Specific drug therapy

Specific PAH treatments target the three pathways (Humbert M. et al,  N Engl J Med 2004;351:1425-36) hat lead to the obliteration of small pulmonary vessels and seek a reduction of PVR by vasodilatation and possibly a vascular de-remodelling that leads to the restoration of cardiac output. In any case, PAH diagnosis must be confirmed by a right heart catheterization before introduction of any of the 4 classes of specific treatment.

Combination therapy of two or three different classes is possible and even recommended for PAH patients deteriorating under monotherapy or presenting functional class NYHA IV at the moment of diagnosis. For class NYHA I or II, initial oral therapy should be preferred.


Calcium Channel Blockers (CCB)

  • Nifedipine [initial dose: 30 mg 2x/d up to 120-240 mg/d]; information
  • Amlodipine [2,5 mg 1x/d up to 20 mg/d]; information
  • Diltiazem [60 mg 3x/d up to 240-720 mg/d]; information

This class of drugs is restricted to the small number of patients (less than 10% of cases, mostly for patients in the group 1.1) who meet responding criteria to the reversibility test performed during right heart catheterization. In these patients, it is important to repeat catheterization and reversibility test after 3-4 months to monitor the effectiveness of treatment. Indeed, a positive reversibility test does not necessarily imply an improvement under treatment calcium channel blockers.

The choice of CCB is based upon the patient’s heart rate at baseline, with a relative bradycardia favoring nifedipine and amlodipine and a relative tachycardia favoring diltiazem. Limiting factors for dose increase are usually systemic hypotension and lower limb peripheral edema.


Endothelin receptor antagonists (ERA)

  • Bosentan (Tracleer®) [62,5 mg 2x/d then 125 mg 2x/d]; information
  • Ambrisentan (Volibris®) [5 mg 1x/d then 10 mg 1x/d]; information

Endothelin is a neuropeptide that exerts vasoconstrictive and mitogenic effect by binding to two distinct receptor isoforms in the pulmonary vascular smooth muscle cells, endothelin-A and endothelin-B receptors. Despite differences in receptor isoform activity, the efficacy in PAH of the dual endothelin-A and B receptor antagonist bosentan and of the selective endothelin-A receptor ambrisentan appears to be comparable. These treatments are administered orally.


Phosphodiesterase type-5 inhibitors

  • Sildenafil (Revatio®) [20 mg 3x/d up to 80 mg 3x/d]; information

Inhibition of the enzyme phosphodiesterase type-5 results in vasodilatation through the NO/cGMP pathway at sites expressing this enzyme, as it is the case for pulmonary vasculature. These treatments are administered orally. Tadalafil belongs to this class of molecules. It is sold in Switzerland but its indication is approved by Swissmedic only for the treatment of erectile dysfunction.


Prostanoids

  • Epoprostenol (Flolan®) [IV 2-4 ng/kg/min, then according to tolerance]; information
  • Treprostinil (Remodulin®) [SC or IV 1-2 ng/kg/min, then according to tolerance]; information
  • Iloprost (Ilomedin®) [IV 0,5 ng/kg/min, then according to tolerance], Ventavis® [inhal. 2,5-5 µg up to 6-9x/d]); information

Prostacyclin is produced essentially by endothelial cells. In addition to a platelets antiaggregant activity, it causes vasodilatation and exerts cytoprotective and antiproliferative effects.

Synthetic prostacyclin (epoprostenol) and its derivatives (Iloprost, Treprostinil) are administered intravenously using an automatic infusion device, or by inhalation (Iloprost) or subcutaneously (Treprostinil). Generally, these treatments require extensive patient’s education and follow up by a specialist nurse.

The short half-life of this treatments and the infectious risk related to administration way (central venous access, pump) imply a permanent availability of the specialized team. Beraprost, administered orally, belongs to this class of molecules but is currently not available in Switzerland. The same is the case for inhaled Treprostinil.