US Pharm. 2013;38(7):HS3-HS8.
ABSTRACT: Pulmonary arterial hypertension (PAH) is a chronic
condition that carries a significant risk of morbidity and mortality.
PAH is generally thought to result from an imbalance of vasoconstrictive
and vasodilatory mediators. The treatment of PAH includes calcium
channel blockers, endothelin receptor antagonists, phosphodiesterase
inhibitors, and prostacyclin analogues. New and emerging therapies
include medications with novel molecular targets and dosing mechanisms.
Pharmacists can play an integral role in managing the needs of patients
with this serious condition.
Pulmonary arterial hypertension (PAH), a serious chronic condition,
is a subcategory of pulmonary hypertension (PH). PAH is defined by a
mean pulmonary arterial pressure (mPAP) greater than 25 mmHg at rest,
pulmonary capillary wedge pressure (PCWP) less than 15 mmHg, and normal
cardiac output.1-3 The prevalence and incidence of PAH are
approximately 15 cases per million and 2.4 cases per million adult
population per year, respectively.4,5 Medications known to
induce PAH include anorexigenics (e.g., aminorex, fenfluramine,
dexfenfluramine), amphetamines, toxic rapeseed oil, and serotonergic
agents (selective serotonin reuptake inhibitors, St. John’s wort,
pergolide).3 PAH is described extensively in the literature;
therefore, most pharmacologic treatments target this subclassification
of PH. Treatment centers on improving quality of life and functional
status (e.g., 6-minute walk distance [6MWD]). The World Health
Organization and New York Heart Association (NYHA) classification scales
are often used interchangeably in practice to categorize functional
status in PAH patients.3,6,7 The NYHA classification—in which
class I denotes no limitations on activity and class IV denotes
symptoms at rest—is used in this review.6,7
The development of PAH is a multifactorial process involving an
increase in pulmonary vascular resistance (PVR) due to vasoconstriction,
proliferative and obstructive remodeling of pulmonary structures,
inflammation, and thrombosis. Endothelial dysfunction leads to impaired
production of vasodilators (e.g., nitric oxide [NO], prostacyclins,
vasoactive intestinal peptides) and overexpression of vasoconstrictive
and proliferative substances (e.g., thromboxane A2, endothelin [ET]-1).
These alterations in physiobiological substances lead to permanent
changes in lung parenchyma. The consequent increases in PVR lead to
right ventricular (RV) overload, hypertrophy, dilation, RV failure, and
death.3 All therapies, whether conventional or
investigational, seek to restore the balance between the vasodilatory
and vasoconstrictive processes in the lung.
Patients with known bone morphogenetic protein receptor type 2
mutation, portal hypertension, connective-tissue disorders, or HIV
should be screened annually.8-10 Since 10% of PAH cases are inherited, patients with multiple affected family members should be screened.8-10 Genetic screening is not recommended, since only 10% to 20% of carriers develop the disorder.9 Less frequent screenings are warranted in cases of atrial septal defect or exposure to toxic agents.9
The clinical presentation of PAH includes slowly progressive dyspnea,
fatigue, angina, and syncope. Lower-extremity edema, palpitations, and
exercise limitation occur in advanced disease.9,10 Typically, diagnosis occurs 2 years after symptom onset and at a mean age of 37 years.9,10
Diagnosis involves several tests, including chest x-ray,
electrocardiogram, and echocardiogram. Right heart catheterization to
measure mPAP, PCWP, and left ventricular (LV) end-diastolic pressure and
vasodilator testing should be performed.8-10 Vasodilator
testing is conducted to determine whether the patient would respond to
calcium channel blocker (CCB) therapy for primary symptom management.2
PHARMACOLOGIC TREATMENT OPTIONS
CCBs: These agents cause smooth-muscle relaxation in
the pulmonary and systemic vascular beds and result in vasodilation.
