Sildenafil

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Used in Switzerland

log Kow = 2.75

2.8

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Cardiovascular Agents; Phosphodiesterase 5 Inhibitors; Urologic Agents; Vasodilator Agents

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

189-190 °C

187-189 °C

Reconstituted sildenafil oral suspension is stable for 30 days when stored as directed; any remaining suspension should be discarded after that time.

Commercially available sildenafil citrate tablets ... has an expiration date of 24 months after the date of manufacture when stored as directed.

Warning

H302 (34%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P264+P265, P270, P273, P280, P301+P317, P305+P351+P338, P330, P337+P317, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 103 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H315: Causes skin irritation [Warning Skin corrosion/irritation]

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl sildenafil citrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sildenafil citrate/

Hidden Risks of Erectile Dysfunction "Treatments" Sold Online.[Available from, as of September 22, 2014: http://www.fda.gov/forconsumers/consumerupdates/ucm048386.htm]

Public Notification: O.M.G. Contains Hhidden Drug Ingredient. The Food and Drug Administration (FDA) is advising consumers not to purchase or use O.M.G., a product promoted and sold for sexual enhancement on various websites ... and possibly in retail stores.[Available from, as of September 22, 2014: http://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/medicationhealthfraud/ucm406236.htm?source=govdeliv]

Public Notification: Miraculous Evil Root Contains Hidden Drug Ingredient. The Food and Drug Administration (FDA) is advising consumers not to purchase or use Miraculous Evil Root, a product promoted and sold for sexual enhancement on various websites and possibly in some retail stores.[Available from, as of September 22, 2014: http://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/medicationhealthfraud/ucm401538.htm?source=govdeliv]

Sildenafil powder for oral suspension should be stored below 30 °C in its original package to protect the drug from moisture. Reconstituted sildenafil oral suspension should be stored below 30 °C or in a refrigerator at 2-8 °C; the suspension should not be frozen.

Commercially available sildenafil citrate injection should be stored at 20-25 °C, but may be exposed to temperatures ranging from 15-30 °C.

Commercially available sildenafil citrate tablets should be stored at 25 °C, but may be exposed to 15-30 °C.

Keep container tightly closed in a dry and well-ventilated place. /Sildenafil citrate/

Accident Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Sildenafil citrate/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Contaminated packaging: Dispose of as unused product. /Sildenafil citrate/

Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Sildenafil citrate/

Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /Sildenafil citrate/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Sildenafil citrate/

Control of environmental exposure: Do not let product enter drains. /Sildenafil citrate/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Sildenafil citrate/

Skin protection: Handle with gloves. /Sildenafil citrate/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Sildenafil citrate/

Body Protection: impervious clothing, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Sildenafil citrate/

Sildenafil and other phosphodiesterase (PDE) type 5 inhibitors (e.g., tadalafil, vardenafil) profoundly potentiate the vasodilatory effects (e.g., a systolic blood pressure reduction exceeding 25 mm Hg with sildenafil) of organic nitrates and nitrites (e.g., nitroglycerin, isosorbide dinitrate), and potentially life-threatening hypotension and/or hemodynamic compromise can result. Nitrates and nitrites promote the formation of cyclic guanosine monophosphate (cGMP) by stimulating guanylate cyclase, and PDE type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) act to decrease the degradation of cGMP via phosphodiesterase (PDE) type 5 by inhibiting this enzyme, resulting in increased accumulation of cGMP and more pronounced smooth muscle relaxation and vasodilation than with either PDE type 5 inhibitors or nitrates/nitrites alone. This interaction probably occurs with any organic nitrate, nitrite, or nitric oxide donor (e.g., nitroprusside) regardless of their predominant hemodynamic site of action.

PDE type 5 inhibitors /including sildenafil/ also may potentiate the hypotensive effects of inhaled nitrites (e.g., amyl or butyl nitrite, sometimes referred to as poppers), which may be misused (recreational use) during sexual activity for purported effects in enhancing the sexual experience. Because these agents are used recreationally, patients may be unaware of their pharmacologic effects and potential risks and may not report their use to clinicians. Concurrent use of PDE type 5 inhibitors with poppers, which dilate blood vessels with a rapid onset of action, could result in sudden and marked blood pressure reduction and potentially serious or even fatal effects. Interactions with organic nitrates and nitrites may be even more pronounced in patients who also are taking certain HIV protease inhibitors concomitantly. Homosexual males may be at particular risk because of the greater likelihood of recreational inhaled nitrite use and antiretroviral therapy in this population.

