Angiotensin-converting enzyme inhibitors

General information

Angiotensin-converting enzyme (ACE) inhibitors inhibit the conversion of angiotensin I to angiotensin II ( Figure 1 ). The ACE is also a kininase, and so ACE inhibitors inhibit the breakdown of kinins. Some of the adverse effects of these drugs are related to these pharmacological effects. For example, cough is thought to be due to the action of kinins on axon fibers in the lungs and hypotension is due to vasodilatation secondary to reduced concentrations of the vasoconstrictor angiotensin II.

Figure 1, The mechanisms of action of ACE inhibitors, angiotensin receptor antagonists, and direct renin inhibitors

Our knowledge of the use of ACE inhibitors has expanded dramatically during recent years, thanks to the publication of the results of a number of large clinical trials [ ].

The Heart Outcomes Prevention Evaluation (HOPE) study showed that virtually all patients with a history of cardiovascular disease, not only those who have had an acute myocardial infarction or who have heart failure, benefit from ACE inhibitor therapy [ ]. The authors selected 9297 patients at increased risk of cardiovascular disease, defined as a history of a cardiovascular event or evidence of disease, such as angina. People with diabetes but no indication of heart disease were included, but they had to have an additional risk factor. They were allocated to receive the ACE inhibitor ramipril 10 mg/day or placebo. The trial was stopped early, according to the predefined rules, because of an overwhelming effect of ramipril on the primary end-point, a 22% reduction in a composite measure of myocardial infarction, stroke, and death from cardiovascular causes. Significance was also achieved on outcomes as diverse as myocardial infarction, revascularization, heart failure, cardiac arrest, and worsening angina. Patients with diabetes had a similar 25% reduction for the composite cardiovascular end-point. Moreover, patients taking ramipril had 16% less overt nephropathy (defined as urine albumin over 300 mg/24 hours, or urine total protein excretion over 500 mg/24 hours, or a urine albumin/creatinine ratio over 36 mg/mmol). They also needed 22% less laser therapy for retinopathy. Since all the patients in the HOPE study were not hypertensive, and since the cardiovascular benefit was greater than that attributable to the fall in blood pressure, the authors suggested that ACE inhibitors are cardioprotective, vasculoprotective, and renal protective, independently of their blood pressure lowering effect.

Relative to the dosage issue, the dosage–plasma concentration relation for enalaprilat (the active metabolite of enalapril) in patients with heart failure and its relation to drug-related adverse effects has been investigated [ ]. In patients taking enalapril for more than 3 months, in dosages of 5–20 mg bd, there were highly variable trough concentrations of enalaprilat. They were affected by serum creatinine, the severity of heart failure, and body weight. Adverse effects, such as cough and rises in serum creatinine and potassium, were more common at high enalaprilat trough concentrations. The authors concluded that these results provide a rationale for individually adjusting ACE inhibitor doses in case of adverse effects.

Use in hypertension

In hypertension, the Captopril Prevention Project (CAPPP) trial evaluated an ACE inhibitor as an alternative first-line agent in mild to moderate hypertension. It was a prospective randomized open study with blinded end point evaluation (PROBE design), comparing an antihypertensive strategy based on either captopril or conventional therapy with a beta-blocker or a diuretic in patients with mild to moderate hypertension. At the end of follow-up the incidence of cardiovascular events was equal with the two strategies. However, imbalances in the assignment of treatment resulted in a 2 mmHg higher average diastolic blood pressure at entry in the group assigned to captopril. This difference in blood pressure alone would be sufficient to confer an excess of cardiovascular risk within this group, could mask real differences between the regimens in their effects on coronary events, and could explain the greater risk of stroke among patients who took captopril. The authors claimed that the overall results support the position that from now on one should consider ACE inhibitors as first-line agents, equal to diuretics and beta-blockers [ ]. The CAPPP study also reported a reduced risk of diabetes with captopril, which may be explained by the fact that thiazides and beta-blockers cause changes in glucose metabolism and by favorable effects of ACE inhibition on insulin responsiveness.

