Associate editor: R.M. Wadsworth
Prostacyclin and its analogues in the treatment of pulmonary hypertension

https://doi.org/10.1016/j.pharmthera.2004.01.003Get rights and content

Abstract

Prostacyclin and its analogues (prostanoids) are potent vasodilators and possess antithrombotic and antiproliferative properties. All of these properties help to antagonize the pathological changes that take place in the small pulmonary arteries of patients with pulmonary hypertension. Indeed, several prostanoids have been shown to be efficacious to treat pulmonary hypertension, while the main mechanism underlying the beneficial effects remains unknown. There are indications of beneficial combination effects of prostaglandins and phosphodiesterase inhibitors and endothelin receptor antagonists. This speaks in favor of combination therapies for pulmonary hypertension in the future.

The mode of application of prostanoids used in randomized controlled studies has been quite variable: continuous i.v. infusion of prostacyclin, continuous s.c. infusion of treprostinil, p.o. application of beraprost, and inhaled application of iloprost. In addition, the applied doses were quite different, ranging from 0.25 ng/kg/min for inhaled iloprost to 30–50 ng/kg/min for i.v. prostacyclin. While the principal pharmacological properties of all prostanoids are very similar due to a main action on IP receptors, there are considerable differences in pharmacokinetics and metabolism, with half-lives of 2 min for prostacyclin and about 34 min for treprostinil for i.v. infused drugs and half-lives of about 85 min for s.c. infused treprostinil. In addition, the adverse effects largely depend on the doses used and the mode of application, although there is great variability between subjects. It remains to be determined which patients will profit most from which substance (or combination) and mode of application.

Introduction

Modern drugs for pulmonary hypertension have given new hope to patients with this terrible life-threatening disease, but still there is no cure in sight. In severe idiopathic pulmonary arterial hypertension (PAH), life expectancy has approximately doubled with i.v. prostacyclin, but this therapy is prone to complications and side effects. Alternative treatments have been developed using stable analogues, the prostanoids. Recently, endothelin (ET) receptor antagonists have also been shown to be efficacious, and phosphodiesterase (PDE) inhibitors are in development. It can be assumed that combination therapy will be more effective than single drug therapy. However, it will be very important to proceed step by step and to carefully evaluate each single component of the therapy. This review provides the most recent data on prostacyclin and its analogues, which appear destined to be important for the foreseeable future in the treatment of pulmonary hypertension.

Section snippets

Treatment of pulmonary hypertension

Severe pulmonary hypertension is a disease that drastically limits physical capability and seriously reduces life expectancy. Without treatment, median life expectancy is only 2.8 years following diagnosis of the illness (D'Alonzo et al., 1991). Very often, the patient is forced to give up their job. Even household chores can only be partially managed. The patients' independence is massively restricted. The treatment of pulmonary hypertension is difficult. This stems from the fact that

Reduced prostacyclin/thromboxane ratio

The synthesis of prostacyclin is reduced in chronic pulmonary hypertension, whereas the synthesis of thromboxane A2 (TXA2), its physiological antagonist, is increased (Christman et al., 1992). Accordingly, there is histological evidence of reduced prostacyclin synthase expression in the pulmonary arteries of patients with PPH (Tuder et al., 1999). This shift in the balance from prostacyclin to TXA2 favors vasoconstriction, proliferation, thrombosis, and inflammation in the affected vessels and

Nitric oxide

Inhalation with NO leads to pulmonary-selective vasodilatation because the gas diffuses into the pulmonary resistance vessels where it activates guanylyl cyclase. According to current theory, it is the product of guanylyl cyclase, cyclic guanosine monophosphate (cGMP), which is mainly responsible for vascular relaxation. NO immediately binds to hemoglobin on entry into the blood and is thus biologically inactivated (Frostell & Zapol, 1995). This eliminates the risk of systemic side effects and

Pharmacological characteristics of prostacyclin analogues and clinical studies

Three prostacyclin analogues have been developed for treatment of pulmonary hypertension: treprostinil, beraprost, and iloprost (Fig. 4). Despite some differences, the substances seem to have quite similar pharmacological and pharmacodynamic properties. They are stable in physiological saline at room temperature and can be diluted with physiological solutions without risk of inactivation. Iloprost is the agent that has been most intensively investigated in different animal models and man. In

Acknowledgments

We thank Mary Kay Steen-Mueller, MD, for carefully reviewing the manuscript.

References (141)

  • E. Giasson et al.

    Cyclic AMP-mediated inhibition of angiotensin II-induced protein synthesis is associated with suppression of tyrosine phosphorylation signaling in vascular smooth muscle cells

    J Biol Chem

    (1997)
  • B.M. Groves et al.

    A comparison of the acute hemodynamic effects of prostacyclin and hydralazine in primary pulmonary hypertension

    Am Heart J

    (1985)
  • T. Higenbottam et al.

    Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin)

    Lancet

    (1984)
  • M. Hildebrand

    Pharmacokinetics of iloprost and cicaprost in mice

    Prostaglandins

    (1992)
  • M. Hildebrand et al.

