Sildenafil (Viagra): Drug Whys


By Mike McEvoy

Generic Name: Sildenafil (no generic available – U.S. patent expires in 2012)
Common Brand Name: Viagra (Pfizer – U.S.)
Popularity: 37th most commonly prescribed drug between 2002 and 2008 (U.S.)
Class: Erectile dysfunction agent, phosphodiesterase inhibitor – type 5 specific.

Treatment Uses — Primary erectile dysfunction, or erectile dysfunction secondary to atherosclerosis, depression, diabetes, dialysis, drug effects, Parkinson's disease, prostatectomy, radiation therapy, or spinal cord injury. Treatment and prevention of rebound pulmonary hypertension following nitric oxide withdrawal. Treatment of Primary Pulmonary Hypertension (PPH) in adults and children (superior to inhaled nitric oxide). Treatment of sexual dysfunction (usually delayed ejaculation) associated with antidepressant drug therapy (requires high dose sildenafil). Used for treatment and prevention of high altitude pulmonary hypertension and high altitude pulmonary edema (HAPE) in mountain climbers. Improves microcirculation in Raynaud's phenomenon resistant to vasodilator therapy. Studied with conflicting results in treatment of female sexual arousal disorder as well as (male) premature ejaculation. May be useful for improving in vitro fertilization (IVF) results in certain women by improving uterine artery blood flow.

Dosing and Administration — Orally, 50 milligrams taken as needed, about 1 hour before sexual activity. Normally effective when taken anywhere from 30 minutes to 4 hours before sexual activity. Dose may be increased to a maximum of 100 milligrams or decreased to 25 milligrams based on effectiveness and tolerance. Use of sildenafil is not recommended more than once per day. Tachyphylaxis, a phenomenon where increasingly higher doses of a drug are needed to obtain similar effects, has been known to occur with sildenafil. For sildenafil, loss of effectiveness seems to occur at an average of 11 months, regardless of frequency of use, and typically requires doubling the dose to regain effect. A note for those unfamiliar with tachyphylaxis: patient susceptibility to drug side effects and toxicity remains unaffected despite requirements for progressively higher doses.

For treatment of pulmonary hypertension in adults (to improve exercise capacity), the recommended dose is 20 milligrams three times daily with spacing of at least 4 to 6 hours between doses. Doses above 20 milligrams have not been shown to offer any greater effectiveness.

A starting dose of 25 milligrams should be used in geriatric (over 65-year-old) patients and patients with kidney failure or impaired liver function. Poor clearance of sildenafil is observed in these populations, necessitating lowered dosing. Caution should be exercised in patients with impaired renal function (as opposed to renal failure) although dose adjustments are not typically needed. Sildenafil is well tolerated in patients following renal transplant and does not appear to affect transplanted kidney function or interact with immunosuppressive drugs.

Pediatric doses used for treatment of PPH follow several different formulas, but tend to approximate 0.3 mg per kilogram per dose given at 4 to 8 hour intervals and titrated to effect.

Healthy volunteers given up to 800 milligrams of sildenafil had side effects similar to those seen with recommended doses, but these side effects happened more frequently and were more significant. In overdoses, hemodialysis is unlikely to accelerate clearance of sildenafil because the drug is highly bound to plasma proteins and not eliminated in the urine.

Pharmacology/Pharmacokinetics/Stability — Following oral administration, sildenafil is rapidly absorbed, reaching peak bloodstream concentrations between 30 and 120 minutes on an empty stomach, and between 90 and 180 minutes with or immediately after meals. While food slows absorption, it does not significantly reduce the total amount of drug absorbed. The average half-life (time needed for half the active drug to be eliminated from the body) of sildenafil is 4 hours. This coincides with the effects of the drug in allowing for adequate erections up to 4 hours after ingestion. Keep in mind that sildenafil does not produce erections; it only improves ability to initiate and sustain adequate erections with sexual stimulation.

The liver processes sildenafil producing byproducts from this metabolism that actually account for some of the drug's effects. Most of the drug (80 percent) is eliminated in feces. The kidneys excrete 13 percent of the drug and small amounts are eliminated in semen. It is unknown whether sildenafil is excreted in breast milk.

