What are ACE inhibitors

ACE inhibitors is short for angiotensin-converting enzyme inhibitors, are blood pressure drugs or antihypertensive medications that are widely used to treat high blood pressure (hypertension). ACE inhibitors medications help relax blood vessels by blocking the formation of a natural chemical that narrows blood vessels. ACE inhibitors may be especially important in treating high blood pressure in people with coronary artery disease, heart failure or kidney failure caused by diabetes. The ACE inhibitors are considered first line drugs for the therapy of hypertension and are considered particularly helpful in preventing the kidney complications of diabetes and high blood pressure. ACE inhibitors are sometimes used even in patients with relatively normal blood pressure for treatment of heart failure and prevention of diabetic nephropathy. For diabetic nephropathy, start ACE inhibitors at onset of microalbuminuria in all diabetic patients ¹. Some small studies have shown slowing of onset of microalbuminuria in nonalbuminuric patients; whether this affects outcome is not known.

Clinical outcomes of ACE inhibition include decreases in heart attack (fatal and non-fatal), reinfarction (another heart attack), angina, stroke, end-stage kidney failure, and morbidity and mortality associated with heart failure ¹.

Most people who have heart failure take ACE inhibitors medicines. ACE inhibitors have been shown to be beneficial with increased benefit in those with more severe systolic dysfunction ¹. ACE inhibitors reduce mortality, rate of progression of heart failure, rate of sudden death or fatal myocardial infarction, and rate of hospital admission. Target dosages should be those used in the therapeutic trials. Several studies suggest that higher dosages produce greater hemodynamic and prognostic benefit than lower dosages ².

ACE inhibitors medicines treat high blood pressure, strokes, or heart attacks. They may help lower your risk for stroke or heart attack.

ACE inhibitors are also used to treat diabetes and kidney problems. This can help keep your kidneys from getting worse. If you have these problems, ask your health care provider if you should be taking ACE inhibitors.

ACE inhibitors generally don’t work as well in people of African heritage when prescribed alone, but they may be effective when combined with other blood pressure medications.

Currently, there are 10 ACE inhibitors approved for use in the United States: captopril (Capoten: 1981), enalapril (Vasotec: 1985), lisinopril (Prinivil, Zestril: 1987), benazepril (Lotensin: 1991), fosinopril (Monopril: 1991), quinapril (Accupril: 1991), ramipril (Altase: 1991), perindopril (Aceon: 1993), moexipril (Univasc: 1995), and trandolapril (Mavik: 1996).

Possible side effects include dizziness and a cough, and these medications aren’t recommended during pregnancy.

What do ACE inhibitors do

ACE inhibitors act by blocking the conversion of angiotensin 1 to angiotensin 2, the active peptide that causes the blood vessels to become narrower (vasoconstriction) and sodium retention induced by activation of the renin-angiotensin pathway, thus inhibiting an intermediate step in the renin-angiotensin pathway. ACE inhibitors have been shown to reduce morbidity or mortality in congestive heart failure, heart attack (myocardial infarction), diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Angiotensin 2 contributes to endothelial dysfunction, altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects.

Figure 1. Angiotensin 1 and Angiotensin 2 production

Figure 2. Renin angiotensin aldosterone system

ACE inhibitors mechanism of action

Ten ACE inhibitors presently approved for use in the United States work by competitive inhibition of angiotensin-converting enzymes (ACE). Captopril (Capoten) and enalapril (Vasotec) are off-patent, which makes them more economical. Enalapril is the only one available in intravenous form, which is called enalaprilat (Vasotec-IV). Drug formularies may dictate which ACE inhibitor a physician is able to prescribe because they are thought to be interchangeable. If a choice is possible, physicians should use those agents that have been proved by clinical trials to reduce morbidity and mortality for the condition being treated and work toward target dosages or clinical end points (Table 1) ².

