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药品详细

Sildenafil(西地那非)

化学结构式图
中文名
西地那非
英文名
Sildenafil
分子式
C22H30N6O4S
化学名
5-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-1-methyl-3-propyl-1H,4H,7H-pyrazolo[4,3-d]pyrimidin-7-one
分子量
Average: 474.576
Monoisotopic: 474.204924168
CAS号
139755-83-2
ATC分类
G04B 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Sildenfail is a vasoactive agent used to treat erectile dysfunction and reduce symptoms in patients with pulmonary arterial hypertension (PAH). Sildenafil elevates levels of the second messenger, cGMP, by inhibiting its breakdown via phosphodiesterase type 5 (PDE5). PDE5 is found in particularly high concentrations in the corpus cavernosum, erectile tissue of the penis. It is also found in the retina and vascular endothelium. Increased cGMP results in vasodilation which facilitates generation and maintenance of an erection. The vasodilatory effects of sildenafil also help reduce symptoms of PAH.

生产厂家
  • Pfizer inc
  • Pfizer ireland pharmaceuticals
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C: Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res. 1996 Jun;8(2):47-52. Pubmed
  2. Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, Zusman RM: ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol. 1999 Jan;33(1):273-82. Pubmed
  3. Fries R, Shariat K, von Wilmowsky H, Bohm M: Sildenafil in the treatment of Raynaud’s phenomenon resistant to vasodilatory therapy. Circulation. 2005 Nov 8;112(19):2980-5. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Benzenesulfonamides
Substructures
  • Pyrazoles
  • Phenols and Derivatives
  • Sulfonyls
  • Piperazines
  • Ethers
  • Benzene and Derivatives
  • Benzenesulfonamides
  • Pyrimidines and Derivatives
  • Aliphatic and Aryl Amines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Sulfonamides
  • Imines
  • Cyanamides
  • Phenyl Esters
适应症
药理
Indication For the treatment of erectile dysfunction and to relieve symptoms of pulmonary arterial hypertension (PAH).
Pharmacodynamics Erections are controlled by the parasympathetic nervous system. Upon sexual stimulation, a decrease in vascular resistance is mediated by acetylcholine and nitric oxide resulting in vasodilation. The hemodynamic mechanism of an erection is comprised of five stages. During the latent stage, arterial and carvernous smooth muscle relaxation occurs. Vasodilation results in high levels of blood flow causing the penis to grow to its full size. This stage is called tumescence. During the full-erection stage, blood flow fills penis sinusoids and outflow is restricted. This is followed by the rigid-erection phase during which the cavernous muscles contract causing the penis to become rigid. Little blood flow occurs during this stage. During the final stage, detumescence, the cavernous muscles relax and blood flows out of the penis. Erectile dysfunction may occur when there is insufficient blood supply to the penis or when the penis is unable to prevent outflow of blood from the penis. Sildenafil is a specific inhibitor of PDE5, an enzyme responsible for the breakdown of cGMP to 5’-GMP. Increased levels of cGMP stimulate vasodilation and facilitate the generation and maintenance of erections. These vasodilatory effects also help decrease symptoms of PAH. Sildenfail also exhibits some activity against PDE6 (10 times less potentcy compared to PDE5), a PDE isoform found predmoninantly in the retina. This activity is responsible for the blue tinged vision experienced by users of sildenafil.
Mechanism of action Sildenafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by sildenafil enhances erectile function by increasing the amount of cGMP.
Absorption >90% absorbed with ~40% reaching systemic circulation unchanged following first-pass metabolism
Volume of distribution
  • 105 L
Protein binding 96%
Metabolism
Sildenafil appears to be completely metabolized in the liver to 16 metabolites. Its metabolism is mediated mainly by cytochrome P450 microsomal isozymes 3A4 (major route) and 2C9 (minor route). The major circulating metabolite, N-demethylated metabolite, has PDE selectivity similar to the parent drug and ~50% of its in vitro potency. The N-demethylated metabolite is further metabolized to an N-dealkylated N,N-de-ethylated metabolite. Sildenafil also undergoes N-dealkylation followed by N-demethylation of the piperazine ring.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Sildenafil
N-Desmethyl sildenafil (UK-103,320) Details
Route of elimination Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
Half life 4 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
melting point 189-190 °C Not Available
water solubility 3.5 mg/mL Not Available
logP 1.9 Not Available
Predicted Properties
Property Value Source
water solubility 4.33e-01 g/l ALOGPS
logP 2.35 ALOGPS
logP 1.65 ChemAxon
logS -3 ALOGPS
pKa (strongest acidic) 7.27 ChemAxon
pKa (strongest basic) 5.97 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 8 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 109.13 ChemAxon
rotatable bond count 6 ChemAxon
refractivity 139.44 ChemAxon
polarizability 51.18 ChemAxon
药物相互作用
Drug Interaction
Amprenavir The protease inhibitor, amprenavir, may increase the effect and toxicity of sildenafil.
Asenapine Increased incidence of adverse effects (hypotension) due to pharmacodynamic synergism. Concomitant therapy should be avoided.
Atazanavir Increases the effect and toxicity of sildenafil
Cimetidine Increases the effect and toxicity of sildenafil
Ciprofloxacin Ciprofloxacin may increase the serum level of sildenafil.
Clarithromycin Increases the effect and toxicity of sildenafil
Conivaptan CYP3A4 Inhibitors (Strong) such as conivaptan may increase the serum concentration of Sildenafil. When sildenanfil is used for treatment of pulmonary arterial hypertension, concurrent use with strong CYP3A4 inhibitors is not recommended. When sildenafil is used for treatment of erectile dysfunction, consider using a lower starting dose of 25 mg in patients who are also taking a strong CYP3A4 inhibitor. Due to the particularly strong effects of ritonavir, sildenafil (for erectile dysfunction) doses greater than 25 mg per 48 hours are not recommended. Of note, the interaction between CYP3A4 inhibitors and sildenafil is predicted to be greater with orally administered than with injected sildenafil.
Erythromycin The macrolide, erythromycin, may increase the effect and toxicity of sildenafil.
Etravirine Sildenafil (and other phosphodiesterase 5 inhibitors), when used concomitantly with etravirine, may experience a decrease in serum concentration. It is recommended to monitor the efficacy of sildenafil therapy.
Fosamprenavir The protease inhibitor, fosamprenavir, may increase the effect and toxicity of sildenafil.
Indinavir The protease inhibitor, indinavir, may increase the effect and toxicity of sildenafil.
Isosorbide Dinitrate Possible significant hypotension with this combination
Isosorbide Mononitrate Possible significant hypotension with this combination
Itraconazole Itraconazole may increase the effect and toxicity of sildenafil.
Ketoconazole Ketoconazole may increase the effect and toxicity of sildenafil.
Nelfinavir The protease inhibitor, nelfinavir, may increase the effect and toxicity of sildenafil.
Nitroglycerin Possible significant hypotension with this combination
Pentaerythritol Tetranitrate Possible significant hypotension with this combination
Telithromycin Telithromycin may reduce clearance of Sildenafil. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Sildenafil if Telithromycin is initiated, discontinued or dose changed.
Terazosin Increased risk of hypotension.
Tipranavir Tipranavir, co-administered with Ritonavir, may increase the concentration of Sildenafil. Alternate therapy should be considered.
Vigabatrin Increased anticonvulsant effects of vigabatrin due to pharmacodynamic synergism. Monitor for adverse effects during concomitant therapy.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of sildenafil by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of sildenafil if voriconazole is initiated, discontinued or dose changed.
食物相互作用
Not Available

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