Losartan: Difference between revisions

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{{Short description|Blood pressure medication}}

{{Infobox drug

| caption =  

<!-- Clinical data -->

| pronounce = {{IPAc-en|l|oʊ|ˈ|s|ɑr|t|ən}}

| ATC_supplemental =  

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability = 25–35%

| excretion = [[Kidney]] 13–25%, [[bile duct]] 50–60%

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| synonyms =  

<!-- Chemical and physical data -->

| IUPAC_name = (2-butyl-4-chloro-1-{[2'-(2''H''-tetrazol-5-yl)biphenyl-4-yl]methyl}-1''H''-imidazol-5-yl)methanol

}}

<!-- Definition and medical uses -->

'''Losartan''', sold under the brand name '''Cozaar''' among others, is a [[medication]] used to treat [[high blood pressure]] (hypertension). It is in the [[angiotensin II receptor antagonist|angiotensin receptor blocker (ARB)]] family of medication, and is considered protective of the kidneys. Besides hypertension, it is also used in [[diabetic kidney disease]], [[heart failure]], and [[left ventricular enlargement]]. It comes as a tablet that is taken [[Oral administration|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.

<!-- Side effects and mechanism -->

Common adverse effects include muscle cramps, stuffy nose, dizziness, cough, [[hyperkalemia|high blood potassium]], and [[anemia]]. Severe adverse 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 works by blocking [[angiotensin II]].

<!-- History and culture -->

Losartan was patented in 1986, and approved for medical use in the United States in 1995. It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]]. It is available as a [[generic medication]]. In 2021, it was the eighth most commonly prescribed medication in the United States, with more than 55{{nbsp}}million prescriptions. A version combined with [[hydrochlorothiazide]] is available which, in 2021, was the 87th most commonly prescribed medication in the United States, with more than 8{{nbsp}}million prescriptions.

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 {{Format molecular formula|C22H23CIKN6O}}, 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]].

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&nbsp;mg/24 hours) or proteinuria (>900&nbsp;mg/24 hours).

Although evidence shows [[calcium channel blockers]] and [[thiazide diuretic|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.

The most common adverse effects for losartan in adults are upper [[respiratory infection]]s, [[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 with kidney problems who take losartan. 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 [[fetus|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 weights were taken into account.

Losartan may have adverse [[drug interaction|interactions]] with [[phenobarbital]], [[rifampin]], or [[fluconazole]], possibly inhibiting its blood pressure-lowering effects.

{{See also|Valsartan#recalls|Angiotensin II receptor blocker#recalls}}

Between November 2018 and September 2019, the FDA announced multiple recalls of tablets containing losartan by [[Sandoz]], [[Torrent Pharmaceuticals]], [[Hetero Drugs|Hetero Labs]], Camber Pharmaceuticals, Legacy Pharmaceutical Packaging, [[Teva Pharmaceutical Industries|Teva Pharmaceuticals]], [[Vivimed Labs|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 ingredient|active pharmaceutical ingredient]] (API).

[[File:Renin-angiotensin-aldosterone system.svg|thumb|Renin-angiotensin-aldosterone system (RAAS)|alt=|612x612px]]

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.

Losartan's [[bioavailability]] is about 33%.

Metabolism is primarily by [[cytochrome P450]] [[isoenzyme]]s [[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.

{{main|Discovery and development of angiotensin receptor blockers}}

* {{cite journal |vauthors=Al-Majed AR, Assiri E, Khalil NY, Abdel-Aziz HA |title=Losartan: Comprehensive Profile |journal=Profiles Drug Subst Excip Relat Methodol |volume=40 |pages=159–94 |date=2015 |pmid=26051686 |doi=10.1016/bs.podrm.2015.02.003 }}

* {{cite journal |vauthors=Sica DA, Gehr TW, Ghosh S |title=Clinical pharmacokinetics of losartan |journal=Clin Pharmacokinet |volume=44 |issue=8 |pages=797–814 |date=2005 |pmid=16029066 |doi=10.2165/00003088-200544080-00003 |s2cid=41326620 }}

* {{cite web | title=Nitrosamine impurities in medications: Guidance | website=Health Canada | date=4 April 2022 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities/medications-guidance.html }}

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{{Angiotensin II receptor antagonists}}

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{{二次利用|date=7 February 2024}}

[[Category:Angiotensin II receptor antagonists]]