sildenafil citrate


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Sildenafil Citrate

 

Definition

Sildenafil citrate (Viagra) is a medication used to treat erectile dysfunction (ED), or impotence, in men.

Purpose

Labeled use

Viagra treats erectile dysfunction, the inability to achieve and/or maintain an erection of the penis that is adequate for sexual intercourse. Ten to fifteen million men in the United States suffer from ED, and by age 65, up to 25% of men have experienced impotence problems. Erectile dysfunction can be caused by a number of physical and psychological conditions, including diabetes, depression, prostate cancer, spinal cord injury, multiple sclerosis, artherosclerosis, and heart disease. Injuries to the penis that cause nerve, tissue, or vascular damage can trigger impotence. It is also a common side effect of some prescription medications, including antihistamines, antidepressants, antihypertensives, antipsychotics, beta blockers, diuretics, tranquilizers, appetite suppressants, cimetidine (Tagamet), and finasteride (Propecia).
A study of African American and Hispanic men published in 2002 reported that Viagra appears to be equally safe and equally effective across different racial and ethnic groups in the United States.

Investigational uses

Although not approved for use in women, clinical studies have shown that sildenafil citrate may be effective in relieving female sexual dysfunction for some women. In one study, both female and male study participants who suffered from sexual dysfunction related to their use of such psychotropic medications as benzodiazepines reported an increase in arousal and overall sexual satisfaction when they began taking Viagra. Several studies have also indicated the drug may be effective in improving libido and arousal in women taking selective serotonin uptake inhibitors (SSRIs).
Another possible use of sildenafil in women is the treatment of infertility. Women who have had repeated failures with in vitro fertilization (IVF) due to poor development of the tissue that lines the uterus may benefit from treatment with vaginal suppositories containing sildenafil. One study reported that 70% of patients had a significant thickening of the uterine lining, with 29% having a successful implantation of a new embryo, and 45% achieving ongoing pregnancies.
Another investigational study conducted by researchers at Johns Hopkins University School of Medicine in Baltimore, and published in the August 2000 issue of the Journal of Clinical Investigation found that Viagra may have additional clinical promise for people with diabetes beyond treating ED. In animal studies, Viagra was effective in relaxing the pyloric muscle of stomach, improving digestion and relieving the symptoms of gastroparesis. Up to 75% of people with diabetes suffer from gastroparesis, which causes bloating, nausea, loss of appetite, and vomiting. Further human studies are needed to evaluate Viagra's effectiveness in treating this common diabetic complication.
Because of its capacity to enhance nitric oxide production, sildenafil has been investigated as a possible treatment for other disorders that are caused by impaired nitric oxide production. One such disorder is esophageal motility dysfunction (achalasia), in which the smooth muscles of the esophagus and the cardiac sphincter remain constricted, causing difficulty in swallowing, regurgitation of food, and chest pain when eating. A study published in 2000 in the journal Gastroenterology found that sildenafil temporarily improved the condition in some patients by relaxing the lower esophageal muscles. An Italian study reported in 2002 that sildenafil shows genuine promise as a treatment for spastic esophageal disorders.

