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sildenafil (Viagra, Revatio, Caverta)

Sildenafil citrate. Tradename: Viagra. Indications: 1) impotence/andropause a) NOT useful in postmenopausal women [6] b) may help some women with sexual dysfunction [7,8] - SSRI-induced sexual dysfunction 2) less likely to help individuals with diabetes or benign prostatic hypertrophy (BPH) 3) pulmonary hypertension* [5,13,17] (Revatio) 4) may be of benefit post prostate surgery (NOT FDA-approved use) [10] 5) Raynaud's phenomenon ? [18], individualized effect [25] 6) sildenafil may reduce risk of Alzheimer's disease (RR=0.31) [27] * NYHA functional pulmonary hypertension class & acute vasoreactivity study needed for Veteran's administration non formulary drug request Contraindications: 1) concurrent administration of nitrates [2] (amyl nitrite) 2) concurrent administration of Viagra & Revatio 3) intermediate-high risk of cardiovascular disease 4) retinitis pigmentosa 5) history of non-arteric ischemic optic neuropathy 6) not for use in treating pulmonary hypertension in children [20] 7) use with caution in patients with a) Peyronie's disease b) conditions predisposing to priapism - multiple myeloma - sickle cell disease c) pulmonary veno-occlusive disease [26] History: - obtain a complete sexual history Dosage: 1) 50 mg PO 1 hour prior to sexual intercourse 2) titrate to effect, 25-100 mg (oral, sublingual) [14] 3) start with 25 mg in patients with hepatic or renal insufficiency (creatinine clearance < 10 mL/min) 4) start with 25 mg in the elderly 5) daily for 12 months post prostate surgery [1] 6) 20 mg PO TID for pulmonary hypertension (Revatio) [13] - 5 mg TID non-inferior to 80 mg TID [27] 7) 50 mg BID for Raynaud's phenomenon 8) maximum recommended daily use is once a day [26] 9) VA formulary maximum: 4 doses/month [16] Tabs: 25, 50, 100 mg Pharmacokinetics: 1) radidly absorbed after oral administration 2) maximum plasma concentrations are reached 30-120 minutes after oral dosing; sublingual form may be faster [14] 3) absorption is delayed with a high-fat meal 4) 96% is bound to plasma proteins 5) volume of distribution is 105 L, indicating distribution into tissues 6) eliminated predominantly by hepatic metabolism a) cyt P450 3A4 (major route); cyt P450 2C9 (minor route) b) N-desmethyl metabolite is active with properties similar to sildenafil 7) elimination 1/2 life is 4 hours & 1/2 life of its active N-desmethyl metabolite is also 4 hours 8) reduced clearance in the elderly Dosage adjustment in renal failure: - none Adverse effects: 1) headaches (12%) 2) GI upset (nausea, diarrhea, dyspepsia) (5-7%) 3) flushing (9%) 4) visual disturbances a) "blue vision" (3%, due to PDE6* inhibition) b) non-arteric ischemic optic neuropathy [12] 5) nasal congestion (2%) 6) dizziness (1%) 7) rash (1%) 8) epistaxis [26] 9) insomnia [26] 10) back pain, mylagias 11) increased risk of melanoma (HR=1.84) [22] - no cause-effect relationship demonstrated 12) NOT associated with hypertension, stress-induced ischemia, dyspnea, decrease in exercise tolerance, angina, exercise- induced cardiac wall motion abnormalities [4,15] 13) toxicity or overdose - dose-related increase in adverse effects - myalgia without evidence of muscle damage most common [26] * phosphodiesterase 6 present in retina, see below Drug interactions: 1) sildenafil potentiates the hypotensive effects of nitrates [2] 2) inhibitors of cyt P450 3A4 inhibitors increase activity of sildenafil - ketoconazole, itraconazole, erythromycin, saquinavir 3) ritonavir increases activity of sildenafil 4) any drug that induces cyt P450 3A4 may diminish levels of sildenafil 5) may increase risk of postural hypotension when administered concurrently with alpha blockers, Cardura, Hytrin, MiniPress, Flomax 6) concurrent use of sildenafil is contraindicated with: - atazanavir, nelfinavir, cobicistat - elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate - isosorbide dinitrate, isosorbide mononitrate, nitroglycerin - riociguat, vericiguat - avanafil, sildenafil, tadalafil, vardenafil [26] Laboratory: - sildenafil citrate in serum/plasma Mechanism of action: 1) sildenafil inhibits phosphodiesterase 5 (PDE5), increasing cGMP levels in the corpus cavernosum by inhibiting its degradation 2) cGMP induces relaxation of smooth muscle allowing inflow of blood into the corpus cavernosum 3) release of nitric oxide into the corpus cavernosum during sexual stimulation induces guanylate cyclase increasing cGMP 4) thus sildenafil enhances vasodilation effects of nitric oxide 5) sildenafil has no effect in the absence of sexual stimulation 6) sildenafil inhibition is selective for PDE5 > 10-fold PDE6, 80-fold PDE1, > 1000-fold PDE2, PDE3, PDE4 7) reduces pulmonary vascular resistance [5] - vasodilates pulmonary vessels [13] 8) improves insulin sensitivity in prediabetes [23] 9) dose-dependent reduction of tau hyperphosphorylation (pTau181 & pTau205) in neurons derived from pleuripotent stem cells [27] 10) overall patient satisfaction is about 50% [9] - prevents & treats heart failure (diastolic dysfunction) in mice [11] Notes: - Pfizer to sell Viagra Online [21] - generic available Dec 11, 2017 [24]

