Vardenafil -Levitra®
Vardenafil - Levitra®
Classification:
Genitourinary Agents
- Impotence Agents
- Phosphodiesterase inhibitors
Description: Vardenafil (Levitra®, formerly Nuviva®) is a drug for treatment of erectile dysfunction (ED), also known as impotence. It is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil (Viagra®) and tadalafil (Cialis®). This class of drugs does not inhibit prostaglandins as do some agents for treating impotence (e.g., alprostadil). Vardenafil and tadalfil are more selective for PDE5 than PDE6, which is present in the retina. This leads to less visual adverse effects such as those reported in sildenafil-treated patients. The advantage of vardenafil may be that it achieves maximum plasma concentration sooner than sildenafil and tadalafil which may result in a faster onset of action. In an analysis of 580 patients, erections improved in 80% of men, and the ability to complete sexual intercourse with ejaculation was increased. Efficacy in treating diabetics and radical prostectomy patients has also been demonstrated. Vardenafil was developed by Bayer AG Corporation and on December 15, 2001, Bayer signed an agreement with Glaxo SmithKline to co-promote vardenafil worldwide, except in Japan. Vardenafil was approved by the FDA August 18, 2003. Vardenafil is also approved for use in Mexico and Paraguay for the treatment of erectile dysfunction.
Mechanism of Action: Vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Vardenafil enhances the effect of NO by inhibiting PDE5, thereby raising concentrations of cGMP in the corpus cavernosum. Vardenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. Vardenafil has a greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Sildenafil, another PDE inhibitor, has a lower selectivity for PDE5 vs PDE6 and is associated with abnormalities related to color vision with higher doses or plasma concentrations of the drug.
Phosphodiesterase type 5 is also abundant in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in pulmonary vasodilation which can be effective in treating pulmonary hypertension. Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the more common adverse reactions associated with PDE inhibitor therapy.
Pharmacokinetics: Vardenafil is administered orally. The drug is well-adsorbed from the gastrointestinal tract. In healthy volunteers, peak plasma concentrations (Cmax) following a single 20 mg oral dose are usually reached between 30 minutes and 2 hours (median 60 minutes) in the fasted state. High-fat meals reduced Cmax by 18 - 50%. Absolute bioavailability is approximately 15%. The onset of action is within 1 hour of administration. Vardenafil is extensively distributed throughout the body. Protein binding is approximately 95%.
Clearance of vardenafil is primarily via the hepatic cytochrome P450 isoenzyme CYP3A4 with minor metabolism by CYP3A5 and CYP2C. The major metabolite, designated M1, is the result of desethylation at the piperazine moiety of vardenafil and is further metabolized. M1 has phosphodiesterase selectivity similar to that of vardenafil and an in vitro inhibitory potency for phosphodiesterase 5 (PDE5) that is 28% of that of vardenafil. M1 also accounts for about 7% of the total pharmacological activity. Vardenafil is excreted as metabolites predominantly in the feces (approximately 91 - 95% of an oral dose) and to a lesser extent in the urine (about 2 - 6% of an oral dose). The elimination half-life of vardenafil and M1 is about 4 - 5 hours.
In a healthy volunteer study of elderly males (>= 65 years) and younger males (18 - 45 years), mean Cmax and AUC were 34% and 52% higher, respectively, in the elderly males; lower starting doses should be considered for patients >= 65 years of age (see Dosage).Pharmacokinetic trials have not been performed in pediatric patients.
Chemical Structure For: Vardenafil
In volunteers with mild renal impairment (CrCl 50 - 80 ml/min), vardenafil pharmacokinetics were similar to those observed in a control group with normal renal function. In those with moderate (CrCl 30 - 50 ml/min) or severe (CrCl < 30 ml/min) renal impairment, the AUC of vardenafil was 20 - 30% higher compared to that observed in a control group with normal renal function. No dosage modifications are required in patients with mild, moderate, or severe renal impairment; vardenafil pharmacokinetics have not been evaluated in patients needing renal dialysis. Volunteers with mild hepatic impairment (Child-Pugh class A) showed an increase in vardenafil Cmax and AUC of 22% and 17%, respectively, following a 10 mg oral dose. In volunteers with moderate hepatic impairment (Child-Pugh class B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Reduced doses are recommended for patients with moderate hepatic impairment (see Dosage). Vardenafil has not been studied in patients with severe (Child-Pugh class C) hepatic impairment.
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[ Revised 10/14/2005 1:02:00 PM ]
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