Pulmonary hypertension part 2 Flashcards
Intro to need for treatment in pulmonary hypertension
Life threatening with poor prognosis if untreated
PH management advanced rapidly with targeted therapy
Meta-analysis of 23 randomised trials = 43% reduction in mortality with specific therapy as compared with placebo
Some patients still have poor prognosis/early identification crucial
pulmonary artery hypertension most common type
and within that connective tissue disease is the largest classification and one of the only ones with treatment available
Primary vs specific targeted therapy in PH
Depends on severity, whether likely to progress, individual drug tolerance Primary therapy: Oxygen Anticoagulants Diuretics Exercise
Specific targeted therapies: Calcium channel blockers Phosphodiesterase type-5 inhibitors e.g. Sildenafil – relaxes smooth muscle cells Prostacyclin analogs Endothelin receptor antagonists
What are the drug targets in pulmonary hypertension
3 pathways
Endothelin pathway
acted upon by endothelin receptor antagonists
can block proliferation and vasoconstriction
block endothelin 1 (block conversion of pre-pro version to pro)
Bosentan is an endothelin receptor antagonist, stops activation of Rho kinase which can cause contraction
nitric oxide pathway
acted on by phosphidesterase type 5 inhibitors like sildefanil
Sildenafil: used from angina to
erectile dysfunction to
pulmonary hypertension
so PDE5 is reduced
reducing eGMP
increases vasodilation and anti proliferation in smooth muscle cells
prostacyclin pathway- prostacyclin derivates act here
these increase cAMP to increase vasodilation and anti proliferation
Describe endothelin 1
Endothelin-1 (ET-1) is a 21-amino acid peptide hormone best known for its potent vasoconstrictor properties
Derived from vascular endothelial cells, the production of ET-1 is tightly regulated and tissue specific
Able to act on a wide range of physiological systems including the cardiovascular, pulmonary, renal, neural as well as the reproductive systems
It is involved in the maintenance of vascular tone, smooth muscle cell proliferation, the promotion of angiogenesis and has pro-inflammatory properties
Describe the endothelin axis
ET-1 belongs to the endothelin family including two other isoforms: ET-2, ET-3
Biologically active peptide ET-1 is formed from pre-pro-ET-1 into pro-ET-1 (otherwise known as big ET-1) by furin-like proteases.
Big ET-1 is cleaved into mature ET-1 by endothelin-converting enzymes (ECE) which are expressed by vascular cells
Describe the differences in ET-RA and ET-RB
Two receptor subtypes for ET-1: ETA and ETB that transduce antagonistic physiological effects of vasoconstriction and vasodilatation
ET-RA Located on smooth muscle cells Mediate vasoconstriction also alpha beta gamma PLC-IP3- Ca2+- contraction also PLC- PKC- CONTRACTION
ET-RB
Located on endothelial and smooth muscle cells
SMCs mediate vasoconstriction
ECs mediate vasodilation
associated with alpha beta gamma GPCR
activates PI3K, activating AKT and eNOS, ultimately releasing NO
NO acts on gulanylyl cyclase-cGMp-PKG- RELAXATION
Targeting ET receptors and examples
Net result produced by ET-1 is determined by the receptor localisation and the counteraction between ETA and ETB receptors
Targeted therapies for ETRs are distinguished by their ability to antagonise both ET receptors (non selective) or whether they are selective (for ETRA)
Bosentan (Tracleer): oral, dual ET-R antagonist, improves exercise capacity, haemodynamic variables and time to clinical worsening
Ambrisentan (Letairis): oral, selective ET-RA antagonist, improves exercise tolerance, haemodynamic variables and quality of life
Macitentan (Opsumit): oral, dual ET-R antagonist, long half-life, potent inhibition profile, and strong lipophilic profile, suggesting stronger affinity for tissue
(WITHDRAWN BY PFIZER)
Sitaxsentan: ET-RA antagonist (Withdrawn – fatal liver toxicity)
Clinical endpoints for targeting ET receptors
Clinical end points include 6MWD (six min walk distance) since trials are not powered significantly to look at mortality (patient numbers too low).
There is no real consensus as to whether dual ET-R inhibitors are more efficacious than selective inhibitors or vice versa
BREATHE-1 (Bosentan) EARLY (Bosentan) ARIES (Ambrisentan) SERAPHIN (Macitentan) AMBITION (Ambrisentan and PDE inhibitor, Tadalafil)
Describe new targets in PH- mTOR
Growth factor mediated pathways e.g. insulin, IGF-1 increase HIF protein synthesis in normoxia
Receptor tyrosine kinase signalling increased
PI3K/AKT/mTOR pathway
Ras/MEK/ERK pathway
mTOR: mammalian target of rapamycin
PI3K: phosphoinositide 3 kinase
AKT: Protein kinase B
ERK : extracellular regulated kinase/MAPK: mitogen activated protein kinase
