Medication Summary
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.
Calcium Channel Blockers
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.
Parenteral Prostanoids
Class Summary
Parenteral prostanoids 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)
The prostanoid treprostinil is used to treat PAH. It is structurally similar to epoprostenol but stable at room temperature and has a longer half-life; therefore, it can be given as an intravenous or subcutaneous continuous infusion via a 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.
PAH, PDE-5 Inhibitors
Class Summary
Inhibition of the antiproliferative effects of the phosphodiesterase-5 (PDE-5) pathway, which regulates cyclic guanosine monophosphate hydrolysis, may be significant in the long-term treatment of pulmonary hypertension.
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. Sildenafil is indicated for treatment of adults and children aged 1-17 years with pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) to improve exercise ability and delay clinical worsening.
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.
Inhaled Prostanoids
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, Tyvaso DPI)
The prostanoid, 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.
Oral Prostacyclin Analogues
Class Summary
Oral prostacyclin (PGI2) synthetic analogues are an alternative to parenteral administration.
Treprostinil tablet (Orenitram)
Treprostinil extended-release tablets are the first oral prostacyclin analogue approved by the FDA for PAH. It acts by causing vasodilation toboth pulmonary and systemic arterial vascular beds. It also decreases ventricular afterload and inhibits platelet aggregation.
Prostacyclin Receptor Agonists
Class Summary
Approval of the first prostacyclin agonist, selexipag, was based on the phase 3 GRIPHON study (n=1,156). Results showed that selexipag decreased the risk of morbidity/mortality by 39% compared with placebo (P<.0001). Efficacy observed was consistent across the key subgroups (eg, age, sex, WHO Functional Class, PAH etiology, and background PAH therapy).
Selexipag (Uptravi)
Selectively activates the prostacyclin receptor (ie, IP-receptor), one of 5 types of prostanoid receptors. Unlike prostacyclin analogs, selexipag is selective for the IP receptor over other prostanoid receptors (ie, EP1-4, DP, FP, TP). Activating the IP receptor induces vasodilation and inhibits proliferation of vascular smooth muscle cells. It is indicated for adults with PAH, WHO Group I to delay disease progression and reduce the risk of hospitalization.
Endothelin Receptor Antagonists
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 WHO group 1 PAH to 1) improve exercise ability and delay clinical worsening; and 2) in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. 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).
Macitentan (Opsumit)
Macitentan is a dual endothelin receptor antagonist that prevents binding of ET1 to both ETA and ETB receptors. It is indicated to delay disease progression of pulmonary arterial hypertension (WHO Group I).
Soluble Guanylate Cyclase (sGC) Stimulators
Class Summary
Soluble guanylate cyclase (sGC) is an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). Pulmonary arterial hypertension (PAH) is associated with endothelial dysfunction, impaired synthesis of NO, and insufficient stimulation of the NO-sGC-cGMP pathway.
Riociguat is the first sGC stimulator approved in the United States. Approval was based on data from the 2 randomized, double-blind, placebo-controlled, global phase III studies CHEST-1 and PATENT-1, as well as long-term data from these studies. In each study, riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension.
Riociguat (Adempas)
Riociguat elicits a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding, and it directly stimulates sGC via a different binding site, independently of NO. It is indicated for chronic thromboembolic pulmonary hypertension and PAH.
Diuretics
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.
Anticoagulants
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.
The efficacy of novel oral anticoagulants (NOACs) has not been evaluated in PAH.
Cardiac Glycosides
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.
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Two-dimensional short-axis echocardiogram image. Note the flattened interventricular septum due to right ventricular overload.
