Mechanism of action
Losartan is a competitive, selective antagonist of the angiotensin II type 1 (AT1) receptor. By blocking AT1 receptors in vascular smooth muscle, adrenal glands, kidneys, and the heart, losartan prevents angiotensin II from exerting its effects.
Angiotensin II normally binds to AT1 receptors and causes:
- Vasoconstriction of arterioles, increasing systemic vascular resistance
- Aldosterone secretion from the adrenal cortex, leading to sodium and water retention
- Sympathetic nervous system activation
- Renal sodium reabsorption
- Vascular and cardiac remodeling and hypertrophy
By blocking these actions, losartan produces vasodilation, reduces blood pressure, decreases cardiac afterload, and promotes natriuresis. Unlike ACE inhibitors, ARBs do not affect bradykinin metabolism, which explains their lower incidence of cough and angioedema.
Losartan is unique among ARBs because it has uricosuric properties. It inhibits the URAT1 transporter in the proximal tubule, increasing renal uric acid excretion. This makes losartan particularly beneficial in hypertensive patients with concurrent hyperuricemia or gout.
Losartan is a prodrug that undergoes first-pass metabolism in the liver via CYP2C9 and CYP3A4 to its active metabolite, EXP3174, which is 10 to 40 times more potent than the parent compound and has a longer half-life.
- Losartan is the only ARB with uricosuric properties, making it ideal for hypertensive patients with gout.
- ARBs like losartan do not cause cough or significantly increase angioedema risk compared to ACE inhibitors.
- Losartan is contraindicated in the second and third trimesters of pregnancy due to fetal renal toxicity.
- Losartan can cause hyperkalemia, especially in patients with CKD, diabetes, or on potassium-sparing agents.
- Losartan is renoprotective in diabetic nephropathy, reducing proteinuria and slowing disease progression.
- Losartan is metabolized to an active metabolite (EXP3174) via CYP2C9 and CYP3A4.
- Bilateral renal artery stenosis is a relative contraindication due to risk of acute kidney injury.
- Losartan blocks AT1 receptors, preventing vasoconstriction and aldosterone release by angiotensin II.
Indications
Losartan is indicated for:
Hypertension
Losartan is a first-line agent for hypertension, particularly in patients with compelling indications such as diabetes, chronic kidney disease, or heart failure. It is effective as monotherapy or in combination with other antihypertensives, commonly thiazide diuretics or calcium channel blockers.
Heart failure with reduced ejection fraction
Losartan reduces mortality and hospitalizations in patients with heart failure and left ventricular systolic dysfunction. It is an alternative to ACE inhibitors in patients who cannot tolerate them due to cough or angioedema.
Diabetic nephropathy
Losartan slows the progression of diabetic nephropathy in patients with type 2 diabetes and proteinuria. It reduces proteinuria and preserves renal function by decreasing intraglomerular pressure through efferent arteriole dilation.
Stroke prevention
Losartan is used to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, though this indication is based on specific trial populations.
Off-label uses
Losartan may be used off-label for Marfan syndrome to slow aortic root dilation, though evidence is mixed.
Pharmacokinetics
Absorption
Losartan is absorbed rapidly after oral administration, with peak plasma concentrations reached in 1 to 2 hours. Bioavailability is approximately 33% due to significant first-pass metabolism.
Distribution
Losartan is highly protein-bound (98 to 99%), primarily to albumin. It has a volume of distribution of approximately 34 liters.
Metabolism
Losartan undergoes extensive hepatic metabolism via CYP2C9 (primary) and CYP3A4 to form the active metabolite EXP3174. This metabolite is responsible for most of the AT1 receptor blockade. The parent drug has a half-life of 2 hours, while EXP3174 has a half-life of 6 to 9 hours.
Excretion
Losartan and its metabolites are excreted in both urine (35%) and feces (60%). Dosage adjustment is not typically required in mild to moderate renal impairment but may be needed in severe hepatic impairment.
