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Last Update: February 14, 2023.

Continuing Education Activity

Sildenafil is a medication used in the management and treatment of erectile dysfunction and pulmonary arterial hypertension. It is in the phosphodiesterase-5 inhibitor (PDE5-I) class of medications. This activity describes the indications, actions, adverse effects, and contraindications of sildenafil as an agent in the clinical setting. Knowledge therein is critical for appropriate healthcare team management of patients with erectile dysfunction, pulmonary arterial hypertension, and/or related conditions.


  • Explain the mechanism of action of sildenafil in the treatment of erectile dysfunction and pulmonary arterial hypertension.
  • Describe the clinically important drug interactions of sildenafil.
  • Outline appropriate monitoring of sildenafil therapy in erectile dysfunction and pulmonary arterial hypertension.
  • Summarize the role of the interprofessional healthcare team in improving care coordination and communication to improve outcomes related to sildenafil therapy.
Access free multiple choice questions on this topic.


FDA-approved Indications

Sildenafil was the first phosphodiesterase-5 (PDE5) inhibitor approved for use, receiving US Food and Drug Administration approval for use in erectile dysfunction on March 27, 1998.[1] 

Sildenafil also has FDA approval for the treatment of World Health Organization Group I pulmonary hypertension (also known as pulmonary arterial hypertension (PAH)) in adults to improve exercise tolerance and delay clinical worsening.[2] Sildenafil-induced delay in clinical worsening is demonstrated when sildenafil was used concomitantly with epoprostenol therapy. Clinical trials have established effectiveness for short-term (12-16 weeks) and included patients, mainly patients with New York Heart Association (NYHA) Functional Class II-III symptoms and having idiopathic etiology or having connective tissue disease (CTD). However, the addition of sildenafil to bosentan therapy did not result in any improvement in exercise capacity. It is not indicated for children.

Off-labeled Uses

Sildenafil is also occasionally used off-label for the treatment of secondary Raynaud phenomenon, female sexual arousal disorder, and as an adjunct in the treatment of altitude-induced hypoxemia.[3][4][5][6]

Mechanism of Action

The molecular structure of sildenafil mimics that of cyclic guanosine monophosphate (cGMP). This similarity protects cGMP from degradation because sildenafil can bind to the catalytic site to act as a competitive inhibitor of cGMP-specific PDE-5, the enzyme that normally catalyzes the breakdown of vasodilatory cGMP. When PDE5 is active, cGMP is degraded, causing the vascular smooth muscle contraction, thereby limiting blood flow.[7] When PDE5 becomes inhibited, the accumulation of cGMP leads to increased cGMP-dependent protein kinase activity, which phosphorylates multiple targets in the smooth muscle cell. The result of smooth muscle cell target protein phosphorylation is a decrease in intracellular calcium, increased efflux of potassium, and deactivation of myosin light chain kinase, ultimately causing smooth muscle relaxation.[7][8]

Relaxation of vascular smooth muscle in the corpus cavernosum leads to penile erection when the cavernosal sinusoids engorge with blood to compress the subtunical veins against the tunica albuginea. In patients with vasoactive pulmonary arterial hypertension, vasodilation of the pulmonary artery leads to reduced resistance to blood flow, with subsequent reductions in mean pulmonary arterial pressure.[9]


Erectile Dysfunction

Sildenafil is available as oral tablets of 25 mg, 50 mg, and 100 mg strength for erectile dysfunction (ED). Most patients receive a prescription for 50 mg of oral sildenafil, taken as needed approximately 1 hour before sexual activity.[7] The dose can be titrated upward to a maximum of 100 mg or down to 25 mg based on individual effectiveness and tolerance.

Patients are advised not to exceed a maximum dosing frequency of once daily. It can be taken 30 min to 4 hours before desired intercourse. The onset of action can occur within 30 minutes, while the duration of the effect can last up to 18 hours.

Consider starting at a dose of 25 mg in patients with hepatic dysfunction (e.g., cirrhosis), patients with CLcr less than 30 mL/minute (severe renal impairment), and patients age 65 years and above, as the administration of sildenafil in these group patients have resulted in higher plasma levels of sildenafil. Patients taking concomitant inhibitors of CYP3A4 may benefit from initiation at the lower dosage.[10]

Pulmonary Arterial Hypertension

In the treatment of PAH, sildenafil is available in tablets 20 mg,  oral suspension 10 mg/mL, and injectable 10 mg/12.5 mL forms. The recommended dosage for tablet and oral suspension formularies is 5 mg or 20 mg three times daily, 4 to 6 hours apart. Injections are dosed at 2.5 mg or 10 mg three times a day, 4 to 6 hours apart, as an intravenous bolus.[11][12] Sildenafil injection is only indicated for the continued treatment of PAH when patients are currently on prescribed oral sildenafil treatment and are temporarily unable to take medicine orally.

