Sildenafil

Sildenafil is a reversible inhibitor of phosphodiesterase type 5, the major enzyme responsible for cGMP hydrolysis in penile erectile tissue.

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Drug Dosages

Keith Kleinman MD , in Harriet Lane Handbook , 2021

Sildenafil

Revatio, Viagra, and generics

Phosphodiesterase type-5 (PDE5) inhibitor

Tabs:

Revatio and generics: 20 mg

Viagra and generics: 25, 50, 100 mg

Oral suspension: 2.5 mg/mL

Revatio and generics: 10 mg/mL (112 mL); may contain sodium benzoate

Injection:

Revatio and generics: 0.8 mg/mL (12.5mL)

Pulmonary hypertension:

Neonate (limited data from case reports and small clinical trials):

PO: Several dosages have been reported and have ranged from 0.5 to 3 mg/kg/dose Q 6–12 hr PO. A single dose of ∼0.3 mg/kg PO has been used in select patients to facilitate weaning from inhaled nitric oxide.

IV (case report from 4 neonates >34 wk gestation and Start with 0.4 mg/kg/dose IV over 3 hr followed by a continuous infusion of 1.6 mg/kg/24 hr (0.067 mg/kg/hr) for up to 7 days.

Infant and child (limited data):

PO: Start at 0.25 mg/kg/dose Q 6 hr or 0.5 mg/kg/dose Q 8 hr; if needed, titrate dose up to 1–2 mg/kg/dose Q 6–8 hr. A single dose of ∼0.4mg/kg PO has been used in select patients to facilitate weaning from inhaled nitric oxide.

Child 1–17 yr (higher doses and long-term use are associated with increased risk for mortality; see remarks).

≥8–20 kg: 10 mg TID

>20–45 kg: 20 mg TID

>45 kg: 40 mg TID

Pulmonary arterial hypertension:

PO: 20 mg TID (take at least 4–6 hr apart)

IV: 10 mg TID

Sildenafil Citrate

4.2 Titrimetric Analysis

4.2.1 Non-aqueous Titration

Sildenafil citrate (250 mg) is dissolved in 50 mL of glacial acetic acid, titrated with 0.1 M perchloric acid, with the end point being detected potentiometrically. Each milliliter of 0.1 M perchloric acid VS is equivalent to 66.67 mg of Sildenafil citrate, calculated as C22H30N6O4S • C6H8O7. This method is suitable to assay Sildenafil citrate in its bulk drug form, and in formulated products [3] .

4.2.2 Aqueous Titration

In this method, 160 mg of Sildenafil citrate was accurately weighed and dissolved in 50 mL of a 20:80 mixture of methanol / water. Titration against 0.1 N sodium hydroxide was carried out using a Mettler DL-67 potentiometric titrator. Each milliliter of 0.1 N sodium hydroxide VS is equivalent to 22.22 mg of Sildenafil citrate, calculated as C22H30N6O4S • C6H8O7 [3] .

Specific product requests

Paul Rutter PhD, FRPharmS, FFRPS, SFHEA , in Community Pharmacy , 2021

Sildenafil (Viagra connect)

Men over the age of 18 should take one tablet with or after food approximately 1 hour before sexual intercourse. If a patient needs to take it a number of times on different occasions before achieving a satisfactory penile erection for sexual activity they should be advised to see a doctor. The most common side effect seen is headache (very common), with dizziness, flushing, nausea, dyspepsia, nasal congestion and visual disturbances reported as common. Sildenafil levels can be affected by concomitant treatment with CYP3A4 inhibitors and may require lower dosing (e.g., 25 mg). Likewise patients may require lower doses of sildenafil if taking alpha-blocker medicines (e.g., alfuzosin, doxazosin or tamsulosin) but ritonavir and sildenafil should not be given together should be avoided.

Sildenafil Citrate

John G. Augoustides , Lee A. Fleisher , in Essence of Anesthesia Practice (Third Edition) , 2011

Overview/Pharmacology

Sildenafil citrate was discovered by accident during testing as a treatment for heart disease.

