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.
- Calcium channel blockers (CCB)
- Endothelin receptor antagonists (ERA)
- Phosphodiesterase type-5 inhibitors (PDG-5i)
- Stimulators of soluble guanylate cyclase (sGC)
Combination therapy of two or three different classes is possible and even recommended for PAH patients NYHA Class II or higher, mandatory for patients deteriorating under monotherapy or presenting functional class NYHA III-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®, Bosentan Mepha®) [62,5 mg 2x/d then 125 mg 2x/d]; information
- Macitentan (Opsumit) 10mg 1x/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 (PDG-5i)
- Sildenafil (Revatio®) [20 mg 3x/d up to 80 mg 3x/d]; information
- Tadalafil (Adcirca) 20mg 20mg 2x/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. A combination with a Stimulator of soluble guanylate cyclase is contraindicated due to the increased vasodilatation and risk of systemic hypotension.
- Epoprostenol (Veletri®) [IV 2-4 ng/kg/min, then according to tolerance]; information
- Treprostinil (Remodulin®/Treprostinil Orpha®) [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.
Stimulator of soluble guanylate cyclase (sGC)
- Riociguat (Adempas®) 0.5mg 3x/d up to 2.5mg 3x/d; information
Nitric oxide (NO) binds to soluble guanylat cycklase (sGC) and mediate the synthesis of cycline guanosine monophosphate cGMP), wich is increased by stimulators of sGC. The effect is vasodilatation through the NO/cGMP pathway at sites expressing this enzyme, as in the pulmonary vasculature. Phosphodiesterase type-5 inhibitors (PDG-5i) act on the same pathway by inhibiting the cGMP methabolism and a combination of a PDG-5i with sGC-stimulator is therefore contraindicated, due to the risk of systemic hypotension. However, in expert centers a switch between the two categories of drugs might be considered. Stimulators of sGC are administrated orally. In Switzerland Riociquat is currently indicated for the treatement of adult patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), persistant PAH after CTEPH-therapy, or for symptomatic PAH patients in the WHO functional NYHA II or III.