FDA approved uses:

1. Angiotensin-converting enzyme (ACE) inhibitors are useful as adjunctive therapy in systolic heart failure (HF). HF guidelines recommend ACE inhibitors to help prevent HF in patients with a reduced ejection fraction (EF) who also have a history of myocardial infarction (MI), to prevent HF in any patient with a reduced ejection fraction or to treat patients with HF and reduced EF.
2. ACE inhibitors can be used for the treatment of hypertension (HTN) either alone or in conjunction with other antihypertensives in adults or children greater than six years old. Hypertension guidelines recommend the initiation of ACE inhibitors for the management of HTN to lower blood pressure (BP). Treatment recommendations in the following populations according to the American College of Cardiology are[1]:

• Patients with daytime BP out of the office at greater than 135 mmHg systolic or greater than 85 mmHg diastolic; this is substitutable with office blood pressure readings of over 140/90 mmHg
• Patients with an in-office or out of office BP exceeding 130 mmHg systolic or over 80 mmHg diastolic and the addition of the following factors:
• History of cardiovascular disease
• Type 2 diabetes mellitus
• Chronic kidney disease
• Age 65 or older

1. Patients with chronic kidney disease (CKD) and HTN:

• Regardless of race or diabetes mellitus status, ACE inhibitors are recommended as initial therapy to improve kidney outcomes.
• In the non-Black population with diabetes mellitus and without CKD, initial antihypertensive therapy should include either thiazide diuretic, calcium channel blocker (CCB), ACE inhibitor, or angiotensin receptor blocker (ARB).
• In the Black population with diabetes mellitus and without CKD, initial antihypertensive therapy should include either a thiazide diuretic or CCB instead of an ACE inhibitor or ARB.

1. Patients with coronary artery disease (CAD) and HTN:

• ACE inhibitors are recommended as part of a regimen in patients with HTN and chronic stable angina if there is a history of left ventricular dysfunction, diabetes mellitus, or CKD.

1. Patients with ST-elevated myocardial infarction (STEMI):

• ACE inhibitors should be initiated within 24 hours of all STEMI, specifically in patients with anterior MI, heart failure, or left ventricular (LV) ejection fraction (EF) of 40% or less.

ACE inhibitors show efficacy in treatment due to the overall reduction of mortality in multiple patient disease states. There is evidence of mortality benefit in patients with hypertension, heart failure, Acute MI, and diabetes mellitus.[2][3][4][3]

Non-FDA approved uses:

ACE inhibitors may delay the progression of nephropathy and reduce the risks of cardiovascular events in hypertensive patients with diabetes mellitus type I and type II. The addition of an ACE inhibitor has shown a significant reduction in serum creatinine in both hypertensive patients and normotensive patients with albuminuria. Therapy has shown a significant decrease in the progression of diabetic nephropathy.[5][6]

ACE is involved in the renin-angiotensin-aldosterone system (RAAS; media item 1) and stimulates the conversion of angiotensin I to angiotensin II. ACE inhibitors are competitive inhibitors of ACE, which prevents the conversion of angiotensin I to angiotensin II. Angiotensin II acts as a potent vasoconstrictor that, when inhibited, can reduce blood pressure by dilating vessels and decreasing aldosterone secretion.[7][2][3]

It is essential to understand the role of the RAS hormonal system in depth to appreciate the therapeutic effects of ACE inhibitors and understand why this is a target for hypertensive therapy. Initially, afferent arteriole juxtaglomerular cells synthesize prorenin, which is actively cleaved to renin. Angiotensinogen produced from the liver is then cleaved by renin to form angiotensin I. The angiotensin I molecule is converted to angiotensin II by ACE. Angiotensin II is the molecule that has significant actions on various systems. Initially, Angiotensin II induces vasoconstriction, which ultimately increases systemic blood pressure.[8] Even further, Angiotensin II stimulates the adrenal cortex and the pituitary to produce Aldosterone and Anti-diuretic hormone (ADH), respectively. Aldosterone induces sodium reabsorption and, in turn, water reabsorption through internal mineralocorticoid receptor activity [9][10]; ADH increases the synthesis of aquaporin-2 channels in the collecting duct inducing selective reabsorption of water.

ACE inhibitors are most commonly oral agents, but intravenous forms are available. Medications most commonly end with the suffix -pril. Examples include lisinopril, ramipril, and captopril.

Most Common Adverse Reactions

• Dry Cough (10% to 20%)
• Dizziness (12% to 19%)
• Hypotension (7% to 11%)
• Increased BUN and Cr (2% to 11%)
• Syncope (5% to 7%)
• Hyperkalemia (2% to 6%)

Commonly, patients on ACE inhibitors have reported dry cough between the one week of initiation up to six months, with some sources citing up to one year after initiation. Discontinuing therapy usually resolves the cough 1 to 4 days after but can be prolonged up to a month.[11] The concern for dry cough with therapy initiation is a decrease in medication adherence. Additionally, there is an increased propensity to develop bronchospasm in these patients.[12] ACE metabolizes bradykinin and other local molecules. Inhibiting ACE in the lung increases the concentration of kinins, causing bronchial irritation.[13] After discontinuation of ACE inhibitor therapy, an angiotensin receptor blocker (ARB) can initiate as an alternate therapy. ARB’s have a lower incidence of cough recurrence compared to reinitiating ACE inhibitor therapy.[14] If cough recurs on ARB therapy, switch to a different drug class entirely.