Total protein binding 96%, also distributed in tissues

Metabolized in liver via the cytochrome P450 isoenzymes, 3A4 (major route) and 2C9 (minor route)

Active N-desmethyl metabolite

Peak plasma concentration 60 min

Excreted via feces (80%), kidney (13%), and semen (

Metabolism may be delayed after a high-fat meal and in pts with liver disease

Contraindicated in pts with hypersensitivity to sildenafil products and pts taking nitroglycerin or other organic nitrates

Precautions: Anatomic deformities of the penis, conditions predisposing pts to priapism, bleeding disorders or active peptic ulceration, retinitis pigmentosa or other retinal abn, coronary ischemia or CHF, multidrug antihypertensive regimens

Excretion in breast milk is unknown

Sexual Dysfunction in Men and Women

Shlomo Melmed MB ChB, MACP , in Williams Textbook of Endocrinology , 2020

Approved But Not Recommended Medication for the Former DSM-IV Hypoactive Sexual Desire Disorder

Flibanserin—a 5HT1A agonist and a 5HT2A antagonist studied originally for potential benefit to depression—was trialed by different pharmaceutical companies and received limited FDA approval for the treatment of HSDD. This approval is despite benefit being similar to placebo and serious risk of harm. 650 There are strict contraindications to alcohol and to medications that inhibit CYP3A4, including oral contraceptives and fluconazole. Safety concerns include hypotension, syncope, somnolence, fatigue, and potential carcinogenicity. Overall risks of sedation or hypotension-related events were 28.6% with flibanserin versus 9.4% with placebo. Two recent meta-analyses have been based on both published and unpublished RCTs. 651 Meta-analysis showed that flibanserin led to a mean increase of 0.49 satisfying sexual events per month. 652 There was an increase of 0.3 (range, 1.2–6.0) on the desire subscale of the validated questionnaire, which was considered not to differ from placebo. Recruited women reported two to three rewarding sexual experiences each month at baseline (i.e., the participants did not have SIAD). Due both to safety concerns and to the short duration of studies and questionable accuracy of 4-week recall along with marginal efficacy, approval had been denied and additional safety studies recommended. Surprisingly, despite lack of additional efficacy data, but with data ruling out driving impairment and assessing alcohol’s enhancement of side effects in 23 men and 2 women, on June 4, 2015, an FDA advisory committee voted 18 to 6 to accept approval of flibanserin, although with reservations. Fifteen members endorsing its approval declared their reluctance to do so. A recent review of scientific knowledge on flibanserin to date seriously questioned its use, noting the tenuous risk-benefit profile along with prohibitive prescribing restrictions and doubtful presence of sexual disorder in trialed women. 653

Sildenafil

Agent-Agent Interactions

Agent Name Mode of Interaction
Cimetidine Cimetidine increases the plasma levels of sildenafil .
Erythromycin Erythromycin increases the plasma levels of sildenafil.
Saquinavir Saquinavir increases the plasma levels of sildenafil.
Ritonavir Ritonavir increases the plasma levels of sildenafil.
Alpha-blockers (Prazosin, Terazosin, Doxazosin) Significant hypotension can result from co-administration of sildenafil and alpha adrenoceptor antagonists.
Organic nitrates When given in combination, sildenafil and organic nitrates can cause a dramatic drop in blood pressure.
Sodium nitroprusside When given in combination, sildenfil and sodium nitroprusside can cause a dramatic drop in blood pressure.

A worldwide yearly survey of new data in adverse drug reactions

Hematologic

Sildenafil has been associated with thrombocytopenia [ 29 A ].

