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45.14 Management of pulmonary hypertension: targeted therapies
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Published:July 2018
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Abstract
Three main signalling pathways are involved in the pathobiology of pulmonary hypertension and are targeted with specific drugs: the endothelin, the nitric oxide–cGMP, and the prostacyclin pathways. The endothelin pathway is over-activated leading to pulmonary vasoconstriction and vessel cells proliferation. Endothelin receptor antagonists are orally available drugs that counteract the endothelin detrimental effects and improve symptoms, exercise capacity, and the outcome of patients with pulmonary arterial hypertension. Phosphodiesterase type 5 inhibitors and guanylate cyclase stimulators are orally available drugs, which promote the activity of the nitric oxide pathway that is downregulated in the pulmonary vessels of pulmonary arterial hypertension patients. Different randomized controlled trials demonstrate favourable effects of these compounds on clinical, exercise, and haemodynamic parameters. Dysregulation of the prostacyclin metabolic pathways has been shown in patients with pulmonary arterial hypertension as assessed by reduction of prostacyclin synthase expression in the pulmonary arteries and of prostacyclin urinary metabolites. The clinical use of prostacyclin in patients with pulmonary arterial hypertension has been extended by the synthesis of stable analogues and by prostacyclin receptor agonists that possess different pharmacokinetic properties but share qualitatively similar pharmacodynamics effects. Prostacyclin analogues are available for intravenous, subcutaneous, inhaled, and oral administration; the prostacyclin receptor agonists are orally available. Multiple randomized controlled trials show variable efficacy of these compounds on symptoms, exercise capacity, haemodynamics, and the outcome of patients with pulmonary arterial hypertension.
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