Sildenafil Citrate is indicated for the treatment of erectile dysfunction in men, a condition characterized by the inability to achieve or maintain an erection sufficient for satisfactory sexual activity. Sexual stimulation is necessary for the drug to be effective. It is also indicated for the treatment of pulmonary arterial hypertension.

Sildenafil is a selective and reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). During sexual stimulation, nitric oxide is released locally, and inhibition of PDE5 by Sildenafil increases cGMP levels in the corpus cavernosum. This leads to smooth muscle relaxation and increased blood flow into penile tissues, resulting in an erection. Sildenafil is ineffective in the absence of sexual stimulation.

Mechanism of Action: Penile erection is mediated by the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP), which causes smooth muscle relaxation and enhanced blood flow into the corpus cavernosum. Sildenafil does not directly relax the corpus cavernosum but enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), the enzyme responsible for cGMP breakdown. This results in increased cGMP levels, smooth muscle relaxation, and improved blood inflow during sexual stimulation. The drug has no effect without sexual arousal.

Pharmacokinetics and Metabolism (Rewritten): Sildenafil is rapidly absorbed after oral administration, with an average absolute bioavailability of about 41% (range 25–63%). It is primarily metabolized in the liver via cytochrome P450 3A4 and converted to an active metabolite with similar properties. The terminal half-life of both Sildenafil and its metabolite is approximately 4 hours.

Absorption and Distribution: Sildenafil is rapidly absorbed, reaching peak plasma concentrations within 30–120 minutes (median 60 minutes) when taken on an empty stomach. High-fat meals reduce the rate of absorption.

Metabolism and Excretion: Sildenafil is metabolized by hepatic microsomal enzymes. After oral or intravenous administration, it is excreted mainly in feces (about 80%) and to a lesser extent in urine (about 13%), primarily as metabolites.

Pharmacokinetics in Special Populations (Geriatrics): In healthy elderly individuals (65 years or older), Sildenafil clearance is reduced, resulting in approximately 84% higher peak plasma exposure (AUC) compared to younger adults.

Erectile dysfunction: For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, Sildenafil may be taken anywhere from 4 hours to 0.5 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended dosing frequency is once per day.

The following factors are associated with increased plasma levels of Sildenafil: age >65, hepatic impairment, severe renal impairment, and concomitant use of potent cytochrome P450 3A4 inhibitors (ketoconazole, itraconazole, erythromycin, saquinavir). Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered in these patients. Sildenafil was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors or nitrates in any form is therefore contraindicated. When Sildenafil is co-administered with an alpha-blocker, patients should be stable on alphablocker therapy prior to initiating Sildenafil treatment and Sildenafil should be initiated at the lowest dose.

Pulmonary arterial hypertension: The recommended dose of sildenafil citrate is 20 mg three times a day and should be taken approximately 4-6 hours apart, with or without food.

Sildenafil is mainly metabolized by cytochrome P450 enzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). Therefore, drugs that inhibit or induce these enzymes can alter Sildenafil clearance. Cimetidine (a non-specific CYP inhibitor) increased Sildenafil plasma concentration by about 56% when co-administered. Erythromycin (a strong CYP3A4 inhibitor) increased Sildenafil exposure (AUC) by 182%. HIV protease inhibitors such as saquinavir increased Sildenafil Cmax by 140% and AUC by 210%, while ritonavir caused a marked increase of about 300% in Cmax and 1000% in AUC. Sildenafil did not affect the pharmacokinetics of these drugs. Strong CYP3A4 inhibitors like ketoconazole and itraconazole are expected to further increase Sildenafil levels. Conversely, CYP3A4 inducers such as bosentan reduced Sildenafil AUC by 63% and Cmax by 55%. Strong inducers like rifampin may further decrease its plasma levels. Antacids (magnesium/aluminum hydroxide) do not affect Sildenafil absorption. No significant interaction was observed with CYP2C9 inhibitors, CYP2D6 inhibitors, thiazide diuretics, ACE inhibitors, or calcium channel blockers. Loop and potassium-sparing diuretics increased levels of the active metabolite by 62%, and non-selective beta-blockers increased it by 102%, though these changes are not clinically significant.

Sildenafil is contraindicated in patients with hypersensitivity to any component of the drug. It is also contraindicated in patients using organic nitrates regularly or intermittently, as it may potentiate their hypotensive effects

Body as a whole: facial edema, photosensitivity, shock, weakness, pain, chills, abdominal pain, chest pain, allergic reactions, accidental injury.

