Treating PAH

PAH is a disorder of vasoconstriction and proliferation, and treatment focuses on medications that act on or reverse these specific events. Conventional therapy consists of diuretics, oxygen, anticoagulants, and digoxin (given only to patients who are continuing to decline and have worsening RV function. Digoxin can help improve RV function, although no scientific evidence supports its use). Diuretics prevent fluid overload and manage peripheral edema, while oxygen prevents hypoxemia that can worsen the pulmonary hypertension. Warfarin is prescribed for prevention of thrombosis in situ with a target international normalized ratio (INR) of 1.5-2.5.    
In addition, disease-specific therapies address the three mechanisms underlying PAH: the nitric oxide, endothelin, and prostacyclin pathways. 

Nitric oxide pathway: A mediator of pulmonary vasodilation, nitric oxide directly stimulates the pulmonary enzyme, guanylate cyclase, which in turn increases the production of cyclic guanosine monophosphate (cGMP). The elevated levels of cGMP cause vasodilation in the pulmonary tissue. Phosphodiesterase-5 is an enzyme that breaks down cGMP to an inactive substance. This process causes a reversal in the cGMP-induced vasodilation. In 2005, sildenafil (Revatio), a phosphodiesterase-5 inhibitor, was approved by the FDA for treatment of PAH (WHO Group I) in an oral dose of 20 mg t.i.d. No routine laboratory monitoring is indicated. Common adverse events are headache, dyspepsia, and flushing. This medication cannot be administered with nitrates of any form.


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Endothelin-1: Patients with PAH have elevated levels of endothelin-1, a potent vasoconstrictor and smooth-muscle mitogen. Endothelin-1 levels are positively correlated with disease severity. Two endothelin isoforms have been identified: ET-A and ET-B. ET-A is located on the smooth-muscle cells and ET-B is located primarily on the endothelial cells, with a small percentage on the smooth-muscle cells. The activation of ET-A causes vasoconstriction and proliferation. ET-B activation (on the endothelial cells) causes vasodilation through the production of nitric oxide. Therapy is aimed at blocking the deleterious effects of endothelin-1. 

Bosentan (Tracleer) is a non-selective endothelin receptor antagonist that is indicated for the treatment of PAH in patients with WHO functional class III and IV symptoms. The usual dose is 62.5 mg b.i.d. for the first month, after which it is increased to 125 mg b.i.d. Bosentan has a half-life of 5.4 hours. A risk of hepatotoxicity mandates the monthly laboratory monitoring of liver function tests (LFTs). Patients with even mild hepatic dysfunction may require a 50% reduction in the dose. If there is severe hepatic dysfunction (LFTs greater than five to eight times the upper limit of normal), the medication should be avoided. Once started, bosentan should be stopped if the LFTs are greater than three times the upper limit of normal with symptoms such as nausea/vomiting, abdominal pain, jaundice, fever, and fatigue (or if the total bilirubin is more than twice the upper limit of normal with elevated LFTs). There is a risk of teratogenicity, so monthly pregnancy testing should be done. Two forms of barrier contraception are to be utilized by women of childbearing age who are taking bosentan. Regular hemoglobin determinations (every three months after the first month) are necessary to monitor for possible decreases. Patients on warfarin may experience a decrease in their INR. Glyburide and cyclosporine should not be taken with bosentan. Common side effects include headache, nasopharyngitis, flushing, and edema.

Ambrisentan (Letairis) is a selective endothelin receptor antagonist that is indicated for functional class II or III PAH. The dosage is 5 or 10 mg daily. Liver enzymes must be monitored monthly, as ambrisentan, too, carries a risk of hepatotoxicity, although the risk, as reported in clinical trials, is less than with bosentan. Pregnancy must be ruled out prior to starting ambrisentan, and pregnancy tests must be performed monthly. Contraception requirements are the same as with bosentan. Caution is required if ambrisentan is co-administered with cyclosporine. Common side effects are edema, nasal congestion, flushing, and headache.

Sitaxsentan (Thelin) is also a selective endothelin receptor antagonist for the treatment of PAH, but it is not approved in the United States for use at this time.

Prostacyclin pathway: Metabolism of arachidonic acid produces prostacyclin, which helps maintain low resistance in the pulmonary vessels. By binding to certain receptors, prostacyclin stimulates adenylate cyclase to increase intracellular cyclic adenosine monophosphate. The result is vasodilation and antiproliferation. 
Epoprostenol (Flolan) was the first drug approved for the treatment of PAH. Until it made its appearance in 1996, the treatment of PAH was very limited. Epoprostenol is approved for the treatment of PAH in patients with functional class III and IV symptoms. 

This drug causes pulmonary and systemic vasodilation, which positively affects hemodynamics, decreasing PVR and median pulmonary arterial pressure and increasing cardiac output and the cardiac index. Epoprostenol also inhibits platelet aggregation and causes thrombocytopenia in some patients. A half-life of approximately six minutes requires continuous IV infusion of epoprostenol 24 hours a day. The medication must be reconstituted with sterile diluent and administered under refrigerated conditions by placing ice packs around the pump. The infusion must be initiated within 24 hours of mixing and completed within 48 hours. The patient or his caregiver is responsible for daily mixing of the medication, although initial doses should be given under the supervision of personnel knowledgeable in its administration. The dosage is slowly uptitrated to relieve symptoms. Abrupt discontinuation or sudden large decreases of the drug must be avoided, as this may result in rebound pulmonary hypertension. Adverse events include flushing, headache, nausea/vomiting, and musculoskeletal pain. 

Treprostinil (Remodulin) is a prostacyclin analog approved for the treatment of functional class II-IV PAH. The action and side-effect profile are very similar to those of epoprostenol. Treprostinil also requires 24-hour-a-day infusion. There are a few differences to note between the two products. Treprostinil has a longer half-life (four hours) and is stable at room temperature, obviating the need for ice packs during administration. Moreover, treprostinil can be administered either IV or subcutaneously, and the manufacturer is working on inhaled and oral formulations. Subcutaneous infusion requires preparation of the medication only every 72 hours. If administered IV, the medication is changed every 24-48 hours depending on the pump used for delivery; multiple pumps are available. Higher dosing of trepostinil is required as compared with epoprostenol, but slow uptitration of both products is required. Abrupt discontinuation or sudden large reductions in dose should be avoided with treprostinil as well.

Iloprost (Ventavis) is a prostacyclin analog approved for WHO group I PAH in patients with functional class III-IV symptoms. The medication exerts effects similar to those of epoprostenol and treprostinil but provides more localized delivery to the pulmonary system. Given as a nebulized treatment, iloprost has a short half-life (20-30 minutes), requiring administration six to nine times a day . The medication can be delivered only through a specific device approved by the manufacturer and cannot be nebulized with a regular aerosol setup. Side effects include cough, flushing, headache, and nausea. Iloprost is also manufactured as an IV infusion, but that formulation is not available in the United States.

Prostacyclin and prostacyclin analogs are often used as a bridge to lung transplant. Unfortunately, some patients do eventually require transplant. Careful monitoring of therapeutic response is indicated, and aggressive treatment is warranted for patients with this devastating disease.

Ms. Steinbis is a clinical consultant specializing in pulmonary arterial hypertension in Jonesboro, Ga.

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All electronic documents accessed September 23, 2008.