US Pharm. 2013;38(10):HS21-HS24.
ABSTRACT: Pulmonary arterial hypertension (PAH)
is a progressively fatal disease of the small pulmonary arteries. In the
last two decades, pharmacotherapeutic advances have improved prognosis.
Standard treatment of PAH includes anticoagulants, diuretics, digoxin,
and calcium channel blockers. Advanced treatment of PAH includes
phosphodiesterase type 5 inhibitors, endothelin antagonists, and
prostanoids. Combination therapy can produce additive and synergistic
benefit. However, drug interactions may occur among PAH therapies or
between medications indicated for PAH and agents used for concomitant
illnesses. These interactions may necessitate medication adjustment or
are serious enough to limit treatment options.
Pulmonary arterial hypertension (PAH) is a complex
disorder of the small pulmonary arteries. It is characterized by
vascular proliferation and obstructive remodeling, which reduces blood
flow through the pulmonary arterial circulation, increases pulmonary
vascular resistance, and eventually causes right heart failure. The
hemodynamic definition of PAH is a resting mean pulmonary arterial
pressure (mPAP) of ≥25 mmHg and a pulmonary capillary wedge pressure
(PCWP) of ≤15 mmHg.1,2
PAH is a rare and fatal disease estimated to affect 10 to 12 per one million Americans.3
Risk factors include connective tissue diseases, congenital heart
disease, portal hypertension, HIV infection, and certain drugs and
toxins (e.g., aminorex, amphetamines, fenfluramine, dexfenfluramine,
L-tryptophan, toxic rapeseed oil).4 Obesity and use of cocaine and amphetamines may be emergent risk factors.5 Patients with PAH have a mean age of 50 years and are predominantly female.5 Traditionally, the mean survival time is 2.8 years, but prognosis has improved with recent effective therapies.
The current World Health Organization (WHO) Group Dana
Point classi-fication delineates PAH as follows: idiopathic; heritable;
associated with collagen vascular disease; congenital
systemic-to-pulmonary shunts; portal hypertension; HIV; schistosomiasis;
drugs and toxins; hereditary hemorrhagic telangiectasia;
hemoglobinopathies; associated with significant venous or capillary
involvement, pulmonary veno-occlusive disease, and pulmonary capillary
hemangiomatosis; and persistent pulmonary hypertension of the newborn.4,6 Chronic hemolysis was removed from Group 1 during the 2013 Pulmonary Hypertension World Symposium in Nice, France.
Genetic mutations (BMPR2, ACVRL1, ALK1), signaling pathway defects (TGF-beta) and dysregulation of receptor and transporter activities (HTR2B, SLC6A4, KCNA5, KCNQ, TRPC6, ANGPT ), have been implicated in the development of PAH.7-12
These abnormalities can produce an imbalance of smooth muscle
proliferation and cellular apoptosis that favors hyper-trophy and
plexiform lesions. In addition, in situ thromboses further obliterate
the vascular lumen.
Clinical Presentation and Diagnosis
The main symptoms of PAH are dyspnea and exercise
limitation. Other symptoms include fatigue, angina, syncope,
palpitations, lightheadedness, and abdominal distention. Patients with
early onset PAH may be asymptomatic, and diagnosis is made by exclusion
of other diseases, such as chronic obstructive pulmonary disease. PAH is
strongly suspected when symptoms occur in the absence of cardiac or
respiratory disease or when they cannot be explained by preexisting
disease. Patients with advanced PAH may additionally present with cold
extremities, hypotension, cardiac murmurs, and reduced pulse pressure.
Ultimately, right heart catheterization is needed to make a definitive
Stages of PAH
The New York Heart Association (NYHA) classification has
been adapted by the WHO to define the clinical stages of PAH. Class I
patients have no limitations to physical activity. Patients with class
II functional activity are comfortable at rest; however, routine
activities can cause undue dyspnea, fatigue, chest pain, or syncope.
With class III status, patients have a marked decline in ability to
carry out daily routines. Although still comfortable at rest, class III
patients experience symptoms when performing less-than-ordinary
activities. Finally, patients with class IV functional status have
significant dyspnea, fatigue, chest pain, or syncope to the extent that
they are unable to carry out routine activities.13 These
patients also exhibit other symptoms of heart failure, such as lower
extremity edema, palpitations, arrhythmia, tachycardia, and nocturia.