No dose adjustment is required in patients with renal impairment (including severe impairment CLcr < 30 mL/min). No dose adjustment is required for mild to moderate hepatic impairment. Its use is not studied in patients with severe hepatic impairment.

Pediatric Patients: Increased mortality with increasing sildenafil dose was observed in a clinical trial of pediatric patients with PAH. Deaths were first reported after approximately one year of use, and hence sildenafil, particularly chronic use, is not recommended in pediatric patients with PAH. 

Pregnant Women: There are increased risks for stroke, heart failure, preterm delivery, and maternal and fetal death for pregnant women with untreated pulmonary arterial hypertension. There are no adequate and well-controlled studies of sildenafil in pregnant women. Small case studies in pregnant women with PAH indicate a low risk of harm, though caution is warranted.[13]

Breastfeeding Women:  There is a lack of information about the effects of sildenafil on milk production and the effects of sildenafil on the breastfed infant.

Adverse Effects

Warnings and Precautions

Sildenafil has systemic vasodilatory effects and, as such, should be prescribed with caution to patients who may be sensitive to such blood pressure changes, such as patients with left ventricular outflow obstruction and impaired autonomic control of blood pressure.[14] Caution is needed when combining sildenafil with alpha-adrenergic blocking drugs and other antihypertensive agents.[15][16] 

The use of sildenafil can infrequently result in a prolonged erection lasting more than 4 hours, also known as priapism, which, if left untreated, may result in damage to the penile tissue. Furthermore, sildenafil use requires caution in patients with anatomical deformation of the penis and patients with conditions potentially predisposing them to priapism, such as sickle cell anemia or multiple myeloma.[17] 

The use of PDE5 inhibitors, such as sildenafil, may increase the incidence of non-arteritic anterior ischemic optic neuropathy (NAION) in males over age 50. Therefore, patients with a previous history of NAION or with a “crowded” optic disk should be prescribed sildenafil with caution.[16] 

Sildenafil metabolism is catalyzed primarily by CYP3A4 and, to a lesser extent, by CYP2C9; thus, strong inhibitors of these isoenzymes may lead to the accumulation of sildenafil with subsequent toxicity.[18][19] The coadministration of sildenafil and ritonavir increased plasma sildenafil concentration (11-fold increase in the AUC) due to CYP 3A4/2C9 inhibition. Accordingly, caution is necessary for patients already on ritonavir when prescribing sildenafil. The recommendation is not to exceed a dose of 25 mg of sildenafil in 48 hours if taking ritonavir.[7] The combination of sildenafil with the endothelin antagonist bosentan to manage pulmonary arterial hypertension has correlated with increased serum concentrations of bosentan and reduced levels of sildenafil.[19] Combining sildenafil with other CYP3A4 inducers can similarly lead to reduced sildenafil levels; thus, such combinations are not recommended with chronic sildenafil dosing as performed in the management of PAH.[20]

Sildenafil, at its lowest dose, is recommended when initiating therapy in patients who are on alpha-blockers due to potential systemic hypotension. Caution is also a requirement in patients taking mixed alpha/beta-blockers unless there is specific information regarding coadministration.[14]

Adverse Effects 

Doses greater than 100 mg of sildenafil have resulted in no increase in efficacy but an increase in side effects. Patients on sildenafil most commonly (2%) reported headaches, flushing, dyspepsia, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.[20]

Sildenafil has shown associations with changes in color vision, alterations in light perception, and hazy vision.[11] Rarely, sildenafil has shown correlations with ototoxicity resulting in hearing loss that may be reversible in some cases.[21]

Epistaxis was reported in 13% of patients taking sildenafil with PAH secondary to connective tissue disorder. Epistaxis was not observed in patients with idiopathic PAH. Epistaxis was reported higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist. The safety of sildenafil is not established in patients with active peptic ulceration or bleeding disorders.

Cases of a sudden loss of hearing or decrease in hearing, sometimes accompanied by tinnitus and dizziness, with the use of PDE-5 inhibitors, including sildenafil. It is not possible to decide if reported cases are related directly to the patient’s underlying risk factors attributing to hearing loss, the use of sildenafil, or both or to other factors. Advise patients to seek prompt medical care in the event of a sudden loss of hearing or decrease while taking sildenafil.


