Direct Renin Inhibitor Aliskiren
Aldosterone Antagonist Eplerenone
Angiotensin I Inactive product
Blocked by ACE inhibitors
Bradykinin Angiotensin II
ACE Kinase
II
Vasodilation
Potassium retention Fetal injury Angiotensin II
results in
•
Blood volume Cardiac and vascular remodeling
Bradykinin results in Vasodilation Cough Angioedema (rarely)
•
•
•
•
•
•
•
Fig. 44.2 ■ Overview of ACE inhibitor actions and pharma- cologic effects.
Angiotensin-converting enzyme (ACE) and kinase II are two names for the same enzyme. When angiotensin II is the substrate, we call the enzyme ACE; when bradykinin is the substrate, we call it kinase II. Inhibition of this enzyme decreases production of angiotensin II (thereby reducing angiotensin II levels) and decreases breakdown of bradykinin (thereby increasing brady- kinin levels).
Therapeutic Uses
When the ACE inhibitors were introduced, their only indication was hypertension. Today, they are also used for heart failure, acute MI, left ventricular (LV) dysfunction, and diabetic and nondiabetic nephropathy. In addition, they can help prevent MI, stroke, and death in patients at high risk for cardiovascular events. It should be noted that no single ACE inhibitor is approved for all of these conditions (Table 44.1). However, given that all ACE inhibitors are very similar, it seems likely that all may produce similar benefits.
Hypertension. All ACE inhibitors are approved for hypertension. These drugs are especially effective against malignant hypertension and hypertension secondary to renal arterial stenosis. They are also useful against essential hyperten- sion of mild to moderate intensity—although maximal benefits may take several weeks to develop.
In patients with essential hypertension, the mechanism underlying blood pressure reduction is not fully understood.
Initial responses are proportional to circulating angiotensin II levels and are clearly related to reduced formation of that compound. (By lowering angiotensin II levels, ACE inhibitors dilate blood vessels and reduce blood volume; both actions help lower blood pressure.) However, with prolonged therapy, blood pressure often undergoes additional decline. During this phase, there is no relationship between reductions in blood bradykinin causes vasodilation (secondary to increased produc-
tion of prostaglandins and nitric oxide) and can also promote cough and angioedema.
Pharmacokinetics
Regarding pharmacokinetics, the following generalizations apply:
• Nearly all ACE inhibitors are administered orally. The only exception is enalaprilat (the active form of enalapril), which is given IV.
• Except for captopril and moexipril, all oral ACE inhibitors can be administered with food.
• With the exception of captopril, all ACE inhibitors have prolonged half-lives, and hence can be administered just once or twice a day. Captopril is administered 2 or 3 times a day.
• With the exception of lisinopril, all ACE inhibitors are prodrugs that must undergo conversion to their active form in the small intestine and liver. Lisinopril is active as given.
• All ACE inhibitors are excreted by the kidneys. As a result, nearly all can accumulate to dangerous levels in patients with kidney disease, and hence dosages must be reduced in these patients. Only one agent—fosinopril—
does not require a dosage reduction.
Generic Name Brand Name Approved Indications Starting Dosagea Usual Maintenance Dosagea
Benazepril Lotensin Hypertension 10 mg once/day 20–80 mg/day in 1 or 2 doses
Captopril Capoten Hypertension 25 mg 2 or 3 times/day 25–50 mg 2 or 3 times/day
Heart failure 6.25–12.5 mg 3 times/day 50 mg 3 times/day
LVD after MI 12.5 mg 3 times/day 50 mg 3 times/day
Diabetic nephropathy 25 mg 3 times/day 25 mg 3 times/day
Enalapril Vasotec,
Epaned Hypertension 2.5–5 mg once/day 10–40 mg/day in 1 or 2 doses
Heart failure 2.5 mg twice/day 10–20 mg twice/day
Asymptomatic LVD 2.5 mg twice/day 10 mg twice/day
Enalaprilat Generic only Hypertension 1.25 mg every 6 hr Not used for maintenance
Fosinopril Generic only Hypertension 10 mg once/day 20–40 mg/day in 1 or 2 doses
Heart failure 5–10 mg once/day 20–40 mg once/day
Lisinopril Prinivil, Zestril,
Qbrelis Hypertension 10 mg once/day 10–40 mg once/day
Heart failure 2.5–5 mg once/day 20–40 mg once/day
Acute MI 5 mg once/day 10 mg once/day
Moexipril Generic only Hypertension 7.5 mg once/day 7.5–30 mg/day in 1 or 2 doses
Perindopril Aceon,
Coversyl Hypertension 4 mg once/day 4–8 mg/day in 1 or 2 doses
Stable CAD 4 mg once/day 8 mg once/day
Quinapril Accupril Hypertension 1020 mg/day 20–80 mg/day in 1 or 2 doses
Heart failure 5 mg twice/day 20–40 mg twice/day
Ramipril Altace Hypertension 2.5 mg once/day 2.5–20 mg/day in 1 or 2 doses
Heart failure after MI 1.25–2.5 mg twice/day 5 mg twice/day Prevention of MI, stroke, and death
in people at high risk for CVD 2.5 mg/day for 1 wk 10 mg once/day
Trandolapril Mavik Hypertension 1 mg once/day 2–4 mg once/day
Heart failure after MI 1 mg once/day 4 mg once/day
LVD after MI 1 mg once/day 4 mg once/day
TABLE 44.1 ■ ACE Inhibitors: Approved Indications and Adult Dosages
aFor all ACE inhibitors except fosinopril, dosage must be reduced in patients with significant renal impairment.
