|Systematic (IUPAC) name|
|Protein binding||99.7% (primarily albumin)|
|Metabolism||Hepatic (CYP2C9, CYP3A4)|
|Excretion||Renal 13–25%, biliary 50–60%|
|(what is this?)|
Losartan (rINN) // is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure (hypertension). It was the first angiotensin II antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar, and is available in generic form.
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.
Mechanism of action and pharmacological actions
Losartan is a selective, competitive angiotensin II receptor type 1 (AT1) receptor 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 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.
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. Patients who are diabetic may also commonly experience diarrhea, fatigue, low blood pressure, low blood sugar, elevated potassium, and chest pain.
More serious side effects include low blood pressure and allergic reaction.
Losartan has been found to downregulate the expression of transforming growth factor beta (TGF-β) types I and II receptors in the kidney of diabetic rats, which may partially account for its nephroprotective effects. Effects on TGF-β expression may also account for its potential efficacy in Marfan syndrome and Duchenne muscular dystrophy – losartan has been shown to prevent aortic aneurysm and certain pulmonary complications in a mouse model of the disease.
Losartan is being studied for use in the treatment of the 20% of breast cancer tumors positive for AGTR1. The University of Michigan Comprehensive Cancer Center announced in 2009 the result of an animal study which found losartan to "block" - reverse neoplastic changes - caused by this gene.
Losartan is being researched as a possible protection against loss of damaged or old muscle.
Losartan has recently been found to be a cognitive enhancer. It improved memory in people with normal blood pressure under standard conditions, as well as during memory-impaired tasks (coadministration of scopolamine).
Losartan has been found to prevent smoking-related lung damage in mice, and trials are underway for the potential treatment of smoking-related chronic obstructive pulmonary disease, the long-term consequence of smoking and for which, until now, no potential treatments to prevent or repair the resulting lung damage are known.
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In conclusion, we demonstrated regression of DAR using ARBs at moderate and supramaximal doses. Intensive ARB therapy offers a promise to reduce the natural progression of disease in patients with DARs.
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