VA Class:CV800

AHFS Class:

• Angiotensin-Converting Enzyme Inhibitors 24:32.04

Generic Name(s):

• Enalaprilat

• Enalapril Maleate

• Enalaprilat

• Enalapril Maleate and Hydrochlorothiazide

Chemical Name:

• ( S )-1-[ N -[1-(Ethoxycarbonyl)-3-phenylpropyl]-l-alanyl]-l-proline( Z )-2-butenedioate (1:1)

• ( S )-1-[ N -(1-Carboxy-3-phenylpropy l)-l-alanyl]-l-proline

Molecular Formula:

• C₂₀H₂₈N₂O₅•C₄H₄O₄C₁₈H₂₄N₂O₅

Enalaprilat and enalapril are angiotensin-converting enzyme (ACE) inhibitors;1,2,3,4,5,6,7,8,9,10,277 enalapril, the ethylester of enalaprilat, is a prodrug and has little pharmacologic activity until hydrolyzed in the liver to enalaprilat.1,2,4,5,6,7,8,16,17,20

Hypertension

Enalapril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1,2,4,5,9,54,110,116,119,120,122,123,124,127,128,129,130,131,140,142,143,144,155,186,203,220,1200 Enalaprilat is used in the management of hypertension when oral therapy is not practical.277,285,286 Because captopril, another angiotensin-converting enzyme (ACE) inhibitor, may cause serious adverse effects (e.g., neutropenia, agranulocytosis), particularly in patients with renal impairment (especially those with collagen vascular disease)1,208,209,210 or in patients receiving immunosuppressive therapy,226,231 the possibility that similar adverse effects may occur with enalapril or enalaprilat should be considered since current experience is insufficient to rule out such risk.1,277 Enalapril has occasionally been used without recurrence of adverse effect in patients who developed intolerable adverse effects (i.e., rash, taste disturbances) during captopril therapy.115,145,211 Further studies are needed to evaluate the possible risks associated with the long-term use of enalapril.1,206 The hypotensive efficacy of enalapril in hypertensive patients is similar to that of captopril108,141,142,143,144,155 or β-adrenergic blocking agents (β-blockers).9,134,135,136,137,139,140,154,156,247,248,249,250 Enalapril may have a greater effect on systolic blood pressure at rest (but not with exercise)231 than do β-blockers,154 but additional study is necessary to establish the comparative efficacy of enalapril and β-blockers.138,231

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics); data from clinical outcome trials indicate that lowering blood pressure with any of these drug classes can reduce the complications of hypertension and provide similar cardiovascular protection.501,502,503,504,1200 However, recommendations for initial drug selection and use in specific patient populations may vary across these expert guidelines.501,502,503,504,1200 This variability is due, in part, to differences in the guideline development process and the types of studies (e.g., randomized controlled studies only versus a range of studies with different study designs) included in the evidence reviews.501,502,503,515,1200 Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501,502,503,504,515,1200,1201 Because many patients eventually will need drugs from 2 or more antihypertensive classes, experts generally state that the emphasis should be placed on achieving appropriate blood pressure control rather than on identifying a preferred drug to achieve that control.424,447,501,502,523,1202

Disease Overview

Worldwide, hypertension is the most common modifiable risk factor for cardiovascular events and mortality.1205 The lifetime risk of developing hypertension in the US exceeds 80%, with higher rates observed among African Americans and Hispanics compared with whites or Asians.1200 The systolic blood pressure and diastolic blood pressure values defined as hypertension (see Blood Pressure Classification under Uses: Hypertension) in a 2017 multidisciplinary guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations (subsequently referred to as the 2017 ACC/AHA hypertension guidelines in this monograph)1200 are lower than those defined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines,500 which results in an increase of approximately 14% in the prevalence of hypertension in the US.1200,1222 However, this change in definition results in only a 2% increase in the percentage of patients requiring antihypertensive drug therapy because nonpharmacologic treatment is recommended for most adults now classified by the 2017 ACC/AHA hypertension guideline as hypertensive who would not meet the JNC 7 definition of hypertension.500,1200,1222 Among US adults receiving antihypertensive drugs, approximately 53% have inadequately controlled blood pressure according to current ACC/AHA treatment goals.1206

Cardiovascular and Renal Sequelae

The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage.502,1200 The relationship between blood pressure and cardiovascular disease is continuous, consistent, and independent of other risk factors.1200 It is important that very high blood pressure be managed promptly to reduce the risk of target organ damage.1200 The higher the blood pressure, the more likely the development of myocardial infarction (MI), heart failure, stroke, and renal disease.502,1200 For adults 40-70 years of age, each 20-mm Hg increment in systolic blood pressure or 10-mm Hg increment in diastolic blood pressure doubles the risk of developing cardiovascular disease across the entire blood pressure range of 115/75 to 185/115 mm Hg.1200,1238 For those older than 50 years of age, systolic blood pressure is a much more important risk factor for developing cardiovascular disease than is diastolic blood pressure.502 The rapidity with which treatment is required depends on the patient's clinical presentation (presence of new or worsening target organ damage) and the presence or absence of cardiovascular complications; the 2017 ACC/AHA hypertension guideline states that treatment of very high blood pressure should be initiated within 1 week.1200

Blood Pressure Classification

Accurate blood pressure measurement is essential for the proper diagnosis and management of hypertension.1200,1225,1226 Error in measuring blood pressure is a major cause of inadequate blood pressure control and may lead to overtreatment.1225,1226 Because a patient's blood pressure may vary in an unpredictable fashion, a single blood pressure measurement is not sufficient for clinical decision-making.1200 An average of 2 or 3 blood pressure measurements obtained on 2-3 separate occasions using proper technique should be used to minimize random error and provide a more accurate blood pressure reading.1200 Out-of-office blood pressure measurements may be useful for confirming and managing hypertension.1200 The 2017 ACC/AHA hypertension guideline document (available on the ACC and AHA websites) should be consulted for key steps on properly measuring blood pressure.1200

According to the 2017 ACC/AHA hypertension guideline, blood pressure in adults is classified into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.1200 (See Table 1.) The 2017 ACC/AHA hypertension guideline lowers the blood pressure threshold used to define hypertension in the US; previous hypertension guidelines (JNC 7) considered adults with systolic blood pressure of 120-139 mm Hg or diastolic blood pressure of 80-89 mm Hg to have prehypertension, those with systolic blood pressure of 140-159 mm Hg or diastolic blood pressure of 90-99 mm Hg to have stage 1 hypertension, and those with systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 100 mm Hg or higher to have stage 2 hypertension.500,1200 The blood pressure definitions in the 2017 ACC/AHA hypertension guideline are based upon data from studies evaluating the association between systolic blood pressure/diastolic blood pressure and cardiovascular risk and the benefits of blood pressure reduction.1200 Individuals with systolic blood pressure and diastolic blood pressure in 2 different categories should be designated as being in the higher blood pressure category.1200

The blood pressure thresholds used to define hypertension, when to initiate drug therapy, and the ideal target blood pressure values remain controversial.505,506,507,508,515,523,530,1200,1201,1207,1209,1222,1223,1229 The 2017 ACC/AHA hypertension guideline recommends a blood pressure goal of less than 130/80 mm Hg in all adults who have confirmed hypertension and known cardiovascular disease or a 10-year atherosclerotic cardiovascular disease (ASCVD) event risk of 10% or higher; the ACC/AHA guideline also states that this blood pressure goal is reasonable to attempt to achieve in adults with confirmed hypertension who do not have increased cardiovascular risk.1200 The lower blood pressure values used to define hypertension and the lower target blood pressure goals outlined in the 2017 ACC/AHA hypertension guideline are based on clinical studies demonstrating a substantial reduction in the composite end point of major cardiovascular disease events and the combination of fatal and nonfatal stroke when a lower systolic blood pressure/diastolic blood pressure value (i.e., 130/80 mm Hg) was used to define hypertension.521,1210,1223 These lower target blood pressure goals also are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210 A linear relationship has been demonstrated between cardiovascular risk and blood pressure even at low systolic blood pressures (e.g, 120-124 mm Hg).1200,1207,1230 The 2017 ACC/AHA hypertension guideline recommends estimating a patient's ASCVD risk using the ACC/AHA Pooled Cohort equations (available online at [Web]), which are based on a variety of factors including age, race, gender, cholesterol levels, statin use, blood pressure, treatment for hypertension, history of diabetes mellitus, smoking status, and aspirin use.1200,1202 While the 2017 ACC/AHA hypertension guideline has lowered the threshold for diagnosing hypertension in adults, the threshold for initiating drug therapy has only been lowered for those patients who are at high risk of cardiovascular disease.1200,1222 Clinicians who support the 2017 ACC/AHA hypertension guideline believe that these recommendations have the potential to increase hypertension awareness, encourage lifestyle modification, and focus antihypertensive drug initiation and intensification in those adults at high risk for cardiovascular disease.1227

The lower blood pressure goals advocated in the 2017 ACC/AHA hypertension guideline have been questioned by some clinicians who have concerns regarding the guideline's use of extrapolated observational data, the lack of generalizability of some of the randomized trials (e.g., SPRINT) used to support the guideline, the difficulty of establishing accurate representative blood pressure values in typical clinical practice settings, and the accuracy of the cardiovascular risk calculator used in the guideline.1224,1229 Some clinicians state the lower blood pressure threshold used to define hypertension in the 2017 ACC/AHA hypertension guideline is not fully supported by clinical data, and these clinicians have expressed concerns about the possible harms (e.g., adverse effects of antihypertensive therapy) associated with classifying more patients as being hypertensive.1222,1223,1229 Some clinicians also state that using this guideline, a large number of young, low-risk patients would need to be treated in order to observe a clinical benefit,1200,1224 while other clinicians state that the estimated gains in life expectancy attributable to long-term use of blood pressure-lowering drugs are correspondingly greater in this patient population.1200

Treatment Benefits

In clinical trials, antihypertensive therapy has been found to reduce the risk of developing stroke by about 34-40%, MI by about 20-25%, and heart failure by more than 50%.424,429,500,1235 In a randomized, controlled study (SPRINT) that included hypertensive patients without diabetes mellitus who had a high risk of cardiovascular disease, intensive systolic blood pressure lowering of approximately 15 mm Hg was associated with a 25% reduction in cardiovascular disease events and a 27% reduction in all-cause mortality.1210,1219 However, the exclusion of patients with diabetes mellitus, prior stroke, and those younger than 50 years of age may decrease the generalizability of these findings.1210 Some experts estimate that if the systolic blood pressure goals of the 2017 ACC/AHA hypertension guideline are achieved, major cardiovascular disease events may be reduced by an additional 340,000 and total deaths by an additional 156,000 compared with implementation of the JNC 8 expert panel guideline goals but these benefits may be accompanied by an increase in the frequency of adverse events.1228 While there was no overall difference in the occurrence of serious adverse events in patients receiving intensive therapy for blood pressure control (systolic blood pressure target of less than 120 mm Hg) compared with those receiving less intense control (systolic blood pressure target of less than 140 mm Hg) in the SPRINT study, hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure occurred in substantially more patients receiving intensive therapy.1210

In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the long-term cardiovascular morbidity and mortality benefit of a long-acting dihydropyridine calcium-channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) were compared in a broad population of patients with hypertension at risk for coronary heart disease.419,420,450,451,1236,1237 Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed.419,420 Patients receiving the ACE inhibitor experienced higher risks of stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving the calcium-channel blocker were at higher risk of developing heart failure.1236,1237 The ALLHAT investigators suggested that the favorable cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of the calcium-channel blocker compared with that of the ACE inhibitor, especially in women and black patients.1236,1237 (See Clinical Benefit of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)

General Considerations for Initial and Maintenance Antihypertensive Therapy

Nonpharmacologic Therapy

Nonpharmacologic measures (i.e., lifestyle/behavioral modifications) that are effective in lowering blood pressure include weight reduction (for those who are overweight or obese), dietary changes to include foods such as fruits, vegetables, whole grains, and low-fat dairy products that are rich in potassium, calcium, magnesium, and fiber (i.e., adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), sodium reduction, increased physical activity, and moderation of alcohol intake.1200 Such lifestyle/behavioral modifications, including smoking cessation, enhance antihypertensive drug efficacy and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.502,504,1200 Lifestyle/behavioral modifications without antihypertensive drug therapy are recommended for individuals classified by the 2017 ACC/AHA hypertension guideline as having elevated blood pressure (systolic blood pressure 120-129 mm Hg and diastolic blood pressure less than 80 mm Hg) and in those with stage 1 hypertension (systolic blood pressure 130-139 mm Hg or diastolic blood pressure 80-89 mm Hg) who do not have preexisting cardiovascular disease or an estimated 10-year ASCVD risk of 10% or greater.1200

Initiation of Drug Therapy

Drug therapy in the management of hypertension must be individualized and adjusted based on the degree of blood pressure elevation while also considering cardiovascular risk factors.352,370,419,420,424,447,502,1200,1201 Drug therapy generally is reserved for patients who respond inadequately to nondrug therapy (i.e., life-style modifications such as diet [including sodium restriction and adequate potassium and calcium intake], regular aerobic physical activity, moderation of alcohol consumption, and weight reduction) or in whom the degree of blood pressure elevation or coexisting risk factors, especially cardiovascular risk, require more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.504,505,506,507,508,515,523,530,1200 Recommendations generally are based on specific blood pressure levels shown in clinical studies to produce clinical benefits and can therefore vary depending on the studies selected for review.502,504,505,507,1200

The 2017 ACC/AHA hypertension guideline and many experts currently state that the treatment of hypertension should be based not only on blood pressure values but also on patients' cardiovascular risk factors.502,1200,1219 For secondary prevention of recurrent cardiovascular disease events in adults with clinical cardiovascular disease or for primary prevention in adults with an estimated 10-year ASCVD risk of 10% or higher, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at an average systolic blood pressure of 130 mm Hg or an average diastolic blood pressure of 80 mm Hg or higher.1200 For primary prevention of cardiovascular disease events in adults with a low (less than 10%) estimated 10-year risk of ASCVD, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher.1200 After initiation of antihypertensive drug therapy, regardless of the ASCVD risk, the 2017 ACC/AHA hypertension guideline generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg is also recommended for noninstitutionalized ambulatory patients 65 years of age or older.1200 While these blood pressure goals are lower than those recommended for most patients in previous guidelines, they are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210

Most data indicate that patients with a higher cardiovascular risk will benefit the most from tighter blood pressure control; however, some experts state this treatment goal also may be beneficial in those at lower cardiovascular risk.1200 Other clinicians believe that the benefits of such blood pressure lowering do not outweigh the risks in those patients considered to be at lower risk of cardiovascular disease and that reclassifying individuals formerly considered to have prehypertension as having hypertension may potentially lead to use of drug therapy in such patients without consideration of cardiovascular risk.1201,1222,1223,1229 Previous hypertension guidelines, such as those from the JNC 8 expert panel, generally recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients.501 Some clinicians continue to support the target blood pressures recommended by the JNC 8 expert panel because of concerns that such recommendations in the 2017 ACC/AHA hypertension guideline are based on extrapolation of data from the high-risk population in the SPRINT study to a lower-risk population.1223,1224 Also, because more than 90% of patients in SPRINT were already receiving antihypertensive drugs at baseline, data are lacking on the effects of initiating drug therapy at a lower blood pressure threshold (130/80 mm Hg) in patients at high risk of cardiovascular disease.1223 The potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs should be considered when deciding a patient's blood pressure treatment goal.1200,1220,1229

The 2017 ACC/AHA hypertension guideline recommends an ASCVD risk assessment for all adults with hypertension; however, experts state that it can be assumed that patients with hypertension and diabetes mellitus or chronic kidney disease (CKD) are at high risk for cardiovascular disease and that antihypertensive drug therapy should be initiated in these patients at a blood pressure of 130/80 mm Hg or higher.1200 The 2017 ACC/AHA hypertension guideline also recommends a blood pressure goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus or CKD.1200 These recommendations are based on a systematic review of high-quality evidence from randomized controlled trials, meta-analyses, and post-hoc analyses that have demonstrated substantial reductions in the risk of important clinical outcomes (e.g., cardiovascular events) regardless of comorbid conditions or age when systolic blood pressure is lowered to less than 130 mm Hg.1200,1213 However, some clinicians have questioned the generalizability of findings from some of the trials (e.g., SPRINT) used to support the 2017 ACC/AHA hypertension guideline.1224 For example, SPRINT included adults (mean age: 68 years) without diabetes mellitus who were at high risk of cardiovascular disease.1209 While benefits of intensive blood pressure control were observed in this patient population, some clinicians have questioned whether these findings apply to younger patients who have a low risk of cardiovascular disease.1223 In patients with CKD in the SPRINT trial, intensive blood pressure management (achieving a mean systolic blood pressure of approximately 122 mm Hg compared with 136 mm Hg with standard treatment) provided a similar beneficial reduction in the composite cardiovascular disease primary outcome and all-cause mortality as in the full patient cohort.1200,1210 Because most patients with CKD die from cardiovascular complications, the findings of this study further support a lower blood pressure target of less than 130/80 mm Hg.1200