CAD, Coronary artery disease; CVD, cardiovascular disease; LVD, left ventricular dysfunction; MI, myocardial infarction.
pressure by reducing levels of angiotensin II, a compound that can raise filtration pressure by two mechanisms. First, angio- tensin II raises systemic blood pressure, which raises pressure in the afferent arteriole of the glomerulus (Fig. 44.3). Second, it constricts the efferent arteriole, thereby generating back- pressure in the glomerulus. The resultant increase in filtration pressure promotes injury. By reducing levels of angiotensin II, ACE inhibitors lower glomerular filtration pressure and thereby slow development of renal injury.
At this time, the only ACE inhibitor approved for nephropa- thy is captopril. However, the American Diabetes Association considers benefits in diabetic nephropathy to be a class effect, and hence recommends choosing an ACE inhibitor based on its cost and likelihood of patient adherence.
Can ACE inhibitors be used for primary prevention of diabetic nephropathy? No. Although use of these agents can slow progression of kidney disease, they ultimately do not prevent it. This conclusion is based on multiple small studies, as well as the Renin-Angiotensin System Study (RASS), which evaluated the effects of an ACE inhibitor (enalapril [Vasotec]) and an ARB (losartan [Cozaar]) in patients with type 1 diabetes who did not have hypertension or any signs of early kidney disease. Both drugs failed to protect the kidney: Compared with patients receiving placebo, those receiving enalapril or losartan developed the same degree of microalbuminuria (an early sign of kidney damage), the same decline in kidney function, and the same changes in glomerular structure (as shown by microscopic analysis of kidney biopsy samples).
Hence, although ACE inhibitors may slow progression of established nephropathy, they do not protect against kidney damage.
Prevention of MI, Stroke, and Death in Patients at High Cardiovascular Risk. One ACE inhibitor (ramipril [Altace]) is approved for reducing the risk of MI, stroke, and death from cardiovascular causes in patients at high risk for a major cardiovascular event—high risk being defined by (1) a history of stroke, coronary artery disease, peripheral vascular disease, or diabetes, combined with (2) at least one other risk factor, such as hypertension, high LDL cholesterol, low HDL cholesterol, or cigarette smoking. Ramipril was approved for this use based on results of the Heart Outcomes Prevention Evaluation (HOPE) trial, a large study in which patients at high cardiovascular risk took either ramipril (10 mg/day) or pressure and reductions in circulating angiotensin II. It may
be that the delayed response is due to reductions in local angiotensin II levels—reductions that would not be revealed by measuring angiotensin II in the blood.
ACE inhibitors offer several advantages over most other antihypertensive drugs. In contrast to the sympatholytic agents, ACE inhibitors do not interfere with cardiovascular reflexes.
Hence, exercise capacity is not impaired and orthostatic hypotension is minimal. In addition, these drugs can be used safely in patients with bronchial asthma, a condition that precludes the use of beta2-adrenergic antagonists. ACE inhibitors do not promote hypokalemia, hyperuricemia, or hyperglycemia—
side effects seen with thiazide diuretics. Furthermore, they do not induce lethargy, weakness, or sexual dysfunction—responses that are common with other antihypertensive agents. Most importantly, ACE inhibitors reduce the risk of cardiovascular mortality caused by hypertension. The only other drugs proved to reduce hypertension-associated mortality are beta blockers and diuretics (see Chapter 47).
Heart Failure. ACE inhibitors produce multiple benefits in heart failure. By lowering arteriolar tone, these drugs improve regional blood flow, and, by reducing cardiac afterload, they increase cardiac output. By causing venous dilation, they reduce pulmonary congestion and peripheral edema. By dilating blood vessels in the kidney, they increase renal blood flow and thereby promote excretion of sodium and water. This loss of fluid has two beneficial effects: (1) it helps reduce edema, and (2) by lowering blood volume, it decreases venous return to the heart and thereby reduces right-heart workload. Lastly, by suppressing aldosterone and reducing local production of angiotensin II in the heart, ACE inhibitors may prevent or reverse pathologic changes in cardiac structure. Although only seven ACE inhibi- tors are approved for heart failure (see Table 44.1), both the American Heart Association and the American College of Cardiology have concluded that the ability to improve symptoms and prolong survival is a class effect. The use of ACE inhibitors in heart failure is discussed further in Chapter 48.