High-dose CCB therapy improves NYHA functional class and extends
survival.10 In two small cohort studies, survival rates at 5 and 7 years were 95% and 97%, respectively.11,12 Long-acting nifedipine, sustained-release diltiazem, and amlodipine are used clinically (TABLE 1).13
If the response to therapy is inadequate after 3 to 6 months, or if the
patient is nonresponsive to vasoreactivity testing, therapy with
prostacyclin analogues, endothelin receptor antagonists (ERAs), and/or
phosphodiesterase type 5 (PDE-5) inhibitors should be initiated.8,14
Prostacyclin Analogues: Three prostacyclin
analogues are available in the United States: epoprostenol (Flolan),
treprostinil (Remodulin, Tyvaso), and iloprost (Ventavis) (TABLE 1).15-18
Prostacyclin analogues cause direct vasodilation of the pulmonary and
systemic arterial vascular beds and inhibit platelet aggregation.13
These agents may potentiate the hemodynamic effects of
antihypertensives and the hematologic effects of anticoagulants and
antiplatelets. Generally, they are available only through specialty
Epoprostenol improves functional class, exercise tolerance, hemodynamics, and survival.19,20
This agent should be administered via ambulatory infusion pump through
central intravenous (IV) access. It should be initiated at 2 ng/kg/min
and titrated at intervals of at least 15 minutes to the desired clinical
effect. Abrupt discontinuation may lead to pronounced rebound PH;
therefore, to avoid interruptions in drug delivery, patients should have
access to a backup infusion pump and IV infusion sets. Epoprostenol is
contraindicated in patients who have chronic heart failure with severe
LV dysfunction and in patients who develop pulmonary edema during
treatment initiation. Reconstituted unused solution should be
refrigerated and protected from light and may be kept for no more than
48 hours. Reconstituted epoprostenol may be administered at 25°C for 8
hours. A cold pouch may be used to extend the duration of administration
for up to 24 hours.15
Treprostinil is available in subcutaneous (SC)/IV (Remodulin) and
orally inhaled (Tyvaso) formulations, all of which lessen clinical
deterioration, improve 6MWD, and confer survival benefits.16,17,21,22
Treprostinil may be administered through central IV access in patients
who cannot tolerate SC infusion. The infusion is initiated at 1.25
ng/kg/min. The initial dose should be reduced by 50% in patients who
cannot tolerate full doses or in those with hepatic impairment. The
dosage should be titrated by 1.25 ng/kg/min at weekly intervals for the
first month, then 2.5 ng/kg/min weekly thereafter. When administered via
SC infusion, treprostinil may be delivered without further dilution;
however, it must be diluted when administered IV. Diluted treprostinil
is stable for up to 48 hours at 25°C in concentrations as low as 4,000
ng/mL. In patients requiring transition from epoprostenol, treprostinil
is generally initiated at 10% of the calculated dosage and gradually
titrated while the epoprostenol is gradually tapered.
Serious adverse effects, such as infusion-site pain/reactions and
sepsis, are associated with the systemic delivery method. There have
been postmarketing reports of thrombophlebitis associated with
peripheral IV infusion, thrombocytopenia, bone pain, and generalized
rashes. Advantages of treprostinil are its standard dose-titration
schedule and multiple methods of administration. Treprostinil may be
initiated in mild-to-moderate disease and in heart failure.16
Orally inhaled treprostinil should be administered during waking
hours via the manufacturer-supplied delivery system. It should be
initiated at three breaths (18 mcg) per treatment, with a daily maximum
of four treatments performed at least 4 hours apart. The dosage should
be increased, in accordance with patient tolerance, by three breaths at
1- to 2-week intervals and titrated to a target of nine breaths (54 mcg)
per treatment. Inhaled treprostinil has not been studied in patients
with asthma or chronic obstructive pulmonary disease; therefore, its use
in these patients may not be advisable. The bioavailability of inhaled
treprostinil at the 18-mcg dosage is 64%; therefore, the same systemic
adverse effects that are possible with this class of drugs should be
expected with this agent. Inhaled treprostinil does not require an
ambulatory infusion pump, so the risk of infection is reduced. One
drawback is that the frequent dosing may impact adherence.17
Iloprost is an inhaled prostacyclin analogue that is administered via
the corresponding inhalation delivery system. The dosage should be
initiated at 2.5 mcg, then increased to 5 mcg if tolerated, and
administered six to nine times per day (about every 2 hours). Dosing
intervals should be extended in patients with hepatic impairment.
