Angiotensin-Converting Enzyme (ACE) Inhibitors

Several factors are important in the section of an ACE inhibitor:

• Indication
• Onset of antihypertensive effect
  • Most ACE inhibitors have an onset of action of 1 to 2 hours with a duration of 24 hours or longer and are dosed once daily
  • Captopril's onset of action is 15 minutes with a duration of action of 4 to 6 hours, requiring 2 to 3 times/day dosing and making it a preferred oral ACE inhibitor for hypertensive emergency and urgency.
  • Enalprilat is the only ACE inhibitor available in an injectable formulation; the onset of hypotensive effect is about 15 minutes with a duration of about 6 hours, making it a viable option for the treatment of hypertensive urgency or emergency when intravenous administration is needed, or for the short-term treatment of hypertension when oral therapy is not feasible.
• Hepatic function
  • Captopril and lisinopril are the only ACE inhibitors that do not require hepatic conversion to active metabolites and may be preferred in patients with severe hepatic impairment.
• Renal function
  • Fosinopril is eliminated by both the liver and the kidneys; as such, a modification in the initial or maximum dose of fosinopril is not necessary.

Comparative Dosages for ACE Inhibitors in the Treatment of Hypertension [62854]

^aadministered in 2 to 3 divided doses; ^bif the patient is on a diuretic therapy, initiate at 50% of the starting dose; ^cmay be administered in 1 or 2 divided doses

A well known side effect associated with ACE inhibitors is a persistent, nonproductive dry cough.[51034] Accumulation of kinins in the respiratory tract has long been the stated mechanism for the development of cough with ACE inhibitor therapy; however, increasing evidence suggests that it may be related to substance P stimulation of C-fiber receptors in the respiratory tract.[24005] Frequency of cough is higher in women, Black patients, Asian patients, and patients with chronic obstructive pulmonary disease or heart failure. Compared to White patients, Asian patients have over a 2.5 times higher incidence of cough.[66452][66459] Onset may occur after 1 week to 6 months of therapy and cough typically resolves within 4 days following discontinuation of the ACE inhibitor.

Angioedema of the face, extremities, lips tongue, glottis and larynx has been reported with ACE inhibitor therapy. Involvement of the upper respiratory tract can induce acute respiratory distress; laryngeal or tongue edema may be fatal.[51046] There are rare reports of intestinal angioedema, which may manifest as abdominal pain with or without nausea or vomiting. Onset of angioedema may occur within hours of starting an ACE inhibitor; however, it can occur at any time. The incidence of angioedema is higher in women and Black patients. One study found an incidence of angioedema to be 0.55% for White patients compared to 1.62% for Black patients. Symptoms resolve after discontinuation of ACE inhibitor therapy.[51047][66451][66459]

Elevations in serum creatinine and blood urea nitrogen can occur with ACE inhibitor therapy. Renal insufficiency has also been reported with ACE inhibitor therapy; both are usually reversible with drug discontinuation. Additionally, more severe reactions such as oliguria, progressive azotemia, and, rarely, acute renal failure and/or death have been reported. Acute renal failure has occurred with ACE inhibitor therapy in patients with severe bilateral renal artery stenosis. Renal function should be closely monitored during initial therapy.[62854][66453][66459]

Captopril has been reported to cause a maculopapular rash with pruritus and erythema and, occasionally, fever, eosinophilia and arthralgia. The rash is generally mild and disappears within a few days following dosage reduction. Rash or maculopapular rash has also been reported with moexipril and perindopril. Enalapril has been associated with acute generalized exanthematous pustulosis (AGEP), a nonfollicular, pustular erythematous rash that starts suddenly and is accompanied by a fever above 38 degrees C.

Hypotension is one of the most commonly reported adverse effects of ACE inhibitors. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment with an ACE inhibitor, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of the ACE inhibitor or concomitant diuretic may be necessary.

Aliskiren-containing products are contraindicated in combination with an ARB in patients with diabetes mellitus and not recommended in patients with renal impairment (CrCl less than 60 mL/min). Do not coadminister two renin-angiotensin-aldosterone (RAAS) inhibitors, such as ACE inhibitors, ARBs or aliskiren. Combination therapy increase the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving combination therapy with 2 RAAS inhibitors do not obtain any additional benefit compared to monotherapy.[62854][66453][66458]

Coadministration of ACE inhibitors and mTOR inhibitors, such as everolimus, sirolimus, and temsirolimus, may increase the risk of angioedema. Avoid coadministration of an ACE inhibitor and everolimus. Use caution with coadministration of an ACE inhibitor and sirolimus or temsirolimus and monitor patients for angioedema.

Since ACE inhibitors have been associated with minor increases in serum potassium, clinically relevant hyperkalemia may occur during coadministration with agents that increase potassium. Some examples of medications that increase potassium include cyclosporine, eplerenone, drospirenone; ethinyl estradiol, potassium-sparing diuretics, potassium substitutes, potassium salts or salt substitutes, and trimethoprim. Monitor serum potassium levels during concomitant therapy.[51048][66458]

Concomitant use of an ACE inhibitor and a neprilysin inhibitor (i.e., sacubitril) is contraindicated due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor.

