<!-- Definition and medical uses -->
Losartan, sold under the brand name Cozaar among others, is a medication used to treat high blood pressure (hypertension). It works by blocking angiotensin II. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2023, it was the eighth most commonly prescribed medication in the United States, with more than 56million prescriptions. A version combined with hydrochlorothiazide as a diuretic is available
Chemistry
Losartan potassium is chemically described as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its empirical formula is , and its molecular weight is 422.9.
Losartan is generally marketed as the (basic) potassium salt of the aromatized negatively charged tetrazole, called "losartan potassium". The molecule has an extended biphenyl group with a tetrazole which is being used in place of the carboxylic acid as a bioisostere.
Medical uses
Losartan is used for hypertension, including in people with left ventricular hypertrophy (enlarged heart muscle), and kidney dysfunction among type II diabetics. It may also delay progression of diabetic nephropathy. It is a suitable pharmacological agent for the reduction of kidney (renal) disease progression in patients with type 2 diabetes, hypertension, and microalbuminuria (>30 mg/24 hours) or proteinuria (>900 mg/24 hours).
Although evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most people (due to both efficacy and cost), an angiotensin II receptor antagonist such as losartan is recommended as first-line treatment in people under the age of 55 who cannot tolerate an ACE inhibitor. One study demonstrated losartan was superior to atenolol in the primary prevention of adverse cardiovascular events (myocardial infarction or stroke), with a reduction in cardiovascular morbidity and mortality for a comparable reduction in blood pressure. The maximal effects on blood pressure usually occur within 3–6 weeks of starting losartan.
Adverse effects
The most common adverse effects for losartan in adults are upper respiratory infections, dizziness, and back pain. As with other angiotensin receptor blockers, losartan may injure the liver, although this effect appears to be rare. Electrolyte imbalances may occur in people with kidney problems who take losartan.
Mechanism of action
thumb|Renin-angiotensin-aldosterone system (RAAS)|alt=|612x612px
Losartan is a selective, competitive angiotensin II receptor type 1 (AT<sub>1</sub>) 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 the 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 the removal of the angiotensin II feedback. Renin is released from the kidneys when there is reduced renal arterial pressure, sympathetic activation, or increased sodium delivery to the distal renal tubule. Renin then acts by converting angiotensinogen to angiotensin I; angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II; angiotensin II causes vasoconstriction and aldosterone release. Therefore, the use of angiotensin II receptor antagonists like losartan results in blocking the downstream effect of renin, and angiotensin II, and ultimately decreasing blood pressure.
Angiotensin II receptor antagonists include losartan, valsartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, and telmisartan. They all have the same mechanism of action and potentially inhibit the actions of angiotensin better than ACE inhibitors, such as lisinopril, because other enzymes than ACE have the capability of producing angiotensin II. Because losartan can cause hyperkalemia, individuals should not use potassium supplements or salt substitutes containing potassium without appropriate monitoring by a physician.
Pharmacokinetics
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 hours) and a noncompetitive antagonist at the AT<sub>1</sub> receptor, contributing to the pharmacological effects of losartan. EXP3174 is 10–40 times more potent in blocking AT<sub>1</sub> receptors than losartan. In addition, the binding to the target enzyme is pH-sensitive, and the negatively charged tetrazole ring, which is similar in size to the negative carboxylic acid derivative, may contribute to the activity of the drug.
Losartan's bioavailability is about 33%.