Sildenafil

Introduction Overview

Generic Name

sildenafil

Brand Name

Viagra, Revatio, Liqrev

Dosage Form

oral tablet, oral suspension, injectable solution

Drug Class

Agents for pulmonary hypertension, Impotence agents

Pharmacokinetics

Absorption: Sildenafil is rapidly absorbed following oral administration, with peak plasma concentrations typically attained within 30 to 120 minutes, averaging around 60 minutes post-dose under fasting conditions. The absolute bioavailability of sildenafil tablets is approximately 40%, with a median time to peak plasma concentration of 1 hour. Food intake, especially high-fat meals, can delay the time to peak concentration but does not significantly affect overall absorption extent. The oral suspension form allows for similar systemic exposure and is indicated when swallowing tablets is difficult.

Distribution: Sildenafil is extensively distributed throughout the body, exhibiting a volume of distribution of approximately 105 L. It is about 96% bound to plasma proteins, predominantly albumin. The drug crosses biological membranes readily and distributes into tissues, including penile tissue and pulmonary vasculature, consistent with its therapeutic targets. Distribution is not significantly altered by age, gender, or hepatic impairment.

Metabolism: Sildenafil undergoes extensive hepatic metabolism primarily via the cytochrome P450 enzymes CYP3A4 (major route) and CYP2C9 (minor route). The principal active circulating metabolite, N-desmethyl sildenafil, has similar pharmacologic activity to sildenafil but circulates at about 40% of the parent drug’s plasma concentration. Hepatic impairment may affect metabolism, leading to increased plasma concentrations.

Elimination: Sildenafil and its metabolites are predominantly eliminated via the feces (approximately 80%) and to a lesser extent via urine (approximately 13%). The terminal half-life is approximately 3 to 5 hours in healthy subjects. Renal impairment has a minimal effect on clearance but caution is advised in severe hepatic and renal dysfunction due to altered metabolism and excretion, potentially necessitating dose adjustments.

Dosage Forms

Available Dosage Forms:
- Oral tablets: 20 mg, 25 mg, 50 mg, and 100 mg strengths typically prescribed for erectile dysfunction (Viagra).
- Oral suspension: 10 mg/mL concentration (such as Liqrev) allowing flexible dosing especially for patients with swallowing difficulties.
- Injectable solution: Intravenous sildenafil is available for pulmonary arterial hypertension in hospital settings.

Dosages for Adults and Adolescents:
- Erectile Dysfunction (Viagra): Typical starting dose is 50 mg taken orally approximately 1 hour before sexual activity; dose may be adjusted from 25 mg to 100 mg based on efficacy and tolerability. Maximum recommended dosing frequency is once per day. It may be taken from 30 minutes to 4 hours before sexual activity.
- Pulmonary Arterial Hypertension (Revatio): Recommended dosing is 20 mg three times daily orally, approximately 4 to 6 hours apart. Dose adjustments may be required in hepatic or renal impairment.

Specific Patient Populations:
- Elderly (over 65 years): No initial dose adjustment required; however, dose titration should be cautious due to potential increased plasma concentration.
- Hepatic Impairment: Dose adjustments recommended, as clearance is reduced; generally, a starting dose of 25 mg is advised.
- Renal Impairment: Mild to moderate impairment requires no adjustment; severe impairment may require caution.
- Pediatric Use: Not recommended for erectile dysfunction; oral suspension may be used for pediatric pulmonary hypertension under specialist supervision.

Clinical guidelines recommend against co-administration with nitrates due to risk of severe hypotension and advise caution when using with alpha-blockers or other antihypertensives.

Mechanism Of Action

Sildenafil functions as a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), an enzyme primarily responsible for degradation of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum and pulmonary vasculature. By inhibiting PDE5, sildenafil prolongs the effects of cGMP, which is elevated upon nitric oxide release during sexual stimulation or in response to endogenous vasodilatory signals.

At the molecular level, increased cGMP levels lead to relaxation of smooth muscle cells in the corpus cavernosum and pulmonary arteries by decreasing intracellular calcium concentrations, resulting in vasodilation and increased blood flow. This vasodilatory effect facilitates erection in men and reduces pulmonary arterial pressure in patients with pulmonary hypertension.

Clinically, sildenafil enhances the natural erectile response when sexual stimulation triggers nitric oxide release; it is not an aphrodisiac and does not induce erection absent sexual stimulation. For pulmonary arterial hypertension, the drug improves exercise capacity and symptoms by reducing pulmonary vascular resistance.

Comparatively, sildenafil shares its mechanism with other PDE5 inhibitors, such as tadalafil and vardenafil, though differences in pharmacokinetics and selectivity profiles influence dosing schedules and side effect profiles. Extensive research supports sildenafil's efficacy and safety in both erectile dysfunction and pulmonary arterial hypertension indications, validated by multiple randomized controlled trials and post-marketing surveillance data.