Data are lacking to determine the ideal blood pressure goal in patients with hypertension and diabetes mellitus; also, studies evaluating the benefits of intensive blood pressure control in patients with diabetes mellitus have provided conflicting results.521,1200,1213 Clinical studies reviewed for the 2017 ACC/AHA hypertension guideline have shown similar quantitative benefits from blood pressure lowering in hypertensive patients with or without diabetes mellitus.1213 In a randomized, controlled study (ACCORD-BP) that compared a higher (systolic blood pressure less than 140 mm Hg) versus lower (systolic blood pressure less than 120 mm Hg) blood pressure goal in patients with diabetes mellitus, there was no difference in the incidence of cardiovascular outcomes (e.g., composite outcome of cardiovascular death, nonfatal MI, and nonfatal stroke).521,1214 However, some experts state that this study was underpowered to detect a difference between the 2 treatment groups and that the factorial design of the study complicated interpretation of the results.1200,1216 Although SPRINT did not include patients with diabetes mellitus, patients in this study with prediabetes demonstrated a similar cardiovascular benefit from intensive treatment of blood pressure as normoglycemic patients.1200 A meta-analysis of data from ACCORD and SPRINT suggests that the findings of both studies are consistent and that patients with diabetes mellitus benefit from more intensive blood pressure control.1202,1217 These data support the 2017 ACC/AHA hypertension guideline recommendation of a blood pressure treatment goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus.1200 Alternatively, the American Diabetes Association (ADA) recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetes mellitus.1214 The ADA states that a lower blood pressure goal (e.g., less than 130/80 mm Hg) may be appropriate for patients with a high risk of cardiovascular disease and diabetes mellitus if it can be achieved without undue treatment burden.1214

Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension, particularly in high-risk groups (e.g., patients with diabetes mellitus, cardiovascular disease, or cerebrovascular disease; black patients); when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies.501,507,515,526,530,1200

Choice of Initial Drug Therapy

In current hypertension management guidelines, ACE inhibitors are recommended as one of several preferred drugs for the initial treatment of hypertension; other options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics.501,502,503,504,1200 The 2017 ACC/AHA hypertension guideline states that an ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, or thiazide diuretic (preferably chlorthalidone) are all acceptable choices for initial antihypertensive drug therapy in the general population of nonblack patients, including those with diabetes mellitus;1200 drugs from any of these classes generally produce similar benefits in terms of overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501,502,1200,1213 ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as heart failure, ischemic heart disease, diabetes mellitus, CKD, or cerebrovascular disease or following myocardial infarction (MI).501,502,523,524,525,526,527,534,535,536,543,1200,1214,1215 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension.)

In patients with hypertension and compelling indications (e.g., CKD with albuminuria [urine albumin 300 mg/day or greater, or urine albumin:creatinine ratio of 300 mg/g or equivalent in the first morning void]), angiotensin II receptor antagonists are usually considered an alternative for ACE inhibitor-intolerant patients.1218 (See Chronic Kidney Disease under Hypertension: Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors, in Uses.) However, data indicate no difference in efficacy between ACE inhibitors and angiotensin II receptor antagonists with regard to blood pressure lowering and clinical outcomes (i.e., all-cause mortality, cardiovascular mortality, MI, heart failure, stroke, and end-stage renal disease).1200,1218 Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy.1218 Because of similar efficacy and a lower frequency of adverse effects, some experts believe that angiotensin II receptor antagonists should be used instead of an ACE inhibitor for the treatment of hypertension or hypertension with certain compelling indications.1218

Experts state that in patients with stage 1 hypertension (especially the elderly, those with a history of hypotension, or those who have experienced adverse drug effects), it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target blood pressure.1200 Although some patients can begin treatment with a single antihypertensive agent, starting with 2 drugs in different pharmacologic classes (either as separate agents or in a fixed-dose combination) is recommended in patients with stage 2 hypertension and an average blood pressure more than 20/10 mm Hg above their target blood pressure.1200 Such combined therapy may increase the likelihood of achieving goal blood pressure in a more timely fashion, but also may increase the risk of adverse effects (e.g., orthostatic hypotension) in some patients (e.g., elderly).424,447,1200 Drug regimens with complementary activity, where a second antihypertensive agent is used to block compensatory responses to the first agent or affect a different pressor mechanism, can result in additive blood pressure lowering and are preferred.1200 Drug combinations that have similar mechanisms of action or clinical effects (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) generally should be avoided.1200 Many patients who begin therapy with a single antihypertensive agent will subsequently require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal.1200 Experts state that other patient-specific factors, such as age, concurrent medications, drug adherence, drug interactions, the overall treatment regimen, cost, and comorbidities, also should be considered when deciding on an antihypertensive drug regimen.1200 For any stage of hypertension, antihypertensive drug dosages should be adjusted and/or other agents substituted or added until goal blood pressure is achieved. (See Follow-up and Maintenance Drug Therapy under Hypertension: General Considerations for Initial and Maintenance Antihypertensive Therapy, in Uses.)

Follow-up and Maintenance Drug Therapy

Several strategies are used for the titration and combination of antihypertensive drugs; these strategies, which are generally based on those used in randomized controlled studies, include maximizing the dosage of the first drug before adding a second drug, adding a second drug before achieving maximum dosage of the initial drug, or initiating therapy with 2 drugs simultaneously (either as separate preparations or as a fixed-dose combination).1200 Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects.1200 After initiating a new or adjusted antihypertensive drug regimen, patients should have their blood pressure reevaluated monthly until adequate blood pressure control is achieved.1200 Effective blood pressure control can be achieved in most hypertensive patients, but many will ultimately require therapy with 2 or more antihypertensive drugs.430,1200 In addition to measuring blood pressure, clinicians should evaluate patients for orthostatic hypotension, adverse drug effects, adherence to drug therapy and lifestyle modifications, and the need for drug dosage adjustments.1200 Laboratory testing such as electrolytes and renal function status and other assessments of target organ damage also should be performed.1200

Enalapril can be used for the management of hypertension as initial monotherapy1,2,9,54,73,107,108,109,110,123,125,186,200,201,206,231,247,352,353 or as a component of a multiple-drug regimen.1,54,105,120 When enalapril alone is used but the patient's hypertension does not respond adequately, addition of a thiazide diuretic often adequately controls blood pressure.1,2,4,5,9,54,110,116,119,120,122,123,124,127,128,129,130,140,142,143,155,186,203,220 Such combined therapy generally produces additive reduction in blood pressure1,54,120,122,123,128,129,131,204,254 and may permit dosage reduction of either or both drugs and minimize adverse effects while maintaining blood pressure control.1,122,123,128,129,131,162,198,203

Enalapril may be effective in the management of hypertension resistant to other drugs.54,120,186,204,231 Although enalapril occasionally may be effective alone in patients with severe hypertension, it is usually necessary to use the drug in conjunction with a diuretic.1,116,155,186,204 (See Drug Interactions: Hypotensive Agents and Diuretics.) Enalapril has been used in some diabetic hypertensive patients with no adverse effect on control or therapy of diabetes;160 however, hypoglycemia has occasionally occurred when the drug was used in patients whose diabetes had been controlled with insulin or oral hypoglycemic agents.176 (See Drug Interactions: Other Drugs.)

Tolerance to the hypotensive effect of enalapril apparently does not occur during long-term administration,1,110,116,131,144 particularly if the drug is used with a diuretic.133,144 Abrupt withdrawal of enalapril or enalaprilat therapy results in a gradual return of hypertension;1,157,277 rapid increases in blood pressure have not been reported to date.1,277

IV enalaprilat may be used in the management of hypertension when oral therapy is not practical.277,285,286 Enalaprilat generally produces a prompt reduction in blood pressure, usually without an orthostatic response, and with a slight reduction in heart rate.277,285,286,287,288,289 Occasional hypotension, or symptomatic postural hypotension in volume-depleted patients, might be anticipated.277,286,287 Enalaprilat also has been used effectively to control blood pressure in adults with severe hypertension or hypertensive emergencies†287,288,289,290 (see Hypertensive Crises under Uses: Hypertension) and in a small number of neonates with severe hypertension†.291,292

Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors

Drug therapy in patients with hypertension and underlying cardiovascular or other risk factors should be carefully individualized based on the underlying disease(s), concomitant drugs, tolerance to drug-induced adverse effects, and blood pressure goal.424,502,1200 See Table 2 on Compelling Indications for Drug Classes based on Comorbid Conditions under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Ischemic Heart Disease

The selection of an appropriate antihypertensive agent in patients with ischemic heart disease should be based on individual patient characteristics and may include ACE inhibitors and/or β-blockers, with the addition of other drugs such as thiazide diuretics or calcium-channel blockers as necessary to achieve blood pressure goals.523,525 Many experts recommend the use of an ACE inhibitor (or an angiotensin II receptor antagonist) and/or a β-blocker in hypertensive patients with stable ischemic heart disease because of the cardioprotective benefits of these drugs; all patients who have survived an MI should be treated with a β-blocker because of the demonstrated mortality benefit of these agents.523,525,527

Heart Failure

While ACE inhibitors as single therapies are not superior to other antihypertensive agents in the reduction of cardiovascular outcomes,501,1200 ACE inhibitors, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers, have been shown to reduce morbidity and mortality in patients with existing heart failure.355,524 (See Uses: Heart Failure.) ACE inhibitors also have been used to prevent subsequent heart failure and reduce morbidity and mortality in patients with systolic dysfunction following acute MI†.307,352,353,524,527 (See Uses: Left Ventricular Dysfunction After Acute Myocardial Infarction.)

Diabetes Mellitus

Experts state that initial treatment of hypertension in adults with diabetes mellitus and hypertension should include any of the usual first-line agents (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, thiazide diuretics).1200,1214,1215 In adults with diabetes mellitus, hypertension, and albuminuria, treatment with an ACE inhibitor or angiotensin II receptor antagonist may be considered to reduce the progression of kidney disease.1200,1215 While there is evidence demonstrating the benefits of ACE inhibitors in reducing the development or progression of microvascular or macrovascular complications in hypertensive patients with type 1 or type 2 diabetes mellitus, 380,411,412 in the absence of albuminuria, the risk of progressive kidney disease is low, and ACE inhibitors and angiotensin II receptor antagonists have not demonstrated superior cardioprotection when compared with other first-line agents.1214,1215 Results of several studies indicate that adequate control of blood pressure in patients with type 2 diabetes mellitus reduces the development or progression of complications of diabetes (e.g., death related to diabetes, stroke, heart failure, microvascular disease).382,383,384,385,387,393,394,400,501,1214,1215 Most patients with diabetes mellitus will require 2 or more antihypertensive agents to achieve blood pressure control.1200,1215

Chronic Kidney Disease

Hypertensive patients with CKD (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m² or kidney damage for 3 or more months) usually will require more than one antihypertensive agent to reach target blood pressure.456,501,536,537,543 Use of ACE inhibitors or angiotensin II receptor antagonists may be reasonable in patients with diabetic or nondiabetic CKD (stage 1 or 2 with albuminuria or stage 3 or higher);1200 these drugs have been shown to slow the progression of kidney disease.501,502,534,535,536,543 Evidence of a renoprotective benefit is strongest in those with higher levels of albuminuria.535,536,543 Increases in serum creatinine (up to 30%) may be observed as a result of a decrease in intraglomerular pressure and concurrent reduction in GFR.1200 The 2017 ACC/AHA hypertension guideline states that in patients with less severe kidney disease (i.e., stage 1 or 2 CKD without albuminuria), any of the first-line antihypertensive agents (e.g., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, thiazide diuretics) can be used for the initial treatment of hypertension.1200 Diuretics also may be useful in the management of CKD, and may potentiate the effects of ACE inhibitors, angiotensin II receptor antagonists, and other antihypertensive agents when used in combination.543 (See Diabetic Nephropathy under Uses: Nephropathy, in Captopril 24:32.04.)

Cerebrovascular Disease

Some experts recommend a blood pressure goal of less than 140/90 mm Hg in patients with ischemic stroke or transient ischemic attack (TIA),526 while others state that a blood pressure goal of less than 130/80 mm Hg may be reasonable.1200 The 2017 ACC/AHA hypertension guideline states that adults not previously treated for hypertension who experience a stroke or TIA and who have an established blood pressure of 140/90 mm Hg should receive antihypertensive therapy within a few days after the event to reduce the risk of recurrent stroke or other vascular events.1200 In patients with a recent lacunar stroke, experts suggest that a systolic blood pressure goal of 130 mm Hg may be reasonable based on results of a randomized open-label study (the Secondary Prevention of Small Subcortical Strokes [SPS3] trial).518,526,1200 Although experts state that the optimal choice of drug for the management of hypertension in patients with a previous TIA or ischemic stroke is uncertain, available data indicate that an ACE inhibitor, angiotensin II receptor antagonist, thiazide diuretic, or the combination of a thiazide diuretic and an ACE inhibitor may be effective.526,1200 Administration of an ACE inhibitor in combination with a thiazide diuretic has been shown to lower rates of recurrent stroke.180,526

Hypertension Associated with Scleroderma Renal Crisis

Enalapril has been effective for the management of hypertension associated with scleroderma renal crisis† in a limited number of patients who were unable to tolerate captopril because of adverse effects.115 Maintenance therapy with enalapril (5-30 mg daily) controlled blood pressure in these patients and was accompanied by improvement in renal function.115 Some clinicians consider ACE inhibitors the drugs of choice for this condition.212,213,214,215,231

Other Special Considerations for Antihypertensive Drug Therapy

Race

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors.419,420,422,501,504,1200 In a prespecified subgroup analysis of the ALLHAT study, a thiazide-type diuretic was more effective than an ACE inhibitor in improving cerebrovascular and cardiovascular outcomes in black patients; when compared with a calcium-channel blocker, the ACE inhibitor was less effective in reducing blood pressure and was associated with a 51% higher rate of stroke.501 (See Clinical Benefit of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.) However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 In addition, some experts state that when use of ACE inhibitors is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients.422

Although enalapril has lowered blood pressure in all races studied, monotherapy with enalapril has produced a smaller reduction in blood pressure in black hypertensive patients, a population associated with low renin hypertension;1,2,9,78,121,269,270,271,419,420,450,451 however, this population difference in response does not appear to occur during combined therapy with enalapril and a thiazide diuretic.1,244,504 In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied.1,348,349,420,1200

For further information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.)

Renovascular or Malignant Hypertension

Enalapril also has been effective in the management of renovascular108,184,203,204 or malignant hypertension,145 renal hypertension secondary to renal-artery stenosis,116 and, in some patients, hypertension associated with chronic renal failure.114,125,126,145 In addition to the drugs' hypotensive effect, ACE inhibitors also have stabilized or improved effective renal blood flow and glomerular filtration rate and decreased proteinuria in some hypertensive patients with moderately impaired renal function,54,124,126,220 moderate to severe renal disease,125,126 or diabetic nephropathy.126,133 However, enalapril should be used with caution in patients with impaired renal function,1,93,94,96 especially those with bilateral renal-artery stenosis or with renal-artery stenosis in a solitary kidney.1,6,50,116,161,167,231,233,234 (See Cautions: Renal Effects and see Hematologic Effects and see Precautions and Contraindications.)

Hypertensive Crises

Enalaprilat has been used effectively to reduce blood pressure in adults with severe hypertension or hypertensive emergencies†.287,288,289,290,1200

Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage.1200 Such emergencies include hypertensive encephalopathy, acute MI, intracerebral hemorrhage, acute left ventricular failure with pulmonary edema, eclampsia, dissecting aortic aneurysm, unstable angina pectoris, acute ischemic stroke, and acute renal failure.1200 Patients with hypertensive emergencies require hospitalization and are treated initially with an appropriate parenteral agent.502,542,1200 Elevated blood pressure alone, in the absence of manifestations or other evidence of target organ damage, rarely requires emergency therapy.1200

Acute enalaprilat therapy (e.g., 1.25-5 mg IV, repeated every 6 hours as necessary) is one of several parenteral regimens currently recommended for rapidly reducing blood pressure in patients with hypertensive crises in whom reduction of blood pressure is considered an emergency.277,1200 However, reduction of blood pressure in a prompt but controlled manner may be more easily achieved with short-acting antihypertensive agents administered by continuous IV infusion (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside), and some clinicians state that such agents generally are preferred.502,542,1200

The risks of overly aggressive therapy in any hypertensive crisis must always be considered, as excessive falls in blood pressure may precipitate renal, cerebral, or coronary ischemia.542,1200

Heart Failure

Enalapril is used in the management of symptomatic heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers.1,4,42,44,57,61,63,64,146,147,148,150,151,152,153,158,159,225,245,260,524,700

Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.524,700,701,703 Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations.524,700 In patients with prior or current symptoms of chronic heart failure with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI (e.g., sacubitril/valsartan) in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality.700 While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction,524 some evidence indicates that therapy with an ARNI (sacubitril/valsartan) may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients.700,702 ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure with reduced LVEF (New York Heart Association [NYHA] class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.700 However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised.700 In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.700 For further information on the use of ARNIs in patients with heart failure, see Uses: Heart Failure, in Sacubitril and Valsartan 24:32.92.