Adverse effects
Losartan is generally well tolerated, with a side effect profile similar to placebo in many trials. Common and serious adverse effects include:
Hyperkalemia
By blocking aldosterone secretion, losartan reduces potassium excretion in the distal nephron. Hyperkalemia is more likely in patients with chronic kidney disease, diabetes, or those taking potassium-sparing diuretics, NSAIDs, or potassium supplements. Monitor serum potassium, especially after initiation.
Hypotension
Orthostatic hypotension and dizziness can occur, particularly in volume-depleted patients (e.g., those on diuretics) or after the first dose. Symptomatic hypotension is more common in heart failure patients.
Acute kidney injury
Losartan can cause acute renal impairment, especially in patients with bilateral renal artery stenosis, severe heart failure, or volume depletion. It reduces intraglomerular pressure by dilating the efferent arteriole, which may transiently decrease GFR. Monitor serum creatinine and potassium within 1 to 2 weeks of initiation.
Angioedema
Though much less common than with ACE inhibitors, angioedema can still occur with ARBs. It presents as swelling of the face, lips, tongue, or airway and requires immediate discontinuation.
Other adverse effects
- Dizziness and fatigue
- Upper respiratory infection
- Back pain
- Diarrhea
- Rarely, hepatotoxicity or rhabdomyolysis
Losartan does not cause cough or significantly elevate bradykinin levels, making it an excellent alternative for patients who develop ACE inhibitor-induced cough.
Contraindications and warnings
Absolute contraindications
- Hypersensitivity to losartan or any component of the formulation
- Pregnancy (second and third trimesters)
- Concomitant use with aliskiren in patients with diabetes mellitus
Pregnancy
Losartan is contraindicated in pregnancy, particularly in the second and third trimesters. ARBs can cause fetal renal dysfunction, oligohydramnios, intrauterine growth restriction, and neonatal hypotension, hyperkalemia, and death. Discontinue losartan as soon as pregnancy is detected.
Bilateral renal artery stenosis
Losartan can precipitate acute renal failure in patients with bilateral renal artery stenosis or stenosis of a solitary functioning kidney, as glomerular filtration becomes dependent on angiotensin II-mediated efferent arteriole constriction.
Severe hepatic impairment
Because losartan is metabolized hepatically to its active form, patients with severe liver disease may have reduced drug activation and clearance. Consider dose reduction.
Hyperkalemia risk
Use caution in patients with baseline hyperkalemia, advanced chronic kidney disease, or those on other potassium-elevating agents.
Dual RAAS blockade
Combining losartan with ACE inhibitors or aliskiren increases the risk of hypotension, hyperkalemia, and renal impairment without additional benefit. Dual blockade is generally not recommended.
Drug interactions
Potassium-sparing agents
Concurrent use with potassium-sparing diuretics (spironolactone, amiloride, triamterene), potassium supplements, or salt substitutes containing potassium increases the risk of hyperkalemia.
NSAIDs
Nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors, can reduce the antihypertensive effect of losartan and increase the risk of acute kidney injury and hyperkalemia by inhibiting prostaglandin-mediated vasodilation.
Lithium
ARBs can increase serum lithium levels and the risk of lithium toxicity. Monitor lithium concentrations closely if concurrent use is necessary.
Diuretics
Combination with diuretics enhances antihypertensive efficacy but may increase the risk of hypotension, especially with the first dose. Volume-depleted patients are at higher risk.
CYP2C9 and CYP3A4 inhibitors/inducers
Drugs that inhibit CYP2C9 (e.g., fluconazole) may reduce conversion to the active metabolite, potentially decreasing efficacy. Inducers (e.g., rifampin) may enhance metabolism.
Aliskiren
Concomitant use of losartan with aliskiren is contraindicated in patients with diabetes and not recommended in patients with renal impairment due to increased risk of renal dysfunction, hyperkalemia, and hypotension.
Clinical pearls
- Losartan is the only ARB with uricosuric properties, making it the preferred ARB in hypertensive patients with gout or hyperuricemia. It increases uric acid excretion by inhibiting URAT1 in the proximal tubule.
- ARBs like losartan do not cause cough, unlike ACE inhibitors. This is because ARBs do not affect bradykinin metabolism. Losartan is a first-line alternative in patients who develop ACE inhibitor-induced cough.