The second Swedish Trial in Old Patients with hypertension, STOP-2, was designed to compare the effects of conventional antihypertensive drugs on cardiovascular mortality and morbidity with those of newer antihypertensive drugs, including ACE inhibitors, in elderly patients [ ]. The study was prospective, randomized, and open, but with a blinded end-point evaluation. It included 6614 patients aged 70–84 years with hypertension (blood pressure over 180 mmHg systolic, or over 105 mmHg diastolic, or both). The patients were randomly assigned to conventional drugs (atenolol 50 mg/day, metoprolol 100 mg/day, pindolol 5 mg/day, or hydrochlorothiazide 25 mg/day plus amiloride 2.5 mg/day) or to newer drugs (enalapril 10 mg/day or lisinopril 10 mg/day, or felodipine 2.5 mg/day or isradipine 2.5 mg/day). Blood pressure fell similarly in all treatment groups. There were equal incidences of the primary end-points (fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease combined) in all groups (20 events per 1000 patient years). Subgroup analyses showed that conventional therapy, ACE inhibitors, and calcium antagonists had similar efficacy in preventing cardiovascular mortality and major morbidity. This finding argues against the hypothesis that some classes of antihypertensive drugs have efficacy advantages over others, at least in this population of elderly hypertensive patients. Therefore, the choice of antihypertensive treatment will be related to other factors, such as cost, co-existing disorders, and adverse effects. With respect to the reported adverse effects, since the study was open, causality cannot be established. Nevertheless, the size of the study and its naturalistic design allowed accurate assessment of the incidence of adverse effects in this population of elderly hypertensive patients. With ACE inhibitors the most frequently reported adverse effects were cough 30%, dizziness 28%, ankle edema 8.7%, headache 7.7%, shortness of breath 7.3%, and palpitation 5.5%. Actually, little detail was given in the section devoted to safety in the main publication of the results of the trial.

Use in heart failure

In heart failure much debate has been generated by the observation of general “under-use” of ACE inhibitors and the use of smaller doses than have been beneficial in clinical trials. This was partly related to concern about safety with the highest doses, especially in high-risk groups, such as the elderly and patients with renal insufficiency [ ]. Actually, outcome trials effectively excluded elderly patients (75–80 years and over) and usually patients with renal insufficiency. As elderly patients have poorer renal function, they are more likely to have vascular disease in their renal and carotid arteries, and may be more prone to symptomatic hypotension, it cannot be assumed that the benefit to harm balance observed in younger patients will be the same, at the same doses, in elderly people. The NETWORK trial, a comparison of small and large doses of enalapril in heart failure, was poorly designed and is not conclusive. However, it suggested that apart from a trend to more fatigue with higher doses (10 mg bd), the incidence of adverse effects, including symptomatic hypotension, was similar across the three dosages (2.5, 5, and 10 mg bd) [ ].

In heart failure the issue of whether it is justified to use doses of ACE inhibitors substantially smaller than the target doses used in the large-scale studies that established the usefulness of these drugs has been examined in the ATLAS (Assessment of Treatment with Lisinopril and Survival) trial [ ]. This trial randomized 3164 patients with New York Heart Association (NYHA) class II–IV heart failure and ejection fractions less than 30% to double-blind treatment with either low doses (2.5–5.0 mg/day) or high doses (32.5–35 mg/day) of the ACE inhibitor lisinopril for 39–58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a non-significant 8% lower risk of death but a significant 12% lower risk of death plus hospitalization for any reason and 24% fewer hospitalizations for heart failure. Dizziness and renal insufficiency were more frequent in the high-dose group, but the two groups were similar in the number of patients who required withdrawal of the study medication. These findings suggest that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor, unless higher doses cannot be tolerated. However, the ATLAS trial did not address this issue properly. The doses in the small-dose arm were actually very small, and much smaller than those used in routine practice, as reported in several other studies [ ]. The doses in the large-dose arm may have been unnecessarily high. The recommendation of using target doses proven to be effective in large-scale trials remains unchallenged.