Some clinicians state that ACE inhibitors usually are prescribed in clinical practice at dosages lower than those determined as target dosages in clinical trials, although results of several studies suggest that high dosages are associated with greater hemodynamic, neurohormonal, symptomatic, and prognostic benefits than lower dosages.399,524 Results of a large, randomized, double-blind study (Assessment of Treatment with Lisinopril and Survival [ATLAS] study) in patients with heart failure (NYHA class II-IV) indicate that high lisinopril dosages (32.5-35 mg daily) were associated with a 12% lower risk of death or hospitalization for any cause and 24% fewer hospitalizations for heart failure than low dosages (2.5-5 mg) of the drug.399

Once ACE inhibitor therapy is initiated for heart failure, it generally is continued indefinitely, if tolerated, since withdrawal of an ACE inhibitor may lead to clinical deterioration.379,416,524 Patients with NYHA class II or III heart failure who are tolerating therapy with an ACE inhibitor may be switched to therapy containing an ARNI to further reduce morbidity and mortality; however, the ARNI should not be administered concomitantly with an ACE inhibitor or within 36 hours of the last dose of an ACE inhibitor.700

Current evidence supports the use of ACE inhibitors and β-blocker therapy to prevent development of left ventricular dilatation and dysfunction (“ventricular remodeling”) in patients with heart failure.524 (See Uses: Asymptomatic Left Ventricular Dysfunction.) The addition of other agents such as diuretics, cardiac glycosides, aldosterone antagonists, and/or sinoatrial modulators in the management of heart failure should be individualized.321,524,700 Unless contraindicated, diuretics are recommended in all patients with heart failure and reduced ejection fraction who have evidence of fluid retention to improve symptoms.524 Digoxin may be beneficial to patients with heart failure with reduced ejection fraction to decrease hospitalization for heart failure, especially in those with persistent symptoms despite treatment with guideline-directed medical therapy.524 The addition of a sinoatrial modulator (i.e., ivabradine) is recommended in selected patients with chronic heart failure and reduced LVEF who are already receiving guideline-directed medical therapy, to reduce heart failure-related hospitalizations.700 (See Uses: Heart Failure, in Ivabradine 24:04.92.)

Results of a randomized, multicenter, double-blind, placebo-controlled study (Randomized Aldactone Evaluation Study [RALES]) indicate that addition of low-dosage spironolactone (25-50 mg daily) to standard therapy (e.g., an ACE inhibitor and a loop diuretic with or without a cardiac glycoside) in patients with severe (NYHA class IV within 6 months before enrollment and NYHA class III or IV at the time of enrollment) heart failure and an LVEF of 35% or less, was associated with decreases in overall mortality and hospitalization (for worsening heart failure) rates of approximately 30 and 35%, respectively, compared with standard therapy and placebo.375,381,391 Based on the results of RALES and other studies, ACCF and AHA recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure (NYHA class II-IV) and reduced LVEF (35% or less) who are already receiving standard therapy to reduce morbidity and mortality.524,700 (See Uses: Heart Failure, in Spironolactone 24:32.20.)

Many patients with heart failure respond to enalapril with improvement in cardiac function indexes, symptomatic (e.g., dyspnea, fatigue) relief, improved functional capacity, and increased exercise tolerance.1,4,42,44,57,61,63,64,146,147,148,150,151,153,158,159,225,245,260 In some studies, improvement in cardiac function indexes and exercise tolerance were sustained for up to 4 months.4,44,146,151,158,225,245 In some patients, beneficial effects have been sustained for up to 2-21 months.4,57,153,245,260 Enalapril also has been effective in conjunction with cardiac glycosides and diuretics for the management of heart failure resistant to or inadequately controlled by cardiac glycosides, diuretics, and vasodilators.153,260 In a multicenter, placebo-controlled study in patients with severe heart failure (NYHA class IV), the addition of enalapril to the therapeutic regimen (which included cardiac glycosides, diuretics, and/or vasodilators) was associated with a 40% reduction in overall mortality at 6 months and a 31% reduction at 12 months compared with patients who did not receive an ACE inhibitor, although the incidence of sudden cardiac death did not differ.245,260,301 In addition, there was a substantial improvement in NYHA functional class for patients receiving enalapril in this study.245,260 Follow-up of surviving patients 2 years after completion of the blinded, placebo-controlled phase showed a carry-over effect of enalapril on mortality reduction despite the availability of enalapril therapy for all surviving patients (whether treated initially with the drug or not) and the poorer clinical condition of the initial enalapril-treated group at the outset of follow-up; during follow-up, the carry-over effect on mortality reduction of initial enalapril therapy persisted for 15 months.301

In 2 multicenter, controlled studies, enalapril substantially reduced mortality in patients with mild to moderate heart failure (NYHA class I-III) when added to a conventional therapeutic regimen (most commonly cardiac glycosides and diuretics);1,293,294 in these patients, enalapril therapy also may substantially reduce the rate of hospitalization.293,448 In one of these studies, the reduction in mortality was substantially greater with enalapril than with combined hydralazine and isosorbide dinitrate, although the latter regimen produced substantially greater improvement in exercise performance and left ventricular function.294 The beneficial effects of enalapril on reduction in mortality may result from a delay in worsening of heart failure, although other mechanisms (e.g., on causes of sudden death) may be involved.260,293,294,295,301 Analysis of the results of these studies according to racial subgroup indicates that white patients had substantially greater reductions in blood pressure and the risk of hospitalization for heart failure than black patients receiving similar dosages of enalapril.448 (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.) However, the risk of death in either racial subgroup was not altered by enalapril therapy.448

It has not been determined whether addition of a vasodilator (e.g., hydralazine) to an ACE inhibitor is more effective than an ACE inhibitor alone.295 The efficacy of enalapril appears to be similar to that of captopril.57,61,63,152,231 However, because of enalapril's relatively long duration of action compared with captopril, enalapril may produce more prolonged hypotensive effects, particularly at high dosages, which potentially could result in adverse cerebral and renal effects.57,152,262 In addition, because the renin-angiotensin system appears to substantially contribute to preservation of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, therapy with an ACE inhibitor in such patients may adversely affect renal function.225,262,416 (See Cautions: Renal Effects.)

ACE inhibitors also are used in patients with ACCF/AHA stage B heart failure (see Uses: Asymptomatic Left Ventricular Dysfunction) to prevent symptomatic heart failure and have been shown to reduce mortality after MI or acute coronary syndrome (ACS).293,295,298,299,300,301,307,308,310,311,331,332,333,334,335,336,337,338,339,340,341,342,343,355,524 (See Uses: Left Ventricular Dysfunction After Acute Myocardial Infarction.)

Asymptomatic Left Ventricular Dysfunction

Enalapril is used in clinically stable asymptomatic patients with left ventricular dysfunction (manifested as an ejection fraction of 35% or less) in an effort to decrease the rate of development of overt heart failure and subsequent hospitalizations for heart failure in these patients.1,295,298,299,360,524,704,705 Experts recommend that all asymptomatic patients with reduced LVEF (ACCF/AHA stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality.524 If ACE inhibitors are not tolerated, then an angiotensin II receptor antagonist is recommended as an alternative.524

Enalapril's beneficial effect in preventing the development of symptomatic heart failure in patients with asymptomatic left ventricular dysfunction may result either from relieving symptoms that otherwise would have become apparent or from slowing the progression of asymptomatic ventricular dysfunction to overt, symptomatic disease.298,299 In a multicenter, placebo-controlled study in patients with left ventricular dysfunction who did not have symptomatic heart failure (NYHA class I and II) and were not being treated for such at initiation of ACE inhibitor therapy, enalapril reduced the incidence of heart failure and rate of related hospitalizations relative to those receiving placebo during an average of 37.4 months of follow-up.298,299 Patients with higher ejection fractions and black patients appeared to benefit less from enalapril therapy than those with lower fractions and white patients, respectively.298,448 The effect of enalapril in preventing the development of heart failure was evident within 3 months after initiation of the drug and continued to increase for the remaining study period (approximately 3 years).298 Mortality rates increased substantially in patients who developed overt heart failure, suggesting the possibility of a secondary benefit on prognosis from prevention of symptomatic progression.298 In a follow-up study, treatment with enalapril for 3-4 years led to a sustained improvement in survival (11-12 years) in patients with reduced LVEF, including those who were asymptomatic at baseline.524,704,705

Left Ventricular Dysfunction After Acute Myocardial Infarction

ACE inhibitors, including enalapril and enalaprilat, have been used to reduce mortality and prevent the development of left ventricular dilatation and dysfunction following acute MI†.299,300,307,308,309,310,311,524 Studies with various ACE inhibitors have shown that these drugs reduce fatal and nonfatal cardiovascular events in patients with recent MI.527,803,1100 The magnitude of benefit appears to be greatest in certain high-risk patients (e.g., those with an anterior infarct, ejection fraction of 40% or less, heart failure, prior infarction, or tachycardia).527,805,1100 Evidence regarding the efficacy of such therapy has been somewhat conflicting,299,300,307,308,309,310,311,333,334,336,337,338,339,340,341 particularly when parenteral therapy was initiated early (within 24-48 hours) and included patients with no evidence of baseline dysfunction.299,300,333,334,336,337,340 While the preponderance of evidence (including a large, multinational, multicenter study) has shown a benefit of early oral therapy involving other ACE inhibitors, even in patients with no baseline dysfunction,299,307,308,309,310,311,331,332,334,335,336,337,338,339,340,342,343 one large study involving parenteral and oral enalapril found little if any early (within several months) benefit, particularly in terms of survival, from such therapy.299,300,333,334,336,337,338,339,341 In this multicenter, controlled study, IV enalaprilat (followed by oral enalapril) was initiated within 24 hours of the onset of chest pain associated with acute MI and continued for up to approximately 6 months; there was no evidence of improved survival from enalapril therapy during the 6-month period after MI and, in some patients, an actual worsening of heart failure was observed.299,300,333,334,337,338,339,340,341 In addition, enalapril therapy was associated with a substantial risk of hypotensive episodes, and long-term mortality was higher among patients who experienced hypotension with the first dose of enalapril than among other patients receiving the drug or among those who experienced hypotension with placebo.300 The lack of survival benefit observed in this study applied overall as well as to subgroups of patients (e.g., those with Q-wave infarction, anterior infarction, previous infarction, or current infarction complicated by pulmonary edema or heart failure).300 The results of this study300 are in contrast to other studies involving other ACE inhibitors initiated within 24 hours to 4 weeks after acute MI in which a beneficial effect was observed, in terms of effects on left ventricular volume, infarct expansion, and/or survival.299,307,308,309,310,311,333,334,337,338,340,341

The reason for the differences in potential benefit observed between studies involving enalapril and those involving other ACE inhibitors (e.g., captopril, lisinopril, ramipril) is unclear, but the lack of benefit in the enalapril study may have resulted in part from an early adverse effect of ACE inhibition (e.g., inhibition of angiotensin II-stimulated protein synthesis involved in healing) combined with a rapid decrease in blood pressure associated with the initial administration of enalaprilat and with an inadequate period of follow-up to detect a delayed beneficial effect.299,300,333,336,337,339,340 Current expert guidelines recommend the use of an oral ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarction, heart failure, or ejection fraction of 40% or less who do not have any contraindications (e.g., hypotension, shock, renal dysfunction).527 While early treatment within the first 24 hours of MI has been shown to be beneficial, ACE inhibitors should be used with caution (and with gradual upward titration) during the initial postinfarction period because of the possibility of hypotension or renal dysfunction.527,1100 ACE inhibitor therapy generally should be continued indefinitely in patients with left ventricular dysfunction or other compelling indications for use (e.g., hypertension, diabetes mellitus, CKD).525,1100 The benefits of long-term ACE inhibitor therapy are less certain in low-risk patients who have undergone revascularization and are receiving aggressive antilipemic therapy.527

Diabetic Nephropathy

Both ACE inhibitors and angiotensin II receptor antagonists have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria†,25,53,54,55,56,57,1232 and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion.535,536,1232 The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed.49 For additional information on the use of ACE inhibitors in the treatment of diabetic nephropathy, see Diabetic Nephropathy under Uses: Nephropathy, in Captopril 24:32.04.

Administration

Oral Administration

Enalapril maleate alone or in fixed combination with hydrochlorothiazide is administered orally.1,2,3,4,5,6,7,8,9,10,350,371 For patients unable to swallow tablets, enalapril maleate may be administered orally as an extemporaneously prepared suspension.1 The drug can be given before, during, or after meals since food does not appear to substantially affect the rate or extent of absorption of enalapril.4,88,91

An extemporaneous suspension containing enalapril maleate 1 mg/mL can be prepared in the following manner.1 First, 50 mL of sodium citrate dihydrate (Bicitra^®) is added to a polyethylene terephthalate (PET) bottle containing ten 20-mg tablets of enalapril maleate, and the contents are shaken for at least 2 minutes.1 The concentrated suspension should be allowed to stand for 60 minutes following reconstitution, and then should be shaken for an additional minute.1 The concentrated suspension of enalapril maleate should be diluted with 150 mL of syrup (Ora-Sweet SF^®), and the container then shaken to disperse the ingredients.1,408 The suspension should be shaken before dispensing of each dose.1

IV Administration

Enalaprilat is administered by slow IV infusion over a period of at least 5 minutes.277 The drug should not be administered by other parenteral routes of administration.277 Enalaprilat may be administered by slow, direct IV infusion, or the injection can be diluted in up to 50 mL of compatible IV infusion solution for administration.277 (See Chemistry and Stability: Stability.) Enalaprilat injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.277

Dosage

Dosage of enalapril maleate and enalaprilat must be adjusted according to the patient's tolerance and response.1,4,6,152,245,277 Since enalapril maleate is a prodrug of enalaprilat and is well absorbed following oral administration, dosage of the two drugs is not identical and clinicians must give careful attention to dosage when converting from oral to IV therapy or vice versa. 277

Because of the risk of inducing hypotension, initiation of enalapril maleate or enalaprilat therapy requires consideration of recent antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances.1,5,6,239 If therapy is initiated in patients already receiving a diuretic, symptomatic hypotension may occur following the initial dose of the angiotensin-converting enzyme (ACE) inhibitor.1,117,122,163,164,236,239 The possibility of hypotension may be minimized by discontinuing the diuretic, reducing the diuretic dosage, or cautiously increasing salt intake prior to initiation of oral enalapril maleate or IV enalaprilat therapy.600,601 (See Cautions: Cardiovascular Effects.) For information on initiating oral enalapril maleate or IV enalaprilat therapy when diuretic therapy is not being withheld, see the disease-specific dosage sections in Dosage and Administration: Dosage.

Hypertension

Oral Dosage

The manufacturer states that the usual initial adult dosage of enalapril maleate for the management of hypertension in patients not receiving a diuretic is 5 mg once daily.600 In patients who are receiving a diuretic, it is recommended that diuretic therapy be discontinued, if possible, 2-3 days before initiating therapy.1,6,236,239 (See Cautions: Precautions and Contraindications.) If blood pressure is not adequately controlled with the ACE inhibitor alone, diuretic therapy may be resumed cautiously.1,2,110,116,119,120,122,123,124,127,128,129,130,140,142,143,203,220 If diuretic therapy cannot be discontinued, an initial enalapril maleate dose of 2.5 mg should be administered under medical supervision for at least 2 hours and until blood pressure has stabilized for at least an additional hour.1

The usual initial pediatric (1 month to 16 years of age) dosage of enalapril maleate is 0.08 mg/kg once daily, up to 5 mg.600,1150 Some experts state that the dose may be administered as a single dose or in 2 divided doses daily.1150 Such experts also state that the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur.1150 The manufacturer states that dosages of enalapril maleate exceeding 0.58 mg/kg or in excess of 40 mg daily have not been studied in pediatric patients.1 (For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.)