Myocardial Infarction. ACE inhibitors can reduce mortality following acute MI (heart attack). In addition, they decrease the chance of developing overt heart failure. Treatment should begin as soon as possible after infarction and should continue for at least 6 weeks. In patients who develop overt heart failure, treatment should continue long term. As for patients who do not develop heart failure, there are no data to indicate whether or not continued treatment would be beneficial. At this time, only three ACE inhibitors—captopril, lisinopril, and trandolapril—are approved for patients with MI.
Diabetic and Nondiabetic Nephropathy. ACE inhibitors can benefit patients with diabetic nephropathy, the leading cause of end-stage renal disease in the United States. In patients with overt nephropathy, as indicated by proteinuria of more than 500 mg/day, ACE inhibitors can slow progression of renal disease. In patients with less advanced nephropathy (30 to 300 mg proteinuria/day), ACE inhibitors can delay onset of overt nephropathy. These benefits were first demonstrated in patients with type 1 diabetes (insulin-dependent diabetes mellitus) and were later demonstrated in patients with type 2 diabetes (non–insulin-dependent diabetes mellitus). More recently, ACE inhibitors have been shown to provide similar benefits in patients with nephropathy unrelated to diabetes.
The principal protective mechanism appears to be reduction of glomerular filtration pressure. ACE inhibitors lower filtration
Afferent arteriole
Efferent arteriole
Glomerulus Bowman’s capsule Fig. 44.3 ■ Elevation of glomerular filtration pressure by angiotensin II.
Angiotensin II increases filtration pressure by (1) increasing pres- sure in the afferent arteriole (secondary to increasing systemic arterial pressure) and (2) constricting the efferent arteriole, thereby generating back-pressure in the glomerulus.
should be instructed to avoid potassium supplements and potassium-containing salt substitutes unless they are prescribed.
Renal Failure. ACE inhibitors can cause severe renal insufficiency in patients with bilateral renal artery stenosis or stenosis in the artery to a single remaining kidney. In patients with renal artery stenosis, the kidneys release large amounts of renin. The resulting high levels of angiotensin II serve to maintain glomerular filtration by two mechanisms: elevation of blood pressure and constriction of efferent glomerular arterioles (see Fig. 44.3). When ACE is inhibited, causing angiotensin II levels to fall, the mechanisms that had been supporting glomerular filtration fail, causing urine production to drop precipitously. Not surprisingly, ACE inhibitors are contraindicated for patients with bilateral renal artery stenosis (or stenosis in the artery to a single remaining kidney).
Fetal Injury. For a long time, we have known that use of ACE inhibitors during the second and third trimesters of pregnancy can injure the developing fetus. Specific effects include hypotension, hyperkalemia, skull hypoplasia, pulmonary hypoplasia, anuria, renal failure (reversible and irreversible), and death. Women who become pregnant while using ACE inhibitors should discontinue treatment as soon as possible.
Infants who have been exposed to ACE inhibitors during the second or third trimester should be closely monitored for hypotension, oliguria, and hyperkalemia.
Are ACE inhibitors safe early in pregnancy? Possibly. Even though an article in the New England Journal of Medicine reported that among 209 children exposed to ACE inhibitors during the first trimester, 18 (8.7%) had major congenital malformations, compared with 3.2% of controls, these data contrast with animal studies, which suggest that such malforma- tions are not likely. Furthermore, no mechanism by which ACE inhibitors might disrupt early embryogenesis is known.
It is now thought that the malformations attributed to ACE inhibitors are more related to hypertension in pregnancy, not the drug itself. As there is lack of complete data, however, the U.S. Food and Drug Administration (FDA) still classifies ACE inhibitors in Pregnancy Risk Category D,a which indicates they should be avoided in pregnancy.
Angioedema. Angioedema is a potentially fatal reaction that develops in up to 1% of patients. Symptoms, which result from increased capillary permeability, include giant wheals and edema of the tongue, glottis, lips, eyes, and pharynx. Severe reactions should be treated with subcutaneous epinephrine. If angioedema develops, ACE inhibitors should be discontinued and never used again. Angioedema is caused by accumulation of bradykinin secondary to inhibition of kinase II.
placebo. Follow-up time was 5 years. The combined endpoint of MI, stroke, or death from cardiovascular causes was sig- nificantly lower in the ramipril group (14% vs. 18%)—a 22%
reduction in risk. Possible mechanisms underlying benefits include reduced vascular resistance and protection of the heart, blood vessels, and kidneys from the damage that angiotensin II and aldosterone can cause over time.
