Continuing Education Activity

Losartan is FDA approved for the treatment of several medical conditions, which include the following: hypertension, diabetic nephropathy. ARBs are known to be renoprotective in type 2 diabetes mellitus. In hypertension with left ventricular hypertrophy, losartan inhibits angiotensin II-induced cardiac remodeling. It reduces the risk of stroke in these patients. This activity covers losartan, 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 losartan.

Objectives:

• Summarize the mechanism of action of losartan.
• Identify the indications for using losartan as a therapeutic intervention.
• Review the potential adverse events for patients using losartan.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with losartan.

Indications

Losartan is FDA approved for the treatment of several medical conditions, which include the following:

• Hypertension[1]: First-line therapy for stage 1 hypertension along with thiazide diuretics, calcium channel blockers, and ACEI. In patients with atherosclerotic cardiovascular disease (ASCVD) risk greater than or equal to 10%, combination therapy is used to attain blood pressure goals. Angiotensin II receptor blockers (ARBs) are useful as monotherapy in the absence of comorbidities like diabetes, ischemic heart disease, cerebrovascular disease, heart failure, and chronic kidney disease.
• Diabetic nephropathy[2]: In patients with type 2 diabetes mellitus and hypertension, losartan is used to treat diabetic nephropathy with elevated serum creatinine and proteinuria. ARBs are known to be renoprotective in type 2 diabetes mellitus.
• Hypertension with left ventricular hypertrophy: Losartan inhibits the angiotensin II-induced cardiac remodeling. It reduces the risk of stroke in these patients.
• Off-label drug for Marfan syndrome[3], acute coronary syndrome, stable coronary artery disease, and intolerant of ACEI
• Treatment of heart failure (off-label use): A study involving elderly heart-failure patients, Evaluation of Losartan in the Elderly Study (ELITE), concluded that compared to captopril, losartan correlated with lower mortality and was tolerated better than captopril.[4] In the ELITE II study, the conclusion was that losartan was as competent as captopril in improving the heart failure-related outcomes, NYHA class, and quality of life.[5]

Mechanism of Action

Angiotensinogen is converted to angiotensin I by an enzyme, renin, that gets released from the juxtaglomerular apparatus of the kidney. Angiotensin-converting enzyme further converts angiotensin I, an inactive decapeptide, to angiotensin II, an active octapeptide. Losartan is a selective and competitive angiotensin II receptor blocker at the AT1 receptor site, resulting in a compensatory elevation of renin and angiotensin I levels. It binds with high affinity to the AT1 receptor and is more than 10000 fold selective for the AT1 receptor than the AT2 receptor. It inhibits angiotensin II-induced vasopressin release, adrenal catecholamine release, rapid and slow pressor response, thirst, cellular hypertrophy and hyperplasia, noradrenergic neurotransmission, and sympathetic tone increase. Losartan also inhibits angiotensin II-induced vasoconstriction and action of aldosterone, which in turn lowers the blood pressure. Losartan increases the urinary flow and increases the excretion of sodium, potassium, chloride, magnesium, uric acid, calcium, and phosphate. Compared to ACE inhibitors, angiotensin II-receptor blockers effectively inhibit the renin-angiotensin system, not affecting the response to bradykinin.[6]

For this reason, the non-renin-angiotensin effects, for example, cough and angioedema, are not commonly seen with ARBs. Hepatic P450 enzyme CYP2C9 metabolizes losartan to a more potent 5-carboxylic acid metabolite, EXP 3174. The onset of action of losartan is 6 hours, lasting for 24 hours, and the half-lives of losartan and EXP 3174 are 1.5 to 2 hours and 6 to 9 hours, respectively. The plasma clearance of losartan and EXP 3174 are through the kidney and liver, respectively.

