Abstract
The mechanism of action of the phosphodiesterase type 5 (PDE5) inhibitors (i.e., sildenafil, tadalafil, and vardenafil) involves inhibition of the PDE5 isoenzyme located in penile vascular smooth muscle cells. Sexual stimulation triggers the release of nitric oxide (NO), stimulating the release of guanylyl cyclase, leading to an increase in intracellular cyclic guanosine monophosphate (cGMP) concentrations, a decrease in intracellular calcium, and ultimately relaxation of the vascular smooth muscle in the corpus cavernosum and penile erection. The PDE5 inhibitors have no effect on the penis in the absence of sexual stimulation. Although the various PDE5 inhibitors differ with respect to selectivity and pharmacokinetic profiles, efficacy and safety of these agents are comparable in broad populations of men with erectile dysfunction (ED), including those with diabetes or those taking multiple antihypertensive agents. The most frequently reported adverse events of the PDE5 inhibitors are related to their mild vasodilatory effects and include headache, flushing, dyspepsia, and nasal congestion or rhinitis. Side effects are generally reversible and tend to diminish during continued treatment. Differences in pharmacokinetic properties among the PDE5 inhibitors include the fact that sildenafil and vardenafil have a shorter duration of action (approximately 4 h) compared with the longer period of responsiveness observed with tadalafil (up to 36 h). In addition, in the presence of high‐fat food, absorption of sildenafil and vardenafil may be delayed; however, the rate and extent of tadalafil absorption are unaffected by high‐fat food.
Keywords: phosphodiesterase type 5 inhibitors, sildenafil, tadalafil, vardenafil, erectile dysfunction, diabetes, hypertension
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References
- 1. Francis SH, Turko IV, Corbin JD: Cyclic nucleotide phosphodiesterases: Relating structure and function In Progress in Nucleic Acid Research and Molecular Biology, vol. 65 (Ed. Moldave K.), p. 1–52. New York: Academic Press, 2001. [DOI] [PubMed] [Google Scholar]
- 2. Corbin JD, Francis SH: Pharmacology of phosphodiesterase‐5 inhibitors. Int J Clin Pract 2002; 56: 453–459 [PubMed] [Google Scholar]
- 3. Sadovsky R, Miller T, Moskowitz M, Hackett G: Three‐year update of sildenafil citrate (Viagra®) efficacy and safety. Int J Clin Pract 2001; 55: 115–128 [PubMed] [Google Scholar]
- 4. Baxendale RW, Wayman CP, Turner L, Phillips SC: Cellular localization of phosphodiesterase type 11 (PDE 11) in human corpus cavernosum and the contribution of PDE11 inhibition on nerve‐stimulated relaxation (abstr 922). J Urol 2001; 165 (suppl): 223‐224 [Google Scholar]
- 5. Lue TF: Erectile dysfunction. N Engl J Med 2000; 342: 1802–1813 [DOI] [PubMed] [Google Scholar]
- 6. Padma‐Nathan H, Giuliano F: Oral drug therapy for erectile dysfunction. Urol Clin North Am 2001; 28: 321–334 [DOI] [PubMed] [Google Scholar]
- 7. Cialis® (tadalafil) (package insert). Indianapolis, Ind.: Lilly ICOS LLC; 2003. [Google Scholar]
- 8. Hellstrom WJG, Overstreet JW, Yu A, Saikali K, Shen W, Beasley CM Jr, Watkins VS: Tadalafil has no detrimental effect on human spermatogenesis or reproductive hormones. J Urol 2003; 170: 887–891 [DOI] [PubMed] [Google Scholar]
- 9. Rajagopalan P, Mazzu A, Xia C, Dawkins R, Sundaresan P: Effect of a high‐fat breakfast and moderate‐fat evening meal on the pharmacokinetics of vardenafil, an oral phosphodiesterase‐5 inhibitor for the treatment of erectile dysfunction. J Clin Pharmacol 2003; 43: 260–267 [DOI] [PubMed] [Google Scholar]
- 10. Levitra® (vardenafil) (package insert). New Haven, Conn.: Bayer Pharmaceuticals Corp., 2003. [Google Scholar]
- 11. Patterson B, Bedding A, Jewell H, Payne C, Mitchell M: The effect of intrinsic and extrinsic factors on the pharmacokinetic properties of tadalafil (IC351). Poster presented at 4th Congress of the European Society for Sexual and Impotence Research, Rome, Italy, September 30‐October 3, 2001.
