Continuing Education Activity

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. 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. This activity covers lisinopril, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, monitoring, and highlights the role of the interprofessional team in the management of hypertension with lisinopril.

Objectives:

• Summarize the mechanism of action of lisinopril.
• Identify the various indications for initiating lisinopril therapy.
• Review the adverse event profile of lisinopril.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with lisinopril.

Indications

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]

FDA-approved Indications

• Lisinopril is approved by the US Food and Drug Administration (FDA) to manage hypertension in adult and pediatric patients six years and older.[2]
• It is used as adjunctive therapy in the treatment of heart failure.[3]
• It is recommended as a treatment of ST-segment elevation myocardial infarction (STEMI) within 24 hours in hemodynamically stable patients to improve survival.[4][5][6]

Off-label Uses

• Lisinopril is used in diabetic nephropathy.[7]
• 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.
• Post-transplant erythrocytosis[8]

Mechanism of Action

Lisinopril is a competitive inhibitor of the 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 a decrease in 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.[9]

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.[10]

Pharmacokinetics[10]

• 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.

Administration

Available Dosage 

• Oral Tablet: 2.5 mg, 5mg, 10 mg, 20 mg, 30 mg, 40mg
• Oral Solution: 1 mg/mL

General Dose Considerations

• The usual adult dosage ranges from 2.5 to 40 mg per day, depending on the indication.[4][5]
• 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.[11] The maximum pondered dose is 0.6 mg/kg/day or 40 mg/day. 
• In general, the recommendation is that dosing and administration adjustments are necessary with lisinopril for patients whose glomerular filtration rate (GFR) is less than or equal to 30 mL/min.[12]

Hypertension

• 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.
• The lisinopril is started at 10 mg and titrated upwards to 40 mg once daily.[5] 
• If the blood pressure is not controlled with lisinopril tablets alone, a low dose of a diuretic can be added. After adding a low-dose diuretic, it is possible to reduce the dose of lisinopril tablets. The recommended starting dose in adult patients with hypertension taking diuretics is 5 mg once per day.

Heart failure

• 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 in death compared to those in the low-dose group.[3][13]

STEMI within 24 hours in Hemodynamically Stable Patients

• 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.[4]

Patients with Diabetes and Hypertension

• The American Diabetes Association (ADA) recommends using 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.[14] 
• 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.

Specific Patient Population

Pregnant Patients: Lisinopril is pregnancy category Class D due to its teratogenic effects (e.g., decreased fetal renal function, oligohydramnios, lung hypoplasia, skeletal malformations, fetal/neonatal death, etc.); thus, its use is contraindicated in pregnant women and/or fertile women without proper contraception.[15]

Breastfeeding Consideration: Manufacturers recommend against using lisinopril in breastfeeding women because the amount secreted in breast milk and its effects in the breastfed infant is unknown.

Patients with Renal Impairment: The manufacturer recommends dose adjustment based on creatinine clearance.

• No dose adjustment is required in patients with creatinine clearance of more than 30 mL/min.
• In patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, reduce the initial dose of lisinopril tablets to 50%f of the usual recommended dose.
• For patients on hemodialysis or creatinine clearance less than 10 mL/min, the recommended initial dose is 2.5 mg once daily.

Patients with Liver Impairment: No contraindications are known for patients with hepatic impairment.

Adverse Effects

• The primary adverse effects of ACE inhibitors include hyperkalemia, dry cough, angioedema, hypotension, dizziness, headache, and renal insufficiency.[10][16] 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.[17][3]

• Historically, ACE inhibitors have correlated with increased 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.[18][19][20]

• 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 discontinuing the medication.

• Deterioration of renal functions can occur in patients whose glomerular function is dependent on event arteriolar vasoconstriction by angiotensin II. A 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. 

Drug Interactions

• Diuretics: When initiating lisinopril in patients on diuretics may result in further reduction of blood pressure and may lead to hypotension. When coadministered with thiazide-type diuretics and/or potassium-sparing diuretics (amiloride, spironolactone,  triamterene, etc.), it might increase the risk of hyperkalemia. Therefore, if coadministration of such agents is indicated, monitor the patient’s serum potassium frequently.

• Antidiabetics: Concomitant administration of antidiabetic medicines (e.g., insulins, oral hypoglycemic agents) and lisinopril can increase the blood-glucose-lowering effect of antidiabetic medicine can increase the risk of hypoglycemia.

• Non-Steroidal Anti-Inflammatory Agents: Coadministration of NSAIDs and lisinopril in patients who are volume-depleted (including those on diuretic therapy), elderly,  or with impaired renal function may result in further worsening of renal function, including possible acute renal injury(AKI). This is usually reversible but monitor renal function periodically in patients receiving lisinopril and NSAID therapy. The antihypertensive effect of ACE inhibitors can be decreased by NSAIDs.

• Renin-Angiotensin System (RAS) Blockers: Dual blockade of the RAS with ACE inhibitors, angiotensin receptor blockers, or aliskiren is associated with higher risks of hyperkalemia, hypotension, and changes in renal function, including AKI, compared to monotherapy. Closely monitor blood pressure, electrolytes, and renal function in these patients.

• Lithium: Lithium toxicity is reported in patients taking ACE inhibitors and lithium, usually reversible. Monitor serum lithium levels if concurrent use is recommended.

• mTOR Inhibitors: Patients using concomitant mTOR inhibitors (e.g., sirolimus, temsirolimus, everolimus) are at increased risk for angioedema.

Contraindications

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.

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, 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 inhibiting 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.

Monitoring

First-dose hypotension is an uncommon adverse effect of ACE inhibitors that clinicians should consider when prescribing lisinopril. Thus a low starting dose is recommended to reduce the risk of this phenomenon.[16]

Monitor serum potassium, blood pressure, and blood urea nitrogen/serum creatinine in patients taking lisinopril after 2 to 3 weeks of initiation.

Caution is necessary when prescribing lisinopril in patients with high potassium diets or among people taking other agents that might exacerbate hypotension and hyperkalemia, such as antihypertensive agents or aldosterone antagonists.

Although cholestatic jaundice is a rare reaction associated with using the ACE inhibitor captopril, monitoring liver function during lisinopril use may be appropriate with timely discontinuation if testing detects the elevation of liver enzymes.[21]

Toxicity

Since lisinopril metabolism depends on renal excretion, overdose management consists of general supportive care, including gastric emptying strategies when appropriate, intravenous fluids, vasopressors, and hemodialysis. Maintenance of optimal blood pressure with fluids is critical in hypotensive patients.[22] Some reports suggest using angiotensin II administration as an alternative supportive treatment for the treatment of ACE inhibitors overdose.[23]

There is no antidote available for lisinopril. 

Enhancing Healthcare Team Outcomes

Lisinopril has been available for three decades and is a relatively safe medication for hypertension. It is often prescribed by primary care clinicians (including PAs and nurse practitioners), emergency department physicians, internists, and cardiologists. However, the drug does require monitoring. Potassium levels and renal function need periodic monitoring, which can be watched by both clinicians and nursing staff. Patients should understand to avoid high potassium diets, which is another area where counsel can be provided by clinicians, nurses, and pharmacists. Female patients also need to be aware of the potential adverse effects on pregnancy while taking lisinopril, so interprofessional counsel from clinicians, nurses, and pharmacists is vital for these patients. Pharmacists should also check for potential interactions and answer any patient questions. Thus, even though lisinopril is a common and well-tolerated drug, it still requires the efforts of an interprofessional team to optimize safety and therapeutic outcomes and minimize or prevent adverse events. [Level 5]