Erections require release of nitric oxide (NO) into the penis during sexual stimulation. NO produces a series of reactions leading to penile smooth muscle relaxation that allows inflow of blood. Sildenafil works to enhance the effect of NO by inhibiting phosphodiesterase type 5 (PDE5) which degrades the reaction necessary for smooth muscle relaxation.

Sildenafil tablets are blue, film-coated, rounded diamond shaped and come in 25, 50, and 100 milligram strengths. They should be stored at room temperature (77 F) but remain stable when briefly kept at extremes between 59-86 F. For children, a compounding pharmacy can prepare an oral suspension of 2.5 milligrams per milliliter which is stable for 91 days in an amber plastic bottle either refrigerated or at room temperature.

Cautions and Warnings — Sildenafil and nitrates are a dangerous mixture and not recommended within 24 hours of each other. The large and sudden drops in blood pressure resulting from this combination prompted the Food and Drug Administration (FDA) to warn emergency physicians they should inquire about sildenafil use before administering nitrates.

While the literature is rife with warnings about deaths resulting from sildenafil nitrate combinations, a careful literature search failed to produce any case reports of deaths directly related to the mixture. Multiple studies have been conducted in an attempt to determine how soon nitrates can be given following sildenafil. It appears that men with stable angina can safely take nitrates 8 hours after using sildenafil and healthy men can safely take nitrates 4 hours after sildenafil.

Oddly, few EMT textbooks mention this contraindication when instructing on assisted medications. Before giving a patient nitroglycerine or isosorbide, inquire about Viagra (or other PDE5 inhibitor) use within the previous 24 hours. "Poppers" or nitrates inhaled for recreational use have similar hypotensive effects when combined with sildenafil. Don't rule out the possibility that your female patients might also be using sildenafil.

Following the hype about precipitous drops in blood pressure, several recent, well-designed studies found no adverse cardiovascular or hemodynamic effects from sildenafil on either healthy or unhealthy patients. On average, a single dose of 25, 50, or 100 milligrams of sildenafil given to healthy volunteers produced a maximal reduction in sitting systolic and diastolic blood pressure by 8.3/5.3 mmHg at 1 to 2 hours after dosing.

Cervical level spinal cord injury (SCI) patients can develop significant hypotension with sildenafil. Multiple studies evaluating the risk of myocardial infarction (MI) with sildenafil found no greater risk of MI with sildenafil than with sexual intercourse (without use of sildenafil). Timing of MI and strokes has also not correlated with use of sildenafil.

Important Side Effects and Interactions — Facial flushing (10 percent) and headache (16 percent) are the most commonly reported side effects of sildenafil. Other side effects include dizziness (2 percent), diarrhea (4 percent), indigestion (5 percent), and skin rash (2 percent). Nasal congestion and visual disturbances (blue haze with increased brightness) are frequently mentioned.

Nasal congestion is a result of vasodilator drug action. All of the aforementioned side effects are typically mild-to-moderate, and of short duration. Sudden loss of vision (some permanent) resulting from non-arteritic ischemic optic neuropathy (NAION) has occurred in a small number of patients taking sildenafil and other PDE5 inhibitors.

It is not known whether the drug caused vision loss or contributed to it in patients with underlying risk factors. NAION results from blood flow blockage to the optic nerve and usually occurs in patients with vascular risk factors. Rare cases of priapism (painful, persistent erections exceeding 6 hours duration) have been reported. Most have occurred in patients already predisposed to priapism including those with sickle cell anemia, multiple myelomas, or leukemia. Any erection lasting longer than 4 hours requires immediate medical attention to avert tissue damage and permanent impotence.

There are 38 drugs reported to interact with sildenafil, most importantly the previously mentioned nitrate family. Patients taking alpha-blocker agents often prescribed for treatment of Benign Prostatic Hyperplasia (BPH) may develop hypotension from more than 25 mg of sildenafil within 4 hours of taking the alpha-blocker. Certain antiretroviral agents considerably prolong the half-life of sildenafil, necessitating not only lower dosing, but longer intervals between doses as well. Grapefruit juice does funny things to the absorption and blood concentrations of sildenafil and although not dangerous, makes response rather unpredictable. The combination should be avoided.

Average Costs — U.S.
• 50 mg tablet (brand name Viagra)
Patient cost: $18.82 each
Large Hospital cost: $14.20 each

References:
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed October, 2009).
2. Albany Medical Center Pharmacy, Albany, New York.

 

 

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