Pharmacological Actions

Selective phosphodiesterase type 5 (PDE5) inhibition, leading to increased cyclic GMP levels.
Smooth muscle relaxation in the corpus cavernosum resulting in enhanced penile erection.
Vasodilation of pulmonary arterial smooth muscle, reducing pulmonary arterial pressure.
Improvement of exercise capacity in pulmonary arterial hypertension patients.
Does not induce erection without sexual stimulation, requiring nitric oxide release.
Modulates vascular tone and blood flow through nitric oxide-cGMP pathway enhancement.
Potential off-target inhibition of PDE6 in the retina, accounting for transient visual disturbances.
Influences platelet aggregation and may have mild antiplatelet effects via cGMP pathways.
Demonstrates synergy with endogenous vasodilators improving systemic and pulmonary hemodynamics.
Alters endothelial function by supporting nitric oxide signaling in vascular tissues.
Metabolically active N-desmethylated metabolite contributes to overall pharmacodynamic effects.
Exhibits tissue selectivity mainly in penis and lungs based on PDE5 tissue distribution.

Therapeutic Or Clinical Uses

Treatment of erectile dysfunction (impotence) in adult males.
Management of pulmonary arterial hypertension to improve exercise capacity and delay clinical worsening.
Off-label use in altitude sickness and Raynaud’s phenomenon in some clinical scenarios.
Use in male patients with erectile dysfunction post-radical prostatectomy.
Treatment adjunct in patients with pulmonary hypertension secondary to connective tissue disease.
Potential benefit in heart failure with preserved ejection fraction studied but not approved.
Improvement of endothelial function in vascular diseases under investigation.
Enhancement of quality of life and sexual satisfaction in men with erectile dysfunction.
Used in both vasculogenic and psychogenic impotence when nitric oxide pathways are intact.
Adjunct to other vasodilator therapies in pulmonary hypertension treatment algorithms.

Side Or Adverse Effects

Common: headache, flushing, and dyspepsia.
Visual disturbances including blurred vision, changes in color perception (cyanopsia).
Nasal congestion and rhinorrhea.
Dizziness and transient hypotension.
Muscle and back pain.
Ringing in the ears and rare sudden hearing loss.
Priapism – prolonged and painful erection lasting more than 4 hours, requiring emergency treatment.
Sudden vision loss potentially due to non-arteritic anterior ischemic optic neuropathy (NAION).
Cardiovascular events including chest pain and arrhythmias, especially in patients with pre-existing heart disease.
Allergic reactions such as rash, urticaria, and angioedema.
Gastrointestinal discomfort including nausea and heartburn.
Peripheral edema and limb swelling.
Seizures in rare cases.
Hypotension especially when used concomitantly with nitrates or other vasodilators.
Rare cases of pulmonary hemorrhage reported in pulmonary hypertension patients.

Precautions

Avoid use with nitrates due to risk of profound hypotension.
Use cautiously in patients with cardiovascular disease, including recent myocardial infarction or stroke.
Evaluate patients with structural deformities of the penis (e.g., Peyronie’s disease) before prescribing.
Monitor patients with retinitis pigmentosa or other retinal disorders closely due to visual side effects.
Dose adjustment recommended in renal and hepatic impairment.
Advise patients about the risk of priapism and seek urgent care if erection lasts longer than 4 hours.
Consider potential drug interactions with CYP3A4 inhibitors such as ketoconazole and ritonavir.
Use with caution in patients with bleeding disorders or those taking anticoagulants.
Avoid use in patients advised against sexual activity for underlying health reasons.
Screen for potential interactions with antihypertensives to prevent excessive hypotension.
Advise patients to avoid grapefruit products due to altered metabolism.
Use caution in elderly patients due to possible increased sildenafil exposure.
Pregnancy Category B for pulmonary hypertension use; safety in pregnancy for erectile dysfunction unestablished.
Uncertain efficacy and safety profile in pediatric patients; pulmonary hypertension use under specialty supervision only.
Instruct patients to report sudden vision or hearing changes immediately.