A 53-year-old woman with multiple pathology was admitted to the intensive care unit in respiratory distress. Sildenafil was added empirically to her extensive drug regimen, because of pulmonary hypertension. Her platelet count fell after 1 week. Heparin was first suspected and withdrawn, without effect. Sildenafil was then withdrawn and the platelet count started to rise. Two rechallenges with sildenafil because of worsening respiratory function led each time to a new pronounced fall in platelet count. Complete withdrawal of sildenafil resulted in sustained recovery.

The mechanism of this effect in this patient is not known.

Life-style drugs, statins, and COX-2 drugs

11.5 Dosage form of sildenafil citrate

Sildenafil is only available in a tablet solid dosage form, with three different strengths – 25 mg, 50 mg, and 100 mg ( Figure 11.11 ). The tablets are film coated a blue color and are diamond shaped.

Figure 11.11 . The tablet dosage form of Viagra

By 2012, Pfizer’s patent for sildenafil will expire and there will be generic versions available on the market. One pharmaceutical company has already developed an oral spray form of sildenafil citrate to market immediately after the Pfizer’s patent expiration. The US FDA has already approved sildenafil citrate to treat other conditions, such as pulmonary hypertention, and Pfizer started marketing a 20 mg tablet with the brand name Revatio. Recently an injectable form of Revatio (10 mg) was made available on the market.

Once swallowed, Viagra tablets undergo rapid absorption with a peak plasma concentration within 30–120 minutes (median 60 minutes). Figure 11.12 shows the pharmacokinetic profile after the administration of a single oral dose of 100 mg to a healthy male volunteer.

Figure 11.12 . Mean sildenafil plasma concentrations in healthy male volunteers 3

Source: Reproduced with permission from Pfixer’s Viagra website 3

What is the Evidence for Drug Therapy in the Prevention and Management of Bronchopulmonary Dysplasia?

Henry L. Halliday MD FRCPE FRCP FRCPCH , Conor P. O’Neill MB BCh BAO MRCPCH , in The Newborn Lung , 2008

S ILDENAFIL

Sildenafil is a cGMP-specific phosphodiesterase inhibitor. In rat studies sildenafil improves alveolar growth and reduces pulmonary hypertension in hyperoxia-induced lung injury. Rat pups were randomly exposed from birth to normoxia, hyperoxia (95% FiO 2; BPD model), and hyperoxia plus sildenafil (100 mg/kg/day subcutaneously). Rat pups exposed to hyperoxia showed fewer and enlarged air spaces as well as decreased capillary density, mimicking pathologic features seen in human BPD. Sildenafil preserved alveolar growth and lung angiogenesis, and decreased pulmonary vascular resistance, right ventricular hypertrophy and medial wall thickness ( 197 ).

Practice Problems

Thorsteinn Loftsson PhD , in Essential Pharmacokinetics , 2015

Sildenafil ( Mw 475 daltons [Da]) is used to treat erectile dysfunction. As a free base, sildenafil is a sparingly soluble (0.01 mg/ml water), lipophilic (log P=2.5) drug that permeates the biologic membranes rather easily (H-bond acceptors: 10; H-bond donors: 1). The aqueous solubility of sildenafil citrate is much greater than that of the free base or 4.1 mg/ml, and thus oral dosage forms usually contain sildenafil citrate. The following information was obtained from a pharmacokinetic study of sildenafil citrate, its oral bioavailability, food effects, and dose proportionality in 12–34 healthy male volunteers, and the data shown are the mean values [6] .

The following profiles were obtained after administration of a single oral dose of sildenafil (25–200 mg) as its citrate salt. Does the drug follow linear pharmacokinetics?

The figure below shows the CP–time profiles of sildenafil after administration of 50 mg of the drug in the form of slow IV infusion and oral tablet. Determine the absolute bioavailability of the tablets. Determine the ClT from the IV data. Studies with radiolabeled sildenafil have shown that 92% of the drug is absorbed, although much less intact drug is detected in plasma. Can you explain this difference?

The figure below shows the CP–time profiles of sildenafil after administration of 100 mg of the drug to fasted and fed volunteers. Describe the food effect on the oral bioavailability of sildenafil.

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