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) phosphodiesterase 5; cGMP-specific phosphodiesterase

General

phosphodiesterase-5 inhibitor

Properties

INHIBITS: phosphodiesterase-5 MISC-INFO: elimination route LIVER protein-binding 96% 1/2life 4 HOURS

Database Correlations

PUBCHEM correlations

References

  1. Pfizer U.S. Pharmaceuticals
  2. Medical Knowledge Self Assessment Program (MKSAP) 19 American College of Physicians, Philadelphia 2022
  3. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  4. Journal Watch 22(6):43, 2002 Arruda-Olson AM et al, JAMA 287:719, 2002
  5. Journal Watch 22(9):68, 2002 Gbofrani HA et al Ann Intern Med 136:515, 2002 Rubin LJ et al N Engl J Med 346:896, 2002
  6. Journal Watch 23(10):80, 2003 Modelska K & Cummings S, Am J Obstet Gynecol 188:286, 2003
  7. Prescriber's Letter 11(2):9 2004 Detail-Document#: 200213 (subscription needed) http://www.prescribersletter.com
  8. Journal Watch 24(4):33, 2004 Berman JR et al Safety and efficacy of sildenafil citrate for the treatment of female sexual arousal disorder: a double-blind, placebo controlled study. J Urol 170:2333, 2003 PMID: 14634409
  9. Journal Watch 24(13):103, 2004 Tomlinson J, Wright D. Impact of erectile dysfunction and its subsequent treatment with sildenafil: qualitative study. BMJ. 2004 May 1;328(7447):1037. Epub 2004 Mar 29. PMID: 15051618 http://bmj.bmjjournals.com/cgi/content/full/328/7447/1037
  10. Prescriber's Letter 11(7):39 2004 Detail-Document#: 200703 (subscription needed) http://www.prescribersletter.com
  11. Journal Watch 25(7):56, 2005 Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005 Feb;11(2):214-22. Epub 2005 Jan 23. PMID: 15665834
  12. Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases. J Neuroophthalmol. 2005 Mar;25(1):9-13. PMID: 15756125 - Prescriber's Letter 12(6): 2005 Viagra and Vision Loss Detail-Document#: 210611 (subscription needed) http://www.prescribersletter.com
  13. Prescriber's Letter 12(7): 2005 Revatio (Sildenafil) Detail-Document#: 210702 (subscription needed) http://www.prescribersletter.com
  14. Prescriber's Letter 12(8): 2005 Sublingual Viagra (Sildenafil) Detail-Document#: 210811 (subscription needed) http://www.prescribersletter.com
  15. Prescriber's Letter 12(9): 2005 Cardiovascular Safety of Viagra (Sildenafil) Detail-Document#: 211012 (subscription needed) http://www.prescribersletter.com
  16. Department of Veterans Affairs, VA National Formulary
  17. Galie N et al, Sildenafil citrate therapy for pulmonary arterial hypertension N Engl J Med 353(20):2148, 2005 PMID: 16291984
  18. Prescriber's Letter 13(1): 2006 Viagra and Raynaud's phenomenon Detail-Document#: 220111 (subscription needed) http://www.prescribersletter.com
  19. Prescriber's Letter 15(9): 2008 Sildenafil (Viagra) for Antidepressant-induced Sexual Dysfunction in Women Detail-Document#: 240910 (subscription needed) http://www.prescribersletter.com