Warnings

Do not use sildenafil concomitantly with any nitrate medications or nitric oxide donors.
Potential for severe hypotension leading to dizziness, fainting, heart attack, or stroke when combined with nitrates.
Risk of sudden vision loss (non-arteritic anterior ischemic optic neuropathy) associated with sildenafil use.
Priapism is a medical emergency; prolonged erection can cause permanent damage.
Do not use sildenafil if allergic to the drug or other PDE5 inhibitors.
Avoid use with riociguat (Adempas) due to risk of hypotension and serious adverse events.
Use with extreme caution in patients with pre-existing cardiovascular conditions.
Discontinue use and seek emergency help if experiencing chest pain, severe dizziness, or prolonged erection.
Potential for interactions with alpha-blockers, leading to symptomatic hypotension.
Risk of sudden hearing loss, sometimes accompanied by tinnitus or dizziness.
Avoid overuse; do not exceed one dose per day or doses recommended by healthcare provider.
Medication should not be shared with others and used strictly according to prescription indications.
Use caution when prescribing to patients with anatomical deformation of the penis (e.g., Peyronie’s disease).
Increased risk of adverse effects in patients with multiple comorbidities such as diabetes, hypertension, and hyperlipidemia.
Emergency medical attention required for signs of allergic reactions such as swelling of face, lips, or throat.

Contraindication

Concomitant use with nitrate drugs, including nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate.
Known hypersensitivity or allergy to sildenafil or any component of the formulation.
Use together with riociguat (Adempas) for pulmonary arterial hypertension.
Patients advised against sexual activity for cardiovascular or other health reasons.
Severe hepatic impairment due to risk of increased sildenafil plasma levels.
Severe renal impairment in the absence of careful monitoring.
Concomitant use with other PDE5 inhibitors like tadalafil, vardenafil, or avanafil.
Hypotension or uncontrolled blood pressure states.
Retinitis pigmentosa patients with a history of hereditary retinal disorders may be contraindicated.
Known bleeding disorders where increased bleeding risk is problematic.
Congenital or idiopathic priapism or conditions predisposing to priapism.
Patients under 18 years of age for erectile dysfunction use.
Concomitant use of potent CYP3A4 inhibitors without dose adjustment.
Patients with structural deformities of the penis posing a risk of injury from sexual activity.
Hemodynamically unstable patients or those with recent stroke or myocardial infarction.

Drug Interactions

Nitrates (e.g., nitroglycerin) – potentiate risk of severe hypotension; contraindicated.
Riociguat (Adempas) – combined use may cause hypotension; contraindicated.
CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir – increase sildenafil plasma concentrations.
Other PDE5 inhibitors (tadalafil, vardenafil, avanafil) – concomitant use increases adverse effects risk.
Alpha-blockers (e.g., doxazosin, tamsulosin) – additive blood pressure lowering effects causing symptomatic hypotension.
Antihypertensives – additive hypotensive effects, monitor blood pressure closely.
Protease inhibitors for HIV/AIDS (e.g., ritonavir) – increase plasma levels of sildenafil, requiring dose adjustment.
Grapefruit juice – may inhibit CYP3A4 metabolism increasing sildenafil plasma levels.
Erythromycin and other macrolide antibiotics – potential CYP3A4 inhibition increasing sildenafil exposure.
Warfarin and other anticoagulants – monitor bleeding risks, though no direct interaction reported.
Bosentan – coadministration may reduce sildenafil plasma concentration due to CYP induction.
Drugs that prolong QT interval may have additive cardiac risks when used with sildenafil.
Alcohol – may increase risk of hypotension and dizziness related to sildenafil.
CYP2C9 inhibitors or inducers – less significant effect but warrants clinical monitoring.
Concomitant use with alprostadil or yohimbine without medical advice is not recommended due to additive vasodilatory effects.

Preparations Of The Drug

Viagra tablets – film-coated tablets for oral administration in strengths of 25 mg, 50 mg, and 100 mg.
Revatio tablets – film-coated tablets indicated for pulmonary arterial hypertension, typically 20 mg strength.
Sildenafil oral suspension – a 10 mg/mL flavored liquid formulation suitable for patients with swallowing difficulties.
Sildenafil injection – intravenous formulation used in hospital settings for pulmonary arterial hypertension.
Liqrev oral suspension – marketed oral suspension facilitating precise dosing in special populations.
Unbranded generic tablets – available in various strengths corresponding to brand formulations.
Combination kits including dosing syringes with oral suspensions to assure accurate dosing.
Packaging options suitable for daily as-needed use or multiple dosing regimens (e.g., blister packs, bottles).
Labeling indicating specific indication for erectile dysfunction or pulmonary arterial hypertension to prevent medication errors.
Storage recommendations: keep at room temperature, away from moisture and heat.
Patient information leaflets included with every preparation detailing usage, contraindications, and warnings.
Manufactured under Good Manufacturing Practices adhering to regulatory agency approvals.
Available through prescription supplied by licensed pharmacies and specialized specialty pharmacies.
Various generic manufacturers of sildenafil provide bioequivalent formulations for economic accessibility.
Several formulations have received FDA approval for pediatric use in pulmonary hypertension under specialist supervision.