Combination antiretroviral therapy usually includes one or more HIV protease inhibitors that are inhibitors of CYP3A4 and/or CYP2C9, and the possibility for an interaction with sildenafil clearance resulting in an increased likelihood of sildenafil-associated adverse effects such as headache, flushing, visual changes, priapism, and possibly hypotension and syncope exists. Patients should inform their clinician if they are taking antiretroviral therapy.

Sildenafil potentiates the hypotensive effect of nitrates /including nitroglycerin/; concomitant use is contraindicated.

For more Interactions (Complete) data for SILDENAFIL (23 total), please visit the HSDB record page.

There have been at least 5 reports of acute liver injury attibuted to sildenafil use, but no instances of acute hepatic failure. The latency in most reports has been unclear because of the intermittent and sometimes unacknowledged use of sildenafil, but appears to be within 1 to 8 weeks. The pattern of serum enzyme elevations has ranged from hepatocellular to cholestatic, sometimes evolving from one to the other. The most convincing cases have been a mild cholestatic or "mixed" hepatitis arising within 1 to 3 months of starting sildenafil. Immunoallergic features and autoantibodies were not observed. Cases of acute onset with high serum aminotransferase levels have been reported after use of sildenafil that have some characteristics of ischemic injury. In other instances, the pattern of injury suggested anabolic steroid use. In two cases, re-exposure did not result in recurrence. Thus, the hepatotoxicity of sildenafil is not completely convincing and must be quite rare, if it occurs at all.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 27,000(SRC), determined from a structure estimation method(2), indicates that sildenafil is expected to be immobile in soil(SRC). The estimated pKa of sildenafil is 5.99(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of sildenafil from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.2X10-21 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Sildenafil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2014).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 27,000(SRC), determined from a structure estimation method(2), indicates that sildenafil is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.2X10-21 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 30(SRC), from its log Kow of 2.75(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2014).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), sildenafil, which has an estimated vapor pressure of 1.9X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase sildenafil may be removed from the air by wet and dry deposition(SRC). Sildenafil contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Sildenafil is a white to off-white crystalline powder that is formulated into film-coated tablets, oral suspension, and parenteral injection. Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor. It is used both for the treatment of erectile dysfunction and for the treatment of pulmonary arterial hypertension (PAH) in adults to improve exercise ability and delay clinical worsening. HUMAN EXPOSURE AND TOXICITY: In general, overdosage of sildenafil may be expected to produce effects that are extensions of common adverse reactions. In studies of healthy individuals receiving single sildenafil doses up to 800 mg, the types of adverse events (e.g., decreased blood pressure, syncope, and prolonged erection) observed were similar to those observed at lower doses, but the incidences were increased. Serious adverse effects have also been reported at therapeutic dose levels including sudden decrease or loss of hearing, sudden loss of vision in one or both eyes, and prolonged erection lasting greater than 4 hours or priapism (a painful erection lasting greater than 6 hours). Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of sildenafil for erectile dysfunction. Most, but not all, of these patients had preexisting cardiovascular risk factors. Therefore it was not possible to determine whether these events were related directly to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors. The use of sildenafil is not recommended in children. In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil dose was observed. Pulmonary vasodilators such as sildenafil may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease. Sildenafil profoundly potentiates the vasodilatory effects of organic nitrates and nitrites. The drug did not exhibit clastogenic potential in an in vitro human lymphocytes test system. ANIMAL STUDIES: Lethality after oral administration occurred at 1000 mg/kg and 500 mg/kg in rats and 1000 mg/kg in mice. Female rats were more affected than male rats. Acute sildenafil treatment stimulated testosterone production in adult male rats. There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males. However, in another study male rats were gavaged with sildenafil citrate (0.06 mg/0.05 mL) and allowed to mate. Fertilization rates and numbers of embryos were evaluated after treatment. Fertilization rates (day 1) were markedly reduced (approximately 33%) in matings where the male had taken sildenafil citrate. Over days 2-4, the numbers of embryos developing in the treated group were significantly fewer than in the control group. There was also a trend for impaired cleavage rates within those embryos, although this did not reach significance. No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. In another study, adult male rabbits received sildenafil at doses up to 9 mg/kg/day for 4 weeks to investigate the testicular histological alterations induced by overdoses of this drug. Abnormality in the germinal epithelium of the seminiferous tubules included spermatocytes karyopyknosis, spermatocytes degeneration, desquamation, spermatid giant cells and arrest of spermatogenesis. Additionally, increased Leydig cells cellularity, tubular degeneration, thickening of the interstitium were also observed. The encountered histological findings indicate that chronic exposure to sildenafil overdoses produces significant morphological and histological alterations in the testes which finally might lead to complete arrest of spermatogenesis. There was no evidence of carcinogenicity when sildenafil was administered orally to rats and mice for up to two years. Sildenafil did not exhibit evidence of mutagenicity in vitro in bacterial and Chinese hamster ovary cell assays. The drug also did not exhibit clastogenic potential in vivo in the mouse micronucleus test. Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a phosphodiesterase (PDE) selectivity profile similar to sildenafil and an in vitro potency for phosphodiesterase type 5 (PDE-5) approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects.

