The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index; none of the 20 sources its claims cite is checked for support yet.
Phosphodiesterase type 5 inhibitor differentiation based on selectivity, pharmacokinetic, and efficacy profiles
Open accessAbstract
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.
Overview
CoChat Summary
TL;DR
This review describes how sildenafil, tadalafil, and vardenafil share PDE5 inhibition as their mechanism for treating erectile dysfunction but differ in selectivity, pharmacokinetics, and duration of action. It concludes that efficacy and tolerability are broadly comparable across noncomparative studies, while tadalafil offers longer responsiveness and no high-fat food interaction.
Key findings
- PDE5 inhibitors are highly selective for PDE5, but selectivity differences may affect adverse events: sildenafil is a relatively potent PDE6 inhibitor and color vision disturbances have been reported in up to 11% of men receiving sildenafil, whereas tadalafil is a weak PDE6 inhibitor with color vision abnormalities occurring in <0.1%; tadalafil is a relatively potent PDE11 inhibitor, but the clinical relevance of PDE11 inhibition is undefined.
- Pharmacokinetic differences are substantial: sildenafil and vardenafil have half-lives of 3–5 h and 4–5 h, respectively, with duration of action about 4 h, while tadalafil has a half-life of 17.5 h and responsiveness up to 36 h. High-fat food reduces sildenafil Cmax by about 29% and vardenafil Cmax by 18–50% and delays Tmax by about 1 h, but tadalafil absorption is unaffected.
- Efficacy appears comparable in broad ED populations: sildenafil 50 mg produced 65% successful intercourse attempts versus 20% for placebo; tadalafil 10 mg produced 61% and 20 mg produced 68–75% versus 32% for placebo; vardenafil 10 and 20 mg each produced 65% versus 32% for placebo.
- In special populations, PDE5 inhibitors remain effective: in men with diabetes, tadalafil 10 mg and 20 mg yielded 44% and 51% successful intercourse attempts versus 16% for placebo, vardenafil 10 mg and 20 mg yielded 49% and 54% versus 23% for placebo, and sildenafil improved erections on the GAQ in 56% versus 10% for placebo. Common adverse events include headache, flushing, dyspepsia, and nasal congestion/rhinitis.
Methods
- Narrative review of the mechanism of action, pharmacodynamic selectivity, pharmacokinetic properties, efficacy, and tolerability of sildenafil, tadalafil, and vardenafil.
- Synthesizes data from noncomparative clinical studies, package inserts, and conference posters/abstracts, including specific trials such as Hellstrom et al. on tadalafil and spermatogenesis and Porst et al. on tadalafil at 24 and 36 h.
- No direct head-to-head comparative trials were identified; efficacy comparisons are drawn from separate placebo-controlled studies.
Limitations
- The paper states that there have been no direct comparative studies of the PDE5 inhibitors to date, so no conclusions can be drawn about their relative efficacy.
- The paper states that limited data are available on the efficacy of vardenafil in patients with ED who are receiving antihypertensive medications.
- Evident from the text: this is a narrative review relying on noncomparative studies, package inserts, and conference posters/abstracts rather than a systematic review or meta-analysis.
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Claims the paper makes
0 Valid · 0 Not valid · 11 Not checked · 1 Own results and interpretations
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Phosphodiesterase Type 5 Inhibitor Differentiation Based on Selectivity, Pharmacokinetic, and Efficacy Profiles > Abstract
What the sources say
- Not checked yetcites [7] Cialis® (tadalafil) (package insert). Indianapolis, Ind.: Lilly ICOS LLC; 2003
- Not checked yetcites [10] Levitra® (vardenafil) (package insert). New Haven, Conn.: Bayer Pharmaceuticals Corp., 2003
- Not checked yetcites [12] Viagra® (sildenafil)(package insert). New York, N.Y.: Pfizer Inc., 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The investigators concluded that daily dosing with tadalafil 10 or 20 mg produced no clinically relevant effect on spermatogenesis.”