Coadministration of an ACE inhibitor and azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided whenever possible. When concurrent therapy is necessary, patients should be closely monitored for myelosuppression.[26208]

Further deterioration of renal function, including acute renal failure, may occur in elderly, volume-depleted (including those on diuretic therapy), or renally impaired patients on both an ARB and nonsteroidal antiinflammatory drug (NSAID); the effects are usually reversible. Monitor renal function in patients receiving concomitant therapy. Additionally, NSAIDs may reduce the antihypertensive effect of ARBs.[24233][51049][66458]

Further deterioration of renal function, including acute renal failure, may occur in elderly, volume-depleted (including those on diuretic therapy), or renally impaired patients on both an ARB and selective cyclooxygenase-2 inhibitors (COX-2 inhibitors); the effects are usually reversible. Monitor renal function in patients receiving concomitant therapy.[24233][51049][66458]

Aspirin may reduce the clinical benefit and hypotensive efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has primarily been reported in patients with heart failure. The clinical impact of this interaction remains controversial. Patients receiving concomitant therapy with aspirin and ACE inhibitors should be monitored for antihypertensive or vasodilatory efficacy; the ACE inhibitor dose can be adjusted if clinically indicated. Non-aspirin antiplatelet agents, such as clopidogrel, do not interact with ACE inhibitors.[28983][29322][46155]

Coadministration of lithium with ACE inhibitors results in elevated serum lithium levels, so caution should be utilized with concomitant administration. Frequent monitoring of lithium levels is recommended.[51049][66458]

When pregnancy is detected, discontinue ACE inhibitor therapy as soon as possible. Use of medications that affect the renin-angiotensin system, such as ACE inhibitors, during the second or third trimesters reduce fetal renal function, increase fetal and neonatal death, and cause fetal and neonatal injury such as hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Anhydramnios and oligohydraminos have also been reported. Women of childbearing age should be made aware of these harmful effects and consideration given to using another drug class.

ACE inhibitor therapy is contraindicated in individuals with a history of ACE inhibitor hypersensitivity or ACE inhibitor-induced, hereditary or idiopathic angioedema. ACE inhibitor hypersensitivity is usually a result of alterations in kinin generation without evidence of a specific immune-mediated reaction. Incidence of ACE inhibitor-induced angioedema is higher in Black patients than non-black patients.[28427][32289][66451][66459]

Patients dependent on the RAAS for renal function, such as those with heart failure, may experience a worsening of renal function with ACE inhibitor therapy. Typically increases in serum creatinine, blood urea nitrogen and potassium are transient in heart failure patients on ACE inhibitor therapy; however, oliguria, progressive azotemia and, rarely acute renal failure has occurred. Increases in blood urea nitrogen and serum creatinine have been reported with ACE inhibitor therapy and patients with unilateral or bilateral renal artery stenosis, preexisting renal impairment, or receiving diuretic therapy may be more likely to experience these effects. Monitor renal function during ACE inhibitor therapy. Dosage adjustments may be needed in patients with renal impairment or failure. ACE inhibitor therapy should be discontinued if renal function worsens acutely.[51051][46155]

Hepatic impairment may decrease ACE inhibitor clearance and/or conversion to active metabolites; thus, the dosages of most ACE inhibitors should be adjusted based on clinical response. However, captopril and lisinopril do not require conversion to an active metabolite and may be preferred in patients with hepatic impairment.

ACE inhibitors are relatively contraindicated in patients with hypotension. Hypotension is an infrequent adverse effect of ACE inhibitors in patients with uncomplicated hypertension; however, it has been reported more frequently in patients with an activated RAAS (e.g. heart failure, volume depleted, prolonged diuretic therapy). Caution should be utilized with ACE inhibitor therapy prior to major surgery or during anesthesia and in patients with aortic stenosis, hypertrophic cardiomyopathy or obstruction in the outflow tract of the left ventricle. Volume and/or salt depletion should be corrected prior to initiation of ACE inhibitor therapy. Lower initial doses of ACE inhibitors should be administered to patients with congestive heart failure. If hypotension occurs, standard medical care should be provided. It is recommended to closely monitor patients ar risk for excessive hypotension for 2 weeks or following dose increases.

ACE inhibitors may increase serum potassium levels; therefore, use caution with administration to patients with or who are at increased risk of hyperkalemia. Risk factors include renal impairment, diabetes mellitus and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Consider correcting potassium levels prior to initiation of ACE inhibitor therapy. Patients with risk factors should be closely monitored for hyperkalemia.[62854][66459]

ACE inhibitor therapy may cause anemia, neutropenia, or agranulocytosis. Patients with renal disease, immunosuppression, collagen-vascular disease (e.g., systemic lupus erythematosus or scleroderma), autoimmune disease or those receiving immunosuppressive therapy may have a higher risk of developing these complications. Caution should be used with administration of ACE inhibitors to patients with pre-existing bone marrow suppression. Monitor complete blood counts prior to and during ACE inhibitor therapy in patients at increased risk.

There are reports of life-threatening anaphylactoid reactions in patients undergoing desensitization treatment with hymenoptera venom while on ACE inhibitor therapy. Anaphylactoid reactions have been reported in patients receiving ACE inhibitor therapy concomitantly with high-flux membrane dialysis. There have also been reports of anaphylactoid reactions in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption while also on ACE inhibitor therapy.