ABSTRACT

Pulmonary hypertension is the presence of median pulmonary pressure › 25 mmHg at rest or 30 mmHg during exercise in the right heart catheterization. It has been described over 100 years, and actually persist many questions about etiology, early diagnosis and treatment. In the last 50 years, has been created many diagnostic and treatment strategies that have modified the disease course. Treatment with digitalis, diuretics, and vasodilators has had a substantial impact on the evolution of this disease, the hemodynamic study evaluate the different drug profile and their effect on pulmonary hypertension. Prostanoids and derivates improve the cardiopulmonary hemodynamics, without the secondary effects of calcium-channel blockers, venous and arterial vasodilators used before.
Iloprost, prostacyclin analogue, initially as vasodilator in peripheric vascular disease, showed since 1980’s pulmonary vasodilator properties by intravenous infusion. In the next years, those actions were confirmed and inhalated administration was introduced, observing pulmonary selectivity and improvement of cardiopulmonary hemodynamics. It has an acute effect, similar to nitric oxide and prostacyclin, which made it useful in the diagnosis and stratification of the patients. When it is used as long-term therapy, permit long term pulmonary pressure control, increase survival, functional improvement on exercise testing, increasing functional class.
Currently, is recommended for pulmonary hypertension, and it is under investigation with sildenafil or bosentan for the long-term treatment of severe pulmonary hypertension, and thus, modify the disease prognosis.

KEYWORDS

Iloprost, inhaled iloprost, idiopathic pulmonary hypertension, pulmonary hypertension.

REFERENCES

1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1998; 336: 111-17.

2. Sandoval J, Bauerle O, Palomar A, et al. Survive in primary pulmonary hypertension: validation of a prognostic equation. Circulation 1994; 89: 1733-44.

3. Pulido-Zamudio T. Tratamiento de la hipertensión arterial pulmonar. Arch Cardiol Mex 2004; 74 (Supl. 2): S349-52.

4. Higenbottam T, Butt AY, McMahon A. Long-term intravenous prostaglandin (epoprostenol or iloprost) for the treatment of severe pulmonary artery hypertension. Heart 1998; 80: 151-55.

5. Higenbottam T, Butt AY, Dinh-Xuan AT. Treatment of pulmonary hypertension with the continuous infusion of a prostacyclin analogue, iloprost. Heart 1998; 79: 175-82.

6. Rich S, Dantzker D, Ayres S, et al. Primary pulmonary hypertension. A national prospective study. Ann Int Med 1987; 107: 216-23.

7. D´Alonzo GE, Barst R, Ayres RJ, et al. Survival in patients with primary pulmonary hypertension. Ann Int Med 1991; 115: 343-49.

8. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609-16.

9. Badesh DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension. ACCP evidence-based clinical practice guidelines. Chest 2004; 126: 35s-62s.

10. Barst RJ, Rubin LJ, long WA. A comparison for continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334: 296-302.

11. Schror K, Darius H, Ohlendorf R, et al. Dissociation of antiplatelet effects from myocardial cytoprotective activity during acute myocardial ischemia in cats by a new carbacyclin derivative (ZK 36 375). J Cardiovasc Pharmacol. 1982; 4:554-61.

12. Kaukinen S, Ylitalo P, Pessi T, Vapatalo H. Hemodynamic effects of iloprost, a prostacyclin analog. Clin Pharmacol Ther 1984; 36: 464-9.

13. Turker RK, Ercan ZS, Zengil H, Akar F. Iloprost (ZK 36 374) modulates the responses to beta-adrenoceptor agonists in guinea-pig airways and pulmonary vasculature. Arch Int Physiol Biochim 1985; 93: 263-9.

14. Olschewsky H, Walmrath D, Schermuly R, et al. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Int Med 1996; 124: 820-4.

15. Walmrath D, Schneider T, Pilch J, et al. Aerosilised prostacyclin in adult respiratory distress syndrome. Lancet 1993; 342: 961-2.

16. Olschewski H, Gofrani HA, Walmrath D, et al. Inhaled prostacyclin and iloprost in severe pulmonary artery hypertension secondary to lung fibrosis. Am J Resp Crit Care Med 1999; 160: 600-7.

