Medications - Professor Richard Kirk 2023

Professor Richard Kirk
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Those who respond to vasoreactivity testing may treated with calcium channel blockers. For those who are non-responders specific therapies target three main pathways in PAH: nitric oxide, endothelin and prostacyclin. Dosing recommendations below were obtained from Tables S4 & S5 in the Supplementary Appendix of the 2019 Updated Consensus Statement on the Diagnosis and Treatment of Pediatric Pulmonary Hypertension.

Nitric Oxide Pathway
Nitric oxide causes vasodilatation by increasing the levels of cyclic guanosine-monophosphate (cGMP) in vascular smooth muscle cells. cGMP is short lived because of the rapid degradation by Phosphodiesterase 5 (PDE5). PDE5 inhibitors (sildenafil and tadalafil) thus cause pulmonary vasodilatation by promoting an enhanced and sustained level of cGMP. Conversely cGMP levels are enhanced by Guanylate Cyclase (GC) Stimulators

The European Medical Agency approves 8-20kg: 10mg/dose three times daily PO (less in neonates / infants < 10kg), ≥ 20kg: 20mg/dose three times daily. An alternative regime is (Table S5) Starting dose: 0.3-0.5 mg/kg/dose three (e.g., > 1 year old) or four times (e.g., < 1 year old) daily PO. Maintenance dose: 0.5-1 mg/kg/dose three (> 1 year old) or four times (< 1 year old) daily PO. <8 kg Starting dose 0.3-0.5 mg/kg/dose four times daily PO, Maintenance dose: 1mg/kg/dose four times daily PO. Maximum dose (controversial): 10mg/dose PO three to four times dail. If oral dosing is not possible then intravenous and sublingual routes may be used. Metabolism is through the cytochrome p450 enzyme system and is rapid.
Tadalafil has a long half-life, dosing is daily and Starting adult dose: 20mg/dose once daily PO, Consider uptitration from 20 to 40 mg/dose once daily PO. Max. adult dose: 40 mg/dose once a day PO. Pediatric maintenance dose probably 1mg/kg/day PO.
Riociguat is a guanylate cyclase (GC) stimulator. Dosage: Starting adult dose 1mg three times daily PO, uptitration required. Maintenance adult dose 1-2.5mg (dose three times daily PO). Maximum adult dose 2.5mg/dose three times daily. There is Limited pediatric data

Endothelin Pathway
Endothelium is a potent vasoconstrictor and endothelin receptor antagonists targeting the endothelin receptors type A (ETA) and type B (ETB) are thus useful in PAH.
Bosentan is an dual endothelin receptor antagonist targeting both ETA  and ETB. It is approved for children > 1yr age. Dosage is Starting dose: 0.3-1 mg/kg/dose twice daily, uptitration. <10 kg: max. 2 mg/kg/dose twice daily PO, 10–20 kg: max. 2mg/kg/dose twice daily PO, 20–40 kg: 62.5 mg/dose, twice daily PO, > 40 kg: 125 mg/dose twice daily PO.
Macitentan is also a dual antagonist. Starting dose (adults): 5 – 10 mg once daily PO. Maintenance adult dose 10mg once daily PO. No published data on pediatric dosing.
Ambrisentan is selective for ET1a.  Adult dosing starts with 5 mg daily up to 10 mg daily

Prostacyclin Pathway
The biological functions of prostacyclin in the pulmonary circulation  are mediated by a specific cell-surface receptor of the G-protein  coupled receptor (GPCR) class. The binding of prostacyclin to the receptor triggers the activation of  the G-protein and increases intracellular cAMP, which activates protein  kinase A. This causes inhibition of platelet aggregation, relaxation of  smooth muscle, and vasodilation of the pulmonary arteries.
Prostacyclin and its analogues
Prostacyclin and its analogues can be used intravenously or by inhalation. Either method brings challenges, usually related to short half-lives, requiring continuous or frequent administration. Epoprostenol (IV) Iloprost (Inhalation) and Treprostinil (SC, IV, inhaled, oral) are the currently available drugs.
Selexipag is a prostacyclin receptor agonist. It is a pro-drug that is rapidly hydrolyzed to its active metabolite, which has a high affinity for the IP receptor. It is givne orally.

Calcium Channel Blockers
Calcium channel blockers are indicated in patients who show a positive response in vasoreactivity testing. For patients with idiopathic or hereditary PAH, a positive adult test is a ≥20% fall in both mean pulmonary artery pressure (mPAP) and PVR/SVR ratio without a decrease in cardiac index. A positive test for children is a decrease in mPAP by at least 10 mmHg to a value <40 mmHg without a fall in cardiac output. Amlodipine, nifedipine and diltiazem are the most commonly used.
Further Reading
  • Supplementary Appendix 2019 Updated Consensus Statement on the Diagnosis and Treatment of Pediatric Pulmonary Hypertension. The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT. J Heart Lung Transplant 2019;38:879-901 Supplement
Last Updated: April 2023
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