In healthy subjects, research demonstrated that single doses up to 800 mg had adverse effects similar to those seen in lower doses but with increased frequency and severity. There are no antidotes available for sildenafil. In case of overdose, patients should receive supportive care. Dose-related visual disturbances occurred more frequently at toxic levels, while blood pressure changes showed a low correlation. As sildenafil is highly bound to plasma proteins and not excreted renally, dialysis does not help expedite sildenafil clearance. When considering the duration of toxicity, the activity of N-desmethyl-sildenafil must be regarded as this metabolite retains PDE5 specificity at lower potency, with plasma concentrations approaching 40% of the parent compound.

Using a structure estimation method based on molecular connectivity indices(1), the Koc for sildenafil can be estimated to be 27,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that sildenafil is expected to be immobile in soil. The estimated pKa of sildenafil is 5.99(3), indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ In general, overdosage of sildenafil may be expected to produce effects that are extensions of common adverse reactions. In studies in healthy individuals receiving single sildenafil doses up to 800 mg, the types of adverse events (e.g., decreased blood pressure, syncope, prolonged erection) observed were similar to those observed at lower doses, but the incidences were increased.

/SIGNS AND SYMPTOMS/ Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of Viagra. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

/SIGNS AND SYMPTOMS/ Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of Viagra. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of Viagra without sexual activity. Others were reported to have occurred hours to days after the use of Viagra and sexual activity. It is not possible to determine whether these events are related directly to Viagra, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors.

/SIGNS AND SYMPTOMS/ When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil.

For more Human Toxicity Excerpts (Complete) data for SILDENAFIL (18 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

sildenafil

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 30 was calculated for sildenafil(SRC), using an estimated log Kow of 2.5(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Henry's Law constant for sildenafil is estimated as 7.2X10-21 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that sildenafil is expected to be essentially nonvolatile from water and moist soil surfaces(2). Sildenafil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.9X10-17 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Acute Exposure/ /Sprague-Dawley rats (5/sex/dose) and CD1 mice (5/sex/dose) were administered a single IV dose of sildenafil. Rats were dosed at 10 mg/kg/day and mice were dosed at 20 mg/kg/day./ All animals survived the treatment and gained weight over the 14-day study period. There were no clinical signs during the study and no abnormalities at necropsy. Under the conditions of this study, the no observed effect level (NOEL) after intravenous administration was 20 mg/kg in mice and 10 mg/kg in rats. /From table/