Iloprost should be avoided in severe hypotension because of the
increased risk of syncope. Patients with pulmonary venous hypertension
and bronchospasms and those with a history of airway hyperreactivity
should not be given iloprost because of the risk of severe pulmonary
edema in these patients.18 Iloprost improves functional class, 6MWD, and clinical symptoms in patients with PAH.23
This formulation offers the same advantages and disadvantages as
inhaled treprostinil; however, iloprost is indicated for PAH patients
with NYHA class III or IV symptoms, as opposed to orally inhaled
treprostinil, which is approved only for NYHA class III PAH.
ERAs: Two nonselective ERAs are available in the U.S.: bosentan (Tracleer) and ambrisentan (Letairis) (TABLE 1).24,25 ERAs cause vasodilation by blocking the binding of ET-1 hormone to the ETA and ETB receptors. ETA receptors act primarily to mediate vasoconstriction and cell proliferation, whereas ETB
receptors mediate vasodilation and ET-1 clearance. Although bosentan
and ambrisentan affect both receptor subtypes, they have higher affinity
for the ETA receptor, which has a net effect on vasodilaton.13
Data from 11 randomized or quasi-randomized trials in 1,457 patients
indicate that ERAs improve dyspnea, functional class, and exercise
capacity in patients with PAH.26 Both agents are known
hepatotoxins; therefore, dose reduction with frequent monitoring or drug
discontinuation should be considered if there is evidence of acute
liver injury.24,25 Owing to the hepatotoxicity and
teratogenicity of these agents, patients and health care professionals
must enroll in monitoring programs and comply with the FDA’s Risk
Evaluation and Mitigation Strategy for that drug (bosentan, Tracleer
Access Program; ambrisentan, Letairis Education and Access Program). The
patient must provide monthly pregnancy test results to the prescribing
Bosentan is indicated to improve exercise ability and delay clinical worsening.24
In randomized trials, bosentan has improved exercise tolerance,
dyspnea, and functional class and has increased the time to clinical
worsening.27,28 It also has been shown to improve cardiac index, PVR, and mPAP.28
Bosentan should be initiated at 62.5 mg orally twice daily and titrated
to 125 mg twice daily after 4 weeks. Patients with a low body weight
(<40 kg) should be maintained at the lower dosage. The dosing
frequency should be reduced when bosentan is given in combination with
ritonavir, with the bosentan being discontinued 36 hours before
ritonavir initiation. Other major drug interactions involve oral
contraceptives, simvastatin, and rifampin.24
Ambrisentan is indicated to improve exercise ability and delay
clinical worsening. It should be initiated at 5 mg orally once daily,
then titrated to 10 mg daily.25 Ambrisentan was shown to improve 6MWD, health-functioning scales, and dyspnea scores.29
It should not be used in combination with cyclosporine. Ambrisentan
offers the advantage of once-daily dosing, which may improve compliance.25
PDE-5 Inhibitors: Two PDE-5 inhibitors are indicated for use in PAH: sildenafil (Revatio) and tadalafil (Adcirca) (TABLE 1).30,31
Phosphodiesterases are responsible for the degradation of cyclic
guanosine monophosphate (cGMP)—a key mediator of vasodilation—in the
smooth muscle. The PDE-5 receptor subtype is found predominantly in the
pulmonary vasculature. PDE-5 inhibitors therefore increase the
concentration of cGMP, resulting in relaxation of pulmonary vascular
smooth-muscle cells and vasodilation of the pulmonary vascular bed.
