Sildenafil

Sildenafil is a Phosphodiesterase-5 Enzyme Inhibitor belonging to Vasodilator.

Sildenafil is a phosphodiesterase inhibitor used to treat erectile dysfunction and pulmonary artery hypertension.

Sildenafil is rapidly absorbed from the GI tract. The Bioavailability is approximately 40%. Time to peak plasma concentration achieved within 30-120 min. Sildenafil is widely distributed in body tissues. The Plasma protein binding is approximately 96%. Sildenafil is hepatically metabolized by CYP3A4 (major route) and CYP2C9 isoenzymes. Sildenafil is excreted mainly via feces (as metabolites); urine (lesser extent). The terminal half-life is approximately 4 hours.

Sildenafil shows common side effects like Dyspepsia, headache, visual disturbance, and flushing.

Sildenafil is available in the form of an Oral Tablet, Oral Capsule, and Injectable solution.

Sildenafil is available in India, the US, Singapore, the UK, Malaysia, France, Spain, Canada, Russia, Japan, China, Italy, and Australia.

Sildenafil belongs to the Vasodilator and acts as a Phosphodiesterase-5 Enzyme Inhibitor.

Mechanism of action for Erectile dysfunction: Does not directly cause penile erections but affects the response to sexual stimulation. The physiologic mechanism of the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE-5), which is responsible for the degradation of cGMP in the corpus cavernosum; when sexual stimulation causes local release of NO, inhibition of PDE-5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum; at recommended doses, it has no effect in the absence of sexual stimulation.

Mechanism of action for Pulmonary arterial hypertension (PAH): Inhibits phosphodiesterase type 5 (PDE-5) in the smooth muscle of pulmonary vasculature where PDE-5 is responsible for the degradation of cyclic guanosine monophosphate (cGMP). Increased cGMP concentration results in pulmonary vasculature relaxation; vasodilation in the pulmonary bed and systemic circulation (to a lesser degree) may occur.

The Onset and duration of action of Sildenafil for Erectile dysfunction are ~60 minutes.

The Duration of action of Sildenafil for Erectile dysfunction is 2 to 4 hours and for Pulmonary arterial hypertension is <8 hours.

The Tmax of Sildenafil is approximately 30-120 minutes.

Sildenafil is available in Oral Tablets, Oral capsules, and Injectable solutions.

Sildenafil tablet is taken orally. Sildenafil injectable solution is given via intravenous route usually 3 times a day.

Sildenafil is used to treat erectile dysfunction and pulmonary artery hypertension.

Sildenafil may cause side effects such as flushing (redness and feeling of warmth), headache, upset stomach, dizziness, blurred vision, etc. Usually, these side effects get resolved on their own.

Sildenafil is a Phosphodiesterase-5 Enzyme Inhibitor belonging to Vasodilator.

Sildenafil inhibits phosphodiesterase type-5 (PDE-5) which is responsible for cyclic guanosine monophosphate (cGMP) degradation in the corpus cavernosum—inhibition of PDE-5 increases cGMP, resulting in the relaxation of pulmonary vascular smooth muscle cells.

Sildenafil is approved for use in the following clinical indications

• Erectile dysfunction
• Pulmonary arterial hypertension

Although not approved, there have been certain off-label indications. These include

• High-altitude pulmonary edema
• Raynaud phenomenon

• Erectile dysfunction

Oral: 50 mg once daily as needed 1 hour before sexual activity; may be taken up to 4 hours before sexual activity. Reduce to 25 mg once daily if side effects occur. May increase to a maximum dose of 100 mg once daily if there is an incomplete response.

• Pulmonary arterial hypertension

Oral: 20 mg 3 times daily; some experts do not recommend titration to higher doses. However, in patients who fail to demonstrate or maintain an adequate clinical response, other experts consider slowly increasing the dose in 20 mg increments to a maximum dose of 80 mg 3 times daily.

IV: 10 mg 3 times daily.