/LABORATORY ANIMALS: Acute Exposure/ /Sprague-Dawley rats (5/sex/dose) and CD1 mice (5/sex/dose) were administered a single oral dose of sildenafil by gavage. Rats were dosed at 300, 500, or 1000 mg/kg/day and mice were dosed at 500 or 1000 mg/kg/day./ At 1000 mg/kg one male mouse died within 24 hours after drug administration. In rats, mortality occurred in three females at 1000 mg/kg and in one female at 500 mg/kg. The dose of 1000 mg/kg induced clinical signs in both species, generally within 24 hours following the administration, which persisted less than 24-48 hours. Some of these signs were similar in mice and rats and consisted of partially-closed eyes, hunched posture, tremors, depression, coldness to the touch (with pallor of ears and paws in rats) and prostration. Female rats were more affected than male rats. Dyspnea was limited to one mouse, and chromodacryorrhea to four female rats. Clinical signs at 500 mg/kg included partially-closed eyes in one mouse and subdued behavior in the female rat which died. No clinical signs were observed in rats at 300 mg/kg. In both species, the doses administered induced no changes in body weight gain and there were no treatment-related macroscopical changes at gross necropsy. These results indicate that the no observed adverse effect level (NOAEL) was 500 mg/kg in mice and 300 mg/kg in rats. /From table/

/LABORATORY ANIMALS: Acute Exposure/ Phosphodiesterase type 5 (PDE5) inhibitors have been established in therapy for a variety of physiological disorders including erectile dysfunction. Despite its popularity and wide usage in erectile dysfunction treatment, the short-term effect of PDE5 inhibition on Leydig cell functionality and testosterone dynamics is missing. This study was designed to assess the acute in vivo effects of sildenafil citrate (Viagra) treatment on testosterone production. Male adult rats were given sildenafil (1.25 mg/kg bw) per os, and testosterone production were analyzed 30, 60, 120, and 180 minutes after treatment. Additionally, in vitro effect of sildenafil extract on Leydig cell steroidogenesis was estimated. The formation of testicular interstitial fluid (TIF), and testosterone, cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP) content was followed. Occurrence and phosphorylation of mature steroidogenic acute regulatory protein (StAR) and interaction with protein kinase G 1 (PRKG1) were assessed by immunoprecipitation and Western blot. Serum testosterone was increased 60 and 120 minutes after sildenafil treatment. In 60 minutes, TIF volume was doubled and stayed increased till the end of the experimental period. cGMP and testosterone content in TIF were increased 30 minutes after treatment, and cAMP decreased in 60 minutes. Further, sildenafil-induced stimulation of testosterone production was abolished by ex vivo addition of PRKG1 inhibitor but not by protein kinase A inhibitor. Sildenafil treatment increased the level of phosphorylated and total StAR protein. Moreover, co-immunoprecipitation of StAR and PRKG1 was increased following sildenafil treatment suggesting the active role of this kinase in initiation of testosterone synthesis. Additionally, sildenafil extract applied in vitro on primary Leydig cell culture increased cGMP accumulation and testosterone production in time- and dose-dependent manner without effect on cAMP level. Acute sildenafil treatment enlarged TIF volume but also stimulated testosterone production which may be significant considering the positive testosterone effect in regulation of sexual activity.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ /Beagle dogs (4/sex/dose) were administered 5, 15 or 50 mg/kg/day of sildenafil for 6 months by oral gavage./ Analyses of plasma sildenafil and UK-103,320 /N-desmethyl metabolite/ showed dose-related concentrations in the dog. The proportion of UK-103,320 relative to sildenafil varied minimally (15-23%) as the dose increased, indicating no saturation of this process. Salivation, emesis and resistance to compound administration were seen when the animals were treated with an initial high dose of 80 mg/kg, and reflected gastric intolerance to the compound at this dose level. These signs were rare after reducing the high dose to 50 mg/kg. A moderate increase in heart rate, associated with decreases in PQ and QT intervals, occurred at the high dose and is considered to be a reflex response to the vasodilatory properties of the drug. Increases in plasma cholesterol and in liver weight were seen in animals treated with 15 and 50 mg/kg. A high-dose male showed a number of clinical signs and changes in hematological parameters and plasma chemistry associated with a disseminated arteritis. These changes correspond to Idiopathic Juvenile Arteritis Syndrome (Beagle Pain Syndrome) which occurs sporadically in Beagle dogs. Another high-dose male showed arteritis in the thymus which indicated a less severe expression of the same disease. It is probable that the high dose precipitated the expression of this latent spontaneous disorder. The NOAEL in this study was 15 mg/kg, given the appearance of Idiopathic Juvenile Arteritis Syndrome at higher doses. /From table/

For more Non-Human Toxicity Excerpts (Complete) data for SILDENAFIL (23 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl sildenafil citrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sildenafil citrate/

G04BE03

G - Genito urinary system and sex hormones

QG - Genito urinary system and sex hormones

It is generally observed that sildenafil and its main circulating N-desmethyl metabolite are both estimated to be about 96% bound to plasma proteins. Nevertheless, it has been determined that protein binding for sildenafil is independent of total drug concentrations.