Precautions

Viagra is not labeled or approved for use by women or children, or by men without erectile dysfunction. The medication may also be contraindicated (not recommended for use) in patients with certain medical conditions.
Because sexual activity can stress the heart, men who have heart problems should check with their physician to see if sexual activity is recommended. Viagra may trigger temporary hypotension (low blood pressure) and is known to increase cardiovascular nerve activity, so it is prescribed with caution in men with a history of heart attack, artherosclerosis, angina, arrhythmia, and chronic low blood pressure problems. However, a study published in the March 15, 2001, British Medical Journal found no evidence that the drug causes a higher incidence of heart attack. A four-year update on the safety of Viagra published in September 2002 corroborated the findings of the British report, and stated that the only absolute contraindication for the use of sildenafil is the concurrent use of nitrates.
Anyone experiencing cardiovascular symptoms such as dizziness, chest or arm pain, and nausea when participating in sexual activity after taking Viagra should stop the encounter. They should also not take Viagra again until they have discussed the episode with their healthcare provider.
It is recommended that men with kidney or liver impairments, and men over age 65, start at the lowest possible dosage of Viagra (25 mg). Clinical studies have shown that the drug builds up in the plasma of these patients to a concentration that is three to eight times higher than normal. Caution is also recommended in prescribing the drug to individuals with retinitis pigmentosa, a rare genetic eye disorder. Viagra should not be taken more than once per day by anyone.
Viagra has not been studied for use on patients with stomach ulcers and bleeding disorders, and its safety in these individuals is unknown. Men who have either of these conditions should let their physician know before taking Viagra. It should also be used with caution in men with misshapen or deformed penises, such as those with Peyronie's disease, cavernosal fibrosis, or with angulation of the penis.
Men who take medications containing nitrates (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate) should never take Viagra, as the interaction between the two drugs may cause a dramatic drop in blood pressure, and possibly trigger a heart attack or stroke. This includes illegal recreational drugs such as amyl nitrates (also known as poppers).
Viagra may also interact with other prescription and over-the-counter (OTC) medications, either magnifying or diluting the intended therapeutic effects of one or both drugs. Some drugs that have a known interaction with Viagra include the protease inhibitor ritonavir and the antibiotic erythromycin. For this reason, it is critical that men who are prescribed Viagra let their healthcare providers know all the medications they are taking.
Other medications and therapies for erectile dysfunction, including vacuum or pump devices, drug injections (Caverject), and urethral suppositories (MUSE), should never be used in conjunction with Viagra.

Description

Sildenafil citrate was originally developed in 1991 as a treatment for angina, or chest pain. The drug, marketed under the name Viagra, received FDA market clearance as a treatment for impotence in March 1998, and since that time it has been prescribed for over 10 million men worldwide. It was the first oral medication approved for ED treatment. A newer drug, tadalafil, has been developed to treat men who do not respond to sildenafil. Tadalafil has gained preliminary approval in the European Union (EU), and is in the final stages of regulatory approval in Canada as of November 2002.
Viagra is a vasodilator, a drug that has the effect of dilating the blood vessels. It works by improving blood circulation to the penis, and by enhancing the effects of nitric oxide, the agent that relaxes the smooth muscle of the penis and regulates blood vessels during sexual stimulation, allowing the penis to become engorged and achieve an erection.
The average recommended dose of Viagra is 50 mg. For men that do not respond adequately to this amount, the dosage may be increased up to 100 mg or decreased to 25 mg. The medication is taken approximately one hour before sexual activity is planned, and may remain effective for up to four hours.
Viagra does not increase sexual desire. Sexual stimulation and arousal are required for the medication to be effective. Despite its widespread use as a recreational drug, it is not an aphrodisiac and there is no clinical evidence that it improves sexual performance in men who are not suffering from ED.
Many insurance plans provide coverage or reimbursement for sildenafil citrate provided it is prescribed to treat erectile dysfunction. A 1999 report issued by a health insurance consulting group indicated that almost half of the men taking Viagra at least once weekly receive insurance reimbursement for the drug. The pills cost approximately $10 each, and insurers may limit coverage to a specific number of pills each month.

Preparation

Viagra requires time to be absorbed by the body and become effective. The average recommended time frame for taking the drug is one hour before initiating sexual activity, although depending on an individual's response to the drug, this time can vary from four hours to 30 minutes.
Men should always consult with their physician before beginning treatment with sildenafil citrate. The medication is not for everyone, and a healthcare professional needs to evaluate medical history and perform a thorough medical examination before prescribing the drug. In addition, erectile dysfunction may be a symptom of an undiagnosed condition (i.e., diabetes) for which treatment is critical, and may actually reverse the impotence problem.

