DESCRIPTION

Sildenafil (Viagra) is an oral selective phosphodiesterase inhibitor that is used to treat erectile dysfunction.

FORMS AND USES

• Sildenafil is used to treat erectile dysfunction of either organic or psychogenic etiology.
• It is formulated as blue diamond-shaped tablets (25, 50, and 100 mg) for oral use.
• A dose of 25 to 100 mg is taken 0.5 to 4 hours before sexual activity once per day.

TOXIC DOSE

• Healthy volunteers tolerated single doses as large as 800 mg with a side effect profile similar to that seen at lower doses.
• Death or other serious effects following overdose have not been reported, although sudden death has occurred during therapeutic use and vigorous sexual activity.

PATHOPHYSIOLOGY

• Inflow of blood into the corpus cavernosum of the penis is increased by smooth muscle relaxation, a process that is enhanced by increased levels of cyclic guanosine monophosphate (cGMP).
• Phosphodiesterase type 5 (PDE5) is found in the penis and degrades cGMP.
• Through the inhibition of PDE5, sildenafil enhances the relaxation of vascular smooth muscle and allows an erection to occur.
• However, concurrent sexual stimulation is required to improve erectile dysfunction.
• Sildenafil inhibits other forms of PDE. Weak inhibition of PDE6 is thought to be the mechanism for the visual symptoms experienced by some patients who use sildenafil.

EPIDEMIOLOGY

• Sildenafil use has been described in an age group that ranges from 19 to 87 years.
• Toxic effects following exposure are typically minor; however, very large ingestions may cause hypotension, vasodilation, and tachycardia. This is particularly true when large doses of sildenafil are taken in the presence of organic nitrates.

CAUSES

• Poisoning is usually accidental.
• Child abuse or neglect should be considered if the patient is less than 1 year of age; suicide attempt in patients over 6 years of age.

DRUG AND DISEASE INTERACTIONS

• Sildenafil is eliminated via hepatic metabolism (predominantly CYP3A4) producing an active metabolite.
• Both the parent compound and the metabolite have similar elimination half-lives of approximately 4 hours.
• Healthy volunteers over the age of 65 had reduced clearance of sildenafil with plasma concentrations 40% higher than younger patients.
• Clearance of sildenafil is reduced in patients with hepatic insufficiency or significant renal impairment (creatinine clearance less than 30 ml/min).
• Concomitant use of cytochrome P450 inhibitors (especially those of the 3A4 isoforms) may reduce the clearance of sildenafil and increase serum concentrations. Examples include cimetidine, erythromycin, ketoconazole, itraconazole, and mibefradil.
• Because sildenafil has been shown to potentiate the hypotensive effects of nitrates, it is contraindicated in patients who use nitrates or other medications that could be nitric acid donors.

PREGNANCY AND LACTATION

• US FDA Pregnancy Category B. There is no evidence of teratogenicity, embryotoxicity, or fetotoxicity in animal models, but there are no controlled studies in pregnant women.
• The appearance of sildenafil in breast milk has not been studied. Sildenafil is not indicated in women or children.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Other toxicants that cause flushing and headache include nitrates, niacin, calcium channel blockers such as nifedipine, alpha-adrenergic antagonists such as prazosin, and scombroid.
• Other toxicants that cause altered vision are digoxin, quinine, quinidine, chloroquine, hydroxychloroquine, and methanol.
• Nontoxic causes of flushing, headache, and altered vision include subarachnoid hemorrhage, pheochromocytoma, carcinoid, and anaphylaxis.

SIGNS AND SYMPTOMS

Adverse effects that have been noted in clinical trials include nausea, vomiting, headache, flushing, hypotension, dyspepsia, rhinitis, and abnormal vision (blue tinge to vision or sensitivity to light). Priapism has not been reported, but could occur, particularly in patients with sickle cell anemia, multiple myeloma, or leukemia.

Vital Signs

Tachycardia may be seen.

Cardiovascular

Hypotension, vasodilation, and tachycardia have been reported, and reduction of blood pressure of up to 10 mm Hg has been observed in healthy subjects.

Pulmonary

No effects have been reported.

Renal

No effects have been reported.