In the studies of left ventricular dysfunction (SOLVD), adverse effects related to the long-term use of enalapril have been thoroughly investigated [ ].

Use in myocardial infarction

In the acute infarction ramipril efficacy (AIRE) study, oral ramipril in 2006 patients with heart failure after acute myocardial infarction resulted in a substantial reduction in deaths within 30 days [ ].

More trials during and after myocardial infarction have been published and subjected to meta-analysis [ ]. This very large database provides valuable information on the rate of the most common adverse effects. Of all trials of the effects of ACE inhibitors on mortality in acute myocardial infarction, only the CONSENSUS II trial did not show a positive effect. In this trial, enalaprilat was infused within 24 hours after the onset of symptoms, followed by oral enalapril. The reasons for the negative result of CONSENSUS II remain unresolved, but hypotension and a proischemic effect linked to a poorer prognosis have been suggested.

Use in nephropathy

The results of two trials in patients with chronic nephropathy have reinforced the benefit of ACE inhibitors in slowing the progression of chronic renal insufficiency due to renal diseases other than diabetic nephropathy [ ], and have provided sufficient information on the safety profile of these agents in chronic renal insufficiency. This was found to be essentially the same as in patients with normal renal function. The current practice of avoiding ACE inhibitors in severe renal insufficiency, to prevent further renal impairment and hyperkalemia, is no longer justified, although careful monitoring should still be observed.

Ramipril has a renal protective effect in non-diabetic nephropathies with nephrotic and non-nephrotic proteinuria [ ]. It also improves cardiovascular morbidity and all-cause mortality in patients with some cardiovascular risk [ ].

The Ramipril Efficacy in Nephropathy (REIN) trial was designed to test whether glomerular protein traffic, and its modification by an ACE inhibitor, influenced disease progression in non-diabetic chronic nephropathies [ ]. Patients were stratified before randomization by 24-hour proteinuria. Treatment with ramipril or placebo plus conventional antihypertensive therapy was targeted at the same blood pressure control. At the second interim analysis, ramipril had slowed the fall in glomerular filtration rate (GFR) more than expected from the degree of blood pressure reduction. In the follow-up study GFR almost stabilized in patients who had been originally randomized to ramipril and had continued to take it for more than 36 months. The combined risk of doubling of the serum creatinine or end-stage renal insufficiency was half that found in those taking placebo plus conventional therapy. In patients with proteinuria of 1–3 g/day the fall in GFR per month was not significantly affected, but progression to end-stage renal insufficiency was significantly less common with ramipril (9/99 versus 18/87) for a relative risk of 2.72 (CI = 1.22, 6.08) [ ]; and so was progression to overt proteinuria (15/99 versus 27/87; RR = 2.40; CI = 1.27, 4.52).

The results of this trial show that ramipril was well tolerated and even protective in cases of advanced renal insufficiency. One major reason for the current practice of underprescription and of prescription of suboptimal doses of ACE inhibitors, especially in patients with heart failure, is the presence of renal insufficiency [ ]. In such patients, not only should ACE inhibitors no longer be avoided, they are indeed indicated for preservation of renal function.

General adverse effects and adverse reactions

The commonest unwanted effects of ACE inhibitors are related to their pharmacological actions (that is inhibition of angiotensin-converting enzyme and kininase II): renal insufficiency, potassium retention, pronounced first-dose hypotension, cough, and the serious but less common angioedema. Skin rashes and taste disturbances are uncommon, but may be more likely with sulfhydryl-containing drugs, particularly captopril. Rare hypersensitivity reactions include rashes, bone-marrow suppression, hepatitis, and alveolitis. If administered in the second or third term of pregnancy, ACE inhibitors can cause a number of fetal anomalies, including growth retardation, renal impairment, oligohydramnios, hypocalvaria, fetal pulmonary hypoplasia, and fetal death. Neonatal anuria and neonatal death can also occur [ , ]. Tumor-inducing effects have not been reported.