Risks

The most commonly reported side effects of Viagra are headache, flushing of the face, upset stomach, and nasal congestion.
Other less common side effects include, but are not limited to:
  • vision problems, including sensitivity to light, blurred vision, and a color tinge to vision
  • urinary tract infection
  • diarrhea
  • dizziness
  • rash
Side effects may be reduced or eliminated through adjustments to dosage. Men who experience these symptoms should consult their physician.
Priapism, a painful and prolonged erection that lasts for two to six hours, is a rare but potentially serious side effect of Viagra. Because prolonged erection can permanently damage the tissues of the penis, anyone who experiences an erection lasting over four hours should call a healthcare professional immediately.
Men who are taking Viagra and inadvertently or intentionally take a medication containing nitrates may suffer from life-threatening hypotension—a severe drop in blood pressure.
The cardiovascular risks of sildenafil citrate are still under investigation. The drug is known to cause dips in blood pressure and to boost cardiovascular nerve activity. Some cardiovascular-related deaths have been reported in men who use Viagra, but it is unclear whether the fatalities were due to the drug itself or to the underlying heart disease. Further complicating the picture is the fact that the stress of sexual activity may have triggered the fatal cardiac event with or without the use of Viagra. The BMJ study, and a report published in the April 18, 2001 issue of the Journal of the American Medical Association (JAMA) suggest that the drug does not increase the risk of heart attack. However, JAMA also notes that further studies are necessary to confirm this finding.

Key terms

Angina — Angina pectoris, or chest pain, caused by an insufficient supply of oxygen and decreased blood flow to the heart muscle. Angina is frequently the first sign of coronary artery disease.
Angulation of the penis — Abnormal bend or angle to the structure of the penis.
Antidepressants — Medications prescribed to relieve major depression. Classes of antidepressants include selective serotonin reuptake inhibitors (fluoxetine/Prozac, sertraline/Zoloft), tricyclics (amitriptyline/ Elavil), MAOIs (phenelzine/Nardil), and heterocyclics (bupropion/Wellbutrin, trazodone/Desyrel).
Antihistamines — A drug used to treat allergic conditions that counteracts histamines—a substance in the body that causes itching, vascular changes, and mucus secretion when released by cells.
Antihypertensives — Medications used to treat high blood pressure.
Antipsychotics — A class of drugs used to control psychotic symptoms in patients with psychotic disorders such as schizophrenia and delusional disorder. Antipsychotics include risperidone (Risperdal), haloperidol (Haldol), and chlorpromazine (Thorazine).
Arrhythmia — Irregular heartbeat caused by erratic electrical signals or nerve impulses to the cardiac muscles.
Artherosclerosis — The cause of coronary artery disease, in which the walls of the coronary arteries thicken due to the accumulation of plaque in the blood vessels.
Beta blockers — Drugs that lower blood pressure and reduce stress to the heart by blocking the actions of beta receptors that control the speed and strength of heart muscle contractions and blood vessel dilation.
Cavernosal fibrosis — The formation of abnormal fibrous tissue in the erectile tissue of the penis.
Diuretics — Any substance that increases urine output.
Erectile dysfunction — Impotence; the inability of a man to achieve and/or maintain an erection of sufficient quality for sexual intercourse.
Gastroparesis — Nerve damage of the stomach that delays or stops stomach emptying, resulting in nausea, vomiting, bloating, discomfort, and weight loss.
Peyronie's disease — A disease which causes a hardening of the corpora cavernosa, the erectile tissue of the penis. The penis may become misshapen and/or curved as a result.
Placebo — An inactive substance with no pharmacological action that is administered to some patients in clinical trials to determine the relative effectiveness of another drug administered to a second group of patients.
Priapism — A painful, abnormally prolonged erection (i.e., four or more hours).
Protease inhibitor — A drug that inhibits the action of enzymes.
Retinitis pigmentosa — An inherited degenerative eye disease that impairs night vision and drastically narrows the field of vision.
Selective serotonin uptake inhibitors (SSRIs) — Drugs that regulate depression by blocking the reabsorption of serotonin in the brain consequently raising serotonin levels. SSRIs include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil).
Serotonin — One of three major neurotransmitters found in the brain that is linked to emotions.
Although it is a prescription drug, as of early 2001 there was still a thriving illicit market for Viagra via the Internet. Aside from the health risks recreational use of the drug poses to individuals with heart conditions and other contraindicated disorders, any adverse effects caused by Viagra cannot be tracked by regulatory authorities if it has been illegally obtained. In addition, the drug appears to be toxic in large doses. In November 2002, a group of French toxicologists reported the case of a 56-year-old male who took a fatal overdose of Viagra.

