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Pulmonary Arterial Hypertension
Drug Interactions in Pulmonary Arterial Hypertension and Their Implications
Hossein-Ardeschir Ghofrani, Ralph Schermuly, Norbert Weissmann,
Robert Voswinckel, Henning Gall, Werner Seeger and Friedrich Grimminger
Medical Clinic II/V, University Hospital Giessen and Marburg GmbH
Abstract
Medical intervention is necessary in the treatment of pulmonary arterial hypertension (PAH) in order to prevent chronic disease
progression and clinical deterioration. Recent years have seen the development of new disease-specific drugs, such as endothelin
receptor antagonists (ERAs). However, there remains the potential for drug–drug interactions (DDIs), which can adversely affect drug
metabolism and therefore treatment efficacy, an especially significant factor to consider in light of the increasing use of combination
therapy in PAH and the ageing patient population who may also suffer age-related diseases requiring concomitant drug therapy.
The ERA ambrisentan has demonstrated lower liver toxicity and fewer DDIs than other ERAs. The lack of any significant drug interactions
with commonly used adjunct therapies such as warfarin or sildenafil could potentially improve treatment efficacy as well as patient safety.
Keywords
Pulmonary arterial hypertension, drug–drug interactions, endothelin receptor antagonist, bosentan, sitaxentan, ambrisentan
Disclosure: Hossein-Ardeschir Ghofrani has received educational and research grants from Bayer Schering, Pfizer, Encysive (until June 2009) and Ergonex and has
provided consulting services for Bayer Schering, Pfizer, Actelion, Encysive, Nycomed, Ergonex and GlaxoSmithKline. In addition, he has performed lectures supported by
Bayer Schering, Pfizer, Actelion and Encysive. Ralph Schermuly has received either educational or research grants or speaker honoraria or performed consulting services
for Bayer Schering, Pfizer, Actelion, Encysive, Nycomed, Ergonex, GlaxoSmithKline, Novartis and Solvay Pharmaceuticals. Werner Seegar has received educational and
research grants from Gilead Colorado, Lung Rx, Myogen Inc. Westminster and Schering Deutschland and has provided consultancy services to Altana Pharma, Bayer
Schering, Lung Rx and Schering AG. In addition, he has received speaker honoraria from Bayer Shering, Encysive and Lung Rx. The remaining authors have no conflicts
of interest to declare.
Received: 1 June 2009 Accepted: 30 June 2009
Correspondence: Hossein-Ardeschir Ghofrani, Medical Clinic II/V, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, 35385 Giessen, Germany.
E: Ardeschir.Ghofrani@innere.med.uni-giessen.de
Pulmonary arterial hypertension (PAH) has an estimated prevalence Current Management of
of 15–25 cases/million population.
1
This chronic, progressive Pulmonary Arterial Hypertension
disease is defined by a mean pulmonary arterial pressure Treatment of PAH can be non-specific or disease-specific (see
>25mmHg in conjunction with normal pulmonary capillary wedge Table 2). Anticoagulants are commonly used as conventional
pressure <15mmHg.
2
The disease is characterised by increased therapy in PAH, despite the fact that there has been no evidence
vascular resistance of the pulmonary microvasculature, ultimately from prospective, randomised, placebo-controlled studies in
resulting in right ventricular overload, right heart failure and death.
3
support of this approach. Studies that support the use of
anticoagulants have largely been retrospective or non-randomised,
Severity of PAH is graded by the New York Heart Association (NYHA) with small study numbers of patients with IPAH.
7,8
A target
functional classifications (see Table 1), a modification of the original international normalised ratio (INR) between 1.5 and 2.5 for oral
classification by the World Health Organization (WHO);
4
symptomatic anticoagulation is recommended.
9
severity has long since been recognised to be related to prognosis.
5
Not only is PAH a rapidly evolving disease, but it is also asymptomatic Diuretics and low-sodium diets are able to relieve hypervolaemia
in the early stages. As such, approximately 75% of patients present and the associated symptoms, but it is not known whether this
with NYHA functional class (FC) III and marked functional impairment approach reduces the burden of right ventricular overload and
at diagnosis.
1
PAH is classified as idiopathic (IPAH), familial (FPAH) or improves prognosis. Digoxin has also been used as PAH therapy
occurring in association with other conditions or risk factors.
6
These due to its ability to increase cardiac output, but doubts regarding its
subgroups share similar clinical and pathological features, but the long-term efficacy have restricted its use to cases of PAH
precise aetiology of PAH remains unknown. associated with atrial fibrillation.
10
The vasodilatory activity of
calcium-channel blockers can be used in a minority of PAH patients
This article will consider the treatments available in PAH, the to counteract vasoconstriction, which was originally assumed to be
increasing use of combination therapies and the implications of the underlying cause of PAH. Favourable response rates to an acute
resulting drug–drug interactions (DDIs) in PAH, with a special focus vasodilator are achieved in fewer than 10% of patients, only half of
on endothelin receptor antagonists (ERAs). whom are able to main long-term responses.
11
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