, et al. Angiotensin-converting-enzyme inhibitors in early pregnancy. Lancet 1997; 350: 1446–7
13. Steffensen FH, et al. Pregnancy outcome with ACE-inhibitor use in early pregnancy. Lancet 1998; 351: 596
14. Shotan A, et al. Risk of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med 1994; 96: 451–6
15. Cooper WO, et al. Major congenital malformations after firsttrimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443–51.

💊 Interactions

Excessive hypotension may occur when ACE inhibitors are used with diuretics, other antihypertensives, or other agents, including alcohol, that lower blood pressure. An additive hyperkalaemic effect is possible in patients receiving ACE inhibitors with potassiumsparing diuretics, potassium supplements (including potassium-containing salt substitutes), or other drugs that can cause hyperkalaemia (such as ciclosporin or indometacin), and serum-potassium concentrations should be monitored. Potassium-sparing diuretics and potassium supplements should generally be stopped before starting ACE inhibitors in patients with heart failure. However, ACE inhibitor therapy does not obviate the possible need for potassium supplementation in patients given potassium-wasting diuretics and potassium concentrations should also be monitored in these patients. The adverse effects of ACE inhibitors on the kidneys may be potentiated by other drugs, such as NSAIDs, that can affect renal function.
1. Shionoiri H. Pharmacokinetic drug interactions with ACE inhibitors. Clin Pharmacokinet 1993; 25: 20–58
2. Mignat C, Unger T. ACE inhibitors: drug interactions of clinical significance. Drug Safety 1995; 12: 334–7.

Allopurinol.

For reports of reactions in patients taking captopril and allopurinol.

Antacids.

Use of captopril with antacids reduced the bioavailability of captopril although this did not significantly alter the effects on blood pressure and heart rate.1 The bioavailability of fosinopril, and possibly other ACE inhibitors, may also be reduced by use with antacids.
1. Mäntylä R, et al. Impairment of captopril bioavailability by concomitant food and antacid intake. Int J Clin Pharmacol Ther Toxicol 1984; 22: 626–9.

Antidiabetics.

Hypoglycaemia was noted in 3 type 1 diabetics when captopril was added to their therapeutic regimen; it was also seen in a type 2 diabetic, in whom withdrawal of hypoglycaemic drugs became necessary.1 Subsequent study suggested that the effect was due to enhanced insulin sensitivity.1 Similar instances of a reduction in blood sugar in both non-diabetic2 and diabetic3 patients given enalapril have occurred. Two case-control studies in diabetic patients receiving insulin or oral hypoglycaemics suggested that patients treated with ACE inhibitors were at increased risk of developing severe hypoglycaemia.4,5 However, other studies in diabetic patients given captopril or enalapril have failed to find any significant alterations in blood-glucose control,6,7 and ACE inhibitors are widely used in the treatment of hypertension in diabetic patients and also have a role in the management of diabetic complications such as nephropathy (see Kidney Disorders under Uses, below).
1. Ferriere M, et al. Captopril and insulin sensitivity. Ann Intern Med 1985; 102: 134–5
2. Helgeland A, et al. Enalapril, atenolol, and hydrochlorothiazide in mild to moderate hypertension: a comparative multicentre study in general practice in Norway. Lancet 1986; i: 872–5
3. McMurray J, Fraser DM. Captopril, enalapril, and blood glucose. Lancet 1986; i: 1035
4. Herings RMC, et al. Hypoglycaemia associated with use of inhibitors of angiotensin converting enzyme. Lancet 1995; 345: 1195–8
5. Morris AD, et al. ACE inhibitor use is associated with hospitalization for severe hypoglycemia in patients with diabetes. Diabetes Care 1997; 20: 1363–7
6. Passa P, et al. Enalapril, captopril, and blood glucose. Lancet 1986; i: 1447
7. Winocour P, et al. Captopril and blood glucose. Lancet 1986; ii: 461.

Azathioprine.

Leucopenia has been reported in a patient given captopril with azathioprine; the effect did not occur when either drug was given alone.1 In a similar report, neutropenia in a patient taking a regimen including azathioprine and captopril did not recur when captopril was reintroduced after stopping azathioprine.2
1. Kirchertz EJ, et al. Successful low dose captopril rechallenge following drug-induced leucopenia. Lancet 1981; i: 1363
2. Edwards CRW, et al. Successful reintroduction of captopril following neutropenia. Lancet 1981; i: 723.

Ciclosporin.

An additive hyperkalaemic effect with ACE inhibitors and ciclosporin is possible. Also, acute renal failure has been reported in 2 patients on ciclosporin after renal transplantation who were given enalapril.1 Renal function recovered when the ACE inhibitor was withdrawn.
1. Murray BM, et al. Enalapril-associated acute renal failure in renal transplants: possible role of cyclosporine. Am J Kidney Dis 1990; 16: 66–9.

Digoxin.

For reports of an increase in serum-digoxin concentrations during therapy with ACE inhibitors.

