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Drug Interactions in Pulmonary Arterial Hypertension and Their Implications
Studies of the underlying molecular mechanism in PAH have Table 1: Functional Classification of
allowed the development of disease-specific therapies in the
Pulmonary Arterial Hypertension*
three established molecular pathways of PAH pathophysiology:
the prostacyclin pathway, the nitric oxide (NO) pathway and the
Class Description
endothelin (ET) pathway.
I Patients with pulmonary arterial hypertension without resulting
limitation of physical activity. Ordinary physical activity does not cause
undue dyspnoea or fatigue, chest pain or near syncope.
Prostacyclin Pathway and Prostanoids
III Patients with pulmonary arterial hypertension resulting in slight
Prostacyclin is a metabolite of arachidonic acid produced by the
limitation of physical activity. They are comfortable at rest. Ordinary
vascular endothelium, and acts as a potent pulmonary and systemic
physical activity causes undue dyspnoea or fatigue, chest pain or
vasodilator through the effects of the secondary messenger cyclic
near syncope.
adenosine monophosphate (cAMP).
12,13
Prostacyclin also has III Patients with pulmonary arterial hypertension resulting in marked
antiproliferative properties and inhibitory effects on platelet limitation of physical activity. They are comfortable at rest. Less than
aggregation. Deficiencies of prostacyclin due to reduced expression
ordinary activity causes undue dyspnoea or fatigue, chest pain or
of prostacyclin synthase in PAH led to the development of prostanoid
near syncope.
replacement therapy, of which there are three prostacyclin analogues
IV Patients with pulmonary arterial hypertension with inability to
available on the market (see Table 2). Although effective in improving
carry out any physical activity without symptoms. These patients
manifest signs of right heart failure. Dyspnoea and/or fatigue
exercise capacity, cardiopulmonary haemodynamics and
may be present even at rest. Discomfort is increased by any
symptoms,
14–18
the short half-lives of these drugs mean that drug
physical activity.
delivery is via continuous intravenous (IV) or subcutaneous (SC)
*Modified from the New York Heart Association (NYHA) classification of patients with cardiac
administration, which can cause infection from venous catheters and
disease. Adapted from the pulmonary arterial hypertension (PAH) functional classification
site pain, respectively, or frequent inhalation therapy.
19 according to the World Health Organization, 1998.
Nitric Oxide Pathway and
Table 2: Medicines in the Management of
Pulmonary Arterial Hypertension
Phosphodiesterase Inhibitors
NO has potent pulmonary vasodilatory effects and inhibits
Non-specific Therapies
platelet activation and vascular smooth-muscle cell proliferation;
Anticoagulants
vasodilation is achieved by activation of the soluble guanylate cyclase
Diuretics
by NO and production of the second messenger cyclic guanosine Digoxin
monophosphate (cGMP).
20
However, increased expression of Calcium-channel blockers
phosphodiesterase-5 (PDE5) in the lungs in PAH leads to enhanced
Oxygen
cGMP degradation. Therefore, selective inhibition of PDE5 by sildenafil PAH-specific Therapies Mode of Administration
blocks cGMP degradation in the pulmonary vasculature, leading to Prostacyclin Analogues
increased vasodilatory activity of endogenous NO.
21
Sildenafil has also
Epoprostenol (Flolan) Intravenous infusion
been shown to improve the six-minute walk distance (6MWD),
Treprostinil (Remodulin) Subcutaneous and intravenous
haemodynamic variables and NYHA FC.
21
infusion/inhalation
Iloprost (Ventavis) Inhalation
Endothelin Pathway and Endothelin
Phosphodiesterase Type-5 Inhibitors
Receptor Antagonists
Sildenafil (Revatio) Oral
Tadalafil (Adcirca)
Levels of ET-1, a potent vasoconstrictor and smooth-muscle
mitogen, are elevated in the plasma and lung tissue of patients with
Endothelin Receptor Antagonists
Bosentan (Tracleer) Oral
PAH.
22
The effects of ET are mediated by two ET receptor isoforms:
Sitaxentan (Thelin) Oral
ET type A (ET
A
) and ET type B (ET
B
). Activation of ET
A
receptors
Ambrisentan (Volibris) Oral
mediates vasoconstriction and cellular proliferation of pulmonary
The pulmonary arterial hypertension (PAH)-specific therapies are European Medicines
vascular smooth-muscle cells; in normal pulmonary vasculature, Agency (EMEA)- and US Food and Drug Administration (FDA)-approved for use in PAH;
ET
FDA approval for sitaxentan is currently under way.
B
receptors mediate vasodilation primarily through clearance of
ET-1 circulating in the vascular beds of the lungs and kidneys, and
increased production of prostacyclin and NO.
23
Bosentan is a non- of 6MWD, NYHA FC and pulmonary haemodynamics.
25
The
selective (dual) ERA; ambrisentan and sitaxentan are specific Ambrisentan in Pulmonary Arterial Hypertension, Randomized,
antagonists of the ET
A
receptor. Currently, there is no clear Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and
evidence suggesting that receptor selectivity confers any 2 (ARIES-1 and ARIES-2) found that patients who were randomised
advantage in terms of the clinical efficacy of these drugs. to the ambrisentan groups had significant improvements in
increased 6MWD, time to clinical worsening, FC, Borg dyspnoea
Large-scale clinical studies have shown that ERAs have proven score and quality of life score.
26
The ERAs are associated with
efficacy in mediating vasoconstriction in PAH. In the Bosentan hepatoxicity requiring monthly liver function testing; bosentan and
Randomized Trial of Endothelin Antagonised Therapy (BREATHE-1), sitaxentan have both been found to induce a dose-dependent
patients receiving bosentan exhibited improvements in FC and increase in hepatic transaminase levels to more than three times
exercise capacity as measured by 6MWD and prolonged time to the upper limit of normal (ULN) in 11 and 5% of patients,
clinical worsening compared with patients receiving placebo.
24
The respectively.
24,27
Clinical trials have found a lower incidence of acute
Sitaxentan to Relieve Impaired Exercise (STRIDE-1) trial showed that hepatotoxicity with ambrisentan, with fewer than 3% of patients
patients receiving sitaxentan benefited in terms of improvements experiencing elevations in hepatic aminotransferases more than
EUROPEAN CARDIOLOGY 47
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