Lisinopril is classified as an angiotensin-converting enzyme inhibitor and has been available for nearly three decades. Lisinopril has some key features that make it different from enalapril and captopril; 1) it has a long half-life 2) it is hydrophilic, and 3) it is not broken down by the liver.[1]

Lisinopril is approved by the Food and Drug Administration (FDA) for the management of hypertension in adult and pediatric patients six years and older and as adjunctive therapy in the treatment of heart failure. It is also FDA-approved for the treatment of ST-segment elevation myocardial infarction (STEMI) within 24 hours in hemodynamically stable patients to improve survival.[2][3][4][5]

Proteinuria

As per the expert opinion, lisinopril has a role in proteinuric chronic kidney disease. In IgA nephropathy, in addition to appropriate blood pressure control, adequate control in proteinuria can be achieved with the use of lisinopril. More frequently, it is used in diabetic nephropathy.

Lisinopril is a competitive inhibitor of angiotensin-converting enzyme (ACE) and prevents the conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. A decrease in angiotensin II subsequently causes a reduction in aldosterone secretion, which causes decrease sodium reabsorption in the collecting duct and decreases potassium excretion that may result in a small increase in serum potassium with lisinopril use. By removing the negative feedback of angiotensin II, lisinopril leads to increased serum renin activity.[6]

The beneficial effects in patients with hypertension derive from the inhibitory effects in the renin-angiotensin-aldosterone system (RAAS), resulting in decreased vasopressor and aldosterone activity even in low-renin patients. 

On the other hand, ACE also degrades bradykinin, and it is this mechanism through which ACE inhibitors may predispose to angioedema.[7]

Lisinopril absorption is unchanged by food and is excreted unchanged in the urine. Lisinopril does not have good bioavailability after oral intake - ranging from 10-30%. The time to peak concentration can vary from 6-8 hours. The drug does not bind to albumin or other proteins, and its distribution in patients with heart failure is poor.[7]

In general, the recommendation is that dosing and administration adjustments are necessary with lisinopril for patients in whom the glomerular filtration rate (GFR) is less than or equal to 30 mL/min.[8]

In adults, the usual dosage ranges from 2.5 to 40 mg per day, depending on the indication.[3][4] For adolescents and children greater than or equal to 6 years, the initial dose is 0.07 to 0.1 mg/kg once daily with a maximum initial dose of 5 mg/day and increments of 1- to 2-week intervals.[9] The maximum pondered dose is 0.6 mg/kg/day or 40 mg/day. 

For heart failure, the 2013 ACCF/AHA Guideline for the Management of Heart Failure (HF) recommends ACE inhibitors in all patients with HF with reduced ejection fraction (HFreEF) to reduce morbidity and mortality with a level A of evidence. The initial dose recommended is 2.5 mg per day, with a maximum daily dose of 40 mg. An inclination to higher doses is influenced by the findings of the SOLVD trial, where people in the high-dose group had an overall 8% decrease of death compared to those in the low-dose group.[2][10]

Lisinopril is also strongly recommended by the 2013 ACCF/AHA Guideline (Level of Evidence, A) within the first 24 hours to all patients with STEMI with the anterior location, HF, or those with reduced Ejection Fraction (EF) less than or equal to 40%, unless contraindicated. The recommended starting dose for this indication is 2.5 to 5 mg per day, with a 10 mg daily titration up to maximal dose tolerated in hemodynamically stable patients.[3]

According to the recent 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, among patients in whom pharmacological therapy is indicated, ACE inhibitors are among the recommended first-line agents for the management of hypertension with a lisinopril starting dose of 10 mg up to 40 mg daily.[4]

The American Diabetes Association (ADA) recommends the use of ACE inhibitors as one of the first-line agents for hypertension in patients with diabetes and urinary albumin–to–creatinine ratio greater than or equal to 300 mg/g creatinine or 30 to 299 mg/g creatinine.[11]

As an off label indication for proteinuric chronic kidney disease, it should be initiated at 2.5 to 10 mg once daily depending on blood pressure and slowly titrate as tolerated to a maximum daily dose of 40 mg. The goal for proteinuria is less than 1 g/day as per KDIGO-2013.

The primary adverse effects of ACE inhibitors include hyperkalemia, dry cough, angioedema, hypotension, dizziness, and renal insufficiency.[7][12] These effects may be more common in patients with renal, autoimmune, or collagen vascular diseases. 

The AHA/ACCF recommends careful use in patients with cardiomyopathy with outflow obstruction, as they may lead to exacerbation of symptoms.[13][2]

Historically, ACE inhibitors have correlated with an increase in morbidity and mortality in patients with aortic stenosis. However, recent randomized and placebo-controlled trials suggest that ACE inhibitors might be safe and might even provide some benefits in certain patients.[14][15][16]

ACE inhibitor-induced cough is a dry, nonproductive, hacking cough. It usually begins in the first few months of treatment and resolves within 1 to 4 weeks after discontinuation of the medication.

Deterioration of renal functions can occur in patients whose glomerular function is dependent on event arteriolar vasoconstriction by angiotensin II. Benign increase in serum creatinine may occur at the beginning of therapy, but medication should only be discontinued if there is a progressive or significant elevation of BUN/creatinine.

Lisinopril is contraindicated in patients with hyperkalemia, a history of angioedema, renal failure with prior lisinopril use, bilateral renal artery stenosis, concomitant use with aliskiren in patients with diabetes mellitus, and during coadministration with a neprilysin inhibitor or within 36 hours of taking one.

Lisinopril is pregnancy category Class D due to its teratogenic effects (e.g., decreased fetal renal function, oligohydramnios, lung hypoplasia, skeletal malformations, death in the fetus/neonate, etc.), thus its use is contraindicated in pregnant women and/or fertile women without proper contraception. Manufacturers recommend against the use of lisinopril in breastfeeding women because the amount secreted in breast milk and its effects in the breastfed infant is unknown.

No contraindications are known for patients with hepatic impairment.

Angioedema is asymmetric swelling of subcutaneous tissue without itching or urticaria involving the face, mouth, and upper airway. ACE inhibitor-induced angioedema can occur anytime during the therapeutic course starting from hours to years, but most commonly occurs within the first three months of therapy.  This adverse event is secondary to elevated bradykinin levels by inhibition of the angiotensin-converting enzyme, causing vasodilatation and extravasation of plasma into the submucosal tissue leading to angioedema. The most crucial step in management is to discontinue the ACE inhibitors and list the drug class under allergies.  Immediate symptomatic treatment and airway protection may be necessary.