The frequencies and the profile of adverse effects of five major classes of antihypertensive agents have been assessed in an unselected group of 2586 chronically drug-treated hypertensive patients [ ]. This was accompanied by a questionnaire-based survey among patients visiting a general practitioner. The percentages of patients who reported adverse effects spontaneously, on general inquiry, and on specific questioning were 16%, 24%, and 62% respectively. With ACE inhibitors the figures were 15%, 22%, and 55%. The percentage of patients in whom discontinuation was due to adverse effects was 8.1% with ACE inhibitors (significantly higher than diuretics). Compared with beta-blockers, ACE inhibitors were associated with less fatigue (RR = 0.57; 95% CI = 0.38, 0.85), cold extremities (RR = 0.11; CI = 0.07, 0.18), sexual urge (RR = 0.52; CI = 0.33, 0.82), insomnia (RR = 0.10; CI = 0.04, 0.26), dyspnea (RR = 0.38; CI = 0.17, 0.85), and more coughing (RR = 13; CI = 5.6, 30). The authors did not find a significant effect of age on the pattern of adverse effects. Women reported more effects and effects that were less related to the pharmacological treatment.

Drug studies

Combination studies

Several trials and reviews have examined the beneficial effects and adverse effects of combining angiotensin II receptor antagonists with ACE inhibitors. A large industry-sponsored randomized controlled trial, the ONTARGET trial (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial), examined the effects of telmisartan, ramipril, or the combination in patients with vascular disease or high-risk diabetes without heart failure [ ]. Telmisartan was equivalent to ramipril in terms of vascular-related death, the primary outcome, and perhaps not surprisingly there were lower rates of angioedema and cough from the angiotensin II receptor antagonist than the ACE inhibitor. The rate of adverse events, especially hypotensive symptoms, syncope, and renal dysfunction, was higher in the combination group than in the monotherapy groups. In the absence of obvious clinical benefits in this type of patient population it is best not to combine these drug classes.

A quantitative review of data from four randomized controlled trials of the adverse effects of this combination of drug classes in patients with symptomatic left ventricular dysfunction also found worsening renal function and symptomatic hypotension [ ]. There was a significant increase in withdrawal rates in the combined groups because of adverse effects. However, the meta-analysis did not show a significantly increased risk of severe hyperkalemia in the pooled cohort, although there was a non-significant increase in the risk of hyperkalemia.

In a smaller crossover study of the effect of angiotensin II receptor antagonists, ACE inhibitors, the combination, or neither in patients with dialysis-dependent chronic kidney disease, neither monotherapy (with either class) nor the combination was associated with an additional risk of hyperkalemia in patients on hemodialysis [ ]. However, the authors concluded that patients with anuria still warrant cautious monitoring of serum potassium concentrations to prevent hyperkalemia.

Organs and systems

Cardiovascular

Marked reductions in blood pressure, without any significant change in heart rate, can occur at the start of ACE inhibitor therapy. Such reductions, which are not orthostatic, are sometimes symptomatic but rarely fatal. The volume of evidence is greatest with the longer established agents, but continues to suggest that the problems of first-dose hypotension are most likely to occur in patients whose renin–angiotensin system is stimulated (renin-dependent states), such as in renovascular hypertension or other causes of renal hypoperfusion, dehydration, or previous treatment with other vasodilators [ ]. These conditions can co-exist, particularly in severe heart failure [ ]. Similar problems have occurred in the treatment of hypertensive neonates and infants [ ], but again were particularly likely in the setting of high plasma renin activity associated with either renovascular disease or concurrent diuretic treatment.

The use of very low doses to avoid first-dose hypotension is common, although the rationale remains unclear [ ]. It is even less clear whether or not there are differences between different ACE inhibitors, that is whether first-dose hypotension is agent-specific or a class effect [ , ].