Like ramipril, perindopril [Aceon, Coversyl ] can reduce morbidity and mortality in patients at risk for major cardio- vascular events. However, the drug is not yet approved for this use. Benefits were demonstrated in the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA). Patients in EUROPA were at lower risk than those in HOPE.
Can ACE inhibitors other than ramipril and perindopril also reduce cardiovascular risk? Possibly. However, at this time there is insufficient evidence to say for sure.
Diabetic Retinopathy. The RASS trial showed that at least one ACE inhibitor—enalapril—can reduce the risk of diabetic retinopathy in some patients. Specifically, in patients with type 1 diabetes who do not have hypertension, nephropathy, or established retinopathy, enalapril prevented or slowed development of retinal change. However, in patients with type 1 diabetes and established retinopathy, enalapril had no benefit.
In patients with type 2 diabetes, enalapril had no benefit, regardless of retinopathy status.
Adverse Effects
ACE inhibitors are generally well tolerated. Some adverse effects (e.g., first-dose hypotension, hyperkalemia) are due to a reduction in angiotensin II, whereas others (cough, angio- edema) are due to elevation of bradykinin.
First-Dose Hypotension. A precipitous drop in blood pressure may occur following the first dose of an ACE inhibitor.
This reaction is caused by widespread vasodilation secondary to abrupt lowering of angiotensin II levels. First-dose hypotension is most likely in patients with severe hypertension, in patients taking diuretics, and in patients who are sodium depleted or volume depleted. To minimize the first-dose effect, initial doses should be low. Also, diuretics should be temporarily discontinued, starting 2 to 3 days before beginning an ACE inhibitor. Blood pressure should be monitored for several hours following the first dose of an ACE inhibitor. If hypotension develops, the patient should assume a supine position. If neces- sary, blood pressure can be raised with an infusion of normal saline.
Cough. All ACE inhibitors can cause persistent dry, irritat- ing, nonproductive cough. Severity can range from a scratchy throat to severe hacking cough. The underlying cause is accumulation of bradykinin secondary to inhibition of kinase II (another name for ACE). Cough occurs in about 10% of patients and is the most common reason for discontinuing therapy. Factors that increase the risk of cough include advanced age, female sex, and Asian ancestry. Cough begins to subside 3 days after discontinuing an ACE inhibitor and is gone within 10 days.
Hyperkalemia. Inhibition of aldosterone release (secondary to inhibition of angiotensin II production) can cause potassium retention by the kidney. As a rule, significant potassium accumu- lation is limited to patients taking potassium supplements, salt substitutes (which contain potassium), or a potassium-sparing diuretic. For most other patients, hyperkalemia is rare. Patients
aAs of 2020, the FDA will no longer use Pregnancy Risk Categories. Please refer to Chapter 9 for more information.
Safety Alert
ACE INHIBITORS
ACE inhibitors can cause angioedema, a potentially life- threatening reaction. If patients report edema of the tongue, lips, or eyes, emergency care should be sought immediately, and the patient must never take ACE inhibitors again.
• Enalaprilat, the active form of enalapril, is available in solution (1.25 mg/mL) for IV therapy of severe hyper- tension. Enalaprilat is the only ACE inhibitor that is given IV.
• Fosinopril is available alone (10-, 20-, and 40-mg tablets) as Monopril, and combined with hydrochlorothiazide.
• Lisinopril is available alone (2.5-, 5-, 10-, 20-, 30-, and 40-mg tablets) as Prinivil and Zestril, as a 1 mg/
mL oral solution sold as Qbrelis, and combined with hydrochlorothiazide.
• Moexipril is available alone (7.5- and 15-mg tablets) and combined with hydrochlorothiazide.
• Perindopril is available alone (2-, 4-, and 8-mg tablets) as Aceon and Coversyl , in combination with amlodipine (3.5/2.5-, 7/5-, and 14/10-mg tablets) sold as Prestalia, and combined with indapamide (2/0.625, 4/1.25, and 8/2.5 mg) as Coversyl Plus .
• Quinapril is available alone (5-, 10-, 20-, and 40-mg tablets) as Accupril, and combined with hydrochloro- thiazide as Accuretic.
• Ramipril is available alone (1.25-, 2.5-, 5-, and 10-mg capsules) as Altace, and combined with hydrochloro- thiazide (2.5/12.5, 5/12.5, 10/12.5, 5/25, 10/25 mg) as Altace HCT .
• Trandolapril is available alone (1-, 2-, and 4-mg tablets) as Mavik, and combined with verapamil as Tarka. The drug is not available in combination with hydrochlorothiazide.