Normal results

When used as directed, Viagra allows men with erectile dysfunction to achieve and maintain a penile erection when aroused during sexual activity. Double-blind, randomized clinical trials of sildenafil citrate have shown that the drug has an 63-82% efficacy rate in improving erectile activity among men with ED, depending on the dose administered (between 25 and 100 mg), compared to a 24% improvement in men receiving a placebo.

Resources

Books

Medical Economics Company. The Physicians DeskReference (PDR). 55th ed. Montvale, NJ: Medical Economics Company, 2001.
Stolar, Mark. Viagra & You. New York:Berkley Books, 1999.

Periodicals

Bortolotti, M., N. Pandolfo, M. Giovannini, et al. "Effect of Sildenafil on Hypertensive Lower Oesophageal Sphincter" European Journal of Clinical Investigation 32 (September 2002): 682-685.
Boyce, E. G., and E. M. Umland. "Sildenafil Citrate: A Therapeutic Update." Clinical Therapeutics 1 (January 2001): 2-23.
Kuan, J., and G. Brock. "Selective Phosphodiesterase Type 5 Inhibition using Tadalafil for the Treatment of Erectile Dysfunction." Expert Opinion on Investigational Drugs 11 (November 11, 2002): 1605-1613.
Mitka, Mike. "Studies of Viagra Offer Some Reassurance to Men With Concerns About Cardiac Effects." The Journal of the American Medical Association 285, no.15 (April 18, 2001): 1950.
Padma-nathan, H., I. Eardley, R. A. Kloner, et al. "A 4-year Update on the Safety of Sildenafil Citrate (Viagra)." Urology 60, no.2, Supplement 2 (September 2002): 67-90.
Shakir, S. A., et al. "Cardiovascular Events in Users of Sildenafil: Results from First Phase of Prescription Event Monitoring in England." British Medical Journal 322, no.7287 (March 17, 2001): 651-2.
Sher, G., and J. D. Fisch. "Effect of Vaginal Sildenafil on the Outcome of in vitro Fertilization (IVF) After Multiple IVF Failures Attributed to Poor Endometrial Development." Fertility and Sterility 78 (November 2002): 1256-1257.
Tracqui, A., A. Miras, A. Tabib, et al. "Fatal Overdosage with Sildenafil Citrate (Viagra): First Report and Review of the Literature." Human and Experimental Toxicology 21 (November 2002): 623-629.
"Viagra Increases Nerve Activity Associated with Cardiovascular Function." Drug Week January 26, 2001: 11.
Young, J. M., C. Bennett, P. Gilhooly, et al. "Efficacy and Safety of Sildenafil Citrate (Viagra) in Black and Hispanic American Men." Urology 60, no. 2, Supplement 2 (September 2002): 39-48.

Organizations

American Heart Association. American Heart Association. 7320 Greenville Ave. Dallas, TX 75231. (214) 373-630 or (800) 242-8721. inquire@heart.org. http://www.americanheart.org.
U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research. Viagra Information. http://www.fda.gov/cder/consumerinfo/viagra/default.htm.

Other

Pfizer, Inc. Viagra Information Site. http://www.viagra.com/.

sildenafil citrate

Viagra

Pharmacologic class: Phosphodiesterase type 5 (PDE5) inhibitor

Therapeutic class: Anti-erectile dysfunction agent

Pregnancy risk category B

Action

Inhibits PDE5, enhancing the effects of nitric oxide released during sexual stimulation. This action inactivates cyclic guanosine monophosphate (cGMP), which then increases cGMP levels in corpus cavernosum. Resulting smooth muscle relaxation promotes increased blood flow and subsequent erection. Also relaxes pulmonary vascular smooth muscle cells and, to a lesser degree, vasodilation in systemic circulation.

