What are losartan’s mechanism of action, FDA‑approved and off‑label indications, typical dosing, contraindications, and alternative treatment options?

Losartan: Mechanism, Indications, Dosing, and Safety

Mechanism of Action

Losartan selectively blocks the angiotensin II type 1 (AT₁) receptor, preventing vasoconstriction and aldosterone secretion without inhibiting ACE or affecting bradykinin metabolism. 1 The drug undergoes hepatic conversion to E-3174, an active metabolite that is 10–40 times more potent than the parent compound and responsible for most of the therapeutic effect. 1, 2 The metabolite has a half-life of 6–9 hours, enabling once-daily dosing, whereas losartan itself has a terminal half-life of only 2 hours. 1, 2

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FDA-Approved Indications and Dosing

Hypertension

• Start losartan 50 mg once daily and titrate to a maximum of 100 mg once daily based on blood pressure response; this is the FDA-approved dosing range for hypertension. 1
• For patients with intravascular volume depletion (e.g., those on diuretics), initiate at 25 mg once daily to reduce the risk of first-dose hypotension. 1
• Pediatric patients (≥6 years): start at 0.7 mg/kg once daily (maximum 50 mg) and adjust according to response; doses above 1.4 mg/kg or 100 mg daily have not been studied in children. 1

Hypertension with Left Ventricular Hypertrophy

• Begin losartan 50 mg once daily, add hydrochlorothiazide 12.5 mg daily, then escalate losartan to 100 mg daily followed by hydrochlorothiazide to 25 mg daily based on blood pressure control. 1
• This indication reduces cardiovascular events (stroke, myocardial infarction, cardiovascular death) in hypertensive patients with left ventricular hypertrophy, though the benefit does not extend to Black patients. 3

Diabetic Nephropathy in Type 2 Diabetes

• Start losartan 50 mg once daily and increase to 100 mg once daily based on blood pressure response. 1
• Losartan slows progression to end-stage renal disease and reduces proteinuria in patients with type 2 diabetes, elevated serum creatinine, and macroalbuminuria, as demonstrated in the RENAAL trial. 4, 3

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Off-Label Indications

Heart Failure with Reduced Ejection Fraction

• Losartan is recommended for patients with heart failure who cannot tolerate an ACE inhibitor (Class I, Level A evidence per ACC/AHA guidelines). 4
• Target dose is 100–150 mg once daily; the HEAAL trial showed that 150 mg daily was superior to 50 mg daily, achieving a 10% relative risk reduction in death or heart failure hospitalization (P = 0.027). 4, 5
• Titrate no more frequently than every 2 weeks to reach the target or maximally tolerated dose. 4

Raynaud Phenomenon and Digital Ulcers in Systemic Sclerosis

• Losartan may provide modest benefit for some patients with secondary Raynaud phenomenon, but it is not included in EUSTAR–EULAR recommendations because the benefit is small and other agents (calcium channel blockers, PDE5 inhibitors, prostacyclin analogues) are preferred. 6

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Contraindications

• Pregnancy (all trimesters): Losartan causes serious fetal toxicity including renal dysfunction, oligohydramnios, skull hypoplasia, and fetal death; discontinue immediately upon pregnancy detection. 4, 1
• Dual renin-angiotensin system blockade: Combining losartan with an ACE inhibitor or direct renin inhibitor (aliskiren) increases the risk of hyperkalemia, syncope, and acute kidney injury by 2–3-fold without added cardiovascular benefit (Class III: Harm). 6, 4, 5
• History of angioedema with ARBs: Prior ARB-induced angioedema contraindicates losartan use. 4
• Severe bilateral renal artery stenosis: Risk of acute renal failure. 4

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Special Populations and Dose Adjustments

Hepatic Impairment

• Start at 25 mg once daily in patients with mild-to-moderate hepatic impairment because plasma concentrations are approximately five-fold higher than in healthy individuals. 4, 1
• Losartan has not been studied in severe hepatic impairment. 1