Respiratory

The adverse respiratory effects of ACE inhibitors are fairly well recognized, especially the association with a dry irritating cough. Several other respiratory adverse effects have been described [ ]. Medication-related cough may reduce the risk of aspiration pneumonia after stroke and patients with obstructive sleep apnea may be more likely to have rhinopharyngeal inflammation, with a risk of worsening their condition.

Cough

A non-productive irritant cough was reported as an adverse effect of ACE inhibitors in the mid 1980s. It can be distressing and inconvenient, leading to withdrawal of therapy. Certain susceptibility factors are clearly recognized (for example non-smoking and female sex), but racial group can also affect the incidence. Cough has been reported as a beneficial side effect of ACE inhibitors in a short report of two patients who were unable to continue smoking owing to excessive coughing during smoking, which started only after they started to take therapy [ ]. The authors pointed out that prescribing ACE inhibitors for patients with hypertension or chronic heart failure who smoke may therefore serve two ends.

The EIDOS and DoTS descriptions of ACE-inhibitor induced cough are shown in Figure 2 .

Figure 2, The EIDOS and DoTS descriptions of ACE-inhibitor-induced cough

Frequency

In different studies there has been large variability in the absolute incidence of cough (0.7–48%), the discontinuation rate (1–10%), and the relative incidences with different ACE inhibitors [ ]. However, the placebo-controlled, randomized, HOPE study has provided a remarkable database, with the largest cohort and the longest follow-up ever reported with such therapy (over 9000 patients followed for 5 years on average). Compared with placebo, ACE inhibitor therapy with ramipril caused cough leading to drug withdrawal in 7.3% of patients (compared with 1.8% for placebo) [ ].

The incidence of cough secondary to different ACE inhibitors has been evaluated in a randomized, double-blind study in the Philippines, which included dechallenge and rechallenge to assess the likelihood of adverse drug effects [ ]. Using an intention-to-treat analysis, the overall incidence of ACE inhibitor-induced cough was 17% and there were statistically significant differences in the incidences of cough among the ACE inhibitors studied: 23% for cilazapril, 22% for enalapril, 13% for imidapril, and 11% for perindopril.

HOPE TIPS was a prospective study of patients with high cardiovascular risk, in which the practicability and tolerability of ramipril titration was tested in 1881 patients [ ]. Cough occurred in 14% over a period of up to 3 months, and 4% discontinued ramipril as a result. The author of an accompanying editorial [ ] pointed out that the true incidence of ramipril-induced cough had conceivably been overestimated in the study, owing to the large proportions of patients with type 2 diabetes (52%) and non-smokers (80%) and the high doses used. The authors suggested that cough was not necessarily more common in Asian patients (79% of the patients in this study), although within this broad category the differential susceptibility to cough may quite large, and the editorial examined this; on the balance of evidence, Chinese patients (and perhaps some other racial groups in Asian countries) probably develop cough more commonly with ACE inhibitors than Caucasian patients do.

Mechanism

The effects of ACE inhibitors on the respiratory system have been reviewed and the probable pathophysiological mechanisms analysed [ ]. It may be more complicated than just an increase in concentrations of bradykinin and substance P, increased microvasculature leakage, and stimulation of vagal C fibers [ ]. Sulindac and indometacin may abolish or reduce the intensity and frequency of cough, supposedly because of inhibition of prostaglandin synthesis [ , ]. Common variant genetics of ACE, chymase, and the bradykinin B ₂ receptor do not explain the occurrence of ACE inhibitor-related cough [ ]. In general, bronchial hyper-reactivity has been causally implicated and may also be associated with exaggerated dermal responses to histamine [ , ]. However, in one report, airways hyper-responsiveness was not a consistent finding [ ].