Table 1. Comparison of ACE inhibitors

Agent	Availability	Dosages*		Considerations	Cost (generic)†
Benazepril (Lotensin)	5, 10, 20, 40 mg	Hypertension		—	$ 27
			Start: 10 mg daily
			Target: 20 to 40 mg daily
			Maximum: 80 mg daily
Captopril (Capoten)	12.5, 25, 50, 100 mg	Hypertension		Food decreases absorption, but blood levels do not correlate with blood pressure response	$59 to 88 (20 to 68)
			25 to 50 mg two or three times daily
		Congestive heart failure			$151 (100 to 118)
			Start: 6.25 to 25 mg three times daily
			Target: 50 to 100 mg three times daily
		Left ventricular dysfunction after myocardial infarction
			Start: 6.25 mg daily
			Target: 50 mg three times daily
		Diabetic nephropathy‡			$88 (58 to 68)
			25 mg three times daily
		Maximum: 450 mg daily
Enalapril (Vasotec)	2.5§, 5§, 10, 20 mg	Hypertension		—	$36 (31 to 32)
			Start: 5 mg daily
			Range: 10 to 40 mg once daily or in two divided doses
		Congestive heart failure			$101 (88 to 91)
			Start: 2.5 mg daily
			Target: 40 mg daily in two divided doses
		Asymptomatic left ventricular dysfunction			$72 (62 to 64)
			Start: 2.5 mg twice daily
			Target: 20 mg daily in two divided doses
			Maximum: 40 mg daily
Fosinopril (Monopril)	10§, 20, 40 mg	Hypertension		May cause false low serum digoxin levels Patients with impaired liver function may have elevated plasma levels	$29
			Start: 10 mg daily
			Target: 40 mg daily
		Congestive heart failure			$29
			Start: 10 mg daily
			Target: 20 to 40 mg daily
			Maximum: 80 mg daily
Lisinopril (Prinivil§, Zestril)	2.5, 5§, 10, 20, 30, 40 mg	Hypertension		—	$30
			Start: 10 mg daily
			Target: 20 to 40 mg daily
		Congestive heart failure			$30
			Start: 5 mg daily
			Target: 20 mg daily
		Acute myocardial infarction			$29
			Start: 5 mg daily for two days, then 10 mg daily for six weeks, then re-evaluate
			Maximum: 40 mg daily
Moexipril (Univasc)	7.5§, 15§ mg	Hypertension		—	$20
			Start: 7.5 mg daily one hour before meals
			Target: 7.5 to 30 mg in one dose or two divided doses one hour before meals
			Maximum: 30 mg daily
Perindopril (Aceon)	2§, 4§, 8§ mg	Hypertension		Cautious administration with gentamicin||	$30
			Start: 4 mg daily
			Target: 4 to 8 mg daily
			Maximum: 16 mg daily
Quinapril (Accupril)	5§, 10, 20, 40 mg	Hypertension		Food decreases absorption	$32
			Start: 10 mg daily
			Target: 80 mg daily
		Congestive heart failure			$64
			Start: 5 mg twice daily, titrate weekly to 20 to 40 mg in divided doses
			Maximum: 80 mg daily
Ramipril (Altace)	1.25, 2.5, 5, 10 mg	Hypertension		Patients with impaired liver function may have elevated plasma levels	$30
			Start: 2.5 mg daily
			Target: 2.5 to 20 mg daily in one dose or two divided dose
		Heart failure after myocardial infarction			$33
			Start: 2.5 mg twice daily
			Target: 5 mg twice daily
		Risk reduction of cardiovascular events in at-risk patients: 10 mg daily¶
		Maximum: 20 mg daily
Trandolapril (Mavik)	1§, 2, 4 mg	Hypertension		Food decreases absorption	$24
			Start: 1 mg daily (2 mg daily in black patients)
			Target: 2 to 4 mg per day
		Heart failure after myocardial infarction			$24
			Start: 1 mg daily
			Target: 4 mg daily
		Left ventricular dysfunction after myocardial infarction			$24
			Start: 1 mg daily
			Target: 4 mg daily
			Maximum: 8 mg daily

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Footnote: Recommendations assume reduction in dosing if hypotension occurs, if the patient is hyponatremic, or if the patient is taking a diuretic.

*—If the patient is taking a diuretic or the creatinine clearance is less than 30 to 40 mL per minute, reduce the starting dose by one half or hold the same dosage for three days before starting ACE inhibitor therapy.

†—Estimated cost to the pharmacist based on average wholesale prices for lowest target dosage level and 30 days of therapy (except where noted), in Red book.

Montvale, N.J.: Medical Economics Data, 2001. Cost to the patient will be higher, depending on prescription filling fee.

‡—Off-label use.

§—Tablet is scored.

∥—Animal studies only.