The goals of PAH therapy are to improve symptoms, enhance quality of life, and slow disease progression.14
Standard treatment with diuretics, digoxin, anticoagulants, and oxygen
is recommended for most patients with PAH. Calcium channel blockers
(CCBs) are recommended for patients with PAH when they respond
positively to acute vasodilator testing, which is defined as a decrease
in mPAP of ≥10 mmHg to an absolute value of <40 mmHg without
decreased cardiac output.14 Therapies for advanced care
include phosphodiesterase type 5 (PDE5) inhibitors, endothelin receptor
antagonists, and prostanoids.
Combining agents may produce additive therapeutic benefit
or allow for similar benefit with lower doses and fewer side effects.
However, combination therapy increases the potential for drug
interactions among medications for PAH or between medications for PAH
and those for concurrent diseases such as hypertension, cardiovascular
disease, depression, obstructive airway disease, and thyroid disease.5
Drug interactions may warrant medication adjustments or limit treatment
choices. Here, we summarize the drug interaction potential of PAH
Drug Interactions of Standard Treatments for PAH
Warfarin: Patients with PAH have increased risk for
thromboembolism. Warfarin (Coumadin, Jantoven) is used to prevent and
treat arterial thromboembolism, and in retrospective studies has been
shown to confer survival benefit.14 It is recommended that warfarin therapy be titrated to an international normalized ratio (INR) of 1.5 to 2.5.14 Given its significant interactions with other CYP-mediated medications, close monitoring of INR is warranted.15,16 Selected warfarin interactions are presented in TABLE 1.15
Diuretics: Diuretics are used to
manage edema and right ventricle volume overload. The major interactions
of loop diuretics exist with agents that can cause nephrotoxicity,
ototoxicity, electrolyte disturbances, or additive hypotension.17-22
Spironolactone (Aldactone) is a potassium-sparing diuretic that is
frequently used for PAH. It has been shown to effectively block
aldosterone and decrease atrial natriuretic peptide.23
Digoxin: Digoxin can improve cardiac
output and help with atrial arrhythmias. Digoxin is a substrate for
P-glycoprotein (Pgp); thus, concomitant use with drugs that affect Pgp
may alter digoxin levels. Serum digoxin levels should be established
before starting new medications and monitored thereafter with
appropriate dosage adjustment.24
Calcium Channel Blockers: CCBs may
have a potential vasodilatory effect. They are usually used in patients
with idiopathic PAH who exhibit a positive response to acute vasodilator
testing. This is defined as a ≥10 mmHg decrease in mPAP to an absolute mPAP <40 mmHg without reduction in cardiac output.14
Nifedipine (Procardia, Adalat), diltiazem (Cardizem, Dilacor), and
amlodipine (Norvasc) are the most commonly used CCBs for PAH.25-27
A summary of drug interactions of standard treatments for PAH is presented in TABLE 2.17-27
Drug Interactions of Advanced Treatments for PAH
PDE5 Inhibitors: PDE5 inhibitors
cause nitric oxide-mediated vasodilation. Together, PDE5 inhibitors and
nitrates can produce profound hypotension, and this combination is
contraindicated. Additive hypotension can also occur with
alpha-blockers.28,29 Concurrent use of sildenafil with potent CYP3A inhibitors is not generally recommended.30 Use of sildenafil (Viagra) and tadalafil (Cialis) should be avoided with other PDE5 inhibitors.
