Primary Pulmonary Hypertension Medication

Current pulmonary vascular therapies appear to exert their actions on the pulmonary circulation by mechanisms that remain poorly defined. Clearly, the magnitude of the pulmonary vasodilator actions of prostanoids, PDE-5 inhibitors, and endothelin antagonists do not account for the degree of clinical benefit observed with these drugs. Rather, additional effects on the "endothelial health" of the pulmonary circulation and on the inhibition of pathologic intimal fibrosis and smooth muscle proliferation are likely to be the predominant mechanisms involved in the treatment responses.

Class Summary

Calcium channel blockers are believed to act on the vascular smooth muscle, dilating the pulmonary resistance vessels and lowering the pulmonary artery pressure. Several studies report clinical and hemodynamic benefits from the use of long-term calcium channel blockade. Long-term treatment improves the quality of life and survival rate in patients who have a proven response to such therapy. In general, CCBs are used at high doses in patients with IPAH.

The use of CCBs should be limited to patients without overt evidence of right-sided heart failure. In patients with IPAH (or any other form of PAH), a cardiac index of less than 2 L/min/m² or a right atrial pressure above 15 mm Hg is a contraindication to CCB therapy, as these agents may worsen right ventricular failure in such cases.

Nifedipine (Adalat CC, Nifedical XL, Procardia)

Nifedipine is a dihydropyridine calcium channel blocker. It is a vasodilator that dilates both systematic and pulmonary vascular beds. Higher doses of nifedipine are required for optimal vasodilation of pulmonary arteries.

Diltiazem (Cardizem, Cardizem LA, Cartia XT, Tiazac)

Diltiazem is a nondihydropyridine calcium channel blocker. During depolarization, diltiazem inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The resultant decrease in intracellular calcium inhibits the contractile processes of myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. It decreases conduction velocity in AV node and increases refractory period via blockade of calcium influx.

Class Summary

Parenteral vasodilators are used for patients whose IPAH fails to respond to calcium channel blockers or who cannot tolerate these agents and who have New York Heart Association (NYHA) type III or IV right-sided heart failure.

Epoprostenol (Flolan, Veletri)

An analogue of aerosolized prostacyclin (PGI2) that was approved by the FDA in 1995 for use in patients with IPAH, and later for use in APAH, epoprostenol has potent vasodilatory properties, an immediate onset of action, and a half-life of approximately 5 min. In addition to its vasodilator properties, this agent also contributes to inhibition of platelet aggregation and plays a role in inhibition of smooth muscle proliferation. The latter effect may have implications for beneficial remodeling of pulmonary vascular bed. Epoprostenol is FDA-approved for treatment of IPAH.

Treprostinil (Remodulin)

Treprostinil is used to treat PAH. It is structurally very similar to epoprostenol but stable at room temperature and has a much longer half-life; therefore, it can be given as a subcutaneous continuous infusion via a much smaller pump. This agent elicits direct vasodilation of pulmonary and systemic arterial vessels and inhibits platelet aggregation. Vasodilation reduces right and left ventricular afterload and increases cardiac output and stroke volume.

Treprostinil recently received FDA approval for IV use as a bioequivalent of subcutaneous treprostinil, using the same delivery pump used for epoprostenol. Dosing is similar to subcutaneous delivery.

Adenosine (Adenocard)

Adenosine is an antiarrhythmic agent that is used for the treatment of paroxysmal supraventricular tachycardia. It slows conduction time through the AV node, which can interrupt the re-entry pathways through the AV nodes, in turn restoring normal sinus rhythm.

Class Summary

Inhibition of the antiproliferative effects of the PDE-5 pathway, which regulates cyclic guanosine monophosphate hydrolysis, may be significant in the long-term treatment of pulmonary hypertension.

Despite concerns regarding ocular toxicity with chronic PDE-5 inhibition, no detrimental effects were observed during a pivotal phase III randomized clinical trial of sildenafil versus placebo for patients with pulmonary arterial hypertension.^[31]

Sildenafil (Revatio)

Sildenafil promotes selective smooth muscle relaxation in lung vasculature, possibly by inhibiting PDE-5. This results in subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output.

Tadalafil (Adcirca)

Tadalafil is a PDE-5 inhibitor indicated for improving and increasing exercise capacity in patients with World Health Organization (WHO) class I PAH. This agent increases cyclic guanosine monophosphate (cGMP), which is the final mediator in the nitric oxide pathway.

