Losartan

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Losartan
Skeletal formula
Space-filling model
Systematic (IUPAC) name
(2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol
Clinical data
Trade names Cozaar
AHFS/Drugs.com monograph
MedlinePlus a695008
Licence data US Daily Med:link
Pregnancy cat. D (AU) D (US)
Legal status Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 25–35%
Metabolism Hepatic (CYP2C9, CYP3A4)
Half-life 1.5–2 hours
Excretion Renal 13–25%, biliary 50–60%
Identifiers
CAS number 114798-26-4 YesY
ATC code C09CA01
PubChem CID 3961
IUPHAR ligand 590
DrugBank DB00678
ChemSpider 3824 YesY
UNII JMS50MPO89 YesY
KEGG D08146 YesY
ChEBI CHEBI:6541 YesY
ChEMBL CHEMBL191 YesY
Chemical data
Formula C22H23ClN6O 
Mol. mass 422.91
 YesY (what is this?)  (verify)

Losartan (rINN) /lˈsɑrtən/ is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure (hypertension). Losartan was the first angiotensin II antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar. Losartan 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 therefore 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).[1]

Although clinical evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most patients (from both efficacy and cost points of view), 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.[2] 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.[3][4] The maximal effects on blood pressure usually occur within 3–6 weeks upon starting losartan.[5]

Losartan is also available as hydrochlorothiazide/losartan, a combination drug with a low dose thiazide diuretic to achieve an additive antihypertensive effect.

Mechanism of action and pharmacological actions[edit]

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 stimulation of 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 a uricosuric. Because losartan can cause hyperkalemia, potassium supplements or salt substitutes containing potassium should not be used without appropriate monitoring by a physician.[6]

Pharmacokinetics[edit]

Losartan is well absorbed following oral administration and undergoes significant first-pass metabolism to produce 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 E-3174 occur about one hour and three to four hours, respectively, after an oral dose. Both losartan and E-3174 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 E-3174 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 trimester.[7]

Adverse Effects[edit]

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.[8]Using losartan while pregnant could result in fetal injury or death.[9]

The most common side effects for losartan are upper respiratory infections or stuffy nose, dizziness, and back pain.[10] Patients who are diabetic may also commonly experience diarrhea, fatigue, low blood pressure, low blood sugar, elevated potassium, and chest pain.[11]

More serious side effects include low blood pressure and allergic reaction.[12]

Contraindications[edit]

Losartan should not be taken with patients who are diabetic and taking aliskiren.[13]

Research[edit]

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.[14] Effects on TGF-β expression may also account for its potential efficacy in Marfan syndrome and Duchenne muscular dystrophy (DMD) – losartan has been shown to prevent aortic aneurysm and certain pulmonary complications in a mouse model of the disease.[15][16]

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.[17]

In 2003, Losartan was studied on 32 subjects for its use in the treatment[18][19]of aortic enlargement in Marfan and related syndromes such as Loeys-Dietz Syndrome.

Losartan is being researched as a possible protection against loss of damaged or old muscle.[20]

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 (co-administration of scopolamine).[21]

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 (COPD), the long-term consequence of smoking and for which, until now, there are no known potential treatments to prevent or repair the resulting lung damage.[22]

See also[edit]

References[edit]