Endothelin Receptor Antagonists: Endothelin-1
(ET-1) is a potent vasoconstrictor and stimulator of pulmonary arterial
smooth muscle cell proliferation. Plasma levels of ET-1 are correlated
with increased severity and worsened prognosis of PAH. Endothelin
receptor antagonists, such as bosentan (Tracleer) and ambrisentan
(Letairis), work by competitively inhibiting ET-1 from binding
endothelin receptors to decrease pulmonary vascular resistance.14 Bosentan has been shown to have more drug interactions than ambrisentan.31 Cyclosporine is contraindicated with bosentan, and efficacy of hormonal contraception may be reduced with bosentan.32,33
Concomitant use of bosentan and glyburide is also contraindicated due
to their CYP3A4-inducing potential, which results in increased plasma
levels of both drugs.32,34 When bosentan and sildenafil are
given concurrently, bosentan levels may increase and sildenafil levels
may decrease, although dosage adjustments may not be necessary.32
To date, ambrisentan is associated with one clinically significant
interaction. If used with cyclosporine, ambrisentan should be limited to
5 mg daily.35,36
Given the risk for liver injury and teratogenic harm
(Pregnancy Category X), bosentan and ambrisentan are only available
through the Tracleer Access Program and Letairis Education and Access
Prostanoids: Prostacyclin synthase is reduced in patients with PAH. As a result, there is insufficient production of prostacyclin (PGI2), a vasodilator with antiproliferative effects.14 Patients with PAH are treated with prostanoids to replace the prostacyclin within the pulmonary arterial vasculature.37 Prostanoids induce pulmonary arterial vasodilation, impede smooth muscle cell growth, and disrupt platelet aggregation.37
Several prostanoids are available. Iloprost (Ventavis) is inhaled using the I-neb AAD System or the Prodose AAD System.37,38
Treprostinil (Tyvaso) is another prostanoid that can be administered by
inhalation. To date, there are no pharmacokinetic studies with inhaled
treprostinil. Drug interaction potential is based upon what is known
with oral or injected treprostinil (Remodulin). Prostanoids available
for parenteral administration include epoprostenol (generic, Flolan,
Veletri) and trepostinil (Remodulin). Epoprostenol is delivered as a
continuous IV infusion pump due to its short half-life of 2.7 minutes.39
It was the first widely used prostanoid and has been shown to
effectively dilate pulmonary arteries, reduce symptoms of PAH, and
provide survival benefit.37 Treprostinil can be given as an
SC infusion, or an as IV infusion for patients who experience
intolerable irritation from SC administration. Dosage adjustment of
trepostinil may be necessary when it is used with gemfibrozil or
A summary of drug interactions of advanced treatments for PAH is presented in TABLE 3.28,29,32-41
Role of the Pharmacist
Treatment for PAH involves a complicated medication
regimen. Pharmacists in hospital and community settings can help
patients understand the need for different types of medications and
nonpharmacologic therapies. By appropriately applying information from
package labeling, medication databases, postmarketing reports, and FDA
MedWatch notices, pharmacists can help to determine the clinical
relevance of drug interactions of PAH therapies and the need for
medication adjustments. Pharmacists can also integrate other medications
into the pharmacotherapy plan.
Although PAH is a rare and fatal disease, prognosis has
improved with expanding therapeutic options. New medications are in
development, such as Selexipag (ACT-293987).42 Pharmacists
with specialized knowledge about medications are well positioned to
perform drug monitoring, which can prevent adverse events and ultimately
optimize patient care.
1. Badesch DB, Abman SH, Simonneau G, et al. Medical
therapy for pulmonary arterial hypertension: updated ACCP evidence-based
clinical practice guidelines. Chest. 2007;131:1917-1928.
2. Hoeper MM. Definition, classification, and epidemiology of pulmonary arterial hypertension. Semin Respir Crit Care Med. 2009;30:369-375.
3. Frost AE, Badesch DB, Barst RJ, et al. The changing
picture of patients with pulmonary arterial hypertension in the United
States: how REVEAL differs from historic and non-US Contemporary
Registries. Chest. 2011;139:128-137.
4. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30:2493-2537.
5. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary
arterial hypertension: baseline characteristics from the REVEAL
registry. Chest. 2010;137:376-387.
6. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
7. Yuan JX, Rubin LJ. Pathogenesis of pulmonary arterial hypertension: the need for multiple hits. Circulation. 2005;111:534-538.
8. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous
germline mutations in BMPR2, encoding a TGF-beta receptor, cause
familial primary pulmonary hypertension. Nat Genet 2000;26:81-84.
9. Deng Z, Morse JH, Slager SL, et al. Familial primary
pulmonary hypertension (Gene PPH1) is caused by mutations in the bone
morphogenetic protein receptor–II gene. Am J Hum Genet. 2000;67:737-744.
10. Girerd B, Montani D, Coulet F, et al. Clinical
outcomes of pulmonary arterial hypertension in patients carrying an
ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010;181:851-861.
11. Harrison RE, Berger R, Haworth SG, et al. Transforming
growth factor-beta receptor mutations and pulmonary arterial
hypertension in childhood. Circulation. 2005;111:435-441.
12. Gurney AM, Joshi S, Manoury B. KCNQ potassium channels: new targets for pulmonary vasodilator drugs? Adv Exp Med Biol. 2010;661:405-417.