• High-altitude pulmonary edema (off-label)

Oral: 50 mg every 8 hours starting the day of ascent; continue for 3 to 5 days after reaching maximal altitude; can extend for up to 7 days in individuals who ascend faster than recommended.

• Raynaud phenomenon (off-label)

Oral: Initial: 20 mg once or twice daily; based on response and tolerability, may increase to 20 mg 3 times daily as needed; if lower doses are ineffective, may increase further to 40 mg 3 times daily if tolerated; others have reported using 50 mg 2 to 3 times daily as tolerated.

Sildenafil is available in various strengths as 10 mg/mL; 10 mg/12.5 mL; 20 mg; 25 mg; 50 mg; 100 mg.

Sildenafil is available in the form of Oral Tablets, Oral Capsules, and Injectable solutions.

• Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute:

No dosage adjustment is necessary.

CrCl <30 mL/minute:

Pulmonary arterial hypertension: No dosage adjustment necessary; use with caution.

Erectile dysfunction: Initial: 25 mg once daily as needed 1 hour before sexual activity; may be taken up to 4 hours before sexual activity. May cautiously increase the dose based on tolerability and response. Maximum dose: 100 mg once daily.

• Dosage Adjustment in Hepatic impairment Patient

Mild to moderate impairment (Child-Pugh classes A and B):

Sildenafil: Starting dose of 25 mg should be considered.

Severe impairment (Child-Pugh class C):

Sildenafil: Starting dose of 25 mg should be considered.

Avoid high-fat meals, Sildenafil may take a longer time to start its action with a high-fat meals.

Avoid Grapefruit juice, it may increase serum levels/toxicity of orally administered Sildenafil.

Sildenafil is contraindicated in patients with

• Nitrates

Consistent with its known effects on the nitric oxide/cGMP pathway. Sildenafil was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated. After patients have taken Sildenafil, it is unknown when nitrates, if necessary, can be safely administered. Although plasma levels of sildenafil at 24 hours post-dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point.

• Hypersensitivity Reactions

Sildenafil is contraindicated in patients with a known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity reactions have been reported, including rash and urticaria.

• Color discrimination

May cause dose-related impairment of color discrimination. Use caution in patients with retinitis pigmentosa; a minority have genetic disorders of retinal phosphodiesterases.

• Hypotension

Caution patients that concurrent use of alcohol, particularly in larger quantities, may increase the risk for orthostatic hypotension, dizziness, tachycardia, and headache. Recommend limiting any alcohol use to smaller quantities and refraining from such combined use as possible.

• Anatomical penis deformation

Use with caution in patients with anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie disease).

• Bleeding disorders

Use with caution in patients with bleeding disorders; safety has not been established. In vitro studies have suggested a decreased effect on platelet aggregation.

• Cardiovascular disease

Use with caution in patients with hypotension (<90/50 mm Hg); uncontrolled hypertension (>170/110 mm Hg); life-threatening arrhythmias, stroke, or MI within the last 6 months; cardiac failure or coronary artery disease causing unstable angina; safety and efficacy have not been studied in these patients. Use caution in patients with left ventricular outflow obstruction (eg, aortic stenosis). Patients should be hemodynamically stable prior to initiating therapy at the lowest possible dose. There is a degree of cardiac risk associated with sexual activity; therefore, healthcare providers should consider the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction.

• Conditions predisposing to priapism

Use with caution in patients who have conditions that may predispose them to priapism (sickle cell anemia, multiple myeloma, leukemia). All patients should be instructed to seek immediate medical attention if the erection persists for>4 hours.

Avoid consumption of alcohol while taking Sildenafil as it lowers blood pressure. Side effects such as dizziness, fainting, flushing, persistent headaches, changes in heart rate, etc. may occur.

Sildenafil is present in breast milk. The excretion of sildenafil and desmethyl sildenafil in breast milk.

