药品详细

Fosinopril (福辛普利 )

基本信息
剂型规格
适应症
药理
临床
理化性质
相互作用
文档
专利
Pathway
文献
序列

化学结构式图

中文名

福辛普利

英文名

Fosinopril

分子式

Not Available

化学名

(2S,4S)-4-cyclohexyl-1-(2-{[2-methyl-1-(propanoyloxy)propoxy](4-phenylbutyl)phosphoryl}acetyl)pyrrolidine-2-carboxylic acid

分子量

Average: 563.6625
Monoisotopic: 563.301189343

CAS号

98048-97-6

ATC分类

C09A 未知

药物类型

small molecule

阶段

商品名

Acecor (SPA (Czech Republic));Monopril (Bristol-Myers Squibb);Staril (BMS (United Kingdom));

同义名

Fosinopril Sodium;

基本介绍

Fosinopril is a phosphinic acid-containing ester prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly hydrolyzed to fosinoprilat, its principle active metabolite. Fosinoprilat inhibits ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Fosinopril may be used to treat mild to moderate hypertension, as an adjunct in the treatment of congestive heart failure, and to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.

生产厂家

Apotex inc etobicoke site
Bristol myers squibb co pharmaceutical research institute
Invagen pharmaceuticals inc
Ranbaxy laboratories ltd
Sandoz inc
Teva pharmaceuticals usa inc
Watson laboratories inc
Watson laboratories inc florida

封装厂家

参考

Synthesis Reference

Not Available

General Reference

David D, Jallad N, Germino FW, Willett MS, de Silva J, Weidner SM, Mills DJ: A Comparison of the Cough Profile of Fosinopril and Enalapril in Hypertensive Patients with a History of ACE Inhibitor-Associated Cough. Am J Ther. 1995 Oct;2(10):806-813. Pubmed
Sharma S, Deitchman D, Eni JS, Gelperin K, Ilgenfritz JP, Blumenthal M: The hemodynamic effects of long-term ACE inhibition with fosinopril in patients with heart failure. Fosinopril Hemodynamics Study Group. Am J Ther. 1999 Jul;6(4):181-9. Pubmed

剂型

Form	Route	Strength
Tablet	Oral	10 mg
Tablet	Oral	20 mg
Tablet	Oral	40 mg

规格

Unit description	Cost	Unit
Monopril HCT 10-12.5 mg tablet	1.71 USD	tablet
Monopril 10 mg tablet	1.68 USD	tablet
Monopril 40 mg tablet	1.67 USD	tablet
Monopril 20 mg tablet	1.62 USD	tablet
Fosinopril Sodium-HCTZ 10-12.5 mg tablet	1.61 USD	tablet
Fosinopril Sodium-HCTZ 20-12.5 mg tablet	1.61 USD	tablet
Fosinopril sodium 20 mg tablet	1.25 USD	tablet
Fosinopril sodium 40 mg tablet	1.25 USD	tablet
Fosinopril sodium 10 mg tablet	1.21 USD	tablet
Monopril 20 mg Tablet	1.1 USD	tablet
Monopril 10 mg Tablet	0.91 USD	tablet
Apo-Fosinopril 20 mg Tablet	0.61 USD	tablet
Fosinopril 20 mg Tablet	0.61 USD	tablet
Jamp-Fosinopril 20 mg Tablet	0.61 USD	tablet
Mylan-Fosinopril 20 mg Tablet	0.61 USD	tablet
Novo-Fosinopril 20 mg Tablet	0.61 USD	tablet
Ran-Fosinopril 20 mg Tablet	0.61 USD	tablet
Apo-Fosinopril 10 mg Tablet	0.51 USD	tablet
Fosinopril 10 mg Tablet	0.51 USD	tablet
Jamp-Fosinopril 10 mg Tablet	0.51 USD	tablet
Mylan-Fosinopril 10 mg Tablet	0.51 USD	tablet
Novo-Fosinopril 10 mg Tablet	0.51 USD	tablet
Ran-Fosinopril 10 mg Tablet	0.51 USD	tablet

化合物类型

Type	small molecule

Classes

Benzene and Derivatives
Amino Acids

Substructures

Carboxylic Acids and Derivatives
Hydroxy Compounds
Acetates
Amino Ketones
Pyrrolidines
Ethers
Benzene and Derivatives
Aliphatic and Aryl Amines
Heterocyclic compounds
Aromatic compounds
Carboxamides and Derivatives
Amino Acids

适应症

ANTIHYPERTENSIVES 降血压;

药理

Indication

For treating mild to moderate hypertension, use as an adjunct in treating congestive heart failure, and may be used to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.

Pharmacodynamics

Following oral administration, fosinopril is rapidly and completely hydrolyzed to its principle active metabolite, fosinoprilat. Hydrolysis is thought to occur in the gastrointestinal mucosa and liver. Fosinoprilat is a competitive inhibitor of ACE, a peptidyl dipeptidase that is part of the RAAS. The 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 the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may further sustain the effects of fosinoprilat by causing increased vasodilation and decreased blood pressure.

Mechanism of action

There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Fosinoprilat, the active metabolite of fosinopril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Fosinoprilat also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.

Absorption

Average absolute absorption is 36%. The primary site of absorption is the proximal small intestine (duodenum/jejunum). Food slows the rate of absorption with no effect on the extent of absorption.

Volume of distribution

Not Available

Protein binding

Fosinoprilat is ≥95% protein bound

Metabolism

Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites.

Route of elimination

After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces.

Half life

12 hours

Clearance

26 – 39 mL/min [healthy]

Toxicity

Human overdoses of fosinopril have not been reported, but the most common manifestation of human fosinopril overdosage is likely to be hypotension. Oral doses of fosinopril at 2600 mg/kg in rats were associated with significant lethality. The most common adverse effects include dizzines, cough, fatigue, and headache.

Affected organisms

Humans and other mammals

Pathways

Pathway	Name	SMPDB ID
	Fosinopril Pathway	SMP00149

理化性质

Properties

State

solid

Melting point

149-153 oC

Experimental Properties

Property	Value	Source
water solubility	Insoluble	PhysProp
logP	6.3	PhysProp

Predicted Properties

Property	Value	Source
water solubility	1.01e-03 g/l	ALOGPS
logP	4.71	ALOGPS
logP	5.49	ChemAxon Molconvert
logS	-5.75	ALOGPS
pKa	10.38	ChemAxon Molconvert
hydrogen acceptor count	5	ChemAxon Molconvert
hydrogen donor count	1	ChemAxon Molconvert
polar surface area	110.21	ChemAxon Molconvert
rotatable bond count	15	ChemAxon Molconvert
refractivity	149.12	ChemAxon Molconvert
polarizability	61.17	ChemAxon Molconvert

药物相互作用

Drug	Interaction
Amiloride	Increased risk of hyperkalemia
Drospirenone	Increased risk of hyperkalemia
Lithium	The ACE inhibitor increases serum levels of lithium
Potassium	Increased risk of hyperkalemia
Spironolactone	Increased risk of hyperkalemia
Tizanidine	Tizanidine increases the risk of hypotension with the ACE inhibitor
Tobramycin	Increased risk of nephrotoxicity
Treprostinil	Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Triamterene	Increased risk of hyperkalemia

食物相互作用

Do not take calcium, aluminum, magnesium or iron supplements, or antacids within 2 hours of taking this medication.
Fosinopril may decrease the excretion of potassium. Salt substitutes containing potassium may increase the risk of hyperkalemia.
Herbs that may attenuate the antihypertensive effect of fosinopril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
High salt intake may attenuate the antihypertensive effect of fosinopril.
Take without regard to meals.

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