There are several classes of drugs available for the treatment of PAH, including calcium channel blockers (CCBs), endothelin antagonists (ERAs), phosphodiesterase type-5 inhibitors (PDE-5s), and prostacyclin analogs.
Background Therapies
Several background therapies are used to treat PAH which are not FDA approved for this use. They include treatments such as anticoagulants, diuretics, digoxin, and oxygen.
These agents are all recommended according to the ACCP guidelines in patients with idiopathic PAH without contraindications. (McLaughlin
2009)
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Calcium Channel Blockers
Calcium channel blockers are a group of drugs which block the movement of calcium into a cell. They are typically used outside PAH to treat high blood pressure and to slow heart rate. By acting on vascular smooth muscle, they can potentially reduce contraction of arteries, including the pulmonary artery. This may be beneficial to a patient with PAH.
Calcium channel blockers are used in a small percentage of PAH patients who display “vasoreactivity” during a right heart catheterization. The definition of vasoreactivity is defined as a fall in mPAP of greater than or equal to 10 mm Hg to an mPAP less than or equal to 40 mm Hg, with an unchanged or increased cardiac output. Very few patients meet this definition of vasoreativity according to the ACCP. Those few patients who meet these criteria may be treated with calcium channel blockers and should be followed closely for both safety and efficacy of calcium channel blocker therapy. To be efficaciously treated on a CCB, patients must typically be in functional class I or II. Side effects of CCB’s include hypotension and peripheral edema. Long-acting nifedipine, diltiazem, or amlodipine are the most commonly used calcium channel blockers. Due to its potential negative inotropic effects, verapamil should be avoided. (McLaughlin 2009)
Treatments Indicated to Treat PAH
Several classes of drugs have been approved to treat PAH (figure 1). These include endothelin receptor antagonists (ERAs), phosphodiesterase type-5 inhibitors (PDE-5), and prostanoids (PGI-2). A brief overview of these drugs can be found below. Each drug and category of drugs has important benefits and safety profiles that need to be considered in the care of a patient with PAH. Monographs and links to important resources such as enrollment forms can be found later in this Treatment Center.
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Endothelin Antagoists
Endothelin antagonists such as Tracleer® and Letairis® work by blocking the effects of endothelin-1, specifically vasoconstriction and cell proliferation, which is elevated in plasma and lung tissue of patients with PAH. Common adverse events related to ERAs include headache, flushing, sinusitis/nasal congestion, fluid retention/peripheral edema, elevated liver enzymes (LFTs) and anemia. For more detailed descriptions of the efficacy and adverse event profiles of these products please see the patient monographs and respective package inserts.
PDE-5
PDE-5 inhibitors such as Revatio® and Adcirca® work as inhibitors of the phosphodiesterase type-5 enzyme, which leads to increased levels of cGMP in pulmonary vascular smooth muscle and vasodilation of the pulmonary vasculature. Common AEs associated with PDE-5 inhibitors include flushing, headache, nasal congestion, back pain (tadalafil), and nosebleeds (sildenafil). Rare but serious AEs include loss or limitation of vision (NAION), sudden loss of hearing which may be accompanied by tinnitus or dizziness, and priapism. For more detailed descriptions of the efficacy and adverse event profiles of these products please see the patient monographs and respective package inserts.
Prostanoids
The first drug approved to treat PAH was the prostanoid epoprostenol (Flolan®). Prostacylin is a naturally occurring vasodilator which may prevent the proliferation of smooth muscle cells. In PAH, prostacyclin production is impaired. There are currently three commercially available prostanoid products: epoprostenol, treprostinil (Remodulin®/Tyvaso®), and iloprost (Ventavis®).
Epoprostenol is available in two commercial forms, Flolan® and Veletri®. The primary difference between the two is that Veletri is stable and may be administered at room temperature, whereas Flolan is less stable at room temperature (8 hours) and is typically administered with the use of cold packs to maintain stability for a longer period (24 hours).
Side Effects of prostacyclins include jaw pain, headache, leg pain, flushing/erythema, nausea, diarrhea, anorexia and thrombocytopenia. Delivery-specific adverse events such as line infections and injection site pain exist with these agents. For more detailed descriptions of the efficacy and adverse event profiles of these products please see the patient monographs and respective package inserts.
Allied health support of patients is critical in patients who take prostanoids. Tips on the role of allied health professionals in treatment of PAH patients with prostacyclin treatments may be found on the Prostanoid Tips page.
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