Pulmonary arterial hypertension 2 Flashcards
What are the vasodilatory drug targets in PAH?
Endothelin
nitric oxide
PGI2
Summary of the endothelin pathway
ET binds to ETa/ETb
signalling via a Gq protein and PLC
converts PIP2 to IP3 - leading to calcium release
vasoconstriction
Summary of the nitric oxide pathway
nitric oxide produced by endothelial cells activates guanylyl cyclase and converts GTP to cGMP
cGMP via PKG inhibits calcium influx and promotes vasodilation
*PDE5 hydrolyzes cGMP to 5’ GMP
Summary of the prostacyclin pathway
PGI2 acts on IP receptors signalling via Gs protein and adenylyl cyclase converts ATP to cAMP activates PKA promotes vasodilation
Calcium channel blockers and their side effects
Diltiazem: oral nifedipine: oral -for patients with IPAH who are 'vasoresponders' respond very well to CCBs side fx: systemic hypotension bradycardia peripheral oedema
What are PDE5 inhibitors?
Sildenafil (Revatio/viagra): oral
tadalafil (adcirca): oral
PDE5= cGMP specific phosphodiesterase
too much cGMP breakdown- less PKG- less vasodilation
PKG activates MLCP, K channels and promotes uptake of calcium into the SR
*useful combination with inhaled iloprost
*do not use with nitrates- can induce systemic hypotension
PDE5 inhibitor side effects?
flushing
headache
epistaxis
altered colour vision
What is riociguat? What are its side effects
new drug- bypasses requirement for NO stimulates guanylyl cyclase licensed for CTEPH avoid combination with PDE5 inhibitors side fx: headache, dizziness, indigestion and diarrhoea ( the gut is heavily vascularised)
Features of endothelin receptors, when and how are ERAs often used?
ETa and ETb are ubiquitously distributed in the body- including the pulmonary vasculature and the heart
Binding of ET to ETa and ETb on VSMCs= vasoconstriction
Binding of ET to ETb on endothelial cells= vasodilation (negative feedback)
ERAs are often used in combination oral therapy
added to a PDE5 inhibitor
What are the endothelial receptor antagonists, and what are their side effects?
Bosentan- ETa and ETb Macitentan- Eta Ambrisentan- Eta all oral drugs side fx: abnormal liver function tests (bosentan) headache peripheral oedema (ambrisentan) anaemia (macitentan)
Why is macitentan considered superior to the others?
Better receptor antagonist
much slower dissociation rate
evidence for increased tissue penetrance
What are the prostacyclin derivatives, and what are their side effects?
Epoprostenol: IV Iloprost: inaled Treprostinil: IV/ sub cutaneous Beraprost (japan and korea only): oral side fx: nausea vomiting diarrhoea headache flushing development of tolerance -line related complictions: infection, thrombosis, pump failure Iloprost: 6-9 inhalations, each take 30 mins, cough, syncope Treprostinil: site pain
How is prostacyclin made and what are its benefits?
Formed by oxidation of arachidonic acid by cyclo-oxygenase - in the endothelial and SMCs
powerful vasodilator
improves right ventricular function through a decrease in PVR and afterload
decreases PAP
*inhibits proliferation of human pulmonary artery SMCs in vitro
How are prostacyclins unselective?
Will bind to and activate other prostanoid receptors
EP1 (gut)= vasoconstriction
EP3- inhibits vasodilation
IP, EP2 and DP1= vasodilation
by activating EP3- and having downregulated levels of IP (as is reported in PAH)= lead to complete failure
Why is it so hard to make a prostacyclin analogue, and what have we achieved?
Its a very transient mediator
we’ve improved the half-life from 2 mins to a few hours