Dosage of enalapril maleate should be adjusted according to the patient's blood pressure response.1 If the blood pressure response diminishes toward the end of the dosing interval during once-daily administration, increasing the dosage or giving the drug in 2 divided doses daily should be considered.1 Because the reduction in blood pressure may be gradual,1 some clinicians suggest that enalapril maleate dosage generally be titrated at 2- to 4-week intervals if necessary.11,231 The manufacturer states that the usual maintenance dosage of enalapril maleate in adults is 10-40 mg daily, given as a single dose or in 2 divided doses daily,1 although most patients can be maintained on once-daily dosing.1,108,109,110,112,113,114,115,116,231 Some experts state that the usual adult dosage is 5-40 mg daily, given as a single dose or in 2 divided doses daily.1200 Optimum blood pressure reduction may require several weeks of therapy in some patients.245 If blood pressure is not adequately controlled with enalapril alone, a second antihypertensive agent (e.g., a diuretic)1,110,116,119,120,122,123,124,127,128,129,130,140,142,143,203,220 may be added.1200

When oral therapy is initiated following IV enalaprilat therapy in adults not receiving a diuretic, the recommended initial dosage of enalapril maleate is 5 mg once daily with subsequent dosage adjustment as necessary.277 When oral therapy is initiated following IV enalaprilat therapy in adults receiving a diuretic, the recommended initial dosage of enalapril maleate in those who responded to enalaprilat 0.625 mg every 6 hours is 2.5 mg once daily with subsequent dosage adjustment as necessary.277

Enalapril/Hydrochlorothiazide Fixed-combination Oral Therapy

To minimize the likelihood of adverse effects, therapy with the commercially available preparations containing enalapril in fixed combination with hydrochlorothiazide should only be initiated in adults after an adequate response is not achieved with enalapril or hydrochlorothiazide monotherapy.254,348 Alternatively, the fixed combination containing enalapril with hydrochlorothiazide may be used in adults who had been receiving the drugs separately and in whom dosage of the individual drugs has been adjusted.254,348 The recommended initial adult dosage of the commercially available fixed-combination tablets is 5 mg of enalapril maleate and 12.5 mg of hydrochlorothiazide or 10 mg of enalapril maleate and 25 mg of hydrochlorothiazide once daily. 254 Further increases of either or both drugs depend on clinical response; however, generally, dosage of hydrochlorothiazide should not be increased for about 2-3 weeks after initiation of therapy.254,348 Because the suggested maximum adult dosage of enalapril maleate and hydrochlorothiazide during combined antihypertensive therapy is 20 or 50 mg daily, respectively, the combined dosage of enalapril maleate and hydrochlorothiazide in the fixed combination should not exceed these respective levels.254,323,348

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with ACE inhibitor monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium-channel blocking agent, thiazide diuretic) may be added; if target blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with enalapril, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While other hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) in all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220 (See General Considerations for Initial and Maintenance Antihypertensive Therapy under Uses: Hypertension.)

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

IV Dosage

When oral therapy is not feasible, the recommended initial IV enalaprilat dosage in adults not receiving a diuretic or in those converting from enalapril maleate therapy (without concomitant diuretic therapy) is 1.25 mg every 6 hours.277 Reduction in blood pressure usually occurs within 15 minutes, but the maximal hypotensive response after the first dose may not occur for up to 4 hours after administration.277 The maximum effects of the second and subsequent doses may exceed those of the first dose.277 Although no regimen has been shown to be more effective than 1.25 mg every 6 hours, dosages as high as 5 mg every 6 hours were well tolerated for up to 36 hours in controlled clinical studies.277 Experience with dosages greater than 20 mg daily is insufficient.277 In studies of patients with hypertension, enalaprilat was not administered for longer than 48 hours, but in other studies it has been administered for as long as 7 days.277

When oral therapy is not feasible in adults receiving a diuretic, the recommended initial IV enalaprilat dose is 0.625 mg.277 A reduction in blood pressure usually occurs within 15 minutes.277 Although most of the effect is usually apparent within the first hour, the maximal hypotensive response may not occur for up to 4 hours after the initial dose.277 If the blood pressure response after 1 hour is inadequate, another dose of 0.625 mg may be given.277 Additional doses of 1.25 mg may be administered at 6-hour intervals.277

To reduce blood pressure rapidly in adults with a hypertensive emergency†, an IV enalaprilat dosage of 1.25-5 mg, repeated every 6 hours as necessary, has been recommended.1200 If IV enalaprilat is used in the management of a hypertensive emergency in adults without a compelling condition, the initial goal of such therapy is to reduce systolic blood pressure by no more than 25% within 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.1200 If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24-48 hours.1200 Enalaprilat is most useful in hypertensive emergencies associated with high plasma renin activity.1200

For information on converting patients from IV to oral therapy, see Oral Dosage under Dosage: Hypertension, in Dosage and Administration.

Heart Failure

Because of the risk of severe hypotension, enalapril maleate therapy for heart failure should be initiated under very close medical supervision (e.g., in a hospital setting) with consideration given to recent diuretic therapy and the possibility of severe sodium and/or fluid depletion.1,152,184,239,524 ACE inhibitor therapy should be initiated with caution in patients with very low systemic blood pressure (systolic blood pressure less than 80 mm Hg), markedly increased serum concentrations of creatinine (greater than 3 mg/dL), bilateral renal artery stenosis, or elevated concentrations of serum potassium (greater than 5 mEq/L).524 Experts recommend that renal function and serum potassium be assessed within 1-2 weeks of initiation of therapy and periodically thereafter in patients receiving an ACE inhibitor, especially in those with preexisting hypotension, hyponatremia, diabetes mellitus, or azotemia, or in those taking potassium supplements.524 Use of low initial enalapril maleate dosages and reduction of the dosage of concomitantly administered diuretics may decrease the initial risk of hypotension.122,148,150,152,239,416 However, the long-term hemodynamic benefit of low enalapril maleate dosages (e.g., 10-20 mg daily) in this condition has not been established.148,150,152

It should be recognized that although symptoms of heart failure may improve within 48 hours after initiating ACE inhibitor therapy in some patients, such improvement usually is not evident for several weeks or months after initiating ACE inhibitor therapy.379,416 In addition, it should be considered that such therapy may reduce the risk of disease progression even if symptomatic improvement is not evident.379,416 Therefore, dosages generally should be titrated to a prespecified target (i.e., at least 20 mg of enalapril daily) or highest tolerated dosage rather than according to response.524

For the management of symptomatic heart failure, enalapril maleate often is administered in conjunction with other agents such as a cardiac glycoside, a diuretic, and a β-blocker.1,42,44,57,63,64,146,147,148,150,151,152,153,158,159,245,260,524,700 Enalapril maleate dosage for heart failure should be initiated at low doses and titrated gradually upward if lower doses have been well tolerated.524 The usual initial enalapril maleate dosage for the management of heart failure in adults with normal renal function and serum sodium concentration is 2.5 mg twice daily.1,524 After the initial dose, the patient should be monitored closely for at least 2 hours and for at least one additional hour after blood pressure has stabilized.1,245 Hypotension occurring after the initial dose does not preclude the administration of subsequent doses of the drug, provided due caution is exercised and the hypotension has been managed effectively.245,416 To minimize the likelihood of hypotension, the dosage of any diuretic given concomitantly with enalapril should be reduced, if possible.1 The usual maintenance dosage of enalapril maleate for heart failure is 2.5-20 mg twice daily.42,44,57,61,63,64,146,147,148,150,151,152,153,154,245,524 The maximum recommended daily dosage of the drug is 40 mg, given in 2 divided doses.245,524

Asymptomatic Left Ventricular Dysfunction

When used in adults with asymptomatic left ventricular dysfunction, enalapril maleate therapy has been initiated using a dosage of 2.5 mg twice daily.1 Therapy is then titrated as tolerated to a target daily dosage of 20 mg given in divided doses.1 After the initial dose of enalapril, the patient should be closely observed for at least 2 hours and for at least one additional hour after blood pressure has stabilized.1 To minimize the likelihood of hypotension, the dosage of any concomitant diuretic should be reduced, if possible.1 The appearance of hypotension after the initial dose of enalapril does not preclude subsequent carefully titrated doses of the drug after the hypotension has been effectively managed.1

Dosage in Renal or Hepatic Impairment, Hyponatremia, Pediatric Patients, and Geriatric Patients

If enalapril maleate or enalaprilat is used in patients with impaired renal function, dosage must be modified in response to the degree of renal impairment, and the theoretical risk of neutropenia must be considered.1,93,94,96,264,277 (See Cautions: Hematologic Effects.)

The manufacturer states that hypertensive adults with moderate renal impairment (i.e., creatinine clearances greater than 30 mL/minute) may receive the usual dosage of enalapril maleate.1,277 In adults with severe renal impairment (i.e., creatinine clearances of 30 mL/minute or less), dosage of enalapril maleate should be initiated at 2.5 mg daily.1 If an adequate response is not achieved, dosage may then be gradually increased until blood pressure is controlled or a maximum dosage of 40 mg daily is reached.1 Alternatively, some clinicians suggest that patients with creatinine clearances of 10-50 mL/minute can receive 75-100% of the usual dosage and those with creatinine clearances less than 10 mL/minute can receive 50% of the usual dosage.264 Patients undergoing hemodialysis should receive a supplemental dose of the drug after dialysis.1,264 The manufacturer recommends that hemodialysis patients be given a dose of 2.5 mg on dialysis days; on days between dialysis periods, enalapril maleate dosage should be adjusted according to the patient's blood pressure response.1

For hypertensive adults with moderate renal impairment (i.e., creatinine clearances greater than 30 mL/minute) in whom oral therapy is not feasible, the recommended dosage of IV enalaprilat is 1.25 mg every 6 hours.277 In adults with severe renal impairment (i.e., creatinine clearances of 30 mL/minute or less), the initial dose of IV enalaprilat should be 0.625 mg; if the blood pressure response is inadequate after 1 hour, another dose of 0.625 mg may be given.277 Additional doses of 1.25 mg may be administered at 6-hour intervals.277 For patients undergoing dialysis, the initial dosage of IV enalaprilat should be 0.625 mg every 6 hours.277 When oral therapy is initiated following IV enalaprilat therapy, the recommended initial dosage of enalapril maleate is 5 mg once daily in patients with creatinine clearances greater than 30 mL/minute and 2.5 mg once daily in patients with creatinine clearances of 30 mL/minute or less.277 Dosage is subsequently adjusted according to the patient's blood pressure response.277

The manufacturer states that adults with heart failure and hyponatremia (serum sodium concentration less than 130 mEq/L) or serum creatinine concentration greater than 1.6 mg/dL should receive an initial enalapril maleate dosage of 2.5 mg daily under close monitoring (see Heart Failure under Dosage and Administration: Dosage).245 Subsequent dosage may be increased gradually as necessary, usually at intervals of 4 or more days, to 2.5 mg twice daily, then 5 mg twice daily, and then higher, provided excessive hypotension or deterioration of renal function is not present at the time of intended dosage adjustment; dosage should not exceed 40 mg daily.245

If concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic is preferred to a thiazide diuretic.254,348 Therefore, use of commercially available preparations containing enalapril maleate in fixed combination with hydrochlorothiazide is not recommended for patients with severe renal impairment.254 The manufacturers state that dosage adjustment of commercially available preparations containing enalapril maleate in fixed combination with hydrochlorothiazide is not needed in patients with renal impairment whose creatinine clearance exceeds 30 mL/minute per 1.73 m².455 (For information on dosage of hydrochlorothiazide in other special populations, see Dosage and Administration, in Hydrochlorothiazide 40:28.20.)

Enalapril maleate is not recommended for neonates or for pediatric patients who have a glomerular filtration rate of less than 30 mL/minute per 1.73 m², since no data are available in such patients.1

Since it is not known whether geriatric patients 65 years of age or older respond the same to enalapril in fixed combination with hydrochlorothiazide as younger adults, the manufacturer suggests that patients in this age group receive initial dosages of the fixed combination in the lower end of the usual range.254,348

Adverse reactions to enalapril usually are mild and transient but have required discontinuance of therapy in about 3 or 6% of patients receiving the drug for the management of hypertension or heart failure, respectively.245 Enalaprilat usually is well tolerated.277 Since enalapril is metabolized to enalaprilat, administration of enalaprilat can be expected to produce adverse effects associated with enalapril therapy.277 Overall, the frequency of many adverse effects produced by enalapril appears to be similar to or less than that produced by captopril.4,5,23,115,142,143,144,145,155,223,231,242 However, unlike captopril, enalapril lacks the sulfhydryl group which has been associated with certain captopril-induced adverse effects (e.g., cutaneous reactions, taste disturbances, proteinuria), and the risk of these effects may be decreased during enalapril therapy.4,5,8,9,11,168,222,231,242,251 Additional experience to determine the relative safety of enalapril is necessary, and the possibility that the risk may be similar should be considered.1,5,6,222 Because of enalapril's long duration of action, the risk of some adverse effects (e.g., hypotension, deterioration in renal function) may be increased compared with short-acting ACE inhibitors, particularly in patients whose cardiovascular and renal systems have increased dependency on the renin-angiotensin system (e.g., those with severe heart failure).152,262,265

Adverse nervous system effects (e.g., headache, dizziness, fatigue) occur most frequently during enalapril therapy for hypertension.1,122,136,142,144,152 Although adverse effects of enalapril generally are mild,1,9,43,45,47,49,50,51,59,60,61,136 discontinuance of the drug has been necessary in about 6% of patients, principally because of dizziness,1,144,152 headache,1 hypotension,1,57,164,260 or rash.1 The manufacturer states that the incidence of the most frequently reported adverse effects was similar in patients receiving enalapril or placebo in clinical trials.1 In patients with heart failure, symptomatic hypotension,57,146,150,152,239,260 deterioration in renal function,152,225,239,245,260 and increased serum potassium concentration151,152,239,260 appear to occur most frequently, particularly during initiation of enalapril therapy in volume- and/or sodium-depleted patients (e.g., those receiving concomitant diuretic therapy).57,146,152,225,239,260

The frequency of some adverse reactions may be increased during therapy with enalapril in fixed combination with hydrochlorothiazide compared with either drug alone, but the manufacturer states that adverse reactions reported to date with the combination have been reported previously with the individual drugs.254 No reactions peculiar to the combination have been reported.254

Nervous System Effects

Headache1,136,245,254 and dizziness1,117,122,128,136,142,144,163,254 occur in about 5% of patients receiving enalapril alone for hypertension,1,245 requiring discontinuance in 0.4 and 0.3% of patients, respectively,1,245 and occur in about 6 and 9%, respectively, of hypertensive patients receiving the drug in fixed combination with hydrochlorothiazide.254 In patients receiving enalapril for heart failure, dizziness and headache occurred in approximately 8 and 2% of patients, respectively, and required discontinuance of the drug in 0.6 and 0.1%, respectively.245 Headache has been reported in about 3% of patients receiving enalaprilat.277 Fatigue has occurred in about 3% of patients receiving the drug alone for hypertension,1,136,245 requiring discontinuance in less than 0.1%,1 and has occurred in about 4% of hypertensive patients receiving the drug in fixed combination with hydrochlorothiazide.254 Fatigue, fever, and dizziness have been reported in 0.5-1% of patients receiving enalaprilat.277 Vertigo has occurred in about 2% of patients receiving enalapril for heart failure and required discontinuance in about 0.1% of patients.245 Insomnia,1,136,254 nervousness,1,254 peripheral neuropathy (e.g., paresthesia,1,254 dysesthesia,1,254,277 asthenia,1,245,254 and somnolence1,254 occur in about 0.5-2% of patients receiving enalapril alone1 or in fixed combination with hydrochlorothiazide.254 Hyperesthesia of the oral mucosa,122 CNS depression,136 malaise,136,163 nightmares,136 confusion,1 ataxia,1 and coldness of the extremities136 have been reported rarely.

