Losartan, sold under the brand name Cozaar among others, is a medication used to treat high blood pressure (hypertension).[ It is in the 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 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 adverse effects include muscle cramps, stuffy nose, dizziness, cough, hyperkalemia, 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.][
]
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.
In 2022, it was the eighth most commonly prescribed medication in the United States, with more than 53million prescriptions.
A version combined with hydrochlorothiazide is available
[ which, in 2022, was the 75th most commonly prescribed medication in the United States, with more than 8million prescriptions.]
Chemistry
Losartan potassium is chemically described as 2-butyl-4-chloro-1-p-(o-1H-tetrazol-5-ylphenyl)benzylimidazole-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".
Medical uses
Losartan is used for hypertension, including in people with left ventricular hypertrophy (enlarged heart muscle), and kidney dysfunction among type II diabetics.
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.
Adverse effects
The most common adverse 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.][ Adverse outcomes do not differ by sex, age, or race.][
]
Pregnancy
In October 2014, the U.S. Food and Drug Administration (FDA) issued a black box warning that losartan can cause fetus toxicity and should be discontinued as soon as pregnancy is detected.[ Using losartan while pregnant could result in fetal injury or death.][
]
Overdose
Overdosing would most likely result in decreased blood pressure, which could manifest as an increased heart rate, dizziness, feeling lightheaded, 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.[
]
Interactions
Losartan may have adverse drug interaction with phenobarbital, rifampin, or fluconazole, possibly inhibiting its blood pressure-lowering effects.[
]
Contamination
Between November 2018 and September 2019, the FDA announced multiple recalls of tablets containing losartan by Sandoz, Torrent Pharmaceuticals, Hetero Drugs, Camber Pharmaceuticals, Legacy Pharmaceutical Packaging, Teva Pharmaceuticals, Vivimed Labs, 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 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.[ Aldosterone serves to retain sodium from the distal renal tubule. Sodium retention ultimately results in increased 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.[
]
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.[RxList. The Internet Drug Index. Clinical pharmacology of Cozaar . Retrieved 6 January 2014.]
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 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 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.
History
Further reading
External links
