Losartan

Article Author:
Sana Mulla
Article Editor:
Waqas Siddiqui
Updated:
10/27/2018 12:31:20 PM
PubMed Link:
Losartan

Indications

Losartan is FDA approved for the treatment of the 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 the blood pressure goals. Angiotensin II receptor blockers (ARBs) can be used 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 that involved the elderly heart-failure patients, Evaluation of Losartan in the Elderly Study (ELITE), concluded that compared to captopril, losartan was related to lower mortality and was tolerated better than captopril.[4] In the ELITE II study, it was concluded 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 is 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 10,000 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 the 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. As 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 is 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 may be administered without regard to meals. It is well absorbed but may be slowed with food. However, it is best to administer about the same time every day.

Adverse Effects

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

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.

Contraindicated in hypersensitivity to losartan or any of its component.

Pregnancy

Losartan is contraindicated in pregnancy[7]: 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. Thus the drug should be discontinued immediately when pregnancy is detected. 

Breastfeeding

It is not known if losartan is 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 required in 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 an episode of 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 with caution in renal artery stenosis and avoided 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.

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

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 can be achieved without undue treatment burden.

For patients 65 and older years 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.