Cardiovascular: angina, AV block, tachycardia, palpitations, hypotension, postural hypotension, myocardial ischemia, arrhythmias, cardiac arrest, heart failure.

Digestive: vomiting, gastritis, dry mouth, diarrhea, dysphagia, abnormal liver tests, rectal bleeding.

Hematologic: anemia, leukopenia.

Metabolic: edema, hyperglycemia, hyperuricemia, hypoglycemia, thirst.

Musculoskeletal: myalgia, arthritis, tendon rupture, joint pain.

Nervous system: dizziness, tremor, paresthesia, insomnia, depression, somnolence, vertigo, seizures.

Respiratory: dyspnea, bronchitis, pharyngitis, cough, asthma.

Skin: rash, pruritus, urticaria, dermatitis, sweating.

Special senses: vision changes, hearing loss, tinnitus, eye pain, photophobia, cataract.

Urogenital: urinary frequency, abnormal ejaculation, priapism, hematuria.

Serious cardiovascular and cerebrovascular events including myocardial infarction, stroke, arrhythmia, hemorrhages, and sudden death have been reported post-marketing, mostly in patients with pre-existing risk factors and often associated with sexual activity. A causal relationship cannot be confirmed.

Neurological events such as seizures and transient global amnesia, and ocular events including vision loss and retinal disorders have also been reported.

Pregnancy Category B. There are no adequate and well-controlled studies of Sildenafil use in pregnant women. Sildenafil is not indicated for use in women. Animal studies have shown no evidence of teratogenicity or embryotoxicity.

General: Evaluation of erectile dysfunction should include identification of underlying causes and appropriate management after complete medical assessment.

Before prescribing Sildenafil, caution is required when Phosphodiesterase type 5 (PDE5) inhibitors are used with alpha-blockers, as both are vasodilators that lower blood pressure. Their combined use may produce an additive hypotensive effect, which can lead to symptomatic hypotension such as dizziness, lightheadedness, or fainting.

• Patients should be stable on alpha-blocker therapy before starting a PDE5 inhibitor. Those with unstable hemodynamics on alpha-blockers alone are at higher risk of hypotension. In stable patients, Sildenafil should be initiated at the lowest dose. If patients are already on a PDE5 inhibitor, alpha-blockers should also be started at the lowest dose with gradual titration, as dose escalation may further reduce blood pressure.
• Other factors such as low blood volume or concurrent antihypertensive therapy may further increase the risk of hypotension.
• Sildenafil may enhance the blood pressure-lowering effects of other antihypertensive drugs. In clinical studies, concomitant use with amlodipine resulted in additional reductions of approximately 8 mmHg systolic and 7 mmHg diastolic blood pressure.
• Safety in patients with bleeding disorders or active peptic ulcer disease has not been established.
• Use with caution in patients with penile anatomical abnormalities (e.g., Peyronie’s disease, cavernosal fibrosis, angulation) or conditions predisposing to priapism such as sickle cell anemia, multiple myeloma, or leukemia.
• Combination therapy with other erectile dysfunction treatments has not been studied and is therefore not recommended.

Sexual activity may pose a cardiac risk in patients with pre-existing cardiovascular disease; therefore, Sildenafil should generally be avoided in men for whom sexual activity is medically inadvisable.

Sildenafil causes mild systemic vasodilation, leading to temporary reductions in blood pressure. Although usually clinically insignificant, caution is advised in patients with cardiovascular disease, especially when combined with sexual activity.

Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) or severe autonomic blood pressure impairment may be particularly sensitive to vasodilators.

There is limited clinical data in certain high-risk groups; therefore, Sildenafil should be used with caution in patients who:

• had myocardial infarction, stroke, or life-threatening arrhythmia within the past 6 months
• have hypotension (BP <90/50) or severe hypertension (BP >170/110)
• have unstable angina or cardiac failure due to coronary artery disease
• have retinitis pigmentosa
• have sickle cell disease or related anemias

Rare cases of prolonged erection (>4 hours) and priapism (>6 hours) have been reported. Immediate medical attention is required; untreated priapism may result in permanent penile damage.

Caution is required when Sildenafil is used with ritonavir due to increased drug exposure. Higher doses are associated with increased adverse effects such as visual disturbances, hypotension, syncope, and prolonged erection. Dose reduction is recommended when co-administered with ritonavir.

In healthy volunteers, single doses up to 800 mg produced adverse effects similar to lower doses but with increased frequency and severity. In overdose cases, supportive treatment should be given as needed. Hemodialysis is not effective because Sildenafil is highly protein-bound and not significantly excreted in urine.

Drugs used for the treatment of erectile dysfunction

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