Portopulmonary hypertension medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
In general, the treatment of PPH is derived from the pulmonary hypertension experience and literature. Though, the best treatment available is the combination of medical therapy and orthotopic liver transplantation. This review will focus on medical therapy.
Medical Therapy
The ideal treatment for PPH management is that which can achieve pulmonary vasodilatation and smooth muscle relaxation without exacerbating systemic hypotension. Most of the therapies for PPH have been adapted from the primary pulmonary hypertension literature. Calcium channel blockers, beta blockers and nitrates have all been used – but the most potent and widely used aids are prostaglandin (and prostacyclin) analogs, phosphodiesterase inhibitors, nitrous oxide and, most recently, endothelin receptor antagonists and agents capable of reversing the remodeling of pulmonary vasculature.
Inhaled nitrous oxide vasodilates by increasing intracellular cGMP in endothelial cells. It decreases pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) without affecting systemic artery pressure because it is rapidly inactivated by hemoglobin,[1] and improves oxygenation by redistributing pulmonary blood flow to ventilated areas of lung.[2] Inhaled nitrous oxide has been used successfully to bridge patients through liver transplantation and the immediate perioperative period, but there are two significant drawbacks: it requires intubation and cannot be used for long periods of time due to methemoglobinemia.
Prostaglandin PGE1 (Alprostadil) binds G-protein linked cell surface receptors that activate adenylate cyclase to relax vascular smooth muscle. [3] Prostacyclin – PGI2, an arachidonic acid derived lipid mediator (Epoprostenol, Flolan, Treprostenil) – is a vasodilator and, at the same time, the most potent inhibitor of platelet aggregation.[4] More importantly, PGI2 (and not nitrous oxide) is also associated with an improvement in splanchnic perfusion and oxygenation. [5] Epoprostenol and ilioprost (a more stable, longer acting variation[6]) can and does successfully bridge for patients to transplant.[7] Epoprostenol therapy can lower PAP by 29-46% and PVR by 21-71%.,[8] Ilioprost shows no evidence of generating tolerance, increases cardiac output and improves gas exchange while lowering PAP and PVR.[9] A subset of patients does not respond to any therapy, likely having fixed vascular anatomic changes.
Phosphodiesterase inhibitors (PDE-i) have been employed with excellent results. Sildenafil (Viagra) increases intracellular cGMP by inhibiting PDE-type 5, which is abundant in pulmonary artery smooth muscle cells.[10]. It has been shown to reduce mean PAP by as much as 50%,[11] though it prolongs bleeding time by inhibiting collagen-induced platelet aggregation.[12] Another drug, Milrinone, a Type 3 PDE-i increases vascular smooth muscle adenosine-3,5-cyclic monophosphate concentrations to cause selective pulmonary vasodilation.[13] Also, by causing the buildup of cAMP in the myocardium, Milrinone increases contractile force, heart rate and the extent of relaxation.
The newest generation in PPH pharmacy shows great promise. Bosentan is a nonspecific endothelin-receptor antagonist capable of neutralizing the most identifiable cirrhosis associated vasoconstrictor,[14] safely and efficaciously improving oxygenation and PVR,[15][16] especially in conjunction with sildenafil. [17] Finally, where the high pressures and pulmonary tree irritations of PPH cause a medial thickening of the vessels (smooth muscle migration and hyperplasia), one can remove the cause –control the pressure, transplant the liver – yet those morphological changes persist, sometimes necessitating lung transplantation. Imatinib, designed to treat chronic myeloid leukemia, has been shown to reverse the pulmonary remodeling associated with PPH. [18][19][20]
References
- ↑ Steudel et al. Inhaled nitrous oxide: Basic biology and clinical applications. Anesthesiology 1999;91:1090-121
- ↑ Lowson. Inhaled alternative to nitrous oxide. Anesthesiology 2002;96:1504-13
- ↑ Kerins et al. Prostacyclin and Prostaglandin E1: Molecular mechanisms and therapeutic utility. Prog Hemostasis Thrombosis 1991;10:307-37
- ↑ Vane et al. Pharmacodynamic profile of prostacyclin. Am J Cardiol 1995;75:3A-10A
- ↑ Eichelbronner et al. Aerosolized prostacyclin and INO in septic shock: Different effects on splanchnic oxygenation. Intensive Care Med 1996;22:880-7
- ↑ Minder et al. Intravenous ilioprost bridging to orthotopic liver transplant in portopulmonary hypertension. Eur Respir J 2004;24:703-707
- ↑ et al. Successful use of chronic epoprostenol as a bridge to liver transplant in severe PPHTN. Transplant 1998 4:457
- ↑ Kuo PC, Johnson LB, Plotkin JS, Howell CD, Bartlett ST, Rubin LJ. Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension. Transplantation 1997; 63: 604
- ↑ Lowson. Inhaled alternative to nitrous oxide. Anesthesiology 2002;96:1504-13
- ↑ Evangelos D et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003;108:2066-2069
- ↑ Makisalo et al. Sildenafil for portopulmonary hypertension in a patient undergoing liver Transplant. Liver Transplant. 2004;10:945-950
- ↑ Berkels et al. Modulation of human platelet aggregation by the phosphodiesterase type 5 inhibitor sildenafil. J Cardiovasc Pharmacolo 2001;37:413-421
- ↑ Haraldsson et al. The additive pulmonary vasodilatory effect of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension. Aesth Analg 2001;93:1439-45
- ↑ Rubin et al. Bosentan therapy for Pulmonary arterial hypertension. N Engl J Med 2002;346:896-903
- ↑ Hoeper et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J. 2005;25:502-8
- ↑ Kuntzen. Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: a safe and effective therapy? Gastroenterology. 2005;128:164-8
- ↑ Wilkins et al.Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292-7
- ↑ Schermuly et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115:2811-2821 (2005).
- ↑ Ghofrani et al. Imatinib for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2005; 353:1412-1413
- ↑ Tapper EB, Knowles D, Heffron T, Lawrence EC, Csete M. Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition. Transplant Proc. 2009 Jun;41(5):1969-71.