17. Olschewski H, Hofrani HA, Walmrath D, et al. Recovery from circulatory shock in severe primary pulmonary hypertension with aerosolization of iloprost. Intens Care Med 1998; 24: 631-4.

18. Davie N, Haleen SJ, Upton PD, et al. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Resp Crit Care Med 2002; 165: 398-405.

19. Belch JJ, Greer I, McLaren M, et al. The effects of intravenous ZK 36 374, a stable prostacyclin analogue, on normal volunteers. Prostaglandins 1984; 28:67-77.

20. Smith EF, Kloster G, Stocklin G, Schror K. Effect of iloprost (ZK 36 374) on membrane integrity in ischemic rabbit hearts. Biomed Biochim Acta 1984; 43: 155s-8s.

21. Hsu HH, Robin LJ. Iloprost inhalation solution for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother 2005; 6 1921-1930.

22. Welte M, Zwissler B, Habazetti H. PGI2 aerosol versus nitric oxide for selective pulmonary vasodilation in hypoxic pulmonary vasoconstriction. Eur Surg Res 1993; 25: 329-40.

23. Olschewsky H, Rohde B, Behr J, Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices in severe pulmonary hypertension. Chest 2003; 124: 1294-304.

24. Krause W, Humpel M, Hoyer GA. Biotransformation of the stable prostacyclin analogue, iloprost, in the rat. Drug Metab Dispos 1984; 12: 645-51.

25. Hildebrand M, Krause W, Fabian H, Koziol T, Neumayer HH. Pharmacokinetics of iloprost in patients with chronic renal failure and on maintenance haemodialysis. Int J Clin Pharmacol Res 1990; 10: 285-92.

26. de Donato G, Gussoni G, de Donato G, et al. The ILAILL study: iloprost as adjuvant to surgery for acute ischemia of lower limbs: a randomized, placebo-controlled, double-blind study by the Italian Society for vascular and endovascular surgery. Ann Surg 2006; 244: 185-93.

27. Bettoni L, Geri A, Airo P, et al. Systemic sclerosis therapy with iloprost: A prospective observational study of 30 patients treated form a median of 3 years. Clin Reumatol 2002; 21: 244-50.

28. Hoeper MM, Spiekerkoetter E, Westerkamp V, et al. Intravenous iloprost for treatment failure of aerosolized iloprost in pulmonary arterial hypertension. Eur Respir J 2002; 20: 339–343.

29. Ghofrani H, Schermuly R, Wiedermann. Ventilation/perfusion patterns in primary and secondary pulmonary hypertension during non selective and selective vasodilatation. Am J Resp Crit Care Med 1998; 157: A592.

30. Gessler T, Schmehl T, Hoeper MM. Ultrasonic versus jet nebulization of iloprost in severe pulmonary hypertension. Eur Resp J 2001; 17: 14-19.

31. Morales-Blanhir J. Hipertensión pulmonar. Rev Inst Nal Enf Resp 2004; 17: 8s-9s.

32. Hoeper MM, Olschewsky H, Ghofrani HA, et al. A comparison of the acute hemodynamics effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. J Am Coll Cardiol 2000; 35: 179-82.

33. Opitz CF, Wensel R, Bettmann M, et al. Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation. European Heart Journal 2003; 24: 356–65.

34. Fruhwald F, Kjellstro B; Perthold W, et al. Continuous hemodynamic monitoring in pulmonary hypertensive patients treated with inhaled iloprost. Chest 2003; 124: 351–59.

35. Wensel R, Opitz F, Ewert R, et al. Effects of iloprost inhalation on exercise capacity and ventilatory efficiency in patients with primary pulmonary hypertension. Circulation 2000; 101: 2388-92.

36. Blumberg F, Riegger G, Pfeifer M. Hemodynamic effects of aerosolized iloprost in pulmonary hypertension at rest and during exercise. Chest 2002; 121: 1566–71.

37. Ghofrani HA, Friese G, Discher T, et al. Inhaled iloprost is a potent acute pulmonary vasodilator in HIV-related severe pulmonary hypertension. Eur Respir J 2004; 23: 321–26.