One percent to 10%: flushing, orthostatic effect, chest pain, altered sense of smell, fatigue, headache, alopecia, diaphoresis, erythema, pruritus, skin photosensitivity, Steven-Johnson Syndrome, toxic epidermal necrolysis, urticaria, diabetes mellitus, gout, SIADH, constipation, diarrhea, dysgeusia, flatulence, pancreatitis, xerostomia, impotence, bone marrow suppression, hemolytic anemia, leukopenia, neutropenia, thrombocytopenia, common cold, weakness, blurred vision, diplopia, photophobia, vision loss, tinnitus, cough.[4][15]

Hypotension can cause intolerance to therapy leading to discontinuation in a small population of patients, which is more common in patients with increased renin baseline concentrations. Allowing repletion of fluids and discontinuing diuretic medication before therapy can minimize hypotensive episodes.[16]

A slight reduction of glomerular filtration rate (GFR) is common when initiating therapy. GFR reduction can become severe in certain settings and co-morbidities. Patients with diseases affecting renal perfusion can cause further reduction of GFR to a severe level warranting discontinuation. Some co-morbidities can include heart failure, chronic kidney disease, and bilateral renal artery stenosis.[17]

Hyperkalemia from ACE inhibitors is a direct result of the mechanism of action. The blockade of angiotensin II prevents the downstream secretion of aldosterone. Aldosterone causes reabsorption of sodium and, subsequently, water. Consequently, protons and potassium get secreted into the urine. Without the secretion of potassium through aldosterone, potassium can easily increase in patients on ACE inhibitors.[18] Co-morbidities that decrease kidney function or medications that cause potassium retention increases the risk of hyperkalemia.

Angioedema is a rare but potentially life-threatening side effect of ACE inhibitor use. The side effect is a swelling of the face, lips, and upper airway in an episodic nature. The inflammation creates difficulty in the patient’s ability to maintain an airway; therefore, endotracheal intubation is necessary to secure the airway. The mechanism of angioedema is thought to be through an extensive accumulation of bradykinins in select individuals. Bradykinin induces prominent vasodilation and plasma extravasation into the local tissue. The primary treatment of ACE inhibitor-induced angioedema is the discontinuation of ACE inhibitor therapy. It is also suggested to avoid ACE inhibitor therapy in individuals with hereditary angioedema or a history of angioedema episodes.

Any Injury

Less than 1%: Acute renal failure, anaphylactoid reactions, angioedema, anuria, arthralgia, arthritis, asthma, ataxia, azotemia, bronchitis, bronchospasm, cardiac arrest, cardiac arrhythmia, cerebrovascular accident, chills, confusion, cutaneous pseudolymphoma, dehydration, drowsiness, dyspepsia, dyspnea, dysuria, eosinophilia, eosinophilic pneumonitis, epistaxis, facial edema, fever, gastritis, hallucination, heartburn, hemoptysis, hepatic necrosis, hepatitis, herpes zoster, hypersomnia, hypervolemia, hypoglycemia, hyponatremia, increased erythrocyte sedimentation rate, insomnia, intestinal angioedema, irritability, laryngitis, leukocytosis, malaise, malignant neoplasm of lung, mastalgia, memory impairment, mood changes, muscle spasm, musculoskeletal pain, myalgia, myocardial infarction, oliguria, orthopnea, orthostatic hypotension, palpitations, paresthesia, paroxysmal nocturnal dyspnea, pemphigus, peripheral edema, peripheral neuropathy, pharyngitis, pleural effusion, pneumonia, positive ANA titer, psoriasis, pulmonary embolism, pulmonary infarct, pulmonary infiltrates, pyelonephritis, rhinitis, rhinorrhea, sinusitis, skin infection, skin lesion, skin rash, sore throat, systemic lupus erythematosus, transient ischemic attacks, tremor, uremia, urinary tract infection, vasculitis, vertigo, viral infection, visual hallucination, weight gain, weight loss, wheezing.

Pregnancy

The use of drugs that inhibit the renin-angiotensin system correlates with teratogenic effects such as oligohydramnios, decreased fetal renal function, anuria, renal failure, skull hypoplasia, and death.

The proposed mechanism behind oligohydramnios is evident at the level of the fetal kidney. The low-pressure hemodynamics of the fetus becomes easily disrupted with a decreased amount of angiotensin II. Fetal renal pressure becomes lower, reducing the ability to maintain GFR, leading to oligohydramnios and anuria.[19]

ACE inhibitors are contraindicated in a patient with a history of hypersensitivity to any ACE inhibitor or component of the formulation, angioedema related to previous treatment with ACE inhibitor, idiopathic or hereditary angioedema, or current use of aliskiren in a patient with diabetes mellitus. Also, consider drugs with cross-reactivity with ACE inhibitors.[20][21]

ACE inhibitors are not recommended in pregnant patients and require discontinuation as soon as pregnancy is detected.

Relative Contraindications

Use with great caution in the following situations:

• Patients with abnormal renal function. ACE inhibitors can cause elevation of potassium and worsen renal function in patients already on ACE inhibitors. If the patient has an abnormal but stable renal function, close monitoring is required while he or she is on an ACE inhibitor. If the renal function starts to decline, the clinician should discontinue the ACE inhibitor immediately.
• Patients with aortic valve stenosis should not be administered afterload reducers like ACE inhibitors because it can lead to severe hypotension.
• Similarly, patients who are dehydrated or have hypovolemia should not receive treatment with ACE inhibitors.