13. Kuhr FK, Smith KA, Song MY, et al. New mechanisms of pulmonary arterial hypertension: role of Ca2+ signaling. Am J Physiol Heart Circ Physiol. 2012;302:H1546-H1562.
14. McLaughlin VV, Archer SL, Badesch DB, et al. ACCP/AHA 2009 expert consensus document on pulmonary hypertension. J Am Coll Cardiol. 2009;53:1573-1619.
15. Coumadin (warfarin) package insert. Princeton, NJ: Bristol-Myers Squibb Co; October 2011.
16. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336:111-117.
17. Bumex (bumetanide) package insert. Parsippany, NJ. Validus Pharmaceuticals LLC; September 2009.
18. Lasix (furosemide) package insert. Bridgewater, NJ: Sanofi-Aventis LLC; August 2011.
19. Demadex (torsemide) package insert. Somerset, NY: Meda Pharmaceuticals, Inc; February 2010.
20. Aldactone (spironolactone) package insert. New York, NY: Pfizer, Inc; January 2008.
21. Micromedex [online subscription database]. Greenwood
Village, CO: Truven Health Analytics, Inc. Updated periodically.
www.micromedexsolutions.com. Accessed March 16, 2013.
22. Lexicomp [online subscription database]. Hudson, OH:
Lexi-Comp, Inc. Updated periodically. http://online.lexi.com. Accessed
March 16, 2013.
23. Pitt B, Zannad F, Remme WJ. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999:341:709-717.
24. Digoxin package insert. Columbus, OH: Roxane Laboratories, Inc; September 2012.
25. Procardia XL (nifedipine) package insert. New York, NY: Pfizer, Inc; August 2011.
26. Cardizem (diltiazem) package insert. Bridgewater, NJ: BTA Pharmaceuticals, Inc; November 2009.
27. Norvasc (amlodipine) package insert. Research Triangle Park, NC: Synthon Pharmaceuticals, Inc; September 2007.
28. Revatio (sildenafil) package insert. New York, NY: Pfizer Inc; August 2012.
29. Adcirca (tadalafil) package insert. Indianapolis, IN: Eli Lilly and Company; March 2012.
30. Muirhead GJ, Wulff MB, Fielding A, et al. Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br J Clin Pharmacol. 2000;50:99-107.
31. Weiss J, Herzog M, Haefeli WE. Differential modulation
of the expression of important drug metabolizing enzymes and
transporters by endothelin-1 receptor antagonists ambrisentan and
bosentan in vitro. Eur J of Pharmacol. 2011;660:298-304.
32. Tracleer (bosentan) package insert. South San Francisco, CA: Actelion Pharmaceuticals; October 2012.
33. Treiber A, Schneiter R, Hausler S, et al. Bosentan is a
substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as
the common mechanism of its interactions with cyclosporine A,
rifampicin, and sildenafil. Drug Metab Dispos. 2007;35:1400-1407.
34. van Giersbergen PL, Treiber A, Clozel M, et al. In
vivo and in vitro studies exploring the pharmacokinetic interaction
between bosentan, a dual endothelin receptor antagonist, and glyburide. Clin Pharmacol Ther. 2002;71:253-262.
35. Frampton JE. Ambrisentan. Am J Cardiovasc Drugs. 2011;11:215-226.
36. Letairis (ambrisentan) package insert. Foster City, CA: Gilead Sciences; October 2012.
37. Bishop BM, Mauro VF, Khouri SJ. Practical considerations for the pharmacotherapy of pulmonary arterial hypertension. Pharmacotherapy. 2012;32:838-855.
38. Ventavis (iloprost inhalation solution) package insert. South San Francisco, CA: Actelion Pharmaceuticals; August 2012.
39. Veletri (epoprostenol for injection) package insert. South San Francisco, CA: Actelion Pharmaceuticals; June 2012.
40. Tyvaso (trepostinil inhalation solution) package
insert. Research Triangle Park, NC: United Therapeutics Corp; February
41. Remodulin (trepostinil injection) package insert. Research Triangle Park, NC: United Therapeutics Corp; February 2011.
42. Selexipag (ACT-293987) in pulmonary arterial
hypertension, GRIPHON trial. ClinicalTrials.gov.
http://clinicaltrials.gov/show/NCT01106014. Accessed September 16, 2013.
To comment on this article, contact email@example.com.