|Trade names||Cozaar, others|
|Drug class||Angiotensin II receptor antagonist|
|Defined daily dose||50 mg |
|Protein binding||99.7% (primarily albumin)|
|Metabolism||Liver (CYP2C9, CYP3A4)|
|Elimination half-life||1.5–2 hours|
|Excretion||Kidney 13–25%, biliary 50–60%|
|Chemical and physical data|
|Molar mass||422.92 g·mol−1|
|3D model (JSmol)|
Losartan, sold under the trade name Cozaar among others, is a medication mainly used to treat high blood pressure. It is also used for diabetic kidney disease, heart failure, and left ventricular enlargement. It is taken by mouth. It may be used alone or in addition to other blood pressure medication. Up to six weeks may be required for the full effects to occur.
Common side effects include muscle cramps, stuffy nose, cough, high blood potassium and anemia. Severe side effects may include angioedema, low blood pressure, and kidney problems. Use during pregnancy may result in harm to the baby. Use is not recommended during breastfeeding. It is in the angiotensin receptor blocker family of medication. It works by blocking angiotensin II.
Losartan was patented in 1986, and approved for medical use in the United States in 1995. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. The wholesale cost in the developing world is about US$0.28–3.45 per month as of 2015. In the United States, as of 2017, the wholesale cost of a typical dose is $1.13 per month. In the UK, as of 2020, a one month supply costs the NHS around £2. In 2017, it was the ninth most commonly prescribed medication in the United States, with more than 51 million prescriptions. A version combined with hydrochlorothiazide in 2017, was the 67th most commonly prescribed medication in the United States, with more than eleven million prescriptions.
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 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. 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.
The defined daily dose is 50 milligram (by mouth). The suggested initial dose of losartan for treatment of hypertension is 50 mg/day, and the usual maintenance dose range is 25–100 mg/day. There is limited data on what dosage is considered toxic in humans; toxicity would most likely result in decreased blood pressure and an increased heart rate.
The most common side effects for losartan in adults are upper respiratory infections, dizziness, and back pain. People with type 2 diabetes and kidney disease may experience diarrhea, fatigue, low blood pressure, low blood glucose, elevated potassium, chest pain, or allergic reaction. Losartan should not be taken by people who are diabetic and taking aliskiren. Anemia may occur, due to inhibition of the renin–angiotensin system. As with other angiotensin receptor blockers, losartan may injure the liver, although this effect appears to be rare. Electrolyte imbalances may occur in people taking losartan with kidney problems. Adverse outcomes do not differ by sex, age or race.
In October 2014, the U.S. Food and Drug Administration (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.
Overdosing would most likely result in decreased blood pressure, which could manifest as an increased heart rate, dizziness, feeling light headed, or loss of consciousness. Mice studies showed that lethality occurred at about 44 to 170 times the maximum recommended dose after the mice weight were adjusted.
Losartan may have adverse interactions with some medications. Its effect may be reduced by indomethacin, phenobarbital and rifampin, and increased by fluconazole and diuretics. Alcohol may also increase the blood pressure lowering effect of losartan. Some herbs and foods such as grapefruit juice and liquorice can reduce the blood pressure lowering effect of losartan, causing high blood pressure. Other herbs and food such as celery, garlic, ginger and St John's wort can increase the effect of losartan resulting in a low blood pressure.
Between November 2018, and September 2019, the FDA announced multiple recalls of tablets containing losartan by Sandoz, Torrent Pharmaceuticals, Hetero Labs, Camber Pharmaceuticals, Legacy Pharmaceutical Packaging, Teva Pharmaceuticals, Vivimed Life Sciences, and Macleods Pharmaceutical Limited due to detection of one of the possible carcinogens N-nitrosodiethylamine, N-methylnitrosobutyric acid, or N-nitroso-N-methyl-4-aminobutyric acid in the active pharmaceutical ingredient (API).
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. 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. Aldosterone serves to retain sodium from the distal renal tubule. Sodium retention ultimately results in increased blood pressure. Therefore, the use of angiotensin II receptor antagonists like losartan result in blocking the downstream effect of renin, 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 there are other enzymes than ACE that have the capability of producing angiotensin II.
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. 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.
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.
Society and culture
Losartan is inexpensive. The wholesale cost in the developing world is about US$0.28–3.45 per month as of 2015. In the United States, as of 2017, the wholesale cost of a typical dose is $1.13 per month. In 2017, it was the ninth most commonly prescribed medication in the United States, with more than 51 million prescriptions. In the UK, as of 2020, a one month supply costs the NHS around £2.
The virus SARS-CoV-2, which causes COVID-19, uses angiotensin II (ACE2) receptors to enter target cells, leading to the question of whether to continue or stop drugs that inhibit the renin-angiotensin-aldosterone system (RAAS), such as losartan. One of the earliest randomised studies attempting to answer his question, did not find any difference in outcomes. As of 2021, two clinical trials of the use of losartan in people with COVID-19 are ongoing.
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