Fluids and Electrolytes

No effects have been reported.

Neurologic

Alterations in color vision, including a blue-green tinge, sensitivity to light, and decreased visual acuity have been noted in a small percentage of patients taking therapeutic doses. These effects appear to be dose related and resolve when the drug is discontinued.

Musculoskeletal

Brief myalgia has been described in individuals taking therapeutic doses.

PROCEDURES AND LABORATORY TESTS

Essential Tests

No tests may be needed in asymptomatic patients.

Recommended Tests

• An ECG with continuous cardiac monitoring is necessary.
• Serum electrolytes, glucose, BUN, and creatinine levels are measured to assess other causes of hypotension or dysrhythmia.
• Serum acetaminophen and aspirin levels in the overdose setting are used to detect occult ingestion.

Not Recommended Tests

Serum sildenafil levels are not clinically useful.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • Cardiovascular
  • Pulmonary
  • Renal
  • Fluids and Electrolytes
  • Neurologic
  • Musculoskeletal
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Treatment should focus on general supportive and symptomatic care.
• The dose and time of exposure must be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Hypotension, dysrhythmia, QRS widening, seizure, or coma are present.
• Toxic effects are not consistent with sildenafil poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual challenge.

The patient should be referred to a health-care facility when:

• Overdose effects are present (including persistent sinus tachycardia).
• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Coingestant, drug interaction, or underlying disease presents an unusual challenge.

Admission Considerations

Inpatient management is warranted for all patients with altered mental status, hypotension, chest pain, or signs consistent with acute ischemic heart disease.

DECONTAMINATION

Out of Hospital

Emesis should not be induced because of low toxic potential.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients. Following a massive ingestion, if serious effects are present or another toxic substance is likely to be present.
• If a substantial ingestion has occurred within the previous few hours, one dose of activated charcoal (1-2 g/kg) without cathartic should be administered.

ANTIDOTES

There is no specific antidote for sildenafil.

ADJUNCTIVE TREATMENT

Hypotension

• The patient should receive 10 to 20 ml/kg of 0.9% saline intravenously and be placed in the Trendelenburg position. Further fluid therapy is guided by central pressure monitoring in order to avoid fluid volume overload.
• If hypotension is unresponsive to the above treatment, a vasopressor should be administered.
  • The dose of dopamine is 2 to 5 µg/kg/min intravenously, titrated upward to effect.
  • Rates greater than 20 µg/kg/min are unlikely to provide further benefit.
• If hypotension is still unresponsive, norepinephrine is added at 0.1 to 0.2 µg/kg/min intravenously and titrated upward to effect.
• Caution must be exercised because too high a rate of infusion may cause tissue ischemia.

Not Recommended Therapies

Because sildenafil is highly bound to plasma proteins and is only minimally excreted in the urine, dialysis probably will not increase the rate of sildenafil clearance.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT
  • Hypotension
  • Not Recommended Therapies

PATIENT MONITORING

• In symptomatic patients, hemodynamic and rhythm monitoring should be performed continuously.
• In asymptomatic patients, 4 to 6 hours of observation with continuous blood pressure monitoring should be instituted in the emergency department.

EXPECTED COURSE AND PROGNOSIS

Most adverse effects are expected to be minor and temporary, resolving with the cessation of drug ingestion, unless sequelae of myocardial ischemia intercede.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Asymptomatic patients may be discharged from the emergency department if their ECG is without ischemic changes and continuous cardiac monitoring does not show tachycardia or dysrhythmia for 4 to 6 hours.
• From hospital. Patients may be discharged from the hospital when clinical effects have resolved and vital signs are normal.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

Because of the nonspecific nature of the signs and symptoms of sildenafil toxicity, it is difficult to attribute these general complaints to sildenafil ingestion.

Smooth muscle relaxants.

RECOMMENDED READING

Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998;338:1397-1404.

Morales A, Gingell C, Collins M, et al. Clinical safety of oral sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Impotence Res 10:69-73.

Pfizer Laboratories. Viagra (sildenafil citrate), Product Information. Pfizer Laboratories, New York, 1998.

Authors: Jeffrey Rogers and Frank F.S. Daly

Reviewer: Richard C. Dart