¶—Heart Outcomes Prevention Evaluation (HOPE) trial ³

[Source ¹ ]

ACE inhibitors for heart failure

ACE inhibitors are first-line therapy in patients with left ventricular systolic dysfunction, as confirmed in multiple trials and meta-analyses ¹. Decreases in dyspnea (shortness of breath), emergency department visits, hospitalizations, disease progression, death, and the need for diuretics have been proved, as well as increases in ejection fraction and exercise tolerance ⁴. All patients with systolic dysfunction, even if they are asymptomatic, should be considered for treatment with an ACE inhibitor. This consideration mandates wide use of cardiac imaging to identify the presence and type of heart failure.

Target dosages used in the clinical trials that showed reduced morbidity and mortality are listed in Table 1 above. Starting doses should be determined individually and based on clinical status (i.e., blood pressure, serum sodium level) and comorbidities (i.e., age, renal insufficiency). When the dosage is titrated up, the diuretic dosage will probably need to be decreased.

Diuretics, while essential for controlling volume overload, do not confer mortality reduction like the first-line therapies of ACE inhibition and beta blockade. The one exception to this is spironolactone (Aldactone), which has shown mortality reduction in Class III and IV heart failure ⁵.

ACE inhibitors other uses

High blood pressure

Guidelines for the pharmacologic management of hypertension issued by the World Health Organization and the International Society of Hypertension place ACE inhibitors with diuretics and beta blockers as first-line therapy. The Sixth Report of the Joint National Committee (1997) removed ACE inhibitors as first-line therapy because they had not been shown in clinical trials to reduce all-cause mortality as had diuretics and beta blockers ⁶.

In 1999, the Captopril Prevention Project19 randomized trial compared the three agents. Captopril and conventional treatment did not differ in cardiovascular end points overall; all events except for stroke were lower in the captopril group. Improper randomization has been cited as a possible reason for increased stroke rates ⁷. The results of the Swedish Trial in Old Patients with Hypertension-2 study ⁸ showed equal outcomes between the three drug classes.

ACE inhibitors have a side effect profile that may place them above thiazides and beta blockers. They do not affect lipid, calcium, or uric acid levels, and are less likely to cause erectile dysfunction than other antihypertensive agents ⁹. There is evidence from several trials that fasting glucose levels, glycosylated hemoglobin levels, and rates of new diagnoses of type 2 diabetes are lower in patients randomized to ACE inhibitor therapy than in those taking placebo. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial will evaluate prospectively whether this ACE inhibitor prevents diabetes ¹⁰. Treatment goals for blood pressure include 140/90 mm Hg (or less) in patients without comorbidities, 130/80 mm Hg (or less) in patients with diabetes (2001 American Diabetes Association [ADA] Guidelines) and 125/75 mm Hg (or less) in those with end organ damage.

Heart attack

In 1996 and 1999, the American Heart Association advocated the administration of an ACE inhibitor to all patients presenting with acute anterior myocardial infarction and/or clinical heart failure in the absence of hypotension or other contraindications. The guidelines recommend starting within the first 24 hours and continuing therapy indefinitely for anterior infarctions and left ventricular dysfunction ¹¹.

A pragmatic approach is to give ACE inhibitors to all patients with acute myocardial infarction who are clinically stable and to continue that therapy indefinitely in those with anterior myocardial infarction or systolic dysfunction. Others should be re-evaluated for continuation of therapy at four to six weeks ¹².

Diabetes

ACE inhibitors slow the onset of diabetic nephropathy in patients with microalbuminuria and type 1 diabetes ¹³. Normotensive, nonalbuminuric diabetics also have a slower onset of nephropathy; however, the American Diabetes Association [ADA] currently does not recommend ACE inhibitors as primary prevention in these patients, and there is no evidence that this practice affects outcomes ¹⁴.

In the MICRO-HOPE trial, patients with diabetes and one cardiac risk factor were studied; subjects were titrated to 10 mg a day of ramipril or placebo. The study was stopped prematurely because of the significant decrease in combined primary outcomes in patients taking ramipril. Total cardiovascular end points were reduced by 25 percent; these included myocardial infarction (22 percent), cerebrovascular accident (33 percent), cerebrovascular death (37 percent), total mortality (24 percent), revascularization (17 percent) and overt nephropathy (24 percent) ³. Ramipril was approved by the U.S. Food and Drug Administration in November 2000 for primary prevention of cardiovascular events in at-risk patients.

A meta-analysis of four trials including 1,123 patients with type 2 diabetes showed improved outcomes in those taking ACE inhibitors as opposed to other antihypertensive agents ¹⁵. The authors noted in their conclusions that atenolol (Tenormin) may be equivalent to captopril and that further studies are needed in regard to these two agents ¹⁵. It will be rare for a patient with diabetes not to meet the criteria for ACE inhibition in the year 2002.