§ Phosphodiesterase Type 5 Inhibitor Differentiation Based on Selectivity, Pharmacokinetic, and Efficacy Profiles > Effects on Spermatogenesis
What the sources say
- Not checked yetcites [8] Hellstrom, 2003, Tadalafil has no detrimental effect on human spermatogenesis or reproductive hormones, J Urol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Phosphodiesterase Type 5 Inhibitor Differentiation Based on Selectivity, Pharmacokinetic, and Efficacy Profiles > Abstract
What the sources say
- Not checked yetcites [7] Cialis® (tadalafil) (package insert). Indianapolis, Ind.: Lilly ICOS LLC; 2003
- Not checked yetcites [10] Levitra® (vardenafil) (package insert). New Haven, Conn.: Bayer Pharmaceuticals Corp., 2003
- Not checked yetcites [12] Viagra® (sildenafil)(package insert). New York, N.Y.: Pfizer Inc., 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“For example, sildenafil is a relatively potent inhibitor of PDE6 (localized in the rods and cones of the retina), which may explain the color vision disturbances reported in up to 11% of men receiving sildenafil.6”
§ Phosphodiesterase Type 5 Inhibitor Differentiation Based on Selectivity, Pharmacokinetic, and Efficacy Profiles > Selectivity and Effects on Vision
What the sources say
- Not checked yetcites [6] Padma-Nathan, 2001, Oral drug therapy for erectile dysfunction, Urol Clin North Am source
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The PDE5 inhibitors have no effect on the penis in the absence of sexual stimulation.”
§ Phosphodiesterase Type 5 Inhibitor Differentiation Based on Selectivity, Pharmacokinetic, and Efficacy Profiles > Abstract
What the sources say
- Not checked yetcites [5] Lue, 2000, Erectile dysfunction, N Engl J Med source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Phosphodiesterase Type 5 Inhibitor Differentiation Based on Selectivity, Pharmacokinetic, and Efficacy Profiles > Efficacy and Tolerability in Special Populations
“The rate of successful intercourse attempts of 49 and 54% was noted in men with diabetes who were taking vardenafil 10 and 20 mg, respectively, compared with the 23% rate observed in the placebo group.26”
§ Phosphodiesterase Type 5 Inhibitor Differentiation Based on Selectivity, Pharmacokinetic, and Efficacy Profiles > References
“26. Rendell MS, Rajfer J, Wicker PA, Smith MD: Sildenafil for treat- ment of erectile dysfunction in men with diabetes.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Phosphodiesterase Type 5 Inhibitor Differentiation Based on Selectivity, Pharmacokinetic, and Efficacy Profiles > Efficacy and Tolerability in Special Populations
“the percentage of successful intercourse attempts averaged 44% in men with diabetes receiving tadalafil 10 mg or 51% in those receiving 20 mg compared with 16% in the placebo group.25”
§ Phosphodiesterase Type 5 Inhibitor Differentiation Based on Selectivity, Pharmacokinetic, and Efficacy Profiles > References
“25. Goldstein I, Young JM, Fischer J, Bangerter K, Setgerson T, Taylor T: The Vardenafil Diabetes Study Group: Vardenafil, a new phos- phodiesterase type 5 inhibitor, in the treatment of erectile dysfunc- tion in men with diabetes.”
Citations
Cites
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Progress in Nucleic Acid Research and Molecular Biology
Cohn, W. E., & Moldave, K. (2001) · Medical Entomology and Zoology · Cited by 1,088
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Sildenafil for Treatment of Erectile Dysfunction in Men With Diabetes
Rendell, M., Rajfer, J., Wicker, P. A., Smith, M. D., & for the Sildenafil Diabetes Study Group (1999) · JAMA · doi:10.1001/jama.281.5.421 · Cited by 606
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Clinical safety of oral sildenafil citrate (VIAGRATM) in the treatment of erectile dysfunction
Morales, Á., Gingell, C., Collins, M., Wicker, P., & Osterloh, I. H. (1998) · International Journal of Impotence Research · doi:10.1038/sj.ijir.3900354 · Cited by 456
Brock, G. B., McMahon, C. G., Chen, K. K., Costigan, T., Shen, W., Watkins, V., Anglin, G., & Whitaker, S. (2002) · Journal of Urology · doi:10.1016/s0022-5347(05)64442-4 · Cited by 421
Goldstein, I., Young, J. M., Fischer, J. J., Bangerter, K., Segerson, T. P., Taylor, T., & The Vardenafil Diabetes Study Group (2003) · Diabetes Care · doi:10.2337/diacare.26.3.777 · Cited by 331
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HELLSTROM, W. J. G., GITTELMAN, M., KARLIN, G., SEGERSON, T., THIBONNIER, M., TAYLOR, T., & PADMA‐NATHAN, H. (2002) · Journal of Andrology · doi:10.1002/j.1939-4640.2002.tb02332.x · Cited by 297
SEXUAL FUNCTION IN MEN WITH DIABETES TYPE 2: ASSOCIATION WITH GLYCEMIC CONTROL
ROMEO, J. H., SEFTEL, A. D., MADHUN, Z. T., & ARON, D. C. (2000) · Journal of Urology · doi:10.1016/s0022-5347(05)67805-6 · Cited by 274
Self-citationPharmacology of phosphodiesterase inhibitors
Boswell-Smith, V., & Page, C. P. (2005) · CRC Press eBooks · doi:10.1201/b14809-12 · Cited by 261
PHARMACOLOGY OF PHOSPHODIESTERASE‐5 INHIBITORS
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Erectile Dysfunction in the Cardiac Patient: How Common and Should We Treat?
