Pulmonary Hypertension II (treatment) Flashcards
PH treatment issues (4)
- Life threatening with poor prognosis if untreated ( hard to diagnosis)
- 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
Treatment of pulmonary hypertension (mostly endothelial -group1) (2)
Depends on severity, whether likely to progress, individual drug tolerance
Primary Therapy:
-Oxygen
-Anticoagulants
-Diuretics
-Exercise
Specific/Targeted Therapies:
(Calcium channel blockers = X increasing vasodilat doesn’t really work)
-Phosphodiesterase type-5 inhibitors e.g. Sildenafil – relaxes smooth muscle cells
-Prostacyclin analogs
-Endothelin receptor antagonists
Drug targets in PH - 3 pathways (3)
images 2x
endothelium pathway - most potent vasoconstrictor - release as Endothelial 1 then bind to r’s for vasocon/prolif : ANTAG’s = bind to r’s on SM cells = inhib
NO pathway - potent vasodilator through cAMP - PDE5 can inhib cAMP: INHIBs inhib PDE5 = more vasodil
Prostacyclin pathway - vaso too through cAMP - not used as much but can do the same using analogs
Sildenafil usage (2)
PDE5 inhib trials : From angina to erectile dysfunction (viagra) to pulmonary hypertension (repurposed)
in PAH: allows more NO to function = to act on MLCK pathway to reduces vasoconstriction
Endothelium r + pathway (2)
r -> Rho signalling -> Rho-kinase -> vasoconstriction (phos of myosin)
Bosentan (=antag) = prevents vasocontriction
Fasudil
can inhib Rho-kinase too
Endothelin-1 (4)
- 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
Endothelin-axis (4)
- 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
G protein coupled receptors image
Differences in ET receptors
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 - ET-RB:
– Located on endothelial and smooth muscle cells
– SMCs mediate vasoconstriction
– ECs mediate vasodilation
Differences in ET receptors
image
Targeting ET receptors - depending on localisation (4)
- 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) - 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)
Targeting ET receptors specifics (4)
- 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
- Sitaxsentan: ET-RA antagonist (Withdrawn – fatal liver toxicity)
Sitaxsentan explained (2)
Pfizer voluntarily withdraws sitaxsentan from the market worldwide and halts ongoing clinical trials due to toxicities + fatalities
= needs to be safe + high efficacy
image
Targeting ET receptors results (2)
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
New targets in PH: mTOR (3)
- 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
