Sildenafil

Usage

• Sildenafil is prescribed for the treatment of erectile dysfunction (ED) in men, and pulmonary arterial hypertension (PAH) in both men and women. It is also used for the treatment of Raynaud’s Phenomenon.
• Pharmacological Classification: Phosphodiesterase-5 (PDE-5) inhibitor.
• Mechanism of Action: Sildenafil inhibits the PDE-5 enzyme, which is responsible for degrading cyclic guanosine monophosphate (cGMP). In ED, this leads to increased cGMP levels in the corpus cavernosum of the penis, promoting smooth muscle relaxation and increased blood flow, facilitating erection. In PAH, the same mechanism results in vasodilation in the pulmonary vasculature, lowering pulmonary arterial pressure and improving exercise capacity.

Alternate Names

• International/Regional Variations: Sildenafil citrate (chemical name).
• Brand Names: Viagra (for ED), Revatio (for PAH).

How It Works

• Pharmacodynamics: Sildenafil’s primary effect is the inhibition of PDE-5. This leads to increased cGMP levels, causing vasodilation in specific tissues (penis for ED, pulmonary vasculature for PAH).
• Pharmacokinetics: Sildenafil is rapidly absorbed after oral administration, reaching peak plasma concentrations within 30 to 120 minutes. Food may delay absorption. It is metabolized primarily by the liver (CYP3A4 enzyme) and eliminated mainly in the feces and to a lesser extent in the urine. Its half-life is approximately 4 hours.
• Mode of Action: Sildenafil selectively binds to and inhibits the PDE-5 enzyme. This inhibition prevents the breakdown of cGMP, leading to its accumulation and subsequent smooth muscle relaxation and vasodilation.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Sildenafil primarily acts through enzyme inhibition (PDE-5).
• Elimination Pathways: Primarily hepatic metabolism via CYP3A4, with subsequent excretion of metabolites mainly in the feces and to a lesser extent in urine.

Dosage

Standard Dosage

Adults:

• ED: 50mg orally approximately 1 hour before sexual activity, adjustable to 25mg or 100mg as needed, not exceeding one dose per day. The dose for elderly patients (≥65 years) is typically 25mg.
• PAH: 20mg orally three times a day, taken approximately 4 to 6 hours apart. Doses up to 80 mg three times a day have been used.

Children:

• PAH: 10mg orally three times a day for children weighing ≤20 kg or 20mg orally three times a day for children weighing >20 kg. For children under 1 year old, sildenafil is not recommended for PAH. Sildenafil is not indicated for children with ED.
• Pediatric Safety Considerations: Safety and efficacy in children younger than 1 year for PAH have not been established. Sildenafil should not be used in children for ED. Higher doses than recommended should not be used in children. Monitor for adverse effects.

Special Cases:

• Elderly Patients: Start with a lower dose (25mg for ED) due to potential age-related decrease in clearance.
• Patients with Renal Impairment: Dose adjustment may be necessary in severe renal impairment (creatinine clearance <30 mL/min). A starting dose of 25mg is recommended for ED, titratable as needed.
• Patients with Hepatic Dysfunction: Start with a lower dose (25mg for ED) due to reduced clearance.
• Patients with Comorbid Conditions: Caution is advised in patients with cardiovascular disease, especially those taking nitrates. Adjustments may be necessary based on specific comorbidities.

Clinical Use Cases

Sildenafil is not typically indicated for use in clinical settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest. Its primary indications remain ED and PAH.

Dosage Adjustments

Dosage adjustments may be required based on patient-specific factors such as renal or hepatic dysfunction, concomitant medications (especially CYP3A4 inhibitors), and individual response to therapy.

Side Effects

Common Side Effects:

Headache, flushing, dyspepsia, nasal congestion, dizziness, visual disturbances (blurred vision, changes in color perception), back pain, myalgia.

Rare but Serious Side Effects:

Priapism (prolonged, painful erection), sudden vision or hearing loss, severe hypotension, myocardial infarction, stroke, allergic reactions.

Long-Term Effects:

Potential long-term effects are not well-established but may include vision changes (non-arteritic anterior ischemic optic neuropathy), hearing impairment, and cardiovascular events with chronic use, especially in patients with pre-existing conditions.

