A 32 y/o female patient on continuous oxygen via nasal cannula presents to the pharmacy window with a prescription for sildenafil [Viagra®]. She seems fatigued and exhibits dyspnea after walking the short distance across the lobby from the internal medicine clinic to the pharmacy window.

Do you reject the prescription immediately, espousing the current Health Affairs policy stating the drug is used for males > 18 years of age for erectile dysfunction of specified causes?

Maybe not. If the patient has pulmonary hypertension (based on observed symptoms and chronic oxygen therapy), she MAY be a candidate for this drug. Obviously, there would need to be a precise diagnosis of this disease before considering this drug therapy. Consultation with the prescribing/attending physician would be in order.

If this is the case, there is some LIMITED (stress limited!) data studying sildenafil alone and/or with other agents in the treatment of severe pulmonary hypertension. The most recent article (published in March 2002 in The Annals of Internal Medicine, citation below) showed sildenafil is a potent pulmonary vasodilator. This study used inhaled nitric oxide and iloprost (inhaled prostaglandin) in all patients to help determine baseline responses to these agents. After returning to baseline after the above treatments, the protocol then assigned them to varying doses of sildenafil alone and sildenafil plus inhaled iloprost. The authors warn that this study's small sample size and lack of long term observation, may limit the ability to extrapolate its' results to other populations. More research is needed before this therapy can be used/recommended routinely. If this therapy is entertained locally, would make sure a pulmonary specialist is involved. An IRB approved protocol would likely be advised/desirable.

Below is some additional information from MICROmedex on sildenafil and iloprost for treatment of pulmonary hypertension:

SILDENAFIL - Effective, when used with nitric oxide, in reducing pulmonary artery pressure and increasing arterial oxygen tension in a woman with pulmonary hypertension (NOTE - VERY small sample size, n=ONE!)

By blocking the phosphodiesterase (PDE-5) and therefore increasing the availability of cyclic guanosine monophosphate, low-dose sildenafil enhanced the effects of nitric oxide in reducing pulmonary artery pressure and increasing arterial oxygen tension (PaO2) in a 52-year-old woman with acute respiratory failure. The patient had severe interstitial pulmonary fibrosis, Crohn's disease, and previous pulmonary thromboembolism. Gram stains of bronchial secretions revealed large number of neutrophils without specific organism. Hemodynamic study indicated that she had a right-to-left intracardiac shunt. After inhaling nitric oxide 5 parts per million, her pulmonary artery pressure decreased from 52 millimeters of mercury (mmHg) to 44 mmHg. Administration of sildenafil 25 milligrams through a nasogastric tube produced similar result, and the combination of sildenafil and nitric oxide further decreased the pressure to 40 mmHg. The PaO2 increased by 76%, 40%, and 112%, and calculated venous admixture decreased from 51% to 37%, 44%, and 34% with nitric oxide, sildenafil, and combination, respectively. There was a marked resolution of the right-to-left intracardiac shunt. Unfortunately, the patient died of worsening lung infection 10 days later. Sildenafil might increase extracardiac shunting and should not be used in patients with hypoxemia from intrapulmonary shunting (such as acute respiratory distress syndrome) where it might further decrease PaO2. It is an absolute contraindication to use sildenafil with nitroglycerin and sodium nitroprusside (Bigatello et al, 2000).

Bigatello LM, Hess D, Dennehy KC et al: Sildenafil can increase the response to inhaled nitric oxide (case report). Anesthesiology 2000; 92:1827-1829.

Ghofrani HA, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515-22.

ILOPROST - Improves exercise tolerance in patients with pulmonary hypertension - Effective when administered long-term in aerosolized form.

     a. Continuous long-term infusion of iloprost increased exercise tolerance in patients with pulmonary hypertension. In a small study (n=8), ambulatory patients were given iloprost and prostacyclin in a cross-over design, with each phase lasting for 3.5 or more weeks. The length of phases varied greatly among patients due to considerations of practicality. Doses were individualized. Distance walked during 12 minutes increased and length of rest periods decreased significantly with both treatments. This study did not show either treatment superior. However, iloprost offers practical advantages over prostacyclin because of its greater stability and its solubility in isotonic solution (Higenbottam et al, 1998).

