Pulmonary Hypertension: Prostacyclin Analogues
Overview
Prostacyclin (PGI2) is a metabolite of arachidonic acid and is endogenously produced by vascular endothelial cells. PGI2 is a potent vasodilator in both the systemic and pulmonary circulations and strongly inhibits platelet activation. A reduction in levels of PGI2 is thought to contribute to the pathogenesis of pulmonary arterial hypertension. Clinical studies over the last two decades have investigated the possibility of using analogues of endogenous PGI2 for the long-term treatment of pulmonary arterial hypertension. Various compounds and methods of administration have been investigated, leading to a range of marketed products that remain the mainstay therapies for this complex disease.
Mechanism Of Action
PGI2 analogues mediate their effects (vasodilation and antiplatelet activity) by activating G-protein-coupled receptors, known as IP receptors, on target cells. These IP receptors are coupled to the adenyl cyclase intracellular signaling cascade, and activation triggers the production of intracellular cyclic adenosine monophosphate (cAMP), culminating in cellular responses.
TABLE . Current Therapies Used for Pulmonary Arterial Hypertension
| Agent | Company/Brand | Daily Dose | Availability | |||
| Prostacyclin analogues | ||||||
| Epoprostenol sodium | GlaxoSmithKline’s Flolan | Initial dose: 2ng/kg/min. Dose increased in increments of 2 ng/kg/min every 15 mins or longer as needed until dose-limiting pharmacologic effects/tolerance limit reached | US, France, Italy, Spain, UK, Japan | |||
| Treprostinil (subcutaneous and intravenous preparations) | United Therapeutics’ Remodulin | Adjusted according to weight. Initial dose:
0.625-1.25 ng/kg/r Dose increased as needed until dose-limiting pharmacologic effects/tolerance limit reached |
US | |||
| lloprost (inhaled preparation)
lloprost (intravenous preparation) |
Schering AG/Cotherix’s
Ventavis Schering AG’s llomedin/llomedine |
2.5-5.0 µg six to nine times
Initial dose: 0.5 ng/kg/min. Dose increased as needed until dose-limiting pharmacologic effects/tolerance limit reached |
US, France, Germany, Italy, Spain,
UK Germany |
|||
| Beraprost | Yamanouchi’s Dorner, Kaken’s Procylin | 60-180 µg | Japan | |||
| Endothelin-recieptor antagonists | ||||||
| Bosentan | Actelion’s Tracleer | 125-250 mg | US, France, Germany, Italy, Spain, UK | |||
| Calcium-channel blockers | ||||||
| Nifedipine | Bayer’s Adalat/Adalat CC, Pfizer’s
Procardia/Procardia XL, generics |
90-480 mg | US, France, Germany, Italy, Spain, UK, Japan | |||
| Diltiazem | Sanofi-Aventis’s Cardizem, generics | 360-720 mg | US, France, Germany, Italy, Spain, UK, Japan | |||
| Vitamin K antagonists | ||||||
| Warfarin | Bristol-Myers Squibb’s Coumadin, Sanofi-Aventis’s Coumadine, generics | Adjusted dose to achieve INR2.5, range 2.0-3.0 (in Japan, target INR of 1.8-2.0) | US, France, Germany, Italy, Spain, UK, Japan | |||
| Diuretics | ||||||
| Furosemide | Sanofi-Aventis’s Lasix, generics | 40-120 mg | US, France, Germany, Italy, Spain, UK, Japan | |||
| Spironolactone | Pfizer’s Aldactone, generics | 25-100 mg | US, France, Germany, Italy, Spain, UK, Japan | |||
| Cardiac glycosides | ||||||
| Digoxin | GlaxoSmith Kline’s Lanoxin/Lanoxicaps, generics | 0.0625-0.25 mg qd | US, France, Germany, Italy, Spain, UK, Japan | |||
bid = Twice daily;
INR = International normalized ratio;
qd = Once daily.
Formulation
The short half-life and lack of bioavailability of PGI2 (three to five minutes) create problems in terms of drug delivery. A range of formulations of PGI2 analogues are available, including intravenous, subcutaneous, inhaled, and oral preparations. The choice of formulation depends on the severity of the disease and the patient’s circumstances.
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