Adverse Drug Reactions (ADR):

Clinically significant ADRs include priapism, severe hypotension, sudden vision or hearing loss, and allergic reactions. These require immediate medical attention.

Contraindications

• Hypersensitivity to sildenafil.
• Concomitant use of nitrates or nitric oxide donors.
• Severe hypotension.
• Recent myocardial infarction or stroke.
• Hereditary retinal disorders like retinitis pigmentosa.
• Severe hepatic impairment.

Drug Interactions

• Nitrates: Concomitant use is contraindicated due to the risk of severe hypotension.
• CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir): Increased sildenafil plasma levels; dose reduction may be required.
• CYP3A4 Inducers (e.g., rifampin): Decreased sildenafil plasma levels; dose adjustment may be necessary.
• Alpha-Blockers: May potentiate hypotensive effects; careful monitoring is essential.
• Alcohol: May increase the risk of hypotension and other side effects.
• Grapefruit Juice: May inhibit CYP3A4 and increase sildenafil plasma levels.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Category B (animal studies have not shown fetal harm, but adequate human studies are lacking). In clinical practice, sildenafil is sometimes used in pregnant women with severe PAH when the benefits outweigh the risks.
• Fetal Risks: Although animal studies have not shown fetal harm, the effects on human fetuses are not fully understood.
• Breastfeeding: Sildenafil passes into breast milk in small amounts. While generally considered safe, monitor infants for potential side effects such as drowsiness, poor feeding, and pallor.

Drug Profile Summary

• Mechanism of Action: PDE-5 inhibitor, increases cGMP, leading to vasodilation.
• Side Effects: Headache, flushing, dyspepsia, visual disturbances, dizziness, nasal congestion. Rarely: priapism, sudden vision or hearing loss.
• Contraindications: Concomitant nitrate use, severe hypotension, recent MI or stroke, retinal disorders.
• Drug Interactions: Nitrates, CYP3A4 inhibitors/inducers, alpha-blockers, alcohol, grapefruit juice.
• Pregnancy & Breastfeeding: Generally safe but use with caution, especially during pregnancy.
• Dosage: ED: 50mg (adjustable); PAH: 20mg TID. Adjustments needed for renal/hepatic impairment and elderly.
• Monitoring Parameters: Blood pressure, heart rate, vision changes, hearing changes.

Popular Combinations

Sildenafil is sometimes used in combination with other PAH medications, but data on specific combinations and their benefits are limited and require careful evaluation based on individual patient needs and potential drug interactions.

Precautions

• Assess cardiovascular status, including blood pressure, before initiating therapy.
• Screen for contraindications and potential drug interactions.
• Caution in patients with hepatic or renal impairment, bleeding disorders, and anatomical penile deformities.
• Advise patients to avoid alcohol or consume it in moderation.
• Monitor for visual or auditory changes.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Sildenafil?

A: For ED, the typical starting dose is 50mg taken approximately one hour before sexual activity. For PAH, the dose is 20mg three times daily. Adjustments may be needed for specific populations.

Q2: What are the common side effects of sildenafil?

A: Common side effects include headache, flushing, dyspepsia, nasal congestion, dizziness, and visual changes.

Q3: What are the contraindications for sildenafil?

A: Contraindications include concomitant nitrate use, severe hypotension, recent MI or stroke, and certain retinal disorders.

Q4: How does sildenafil interact with other medications?

A: Sildenafil interacts significantly with nitrates, CYP3A4 inhibitors/inducers, and alpha-blockers. It may also interact with alcohol and grapefruit juice.

Q5: Can sildenafil be used during pregnancy or breastfeeding?

A: Sildenafil should be used with caution during pregnancy and breastfeeding. Consult a specialist for guidance if its use is necessary.

Q6: How long does sildenafil last?

A: The effects of sildenafil typically last for about 4 hours.

Q7: What should patients do if they experience priapism while taking sildenafil?

A: Patients experiencing priapism should seek immediate medical attention as it can lead to permanent penile damage.

Q8: Does sildenafil cure ED?

A: No, sildenafil does not cure ED. It is a treatment that facilitates erections when sexual stimulation is present.

Q9: Can women take sildenafil?

A: Yes, women can take sildenafil, primarily for the treatment of PAH. It is not indicated for ED in women.