    Pharmacokinetics of 3H-cicaprost in healthy volunteers

    Prostaglandins

    (1989)
  • M.M. Hoeper et al.

    A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH Study Group

    J Am Coll Cardiol

    (2000)
  • T.K. Jeffery et al.

    Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension

    Prog Cardiovasc Dis

    (2002)
  • J.P. Kinsella et al.

    Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn

    J Pediatr

    (1997)
  • C.J. Lo et al.

    Prostaglandin I2 analogue, iloprost, down regulates mitogen-activated protein kinases of macrophages

    J Surg Res

    (1998)
  • O.I. Miller et al.

    Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide

    Lancet

    (1995)
  • N. Nagaya et al.

    Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension

    J Am Coll Cardiol

    (1999)
  • M. Negishi et al.

    Molecular mechanisms of diverse actions of prostanoid receptors

    Biochim Biophys Acta

    (1995)
  • S. Nishio et al.

    The in vitro and ex vivo antiplatelet effect of TRK-100, a stable prostacyclin analog, in several species

    Jpn J Pharmacol

    (1988)
  • Y. Okano et al.

    Orally active prostacyclin analogue in primary pulmonary hypertension

    Lancet

    (1997)
  • H. Olschewski et al.

    Physiologic basis for the treatment of pulmonary hypertension

    J Lab Clin Med

    (2001)
  • H. Olschewski et al.

    Cellular pathophysiology and therapy of pulmonary hypertension

    J Lab Clin Med

    (2001)
  • J. Pepke-Zaba et al.

    Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension

    Lancet

    (1991)
  • K.L. Pierce et al.

    Prostanoid receptor heterogeneity through alternative mRNA splicing

    Life Sci

    (1998)
  • K.L. Pierce et al.

    Activation of FP prostanoid receptor isoforms leads to Rho-mediated changes in cell morphology and in the cell cytoskeleton

    J Biol Chem

    (1999)
  • G.G. Pietra

    Histopathology of primary pulmonary hypertension

    Chest

    (1994)
  • J.D. Roberts et al.

    Inhaled nitric oxide in persistent pulmonary hypertension of the newborn

    Lancet

    (1992)
  • S.W. Allen et al.

    Circulating immunoreactive endothelin-1 in children with pulmonary hypertension. Association with acute hypoxic pulmonary vasoreactivity

    Am Rev Respir Dis

    (1993)
  • D.B. Badesch et al.

    Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial

    Ann Intern Med

    (2000)
  • R.J. Barst et al.

    Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin

    Ann Intern Med

    (1994)
  • R.J. Barst et al.

    A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group

    N Engl J Med

    (1996)
  • R.J. Barst et al.

    Vasodilator therapy for primary pulmonary hypertension in children

    Circulation

    (1999)
  • B.H. Brundage

    Medical treatment of pulmonary hypertension with prostacyclin

  • B.W. Christman et al.

    An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension

    N Engl J Med

    (1992)
  • L.H. Clapp et al.

    Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery

    Am J Respir Cell Mol Biol

    (2002)
  • R.A. Coleman et al.

    International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes

    Pharmacol Rev

    (1994)
  • D.J. Crutchley et al.

    Effects of prostacyclin analogues on human endothelial cell tissue factor expression

    Arterioscler Thromb

    (1993)
  • E. Cueto et al.

    Life-threatening effects of discontinuing inhaled nitric oxide in children

    Acta Paediatr

    (1997)
  • G.E. D'Alonzo et al.

    Survival in patients with primary pulmonary hypertension. Results from a national prospective registry

    Ann Intern Med

    (1991)
  • N. Davie et al.

    ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells

    Am J Respir Crit Care Med

    (2002)
  • A.P. De Jaegere et al.

    Endotracheal instillation of prostacyclin in preterm infants with persistent pulmonary hypertension

    Eur Respir J

    (1998)
  • B.S. Della et al.

    Differential effects of cyclo-oxygenase pathway metabolites on cytokine production by T lymphocytes

    Prostaglandins Leukot Essent Fatty Acids

    (1997)
  • B.S. Della et al.

    Cytokine production in scleroderma patients: effects of therapy with either iloprost or nifedipine

    Clin Exp Rheumatol

    (1997)
  • R.P. Dellinger

    Inhaled nitric oxide in acute lung injury and acute respiratory distress syndrome. Inability to translate physiologic benefit to clinical outcome benefit in adult clinical trials

    Intensive Care Med

    (1999)
  • R.P. Dellinger et al.

    Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group

    Crit Care Med

    (1998)
  • M. Dumas et al.

    Role of potassium channels and nitric oxide in the effects of iloprost and prostaglandin E1 on hypoxic vasoconstriction in the isolated perfused lung of the rat

    Br J Pharmacol

    (1997)

    • Cited by (0)

    View full text
    Copyright © 2004 Elsevier Inc. All rights reserved.