Phosphodiesterase-5 Enzyme Inhibitors
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Authored by: Wqli 12:15, 29 March 2007 (PDT) |
Contents |
Discussion
Phosphodiesterase-5 enzyme inhibitors (PDE5) have dramatically transformed the treatment of erectile dysfunction (ED). ED is defined as the inability to attain and/or maintain a satisfactory erection for intercourse. Prior to the introduction of PDE5 inhibitors, most treatments involved non-oral routes of administration (i.e. injection, suppository). Currently, there are three drugs in this class; sildenafil, vardenafil, and tadalafil. Overall, the agents were well tolerated and the discontinuation rates due to any adverse event were low throughout the clinical trials. These PDE5 inhibitors have similar efficacy and safety profiles. Sildenafil (Viagra®) was the first agent of this class to be marketed in 1998, followed by vardenafil and tadalafil in 2003. Both sildenafil and vardenafil have a duration of action of ~8 hours, while tadalafil has the longest; 36 hours. Vardenafil and tadalafil are both more selective compared to sildenafil for PDE5 than PDE6 receptors, which is present in the retina, which would explain the higher case reports of visual adverse events associated with sildenafil. High-fat meals can reduce the Cmax of both sildenafil and vardenafil, but doesn't affect tadalafil.[1] [2]
Mechanism of Action
The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.[3] [4] [5]
Charts
| Parameter | Sildenafil 100 mg | Vardenafil 20 mg | Tadalafil 20 mg |
|---|---|---|---|
| IC50(nmol/L) | 3.5 - 3.9 | 0.7 | 0.94 |
| Bioavailability (F) | 40% | 15% | No data |
| tmax(h) | 0.5 - 2.0 | 0.5 - 2.0 | 0.5 - 6.0 |
| t1/2(h) | 4 | 4 - 5 | 17.5 |
| Cmax(ug/L) | 411 | 17 | 378 |
| Vss(L) | 105 | 208 | 63 |
| Protein Binding(%) | 96 | 95 | 94 |
| Metabolism | CYP3A4 major, CYP2C9 minor | CYP3A4 major, CYP2C9 minor | CYP3A4 |
| Active Metabolite | N-desmethyl | M1 | No |
| Excretion | 80% feces, 13% urine | 91-95% feces, 2-6% urine | 61% feces, 36% urine |
Available Medications in this Class
- Sildenafil (Viagra®)
- Vardenafil (Levitra®)
- Tadalafil (Cialis®)
Complete Medication Classification List
References
- ↑ Shabsigh R. Seftel AD. Rosen RC. Porst H. Ahuja S. Deeley MC. Garcia CS. Giuliano F. Review of time of onset and duration of clinical efficacy of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction. Urology. 68(4):689-96, 2006 Oct.
- ↑ Setter SM. Iltz JL. Fincham JE. Campbell RK. Baker DE. Phosphodiesterase 5 inhibitors for erectile dysfunction. Annals of Pharmacotherapy. 39(7-8):1286-95, 2005 Jul-Aug.
- ↑ Cialis® (Tadalafil) Package Insert. Indianapolis, IN; Eli Lilly and Company; 2007 Jan.
- ↑ Levitra® [Package Insert]. West Haven, CT: Bayer Pharmaceuticals Corporation, 2005.
- ↑ Viagra® [Package Insert]. New York, NY: Pfizer Pharmaceuticals, 2006.