GI Effects

Diarrhea1,73,136,254 and nausea1,117,136,142,254 occur in about 1-2% of patients with hypertension receiving enalapril alone1,245 or in fixed combination with hydrochlorothiazide254 and in patients with heart failure receiving the drug,245 and have required discontinuance of the drug in 0.2% or less of patients.1,245,254 Nausea has been reported in about 1% of patients receiving enalaprilat.277 Abdominal pain, vomiting, stomatitis, and dyspepsia occur in 0.5-2% of patients receiving enalapril,1,245,254 and ulceration of the oral mucosa,42 ileus, melena, anorexia, glossitis, dry mouth, and flatulence1,45,254 have been reported rarely.45 Constipation has been reported in 0.5-1% of patients receiving enalaprilat.277

Hepatic Effects

A clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (which occasionally may be fatal), has been reported rarely in patients receiving ACE inhibitors.1 The mechanism of this reaction is not known.1

Cardiovascular Effects

The most frequent adverse cardiovascular effect of enalapril or enalaprilat is hypotension (including postural hypotension and other orthostatic effects), which occurs in about 1-2% of patients with hypertension and in about 5-7% of those with heart failure, following an initial dose or during extended therapy.1,57,117,122,142,144,146,148,150,152,163,164,165,245,260,277 Syncope occurred in approximately 0.5 or 2% of patients with hypertension or heart failure, respectively.1,165,245 Hypotension1,57,245 or syncope1,165,245 has required discontinuance of therapy in about 0.1 or 2% of patients with hypertension or heart failure, respectively, receiving enalapril.1,244,245

Hypotensive effects, including excessive and/or symptomatic hypotension, appear to occur more frequently in patients receiving enalapril for heart failure rather than for uncomplicated hypertension.245 Some reduction in blood pressure occurs in most patients receiving the drug for heart failure245,260 and generally is beneficial when secondary to afterload reduction;260 however, pronounced hypotension can occur and may adversely affect renal and myocardial perfusion (see later discussion in this section).1,57,152,245,260 Enalapril-induced hypotension may occasionally be alleviated by dosage reduction,122,148,150,260 but severe hypotension has also occurred after low doses (i.e., a single 2.5- or 5-mg dose) of the drug.57,152

The value of initiating enalapril therapy at low doses to decrease the risk of hypotension has not been fully elucidated,57,117 but such dosing has been suggested, particularly for patients at risk (e.g., those with heart failure).245,260 Orthostatic hypotension appears to occur more frequently during initiation of therapy1,57,122,152,163,164,165,245,260 and in patients with sodium depletion or hypovolemia.1,5,6,236,239,240,245,260 Transient hypotension in patients with heart failure or with hypertension may occur after any of the first several doses (i.e., with the first 24-48 hours),1,57,117,122,142,144,146,148,150,152,163,164,165,183,239,245,260 and sometimes is associated with dizziness,117,122,136,142,144,152,163,239 blurred vision,239 nausea,117 syncope,379 and, rarely, bradycardia.165 Patients who are volume and/or sodium depleted such as those receiving diuretics, especially those in whom diuretic therapy was recently initiated (e.g., patients with severe congestive heart failure),1,6,57,122,152,239,245,260 those whose sodium intake is severely restricted,1,6,239,260 and those who are undergoing dialysis,1,164,245 may occasionally experience a precipitous reduction in blood pressure within the first 3-4 hours after a dose of enalapril.1,57,122,152,163,164,165 The risk of orthostatic hypotension associated with concomitant use of enalapril and a diuretic may be affected by the sequence of initiation of therapy with each drug; the risk may be higher when enalapril is added to diuretic therapy than when a diuretic is added to enalapril therapy.4,122,231,244 Symptomatic hypotension that occurs later in a course of enalapril therapy (e.g., after the first 48 hours) may indicate the presence of sodium depletion (e.g., secondary to restriction of sodium intake or increased diuretic dosage).239

When enalapril was used in fixed combination with hydrochlorothiazide in clinical trials in hypertensive patients, hypotension, orthostatic hypotension, and other orthostatic effects occurred in 0.9, 1.5, and 2.3% of patients, respectively.254 Syncope occurred in 1.3% of patients receiving the fixed combination, but the frequency of this effect can be minimized by proper titration of each drug separately and substitution with the combination preparation only when the optimum dosages correspond to the fixed ratio in the preparation.254

Severe enalapril-induced hypotension may be associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure, myocardial ischemia, and/or death in patients with heart failure, hyponatremia, or severe sodium or volume depletion of any etiology; patients undergoing dialysis; and those receiving high-dose or recent intensive diuretic therapy or in whom the diuretic dosage was recently increased.57,152,260,600 In such patients, it may be advisable to discontinue diuretic therapy (except in patients with heart failure), reduce the diuretic dosage, or cautiously increase salt intake, if possible, prior to initiating therapy with enalapril.600 Patients at risk for excessive hypotension should be closely monitored after an initial dose of the drug,165,183,260,600 and should be followed closely for 2 weeks after initiation of enalapril therapy and whenever dosage of enalapril and/or a concomitantly administered diuretic is increased.1,245,260 Some experts state that patients with heart failure should be under very close medical supervision (e.g., in a hospital setting) when enalapril therapy is initiated, since severe hypotension could potentially compromise the patient's hemodynamic status.57,152,260 The risk of hypotension and potential detrimental hemodynamic and clinical effects in patients with severe heart failure appears to be higher during therapy with a long-acting ACE inhibitor such as enalapril than with a short-acting inhibitor.152

If hypotension occurs in patients receiving enalapril, the patient should be placed in the supine or Trendelenburg's position;1,4,5,245,254 if hypotension is severe or prolonged, IV infusion of 0.9% sodium chloride injection to expand fluid volume should be considered.1,4,5,183,245,254 Transient hypotension is not a contraindication to additional doses of enalapril, and therapy with the drug can usually be cautiously reinitiated after blood pressure has been stabilized (e.g., with volume expansion); enalapril dosage reduction and/or dosage reduction or discontinuance of concomitantly administered diuretics may be necessary.245 Some clinicians state that asymptomatic hypotension often does not require specific therapy and may be well tolerated with continued enalapril therapy.239 However, severe hypotension occasionally may require discontinuance of enalapril therapy,1,57,164 and the possibility should be considered that hypotension may persist for prolonged periods (e.g., for a week or longer) after discontinuance because of the drug's long duration of action.152,164 Patients with heart failure152 or those undergoing dialysis164 may be at particular risk of prolonged hypotension. The possibility of severe hypotension may be minimized by withholding diuretic therapy and/or increasing sodium intake for 2-3 days prior to initiating enalapril therapy.1,6,236,239,245

Hypotension also may occur in enalapril-treated patients during major surgery or during anesthesia with agents that produce hypotension.1 This hypotensive effect results from inhibition by enalapril of the angiotensin II formation that occurs subsequent to compensatory renin release, and, if it is thought to be caused by enalapril, can generally be corrected with fluid volume expansion.1

Palpitation1,136,254 and chest pain1,136,152,254 occur in about 0.5-2% of patients with hypertension receiving enalapril alone1 or in fixed combination with hydrochlorothiazide.254 Tachycardia,50,116 bradycardia,165 and development or worsening of Raynaud's phenomenon116 have been reported rarely in patients receiving the drug. Cardiac arrest or cerebrovascular accident, possibly secondary to excessive hypotension in high-risk patients, pulmonary embolism and infarction, pulmonary edema, rhythm disturbances (including atrial tachycardia and bradycardia), flushing, and atrial fibrillation have been reported in about 0.5-1% of patients with hypertension or heart failure.1,245,254 Angina or myocardial infarction (MI) was reported in about 1-1.5% of patients receiving enalapril for heart failure in controlled and uncontrolled studies, and required discontinuance in about 0.1-0.3% of patients, but a similar incidence for these effects was reported in patients receiving placebo in controlled studies.1,245 MI was reported in 0.5-1% of patients receiving enalaprilat.277

Renal Effects

Deterioration in renal function, manifested as transient increases in BUN and serum creatinine concentrations, has occurred in about 20% of patients with renovascular hypertension, especially those with bilateral renal-artery stenosis or those with renal-artery stenosis in a solitary kidney.1,6,50,116,161,167,169,231,234,379 This effect was usually reversible following discontinuance of enalapril and/or diuretic therapy.1,161,167,234,379 Renal function should be monitored closely during the first few weeks of therapy in these patients.1,245 (See Cautions: Precautions and Contraindications.) Transient increases in BUN and serum creatinine concentrations have also occurred in about 0.2% of patients with hypertension,1,166 but without preexisting renal vascular disease, who were receiving enalapril alone.1 These effects occur more frequently in patients receiving concomitant diuretic therapy,1,4,234,254,262 in patients with heart failure,4,42,152,168,225,239,260,262 and in patients with some degree of preexisting renal dysfunction.1 Dosage reduction of enalapril and/or dosage reduction or discontinuance of diuretic therapy may be necessary.1,42,152,166,236,239,260,262 The rapidity of onset and magnitude of enalapril-induced renal insufficiency in patients with heart failure may depend in part on the degree of sodium depletion.239,260,262 About 5-15 or 15-30% of patients with mild to moderate or severe heart failure, respectively, treated with an ACE inhibitor develop substantial elevations of serum creatinine concentrations (e.g., greater than 5 mg/dL).379 Acute reversible renal failure,42,79,152,170,234,236,237,245 flank pain,1,254,277 oliguria,42,245 uremia,50,158,166,168 glycosuria,166 and proteinuria6,9,168,247,249 have been reported rarely in patients receiving enalapril. Urinary tract infection has been reported in about 1% of patients receiving enalapril for heart failure in controlled and uncontrolled studies, but this effect occurred in about 2% of patients receiving placebo in controlled studies.245

Because the renin-angiotensin system appears to contribute substantially to maintenance of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly during therapy with an ACE inhibitor in these patients.152,225,239,245,260,262 Such drug-induced deterioration is generally well tolerated, and does not usually necessitate discontinuance of effective therapy with the drug when symptomatic improvement of the heart failure occurs.225,239 In addition, the magnitude of deterioration in renal function can usually be ameliorated by reducing the dosage of concomitantly administered diuretics and/or by liberalizing dietary sodium intake, since concomitant diuretic therapy and/or sodium restriction potentially increase the role of angiotensin II in maintaining glomerular filtration in these patients.225,239,260,262 In patients in whom renal perfusion pressure is very low and is further reduced by ACE-inhibitor therapy, however, deterioration in renal function may be clinically important.225,233,234,262 Patients with concomitant underlying diabetes mellitus may be at particular risk for developing renal insufficiency during ACE-inhibitor therapy.262 In some patients with severe heart failure, with or without associated renal insufficiency, treatment with an ACE inhibitor, including enalapril, may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death.152,245,254,262 The risk of developing functional renal insufficiency appears to be higher during therapy with a long-acting ACE inhibitor such as enalapril than with a short-acting inhibitor.152,262,265

Dermatologic and Sensitivity Reactions

The most frequent adverse dermatologic effect of enalapril is rash,1,4,42,171,172,185,245,254 which occurs in about 1.5% of patients245 and is usually maculopapular and rarely urticarial.172,185 Rash may sometimes be accompanied by pruritus,4,185 erythema,171 or eosinophilia,172 and has required discontinuance of the drug in approximately 0.3% of patients.1,42 A patient who developed enalapril-induced rash was subsequently treated with captopril without recurrence.185 However, the frequency of enalapril-induced rash appears to be less than that of captopril, possibly because enalapril lacks the sulfhydryl group,1,4,5,23,115,142,143,144,145,211,226,242,251 and several patients who developed captopril-induced rash have subsequently been treated with enalapril without recurrence of rash.61,115,145,211 Rash has been reported in 0.5-1% of patients receiving enalaprilat.277

Pruritus, without rash,1,4,158,254 and excessive sweating1,128,136,254 have been reported in 0.5-2% of patients receiving enalapril alone1 or in fixed combination with hydrochlorothiazide.254 Alopecia has been reported in 0.5-1% of patients receiving enalapril.245 A symptom complex, consisting of positive ANA titer, increased erythrocyte sedimentation rate (ESR), arthralgias and/or arthritis, myalgias, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash, and other dermatologic reactions has been reported in 0.5-1% of patients receiving enalapril therapy.245 Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, and erythema multiforme have been reported rarely in patients receiving enalapril therapy.1,277

Severe, sudden anaphylactoid reactions, which can be fatal, have been reported following initiation of hemodialysis that utilized a high-flux polyacrylonitrile [PAN] membrane (e.g., AN 69^®) in patients receiving an ACE inhibitor.1,254,277,302,304,306 Manifestations of these reactions included nausea, abdominal cramps, burning, angioedema, and shortness of breath; progression to severe hypotension can develop rapidly.302,304,306,333 Dialysis should be stopped immediately and aggressive supportive and symptomatic therapy should be initiated as indicated.302 Antihistamines do not appear to be effective in providing symptomatic relief.302 While it currently does not seem to be necessary to exclude the use of ACE inhibitors in patients undergoing hemodialysis that involves PAN membranes, caution should be exercised during concomitant use.302 The mechanism of this interaction has not been established, and the incidence and risk of its occurrence remain to be elucidated.302 The possibility that ACE inhibitors may precipitate similar reactions in patients undergoing hemodialysis involving other membrane types (new or reprocessed) should be considered.302 In addition, anaphylactoid reactions also have been reported in patients undergoing low-density lipoprotein (LDL) apheresis with dextran sulfate absorption.1,254,277,319,320,321 Manifestations of these reactions included flushing, dyspnea, bradycardia, and hypotension.319,320,321 It has been postulated that these reactions may be associated with accumulation of polypeptides (e.g., bradykinin) since endogenous concentration of such polypeptides may be increased by LDL-apheresis with dextran sulfate and their metabolism may be decreased by ACE inhibitors.254,277,319,320 To avoid these anaphylactoid reactions, some clinicians recommend withdrawal of ACE inhibitors 12-30 hours before apheresis,319,321 while others state that ACE inhibitors should not be used in patients treated with LDL apheresis.321

Life-threatening anaphylactoid reactions have been reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom. When ACE inhibitors were temporarily discontinued 24 hours before desensitization with the venom, anaphylactoid reactions did not recur;1,254,277 however, such reactions recurred after inadvertent rechallenge.1,254,277

Angioedema of the face, lips, tongue, larynx, glottis, or extremities has occurred in patients receiving ACE inhibitor therapy, including enalapril.1 (See Cautions: Precautions and Contraindications.) In addition, intestinal angioedema (occasionally without a prior history of facial angioedema or elevated serum levels of complement 1 [C1] esterase inhibitor) has been reported in patients receiving ACE inhibitors.452 Intestinal angioedema, which frequently presents as abdominal pain (with or without nausea or vomiting), usually is diagnosed by abdominal CT scan, ultrasound, or surgery;452 manifestations usually have resolved after discontinuance of the ACE inhibitor.452 Intestinal angioedema should be considered in the differential diagnosis of patients who develop abdominal pain during therapy with an ACE inhibitor.452

Hematologic Effects

Decreases in hemoglobin and hematocrit averaging approximately 0.3 g/dL and 1%, respectively, occur frequently in hypertensive patients receiving enalapril alone or in fixed combination with hydrochlorothiazide,1,171,232,254 but rarely are clinically important unless another cause of anemia also exists.1 Enalapril-induced anemia has required discontinuance of therapy in less than 0.1% of patients.1 Hemolytic anemia, including cases of hemolysis in a few patients with glucose-6-phosphate-dehydrogenase (G-6-PD) deficiency, has been reported in patients receiving enalapril maleate therapy; a causal relationship has not been established.1,245,254,277

Neutropenia (less than 1000 neutrophils/mm³) and agranulocytosis, both associated with myeloid hypoplasia, have occurred rarely in patients receiving captopril.1,215,226,227 (See Cautions: Hematologic Effects, in Captopril 24:32.04.) Several cases of neutropenia, agranulocytosis, or thrombocytopenia have been reported, and a causal relationship to enalapril cannot be excluded.1,6,175 Because of pharmacologic and structural similarities between captopril and enalapril and the current lack of sufficient data to establish the relative risk of these adverse hematologic effects in patients receiving enalapril, the possibility that bone marrow depression, neutropenia, and agranulocytosis could occur in patients receiving enalapril should be considered.1 Experience with captopril indicates that patients with renal impairment, especially those with collagen vascular disease, appear to be at increased risk of these adverse hematologic effects,1,223,226 and complete and differential leukocyte counts should be performed periodically during enalapril therapy in these patients.1 Enalapril lacks a sulfhydryl group,5,23,108,142,143,144,145,251 the structural feature suggested as being associated with this toxicity in patients receiving captopril;5,23,108 however, this structural relationship has not been established and the lack of this group in enalapril may not exclude the possibility of these effects in patients receiving the drug.231

Effects on Taste

Loss of taste perception4,6,9 and decrease in taste acuity4,136,175,242 have been reported infrequently during enalapril therapy. Hyperesthesia of the oral mucosa has occurred in at least one patient receiving enalapril but was reversible following discontinuance of the drug.122 Patients with intolerable captopril-induced taste disturbances may tolerate enalapril better.115,145

Effects on Potassium

Although small increases (i.e., by an average of 0.2 mEq/L) in serum potassium concentrations frequently occur in patients receiving enalapril without a thiazide diuretic,1 hyperkalemia (i.e., increases to greater than 5.7 mEq/L) occurs in approximately 1 or 4% of patients with hypertension or heart failure, respectively, receiving the drug.1,50,116,174,245 In most cases, these were isolated increases that resolved despite continued therapy with the drug; however, hyperkalemia required discontinuance of enalapril therapy in about 0.3% of patients receiving the drug for hypertension.245 Hyperkalemia is less frequent in patients receiving enalapril and hydrochlorothiazide concomitantly, occurring in about 0.1% of patients.254 Patients with diabetes mellitus, impaired renal function, or heart failure and patients concomitantly receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes) may be at increased risk of developing hyperkalemia during enalapril therapy;1,64,152,172,174,235,239,245,254 serum potassium concentration should be monitored frequently in these patients,1,235,245 and potassium intake should be controlled and therapy with drugs that can increase serum potassium modified or discontinued as necessary.152,235,239,245 The manufacturer recommends that potassium-sparing diuretics generally not be used in patients receiving enalapril for heart failure.245

Respiratory Effects

Cough has been reported in 1.3 or 3.5% of patients receiving enalapril alone or in fixed combination with hydrochlorothiazide for hypertension, respectively,1,173,245,252,253,254,256,257,258 and in about 2% of those receiving the drug for heart failure;245 discontinuance of the drug was required in less than 0.5% of patients.1,254,256 Nonproductive cough, particularly at night, may occur more frequently, especially in patients with chronic obstructive pulmonary disease.231 Some clinicians state that cough often is overlooked as a potential adverse effect of ACE inhibitors173,231 and may occur more frequently (in about 5-15% of patients).379 The cough generally is persistent and nonproductive,1,277 is not associated with other respiratory symptoms,173,241,252,256,258 and is reversible following discontinuance of the drug.1,173,241,252,256,258,277 Nasal congestion also has been reported.259 It has been suggested that accumulation of kinins in the respiratory tract secondary to ACE inhibition may in part be responsible for cough and nasal congestion.1,173,241,253,254,259 Concomitant therapy with a nonsteroidal anti-inflammatory agent (i.e., sulindac) appeared to minimize cough in a few patients, but additional study of the safety (e.g., effects on renal function) of such combined therapy is necessary.257 If cough develops in a patient receiving enalapril, ACE inhibitor-induced cough should be considered as part of the differential diagnosis.1,254,277

Dyspnea1,136,173 and wheezing,173 which may persist if therapy with the drug is continued,173 have been reported in about 1% or less of patients receiving enalapril.245 Pneumonia or bronchitis has been reported in about 1% of patients receiving enalapril for heart failure.245 Asthma, upper respiratory infection, bronchospasm, pulmonary infiltrates, eosinophilic pneumonitis, 407 and rhinorrhea also have been reported in patients receiving enalapril maleate therapy.1,254,277 Angioedema has occurred in 0.2 or 0.6% of patients receiving enalapril alone or in fixed combination with hydrochlorothiazide, respectively, and, if associated with laryngeal edema, may be fatal.245,254 ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied.1,348,349 (See Cautions: Precautions and Contraindications.)

