INDICATIONS

The World Health Organization (WHO) has classified PAH into several categories. Citrate (Revatio, Pfizer) is an oral treatment that has been approved by the FDA to improve the exercise ability of patients in New York Heart Association Class I (Table 1). Revatio is a new formulation of Pfizer’s Viagra, which is indicated for erectile dysfunction. The efficacy of sildenafil has not been evaluated in patients currently receiving therapy with bosentan (Tracleer, Actelion), another agent approved for patients with PAH.

PHARMACOLOGY

Sildenafil inhibits cyclic guanosine monophosphate (cGMP) and is selective for phosphodiesterase type 5 (PDE^), thereby inhibiting nitric oxide. This action results in the relaxation of pulmonary vascular smooth muscle and promotes vasodilation in smooth muscle. Sildenafil canadian thus increases cGMP within pulmonary vascular smooth-muscle cells, resulting in relaxation. In patients with pulmonary hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, to vaso-dilation in the systemic circulation.

Table 1 NewYork Heart Association/World Health Organization Functional Assessment of Pulmonary Arterial Hypertension

Class

Description

I

Symptoms do not limit physical activity. Ordinary physical activity does not cause undue discomfort.

II

There is slight limitation of physical activity.The patient is comfortable at rest yet experiences symptoms with ordinary physical activity.

III

There is marked limitation of physical activity.The patient is comfortable at rest yet experiences symptoms with minimal activity.

IV

There is an inability to carry out any physical activity.The patient may experience symptoms even at rest. Discomfort is increased by any physical activity.The patient manifests signs of right-sided heart failure.
Adapted with permission from Cohen H, Chahine C, Hui A, et al. Am J Health Syst Pharm 2004;61(11):1107-1119.© 2004, American Society of Health-System Pharmacists, Inc.

 

PHARMACOKINETICS

Absorption and Metabolism Sildenafil is absorbed rapidly after oral administration, with an absolute bioavail-ability of about 40%. In the fasting state, the peak plasma concentration (Cmax) is obtained within 30 to 120 minutes (median, 60 minutes) of oral dosing. With high-fat meals, the rate of absorption is reduced, the time to peak levels (Tmax) is delayed by 60 minutes, and the Cmax is reduced by about 29%. Sildenafil is distributed into the tissues, as indicated by the mean steady-state volume of distribution (Vss) of 105 liters.

Both sildenafil and W-desmethyl, a major active circulating metabolite, are 96% bound to plasma proteins. Protein binding is independent of total drug con-centrations.

Sildenafil is metabolized by hepatic microsomal cytochrome P450 iso-enzymes CYP 3A4 and CYP 2C9. CYP 3A4 is the major metabolizing enzyme and is derived from the W-desmethyla-tion of sildenafil. W-desmethyl’s PDE selectivity is similar to that of sildenafil medication. Its potency for PDE5 in vitro is approximately 50% of that of the parent drug.
In normal, healthy patients, the metabolite’s plasma concentrations are about 40% of those observed for sildenafil and the metabolite accounts for about 20% of sildenafil’s pharmacological effects. In patients with PAH, the ratio of the metabolite to sildenafil is higher.

Sildenafil and the active metabolite have terminal half-lives of about four hours. Inhibitors of CYP450 3A4  (Abbott), (Nizoral canadian, Janssen),  (Janssen), as well as nonspecific CYP inhibitors such as cimeti-dine (Tagamet, GlaxoSmithKline), may increase plasma levels of sildenafil. W-desmethyl is then further metabolized to inactive compounds.

Sildenafil is eliminated as metabolites; about 80% of the oral dose is eliminated in the feces, and about 13% is excreted in the urine.

SPECIAL POPULATIONS

Geriatric Patients Age may be a consideration in the administration of other medications, but the impact of age, sex, race, and renal or hepatic dysfunction has not had statistically significant effects on the pharmacokinetics of sildenafil.

Healthy geriatric patients aged 65 years or older had a reduced clearance; their free plasma concentrations were approximately 40% more than those seen in healthy volunteers of 18 to 45 years of age.

Patients with Renal Insufficiency

Subjects with mild renal insufficiency (a creatinine clearance [CrCl] from 50 to 80 ml/minute) and those with moderate renal insufficiency (a CrCl from 30 to 49 ml/minute) did not show renal impairment after taking a single oral dose of sildenafil 50 mg. In patients with severe renal impairment (a CrCl below 30 ml/ minute), clearance of the drug was decreased. The result was a doubling of the area-under- the-curve (AUC) concentration and the Cmax in these patients, compared with volunteers of the same age who did not have renal impairment.

Patients with Hepatic Insufficiency

In patients with hepatic cirrhosis, the CrCl was reduced, resulting in elevated AUC concentrations (84%) and in the Cmax (47%), compared with volunteers of the same age with no hepatic impairment. Patients with severe hepatic impairment were not evaluated.