Diuretics.

Excessive hypotension may occur when ACE inhibitors are used with diuretics. Deterioration in renal function has also been reported with metolazone. Severe hyperkalaemia may occur if ACE inhibitors are used with spironolactone.

Epoetins.

An additive hyperkalaemic effect may occur when ACE inhibitors are given with epoetins. ACE inhibitors have also been reported to antagonise the haematopoietic effects of epoetins.

General anaesthetics.

Marked hypotension may occur during general anaesthesia in patients taking ACE inhibitors. In addition corrected cerebral blood flow was significantly lower in 11 patients who took captopril before general anaesthesia induced with thiopental and maintained with nitrous oxide and enflurane, than in 9 patients pretreated with metoprolol and 9 untreated controls.1 Although there were no complications of anaesthesia associated with captopril pretreatment, stopping ACE inhibitor therapy before anaesthesia should be considered. However, others have suggested2 that since there is no clear evidence for stopping them, ACE inhibitors may be continued with care.
1. Jensen K, et al. Cerebral blood flow during anaesthesia: influence of pretreatment with metoprolol or captopril. Br J Anaesth 1989; 62: 321–3
2. Anonymous. Drugs in the peri-operative period: 4 – cardiovascular drugs. Drug Ther Bull 1999; 37: 89–92.

Gold salts.

The nitritoid reaction (flushing, nausea, dizziness, and hypotension associated with the first weeks of gold treatment) occurred soon after commencing treatment with an ACE inhibitor (captopril, lisinopril, or enalapril) in 4 patients who had been receiving sodium aurothiomalate for at least 2 years.1
1. Healey LA, Backes MB. Nitritoid reactions and angiotensinconverting-enzyme inhibitors. N Engl J Med 1989; 321: 763.

Interferons.

Severe granulocytopenia has been reported1 in 3 patients with mixed cryoglobulinaemia treated with interferon alfa-2a who also received ACE inhibitors. The effect was considered to be due to synergistic haematological toxicity. However, in a further report,2 2 patients developed only mild granulocytopenia that was reversible despite continued therapy, while a third patient retained a normal granulocyte count.
1. Casato M, et al. Granulocytopenia after combined therapy with interferon and angiotensin-converting enzyme inhibitors: evidence for a synergistic hematologic toxicity. Am J Med 1995; 99: 386–91
2. Jacquot C, et al. Granulocytopenia after combined therapy with interferon and angiotensin-converting enzyme inhibitors: evidence for a synergistic hematologic toxicity. Am J Med 1996; 101: 235–6.

Interleukin-3.

Marked hypotension occurred in 3 patients1 receiving ACE inhibitors who were given interleukin-3 following chemotherapy; blood pressure returned to normal when the ACE inhibitors were stopped.
1. Dercksen MW, et al. Hypotension induced by interleukin-3 in patients on angiotensin-converting enzyme inhibitors. Lancet 1995; 345: 448.

Lithium.

For reports of lithium toxicity in patients taking ACE inhibitors.

Muscle relaxants.

For a report of severe hypotension in a patient taking lisinopril and tizanidine.

NSAIDs.

Indometacin and possibly other NSAIDs, including aspirin, have been reported to reduce or abolish the hypotensive action of ACE inhibitors. A similar effect has been reported1with rofecoxib. NSAIDs cause sodium and water retention and thus may attenuate the effects of various antihypertensives. It has also been suggested that part of the hypotensive effect of ACE inhibitors is prostaglandin-dependent, which might explain this interaction with drugs such as NSAIDs that block prostaglandin synthesis. However, in a double-blind study designed to assess the role of prostaglandins,2 indometacin did not influence the hypotensive effect of captopril or enalapril, suggesting that the effects on prostaglandins are not significant. The possibility of an interaction between low-dose aspirin and ACE inhibitors has caused concern.3-5 Retrospective analysis of some studies of ACE inhibitors in patients with heart failure after myocardial infarction suggested that outcome was poorer in those who were also receiving aspirin. A number of small studies have investigated the effects of aspirin plus ACE inhibitors on haemodynamic parameters, but results have been conflicting and the clinical relevance of these findings is not clear. Given the well-established benefits of both ACE inhibitors and aspirin in patients with heart failure associated with ischaemic heart disease, it is generally recommended that patients should continue to receive treatment with both.4,5 A systematic review6 of longterm studies using ACE inhibitors came to a similar conclusion, and an observational study7 in patients with both ischaemic and non-ischaemic heart failure found that ACE inhibitors improved outcomes, irrespective of whether or not patients were taking aspirin. The combination of NSAIDs and ACE inhibitors may also have variable effects on renal function since they act at different parts of the glomerulus.8 When given to patients whose kidneys are underperfused, for example because of heart failure, liver cirrhosis, or haemorrhage, renal function may deteriorate. Use of NSAIDs in patients taking ACE inhibitors with diuretics may be particularly hazardous.9 However, specific patient groups without reduced renal perfusion may benefit from combining an NSAID with an ACE inhibitor. Indometacin, and possibly other NSAIDs, may have an additive hyperkalaemic effect.
1. Brown CH. Effect of rofecoxib on the antihypertensive activity of lisinopril. Ann Pharmacother 2000; 34: 1486
2. Gerber JG, et al. The hypotensive action of captopril and enalapril is not prostacyclin dependent. Clin Pharmacol Ther 1993; 54: 523–32
3. Stys T, et al. Does aspirin attenuate the beneficial effects of angiotensin-converting enzyme inhibition in heart failure? Arch Intern Med 2000; 160: 1409–13
4. Mahé I, et al. Interaction between aspirin and ACE inhibitors in patients with heart failure. Drug Safety 2001; 24: 167–82
5. Olson KL. Combined aspirin/ACE inhibitor treatment for CHF. Ann Pharmacother 2001; 35: 1653–8
6. Teo KK, et al. Effects of long-term treatment with angiotensinconverting-enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet 2002; 360: 1037–43. Correction. ibid. 2003; 361: 90
7. McAlister FA, et al. Aspirin use and outcomes in a communitybased cohort of 7352 patients discharged after first hospitalization for heart failure. Circulation 2006; 113: 2572–8
8. Sturrock NDC, Struthers AD. Non-steroidal anti-inflammatory drugs and angiotensin converting enzyme inhibitors: a commonly prescribed combination with variable effects on renal function. Br J Clin Pharmacol 1993; 35: 343–8
9. Australian Adverse Drug Reactions Advisory Committee (ADRAC). Beware the triple whammy! Aust Adverse Drug React Bull 2006; 25: 18. Also available at: http://www.tga.gov.au/ adr/aadrb/aadr0610.pdf (accessed 04/04/08)