Renal Impairment

• No dose adjustment is required for mild-to-moderate renal insufficiency; losartan is not removed by hemodialysis. 2
• Losartan is recommended for chronic kidney disease with eGFR >30 mL/min/1.73 m², with regular monitoring of electrolytes and serum creatinine. 4

Elderly Patients (≥75 years)

• Initiate at a low dose and titrate slowly to reduce the risk of hypotension, renal insufficiency, dizziness, falls, and fatigue. 4
• Measure blood pressure in both sitting and standing positions (after 5 minutes seated, then at 1 and 3 minutes after standing) to detect orthostatic hypotension. 4

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Monitoring Requirements

• Check serum creatinine/eGFR and potassium within 1–2 weeks after initiating losartan or increasing the dose, then at least annually during maintenance therapy. 4, 5
• Acceptable laboratory changes: A rise in serum creatinine up to 50% and potassium up to 5.5 mmol/L is considered acceptable; larger increases (≥100% or creatinine ≥310 µmol/L) require discontinuation and specialist referral. 4
• High-risk patients (chronic kidney disease, diabetes, heart failure, baseline systolic BP <80 mmHg, or concurrent use of potassium-sparing diuretics/NSAIDs) require more frequent monitoring every 1–2 weeks initially. 4

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Combination Therapy

• If blood pressure remains ≥140/90 mmHg on losartan 100 mg daily after 4–8 weeks, add hydrochlorothiazide 12.5–25 mg once daily rather than exceeding the maximum losartan dose. 4, 5
• For grade 2 hypertension (≥160/100 mmHg), initiate two antihypertensive agents from the outset (e.g., losartan plus a thiazide diuretic or calcium channel blocker). 4
• Triple therapy (ARB + thiazide + calcium channel blocker) is recommended if blood pressure remains uncontrolled on dual therapy. 4
• For resistant hypertension (uncontrolled on triple therapy), add spironolactone 25 mg daily as the fourth agent. 4

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Blood Pressure Targets

• Aim for <130/80 mmHg in most adults to reduce cardiovascular risk (minimum acceptable goal <140/90 mmHg). 4
• Reassess blood pressure every 2–4 weeks after initiating or adjusting therapy, with the goal of reaching the target within 3 months. 4

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Drug Interactions

• Potassium supplements or potassium-sparing diuretics: Markedly increase hyperkalemia risk, especially in chronic kidney disease. 4
• NSAIDs: May blunt losartan's antihypertensive effect and worsen renal function. 4
• Lithium: Co-administration can precipitate lithium toxicity; monitor lithium levels. 4

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Alternative Treatment Options

For Hypertension

• ACE inhibitors (e.g., lisinopril, enalapril) are first-line alternatives with similar efficacy but a higher incidence of cough and angioedema. 7
• Calcium channel blockers (e.g., amlodipine) and thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone) are effective alternatives or combination partners. 4

For Heart Failure with Reduced Ejection Fraction

• ACE inhibitors remain first-line therapy; losartan is reserved for ACE-intolerant patients. 4
• Sacubitril/valsartan (ARNI) is superior to ACE inhibitors or ARBs alone in reducing heart failure hospitalization and mortality. 4

For Diabetic Nephropathy

• ACE inhibitors are equally effective in slowing GFR decline and reducing proteinuria in type 2 diabetes with macroalbuminuria. 4

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Common Pitfalls to Avoid

• Underdosing: Less than 25% of patients are titrated to target doses in clinical practice; higher doses provide greater cardiovascular and renal benefits. 4
• Premature discontinuation for mild creatinine elevation: A rise of 0.1–0.3 mg/dL is expected and reflects hemodynamic changes rather than tubular injury; discontinuation is not required unless acute tubular necrosis is evident. 4
• Combining losartan with ACE inhibitors: This combination is contraindicated and increases adverse events without improving outcomes. 6, 4, 5
• Failing to monitor potassium and renal function: Hyperkalemia and acute kidney injury are serious risks, especially in high-risk populations. 4, 5