Nitrates increase cGMP formation, while sildenafil inhibits cGMP degradation causing the combination to produce severe life-threatening hypotension synergistically; coadministration of sildenafil with nitrates is contraindicated.[7] Nitrate administration is safe after five or more sildenafil elimination half-lives (24 or more hours) have elapsed since the last sildenafil dose administration.[15]

Similarly, severe hypotension from other causes (e.g., volume depletion) contraindicates using sildenafil. Other contraindications include hypersensitivity to any component of the formulation, pulmonary veno-occlusion, left ventricular outflow obstruction, PAH associated with sickle cell anemia, and multiple system atrophy.[16]

Ischemic optic neuropathy and inherited degenerative retinal disorders contraindicate sildenafil use; discontinuation of sildenafil is recommended if sudden vision loss occurs.[16]


Typically, no regular monitoring is necessary for this medication. Occasionally patients may be asked to monitor their blood pressure and pulse after being newly prescribed sildenafil, after an increase in dosage, or after the addition of CYP3A4 inhibitors. During the review of systems, assessment for visual changes is recommended. In the treatment of pulmonary arterial hypertension, patients should also receive monitoring for signs and symptoms of pulmonary edema.[18]


In healthy subjects, research demonstrated that single doses up to 800 mg resulted in adverse effects similar to those seen in lower doses but with increased frequency and severity. There are no antidotes available for sildenafil. In case of overdose, patients should receive supportive care. Dose-related visual disturbances occurred more frequently at toxic levels, while blood pressure changes showed a low correlation.[22] As sildenafil is highly bound to plasma proteins and not excreted renally, dialysis does not help expedite the clearance of sildenafil. When considering the duration of toxicity, the activity of N-desmethyl-sildenafil must be considered; this metabolite retains PDE5 specificity at lower potency, with plasma concentrations that approach 40% of the parent compound.[18]

Enhancing Healthcare Team Outcomes

Sildenafil is a safe therapeutic option for erectile dysfunction and PAH that has been available on the market for over two decades. Some barriers to successful sildenafil therapy in the treatment of erectile dysfunction include cost and social stigma surrounding erectile dysfunction.[23] All members of the interprofessional health team (clinicians, mid-level practitioners, nurses, and pharmacists) can help eliminate these barriers through compassionate education, a thorough review of systems during clinic visits, and establishing an open line of communication with the patient to better address his medical needs. This will result in better patient outcomes, increased patient quality of life, and fewer adverse events. [Level 5]

The use of sildenafil in the management of erectile dysfunction can significantly impact patient quality of life. ED is associated with depression, anxiety, and loss of self-esteem. A small placebo-controlled 12-week study performed on 512 men with erectile dysfunction used the Self Esteem and Relationship (SEAR) questionnaire to assess the impact of sildenafil treatment on patients. The trial results revealed that sildenafil had improved the patients' depression, anxiety, and self-esteem.[24]

Current guidelines for treating pulmonary arterial hypertension in adults call for closely coordinated collaboration between the patient's local healthcare team and the providers with expertise in the management of PAH. Sildenafil plays a secondary role as an alternative for patients who demonstrate acute vasoreactivity in WHO functional class II to improve their 6-minute walking distance (6MWD) and those in functional class III to improve 6MWD and improve the functional class.[25]