Other Adverse Effects

Muscle cramps,1,245,254 and impotence1,136,163 have been reported in 0.5-1% of patients receiving enalapril alone,1 and decreased libido has been reported rarely.122 These effects have occurred more frequently when the drug was administered in fixed combination with hydrochlorothiazide.254 Hearing loss, which was reversible following discontinuance of the drug, has been reported rarely; however, the mechanism of this adverse effect is not known.255 Pancreatitis, hepatitis or cholestatic jaundice, hepatic failure, sore throat, hoarseness, anosmia, conjunctivitis, dry eyes, tearing eyes, gynecomastia, and myalgia have been reported in patients receiving enalapril.1,245,254,272,274,277 Vulvovaginal pruritus, burning urination, and dysuria were reported in at least one patient receiving enalapril.275

Although a definite causal relationship to enalapril has not been established, elevations of serum hepatic enzymes and/or bilirubin concentrations have been reported rarely when enalapril was administered alone or in fixed combination with hydrochlorothiazide.1,129,254

Precautions and Contraindications

Since enalapril is metabolized to enalaprilat, both drugs share the same cautions, precautions, and contraindications.1,277 Because captopril, another ACE inhibitor, can cause serious adverse effects (e.g., neutropenia, agranulocytosis), particularly in patients with renal impairment (especially those with collagen vascular disease),1,208,209,210 the possibility that similar adverse effects may occur with enalapril should be considered.1,175 Periodic monitoring of leukocyte counts should be considered in these patients.1 (See Cautions: Hematologic Effects.) Patients should be instructed to notify their clinician if any sign or symptom of infection such as fever or sore throat occurs.1 When enalapril is used in fixed combination with hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with enalapril.254 To minimize dose-independent adverse effects, it is recommended that therapy with enalapril in fixed combination with hydrochlorothiazide only be initiated in patients in whom an adequate response is not achieved with enalapril or hydrochlorothiazide monotherapy.254,348

Renal function should be evaluated prior to initiation of enalapril therapy,231,245 and the drug should be used with caution in patients with renal impairment, particularly those with known or suspected renovascular disease.1,93,94,96,161,167,231,233,234,237 Reduction of enalapril dosage, reduction in dosage or discontinuance of diuretic therapy, and/or adequate sodium repletion may be necessary in some patients who develop impaired renal function during enalapril therapy.1,93,96,152,237,239,260,262 Because of an increased risk of reducing renal perfusion to a critically low level, enalapril should be used with caution and renal function monitored closely for the first few weeks of therapy in patients with bilateral renal-artery stenosis and those with renal-artery stenosis in a solitary kidney.1,50,116,167,231,233,234 Serum creatinine and electrolyte concentrations should be evaluated prior to and 1 week following initiation of therapy with ACE inhibitors in patients with heart failure.410 In patients with heart failure who have some degree of renal impairment (baseline serum creatinine concentrations less than 2 mg/dL) or more severe renal impairment (baseline serum creatinine concentrations exceeding 2 mg/dL), an increase in serum creatinine concentration exceeding 0.5 or 1 mg/dL, respectively, should prompt consideration of discontinuing ACE inhibitor therapy while additional renal evaluation and corrective action is undertaken. 410 The possibility that ACE inhibitors might precipitate severe, sudden, potentially life-threatening anaphylactoid reactions in patients undergoing hemodialysis involving a high-flux membrane should be considered.1,254,277,302,304,306,410 (See Cautions: Dermatologic and Sensitivity Reactions.)

Enalapril should be used with caution in patients with sodium depletion or hypovolemia, those receiving diuretics, and those undergoing dialysis since severe hypotension may occur.1,236,239,240,245 The drug should also be used with caution in patients in whom excessive hypotension may have serious consequences (e.g., patients with coronary or cerebrovascular insufficiency).152,245 Because of the potential decrease in blood pressure in patients with heart failure, enalapril therapy should be initiated under very close medical supervision in these patients.1,152,183,184,245,260 (See Cautions: Cardiovascular Effects.) Like all vasodilators, enalapril should be administered with caution in patients with obstruction in the outflow tract of the left ventricle (e.g., aortic stenosis, hypertrophic cardiomyopathy).407 Patients at risk for excessive hypotension should be monitored closely for the first 2 weeks of therapy and whenever the dosage of enalapril and/or a concomitantly administered diuretic is increased.1,245,260,600 Patients receiving enalapril therapy should be informed that vomiting, diarrhea, excessive perspiration, and dehydration may lead to an exaggerated decrease in blood pressure because of fluid volume reduction; patients should notify their clinician if any of these conditions occurs.1 Patients should also be warned to report light headedness, especially during the first few days of therapy; if actual syncope occurs, they should discontinue enalapril therapy and contact their clinician.1 Since therapy with ACE inhibitors has been associated with development of a rare syndrome that usually is manifested initially by cholestatic jaundice, which may progress to fulminant hepatic necrosis and occasionally may be fatal, patients receiving an ACE inhibitor, including enalapril, who develop jaundice or marked elevations of hepatic enzymes should discontinue the drug and receive appropriate medical follow-up.1 (See Cautions: Hepatic Effects.)

Angioedema may occur, especially following the first dose of enalapril, and, if associated with laryngeal edema, may be fatal.245,254 If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, enalapril should be discontinued and the patient carefully observed until swelling disappears.245,254 If swelling is confined to the face and lips, the condition generally responds without treatment; however, antihistamines may provide symptomatic relief.245,254 Swelling of the tongue, glottis, or larynx may cause airway obstruction, and appropriate therapy (e.g., epinephrine, maintenance of patent airway) should be initiated immediately.1,245,254 Patients should be informed that swelling of the face, eyes, lips, or tongue or difficulty in breathing may be signs and symptoms of angioedema, and that they should discontinue enalapril and notify their clinician immediately if any of these conditions occurs.1 The possibility that patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of developing angioedema while receiving the drugs should be considered.1,254,277 Enalapril is contraindicated in patients with a history of angioedema related to ACE inhibitor therapy and those with hereditary or idiopathic angioedema.1,407 Enalapril also is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1

Pediatric Precautions

Antihypertensive effects of enalapril maleate have been established in hypertensive pediatric patients 1 month to 16 years of age.1 Enalapril maleate is not recommended for neonates or for pediatric patients with a glomerular filtration rate of less than 30 mL/minute per 1.73 m², since no data are available.1 The adverse effect profile of enalapril maleate in pediatric patients is similar to that in adults.1 Safety and efficacy of enalaprilat injection or of enalapril in fixed combination with hydrochlorothiazide in children have not been established.245,254 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Geriatric Precautions

Clinical studies of enalapril in fixed combination with hydrochlorothiazide did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.455 While other clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.455 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.455 Enalapril is substantially eliminated by the kidneys; because geriatric patients may have decreased renal function and because patients with renal impairment may be at increased risk of toxicity, renal function should be monitored and dosage should be selected carefully.455

Mutagenicity and Carcinogenicity

No evidence of enalapril- or enalaprilat-induced mutagenicity or of mutagenicity induced by concomitant testing of enalapril and hydrochlorothiazide was seen with an in vitro microbial test system (Ames test) with or without metabolic activation.245,254,277 Enalapril alone or combined with hydrochlorothiazide also was not mutagenic in several other in vitro test systems, including mammalian systems,1,2 and in in vivo cytogenetic tests using mouse bone marrow.1,254

No evidence of carcinogenesis was seen in rats or in male and female mice receiving enalapril maleate dosages up to 90 or 90 and 180 mg/kg daily, respectively (about 26 or 13 times the maximum daily human dosage on a mg/m² basis, respectively), for 106 or 94 weeks, respectively.1,2,254 Carcinogenicity studies have not been performed with enalaprilat.277

While an excess rate of GI cancer relative to placebo has been observed in several large trials in patients receiving prolonged ACE-inhibitor therapy, a causal relationship to the drugs has not been established.293,298 Some evidence suggests that such a relationship is unlikely since the observed risk did not increase with increasing exposure to the drugs and because of the heterogeneity of the reported cancers (involving the rectum, cecum, colon, esophagus, stomach, gallbladder, pancreas, or liver).293,298 However, the possibility of a causal relationship cannot be excluded, and additional study to further elucidate any possible relationship between use of ACE inhibitors and these cancers is necessary.298

Pregnancy, Fertility, and Lactation

Pregnancy

Fetal and neonatal morbidity and mortality have been reported in at least 50 pregnant women who were receiving ACE inhibitors during pregnancy.1,245,254,263,277,296,297,303 Very limited epidemiologic data indicate that the rate of fetal and neonatal morbidity resulting from exposure to ACE inhibitors during the second and third trimesters may be as high as 10-20%.297 Hypotension, reversible or irreversible renal failure, anuria, skull hypoplasia (defective skull ossification in some cases), and/or death were reported in neonates whose mothers had received ACE inhibitors during the second and third trimesters of pregnancy.1,245,254,263,276,277,296,297,303,305 In one premature neonate (35 weeks' gestation) born with acute, reversible renal failure following exposure to enalapril for several weeks prior to delivery, plasma ACE activity was completely suppressed at birth, and plasma active and total renin concentrations and renin activity were substantially increased in the neonate; the renal failure was managed with peritoneal dialysis, which was discontinued after 10 days.263 Other adverse effects associated with such use included oligohydramnios, presumably due to decreased renal function in the fetus,1,245,254,277,296,303 prematurity, fetal death, and patent ductus arteriosus; however, it is not known whether these effects were associated with ACE inhibition or underlying maternal disease.1,245,254,277 Oligohydramnios has been associated with contractures of the limbs, craniofacial deformities, hypoplasia of the lungs, and intrauterine growth retardation.1,254,277,296,297

Although fetal exposure limited to the first trimester previously was considered not to be associated with substantial risk, data from an epidemiologic study have shown that infants whose mothers had taken an ACE inhibitor during the first trimester of pregnancy have an increased risk of major congenital malformations compared with infants who had not undergone first trimester exposure to ACE inhibitors.453,454 The risk of major congenital malformations, primarily affecting the cardiovascular and central nervous systems, was increased by about 2.7 times in infants whose mothers had taken an ACE inhibitor during the first trimester of pregnancy compared with infants who had not undergone such exposure.453,1,254,277,296 Every effort should be made to discontinue enalapril or enalaprilat therapy as soon as possible in any woman who becomes pregnant while receiving either of the drugs, regardless of the period of gestation.1,254,277,296,453,454 In addition, all women of childbearing potential who are receiving an ACE inhibitor should be advised to report pregnancy to their clinician as soon as possible.1,254,277,296 Women of childbearing potential who are receiving an ACE inhibitor also should be advised to inform their clinician if they are planning to become pregnant or think they might be pregnant.454 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.297 Rarely (probably less frequently than once in every 1000 pregnancies), no adequate alternative can be identified; in such rare cases, the woman should be informed of the potential hazard to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment.1,254,277,296 If oligohydramnios is present, enalapril therapy should be discontinued, unless use of the drug is considered life-saving for the woman.1,254,277,296 Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling may be performed, if appropriate depending on the period of gestation.1,254,277,296 However, both clinicians and patients should realize that oligohydramnios may not become apparent until after irreversible fetal injury already has occurred.1,254,277,296

Infants exposed in utero to ACE inhibitors should be observed closely for hypotension, oliguria, and hyperkalemia.245,254,277,296 If oliguria occurs, supportive measures (e.g., administration of fluids and pressor agents) to correct hypotension and renal perfusion should be considered.1,245,254,277,296 Exchange transfusion or dialysis may be required to reverse hypotension and/or substitute for impaired renal function.1,254,277,296 Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit.1,254,277 The manufacturer states that the drug theoretically may be removed by exchange transfusion; however, this latter procedure has not been used to date.1

Reproduction studies in rats using enalapril maleate dosages up to 200 mg/kg daily (about 333 times the maximum daily human dosage) have not revealed evidence of teratogenicity or fetotoxicity.1,2 Decreases in average fetal weight occurred in rats receiving enalapril maleate dosages of 1200 mg/kg daily,1 but fetotoxicity did not occur when rats received a diet supplemented with sodium chloride.1,2 Fetotoxicity (decreased fetal weight) has been observed in rats receiving oral dosages up to 90 mg/kg of enalapril maleate combined with 10 mg/kg of hydrochlorothiazide daily (representing 26 and 1.6 times the maximum recommended human daily dosage of enalapril maleate and hydrochlorothiazide, respectively, on a mg/m² basis) and in mice receiving combined oral therapy with up to 30 and 10 mg/kg daily of enalapril maleate and hydrochlorothiazide, respectively (representing 4.3 and 0.8 times the maximum recommended human daily dosage of enalapril maleate and hydrochlorothiazide, respectively, on a mg/m² basis), but did not occur when lower dosages of enalapril maleate (30 and 10 mg/kg daily, respectively) were combined with 10 mg/kg of hydrochlorothiazide daily in these animals.254 Reproduction studies in rabbits receiving enalapril maleate dosages up to 30 mg/kg daily during days 6-18 of gestation did not reveal evidence of teratogenicity, but maternotoxicity and fetotoxicity occurred in rabbits at dosages of 1 mg/kg daily.1,2 Fetotoxicity and maternotoxicity did not occur in rabbits receiving enalapril maleate dosages of 3-10 mg/kg daily when their diet was supplemented with sodium chloride, but did occur at dosages of 30 mg/kg daily even when the diet was supplemented.1,2

Fertility

Reproduction studies in male and female rats using enalapril maleate dosages of 10-90 mg/kg daily (representing up to 4.3 and 0.8 times the maximum recommended human daily dosage of enalapril maleate and hydrochlorothiazide, respectively, on a mg/m² basis) have not revealed adverse effects on reproductive performance.1 Impotence1,136,163,254 and decreased libido122,254 have been reported occasionally in patients receiving enalapril alone or in fixed combination with hydrochlorothiazide.