Class Summary

Inhaled prostacyclin (PGI₂) synthetic analogues are an alternative to parenteral administration. They are used in an attempt to limit systemic adverse effects.

Iloprost (Ventavis)

A synthetic analogue of PGI2 that dilates systemic and pulmonary arterial vascular beds, iloprost is indicated for WHO class I PAH in patients with NYHA class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration.

Treprostinil, inhaled (Tyvaso)

A prostacyclin vasodilator, treprostinil is indicated for PAH in patients with NYHA class III symptoms. It elicits direct vasodilation of pulmonary and systemic arterial vessels and inhibits platelet aggregation. Vasodilation reduces right and left ventricular afterload and increases cardiac output and stroke volume.

Class Summary

Endothelin receptor antagonists (ERAs) are therapeutic alternatives to parenteral prostacyclin agents. Given orally, they competitively bind to endothelin 1 (ET-1) receptors endothelin-A and endothelin-B, causing a reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP). This agent is indicated for treatment of PAH in patients with WHO class III or IV symptoms to improve exercise ability and decrease the rate of clinical deterioration.

Bosentan (Tracleer)

The first oral IPAH therapy to be approved in United States, bosentan is a mixed endothelin-A and endothelin-B receptor antagonist indicated for PAH, including IPAH. In clinical trials, bosentan improved exercise capacity, decreased the rate of clinical deterioration, improved functional class, and improved hemodynamics.

Bosentan improves pulmonary arterial hemodynamics by competitively binding to ET-1 receptors endothelin-A and endothelin-B in pulmonary vascular endothelium and pulmonary vascular smooth muscle. This leads to a significant increase in the cardiac index associated with a significant reduction in PAP, PVR, and mean RAP. These changes result in an improvement in exercise capacity (as measured by the 6-min walk test) and improved PAH symptoms.

Because this drug has teratogenic potential and because of the need for careful scrutiny in choosing appropriate candidates for ERA therapy, bosentan can be prescribed only through the Tracleer Access Program. Call 1-866-228-3546.

Ambrisentan (Letairis)

Ambrisentan is an endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with WHO class II or III symptoms. It improves exercise ability and decreases progression of clinical symptoms. It inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reduction in PAP, PVR, and mean RAP. Because of the risks of hepatic injury and teratogenic potential, this agent is available only through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com[http://www.letairis.com/] or call (866) 664-LEAP (5327).

Class Summary

Diuretics are used in pulmonary hypertension to manage peripheral edema. The use of loop diuretics (eg, furosemide, bumetanide) requires potassium supplementation and close monitoring of serum potassium.

Furosemide (Lasix)

Furosemide is a loop diuretic that increases excretion of water by interfering with chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. It increases renal blood flow without increasing the filtration rate. It increases potassium, sodium, calcium, and magnesium excretion.

Diuretics have major clinical uses in managing disorders involving abnormal fluid retention (edema) or in treating hypertension, in which their diuretic action causes decreased blood volume.

Bumetanide

Bumetanide increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced.

Spironolactone

Spironolactone is a potassium-sparing diuretic. Potassium-sparing diuretics may have a role in ameliorating the sometimes-intractable hypokalemia observed with daily diuretic use.

Class Summary

Several studies, using both univariate and multivariate analyses, have shown that survival in IPAH, regardless of histopathologic subtype, is increased when patients are treated with anticoagulant therapy. However, these studies were retrospectively performed. No randomized, controlled clinical trials of anticoagulation in IPAH exist; thus, the data are mostly consensus-driven rather than based on prospective evidence-based medicine.

Warfarin should be used, provided the patient has no contraindications to anticoagulation. Maintain an international normalized ratio (INR) of 1.5 to 2.

Warfarin (Coumadin, Jantoven)

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.

Class Summary

Digoxin therapy can be used to improve right ventricular function in patients with right ventricular failure. However, no randomized controlled clinical study has been performed to validate this strategy for patients with IPAH or any other form of PAH.

Digoxin (Lanoxin)

Digoxin enhances myocardial contractility by inhibition of Na+/K+ ATPase, a cell membrane enzyme that extrudes Na+ and brings K+ into the myocyte. It has direct inotropic effects in addition to indirect effects on the cardiovascular system. It increases myocardial systolic contractions and exerts vagomimetic action on sinus and AV nodes (slowing heart rate and conduction). Also, it decreases the degree of activation of sympathetic nervous system and renin-angiotensin system, which is referred to as the deactivating effect.