In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5). Its effect is more potent on PDE5 than on other known phosphodiesterases. In particular, there is a 10-times selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-times selectivity over PDE1, and over 700-times over PDE 2, 3, 4, 7, 8, 9, 10 and 11. And finally, sildenafil has greater than 4,000-times selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. 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 (via the use of 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. Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg, three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mmHg respectively. After chronic dosing of 80 mg, three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg) . At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported either. In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries. Mild and transient differences in color discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (which included visual acuity, Amsler grid, color discrimination simulated traffic light, and the Humphrey perimeter and photostress test).

Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. The physiological mechanism responsible for the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects. Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), an enzyme responsible for degrading cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. By diminishing the effect of PDE5, sildenafil facilitates the effect of nitric oxide during sexual stimulation; cGMP levels increase, smooth muscle relaxes, and blood flows into the corpus cavernosum, producing an erection. Without sexual stimulation, sildenafil has no effect on erections.

It has been extensively demonstrated that hydrogen sulfide (H2S) is implicated is several physiological and pathological conditions. In particular, it has been shown that H2S causes relaxation in human penile tissues and inhibits phosphodiesterase (PDE) activity in vessels. Beside sildenafil increases H2S generation in human bladder and tadalafil in myocardial tissues. Therefore, /the/ aim /of the study/ was to demonstrate the link between H2S and PDE-5 in mice corpus cavernosum tissues. ... The effects of sildenafil (10 uM, 0.5 hr); PDE-5 inhibitor, on H2S production as well as the H2S -induced relaxations in mice penile tissues /was investigated/. Penile tissues from CD1 mouse corpus cavernosum (MCC) were used. Functional studies were performed by myograph in Krebs solution. Western blot analysis was performed in order to evaluate CBS and CSE expression and methylene blue assay for measurement of H2S levels. In order to investigate functional significance of H2S on sildenafil-induced augmentation of endothelial relaxation in MCC the sildenafil effect was evaluated on acetylcholine (ACh), L-cysteine and NaHS-induced relaxations in presence or not of CSE enzyme inhibitor PPG (10 uM, 0.5 hr). In order to achieve this issue the H2S production in MCC tissues was also evaluated by incubating the penile tissue with sildenafil in presence or absence of the CSE inhibitor PPG (10 uM, 0.5 hr) Both CBS and CSE were expressed in MCC and the enzymes efficiently converted L-cysteine into H2S. Further /it was shown/ that sildenafil caused a significant increase in H2S production and this augmentation was reversed by CSE inhibition. /It was/ found that sildenafil induced an increase in both ACh and L-cysteine-induced relaxations and these augmentations reversed by CSE inhibitor PPG in MCC pre-contracted with phenylephrine (3.10-5M). Beside sildenafil did not significantly increase the NaHS -induced relaxations. Therefore /it was/ suggested that both gaseous transmitters NO and H2S affect sildenafil action. In particular ... results demonstrate that sildenafil effect is partially mediated by H2S pathway. Thus, H2S signaling may represent a new mechanism involved in the effect of sildenafil on erectile dysfunction.