Availability

Injection (Revatio): 10 mg in 12.5-ml single-use vial

Tablets: 20 mg (Revatio); 25 mg, 50 mg, 100 mg (Viagra)

Indications and dosages

Erectile dysfunction

Adults: 50 mg P.O., preferably 1 hour before anticipated sexual activity. Range is 25 to 100 mg taken 30 minutes to 4 hours before sexual activity, not to exceed one dose daily.

Pulmonary hypertension (Revatio only)

Adults: 20 mg P.O. t.i.d. approximately 4 to 6 hours apart, with or without food. Higher doses not recommended. Or, 10 mg by I.V. bolus t.i.d.

Dosage adjustment

• Hepatic or renal impairment (Viagra)
• Concurrent use of hepatic isoenzyme inhibitors (such as cimetidine, erythromycin, itraconazole, ketoconazole) (Viagra)
• Elderly patients (Viagra)

Contraindications

• Hypersensitivity to drug
• Concurrent use of nitrates (nitroglycerin, isosorbide mononitrate or dinitrate)

Precautions

Use cautiously in:
• serious cardiovascular disease (such as history of myocardial infarction, cerebrovascular accident, or serious arrhythmia within past 6 months); coronary artery disease (current or previous) with unstable angina; resting blood pressure below 90/50 mm Hg or above 170/110 mm Hg (current or previous); heart failure (current or previous); renal or hepatic impairment (current or previous); bleeding disorder; active peptic ulcer; anatomic penile deformity; retinitis pigmentosa; conditions associated with priapism (sickle cell anemia, multiple myeloma, leukemia); pulmonary veno-occlusive disease; use not recommended for any of these conditions
• history of uncontrolled hypertension or hypotension
• concurrent use of alpha blockers and antihypertensives (particularly bosentan)
• concurrent use of potent CYP3A inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, or saquinavir (use not recommended)
• patients older than age 65
• pregnant or breastfeeding patients
• children (safety and efficacy not established).

Administration

Don't give concurrently with nitrates.
• Administer Viagra 30 minutes to 4 hours before sexual activity.
• If administering Revatio I.V., give by bolus injection only.

Adverse reactions

CNS: headache, dizziness, anxiety, drowsiness, vertigo, transient global amnesia, insomnia, paresthesia, seizures, cerebrovascular hemorrhage, transient ischemic attack

CV: hypertension, hypotension, myocardial infarction (MI), cardiovascular collapse, ventricular arrhythmias, sudden death

EENT: transient vision loss, blurred or color-tinged vision, increased light sensitivity, ocular redness, retinal bleeding, vitreous detachment or traction, photophobia, hearing loss, epistaxis, rhinitis, sinusitis nasal congestion

GI: diarrhea, dyspepsia, gastritis

Musculoskeletal: myalgia

Respiratory: exacerbation of dyspnea

GU: hematuria, urinary tract infection, priapism

Skin: flushing, rash, erythema, pyrexia

Other: hypersensitivity including anaphylactic reactions (rare)

Interactions

Drug-drug.Alpha blockers, Antihypertensives, nitrates: increased risk of hypotension

Enzyme inducers, rifampin: reduced sildenafil blood level

Hepatic isoenzyme inhibitors (such as cimetidine, erythromycin, itraconazole, ketoconazole), protease inhibitors (such as indinavir, nelfinavir, ritonavir, saquinavir): increased sildenafil blood level and effects

Drug-food.High-fat diet: reduced drug absorption, decreased peak level

Patient monitoring

• Monitor cardiovascular status carefully.
• Evaluate patient's vision and hearing.
• Assess for drug efficacy.

Patient teaching

• Advise patient taking drug for erectile dysfunction to take 30 minutes to 4 hours before sexual activity.
• Tell patient not to exceed prescribed dosage or take more than one dose daily.

Instruct patient to stop sexual activity and contact prescriber immediately if chest pain, dizziness, or nausea occurs.