Review Questions


Goldstein I, Burnett AL, Rosen RC, Park PW, Stecher VJ. The Serendipitous Story of Sildenafil: An Unexpected Oral Therapy for Erectile Dysfunction. Sex Med Rev. 2019 Jan;7(1):115-128. [PubMed: 30301707]
Mitidieri E, Cirino G, d'Emmanuele di Villa Bianca R, Sorrentino R. Pharmacology and perspectives in erectile dysfunction in man. Pharmacol Ther. 2020 Apr;208:107493. [PubMed: 31991196]
Roustit M, Giai J, Gaget O, Khouri C, Mouhib M, Lotito A, Blaise S, Seinturier C, Subtil F, Paris A, Cracowski C, Imbert B, Carpentier P, Vohra S, Cracowski JL. On-Demand Sildenafil as a Treatment for Raynaud Phenomenon: A Series of n-of-1 Trials. Ann Intern Med. 2018 Nov 20;169(10):694-703. [PubMed: 30383134]
Tuiten A, van Rooij K, Bloemers J, Eisenegger C, van Honk J, Kessels R, Kingsberg S, Derogatis LR, de Leede L, Gerritsen J, Koppeschaar HPF, Olivier B, Everaerd W, Frijlink HW, Höhle D, de Lange RPJ, Böcker KBE, Pfaus JG. Efficacy and Safety of On-Demand Use of 2 Treatments Designed for Different Etiologies of Female Sexual Interest/Arousal Disorder: 3 Randomized Clinical Trials. J Sex Med. 2018 Feb;15(2):201-216. [PubMed: 29289554]
Zeinalzadeh S, Mohagheghzadeh AA, Ahmadinezhad F, Akbarzadeh M. Comparison of the effect of Elaeagnus angustifolia flower capsule and sildenafil citrate tablet female sexual interest/arousal disorder in clinical trial study. J Family Med Prim Care. 2019 Nov;8(11):3614-3620. [PMC free article: PMC6881950] [PubMed: 31803662]
Perimenis P. Sildenafil for the treatment of altitude-induced hypoxaemia. Expert Opin Pharmacother. 2005 May;6(5):835-7. [PubMed: 15934909]
McCullough AR. Four-year review of sildenafil citrate. Rev Urol. 2002;4 Suppl 3(Suppl 3):S26-38. [PMC free article: PMC1476025] [PubMed: 16986012]
Albersen M, Shindel AW, Mwamukonda KB, Lue TF. The future is today: emerging drugs for the treatment of erectile dysfunction. Expert Opin Emerg Drugs. 2010 Sep;15(3):467-80. [PMC free article: PMC3163612] [PubMed: 20415601]
Fallah F. Recent strategies in treatment of pulmonary arterial hypertension, a review. Glob J Health Sci. 2015 Jan 26;7(4):307-22. [PMC free article: PMC4802183] [PubMed: 25946920]
Muirhead GJ, Wulff MB, Fielding A, Kleinermans D, Buss N. Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br J Clin Pharmacol. 2000 Aug;50(2):99-107. [PMC free article: PMC2014393] [PubMed: 10930961]
Coons JC, Pogue K, Kolodziej AR, Hirsch GA, George MP. Pulmonary Arterial Hypertension: a Pharmacotherapeutic Update. Curr Cardiol Rep. 2019 Nov 22;21(11):141. [PubMed: 31758342]
Han MK, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, Anstrom KJ, Martinez FJ., IPFnet Investigators. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest. 2013 Jun;143(6):1699-1708. [PMC free article: PMC3673665] [PubMed: 23732584]
Huang S, DeSantis ER. Treatment of pulmonary arterial hypertension in pregnancy. Am J Health Syst Pharm. 2007 Sep 15;64(18):1922-6. [PubMed: 17823103]
Jackson G, Montorsi P, Cheitlin MD. Cardiovascular safety of sildenafil citrate (Viagra): an updated perspective. Urology. 2006 Sep;68(3 Suppl):47-60. [PubMed: 17011375]
Kloner RA. Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions. Am J Cardiol. 2005 Dec 26;96(12B):42M-46M. [PubMed: 16387566]
Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov. 2006 Aug;5(8):689-702. [PMC free article: PMC7097805] [PubMed: 16883306]
Ekeke ON, Omunakwe HE, Eke N. Management of priapism in adult men. Int Surg. 2015 Mar;100(3):552-7. [PMC free article: PMC4370551] [PubMed: 25785343]
Ramani GV, Park MH. Update on the clinical utility of sildenafil in the treatment of pulmonary arterial hypertension. Drug Des Devel Ther. 2010 May 25;4:61-70. [PMC free article: PMC2880338] [PubMed: 20531962]
Vorhies EE, Ivy DD. Drug treatment of pulmonary hypertension in children. Paediatr Drugs. 2014 Feb;16(1):43-65. [PMC free article: PMC3946901] [PubMed: 24114695]
Dhariwal AK, Bavdekar SB. Sildenafil in pediatric pulmonary arterial hypertension. J Postgrad Med. 2015 Jul-Sep;61(3):181-92. [PMC free article: PMC4943407] [PubMed: 26119438]
Skeith L, Yamashita C, Mehta S, Farquhar D, Kim RB. Sildenafil and furosemide associated ototoxicity: consideration of drug-drug interactions, synergy, and broader clinical relevance. J Popul Ther Clin Pharmacol. 2013;20(2):e128-31. [PubMed: 23756362]
Giuliano F, Jackson G, Montorsi F, Martin-Morales A, Raillard P. Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database. Int J Clin Pract. 2010 Jan;64(2):240-55. [PMC free article: PMC2810448] [PubMed: 19900167]
Rezaee ME, Ward CE, Brandes ER, Munarriz RM, Gross MS. A Review of Economic Evaluations of Erectile Dysfunction Therapies. Sex Med Rev. 2020 Jul;8(3):497-503. [PubMed: 31326359]
Althof SE, O'leary MP, Cappelleri JC, Hvidsten K, Stecher VJ, Glina S, King R, Siegel RL., International SEAR Study Group. Sildenafil citrate improves self-esteem, confidence, and relationships in men with erectile dysfunction: Results from an international, multi-center, double-blind, placebo-controlled trial. J Sex Med. 2006 May;3(3):521-9. [PubMed: 16681478]
Klinger JR, Elliott CG, Levine DJ, Bossone E, Duvall L, Fagan K, Frantsve-Hawley J, Kawut SM, Ryan JJ, Rosenzweig EB, Sederstrom N, Steen VD, Badesch DB. Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report. Chest. 2019 Mar;155(3):565-586. [PubMed: 30660783]

Disclosure: Benjamin Smith declares no relevant financial relationships with ineligible companies.

Disclosure: Mary Babos declares no relevant financial relationships with ineligible companies.

Copyright © 2023, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK558978PMID: 32644404


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