38. Olschwesky H, Ghofrani HA, Schmehl T, et al. Inhaled iloprost to treat severe pulmonary hypertension: an uncontrolled trial. German PHH Study Group. Ann Int Med 2000; 132: 435-43.

39. Olschewsky H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347: 322-29.

40. 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: 1866-70.

41. Badesch DB, McLaughlin VV, Delcroix M. Prostanoid therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 56s-61s.

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

43. Seyfarth HJ, Pankau H, Hammerschmidt S, et al. Bosentan improves exercise tolerance and Tei index in patients with pulmonary hypertension and prostanoid therapy. Chest 2005; 128: 709-13.

44. Gomberg-Maitland M, Preston IR. Prostacyclin therapy for pulmonary arterial hypertension: new directions. Sem Resp Crit Care Med 2005; 26: 394-402.

45. Dembinski R, Brackhahn W, Henzler D, et al. Cardiopulmonary effects of iloprost in experimental acute lung injury. Eur Respir J 2005; 25: 81–7.

46. Schermuly RT, Schulz A, Ghofrani HA, et al. Pharmacokinetics and metabolism of infused versus inhaled iloprost in isolated rabbit lungs. J Pharmacol Exp Ther 2002; 303: 741–45.

47. European TAO Study Group. Oral iloprost in the treatment of tromboangiitis obliterans (Buerger’s disease): a double blind, randomized, placebo-controlled trial. Eur J Vasc Endovasc Surg 1998; 16: 300-7.

48. Frishman WH, Fink AN, Azizad M, Agarwal Y. Use of prostacyclin and its analogues in the treatment of cardiovascular disease. Heart Dis 1999; 1: 29-40.

49. Ylitalo P, Kaukinen S, Seppala E, et al. Pharmacological effects of iloprost (ZK 36 374), a stable prostacyclin analogue, in man. Biomed Biochim Acta 1984; 43: 399s-402s.

50. Angeli P, Gatta A, Caregaro L, et al. Effects of iloprost, a prostacyclin analog derivate, on renal plasma flow, renal function, and renin-aldosterone system in humans. Clin Pharmacol Ther 1988; 44: 211–16.

51. Lifschitz MD, Barnes JL. Prostaglandin I2 attenuates ischemic acute renal failure in the rat. Am J Physiol 1984; 247: 714–17.

52. Langer F, Wendler O, Wilheim W. Treatment of a case of acute right heart failure by inhalation of iloprost, a long-acting prostacyclin analogue. Eur J Anaesthesiol 2001; 18: 770-3.

53. Sablotzki A, Czeslick E, Schubert S, et al. Iloprost improves hemodynamics in patients with severe chronic cardiac failure and secondary pulmonary hypertension. Can J Anesth 2002; 49: 1076–1080.

54. Hildebrand M, Krause W, Oberender HA, Zurdel-Dillinger S, Junger M, Bodenburg H. Pharmacokinetics of iloprost in patients with severe peripheral arterial occlusive disease. Eicosanoids 1990; 3: 145-8.

55. Hildebrand M, Krause W, Angeli P, et al. Pharmacokinetics of iloprost in patients with hepatic dysfunction. Int J Clin Pharmacol Ther Toxicol 1990; 28: 430-4.

56. Thurm CA, Wigley FM, Dole WP, Wise RA. Failure of vasodilator infusion to alter pulmonary diffusing capacity in systemic sclerosis. Am J Med 1991; 90: 547-52.

57. Paolisso G, Gambardella A, Saccomanno F, et al. Low-dose iloprost infusion improves insulin action and non-oxidative glucose metabolism in hypertensive patients. Eur J Clin Pharmacol 1995; 48: 333-8.

58. Spinks NR, O’Neill C. Antagonists of embryo-derived platelet-activating factor prevent implantation of mouse embryos. J Reprod Fertil 1988; 84: 89-98.

59. Adis International Limited. Inhaled iloprost in primary pulmonary hypertension: profile report. Drugs & Therapy Perspectives 2004; 20: 6-8.