Kloner, R. A., Mullin, S., Shook, T., Matthews, R. V., Mayeda, G. S., Burstein, S., Peled, H. B., Pollick, C., CHOUDHARY, R., Rosen, R. C., et al. (2003) · The Journal of Urology · doi:10.1097/01.ju.0000075055.34506.59 · Cited by 232
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THREE‐YEAR UPDATE OF SILDENAFIL CITRATE (VIAGRA®) EFFICACY AND SAFETY
D, R. S. M., Miller, T., Moskowitz, M. A., & Hackett, G. I. (2001) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2001.tb10992.x · Cited by 125
Tadalafil has no detrimental effect on human spermatogenesis or reproductive hormones
HELLSTROM, W. J. G., OVERSTREET, J. W., YU, A., SAIKALI, K., SHEN, W., BEASLEY, C. M., & WATKINS, V. S. (2003) · Journal of Urology · doi:10.1097/01.ju.0000081053.97792.da · Cited by 103
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GRANULOCYTIC SARCOMA PRESENTING AS TESTICULAR AND PARATESTICULAR MASSES IN INFANCY
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- Cialis® (tadalafil) (package insert). Indianapolis, Ind.: Lilly ICOS LLC; 2003
- Levitra® (vardenafil) (package insert). New Haven, Conn.: Bayer Pharmaceuticals Corp., 2003
- Viagra® (sildenafil)(package insert). New York, N.Y.: Pfizer Inc., 2002
- Padma-Nathan, 2001, Cialis™ (IC351) provides prompt response and extended period of responsiveness for the treatment of men with erectile dysfunction (ED) (abstr 923), J Urol, 165, 224
- 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
Cited by
Defective acute inflammation in Crohn's disease: a clinical investigation
Marks, D. J., Harbord, M., MacAllister, R. J., Rahman, F. Z., Young, J., Al‐Lazikani, B., Lees, W. R., Novelli, M. R., Bloom, S. L., & Segal, A. W. (2006) · The Lancet · doi:10.1016/s0140-6736(06)68265-2 · Cited by 389
Addressing male sexual and reproductive health in the wake of COVID-19 outbreak
Sansone, A., Mollaioli, D., Ciocca, G., Limoncin, E., Colonnello, E., Vena, W., & Jannini, E. A. (2020) · Journal of Endocrinological Investigation · doi:10.1007/s40618-020-01350-1 · Cited by 171
Zhang, L., Zhang, Z., Zhang, R. L., Cui, Y., LaPointe, M. C., Silver, B., & Chopp, M. (2006) · Brain Research · doi:10.1016/j.brainres.2006.08.028 · Cited by 135
Ferrini, M. G., Kovanecz, I., Nolazco, G., Rajfer, J., & González-Cadavid, N. F. (2006) · British Journal of Urology · doi:10.1111/j.1464-410x.2006.05955.x · Cited by 132
The cGMP system: components and function
Hofmann, F. B. (2019) · Biological Chemistry · doi:10.1515/hsz-2019-0386 · Cited by 88
Metadata
- Authors
- Seftel, A. D.
- Affiliations
- University Hospitals of Cleveland (US)
- Corresponding author
- Seftel, Allen D.
- Venue
- Clinical Cardiology
- Publisher
- Wiley
- Published
- 2004-04
- Volume
- 27
- Issue
- S1
- Pages
- 14-19
- ISSN
- 0160-9289 (ISSN-L)
- 1932-8737
- PMC
- PMC6654274
- OpenAlex
- W1981858937
- Cited by
- 79
- References
- 24
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 7 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 2
- FWCI
- 0.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 4170 d)
- Locations
- Clinical Cardiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Sexual function and dysfunction studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Health Sciences › Medicine › Urology › Urological Disorders and Treatments
- Keywords
- phosphodiesterase-5 inhibitors, sildenafil, tadalafil, vardenafil, erectile dysfunction, pharmacokinetics, mechanism of action, nitric oxide, cyclic GMP, adverse events, duration of action, diabetes mellitus, antihypertensive drugs
- MeSH terms
- Cardiovascular Diseases, Humans, Male, Phosphodiesterase Inhibitors, Phosphoric Diester Hydrolases, Spermatogenesis, Vision Disorders, 3',5'-Cyclic-GMP Phosphodiesterases, Diabetes Complications, Cyclic Nucleotide Phosphodiesterases, Type 5
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