- 12. Viagra® (sildenafil)(package insert). New York, N.Y.: Pfizer Inc., 2002. [Google Scholar]
- 13. Boolell M, Allen MJ, Ballard SA, Gepi‐Atlee S, Murihead GJ, Naylor AM, Osterloh JH, 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; 8: 47–52 [PubMed] [Google Scholar]
- 14. Padma‐Nathan H, Rosen RC, Shabsigh R, Saikali K, Watkins VS, Pullman B: Cialis™ (IC351) provides prompt response and extended period of responsiveness for the treatment of men with erectile dysfunction (ED) (abstr 923). J Urol 2001; 165 (sppl): 224 11125412 [Google Scholar]
- 15. Porst H, Padma‐Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R: Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: A randomized controlled trial. Urology 2003; 62: 121–126 [DOI] [PubMed] [Google Scholar]
- 16. Brock GB, McMahon CG, Chen KK, Costigan T, Shen W, Watkins VS, Anglin G, Whitaker S: Efficacy and safety of tadalafil for the treatment of erectile dysfunction: Results of integrated analyses. J Urol 2002; 168: 1332–1336 [DOI] [PubMed] [Google Scholar]
- 17. Padma‐Nathan H, Stecher VJ, Sweeney M, Orazem J, Tseng LJ, Deriesthal H: Minimal time to successful intercourse after sildenafil citrate: Results of a randomized, double‐blind, placebo‐controlled trial. Urology 2003; 62: 400–403 [DOI] [PubMed] [Google Scholar]
- 18. Padma‐Nathan H, McCullough AR, Giuliano F, Toler S, Wohlhuter C, Shpilsky A: Postoperative nightly administration of sildenafil citrate significantly improves the return of normal spontaneous erectile function after bilateral nerve‐sparing radical prostatectomy. Poster presented at Satellite Symposium at Annual Meeting of the American Urological Association, Chicago, Ill., April 26‐May 1, 2003.
- 19. Padma‐Nathan H, Steers WD, Wicker PA: Efficacy and safety of oral sildenafil in the treatment of erectile dysfunction: A double‐blind, placebo‐controlled study of 329 patients. Sildenafil Study Group. Int J Clin Pract 1998; 52: 375–379 [PubMed] [Google Scholar]
- 20. Seftel AD, Wilson SK, Knapp P, Shin J, Wang CW, Ahuja S: Efficacy and safety of tadalafil in US men with ED. Poster presented at the 98th Annual Meeting of the American Urological Association Meeting, Chicago, Ill., April 27‐May 1, 2003.
- 21. Hellstrom WJG, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T, Padma‐Nathan H: Vardenafil for treatment of men with erectile dysfunction: Efficacy and safety in a randomized, double‐blind, placebo‐controlled trial. J Androl 2002; 23: 763–771 [PubMed] [Google Scholar]
- 22. Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH: Clinical safety of oral sildenafil citrate (Viagra™) in the treatment of erectile dysfunction. Int J Impot Res 1998; 10: 69–74 [DOI] [PubMed] [Google Scholar]
- 23. Romeo JH, Seftel AD, Madhun ZT, Aron DC: Sexual function in men with diabetes type 2: Association with glycemic control. J Urol 2000; 163: 788–791 [PubMed] [Google Scholar]
- 24. Sáenz de Tejada I, Emmick J, Anglin G, Fredlund P, Pullman WE: The effect of IC351 taken as needed for treatment of erectile dysfunction in men with diabetes. Poster presented at 16th Congress of the European Association of Urology, Geneva, Switzerland, April 7‐10, 2001.
- 25. Goldstein I, Young JM, Fischer J, Bangerter K, Setgerson T, Taylor T: The Vardenafil Diabetes Study Group: Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes. A multicenter double‐blind placebo‐controlled fixed‐dose study. Diabetes Care 2003; 26: 777–783 [DOI] [PubMed] [Google Scholar]
- 26. Rendell MS, Rajfer J, Wicker PA, Smith MD: Sildenafil for treatment of erectile dysfunction in men with diabetes. J Am Med Assoc 1999; 281: 421–426 [DOI] [PubMed] [Google Scholar]
- 27. Kloner RA, Mullin SH, Shook T, Matthews R, Mayeda G, Burstein S, Peled H, Pollick C, Choudhary R, Rosen R, Padma‐Nathan H: Erectile dysfunction in the cardiac patient: How common and should we treat? J Urol 2003; 170: S46–S50 [DOI] [PubMed] [Google Scholar]
- 28. Kloner RA, Mitchel M, Emmick JF: Cardiovascular effects of tadalafil in patients on common antihypertensive therapies. Am J Cardiol 2003; 92 (suppl): 47M–57M [DOI] [PubMed] [Google Scholar]
- 29. Mancia G, Pickering TG, Glasser DB, Orazem J: Efficacy of Viagra (sildenafil citrate) in men with erectile dysfunction and arterial hypertension who are taking antihypertensive treatments (abstr). Am J Hypertens 2002; 15 (suppl 1): A55 [Google Scholar]
- 30. Brock G: Tadalafil effective treatment for men with ED. Presented at 5th Congress of the European Society for Sexual and Impotence Research, Hamburg, Germany, December 1‐4, 2002. [PubMed]