Susceptibility factors

Cough is more common in non-smokers [ ] and in women [ , ]. It has been speculated that the risk of cough is genetically predetermined. The possibility that polymorphisms of the human bradykinin B ₂ receptor gene may be involved in ACE inhibitor-related cough has been investigated in a case–control study [ ]. The DNA of 60 subjects with and without cough who were treated with ACE inhibitors was compared with that of 100 patients with untreated essential hypertensive and 100 normotensive subjects. The frequencies of the TT genotype and T allele were significantly higher in the subjects with cough than in subjects without. These tendencies were more pronounced in women. Subjects with the CC genotype were less susceptible to cough. According to the authors, high transcriptional activity of the bradykinin B2 receptor promoter may be related to the risk of ACE inhibitor-related cough. This is the first demonstration that a genetic variant is involved in ACE inhibitor-related cough. It may therefore be possible to predict the occurrence of cough related to ACE inhibitor use.

The genetic basis of ACE inhibitor-induced cough and its relation to bradykinin have been further explored in a study of the effect of cilazapril in two groups of healthy volunteers genotyped for ACE insertion/deletion (I/D) polymorphism [ ]. The cough threshold to inhaled capsaicin was significantly lower in the genotype II group than in the DD group. Skin responses to intradermal bradykinin were significantly enhanced in the genotype II group. There was no difference in responsiveness to intradermal substance P. The authors suggested that these findings provide further evidence of the link between ACE inhibitor-induced cough and I/D polymorphism of the ACE gene, and that this supports the hypothesis that ACE inhibitors cause cough by modulating tissue concentrations of bradykinin.

Chinese patients experience more cough from ACE inhibitors than Caucasians. A review of the pharmacokinetics and blood pressure-lowering efficacy of ACE inhibitors as well as of ACE and angiotensinogen gene polymorphism did not find significant differences between Chinese and Caucasians to account for the difference in cough incidence [ ].

Management

The American College of Chest Physicians has produced evidence-based clinical practice guidelines about ACE inhibitor-induced cough [ ]. In the summary they concluded that in patients with chronic cough, ACE inhibitors should be considered wholly or partially causative, regardless of the temporal relation between the start of therapy and the onset of the cough. Their advice is that the only uniformly effective treatment for ACE inhibitor-induced cough is withdrawal of therapy and that a switch to an angiotensin II receptor antagonist should be undertaken if considered appropriate.

ACE inhibitor-associated cough seems to be a class effect: switching to another ACE inhibitor rarely solves the problem, although there are occasional anecdotal reports [ , ]. However, most patients who develop a cough related to an ACE inhibitor are able and willing to continue therapy. In a small randomized study inhaled sodium cromoglicate relieved the symptom [ ]. In those in whom the symptom is intolerable, a switch to an angiotensin receptor antagonist is justified.

Obstructive airways disease

It has been suggested that ACE inhibitors are also associated with an increased incidence of symptomatic obstructive airways disease, leading to bronchospasm and asthma [ ]. However, a prescription event monitoring study of more than 29 000 patients taking ACE inhibitors, compared with 278 000 patients taking other drugs, failed to confirm this association [ ].

Sensory systems

The effects of statins and ACE inhibitors on the incidence of age-related macular degeneration have been investigated in a case–control study [ ]. There was a slightly higher but significant increased risk of macular degeneration in users of ACE inhibitors (RR = 1.19; 95% CI = 1.07, 1.33).

Endocrine

Gynecomastia has been reported in a patient taking captopril 75 mg/day; it resolved when captopril was withdrawn but recurred when the patient was given enalapril [ ]. This suggests that gynecomastia may not be simply attributable to the sulfhydryl group of captopril.

Metabolism

ACE inhibition has been associated with increased insulin sensitivity in diabetic patients, and it has therefore been hypothesized that ACE inhibitors can precipitate hypoglycemia in such patients. A Dutch case–control study suggested that among users of insulin or oral hypoglycemic drugs, the use of ACE inhibitors was significantly associated with an increased risk of hospital admission for hypoglycemia [ ]. However, a French case/non-case study from the pharmacovigilance database did not confirm this finding [ ].