Sildenafil citrate (Viagra), a cGMP-selective phosphodiesterase (PDE) inhibitor, is widely used to treat erectile dysfunction and pulmonary arterial hypertension. In contrast to its well established action on erectile dysfunction, little is known on the action of sildenafil on cGMP/cAMP signaling and testicular steroidogenesis. This study was designed to assess the effects of prolonged sildenafil treatment on NO synthase-dependent signaling and steroidogenic function of rat Leydig cells. Male adult rats were treated with Viagra (1.25 mg/kg body wt) daily for 30 days. /Studies indicate/, serum testosterone and ex vivo testosterone production significantly increased in sildenafil-treated animals. Human chorionic gonadotropin-stimulated testosterone production and cAMP accumulation were also significantly higher in Leydig cells obtained from sildenafil-treated rats. The expression of soluble guanylyl cyclase (GUCY1) subunits (Gucy1a1, Gucy1b1) significantly increased; cAMP-specific Pde4a, cGMP-specific Pde6c, and dual Pde1c and Nos2 were inhibited and expression of Nos3, protein kinase G1 (Pkg1), and Pde5 remained unchanged. Treatment of purified Leydig cells with NO donor caused a dose-dependent increase in both testosterone and cGMP production. Testosterone and cGMP production was significantly higher in Leydig cells obtained from sildenafil-treated animals. The stimulatory effect of NO donor was significantly enhanced by saturating concentrations of hCG in both Leydig cells obtained from control and sildenafil-treated animals. Occurrence of mature steroidogenic acute regulatory protein also increased in sildenafil treated animals in accord with increased cAMP and cGMP production. In summary, inhibition of PDE activity during prolonged sildenafil treatment increased serum testosterone level and Leydig cells' steroidogenic capacity by coordinated stimulatory action on cAMP and cGMP signaling pathway.

The terminal phase half-life observed for sildenafil is approximately 3 to 5 hours.

Plasma sildenafil concentrations appear to decline in a biphasic manner following oral administration, with a terminal elimination half-life of about 4 hours (range: 3-5 hours).

High clearance was the principal determinant of short elimination half-lives in rodents (0.4-1.3 hr), whereas moderate clearance in dog and man resulted in longer half-lives (6.1 and 3.7 hr respectively).

The metabolism of sildenafil is facilitated primarily by the CYP3A4 hepatic microsomal isoenzymes and to a minor extent, via the CYP2C9 hepatic isoenzymes. The predominant circulating metabolite results from the N-demethylation of sildenafil. This particular resultant metabolite possesses a phosphodiesterase selectivity that is similar to the parent sildenafil molecule and a corresponding in vitro potency for PDE5 that is approximately 50% that of the parent drug. Moreover, plasma concentrations of the metabolite are about 40% of those recorded for sildenafil, a percentage that accounts for about 20% of sildenafil’s pharmacologic effects. This primary N-desmethyl metabolite of sildenafil also undergoes further metabolism, with a terminal half-life of about 4 hours. In patients with pulmonary arterial hypertension, plasma concentrations of the primary N-desmethyl metabolite are about 72% those of the original parent sildenafil molecule after a regimen of 20 mg three times a day - which is consequently responsible for about a 36% contribution to sildenafil’s overall pharmacological effects.

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a phosphodiesterase (PDE) selectivity profile similar to sildenafil and an in vitro potency for phosphodiesterase type 5 (PDE-5) approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects.

Pharmacokinetics were studied in mouse, rat, rabbit, dog and man after single intravenous and/or oral doses of sildenafil or (14)C-sildenafil (Viagra). .... Five principal pathways of metabolism in all species were piperazine N-demethylation, pyrazole N-demethylation, loss of a two-carbon fragment from the piperazine ring (N,N'-deethylation), oxidation of the piperazine ring and aliphatic hydroxylation. Additional metabolites arose through combinations of these pathways. Sildenafil was the major component detected in human plasma. Following oral doses, AUC (infinity) for the piperazine N-desmethyl and piperazine N,N'-desethyl metabolites were 55 and 27% that of parent compound respectively.

Sildenafil is eliminated mainly in the feces as metabolites. In healthy adults and those with erectile dysfunction, approximately 80% of an oral dose is excreted as metabolites in feces and 13% is excreted in urine. In feces, the N-dealkylated, hydroxylated, N-demethylated, and N-dealkylated/demethylated metabolites of sildenafil comprise about 22, 13, 3, and 3% of total fecal excretion. In healthy individuals, sildenafil is excreted in urine mainly as the hydroxylated metabolite, with this metabolite representing about 41% of total urinary excretion of the drug.