Lactation

Because enalapril alone or thiazide diuretics alone are distributed into human milk and potentially may cause serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or enalapril (either alone or in fixed combination with hydrochlorothiazide), taking into account the importance of the drug(s) to the woman.1,254

In addition to the drug interactions described, the possibility that other drug interactions reported with other angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril) might occur with enalapril should be considered.261

Hypotensive Agents and Diuretics

When enalapril is administered with diuretics or other hypotensive drugs, the hypotensive effect of enalapril is increased.1,4,5,9,110,116,119,120,122,123,124,127,128,129,130,137,140,142,143,144,155,163,203,220 The effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly.1

Enalapril and diuretics appear to have additive hypotensive effects;1,4,120,122,128,129,131,254 however, severe hypotension1,236,239,240 and reversible renal insufficiency1,4,234,239 may occasionally occur, especially in volume- and/or sodium-depleted patients.1,5,6,236,239,240 (See Cautions: Cardiovascular Effects; and Renal Effects.) Hypotensive drugs that cause release of renin (e.g., diuretics) will increase the hypotensive effect of enalapril.1 Reduction of enalapril dosage and/or dosage reduction or discontinuance of diuretic therapy may be necessary.1,6,42,152,166,236,239 Patients should be monitored closely during initiation and dosage adjustment of concomitant therapy with enalapril and a diuretic; in patients already receiving diuretics, the risk of these effects may be minimized by withholding diuretic therapy and/or increasing sodium intake for 2-3 days prior to initiating enalapril therapy.1,6,236,239 If diuretic therapy cannot be withheld, the patient should be under medical supervision for at least 2 hours after the initial dose of enalapril and until blood pressure has stabilized for at least an additional hour.1

Drugs Increasing Serum Potassium Concentration

Potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes should be used with caution and serum potassium should be determined frequently in patients receiving enalapril, since hyperkalemia may occur.245 Dosage of the potassium-sparing diuretic and/or potassium supplement should be reduced or the diuretic and/or supplement discontinued as necessary.235,239,245 The manufacturer recommends that potassium-sparing diuretics generally not be used in patients receiving enalapril for heart failure.245 However, ACE inhibitors have been administrated with low-dosage spironolactone therapy and hyperkalemia was reported rarely.375,377,381 (See Uses: Heart Failure.) Patients should be advised to not use potassium-containing salt substitutes unless otherwise instructed by their clinician.245,254 Patients with renal impairment may be at increased risk of hyperkalemia.235,245

Nonsteroidal Anti-inflammatory Agents

Because ACE inhibitors may promote kinin-mediated prostaglandin synthesis and/or release, concomitant administration of drugs that inhibit prostaglandin synthesis (e.g., aspirin, ibuprofen) may reduce the blood pressure response to ACE inhibitors, including enalapril.322,323,324,325,326,327,328,329 404 Limited data indicate that concomitant administration of ACE inhibitors with nonsteroidal anti-inflammatory agents (NSAIAs) occasionally may result in acute reduction of renal function;324,330 however, the possibility cannot be ruled out that one drug alone may cause such an effect.324,404 Blood pressure should be monitored carefully when an NSAIA is initiated in patients receiving ACE inhibitor therapy; in addition, clinicians should be alert for evidence of impaired renal function.324 Some clinicians suggest that if a drug interaction between an ACE inhibitor and an NSAIA is suspected, the NSAIA should be discontinued, or a different hypotensive agent used or, alternatively, the dosage of the hypotensive agent should be modified.324,325

Aspirin and other NSAIAs also can attenuate the hemodynamic actions of ACE inhibitors in patients with heart failure.379,404 Because ACE inhibitors share and enhance the effects of the compensatory hemodynamic mechanisms of heart failure, with aspirin and other NSAIAs interacting with the compensatory mechanisms rather than with a given ACE inhibitor per se, these desirable mechanisms are particularly susceptible to the interaction and a subsequent potential loss of clinical benefits.404 As a result, the more severe the heart failure and the more prominent the compensatory mechanisms, the more appreciable the interaction between NSAIAs and ACE inhibitors.404 Even if optimal dosage of an ACE inhibitor is used in the treatment of heart failure, the potential cardiovascular and survival benefit may not be seen if the patient is receiving an NSAIA concomitantly.379 In several multicenter studies, concomitant administration of a NSAIA (i.e., a single 350-mg dose of aspirin) in patients with heart failure inhibited favorable hemodynamic effects associated with ACE inhibitors, attenuating the favorable effects of these drugs on survival and cardiovascular morbidity.379,398,404 However, these findings have not been confirmed by other studies. In one retrospective analysis of pooled data, patients who received an ACE inhibitor concomitantly with aspirin (160- 325 mg daily) during the acute phase following myocardial infarction (MI) had proportional reductions in 7- and 30-day mortality rates comparable to patients who received an ACE inhibitor alone.403,404 Some clinicians have questioned the results of this study because of methodologic concerns (e.g., unsubstantiated assumptions about aspirin therapy [dosage, time of initiation, duration]; disparate distribution of patients).403,404 Although it has been suggested that patients requiring long-term management of heart failure avoid the concomitant use of ACE inhibitors and aspirin (and perhaps substitute another platelet-aggregation inhibitor for aspirin [e.g., clopidogrel, ticlopidine]),404 some clinicians state that existing data are insufficient to recommend a change in the current prescribing practices of clinicians concerning the use of aspirin in patients receiving therapy with an ACE inhibitor.706

Lithium

Lithium toxicity has occurred following concomitant administration of enalapril and lithium carbonate1,79,180 and was reversible following discontinuance of both drugs.1 In one patient, the toxicity was associated with elevated plasma lithium concentration and was manifested as ataxia, dysarthria, tremor, confusion, and altered EEG; bradycardia and T-wave depression also occurred.180 Moderate renal insufficiency (serum creatinine of 2.2 mg/dL)180 or acute renal failure79 has also occurred in these patients. The exact mechanism of this interaction remains to be established, but it has been suggested that enalapril may decrease renal elimination of lithium, possibly by increasing sodium excretion secondary to decreased aldosterone secretion or by altering renal function secondary to ACE inhibition.180 Renal function has returned to baseline within 2-4 days after discontinuing enalapril,79,180 and plasma lithium concentrations have returned to within normal limits following discontinuance of enalapril and temporary withdrawal of lithium therapy.180 The manufacturer of enalapril recommends that serum lithium concentrations be monitored frequently when enalapril and lithium are administered concomitantly.1

Other Drugs

Enalapril may reduce fasting blood glucose concentrations in nondiabetic individuals and may produce hypoglycemia in diabetic patients whose diabetes has been controlled with insulin or oral antidiabetic agents.176 Further studies are needed to evaluate the hypoglycemic effect of enalapril;176,177 however, similar effects have been reported in patients receiving captopril, and the risk of precipitating hypoglycemia should be considered when therapy with an ACE inhibitor is initiated in diabetic patients.229

Concomitant use of enalapril and some vasodilating agents (e.g., nitrates) or anesthetic agents may cause an exaggerated hypotensive response.1,5 Patients receiving enalapril concomitantly with nitrates or with anesthetic agents that produce hypotension should be observed for possible additive hypotensive effects.5 Fluid volume expansion can correct hypotension during surgery or anesthesia if it is thought to result from an enalapril-induced inhibition of the angiotensin II formation that occurs secondary to compensatory renin release.1

Acute Toxicity

Limited information is available on the acute toxicity of enalapril in humans.1,2,178,179 Specific information on overdosage with the fixed combination of enalapril and hydrochlorothiazide currently is not available.254

Pathogenesis

The oral LD₅₀ of enalapril maleate ranged from 2000-3500 mg/kg in mice and male rats and 2000-3000 mg/kg in female rats.2,112 The IV LD₅₀ ranged from 700-950 mg/kg in female mice and male rats,2,12 and the subcutaneous LD₅₀ was 1150, 1400, 1500, and 1750 mg/kg in male mice, female rats, female mice, and male rats, respectively.2 The IV LD₅₀ of enalaprilat was 3740-5890 mg/kg in female mice.277 In clinical studies, some hypertensive patients received a maximum IV enalaprilat dose of 80 mg over a 15-minute period, but no adverse effects other than those associated with the recommended dosages were observed.277 In animals, sublethal doses of enalapril produced ptosis, decreased activity, and bradypnea.2 In dogs, a single 200-mg/kg dose was lethal, but a single 100-mg/kg dose was not toxic.2 In mice and rats, single oral doses exceeding 1000 mg/kg or at least 1775 mg/kg, respectively, were lethal.254

Manifestations

Overdosage of enalapril produces effects that are mainly extensions of the drug's pharmacologic effects as an ACE inhibitor.1,2,178,179 Plasma ACE activity was completely suppressed within 10-15 hours after acute ingestion of 300-440 mg of enalapril maleate in 2 patients.178,179 The most likely manifestation of enalapril overdosage is hypotension,1,2,178,179 which may be profound.179 Onset and duration of the hypotensive effect may be prolonged following acute overdosage.178,179 Hypotension may be accompanied by stupor.178,179 Renal dysfunction, including acute renal failure;2,179 hyperkalemia;179 and hyponatremia179 may also occur.

Treatment

Management of enalapril overdosage is mainly supportive and symptomatic.1,2,178,179,231 Hypotension can be corrected with fluid volume expansion (e.g., IV infusion of 0.9% sodium chloride injection).1,2,178,179 Renal function also improves during supportive therapy with sodium chloride infusion.179 Because of the long ACE-inhibitory effect of enalapril, prolonged observation (e.g., for several weeks) and supportive treatment may be necessary following overdosage with the drug.178,179 Treatment of acute oral overdosage may also include gastric lavage and administration of activated charcoal to prevent further GI absorption of the drug.2 The active metabolite enalaprilat may be removed by hemodialysis.1,2,89,94 Management of overdosage with the fixed combination of enalapril and hydrochlorothiazide should also include measures for the management of thiazide overdosage.254

Pharmacology

Enalapril maleate is a prodrug of enalaprilat and has little pharmacologic activity until hydrolyzed in vivo to enalaprilat.1,2,4,5,6,7,8,16,17,20 Pharmacologic effects described for enalapril generally apply to enalaprilat, although the latter drug is substantially more potent on a weight basis. The mechanism(s) of action of enalaprilat and enalapril have not been fully elucidated.5,24,27,28,34,277 The drugs appear to reduce blood pressure in normotensive individuals45,47,49,52,55,60,65,69,70,71,72,74,77 and hypertensive patients41,43,46,48,50,51,54,56,62,66,68,73,75,78,79,80,81,82 and to produce beneficial hemodynamic effects in patients with heart failure42,44,57,61,63,64,67 mainly by suppressing the renin-angiotensin-aldosterone system.1,2,4,5,10,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,277

Effects on Renin-Angiotensin-Aldosterone System

Enalapril prevents the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) through inhibition of angiotensin-converting enzyme (ACE).1,2,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75 The drug competes with physiologic substrate (angiotensin I) for the active site of ACE;1,2,23,85,92 the affinity of enalaprilat for ACE is approximately 200,000 times greater than that of angiotensin I.244 In vitro on a molar basis, the affinity of enalaprilat for ACE is 300-1000 or 2-17 times that of enalapril16,17,20 or captopril,14,15,16,17,18,20,21,22 respectively. However, in vitro on a molar basis, the ACE-inhibitory effect of enalapril was shown to be similar to that of enalaprilat in rat plasma and kidneys, because these tissues extensively hydrolyze enalapril to form enalaprilat.20 The drug apparently does not inhibit brain ACE in animals.24,196

Inhibition of ACE initially results in decreased plasma angiotensin II concentrations and, consequently, blood pressure may be reduced in part through decreased vasoconstriction.1,2,41,42,43,44,45,46,47,49,51,58,224 Plasma renin activity (PRA) increases,1,2,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,62,69,70,73,76 possibly as a result of loss of feedback inhibition (mediated by angiotensin II) on the release of renin from the kidneys1,4,11,33,41,44,61,77 and/or stimulation of reflex mechanisms via baroreceptors (as a result of the decrease in blood pressure).41,70,71 Enalapril-induced increases in PRA are greater in the upright than in the supine position,53 and the effects of the drug on PRA and plasma angiotensin II concentrations may be potentiated by restriction of sodium intake.10,42,46,47,55,56 The initial hypotensive effect of enalapril appears to be proportional to inhibition of ACE in blood,41,46,49,52,56,224 but the hypotensive effect of the drug appears to persist longer than decreased angiotensin II concentrations.51,58,59,60,62 It has been suggested that the hypotensive effect of ACE inhibitors may in part also result from a local effect (e.g., in vascular wall).11,27,40,196,216,224,228 By decreasing local angiotensin II production, ACE inhibitors may decrease vascular tone by reducing direct angiotensin II-induced vasoconstriction and/or angiotensin II-induced increases in sympathetic activity.11,27,40,224 During prolonged enalapril use, plasma angiotensin II concentrations may return toward pretreatment levels,51,58,60 and inhibition of the renin-angiotensin system in various tissues (e.g., arterial wall, kidneys) rather than in blood may be more important determinants of the hypotensive effect of the drug, particularly long term.11,27,40,196,216,221,224,228

Enalapril alone may be more effective in reducing blood pressure in patients with high or normal renin hypertension,42,50,51,64 but the drug may also lower blood pressure in patients with low renin hypertension.1,2,66,67 Although enalapril has lowered blood pressure in all races studied, the drug was less effective in black hypertensive patients, a population associated with low renin hypertension.1,2,9,78,121 Correlation between pretreatment PRA and short-term reduction in blood pressure has varied.5,41,67,68,73 Some clinicians have reported no correlation between pretreatment PRA and short-term reduction in blood pressure,41,43,44,67,69,73,80,81,108,142 while others have reported initial decreases in blood pressure to be proportional to pretreatment PRA.50,68,73 Correlation between pretreatment PRA and long-term response to the drug has not been consistently found.50,67

Initial decreases in plasma angiotensin II concentrations lead to decreased aldosterone secretion from the adrenal cortex and, therefore, to decreased plasma concentrations and urinary excretion of aldosterone.1,2,41,42,43,44,45,46,47,49,51,52,53,54,60,76,250 However, there is increasing evidence to suggest that plasma aldosterone concentrations may not decrease with usual dosages of ACE inhibitors in some patients64,77 and may return to pretreatment levels in others during prolonged therapy.46,48,50,250,375,381,388,389,390,397 In addition, plasma aldosterone concentrations may not accurately reflect changes in aldosterone secretion, and reductions in these concentrations are usually greater when measured during ambulation than during rest in the supine position.53 It has been suggested that the addition of spironolactone, a drug that competitively inhibits the physiologic effects of aldosterone, appears to augment the suppressive effect of ACE inhibitors on aldosterone.375,376,377,378,381,386,388 Enalapril has blunted secondary hyperaldosteronism in healthy individuals receiving diuretics; the drug corrected hypokalemia associated with thiazides and increased sodium excretion.11,162,230 The drug has also improved potassium balance, increased PRA, decreased aldosterone secretion, and reduced blood pressure in a limited number of patients with idiopathic hyperaldosteronism.238

Effects on Catecholamines and Autacoids

Circulating plasma norepinephrine concentration generally is not affected by enalapril,47,60,78,107 but the drug has reduced these concentrations in some patients with hypertension41,247 or heart failure.57,63 In addition, the drug has attenuated the increase in plasma norepinephrine concentration that results from orthostatic reflexes.62,64 By inhibiting angiotensin II formation, ACE inhibitors may affect catecholamine release and reuptake by noradrenergic nerve endings224 and/or may decrease vascular sensitivity to vasopressors.202,224 There is some evidence that high doses of ACE inhibitors may inhibit presynaptic norepinephrine release and postsynaptic α₂-adrenoceptor activity, thereby interfering with sympathetic reflexes, but the clinical importance of this finding is not known since dosages tested in animals substantially exceed usual human hypotensive dosages.11,221

Because ACE also degrades the vasodilator bradykinin, it has been suggested that inhibition of ACE may cause accumulation of bradykinin in plasma or tissues with resultant vasodilation;1,2,4,5,11,44,218,224 however, plasma and/or urinary concentrations of bradykinin and/or its metabolites have been unchanged in enalapril-responsive patients.46,56,60,65 Plasma and urinary concentrations of bradykinin may not indicate tissue activity of the peptide, and its role, if any, in the therapeutic effects of enalapril remains to be elucidated.1,2,5,11,57,65,83 It has been suggested that prostaglandins also may mediate some of the pharmacologic effects of enalapril since there is some evidence that the drug may increase prostaglandin production or release;66 however, most available evidence currently indicates that enalapril does not substantially affect prostaglandins, and further evaluation is necessary to determine the importance of any prostaglandin-mediated effects.47,57,60,66,76,77,81,224,246 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.) Urinary concentration of thromboxane and prostacyclin metabolites have been unchanged during enalapril therapy.11,217

Cardiovascular Effects

In hypertensive patients, enalapril reduces blood pressure by decreasing total peripheral resistance with a slight increase or no change in heart rate, stroke volume, or cardiac output.1,2,11,41,43,51,62,73,75,80,82 The drug causes arterial and possibly venous dilation.41,44,61,63,248 Enalapril generally decreases systolic and diastolic blood pressures by approximately 10-15%;1,2,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80 blood pressure is decreased to about the same extent in both the supine and standing positions.1,2,41,45,46,47,52,58 Orthostatic hypotension1,2,41,43,44,47,57,73,80,117,122,142,144,146,148,150,152,163,164,165 and tachycardia occur infrequently41,43,44,45,46,48 but are more common in sodium-depleted or hypovolemic patients.1,2,5,6 (See Cautions: Cardiovascular Effects.) Plasma volume has been reported to be unchanged54,78,123 or slightly increased;41,73 erythrocyte volume, extracellular fluid volume, and total body water have been unchanged.54,123 The drug appears to have no direct effect on baroreceptor sensitivity in normotensive45,69,72,74 or hypertensive73,75 individuals on a normal sodium diet. However, slight potentiation of baroreceptor sensitivity has been reported in mildly sodium-depleted individuals.70,71