Administration

Losartan administration can be without regard to meals. It is well absorbed but may be slower with food. However, it is best to administer at about the same time every day.[7]

Adverse Effects

The primary adverse effects of losartan include hyperkalemia, renal insufficiency, and angioedema.[8]

Greater than 10%

• Cough: The incidence of a cough is higher if it was associated previously with angiotensin-converting enzyme inhibitor therapy
• Fatigue
• Hypoglycemia
• Anemia
• Urinary tract infection (UTI)
• Chest pain
• Weakness
• Diarrhea

One percent to 10%

• Upper respiratory tract infection
• Hypotension
• Dizziness
• Cellulitis
• Gastritis
• Nausea

Frequently Not Defined

• Angioedema
• Edema/swelling
• Hypotension in hypovolemic patients
• Asthenia
• Headache
• Malaise
• Nausea
• Abdominal pain
• Hyperkalemia
• Back pain 
• Worsening renal failure

Contraindications

Losartan use is contraindicated with the use of aliskiren in diabetes mellitus.[9]

It is also contraindicated in hypersensitivity to losartan or any of its components.

Pregnancy

Losartan is contraindicated in pregnancy: As losartan acts on the renin-angiotensin system, it causes oligohydramnios, thus resulting in fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects are skull hypoplasia, hypotension, anuria, renal failure, and death. Therefore therapy with the drug should immediately stop when pregnancy is detected.[10]

Breastfeeding

It is not known if losartan gets excreted in the milk. Hence, its use is not recommended while breastfeeding.

Precautions

• Angioedema: The incidence of angioedema and cough with ARBs is less as compared to ACEI. However, it may involve the airway and intestine, causing abdominal pain. Patients with previous episodes of angioedema associated with the use of ACEI, hereditary angioedema, or idiopathic angioedema may be at an augmented risk. Frequent monitoring is necessary for such patients. Discontinue losartan if any episode of angioedema occurs and manage the patient aggressively with intramuscular epinephrine. Do not restart the patients on losartan after they had angioedema.
• Hyperkalemia: Risk factors include the use of potassium-sparing diuretics, potassium supplements, potassium salts. In such cases, monitor potassium levels closely.
• Hypotension: correct salt or volume depletion before administration as it may increase the risk of hypotension.
• Renal function: It may decline the renal function resulting in elevated serum creatinine levels, oliguria, azotemia, and acute renal failure. Discontinue losartan if there is a critical decrease in renal function.
• Use losartan with caution in renal artery stenosis and avoid using it in bilateral renal artery stenosis.
• Hepatic and renal impairment: Use with caution in patients with previous or current hepatic and renal impairment.

Monitoring

Monitor blood pressure, renal function (BUN and serum creatinine [SCr]), and potassium levels in patients taking losartan.[11]

Heart Failure

Reevaluate blood pressure (including orthostatic blood pressure), renal function, and serum potassium. Patients with systolic blood pressure <80 mm Hg, low serum sodium, diabetes mellitus, and impaired renal function should be closely monitored (ACC/AHA).

Hypertension

The 2017 Guideline for Management, Prevention, Detection, Evaluation of High Blood Pressure in Adults (ACC/AHA)

Confirmed hypertension with known CVD or 10-year ASCVD risk greater than or equal to 10%: blood pressure less than 130/80 mm Hg is the recommended target. Confirmed hypertension without markers of increased ASCVD risk.

Diabetes and Hypertension

The American Diabetes Association (ADA) Guidelines

The goal of therapy for patients 18 to 65 years of age is systolic blood pressure (SBP) less than 140 mm Hg and diastolic blood pressure (DBP) less than 90 mm Hg. The goal for patients 18 to 65 years and at high risk of cardiovascular disease is SBP less than 130 mm Hg and DBP less than 80 mm Hg if this is achievable without undue treatment burden.

For patients 65 years and older who are healthy or of complex/intermediate health), the goal of therapy is SBP less than 140 mm Hg and DBP greater than 90 mm Hg.

The goal of therapy for patients 65 years of age and older and of very complex/poor health is SBP less than 150 mm Hg and DBP less than 90 mm Hg.