/Sprague Dawley rats (10/sex/dose) were administered 10, 45 or 200 mg/kg/day of sildenafil for 1 month by oral gavage./ Plasma concentrations of sildenafil were higher in females than in males, while concentrations of the metabolite, UK-103,320, were higher in males than in females. As a result, females were exposed predominantly to the unchanged drug and males to an almost equal balance of drug and metabolite. These data indicate that N-demethylation of sildenafil to UK-103,320 is an important route of sildenafil biotransformation in male rats. Concentrations of UK-95,340 were generally below the limit of determination (30 ng/mL). ... /From table/

Sildenafil appears to be completely metabolized in the liver to up to 16 metabolites, most of which represent only a small fraction of a dose; little or no unchanged drug is detectable in urine or feces following oral or IV administration. Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route), and potent inhibitors of CYP3A4 can substantially reduce sildenafil clearance. Hepatic metabolism of sildenafil is complex, generally involving the piperazine ring, N,N-de-ethylation (ring opening) or N-demethylation of the piperazine ring and aliphatic hydroxylation; the drug and its metabolites do not appear to undergo conjugation. The N-demethylated metabolite, the major circulating metabolite, has a phosphodiesterase selectivity profile similar to that of sildenafil and an in vitro potency for PDE type 5 of approximately 50% of the parent drug. The N-demethylated metabolite is further metabolized to an N-dealkylated N,N-de-ethylated) metabolite. The drug also undergoes N-dealkylation followed by N-demethylation of the piperazine ring.

3M7OB98Y7H

SILDENAFIL

Established Pharmacologic Class [EPC] - Phosphodiesterase 5 Inhibitor

Mechanisms of Action [MoA] - Phosphodiesterase 5 Inhibitors

Sildenafil is a Phosphodiesterase 5 Inhibitor. The mechanism of action of sildenafil is as a Phosphodiesterase 5 Inhibitor.

SILDENAFIL

Drugs used to cause dilation of the blood vessels.

Compounds that specifically inhibit PHOSPHODIESTERASE 5.

Drugs used in the treatment of urological conditions and diseases such as URINARY INCONTINENCE and URINARY TRACT INFECTIONS.

Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient. Moreover, the mean absolute bioavailability observed for sildenafil is about 41% (from a range of 25-63%). In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg. When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses. Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29%. Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 %.

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).

The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues.

The total body clearance documented for sildenafil is 41 L/h.

Sildenafil is rapidly and almost completely absorbed following oral administration. Bioequivalence has been established between the 20-mg tablet and the 10-mg/mL oral suspension when administered as a single oral dose of 20 mg. Although single-dose studies indicate that more than 90% of an oral sildenafil dose is absorbed from the GI tract, the drug undergoes extensive metabolism in the GI mucosa during absorption and on first pass through the liver, with only about 40% of a dose reaching systemic circulation unchanged. Pharmacokinetics of the drug (as determined by peak plasma concentrations or area under the plasma concentration-time curve (AUC)) are dose proportional over the single-dose range of 1.25-200 mg. Peak plasma concentrations of sildenafil and its active N-desmethyl metabolite are achieved within 30-120 (median: 60) minutes following oral administration in fasting adults.

Sildenafil appears to be widely distributed in the body, with a reported volume of distribution at steady state averaging 105 L. It is not known whether sildenafil is distributed into milk. Sildenafil and its major circulating N-desmethyl metabolite are each approximately 96% bound to plasma proteins; protein binding reportedly is independent of plasma concentration over the range of 0.01-10 ug/mL. Plasma protein binding of the drug in geriatric adults older than 65 years of age is slightly greater (97%) than that observed in individuals younger than 45 years of age (96%). Sildenafil is distributed to a limited extent in semen following oral administration, with less than 0.001% of a single dose appearing in semen 90 minutes after dosing in healthy individuals Such concentrations are unlikely to cause any effects in sexual partners exposed to the semen.

Phosphodiesterase 5 Inhibitors; Urological Agents; Vasodilator Agents

MEDICATION

Use (kg; approx.) in Germany (2009): >750

The target protein of the drug is phosphodiesterase 5 (PDE5), which is an intracellular cGMP regulator. The drug initially was intended to treat hypertension and angina but showed disappointing early clinical results. Follow-up research showed sildenafil citrate-mediated inhibition of PDE5 enhanced the relaxation of the corpus cavernosal smooth muscle and could be used in the treatment of erectile dysfunction. /Sildenafil citrate/