Group 2 Pulmonary Hypertension Medication

Updated: Jul 30, 2021
  • Author: Nikhil Barot, MD, MS; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Medication

Medication Summary

The goal of medication treatment of group 2 pulmonary hypertension is to lower filling pressures and provide afterload reduction in patients with heart failure. For management of heart failure with reduced ejection fraction (HFrEF), medication classes consist of diuretics, angiotensin-receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers. In settings of combined postcapillary and precapillary pulmonary hypertension, pulmonary vasodilators have not consistently been shown to improve symptoms or hemodynamics and some harm has been demonstrated in trials of these medications.

Diuretics

Diuretics are the mainstay of therapy for pulmonary hypertension due to left-sided heart disease (PH-LHD). The most commonly used diuretics are loop diuretics (furosemide, bumetanide, or torsemide). In cases of refractory volume overload, thiazide diuretics can also be used in conjunction with loop diuretics for synergistic effect. The goal of diuretics is to alleviate volume overload and to lower both right- and left-sided filling pressures. A stable dose of diuretic therapy is needed to manage volume and prevent decompensated heart failure.

ARBs and ACE inhibitors

Owing to survival benefit in patients with left ventricular systolic dysfunction, patients should be initiated on an ACE inhibitor or, if unable to tolerate, an ARB. These two classes of medications cause vasodilation, neurohormonal modification, and improvement in left ventricular ejection fraction. Examples of ACE inhibitors include benazepril, lisinopril, ramipril, and enalapril. Examples of ARBs include losartan and valsartan.

Beta-blockers

Beta-blockers inhibit sympathetic activity and have been shown to reduce mortality in patients with heart failure with reduced ejection fraction. Common beta-blockers used are bisoprolol and metoprolol. Additionally, beta-blockers with alpha activity like carvedilol can also reduce afterload.

Prostacyclins

Prostacyclins are pulmonary vasodilators that cause dilation of vascular beds through activation of intracellular adenylate cyclase. A large randomized controlled trial (Flolan International Randomized Survival Trial [FIRST]) evaluated the use of epoprostenol infusion with standard of care in patients with advanced heart failure versus standard of care alone. [14] Although there were improvements in pulmonary vascular resistance (PVR), pulmonary capillary wedge pressure (PCWP), and cardiac output (CO), an increased mortality rate with the use of epoprostenol was observed. The use of prostacylins is contraindicated in PH-LHD owing to an increased risk of mortality.

Endothelin receptor antagonists

Endothelin 1 is a potent endogenous vasoconstrictor that causes vascular smooth muscle hyperplasia in addition to direct vasoconstrictor effects. Endothelin receptor antagonists bind endothelin 1 receptors, causing a decrease in pulmonary arterial pressure through decreases in PVR. Approved for use in group 1 pulmonary arterial hypertension, there have been few trials evaluating their efficacy in group 2 pulmonary hypertension.

The Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure [ENABLE]) study evaluated the use of bosentan in patients with severe heart failure (ejection fraction < 35%, New York Heart Association class III-IV). In this study, 1613 patients were randomized to bosentan versus placebo, with results showing no improvement in outcome between the two groups. [15] However, there was an increased risk of heart failure exacerbation in the bosentan group due to fluid retention.

Phosphodiesterase-5 inhibitors

Phosphodiesterase-5 (PDE-5) inhibitors cause smooth muscle relaxation and antiproliferative effects in the vasculature, leading to a reduction in pulmonary artery pressure in patients with WHO group 1 pulmonary hypertension. In patients with PH-LHD, use of PDE-5 inhibitors has shown mixed results. In one study, exercise capacity and cardiac output improved with the use of sildenafil. [16] Additionally, a smaller study looking at 34 patients with symptomatic heart failure and pulmonary hypertension showed improvement in exercise capacity, quality of life, and fewer hospitalizations for heart failure exacerbations in the sildenafil group compared with placebo. [17]

In a multicenter, randomized controlled study, 216 patients with stable heart failure (ejection fraction >50%) and PH-LHD were randomized to sildenafil or placebo for 24 weeks. The study found there was no difference between clinical status or exercise capacity between the two groups. [18] The use of sildenafil in PH-LHD from valvular disease was evaluated in a study comparing the use of sildenafil (40 mg thrice daily) versus placebo in 200 patients who had been 2 years removed from successful valvular repair or replacement. [19] The study showed an increased rate of heart failure exacerbation leading to hospitalization and a worsening of functional capacity in the sildenafil group. Currently, sildenafil is not yet recommended in WHO group 2 pulmonary hypertension, owing to the lack of long-term studies or consistent results.

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Diuretics

Class Summary

Diuretics promote excretion of water and electrolytes by the kidneys. They are used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention has resulted in edema or ascites. They may be used as monotherapy or combination therapy to treat hypertension. Loop diuretics are commonly used. Thiazide diuretics can also be used in concurrently for synergistic effect in cases of refractory volume overload.