Sildenafil was shown to cross the placenta in an ex vivo placenta perfusion study. Because sildenafil causes vasodilation in the uterus, it is currently under study for various obstetric uses. However, due to adverse events in the newborn observed using preliminary data from a study evaluating sildenafil for fetal growth restriction, the use of sildenafil in pregnant women outside of a controlled clinical study is not currently recommended.

Avoid high-fat meals, Sildenafil may take a longer time to start its action with high-fat meals.

Avoid Grapefruit juice, it may increase serum levels/toxicity of orally administered Sildenafil.

• Headache, flushing, dyspepsia, visual disturbances (e.g. blurred vision, photophobia, chromatopsia, cyanopsia, eye irritation, eye pain, and redness); dizziness, insomnia, anxiety, vertigo, epistaxis, nasal congestion, pyrexia, GI disturbances (e.g. diarrhea, vomiting), priapism; skin rashes, erythema, alopecia, limb/back pain, myalgia, facial edema, fluid retention, paraesthesia, UTI, dyspnoea, cough, rhinitis, sinusitis, bronchitis, cellulitis, a sudden decrease or loss of hearing, anemia, leucopenia, gynaecomastia, urinary frequency or incontinence, haematuria, seizures, cerebrovascular hemorrhage, transient ischaemic attack, palpitations, syncope, HTN, hypotension. Rarely, hypersensitivity reactions, NAION causing permanent loss of vision, and retinal hemorrhage.

• Nitrates

Administration of Sildenafil with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, Sildenafil was shown to potentiate the hypotensive effects of nitrates.

• Alpha-blockers

Use caution when co-administering alpha-blockers with Sildenafil because of potential additive blood pressure-lowering effects. When Sildenafil is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating Sildenafil treatment and Sildenafil should be initiated at the lowest dose.

• Amlodipine

When Sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction in supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

• Ritonavir And Other CYP3A4 Inhibitors

Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (an 11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose of 25 mg of Sildenafil in a 48-hour period.

Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in 160% and 182% increases in sildenafil Cmax and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil Cmax and AUC, respectively. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of Sildenafil should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, and itraconazole).

The common side effects of Sildenafil include the following

• Common

Dyspepsia, headache, visual disturbance, and flushing.

• Rare

Epistaxis, insomnia, nasal congestion, and rhinitis.

• Pregnancy

Pregnancy Category B

SILDENAFIL is not indicated for use in women. There are no adequate and well-controlled studies of sildenafil in pregnant women. Based on animal data, Sildenafil is not predicted to increase the risk of adverse developmental outcomes in humans.

• Nursing Mothers

Sildenafil is present in breast milk. The excretion of sildenafil and desmethyl sildenafil in breast milk.

• Pediatric Use

Sildenafil is not indicated for use in pediatric patients. As per FDA, safety and effectiveness have not been established in pediatric patients.

• Geriatric Use

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18-45 years). Due to age differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Of the total number of subjects in clinical studies of Sildenafil, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older (> 65 years of age) and younger (< 65 years of age) subjects. However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure.

In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were like those seen at lower doses, but incidence rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

Pharmacodynamic

Effects of Sildenafil on Erectile Response

In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan®), after Sildenafil administration compared with placebo. Most studies assessed the efficacy of Sildenafil approximately 60 minutes post dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.

Effects of Sildenafil on Blood Pressure

Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1-2 hours after dosing and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of Sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates.

Pharmacokinetics

• Absorption

Sildenafil is rapidly absorbed from the GI tract. The Bioavailability is approximately 40%. Time to peak plasma concentration achieved within 30-120 min.

• Distribution

Sildenafil widely distributed into body tissues. The Plasma protein binding is approximately 96%.

• Metabolism

Sildenafil hepatically metabolized by CYP3A4 (major route) and CYP2C9 isoenzymes.

• Excretion

Sildenafil is excreted mainly via faeces (as metabolites); urine (lesser extent). The terminal half-life is approximately 4 hours.

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