In a matched case–control study of 404 cases of hospitalization for hypoglycemia in diabetic patients and 1375 controls, the risk of hypoglycemia was greater in those who used insulin versus a sulfonylurea and was not influenced by the use of ACE inhibitors [ ]. However, the use of enalapril was associated with an increased risk of hypoglycemia (OR = 2.4; CI = 1.1, 5.3) in sulfonylurea users. Although the authors emphasized the fact that previous reports of ACE inhibitor-related hypoglycemia were more frequent with enalapril, it is unclear why only enalapril, and not ACE inhibitors as a class, was associated with a significantly increased risk of hypoglycemia, and why this occurred only in sulfonylurea users.

Conversely, it has been suggested that the protective effect of ACE inhibitors against severe hypoglycemia should be tested in high-risk patients with high ACE activity. About 10–20% of patients with type 1 diabetes mellitus have a risk of severe hypoglycemia. In 307 unselected consecutive diabetic outpatients, those with the ACE DD genotype had a relative risk of severe hypoglycemia of 3.2 (95% CI = 1.4, 7.4) compared with those with the genotype II [ ]. There was a significant relation between serum ACE activity and the risk of severe hypoglycemia.

Electrolyte balance

Antihypertensive drugs and their effects on potassium homeostasis have been reviewed, in particular the problem of ACE inhibitor- and angiotensin II receptor antagonist-induced hyperkalemia [ ]. The uncertainty about the best way to monitor potassium concentrations is also described and the fact that monitoring guidelines are at best makeshift and drawn from the know-how of the treating physician.

Previously published guidelines have been described, together with two case studies that illustrate the role of electrolyte measurement in hypertensive patients taking ACE inhibitors or potassium-sparing diuretics [ ]. Prevention of serious adverse effects with monitoring is important, and it is clear that early changes in biochemical parameters may be important and indicate the need for more frequent monitoring or modification of therapy.

ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired kidney function and/or in patients taking potassium supplements (including salt substitutes) or potassium-sparing diuretics, and especially aldosterone antagonists, hyperkalemia can occur. In two cases, hypoaldosteronism with diabetes was implicated [ , ].

Hyponatremia, defined as a plasma sodium concentration of 133 mmol/l or under, has been investigated in a prospective study of elderly patients with hip fractures. ACE inhibitors were the most frequently used drugs (five of 14 cases) [ ]. Of course, this does not prove a cause and effect relation, since in elderly people ACE inhibitors are likely to be among the most frequently prescribed drugs. However, hypoaldosteronism would be a likely mechanism.

Hematologic

ACE inhibitors are used to treat erythrocytosis, for example after transplantation [ ]. Efficacy in treating erythrocytosis in chronic obstructive pulmonary disease has also been described with the angiotensin II receptor antagonist losartan [ ]. ACE inhibitors can also lower normal erythrocyte counts and cause anemia [ ]. This effect has been assessed in a retrospective study of 92 patients after transplantation with and without erythrocytosis, comparing patients taking the same anti-rejection therapy (steroids plus ciclosporin or steroids, ciclosporin, and azathioprine) taking ACE inhibitors with those not taking ACE inhibitors [ ]. There were significantly lower hemoglobin and erythropoietin concentrations in patients taking ACE inhibitors. When enalapril was given to those who had not previously taken an ACE inhibitor, the hemoglobin concentration fell by around 10% and erythropoietin by around 40%. These effects were not affected by the presence or absence of azathioprine. Although the hemoglobin-lowering effect of ACE inhibition is not a new finding, the lack of an influence of azathioprine adds some further understanding to the effect.

Liver

Hepatic injury is a rare adverse effect of the ACE inhibitors [ , ]. Both acute and chronic hepatitis and cholestatic jaundice can occur [ , ], as can cross-reactivity, as identified in a report involving enalapril and captopril [ ].

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