Lisinopril

Article Author:
Edgardo Olvera Lopez
Article Editor:
Jamie Terrell
Updated:
6/16/2019 9:41:36 AM
PubMed Link:
Lisinopril

Indications

Lisinopril is classified as an angiotensin converting enzyme inhibitor and has been available for nearly 3 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]

Mechanism of Action

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]

Administration

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, it is recommended that the administration of lisinopril should be adjusted 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. 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]

Adverse Effects

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 been associated 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]

Contraindications

It 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.

It 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 woman 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.

Monitoring

First-dose hypotension is an uncommon adverse effect of ACE inhibitors that clinicians should bear in mind when prescribing lisinopril, and thus a low starting dose is recommended to reduce the risk of this phenomenon. [12]

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

Caution must be exercised 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 to captopril use, another ACE inhibitor drug, monitoring of liver function during lisinopril use may be appropriate with timely discontinuation if the elevation of liver enzymes has been detected. [17]

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 patients who are hypotensive. [18] Some reports suggest the use of Angiotensin II administration as an alternative supportive treatment for the treatment of ACE inhibitors overdose. [19]

There is no antidote available for lisinopril. 

Enhancing Healthcare Team Outcomes

Lisinopril has been around for 3 decades and is a relatively safe medication for hypertension. It is often prescribed by primary care physicians, nurse practitioner, emergency department physicians, internists and the cardiologist. However, the drug does need to be monitored. Levels of potassium and renal function should be monitored periodically. Patients should be told to avoid high potassium diets.


References

[1] Safety profiles of the angiotensin-converting enzyme inhibitors., Warner NJ,Rush JE,, Drugs, 1988     [PubMed PMID: 3063490]
[2] 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines., Yancy CW,Jessup M,Bozkurt B,Butler J,Casey DE Jr,Drazner MH,Fonarow GC,Geraci SA,Horwich T,Januzzi JL,Johnson MR,Kasper EK,Levy WC,Masoudi FA,McBride PE,McMurray JJ,Mitchell JE,Peterson PN,Riegel B,Sam F,Stevenson LW,Tang WH,Tsai EJ,Wilkoff BL,, Circulation, 2013 Oct 15     [PubMed PMID: 23741057]
[3] 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines., O'Gara PT,Kushner FG,Ascheim DD,Casey DE Jr,Chung MK,de Lemos JA,Ettinger SM,Fang JC,Fesmire FM,Franklin BA,Granger CB,Krumholz HM,Linderbaum JA,Morrow DA,Newby LK,Ornato JP,Ou N,Radford MJ,Tamis-Holland JE,Tommaso CL,Tracy CM,Woo YJ,Zhao DX,Anderson JL,Jacobs AK,Halperin JL,Albert NM,Brindis RG,Creager MA,DeMets D,Guyton RA,Hochman JS,Kovacs RJ,Kushner FG,Ohman EM,Stevenson WG,Yancy CW,, Journal of the American College of Cardiology, 2013 Jan 29     [PubMed PMID: 23256914]
[4] 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: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines., Whelton PK,Carey RM,Aronow WS,Casey DE Jr,Collins KJ,Dennison Himmelfarb C,DePalma SM,Gidding S,Jamerson KA,Jones DW,MacLaughlin EJ,Muntner P,Ovbiagele B,Smith SC Jr,Spencer CC,Stafford RS,Taler SJ,Thomas RJ,Williams KA Sr,Williamson JD,Wright JT Jr,, Journal of the American College of Cardiology, 2017 Nov 7     [PubMed PMID: 29146535]
[5] Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group.,, Circulation, 1998 Jun 9     [PubMed PMID: 9631869]
[6] Regulski M,Regulska K,Stanisz BJ,Murias M,Gieremek P,Wzgarda A,Niznik B, Chemistry and pharmacology of Angiotensin-converting enzyme inhibitors. Current pharmaceutical design. 2015;     [PubMed PMID: 25388457]
[7] Angiotensin-converting enzyme inhibitor-induced angioedema., Bezalel S,Mahlab-Guri K,Asher I,Werner B,Sthoeger ZM,, The American journal of medicine, 2015 Feb     [PubMed PMID: 25058867]
[8] Safety issues during antihypertensive treatment with angiotensin converting enzyme inhibitors., Weber MA,, The American journal of medicine, 1988 Apr 15     [PubMed PMID: 3064605]
[9] Lisinopril in paediatric medicine: a retrospective chart review of long-term treatment in children., Raes A,Malfait F,Van Aken S,France A,Donckerwolcke R,Vande Walle J,, Journal of the renin-angiotensin-aldosterone system : JRAAS, 2007 Mar     [PubMed PMID: 17487821]
[10] Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group., Packer M,Poole-Wilson PA,Armstrong PW,Cleland JG,Horowitz JD,Massie BM,Rydén L,Thygesen K,Uretsky BF,, Circulation, 1999 Dec 7     [PubMed PMID: 10587334]
[11] American Diabetes Association Standards of Medical Care in Diabetes 2017., Marathe PH,Gao HX,Close KL,, Journal of diabetes, 2017 Apr     [PubMed PMID: 28070960]
[12] Blood pressure response to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure., Reid JL,MacFadyen RJ,Squire IB,Lees KR,, The American journal of cardiology, 1993 Jun 24     [PubMed PMID: 8392282]
[13] Pharmacological treatment of hypertrophic cardiomyopathy: current practice and novel perspectives., Ammirati E,Contri R,Coppini R,Cecchi F,Frigerio M,Olivotto I,, European journal of heart failure, 2016 Sep     [PubMed PMID: 27109894]
[14] Aortic valvular heart disease: Is there a place for angiotensin-converting-enzyme inhibitors?, Elder DH,McAlpine-Scott V,Choy AM,Struthers AD,Lang CC,, Expert review of cardiovascular therapy, 2013 Jan     [PubMed PMID: 23259450]
[15] A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial)., Bull S,Loudon M,Francis JM,Joseph J,Gerry S,Karamitsos TD,Prendergast BD,Banning AP,Neubauer S,Myerson SG,, European heart journal cardiovascular Imaging, 2015 Aug     [PubMed PMID: 25796267]
[16] Short-term hemodynamic effect of angiotensin-converting enzyme inhibition in patients with severe aortic stenosis: a placebo-controlled, randomized study., Dalsgaard M,Iversen K,Kjaergaard J,Grande P,Goetze JP,Clemmensen P,Hassager C,, American heart journal, 2014 Feb     [PubMed PMID: 24439984]
[17] Captopril-induced jaundice: report of 2 cases and a review of 13 additional reports in the literature., Schattner A,Kozak N,Friedman J,, The American journal of the medical sciences, 2001 Oct     [PubMed PMID: 11678523]
[18] Lisinopril overdose., Dawson AH,Harvey D,Smith AJ,Taylor M,Whyte IM,Johnson CI,Cubela RB,Roberts MJ,, Lancet (London, England), 1990 Feb 24     [PubMed PMID: 1968218]
[19] Lisinopril overdose and management with intravenous angiotensin II., Trilli LE,Johnson KA,, The Annals of pharmacotherapy, 1994 Oct     [PubMed PMID: 7841571]