Sildenafil

Sildenafil: A Comprehensive Review

Sildenafil, commercially recognised as Viagra, stands as a pivotal pharmacological intervention for erectile dysfunction (ED) and pulmonary arterial hypertension (PAH). Originally synthesised for angina pectoris, its unexpected vasodilatory effect on penile vasculature reshaped its clinical application, establishing Sildenafil as a cornerstone in sexual medicine and cardiovascular therapeutics. Since its approval, Sildenafil has revolutionised the management of these conditions, delivering targeted mechanisms of action with favourable safety and tolerability profiles.

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Therapeutic Indications

Sildenafil is primarily indicated for the treatment of ED, enhancing erectile function through the potentiation of nitric oxide-mediated vasodilation. In PAH, Sildenafil reduces pulmonary vascular resistance, thereby improving haemodynamics and exercise capacity. Emerging off-label applications include managing Raynaud's phenomenon and high-altitude pulmonary oedema, underscoring the drug's expanding therapeutic potential.

Dosage and Administration

For ED, the recommended starting dose is 50 mg, administered approximately 30 to 60 minutes before sexual activity, with adjustments ranging from 25 mg to 100 mg depending on individual response and tolerability. For PAH, a regimen of 20 mg thrice daily is standard. Administration is oral, with or without food; however, high-fat meals may delay absorption. Intravenous formulations are occasionally employed in hospital settings for acute PAH management, offering a vital alternative for patients unable to tolerate oral administration.

Dose Adjustment in Special Populations

• Renal Impairment: In patients with severe renal dysfunction (creatinine clearance <30 mL/min), a reduced initial dose of 25 mg is recommended due to impaired drug clearance. Close monitoring is essential to mitigate the risk of accumulation and associated adverse effects.
• Hepatic Impairment: As Sildenafil undergoes hepatic metabolism via the cytochrome P450 (CYP) 3A4 pathway, individuals with hepatic impairment should commence treatment with a 25 mg dose. Regular liver function tests are advised to optimise safety and efficacy.
• Pregnancy: Sildenafil's use during pregnancy is typically contraindicated unless prescribed for PAH under specialist supervision. Current data regarding foetal safety are inconclusive, necessitating cautious use and continued research.

Pharmacodynamics and Pharmacokinetics

• Pharmacodynamics: Sildenafil selectively inhibits phosphodiesterase type 5 (PDE5), preventing cyclic guanosine monophosphate (cGMP) degradation. Elevated cGMP concentrations induce smooth muscle relaxation and vasodilation, predominantly affecting the penile and pulmonary vasculature due to tissue-specific PDE5 expression.
• Pharmacokinetics: Following oral administration, peak plasma concentrations occur within 30 to 120 minutes. Sildenafil’s terminal half-life is approximately 3-5 hours, with hepatic metabolism and renal excretion as primary elimination routes. Bioavailability hovers around 40%, exhibiting dose-proportional pharmacokinetics across the therapeutic range.

Adverse Effects

Common adverse effects include headache, flushing, dyspepsia, and nasal congestion. Severe reactions, though rare, encompass non-arteritic anterior ischaemic optic neuropathy (NAION), sudden hearing loss, and priapism. Cardiovascular complications, such as myocardial infarction and arrhythmia, have been reported, particularly in individuals with pre-existing cardiovascular conditions. Immediate medical attention is warranted for erections lasting over four hours.

Drug Interactions

Sildenafil should not be co-administered with nitrates or nitric oxide donors due to the risk of profound hypotension. Concurrent use with CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) necessitates dosage adjustments owing to elevated plasma Sildenafil concentrations. Furthermore, combining Sildenafil with antihypertensives or alpha-blockers may potentiate hypotensive effects, requiring careful consideration.

Presentation and Form

Sildenafil is available in diverse formulations tailored to clinical needs:

• Tablets: The most common form, available in 25 mg, 50 mg, and 100 mg strengths for oral administration.
• Oral Suspension: A liquid formulation, typically 10 mg/mL, employed for PAH management or patients with dysphagia.
• Intravenous Injection: Reserved for hospital settings, particularly in acute PAH cases, offering rapid administration.
• Soft Tabs and Chewable Tablets: Providing convenience and faster onset, these alternatives are increasingly popular for ED treatment.

Comparative Analysis of PDE5 Inhibitors

Parameter	Sildenafil	Tadalafil	Vardenafil
Onset of Action	30-60 minutes	30 minutes	30-60 minutes
Duration	4-6 hours	Up to 36 hours	4-5 hours
Common Side Effects	Headache, flushing	Back pain, nasal congestion	Nausea, dizziness
Metabolism	Hepatic (CYP3A4)	Hepatic (CYP3A4)	Hepatic (CYP3A4)
Food Interaction	Delayed by fat	Minimal effect	Delayed by fat

Special Precautions

Particular caution is warranted in patients with cardiovascular disease, hypotension, or those on antihypertensive therapy. Alcohol consumption may exacerbate hypotensive effects. In patients with retinitis pigmentosa or degenerative retinal disorders, the risk of ocular side effects necessitates vigilant monitoring. Patients should be counselled on recognising signs of serious adverse effects, such as sudden vision or hearing loss.

Toxicity and Management of Overdose

Overdose typically presents as pronounced hypotension, syncope, and priapism. Treatment is largely supportive, with an emphasis on cardiovascular stabilisation. No specific antidote exists, though interventions such as fluid resuscitation and vasopressors may be necessary. Haemodialysis is ineffective due to Sildenafil's high protein-binding capacity.

Recent Advances and Guidelines (2025)

Recent findings suggest potential benefits of Sildenafil in conditions such as Raynaud's phenomenon and high-altitude pulmonary oedema. The 2025 guidelines highlight personalised dosing strategies, particularly in geriatric populations, to mitigate adverse outcomes. Additionally, ongoing investigations into its anti-inflammatory properties in pulmonary diseases are expanding its therapeutic horizon.

Key Takeaways

• Sildenafil exerts its effect through PDE5 inhibition, enhancing cGMP-mediated vasodilation.
• It is contraindicated with nitrates and requires dose adjustments with CYP3A4 inhibitors.
• Optimal administration considers comorbidities and concurrent pharmacotherapies.
• Dose modifications are crucial in renal and hepatic impairment to prevent accumulation.
• Novel applications beyond ED are under investigation, broadening its clinical utility.

References

1. British National Formulary (BNF)
2. European Medicines Agency Guidelines
3. National Health Service (NHS) UK
4. Recent studies published in The Lancet
5. 2025 PAH Management Guidelines