  20. FDA MedWatch, Aug 30, 2012 Revatio (sildenafil): Drug Safety Communication - Recommendation Against Use in Children http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm317743.htm
  21. Pfizer News and Media. May 6, 2013 Facing Off Against Counterfeit Online Pharmacies: Pfizer Launches New Purchasing Website To Help Alleviate the Guesswork Around Buying Legitimate Viagra (sildenafil citrate) Online http://pfizer.newshq.businesswire.com/press-release/facing-against-counterfeit-online-pharmacies-pfizer-launches-new-purchasing-website-he
  22. Husten L Physician's First Watch, April 9, 2014 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Li WQ, Qureshi AA, Robinson KC, Han J Sildenafil Use and Increased Risk of Incident Melanoma in US Men. A Prospective Cohort Study. JAMA Intern Med. Published online April 07, 2014 PMID: 24710960 http://archinte.jamanetwork.com/article.aspx?articleID=1857095 - Robinson JK Role of Sildenafil in Melanoma Incidence and Mortality. JAMA Intern Med. Published online April 07, 2014 PMID: 24710720 http://archinte.jamanetwork.com/article.aspx?articleid=1857089
  23. Ramirez CE et al Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. J Clin Endocrinol Metab. Nov 18, 2015 PMID: 26580240 http://press.endocrine.org/doi/pdf/10.1210/jc.2015-3415
  24. NEJM editors. Generic Viagra to Hit Market on Monday. Physician's First Watch, Dec 8, 2017 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Young KD Little Blue Pill Goes Generic Today, and Pfizer Joins In. Medscape. Dec 11, 2017 https://www.medscape.com/viewarticle/889846
  25. Roustit M, Giai J, Gaget O et al On-Demand Sildenafil as a Treatment for Raynaud Phenomenon: A Series of n-of-1 Trials. Ann Intern Med. 2018. Oct 30. PMID: 30383134 http://annals.org/aim/article-abstract/2709822/demand-sildenafil-treatment-raynaud-phenomenon-series-n-1-trials
  26. Windle ML Fast Five Quiz: Sildenafil (Viagra) Medscape. Aug 4, 2021 https://reference.medscape.com/viewarticle/955912_2
  27. George J Can Viagra Prevent Alzheimer's? Sildenafil shows potential for drug repurposing MedPage Today December 6, 2021 https://www.medpagetoday.com/neurology/alzheimersdisease/96018 - Fang J, Zhang P, Zhou Y et al Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease. Nat Aging (2021) Not indexed in PubMed https://www.nature.com/articles/s43587-021-00138-z - Brooks M New Data Support Viagra for Alzheimer's Prevention. Medscape. March 12, 2024 https://www.medscape.com/viewarticle/new-data-support-viagra-alzheimers-prevention-2024a10004md - Gohel D, Zhang P, Gupta AK et al Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons. J Alzheimers Dis. 2024 Mar 1. PMID: 38427489
  28. Hoeper MM, Ewert R, Jansa P et al. Randomized, Multicenter Study to Assess the Effects of Different Doses of Sildenafil on Mortality in Adults With Pulmonary Arterial Hypertension. Circulation. 2024 May 16. PMID: 38752352 Free article
  29. HIGHLIGHTS OF PRESCRIBING INFORMATION VIAGRA (sildenafil citrate) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/20895s039s042lbl.pdf