Furosemide (Lasix)

Furosemide primarily appears to inhibit reabsorption of sodium and chloride in the ascending limb of the loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis.

Bumetanide (Bumex)

Bumetanide increases excretion of water by interfering with the chloride-binding cotransport system; this, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle. Bumetanide does not appear to act in the distal renal tubule.

Torsemide (Demadex)

Torsemide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. It increases excretion of water, sodium, chloride, magnesium, and calcium. If a switch is made from intravenous to oral administration, an equivalent oral dose should be used.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water and potassium and hydrogen ions.

Chlorothiazide (Diuril)

Chlorothiazide inhibits the reabsorption of sodium and chloride in distal tubules, causing increased excretion of chloride, sodium, and water as well as of potassium, magnesium, phosphate, bicarbonate, and hydrogen ions.

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Anigiotensin Receptor Blockers (ARBs)

Class Summary

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS) and plays an important role in the pathophysiology of hypertension. Besides being a potent vasoconstrictor, angiotensin II stimulates aldosterone secretion by the adrenal gland; thus, ARBs decrease systemic vascular resistance without a marked change in heart rate by blocking the effects of angiotensin II.

Type I angiotensin receptors are found in many tissues, including vascular smooth muscle and the adrenal gland. Type II angiotensin receptors also are found in many tissues, although their relationship to cardiovascular hemostasis is not known. The affinity of ARBs for the type I angiotensin receptor is approximately 1000 times greater than that for the type II angiotensin receptor. In general, ARBs do not inhibit the angiotensin converting enzyme (ACE), other hormone receptors, or ion channels. They interfere with the binding of formed angiotensin II to its endogenous receptor.

Losartan (Cozaar)

Losartan is appropriate for patients unable to tolerate ACE inhibitors. It may induce a more complete inhibition of the RAAS than ACE inhibitors do, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. Compared with the ACE inhibitors, losartan is associated with a lower incidence of drug-induced cough, rash, and taste disturbances.

Valsartan (Diovan)

Valsartan is appropriate for patients unable to tolerate ACE inhibitors. It may induce a more complete inhibition of the RAAS than ACE inhibitors do, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. Compared with ACE inhibitors, losartan is associated with a lower incidence of drug-induced cough, rash, and taste disturbances.

Olmesartan (Benicar)

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking binding of angiotensin II to the AT-1 receptor in vascular smooth muscle. Its action is independent of pathways for angiotensin II synthesis.

Candesartan (Atacand)

Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. It is used in patients unable to tolerate ACE inhibitors.

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Angiotensin Converting Enzyme (ACE) Inhibitors

Class Summary

These agents minimize an ischemia-induced rise in angiotensin production. Because hypertension may be dependent on angiotensin II, antihypertensives that inhibit renin or angiotensin II are used widely. All drugs in this class have similar action and adverse effects.

Benazepril (Lotensin)

Benazepril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Lisinopril (Prinivil, Qbrelis, Zestril)

Lisinopril prevents conversion of angiotensin I to angiotensin II, resulting in decreased aldosterone secretion and subsequently, a decrease in vasoconstriction.

Ramipril (Altace)

Ramipril partially inhibits both tissue and circulating ACE activity, therefore reducing the formation of angiotensin II in the tissue and plasma. Ramipril has an antihypertensive effect even in patients with low-renin hypertension.

Enalapril (Epaned, Vasotec)

Enalapril is a competitive ACE inhibitor that prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, causing angiotensin II levels and aldosterone secretion to decrease.

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Beta-Blockers, Beta-1 Selective

Class Summary

Beta-blockers are especially useful in the concurrent treatment of hypertension and migraine. Dosing is limited by the bradycardia adverse effect. This drug class should not be used in patients with type 1 diabetes, because these drugs blunt the normal warning symptoms of hypoglycemia.

Bisoprolol

Bisoprolol is a selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. It has little or no effect on beta2-receptors at doses of 20 mg or less.

Metoprolol (Lopressor, Toprol XL)

Metoprolol is a selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. During intravenous administration, carefully monitor blood pressure, heart rate, and the electrocardiogram. No dosage adjustment is required with renal failure.

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Beta-Blockers, with Alpha-Blocking Activity

Class Summary

These agents have nonselective beta-adrenoreceptor and alpha-adrenergic blocking activity. Therapy should be initiated at low dosages, which should be increased gradually over several weeks. Patients' conditions may deteriorate over the short term, but they generally improve in the long term with continued therapy.

Carvedilol (Coreg, Coreg CR)

Carvedilol blocks beta1-, alpha-, and beta2-adrenergic receptor sites, decreasing adrenergic-mediated myocyte damage. Effects in hypertension may include vasodilation, reduction in cardiac output, decreased peripheral resistance, exercise- or beta-agonist–induced tachycardia, decreased renal vascular resistance, and increased level of atrial natriuretic peptide.

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