Sildenafil
PDE-5 inhibitor for erectile dysfunction and pulmonary arterial hypertension
Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE-5), approved by Pfizer in 1998 under the trade name Viagra for the treatment of erectile dysfunction (ED). It was the first orally available drug of this class and revolutionised the management of ED. A second indication is pulmonary arterial hypertension (PAH), where sildenafil is used under the trade name Revatio.
Numerous generics have entered the market since patent expiry. Sildenafil belongs alongside tadalafil and vardenafil to the drug class of PDE-5 inhibitors, which are now also being investigated for other conditions including Raynaud's phenomenon and pelvic floor dysfunction.
Mechanism of Action
Sexual stimulation causes the release of nitric oxide (NO) from non-adrenergic non-cholinergic (NANC) nerve fibres and from the endothelium in the corpus cavernosum. NO activates guanylate cyclase, leading to increased intracellular cyclic guanosine monophosphate (cGMP). Elevated cGMP relaxes the smooth muscle of the cavernous bodies and supplying blood vessels, allowing increased blood inflow and enabling an erection.
PDE-5 degrades cGMP and thereby ends relaxation. Sildenafil competitively and reversibly inhibits PDE-5, prolonging the duration of action of cGMP and thus amplifying the relaxant effect of the NO-cGMP cascade. Importantly, sildenafil does not itself trigger an erection but enhances the physiological response to sexual stimulation.
In the lungs, sildenafil inhibits PDE-5 in pulmonary arterial vascular smooth muscle, leading to vasodilation and pressure reduction in the pulmonary circulation. This improves exercise capacity and haemodynamics in patients with PAH.
Indications
- Erectile dysfunction (ED): In men with organic, psychogenic, or mixed ED; as on-demand medication prior to sexual intercourse
- Pulmonary arterial hypertension (PAH, WHO class I): Continuous therapy to improve exercise tolerance and delay clinical deterioration
Dosage and Administration
Erectile dysfunction: Standard dose 50 mg approximately 1 hour (30 minutes to 4 hours) before sexual intercourse. Adjust to 25 mg or 100 mg depending on efficacy and tolerability; maximum one dose per day. Elderly patients (over 65 years): Starting dose 25 mg recommended. Renal insufficiency (GFR below 30 ml/min): Starting dose 25 mg. Hepatic insufficiency (Child-Pugh A or B): Starting dose 25 mg.
Pulmonary arterial hypertension: 20 mg three times daily (every 8 hours), independent of meals. For ED, sildenafil should be taken on an empty stomach or after a light meal as fatty meals slow absorption and may delay onset of action.
Side Effects
Common (over 10 percent): Headache (due to systemic vasodilation), flushing, dyspepsia, nasal congestion.
Occasional (1 to 10 percent): Visual disturbances (altered colour vision, blue tinge due to minor PDE-6 inhibition in the retina), dizziness, back pain, myalgia, palpitations, blood pressure drop.
Rare but clinically significant: Sudden hearing loss (reportable), non-arteritic anterior ischaemic optic neuropathy (NAION, very rare — risk factors: glaucoma, diabetes, hypertension, prior NAION), severe hypotension in combination with nitrates, priapism (erection lasting over 4 hours, urological emergency).
Interactions
- Nitrates (nitroglycerin, isosorbide dinitrate and mononitrate) and NO donors (molsidomine): Absolute contraindication; additive vasodilation can cause life-threatening blood pressure drop; minimum interval: 24 hours
- Alpha-1 blockers (doxazosin, tamsulosin): Additive blood pressure reduction possible; cautious dosing at start of therapy; minimum interval with on-demand dose
- Strong CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, clarithromycin): Markedly elevated sildenafil levels; dose reduction to 25 mg; with ritonavir maximum 25 mg every 48 hours
- CYP3A4 inducers (rifampicin, carbamazepine, phenytoin): Markedly reduced sildenafil efficacy
- Antihypertensives: Additive blood pressure reduction; generally clinically relevant only with high-dose combinations
- Alcohol: Potentiates the blood pressure lowering effect; increased risk of dizziness and fainting
Special Notes
Cardiovascular risk: Sexual activity carries a certain cardiac stress risk. In patients with severe heart failure, recent myocardial infarction (within 6 months), uncontrolled hypertension, or severe hypotension, prescription should only proceed after cardiological assessment.
Priapism: Patients with conditions predisposing to priapism (sickle cell anaemia, multiple myeloma, leukaemia) should use sildenafil with particular caution. An erection lasting more than 4 hours requires immediate medical attention to avoid permanent damage to cavernous tissue.
Visual disturbances: In the event of sudden vision loss in one or both eyes, sildenafil should be discontinued immediately and an ophthalmologist consulted. Patients with known vascular risk factors for NAION are at particular risk.
Not approved for women: Sildenafil for the indication of ED is exclusively approved for men. For PAH it can be used in both sexes. Studies on female sexual dysfunction have not shown convincing evidence of efficacy to date.
Related Topics
- Tadalafil — Longer-acting PDE-5 inhibitor with up to 36 hours duration of action
- Vardenafil — PDE-5 inhibitor with rapid onset of action
- All active ingredients overview
Frequently Asked Questions
How long does sildenafil work?
The effect of sildenafil begins after approximately 30 to 60 minutes and lasts 4 to 6 hours in most users. It is dependent on sexual stimulation — without stimulation no effect occurs. Fatty meals can delay onset of action by up to 2 hours.
Can sildenafil be combined with blood pressure medication?
Generally yes, but with caution. Sildenafil can moderately lower blood pressure, which is amplified with concurrent antihypertensives. Nitrates are absolutely contraindicated. With alpha-blockers a sufficient time interval should be maintained. Coordination with the treating physician is important.
What is the difference between sildenafil and tadalafil?
Both are PDE-5 inhibitors. Sildenafil works for 4 to 6 hours, tadalafil for up to 36 hours (known as the "weekend pill"). Tadalafil is also approved as a once-daily dose of 2.5 to 5 mg for continuous therapy enabling more spontaneous sexual activity. Sildenafil has a slightly faster onset of action.
Is sildenafil prescription-only?
In Germany, sildenafil (Viagra and generics) for the indication of ED has been available without a prescription in pharmacies in the 50 mg dosage (maximum 4 tablets per pack) since 2017. Higher doses and the PAH indication require a prescription. Online orders from unauthorised sources are dangerous and legally problematic.