Substance
ID:561
Names and Identifiers
Brand Name
CozaarLortaanLacidipineHyzaar
IUPAC name
[2-butyl-4-chloro-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-imidazol-5-yl]methanol
Synonyms
DUP 89LosartanLosartan Potassium
IUPAC Traditional name
losartan
Properties
Physical Property
Hydrophobicity(logP)
6.1
Solubility
0.82 mg/L
Molecule Details
Drug Groups
approved
Description
Losartan is an angiotensin-receptor blocker (ARB) that may be used alone or with other agents to treat hypertension. Losartan and its longer acting metabolite, E-3174, lower blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); they compete with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough. Losartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy. It may also be used as an alternative agent for the treatment of systolic dysfunction, myocardial infarction, coronary artery disease, and heart failure.
Indication
May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Losartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors.
Pharmacology
Losartan is the first of a class of antihypertensive agents called angiotensin II receptor blockers (ARBs). Losartan and its longer acting active metabolite, E-3174, are specific and selective type-1 angiotensin II receptor (AT1) antagonists which block the blood pressure increasing effects angiotensin II via the renin-angiotensin-aldosterone system (RAAS). RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: AT1 and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure.
Toxicity
Hypotension and tachycardia; Bradycardia could occur from parasympathetic (vagal) stimulation, LD50= 1000 mg/kg (orally in rat)
Affected Organisms
Humans and other mammals
Biotransformation
Hepatic. Losartan is metabolized to a 5-carboxylic acid derivative (E-3174) via an aldehyde intermediate (E-3179) primarily by cytochrome P450 (CYP) 2C9 and CYP3A4. E-3174 is an active metabolite with 10- to 40-fold higher potency than its parent compound, losartan. Approxiamtely 14% of losartan is converted to E-3174; however, the AUC of E-3174 was found to be 4- to 8-fold higher than losartan and E-3174 is considered the main contributor to the pharmacologic effects of this medication.
Absorption
Well absorbed, the systemic bioavailability of losartan is approximately 33%
Half Life
The terminal t1/2 of losartan is 2 hours and that of E-3174 is 6-9 hours.
Protein Binding
99.7%, primarily to albumin
Elimination
After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites.
Distribution
* 34 L [losartan]
* 12 L [active metabolite]
* 12 L [active metabolite]
Clearance
* 600 mL/min [Healthy volunteers after IV administration]
* Renal cl=56 +/- 23 mL/min [Hypertensive adults given 50?mg once daily for 7 days]
* Renal cl=53 +/- 33 mL/min [Hypertensive children (6-16 years old) given 0.7 mg/kg once daily for 7 days]
* Renal cl=56 +/- 23 mL/min [Hypertensive adults given 50?mg once daily for 7 days]
* Renal cl=53 +/- 33 mL/min [Hypertensive children (6-16 years old) given 0.7 mg/kg once daily for 7 days]
References
•
Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002 Mar 23;359(9311):995-1003.
[Pubmed]
•
Guo ZX, Qiu MC: [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. 2003 Jun;42(6):403-8.
[Pubmed]
•
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: Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7;312(5770):117-21.
[Pubmed]
•
Bader, M. (2004). Renin-angiotensin-aldosterone system. In S. Offermanns, & W. Rosenthal (Eds.). _Encyclopedic reference of molecular pharmacology_ (pp. 810-814). Berlin, Germany: Springer.
•
Sica, D.A., Gehr, T.W.B., & Ghosh, S. (2005). Clinical pharmacokinetics of losartan. _Clinical Pharmacokinetics, 44_(8), 797-814. "PMID: 16029066":http://www.ncbi.nlm.nih.gov/pubmed/16029066
•
Stanfield, C.L., & Germann, W.J. (2008). _Principles of human physiology_ (3 ^rd^ ed.). San Francisco, CA: Pearson Education, Inc.
External Links
Molecular Spectra
No Data Available
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References
• 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: Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7;312(5770):117-21. Pubmed
• Stanfield, C.L., & Germann, W.J. (2008). _Principles of human physiology_ (3 ^rd^ ed.). San Francisco, CA: Pearson Education, Inc.
• Guo ZX, Qiu MC: [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. 2003 Jun;42(6):403-8. Pubmed
• Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002 Mar 23;359(9311):995-1003. Pubmed
• Sica, D.A., Gehr, T.W.B., & Ghosh, S. (2005). Clinical pharmacokinetics of losartan. _Clinical Pharmacokinetics, 44_(8), 797-814. "PMID: 16029066":http://www.ncbi.nlm.nih.gov/pubmed/16029066
• Bader, M. (2004). Renin-angiotensin-aldosterone system. In S. Offermanns, & W. Rosenthal (Eds.). _Encyclopedic reference of molecular pharmacology_ (pp. 810-814). Berlin, Germany: Springer.