  1. ^ Boersma C, Atthobari J, Gansevoort RT, de Jong-Van den Berg LT, de Jong PE, de Zeeuw D, Annemans LJ, Postma MJ (2006). "Pharmacoeconomics of angiotensin II antagonists in type 2 diabetic patients with nephropathy: implications for decision making." Pharmacoeconomics. 24 (6) : 523-35. PMID: 16761901
  2. ^ http://www.nice.org.uk/nicemedia/pdf/CG034NICEguideline.pdf, p19
  3. ^ "Switch in cell's 'power plant' declines with age; rejuvenated by drug". Johns Hopkins Medicine. August 16, 2011. 
  4. ^ Abadir, P. M.; Foster, D. B.; Crow, M.; Cooke, C. A.; Rucker, J. J.; Jain, A.; Smith, B. J.; Burks, T. N.; Cohn, R. D.; Fedarko, N. S.; Carey, R. M.; O'Rourke, B.; Walston, J. D. (2011). "Identification and characterization of a functional mitochondrial angiotensin system". Proceedings of the National Academy of Sciences 108 (36): 14849. doi:10.1073/pnas.1101507108. 
  5. ^ Abrams, Anne (2007).Clinical Drug Therapy Rationales for Nursing Practice,p.846. Lippincott Williams & Wilkins, Philadelphia, Pa. ISBN 0-7817-6263-4.
  6. ^ RxList. The Internet Drug Index. Clinical pharmacology of Cozaar. Retrieved January 6 2014.
  7. ^ Sica DA, Gehr TW, Ghosh S. (2005). "Clinical pharmacokinetics of losartan." Clin Pharmacokinet.44(8):797-814.PMID: 16029066 Retrieved 6 January 2014.
  8. ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm169666.htm
  9. ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm169666.htm
  10. ^ http://www.merck.com/product/usa/pi_circulars/c/cozaar/cozaar_ppi.pdf
  11. ^ http://www.merck.com/product/usa/pi_circulars/c/cozaar/cozaar_ppi.pdf
  12. ^ http://www.merck.com/product/usa/pi_circulars/c/cozaar/cozaar_ppi.pdf
  13. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020386s060lbl.pdf
  14. ^ Guo ZX, Qiu MC (June 2003). "Losartan downregulates the expression of transforming growth factor beta type I and type II receptors in kidney of diabetic rat" [Losartan downregulates the expression of transforming growth factor beta type I and type II receptors in kidney of diabetic rat]. Zhonghua Nei Ke Za Zhi (in Chinese) 42 (6): 403–8. PMID 12895325. 
  15. ^ Habashi, JP; Judge, DP; Holm, TM; Cohn, RD; Loeys, BL; Cooper, TK; Myers, L; Klein, EC; Liu, G; Calvi, C; Podowski, M; Neptune, ER; Halushka, MK; Bedja, D; Gabrielson, K; Rifkin, DB; Carta, L; Ramirez, F; Huso, DL; Dietz, HC (April 2006). "Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome". Science 312 (5770): 117–21. Bibcode:2006Sci...312..117H. doi:10.1126/science.1124287. PMC 1482474. PMID 16601194. 
  16. ^ Kolata, Gina (3 December 2013). "Learning to Defuse the Aorta". The New York Times. Retrieved 3 December 2013. 
  17. ^ Rhodes, DR; Ateeq, B; Cao, Q; Tomlins, SA; Mehra, R; Laxman, B; Kalyana-Sundaram, S; Lonigro, RJ; Helgeson, BE; Bhojani, M. S.; Rehemtulla, A.; Kleer, C. G.; Hayes, D. F.; Lucas, P. C.; Varambally, S.; Chinnaiyan, A. M. (June 2009). "AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist". Proceedings of the National Academy of Sciences 106 (25): 10284–9. Bibcode:2009PNAS..10610284R. doi:10.1073/pnas.0900351106. PMC 2689309. PMID 19487683. 
    Related news articles: "Breast Cancer Gene Can Be Blocked By Blood Pressure Drug" (Press release). ScienceDaily. June 7, 2009. 
  18. ^ Molecular Determinants of Aortic Aneurysm and Other Manifestations of Connective Tissue Disorders
  19. ^ Weinberg, Marc S.; Adam J. Weinberg; Raymond B Cord; Horace Martin (2003). "P-609: Regression of dilated aortic roots using supramaximal and usual doses of angiotensin receptor blockers". American Journal of Hypertension 16 (5): A259. doi:10.1016/S0895-7061(03)00782-9. Retrieved 2011-11-02. "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." 
  20. ^ Burks, TN; Andres-Mateos, E; Marx, R; Mejias, R; Van Erp, C; Simmers, JL; Walston, JD; Ward, CW; Cohn, RD (May 11, 2011). "Losartan Restores Skeletal Muscle Remodeling and Protects Against Disuse Atrophy in Sarcopenia". Science Translational Medicine 3 (82): 82ra37. doi:10.1126/scitranslmed.3002227. 
    Related news articles: "Blood Pressure Drug Shows Some Muscle" (Press release). Johns Hopkins. May 11, 2011. 
  21. ^ Mechaeil, R; Gard, Paul; Jackson, Anne; Rusted, Jennifer (September 2011). "Cognitive enhancement following acute losartan in normotensive young adults". Psychopharmacology 217 (1): 51–60. doi:10.1007/s00213-011-2257-9. PMID 21484242. 
  22. ^ http://www.hopkinsmedicine.org/news/media/releases/commonly_used_blood_pressure_drug_prevents_smoking_related_lung_damage_in_mice

External links[edit]