Tìm theo
Losartan
Các tên gọi khác (4 ) :
  • (2-Butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol
  • 2-N-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole
  • DuP 89
  • Losartan
Thuốc tim mạch
Thuốc Gốc
Small Molecule
CAS: 114798-26-4
ATC: C09CA01
ĐG : AQ Pharmaceuticals Inc. , http://www.aqpharmaceuticals.com
CTHH: C22H23ClN6O
PTK: 422.911
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.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
Công thức hóa học
C22H23ClN6O
Phân tử khối
422.911
Monoisotopic mass
422.162187095
InChI
InChI=1S/C22H23ClN6O/c1-2-3-8-20-24-21(23)19(14-30)29(20)13-15-9-11-16(12-10-15)17-6-4-5-7-18(17)22-25-27-28-26-22/h4-7,9-12,30H,2-3,8,13-14H2,1H3,(H,25,26,27,28)
InChI Key
InChIKey=PSIFNNKUMBGKDQ-UHFFFAOYSA-N
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
Traditional IUPAC Name
losartan
SMILES
CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=C1)C1=CC=CC=C1C1=NNN=N1
Độ tan chảy
184 °C
Độ hòa tan
0.82 mg/L
logP
6.1
logS
-5
pKa (strongest acidic)
7.4
pKa (Strongest Basic)
4.12
PSA
92.51 Å2
Refractivity
131.85 m3·mol-1
Polarizability
44.86 Å3
Rotatable Bond Count
8
H Bond Acceptor Count
5
H Bond Donor Count
2
Physiological Charge
0
Number of Rings
4
Bioavailability
1
MDDR-Like Rule
true
pKa
5.5
Dược Lực Học : 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.
Cơ Chế Tác Dụng : 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. Losartan competitively inhibits the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. Losartan is metabolized to its active metabolite, E-3174, which is 10 to 40 times more potent than losartan and acts as a non-competitive AT1 antagonist. Inhibition of angiotensin II binding to AT1 inhibits its AT1-mediated vasoconstrictive and aldosterone-secreting effects and results in decreased vascular resistance and blood pressure. Losartan is 1,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. Losartan is effective for reducing blood pressure and may be used to treat essential hypertension, left ventricular hypertrophy and diabetic nephropathy.
Dược Động Học :
▧ Absorption :
Losartan is well absorbed and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. When given with a meal, absorption is slows down and Cmax decreases.
▧ Volume of Distribution :
* 34 L [losartan, healthy subjects] * 12 L [active metabolite, healthy subjects]
▧ Protein binding :
99.7% protein bound, primarily to albumin
▧ Metabolism :
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.
▧ Route of Elimination :
Following oral administration of losartan, 35% of the dose is recovered in the urine and about 60% in the feces. Following an intravenous dose, 45% is recovered in the urine and 50% in the feces.
▧ Half Life :
The terminal t1/2 of losartan is 2 hours. The active metabolite has a half-life of 6-9 hours.
▧ Clearance :
* Total plasma clearance = 600 mL/min [losartan] * Total plasma clearance = 50 mL/min [active metabolite] * Renal clearance = 75 mL/min [losartan] * Renal clearance = 25 mL/min [active metabolite]
Độc Tính : Hypotension and tachycardia; Bradycardia could occur from parasympathetic (vagal) stimulation, LD50= 1000 mg/kg (orally in rat)
Chỉ Định : 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.
Tương Tác Thuốc :
  • Amiloride Increased risk of hyperkalemia
  • Drospirenone Increased risk of hyperkalemia
  • Indomethacin Indomethacin decreases the effect of losartan
  • Insulin Lispro Concomitant therapy with angiotensin II receptor blockers may increase the blood-glucose-lowering effect of insulin lispro and thus the chance of hypoglycemia should be monitored closely.
  • Lithium Losartan increases serum levels of lithium
  • Potassium Increased risk of hyperkalemia
  • Quinupristin This combination presents an increased risk of toxicity
  • Rifampicin Rifampin decreases the effect of losartan
  • Spironolactone Increased risk of hyperkalemia
  • Tobramycin Increased risk of nephrotoxicity
  • Tolbutamide Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Losartan. Consider alternate therapy or monitor for changes in Losartan therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
  • Trandolapril The angiotensin II receptor blocker, Losartan, may increase the adverse effects of Trandolapril.
  • Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
  • Tretinoin The moderate CYP2C8 inhibitor, Losartan, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Losartan is initiated, discontinued to dose changed.
  • Triamterene Increased risk of hyperkalemia
Liều Lượng & Cách Dùng : Tablet - Oral - 25 mg, 50 mg, 100 mg
Dữ Kiện Thương Mại
Giá thị trường
Nhà Sản Xuất
  • Công ty : Merck & Co.
    Sản phẩm biệt dược : Cozaar
  • Công ty : Merck & Co.
    Sản phẩm biệt dược : Hyzaar
  • Công ty :
    Sản phẩm biệt dược : Lortaan
Đóng gói
Tài Liệu Tham Khảo Thêm
drugbank
http://www.drugbank.ca/drugs/DB00678
PubChem Compound
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=3961
PubChem Substance
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=46506538
KEGG Compound
http://www.genome.jp/dbget-bin/www_bget?cpd:C07072
KEGG Drug
http://www.genome.jp/dbget-bin/www_bget?drug:D08146
ChemSpider
http://www.chemspider.com/Chemical-Structure.3824.html
National Drug Code Directory
http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0006-0951-54
PharmGKB
http://www.pharmgkb.org/drug/PA450268
Wikipedia
http://en.wikipedia.org/wiki/Losartan
RxList
http://www.rxlist.com/cgi/generic/losar.htm
Drugs.com
http://www.drugs.com/cdi/losartan.html
... loading
... loading