|Protein binding||99.7% (primarily albumin)|
|Metabolism||Hepatic (CYP2C9, CYP3A4)|
|Biological half-life||1.5–2 hours|
|Excretion||Renal 13–25%, biliary 50–60%|
|Chemical and physical data|
|Molar mass||422.91 g/mol|
|3D model (JSmol)|
It was the first angiotensin II antagonist to be marketed. It was initially marketed by Merck & Co. Inc. and is available in generic form. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.
As with all angiotensin II type 1 receptor (AT1) antagonists, losartan is indicated for the treatment of hypertension. It may also delay progression of diabetic nephropathy and is associated with a positive clinical outcome in that regard. It is a suitable pharmacological agent for the reduction of renal disease progression in patients with type 2 diabetes, hypertension, and microalbuminuria (>30 mg/24 hours) or proteinuria (>900 mg/24 hours).
Although clinical evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most patients (due to both efficacy and cost), an angiotensin II receptor antagonist such as losartan is recommended as first-line treatment in patients under the age of 55 who cannot tolerate an ACE inhibitor. The LIFE study demonstrated losartan was significantly superior to atenolol in the primary prevention of adverse cardiovascular events (myocardial infarction or stroke), with a significant reduction in cardiovascular morbidity and mortality for a comparable reduction in blood pressure. A study hints that losartan has a beneficial effect on mitochondria by reversing age related dysfunction in maintaining normal blood pressure and cellular energy usage. The maximal effects on blood pressure usually occur within 3–6 weeks of starting losartan.
In January 2014, the FDA issued a black box warning that losartan can cause fetal toxicity, and should be discontinued as soon as pregnancy is detected. Using losartan while pregnant could result in fetal injury or death.
The most common side effects for losartan are upper respiratory infections or stuffy nose, dizziness, and back pain. Type 2 diabetics with diabetic kidney disease may experience diarrhea, fatigue, low blood pressure, low blood glucose, elevated potassium, and chest pain.
More serious side effects include low blood pressure and allergic reaction.
Mechanism of action
Losartan is a selective, competitive angiotensin II receptor type 1 (AT1) antagonist, reducing the end organ responses to angiotensin II. Losartan administration results in a decrease in total peripheral resistance (afterload) and cardiac venous return (preload). All of the physiological effects of angiotensin II, including release of aldosterone, are antagonized in the presence of losartan. Reduction in blood pressure occurs independently of the status of the renin-angiotensin system. As a result of losartan dosing, plasma renin activity increases due to removal of the angiotensin II feedback.
Losartan is a uricosuric. As a specific inhibitor of the urate transporter 1 (SLC22A12, URAT1), losartan blocks the uptake of uric acid into cells, thus leaving more available in the bloodstream to be filtered and excreted by the kidneys. Because losartan can cause hyperkalemia, individuals should not use potassium supplements or salt substitutes containing potassium without appropriate monitoring by a physician.
Losartan is well absorbed following oral administration and undergoes significant first-pass metabolism to produce the 5-carboxylic acid metabolite, designated as EXP3174. About 14% of an oral dosage is converted to this metabolite, which is long-acting (6 to 8 hr) and a noncompetitive antagonist at the AT1 receptor, contributing to the pharmacological effects of losartan. EXP3174 is 10-40 times more potent in blocking AT1 receptors than losartan. Losartan's bioavailability is about 32%.
Metabolism is primarily by cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Peak plasma concentrations of losartan and EXP3174 occur about one hour and three to four hours, respectively, after an oral dose. Both losartan and EXP3174 are more than 98% bound to plasma proteins. Losartan is excreted in the urine, and in the feces via bile, as unchanged drug and metabolites. About 4% of an oral dose is excreted unchanged in urine, and about 6% is excreted in urine as the active metabolite. The terminal elimination half lives of losartan and EXP3174 are about 1.5 to 2.5 hours and 3 to 9 hours, respectively.
Losartan and other angiotensin-receptor antagonists exhibit fetal toxicity and should be avoided during pregnancy, particularly in the second and third trimesters.
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