Enhancing Healthcare Team Outcomes

Any clinician (MD, DO, NP, PA) can prescribe losartan for the treatment of hypertension and diabetic nephropathy. However, clinicians should follow the patients and regularly monitor their renal function and blood pressure. The drug is effective for hypertension and can be part of long-term therapy. However, it still requires the participation of an interprofessional team to optimize treatment. When initially prescribed, a pharmacist should verify appropriate dosing, perform medication reconciliation, and can counsel the patient about the drug. Nursing can also provide valuable patient counseling, as well as answer questions and assess therapeutic effectiveness on subsequent visits.  If the pharmacist or nursing staff encounter any concerns, they should report these to the prescriber promptly so that therapeutic adjustments can take place. This interprofessional team approach to losartan therapy can optimize patient outcomes while minimizing potential adverse effects. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Al-Majed AR, Assiri E, Khalil NY, Abdel-Aziz HA. Losartan: Comprehensive Profile. Profiles Drug Subst Excip Relat Methodol. 2015;40:159-94. [PubMed: 26051686]

2.

Ruggenenti P. Dual renin-angiotensin system blockade for nephroprotection. Nephrol Ther. 2017 Apr;13 Suppl 1:S43-S45. [PubMed: 28577742]

3.

den Hartog AW, Franken R, van den Berg MP, Zwinderman AH, Timmermans J, Scholte AJ, de Waard V, Spijkerboer AM, Pals G, Mulder BJ, Groenink M. The effect of losartan therapy on ventricular function in Marfan patients with haploinsufficient or dominant negative FBN1 mutations. Neth Heart J. 2016 Nov;24(11):675-681. [PMC free article: PMC5065542] [PubMed: 27704402]

4.

Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997 Mar 15;349(9054):747-52. [PubMed: 9074572]

5.

Konstam MA, Neaton JD, Poole-Wilson PA, Pitt B, Segal R, Sharma D, Dasbach EJ, Carides GW, Dickstein K, Riegger G, Camm AJ, Martinez FA, Bradstreet DC, Ikeda LS, Santoro EP., ELITE II Investigators. Comparison of losartan and captopril on heart failure-related outcomes and symptoms from the losartan heart failure survival study (ELITE II). Am Heart J. 2005 Jul;150(1):123-31. [PubMed: 16084158]

6.

He YM, Feng L, Huo DM, Yang ZH, Liao YH. Enalapril versus losartan for adults with chronic kidney disease: a systematic review and meta-analysis. Nephrology (Carlton). 2013 Sep;18(9):605-14. [PubMed: 23869492]

7.

Dickstein K, Timmermans P, Segal R. Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure. Expert Opin Investig Drugs. 1998 Nov;7(11):1897-914. [PubMed: 15991937]

8.

Bolotova O, Yoo J, Chaudhri I, Marcos LA, Sahib H, Koraishy FM, Skopicki H, Ahmad S, Mallipattu SK. Safety, tolerability, and outcomes of losartan use in patients hospitalized with SARS-CoV-2 infection: A feasibility study. PLoS One. 2020;15(12):e0244708. [PMC free article: PMC7773257] [PubMed: 33378401]

9.

Woo KT, Choong HL, Wong KS, Tan HK, Foo M, Fook-Chong S, Lee EJ, Anantharaman V, Lee GS, Chan CM. Aliskiren and losartan trial in non-diabetic chronic kidney disease. J Renin Angiotensin Aldosterone Syst. 2014 Dec;15(4):515-22. [PubMed: 24742970]

10.

Daïkha-Dahmane F, Levy-Beff E, Jugie M, Lenclen R. Foetal kidney maldevelopment in maternal use of angiotensin II type I receptor antagonists. Pediatr Nephrol. 2006 May;21(5):729-32. [PubMed: 16565869]

11.

Comparison chart: Some drugs for HFrEF. Med Lett Drugs Ther. 2021 Jun 14;63(1626):e1-e14. [PubMed: 34181629]

12.

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 May 03;145(18):e895-e1032. [PubMed: 35363499]

13.

Kittleson MM, Panjrath GS, Amancherla K, Davis LL, Deswal A, Dixon DL, Januzzi JL, Yancy CW. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023 May 09;81(18):1835-1878. [PubMed: 37137593]

Disclosure: Sana Mulla declares no relevant financial relationships with ineligible companies.

Disclosure: Waqas Siddiqui declares no relevant financial relationships with ineligible companies.