Teach patient to recognize and immediately report serious cardiac and vision problems and sudden decrease in or loss of hearing.
• Inform patient that drug can cause serious interactions with many common drugs. Instruct him to tell all prescribers he's taking it.

Caution patient never to take drug with nitrates, because of risk of potentially fatal hypotension.
• Instruct patient not to take other PDE5 inhibitors.
• Instruct patient to report priapism (persistent, painful erection) or erections lasting more than 4 hours.
• Tell patient that high-fat diet may interfere with drug efficacy.
• Caution patient to avoid driving and other hazardous activities until he knows how drug affects concentration and alertness.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and foods mentioned above.

An agent used to manage erectile dysfunction, which enhances endogenous nitric acid, relaxing penile smooth muscle, allowing inflow of blood, ergo erection; it is ± 70% effective
Mechanism Phosphodiesterase inhibition
Indications Erectile dysfunction due to diabetes, hypertension hypercholesterolemia, prostate surgery, spinal cord injuries and psychological factors
Complications Flushed skin, headaches, upset stomach, blue-tinted vision, pregnancy
Adverse effects Stroke, acute MI, priapism
Contraindications Nitrate therapy—e.g., nitroglycerin

sildenafil citrate

An oral therapy for impotence in men. During sexual stimulation nitric oxide is released in the corpora cavernosa of the penis. Nitric oxide activates the enzyme guanylate cyclase, which leads indirectly to higher levels of cyclic guanosine monophosphate. This relaxes smooth muscle in the corpora cavernosa so that blood can flow in easily under arterial pressure. The monophosphate is, however, broken down by a phosphodiesterase enzyme (type 5) which limits its action. Sildenafil is a selective inhibitor of this type of the enzyme resulting in prolonged action of cyclic guanosine monophosphate and a more substantial and better-sustained erection. The drug has its maximal effect about an hour after ingestion. It is said to have no effect in the absence of sexual stimulation. The drug improves exercise tolerance in patients with symptomatic pulmonary arterial hypertension. It potentiate the blood pressure-lowering effect of nitrates and should not be taken by patients using organic nitrates in any form. Other side effects include headache and transient blue-green colour perception defect. Men taking the drug should avoid grapefruit juice and should be aware of the other possible interactions. It should be avoided by those thought to be at risk of heart attacks. More recently, sildenafil has been found to be useful in the treatment of pumonary arterial hypertension. A brand name is Viagra.
References in periodicals archive ?
In the second group, the participants had to consume 50 mg sildenafil citrate tablets for 4 weeks.
Sildenafil citrate alone can cause mean peak reductions in systolic/diastolic blood pressure that are not dose related, whereas the heart rate is unchanged (3).
MF and EF were significantly altered in the treatment groups on the 15th and 28th day and 7 and 15 days after treatment withdrawal, whereas sildenafil citrate altered these parameters only on the 15th and 28th day of the treatment but not after withdrawal of the treatment.
Dinsmore WW, Hodges M, Hargreaves C, et al: Sildenafil citrate (Viagra) in erectile dysfunction: Near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects.
Based upon the enormous popularity, physiological safety, and proven effectiveness of sildenafil citrate (Viagra[TM]), (1) strong arguments can be made that this medication should be considered a modern miracle drug.
DRUG company Pfizer undertook a six-year clinical development programme with sildenafil citrate in PAH.
Named sildenafil citrate, it's better known as Viagra.
Sildenafil citrate, Viagra's active ingredient, has side-effects, including heart problems, breast enlargement and blurred vision.
Validation of a capillary gas chromatographic method for the determination of sildenafil citrate in its pharmaceutical formulations (Viagra).
SILDENAFIL NOT FOR WOMEN Pfizer will not seek regulatory approval for the use of sildenafil citrate (Viagra) as a treatment for female sexual arousal disorder, the company recently announced.
Originally known by its chemical name, sildenafil citrate, Viagra was initially developed to treat angina, a condition marked by a sudden decrease of blood to the heart.