In patients with heart failure, enalapril, usually in conjunction with cardiac glycosides and diuretics, decreases total peripheral resistance, pulmonary capillary wedge pressure, heart size, and mean arterial and right atrial pressures.42,44,57,63,64,225,245,260 Cardiac index, cardiac output, stroke volume, and exercise tolerance increase in these patients;42,44,57,61,63,64,225,245 mean ejection fraction increases245 or remains unchanged;245 and heart rate decreases slightly42,44,64 or is unchanged.57,63,245 The drug may also cause a regional redistribution of blood flow, principally increasing renal blood flow with slight or no increase in flow in the forearm or hepatic vasculature, respectively.61

Renal and Electrolyte Effects

Renal blood flow may increase, but glomerular filtration rate is usually unchanged during enalapril therapy.1,44,46,48,55,61,75,77 In some patients, however, both renal blood flow and glomerular filtration rate have increased.54,79,124,262 BUN and serum creatinine concentrations have occasionally increased during long-term enalapril therapy.1,50,116,166,167,169,225 Increased BUN and serum creatinine occur more frequently in patients with preexisting renal impairment, in those receiving concomitant therapy with a diuretic,1,4,6,50,116,161,167,169,236,237,262 and in those with heart failure.4,42,152,168,225,236,237,262 However, in some hypertensive patients with preexisting renal impairment, renal blood flow and glomerular filtration rate have increased, presumably secondary to enalapril-induced intrarenal effects.54,111,125,126,231 In patients with heart failure and renal perfusion pressures less than 70 mm Hg, changes in creatinine clearance induced by 1-3 months of enalapril therapy have varied linearly and inversely with pretreatment PRA; however, creatinine clearance was not substantially affected by the drug in patients with renal perfusion pressures of 70 mm Hg or greater.225 Enalapril's effects on renal blood flow and glomerular filtration in patients with renovascular hypertension appear to be similar to those in hypertensive patients with normal renal function;1,125 however, transient increases in BUN and serum creatinine concentrations are more frequent in patients with renovascular hypertension than in hypertensive patients with normal renal function.1,6,50,116,161,167,169,234 In addition, renal function can markedly deteriorate during therapy with an ACE inhibitor in patients with preexisting, severely compromised renal perfusion.225,233,234 (See Cautions: Renal Effects.)

Increases in serum potassium concentration may occur secondary to enalapril-induced decreases in aldosterone secretion,1,45,50,64,116 especially in patients with impaired renal function.1,125 Concomitant administration of thiazide diuretics generally offsets this increase.1,124,127,128 Urinary sodium excretion may be increased during the first 2-3 days of enalapril therapy45,47,48,52,77,98 and may persist for longer periods in some patients with normal sodium intake,48,127 probably secondary to reduced tubular reabsorption of the ion.48 The hypotensive effect of enalapril may also result in part from decreased sodium and water retention secondary to reduced aldosterone secretion;41,48,52,130,131 however, decreases in aldosterone secretion during enalapril therapy are generally small.1,53,64,77

Pharmacokinetics

Absorption

Enalapril maleate,1,2,8,83,84,187 unlike enalaprilat,1,4,10,12,17,85,97,187 is well absorbed following oral administration. Although enalaprilat is a more potent angiotensin-converting enzyme (ACE) inhibitor than enalapril,1,2,4,5,6,7,8,9,10,15,16,17,18,20,99 it is poorly absorbed from the GI tract1,12,17,85,97,187 because of its high polarity,193 with only about 3-12% of an orally administered dose being absorbed.4,12,187 Approximately 55-75% of an oral dose of enalapril maleate is rapidly absorbed from the GI tract in healthy individuals and hypertensive patients.1,2,83,84 Food does not appear to substantially affect the rate or extent of absorption of enalapril maleate.1,88,91 Following oral administration, enalapril maleate appears to undergo first-pass metabolism principally in the liver, being hydrolyzed to enalaprilat.1,2,10,46,83,95,97,99,190 Concomitant oral administration of enalapril maleate and hydrochlorothiazide has little, if any, effect on the bioavailability of either drug.254 Oral administration of the commercially available fixed combination containing the drugs reportedly is bioequivalent to concurrent administration of the drugs as individual preparations.254 (See Pharmacokinetics: Elimination.)

Peak serum enalapril concentrations of 40-80 ng/mL4,5,84,86,244,283,284 occur within about 0.5-1.5 hours following oral administration of a single 10-mg dose of enalapril maleate in healthy individuals or hypertensive patients.1,2,4,5,84,86,244,283,284 Peak serum enalaprilat concentrations reportedly increase proportionally with oral doses of enalapril maleate ranging from 2.5-40 mg.4,5,43,46,86,90 Following oral administration of a single 2.5-, 5-, 10-, 20-, or 40-mg dose of enalapril maleate in these patients, average peak serum enalaprilat concentrations of 6-8,43,90,244 15-28,4,5,43,83,90 37-50,4,5,43,46,86,90,283,284 70-80,50,90 or 123-150 ng/mL,5,88,91 respectively, occur within about 3-4.5 hours.1,2,5,10,46,83,84,86,88,91,283,284 Steady-state serum concentrations of enalaprilat were reached within 30-60 hours in patients with normal renal function receiving oral enalapril maleate dosages of 10 mg daily for 8 days; appreciable accumulation of the metabolite did not occur.87

The hypotensive effect of a single oral dose of enalapril maleate is usually apparent within 1 hour and maximal in 4-8 hours.1,43,46,90 The hypotensive effect of usual doses of the drug generally persists for 12-24 hours but may diminish toward the end of the dosing interval in some patients.1,41,43,44,45,46,48,50,58,231 The reduction in blood pressure may be gradual, and several weeks of therapy may be required before the full effect is achieved.1,46,51,62,79 Following IV administration of enalaprilat, the hypotensive effect is usually apparent within 5-15 minutes with maximal effect occurring within 1-4 hours;277,286,287,288,289 the duration of hypotensive effect appears to be dose related,277 but with the recommended doses, the duration of action in most patients is approximately 6 hours.277,286 Plasma ACE inhibition and reduction in blood pressure appear to be correlated to a plasma enalaprilat concentration of 10 ng/mL, a concentration at which maximal blockade of plasma ACE is achieved.43,86 After withdrawal of enalapril or enalaprilat, blood pressure gradually returns to pretreatment levels;1,157,277 rebound hypertension following abrupt withdrawal of the drug has not been reported to date.1,277

The onset and duration of hemodynamic effects of enalapril maleate appear to be slower and more prolonged than those of captopril.57,61,63,64,152,187 In patients with heart failure, the hemodynamic effects of enalapril maleate are generally apparent within 2-4 hours11,57,61,63,148,150 and may persist for up to 24 hours11,57,61,64,148,150 after an oral dose.

Distribution

Distribution of enalapril into human body tissues and fluids has not been fully characterized.231

Approximately 50-60% of enalaprilat is bound to plasma proteins.2,4,10 Two binding sites have been identified,4,10,12 a low-affinity, high-capacity site and a high-affinity, low-capacity site.4,10,12 Drug bound to the latter site may represent enalaprilat bound to circulating serum ACE, possibly accounting for the prolonged terminal elimination of the drug.1,4,10,12

Information on distribution into the CNS is limited, but enalapril appears to cross the blood-brain barrier poorly, if at all, and enalaprilat does not appear to distribute into the CNS.1,2 The drug did not accumulate in any tissue following multiple-dose administration in animals.1 The drug crosses the placenta.263 In a premature neonate (35 weeks' gestation) whose mother received 20 mg of enalapril maleate daily for 17 days prior to delivery, plasma enalaprilat concentration soon after birth in the neonate was 28 ng/mL.263 Enalapril and enalaprilat are distributed into milk in trace amounts.1,277

Elimination

Following oral administration, the half-life of unchanged enalapril appears to be less than 2 hours in healthy individuals and in patients with normal hepatic and renal functions,86,100,101,283,284 but may be increased in patients with heart failure.100 Following oral administration of a single 5- or 10-mg dose of enalapril maleate in patients with heart failure, the half-life of enalapril was 3.4 or 5.8 hours, respectively.100 Serum concentrations of enalaprilat, the active metabolite of enalapril, appear to decline in a multiphasic manner.1,2,84,87,102,277 Elimination of enalaprilat may also be prolonged in patients with heart failure100 or impaired hepatic function283,284 compared with healthy individuals and patients with hypertension.87,100,101,283,284 Observations of serum concentrations of enalaprilat over long periods following oral2,84,87,102 or IV administration102 suggest that enalaprilat has an average terminal half-life of about 35-38 hours (range: 30-87 hours).2,84,87 The observed prolonged terminal phase may actually reflect enalaprilat binding to the high-affinity, low-capacity binding site of circulating serum ACE.4,10,12,87 The effective half-life for accumulation of enalaprilat (determined from urinary recovery) has been reported to average about 11 or 14 hours in healthy adults with normal renal function or in hypertensive pediatric patients, respectively.1,2,87

Peak and trough enalaprilat concentrations and areas under the serum concentration-time curves (AUCs) may increase, time to peak and steady-state serum concentration may be delayed, and the effective half-life for accumulation may be prolonged in patients with impaired renal function.1,89,93,94,96,281 In patients with creatinine clearances less than 30 mL/minute, the effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is prolonged.1,93 In patients with moderate renal impairment (i.e., creatinine clearances of 30-60 mL/minute), this half-life is not substantially prolonged,1,93,94 and there appears to be a lack of correlation between AUCs and creatinine clearance.93,94 Decreased urinary excretion of enalapril may increase the extent of hydrolysis of enalapril to enalaprilat or may increase extrarenal elimination of the drug (e.g., via biliary excretion).93,94

About 60% of an absorbed dose of enalapril is extensively hydrolyzed to enalaprilat, principally in the liver via esterases.1,2,10,46,95,97,99 About 20% appears to be hydrolyzed on first pass through the liver;83,244 this hydrolysis does not appear to occur in plasma in humans.97 Enalaprilat is a more potent ACE inhibitor than enalapril.1,2,4,5,6,7,8,9,10,15,16,17,18,20,99 There is no evidence of other metabolites of enalapril in humans, rats, or dogs.1,2,12,84,85,87 However, a despropyl metabolite of enalaprilat was identified in urine in rhesus monkeys, accounting for 13% of an oral dose of enalapril maleate.12 Hydrolysis of enalapril to enalaprilat may be delayed88,95,283 and/or impaired283 in patients with severe hepatic impairment,88,95,283 but the pharmacodynamic effects of the drug do not appear to be significantly altered.283,284

Following oral administration, enalapril and enalaprilat are excreted in urine and feces.1,2,88,91 In healthy individuals, a mean of 60-78% (a mean of 43-56% as enalaprilat and the remainder as unchanged drug) of a 10-mg oral dose of enalapril maleate is excreted in urine within 24-48 hours after administration4,84,87,244 and approximately 33% (about 27% as enalaprilat and 6% as unchanged drug) is excreted in feces within 24-48 hours.1,2,4,84 In a multiple-dose study (10 mg daily) in healthy individuals with normal renal function, urinary excretion of enalaprilat and total drug increased during the first 4 days of therapy and then stabilized; urinary excretion of the metabolite averaged 45% of the cumulative dose and that of total drug averaged 62%.87 In a multiple-dose study (0.07-0.14 mg/kg of enalapril maleate daily) in hypertensive pediatric patients (2 months to 16 years), 67% (64-76% as enalaprilat and the remainder as unchanged drug) of the administered dose is recovered in urine within 24 hours.1 It is not known whether enalapril and enalaprilat excreted in feces represent unabsorbed drug or that excreted via biliary elimination.4 Biliary excretion of enalapril and enalaprilat occurs in animals;97,190,193 however, this route of elimination has not been demonstrated in humans.4

Renal clearance of enalaprilat and enalapril are reported to be approximately 100-158 and 300 mL/minute, respectively, in adults with normal renal function.84,191,192 The higher renal clearance of enalapril compared with that of the metabolite may indicate some degree of active tubular secretion of unchanged drug.4,191,192 Renal clearance may be decreased in hypertensive patients.100 In geriatric individuals, renal clearance and/or volume of distribution may decrease.102,244

Enalaprilat is removed by hemodialysis.1,2,89,94,282 The amount of drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate);188,189,194,195 however, the hemodialysis clearance of enalaprilat is reportedly 62 mL/minute.1,2,89,94,277 Enalaprilat also appears to be removed by peritoneal dialysis.245,254,263

Chemistry and Stability

Chemistry

Enalaprilat and enalapril are angiotensin-converting enzyme (ACE, bradykininase, kininase II) inhibitors.1,2,3,4,5,6,7,8,9,10,277 Enalapril, the ethylester of enalaprilat, is a prodrug and has little pharmacologic activity until hydrolyzed in the liver to enalaprilat.1,2,4,5,6,7,8,16,17,20 Enalapril is commercially available as the maleate salt1,2,4,5,8 and differs structurally from enalaprilat by the presence of an ethoxycarbonyl group rather than a carboxy group at position 1 of l-alanyl-l-proline and by the presence of the maleate salt.1,2,4,5,7,8,9,10,11,12,85 These structural modifications result in increased GI absorption of enalapril compared with enalaprilat, which is poorly absorbed from the GI tract.1,4,12,17,24,85 Enalapril is structurally and pharmacologically similar to captopril4,7 but contains a disubstituted nitrogen rather than a sulfhydryl group at position 3 of 2-methyl-1-oxopropyl-l-proline.7,23 The lack of the sulfhydryl group in enalapril may result in decreased risk of certain adverse effects (e.g., cutaneous reactions, taste disturbances, proteinuria).5,23,115,125,142,143,144,145,211,226,251

Enalaprilat occurs as a white to off-white crystalline powder and is slightly soluble in water and sparingly soluble in methanol.277 Commercially available enalaprilat injection is a sterile, clear, colorless solution of the drug.277 Sodium chloride is added during manufacture of the injection to adjust tonicity, and sodium hydroxide is added to adjust pH; the injection also contains 0.9% benzyl alcohol as a preservative.277 Enalapril maleate occurs as a white to off-white, crystalline powder1,2 and has solubilities of 25 mg/mL in water and 80 mg/mL in alcohol at room temperature.2,244 The apparent pK_as of enalapril are 3 and 5.4 at 25°C.2

Stability

Commercially available enalaprilat injection should be stored at a temperature less than 30°C. 277 Following dilution of enalaprilat injection in 5% dextrose, 0.9% sodium chloride, 5% dextrose and 0.9% sodium chloride, 5% dextrose in lactated Ringer's, or Isolyte^® E, solutions of the drug are stable for 24 hours at room temperature.277 Enalaprilat is physically incompatible with amphotericin B and phenytoin sodium.278 Specialized references should be consulted for specific compatibility information.

The manufacturer recommends that enalapril maleate tablets be stored in tight containers at a temperature less than 30°C and that transient exposure to temperatures warmer than 50°C be avoided.1,2 The tablets should be protected from moisture.1 The tablets have an expiration date of 30 months following the date of manufacture when stored at less than 30°C.2 The manufacturer states that extemporaneous preparation of oral solutions of enalapril maleate should be avoided since the drug is not sufficiently stable in solution.244

An extemporaneous preparation of enalapril maleate tablets in syrup (Ora-Sweet SF^®) and sodium citrate dihydrate (Bicitra^®) containing enalapril maleate 1 mg/mL is stable for 30 days when stored at 2-8°C.1,408

1. Biovail Pharmaceuticals, Inc. Vasotec^® (enalapril maleate) tablets prescribing information. Morrisville, NC; 2002 Aug.

2. Merck Sharp & Dohme. Vasotec^® (enalapril maleate) formulary information monograph. West Point, PA; 1986.

3. Windholz M, ed. The Merck index. 10th ed. Rahway, NJ: Merck & Co, Inc; 1983: APP-1-2.

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13. Douglas WW. Polypeptides—angiotensin, plasma kinins, and others. In: Gilman AG, Goodman L, Rall TW et al. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985: 639-60.

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18. Natoff IL, Nixon JS, Francis RJ et al. Biological properties of the angiotensin-converting enzyme inhibitor cilazapril. J Cardiovasc Pharmacol . 1985; 7:69-80.

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27. Unger T, Ganten D, Lang RE et al. Is tissue converting enzyme inhibition a determinant of the antihypertensive efficacy of converting enzyme inhibitors? Studies with the two different compounds, Hoe 498 and MK421, in spontaneously hypertensive rats. J Cardiovasc Pharmacol . 1984; 6:872-80. [PubMed 6209494]

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