Sildenafil and tadalafil have additive blood pressure–lowering effects
and should be not be used in patients taking nitrates, alpha blockers,
or alcohol. Hearing loss, visual impairment, and priapism may occur with
use of these PDE-5 inhibitors. Concomitant use of potent inducers and
inhibitors of CYP450 3A should be avoided.30,31
Sildenafil is indicated to improve exercise ability and delay
clinical worsening. In randomized short-term and long-term studies,
sildenafil significantly improved exercise capacity, 6MWD, functional
class, PAP, and PVR.32-34 Sildenafil is available as an oral
tablet and suspension and an IV bolus injection. The oral tablet and
suspension are dosed at 20 mg three times daily, and the injection is
dosed at 10 mg IV bolus three times daily. There have been limited
clinical trials of the combination of sildenafil and bosentan.30
Tadalafil is approved to improve exercise capacity in PAH patients.
One randomized trial demonstrated increased 6MWD and time to clinical
worsening. Of note, 50% of patients were also receiving bosentan.31 Over 16 weeks, tadalafil produced a mean 44-meter increase in 6MWD.35
Tadalafil, which is available as a 20-mg tablet, is dosed at 40 mg once
daily. It should be dosed at 20 mg daily in mild-to-moderate renal and
hepatic disease and should be avoided in severe disease. Once-daily
dosing may improve compliance; however, caution must be taken in special
Research is currently under way to evaluate the utility of multiple
new molecular targets for PAH treatment. Fasudil, a Rho-kinase inhibitor
currently in phase I trials, inactivates myosin light chain (MLC)
phosphatase, thereby shifting MLC equilibrium toward an unphosphorylated
state resulting in vasorelaxation.36 Fasudil has a short half-life (45 minutes) and lacks selectivity for the pulmonary circulation.37,38
Riociguat, the first soluble guanylate cyclase (sGC) stimulator is
currently in phase II trials. It works by mimicking the effects of NO
and increasing the sensitivity of sGC to endogenous NO, thereby reducing
the workload of the right ventricle.39,40
Imatinib is a platelet-derived growth factor receptor currently used
for certain cancers. In phase III studies, it appears promising for the
treatment of PAH.41 Imatinib has been shown to reduce PVR and improve 6MWD by lessening vascular smooth-cell proliferation in the pulmonary artery.41
Selexipag (oral selective prostacyclin receptor antagonist) and oral
treprostinil (prostacyclin analogue) are undergoing phase II and III
trials, respectively. Both agents have been shown to reduce PVR and
systemic vascular resistance while increasing CI, and they may prove to
be therapeutic alternatives to current prostacyclin analogues.42-44
Macitentan, a dual ERA currently in phase I trials, antagonizes the
action of ET-1 on cell membranes. The benefit of using a dual ERA is
that it reduces the crosstalk between receptors that causes increased
expression of one subtype when the other subtype is blocked.45,46
Guidelines developed in 2009 by the American College of Cardiology
Foundation/American Heart Association (ACCF/AHA) recommend that
appropriate general and supportive care measures, including education
and anticoagulation, be provided to patients with PH. See TABLE 2 for a summary.
THE PHARMACIST’S ROLE
A medication history is important, since agents used to treat PAH may
be dispensed by specialty pharmacies, whereas other agents are
dispensed by community pharmacies. Counseling includes administration
techniques.8 Monitoring includes medication safety, signs and symptoms, and quality of life, with physician visits every 3 to 6 months.18 Pneumococcal and influenza immunizations are recommended.8,9
Nondrug therapies include limiting sodium intake and aerobic
exercise, as well as avoiding pregnancy, high altitudes, and heavy
physical exertion.8,9 Patients may require oxygen when traveling on commercial aircraft.8
There is no consensus regarding the use of oral contraceptives.
Options include low-dose estrogen with warfarin, surgical sterilization,
and barrier methods.8,9 OTC vasoconstrictive medications should be avoided, and herbal products should be used with caution.47
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Accessed March 13, 2013.
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