- Monitor renal function and potassium within 1 to 2 weeks of starting losartan, especially in patients with chronic kidney disease, diabetes, or those on other RAAS inhibitors or potassium-sparing agents.
- Losartan is renoprotective in diabetic nephropathy, reducing proteinuria and slowing progression to end-stage renal disease. This benefit is independent of blood pressure reduction.
- ARBs are as effective as ACE inhibitors for heart failure and post-MI left ventricular dysfunction but have a lower incidence of cough and angioedema.
- Losartan is teratogenic and must be discontinued immediately if pregnancy is detected. Use effective contraception in women of childbearing potential.
- First-dose hypotension is uncommon with losartan but can occur in volume-depleted patients. Consider holding diuretics or ensuring adequate hydration before initiating therapy.
- Losartan is often combined with hydrochlorothiazide in fixed-dose combinations for synergistic antihypertensive effect and to mitigate the hyperkalemia risk from the ARB with the hypokalemia from the thiazide.
ARBS: Angioedema (rare), Renal artery stenosis (caution), Birth defects (teratogenic), Serum K+ (hyperkalemia)
Practice questions
1. A 58-year-old man with type 2 diabetes and hypertension is started on losartan for blood pressure control and renal protection. Two weeks later, laboratory tests show serum creatinine increased from 1.2 to 1.6 mg/dL and potassium elevated to 5.8 mEq/L. Which of the following best explains these findings?
2. A 62-year-old woman with hypertension and a history of chronic gout is being considered for antihypertensive therapy. Her current medications include allopurinol and ibuprofen as needed. Which antihypertensive agent would be most appropriate given her comorbidities?
3. A 45-year-old man with hypertension treated with lisinopril for 3 months presents with a persistent dry cough that is interfering with his sleep. He has no signs of heart failure or respiratory infection. Blood pressure is well controlled at 128/78 mmHg. What is the most appropriate next step in management?
Frequently asked questions
How does losartan work?
Losartan works by selectively blocking angiotensin II type 1 (AT1) receptors, preventing angiotensin II from causing vasoconstriction, aldosterone release, and sodium retention. This leads to vasodilation, reduced blood pressure, and decreased cardiac afterload. Unlike ACE inhibitors, losartan does not affect bradykinin, so it does not cause cough. Losartan is unique among ARBs because it also has uricosuric properties, promoting renal uric acid excretion.
What are the side effects of losartan?
The most common side effects of losartan include dizziness, fatigue, and upper respiratory infections. Serious adverse effects include hyperkalemia (elevated potassium), hypotension (low blood pressure), and acute kidney injury, particularly in patients with renal artery stenosis or chronic kidney disease. Angioedema is rare but can occur. Unlike ACE inhibitors, losartan does not cause cough. Losartan is contraindicated in pregnancy due to fetal toxicity.
Is losartan a controlled substance?
No, losartan is not a controlled substance. It is a prescription medication used to treat high blood pressure, heart failure, and diabetic kidney disease. Losartan is an angiotensin II receptor blocker (ARB) with no potential for abuse or dependence. It is widely available and does not require special prescribing regulations like controlled substances do.
Losartan vs lisinopril — what is the difference?
Losartan is an angiotensin II receptor blocker (ARB), while lisinopril is an ACE inhibitor. Both lower blood pressure and protect the kidneys and heart, but they work at different points in the renin-angiotensin system. Losartan blocks the AT1 receptor, while lisinopril prevents angiotensin II formation. Losartan is preferred in patients who develop a dry cough or angioedema with ACE inhibitors, as it does not affect bradykinin. Losartan also has unique uricosuric properties beneficial in gout.
Can losartan be taken during pregnancy?
No, losartan is contraindicated in pregnancy, especially in the second and third trimesters. Losartan can cause serious fetal harm, including renal dysfunction, oligohydramnios, skeletal malformations, and neonatal death. If pregnancy is detected, losartan should be discontinued immediately. Women of childbearing potential should use effective contraception while taking losartan. Alternative antihypertensive agents such as methyldopa, labetalol, or nifedipine are preferred during pregnancy.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: C09CA01
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.