Renal insufficiency

The Kidney Disease: Improving Global Outcomes guideline ¹⁶ recommends ACE inhibitors or angiotensin receptor blockers (ARBs) for adults with chronic kidney disease (CKD) with or without diabetes who have a urinary albumin excretion rate of 30 to 300 mg per 24 hours and in whom blood pressure medications are indicated. The guideline recommends a blood pressure goal of 130/80 mm Hg or less in these patients ¹⁶. The American Diabetes Association recommends ACE inhibitors or angiotensin receptor blockers (ARBs) for nonpregnant patients with diabetes and microalbuminuria, but it makes no specific recommendations for blood pressure beyond its standard goals ¹⁷. The National Kidney Foundation recommends an ACE inhibitor or angiotensin receptor blocker (ARB) in normotensive patients with diabetes and an albumin level greater than 30 mg per g who are at high risk of chronic kidney disease (CKD) or progression ¹⁸. The National Kidney Foundation guideline does not provide recommendations for normotensive patients without diabetes.

ACE inhibitors in nondiabetic patients with nephropathy are more effective than other antihypertensives at slowing progression to end-stage renal disease ¹⁹. The Ramipril Efficacy in Nephropathy (REIN) study ¹⁹ (treatment goal: diastolic blood pressure less than 90 mm Hg) and the Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency (AIPRI) study ¹⁹ (treatment: benazepril, in a dosage of 10 mg daily) demonstrated improved renal survival. Even in normotensive patients with nondiabetic proteinuria, the EUCLID study group demonstrated slowing of progression of renal disease ²⁰. Unless contraindicated, ACE inhibitors should be used in patients with renal insufficiency of any cause with a goal blood pressure of 125/75 mm Hg in those with more than 1,000 mg per 24 hours (1 g per 24 hours) proteinuria ¹⁹.

ACE inhibitors also reduce the risk of progression to macroalbuminuria in normotensive patients with microalbuminuria and type 1 diabetes mellitus ²¹. ACE inhibitors and angiotensin receptor blockers (ARBs) reduce the risk of progression to macroalbuminuria in normotensive patients with microalbuminuria and type 2 diabetes ²¹. ACE inhibitors and angiotensin receptor blockers (ARBs) do not reliably affect serum creatinine levels. Recommendations are not available for normotensive patients without diabetes who have microalbuminuria ²¹.

ACE inhibitors contraindications

ACE inhibitors are contraindicated in patients who are hypersensitive to any other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor). Angioneurotic edema, which occurs in 0.1 to 0.2 percent of patients, usually develops within the first week of therapy but can occur at any time ¹. This potentially life-threatening adverse effect also occurs with angiotensin 2 receptor blockers but to a lesser extent ⁹. Any patient with a history of angioneurotic edema, whether related to an ACE inhibitor, angiotensin receptor blockers, or another cause, should not be given an ACE inhibitor. Other contraindications include pregnancy, renal artery stenosis, and previous allergy to ACE inhibitors.

ACE inhibitors side effects

Side effects from ACE inhibitors are rare.

You may have a dry cough. This may go away after a while. If it does not, tell your provider. Sometimes reducing your dose helps. But sometimes, your provider will switch you to a different medicine. DO NOT lower your dose without talking with your provider first.

You may feel dizzy or lightheaded when you start taking these medicines, or if your provider increases your dose. Standing up slowly from a chair or your bed may help. If you have a fainting spell, call your provider right away.

Other side effects include:

• Headache
• Fatigue
• Loss of appetite
• Upset stomach
• Diarrhea
• Numbness
• Fever
• Skin rashes or blisters
• Joint pain

If your tongue or lips swell, call your provider right away, or go to the emergency room. You may be having a serious allergic reaction to the medicine. This is very rare.

See your doctor if you are having any of the side effects listed above. Also see your doctor if you are having any other unusual symptoms.

Angioedema

Presumably because ACE inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors may be subject to a variety of adverse reactions, some of them serious.

Angioedema is swelling underneath the skin. It’s usually a reaction to a trigger, such as a medication ACE inhibitors for high blood pressure – this is known as “drug-induced angioedema”  or something you’re allergic to. Angioedema occurring with ACE inhibitors was first reported in 1980 ²² and may account for 40% of angioedema presentations to hospital ²³. An incidence of 0.68% over six months has been reported, so annual incidence may be greater than 1% ²⁴. Rates in people of African origin are even higher, at 1.62% over six months, so may be over 3% annually ²⁴.