Probenecid.

Giving probenecid to 4 healthy subjects during intravenous infusion of captopril caused increases in the steadystate plasma-captopril concentration. The interaction was considered to be due to a reduction of tubular secretion of captopril by probenecid.1
1. Singhvi SM, et al. Renal handling of captopril: effect of probenecid. Clin Pharmacol Ther 1982; 32: 182–9.

💊 Pharmacokinetics

Most ACE inhibitors are given orally. Apart from captopril and lisinopril, they are generally prodrugs and after absorption undergo rapid metabolism by ester hydrolysis to the active diacid form; for example, enalapril is converted to enalaprilat. Metabolism occurs mainly in the liver. Excretion as active drug or active metabolite is principally in the urine; some, such as benazeprilat and fosinoprilat, are also excreted via the biliary tract. Elimination of the diacid is polyphasic and there is a prolonged terminal elimination phase, which is considered to represent binding to the angiotensin-converting enzyme at a saturable binding site. This bound fraction does not contribute to accumulation of drug following multiple doses. The terminal elimination half-life does not therefore predict the kinetics observed with multiple dosing and the effective half-life for accumulation is the value usually quoted.
1. Burnier M, Biollaz J. Pharmacokinetic optimisation of angiotensin converting enzyme (ACE) inhibitor therapy. Clin Pharmacokinet 1992; 22: 375–84
2. Hoyer J, et al. Clinical pharmacokinetics of angiotensin converting enzyme (ACE) inhibitors in renal failure. Clin Pharmacokinet 1993; 24: 230–54
3. Song JC, White CM. Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet 2002; 41: 207–24.

💊 Uses and Administration

ACE inhibitors are antihypertensive drugs that act as vasodilators and reduce peripheral resistance. They inhibit angiotensin-converting enzyme (ACE), which is involved in the conversion of angiotensin I to angiotensin II. Angiotensin II stimulates the synthesis and secretion of aldosterone and raises blood pressure via a potent direct vasoconstrictor effect. ACE is identical to bradykininase (kininase II) and ACE inhibitors also reduce the degradation of bradykinin, which is a direct vasodilator and is also involved in the generation of prostaglandins. The pharmacological actions of ACE inhibitors are thought to be primarily due to the inhibition of the renin-angiotensin-aldosterone system, but since they also effectively reduce blood pressure in patients with low renin concentrations other mechanisms are probably also involved. ACE inhibitors produce a reduction in both preload and afterload in patients with heart failure. They also reduce left ventricular remodelling, a process that sometimes follows myocardial infarction. Normally, renal blood flow is increased without a change in glomerular filtration rate. ACE inhibitors also reduce proteinuria associated with glomerular kidney disease. ACE inhibitors are used in the treatment of hypertension and heart failure and are given to improve survival after myocardial infarction and for the prophylaxis of cardiovascular events in patients with certain risk factors. They are also used in the treatment of diabetic nephropathy. They are generally given orally. In some hypertensive patients there may be a precipitous fall in blood pressure when starting therapy with an ACE inhibitor and the first dose should preferably be given at bedtime; if possible, any diuretic therapy should be stopped a few days beforehand and resumed later if necessary. In patients with heart failure taking
Published October 13, 2018.