     b. Treatment of primary pulmonary hypertension with aerosolized iloprost for 3 months improved pulmonary arterial pressure, right atrial pressure, systemic vascular resistance, pulmonary vascular resistance, stroke volume, and mixed venous oxygen saturation (p less than 0.05 for each parameter). Pre-inhalation improvements were sustained at 12 months or, for systemic vascular resistance and stroke volume, were further improved. Walking distance in the 6-minute test increased significantly (p less than 0.001), from 278 meters (m) to 353 m, during 3 months of treatment; improvement was sustained at 12 months but not further increased. Twenty-four patients with New York Heart Association functional class III or IV pulmonary hypertension received an initial daily dose of 100 micrograms (mcg) of iloprost in 6 or inhalations every 2 to 3 hours (except during the night). For 6 patients whose exercise capacity had not increased after 3 months, the daily dose was increased to 150 mcg. Patients with a more pronounced short-term response were more likely to have a sustained long-term response (r=0.66, p less than 0.001). Coughing during inhalation, which was common during the first few days of treatment, disappeared spontaneously in all cases within 4 weeks. Advantages of aerosolized iloprost over continuously infused iloprost include pulmonary selectivity, not requiring a permanent central venous catheter, and lower cost of treatment (Hoeper et al, 2000). Hemodynamic results were similar in a study of more seriously ill patients, except that systemic vascular resistance was unchanged (Olschewski et al, 2000). Of 19 patients with progressive right-heart failure receiving daily doses of aerosolized iloprost 50 to 200 mcg, function class improved in 8 patients and was unchanged in 7; 4 died during the first 3 months due to disease progression. Among the survivors, average walking distance increased significantly over 3 months (p=0.048).

     c. Intermittent inhalation of aerosolized iloprost overcame circulatory shock in a 45-year-old woman with primary pulmonary hypertension (PPH). The woman presented with decompensating right heart failure, circulatory shock, renal and hepatic failure and severe hypoxemia, despite high-dose nasal oxygen and extreme hyperventilation. PPH had been diagnosed 2 years previously, and she was being treated with diltiazem, digitalis, diuretics, and anticoagulants while waiting for a heart-lung transplant. Intravenous epoprostenol for pulmonary vasodilation was not tolerated because of decreased systemic arterial pressure. Inhaled nitric oxide increased her pO2 but did not significantly decrease her pulmonary artery pressure. In contrast, inhalation of aerosolized iloprost 9 micrograms within 10 minutes markedly decreased pulmonary artery pressure and pulmonary vascular resistance without changing systemic arterial pressure, and increased arterial pO2 and central venous oxygen saturation. During the first night, with 8 doses of 10 micrograms iloprost, her renal function and liver enzymes improved dramatically. With continued treatment of 150 mcg inhaled iloprost per day in 8 to 12 divided doses, her hepatic and renal function normalized within a few days. After 6 weeks, she was released from the hospital and at 6 months took a 6-minute walk. At 12 months, her daily activity had further improved, and she was able to walk further in 6 minutes. Her name was removed from the heart-lung transplant list (Olschewski et al, 1998).

     d. An increase in exhaled nitric oxide (NO) in response to pharmacological stimuli may be a good indicator of which patients with pulmonary hypertension will be responsive to vasodilators, such as iloprost. In a small research report, 2 women with systemic sclerosis and pulmonary hypertension were administered L-arginine (NO precursor) and glyceryl trinitrate infusions as pharmacological stimuli. Patient 1 showed an increase in exhaled NO, while patient 2 showed no change. Before stimulation, both patients had subnormal NO exhalation. Both patients were then given aerosolized iloprost 20 micrograms (mcg). Patient 1 demonstrated an increase in exhaled NO (from 2.2 to 9.5 parts per billion) and arterial oxygen concentration (PaO2) (from 65 to 80 millimeters (mm) mercury (Hg)), along with a decrease in pulmonary artery pressure (from 54 to 29 mm Hg). Patient 2 showed no change in these parameters. Patient 1 was then administered long-term iloprost therapy (100 mcg daily in five aerosols), with sustained responsiveness observed over a 3-month period as measured by pulmonary artery pressure, PaO2, and exhaled NO. Her dyspnea on effort decreased, and the 6 minute walking test distance increased (from 285 meters to 510 meters). Because the exhaled NO measurement increased following pharmacological stimuli and was associated with a positive response to the iloprost administration, this may prove to be a simple non-invasive test for identifying which systemic sclerosis patients with pulmonary hypertension are likely to respond to iloprost administration (Rolla et al, 1998).

Higenbottam TW, Butt AY, Dinh-Xaun AT et al: Treatment of pulmonary hypertension with the continuous infusion of a prostacyclin analogue, iloprost. Heart 1998; 79:175-179.

Hoeper MM, Schwarze M, Ehlerding S et al: Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000; 342(25):1866-1870.

Olschewski H, Ghofrani HA, Schmehl T et al: Inhaled iloprost to treat severe pulmonary hypertension: an uncontrolled trial. Ann Intern Med 2000; 132(6):435-443.

Rolla G, Colagrande P, Brussino L et al: Exhaled nitric oxide and pulmonary response to iloprost in systemic sclerosis with pulmonary hypertension. Lancet 1998; 351:1491-1492.

Ghofrani HA, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med. 2002;136:515-22.