Good for some, excellent for others

EDITORIAL

Good for some, excellent for others

Sérgio Saldanha Menna Barreto (te sbpt)

Full Professor at the Universidade Federal do Rio Grande do Sul Medical School. Specialist, as designated by the Sociedade Brasileira de Pneumologia e Tisiologia (Brazilian Society of Pulmonology and Phthisiology)

Sildenafil, an inhibitor of certain phosphodiesterase (PDE) enzymes (namely PDE5 and PDE6), was originally developed to treat erectile dysfunction and has been shown to be quite efficient as a pulmonary vasodilator.⁽¹⁾ Sildenafil inhibits hydrolysis and increases the concentrations of cyclic guanosine monophosphate (cGMP), which is the second messenger for the intracellular actions of nitric oxide (NO) in the smooth muscle cells (SMC) of the vessels walls. Accumulation of cGMP inhibits the action of PDE3, resulting in reduced hydrolysis and increased concentrations of cyclic monophosphate adenosine (cAMP), the second messenger for prostacyclins in the SMC.^(2,3) Subsequently, sildenafil produces a wide range of effects within the SMC. These effects have been observed in some experimental studies.^{(4, 5)} Higher concentrations of PDE5 are found in the corpus cavernosum, pulmonary SMC and retina.⁽²⁾

The first articles on the clinical use of sildenafil in the treatment of pulmonary hypertension (PH) were case reports.⁽⁶⁾ Those were followed by descriptions of case series in which sildenafil was used in association with prostanoids or nitric oxide in order to increase and prolong the effects of the main drug.^(7-14) The most relevant aspects of some original articles are described bellow.

The above-mentioned studies allow the following assumptions to be made: (1) sildenafil is an efficient vasodilator, more potent than NO and equivalent to parenteral prostanoids at their full dosage; (2) sildenafil acts mainly on pulmonary circulation, hemodynamic parameters and gas exchange; (3) even in small doses, sildenafil acts synergistically with the vasodilators with which it has been tested, such as NO and prostanoids; (4) both in isolated reports and in case series, sildenafil shows confirmed favorable effects and few adverse events; (5) the so called antimitogenic (antiproliferative or reversion of remodeling) effect attributed to other vasodilators has not yet been confirmed for sildenafil, and its vasodilator action is attributed to a potent amplifying effect upon the vasoregulatory mechanisms of pulmonary circulation; (6) well-controlled clinical studies are still needed to evaluate the long-term and adverse effects of sildenafil; (7) since the first studies were conducted^*, there has been evidence of adverse sildenafil effects on the eyes, due to retinal lesions (an experimental study showed dose-dependent pigmentary retinitis in the mouse)⁽¹⁵⁾; (8) the related adverse sildenafil effects found so far have been mild, such as dose-dependent nausea, headaches and hypotension; (9) sildenafil may be a new option for the treatment of primary pulmonary hypertension (PPH) (either alone or associated with other drugs) or PH associated with vascular-collagenous diseases; (10) sildenafil may even be an alternative for the clinical treatment of non operable chronic thromboembolic pulmonary hypertension.

In the current issue of the Journal of Pulmonology, two case reports relating to the use of sildenafil are presented.^{(16, 17)}

Souza et al.⁽¹⁶⁾ used sildenafil in a 33-year-old patient who had systemic lupus erythematosus and anti-phospholipid syndrome and was presenting a progressive increase in systolic pulmonary artery pressure (SPAP), which increased from 74 mmHg to 102 mmHg over an 18-month follow-up period, during which the patient had been taking diltiazem, warfarin and pulses of cyclophosphamide and methylprednisolone. Sildenafil was introduced cautiously and progressively, starting with 25 mg a day and reaching 100 mg a day, divided into two daily administrations. After 6 months of treatment, SPAP decreased by 34% without adverse effects. The (justifiably) cautious strategy, together with the favorable blood pressure response, suggests that the full response potential may not have been achieved.

Silva et al.⁽¹⁷⁾ present a case of severe primary pulmonary hypertension (PPH), with an SPAP of 116 mmHg, in a 21-year-old patient who experienced a sudden reduction in arterial oxygen saturation (from 95% to 65% in ambient air) after a right-to-left shunt occurred due to opening of the foramen ovale (not identified in a previous test). Sildenafil was started at 25 mg every eight hours, with rapid daily increments of 25 mg per dose until 225 mg/day was reached (probably 75 mg every eight hours). There was a progressive improvement in overall condition and arterial saturation, and the shunt had disappeared within approximately 30 days of treatment.

The authors considered this to be a consequence of a global increase in pulmonary circulation capacitance, which effectively reduced the right ventricular end systolic volume, resulting in improved cardiac output. Despite the interruption of the right-to-left shunt, SPAP remained unchanged (109 mmHg). It is regrettable that other hemodynamic parameters were not measured, because they likely would have supported the authors’ interpretation.

Thus, sildenafil is in our midst.

References

1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile function. Sildenafil Study Group. N Engl J Med 1998;338:1397-404.

2. Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995;75:725-48.

3. Corbin JD, Francis SH. Cyclic GMP phosphodiesterase-5: a target of sildenafil. J Biol Chem 1999;274:13729-32.

4. Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L, et al. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 2001;29:1000-5.

5. Kleinsasser A, Loeckinger A, Hoermann C, Puehringer F, Mutz N, Bartsch G, Lindner KH. Sildenafil modulates hemodynamics and pulmonary gas exchange. Am J Respir Crit Care Med 2001;163:339-43.

6. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000;343:1342.

7. Wilkens H, Guth A, König J, Forestier N, Cremers B, Hennen B, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001;104:1218-22.

8. Ghofrani HA, Wiedermann R, Rose F, Olschewski H, Schermuly RT, Weissman N. et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002; 136:515-22.

9. Ghofrani HA, Rose F, Schermuly RT et al.Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158-64.

10. Lepore JJ, Maroo A, Pereira NL, et al. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002;90:677-80.

11. Ghofrani HA, Wiedermann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002;360:895-900.

12. Stiebellehner L, Petkov V, Vonbank K, et al. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003;123:1293-5.

13. Ghofrani HA, Schermuly RT, Rose F, et al. Sildenafil for long term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2003;167:1139-41.

14. Sastry BK, Narasimhan C, Reddy NK et al. A study of clinical efficacy of sildenafil in patients with primary pulmonary hypertension. Indian Heart J 200;54:410-5.

15. Behn D, Potter MJ. Sildenafil-mediated reduction in retinal function in heterozygous mice lacking the gamma-subunit of phosphodiesterase. Invest Ophthalmol Vis Sci 2001;42:523-7.

16. Souza EJR, Garib JR, Garib NM, Pádua PM. Sildenafil no tratamento da hipertensão pulmonar associada ao LES e síndrome antifosfolipídio. J Pneumol 2003;29:302-4.

17. Silva SM, Valeri CB, Bogossian HB, Jardim C, Demarzos SE, Souza R. Resolução do shunt direita-esquerda após o uso de sildenafil como tratamento da hipertensão pulmonar primária. J Pneumol 2003;29: 305-8.

*

In the most recent congress of the American Thoracic Society-ATS, which took place in Seattle in May, 2003, Dr. LJ Rubin, when presenting sildenafil, said that its effects are good for some and excellent for others. He was implicitly referring to the opinions of researchers, but the audience found it quite amusing.

Publication Dates

• Publication in this collection
  15 June 2004
• Date of issue
  Oct 2003