Angioedema isn’t normally serious, but it can be a recurring problem for some people and can very occasionally be life-threatening if it affects breathing.

Treatment can usually help keep the swelling under control.

Symptoms of angioedema

The swelling most often affects the:

• hands
• feet
• area around the eyes
• lips and tongue
• genitals

Many people also have a raised, itchy rash called urticaria (hives).

In more serious cases, angioedema can also cause breathing difficulties, tummy (abdominal) pain and dizziness.

Treatments for angioedema

The swelling will usually get better by itself in a few days, but there are treatments that can help it settle faster and reduce the risk of it happening again.

The treatments recommended depend on the type of angioedema you have. For example:

• allergic and idiopathic angioedema are usually treated with antihistamines or occasionally steroid medication to reduce the swelling
• drug-induced angioedema will usually resolve if you change to a different medication – your doctor will advise you about this. This is usually all that needs to be done. Tell your doctor if your symptoms continue or come back after switching medication.
• hereditary angioedema can’t be cured, but medications can help prevent swelling and quickly treat swelling when it occurs

Angioedema can usually be treated at home, although treatment in hospital may be necessary in serious cases. If you have a particularly serious allergy, you may be given adrenaline auto-injectors to use if you experience a severe allergic reaction (anaphylaxis). There are several types of auto-injector, which are used in slightly different ways.

ACE inhibitors hyperkalemia

Hyperkalemia (high blood potassium) does not usually occur in patients with normal kidney function, but those who have renal insufficiency or diabetes. Patients who are taking potassium, salt substitutes, potassium-sparing diuretics, beta blockers, and NSAIDs (nonsteroidal anti-inflammatory drugs) are susceptible. Most clinicians discontinue potassium and potassium-sparing diuretics when starting patients on ACE inhibitor therapy. Potassium levels should be monitored carefully in patients at risk. Up to 5 percent of patients experience serum potassium levels greater than 5.7 mEq per L (5.7 mmol per L), and if levels remain higher than that on repeat testing, ACE inhibitor therapy should be discontinued.

Cough

Cough occurs in 5 to 20 percent of patients. It is not dose- or brand-related, is more frequent in women than men, and is more frequent in blacks than whites. It develops within one week to six months and resolves within four days of cessation. Physicians should be aware of a confounding congestive heart failure cough and remember that changing to another formulation sometimes helps. Cough is not a reason to discontinue treatment unless the patient cannot tolerate it. A few studies have looked at the use of nonsteroidal anti-inflammatory drugs (NSAIDs), nifedipine (Procardia), cromolyn (Intal), or nebulized bupivacaine (Marcaine) for managing cough, but further studies are needed ²⁵.

Renal insufficiency

In patients with renal insufficiency, no creatinine level is an absolute contraindication to ACE inhibitor therapy. ACE inhibitors are not nephrotoxic. Baseline serum creatinine levels of up to 3.0 mg per dL (27 μmol per L) are generally considered safe. The manufacturers make recommendations for initiating treatment and suggest titrating the dosage slowly. An increase of 20 percent in the serum creatinine level is not uncommon and is not a cause for discontinuing the medication. For any higher increase, the family physician should consider a nephrologist. During the first four weeks of treatment, serum potassium and creatinine levels should be monitored closely.

Hypotension

Hypotension can occur in patients with volume depletion or hyponatremia (sodium <130 mEq per L [<130 mmol per L]), those taking vasodilators, those in acute congestive heart failure, and those on dialysis. The underlying problem should be corrected, starting with a low dosage and titrating slowly. Any patient with a high plasma renin level is vulnerable to first-dose hypotension, but this effect is transient and unpredictable ²⁶. Hypotension is not a reason to discontinue ACE inhibition. Patients should be rechallenged at one half the previous dosage. If they are taking a diuretic, the dosage should be reduced or held for three days before reattempting therapy.

Other Considerations

Neutropenia occurs rarely and tends to occur in patients with renal impairment and concurrent collagen vascular disease. Lithium toxicity is also rare, but lithium levels should be monitored if the patient is on concurrent lithium therapy. Aortic stenosis and hypertropic cardiomyopathies are considered relative contraindications because of the risk of hypotension from fixed outlet obstruction.

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