Cardiology Test 5- Lapinsky Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is high blood pressure specifically in the ___ __, eventually leading to right-sided HF

pulmonary arteries

Pulmonary arteries= the blood vessels that carry __ blood from the right ventricle of the heart to the lungs to pick up oxygen

deoxygenated

PAH is essentially "relentless" ____ and vascular ____ of the pulmonary arteries

vasoconstriction, remodeling

3 pathways that drive PAH

-↓ __ __ pathway

-↓ ___ pathway

-↑ ___ pathway

nitric oxide, prostacyclin, endothelin

↓ nitric oxide pathway

-↓NO causes ↓_____, which leads to decreased _____

-so this contributes to vasoconstriction and pulmonary artery smooth muscle proliferation in PAH

cGMP, vasodilation

↓ prostacyclin pathway

-↓____ contributes to vasoconstriction, blood platelet aggregation, and pulmonary artery smooth muscle remodeling in PAH

PGI2

↑ endothelin pathway

-too much ____-___ contributes to potent vasoconstriction and pulmonary arterial smooth muscle growth in PAH

endothelin-1

PAH in one sentence

-___ pulmonary vascular resistance

-leads to right ventricle ___

-leads to right ventricle __

high, strain, failure

Drug Targets for PAH

-drugs that work in __ __ pathway are sGc stimulators and PDE-5 inhibitors

-drugs that work in __ pathway are prostacyclin receptor agonists

-drugs that work in ___ pathway are endothelin receptor antagonists

nitric oxide, prostacyclin, endothelin

Drug Targets for PAH

-in the nitric oxide pathway, NO usually stimulates __ ___ ____ (sGc) to convert GTP to cGMP

soluble guanylate cyclase

cGMP causes ____ and reduced ___ of pulmonary arterial smooth muscle cells (desirable)

vasodilation, proliferation

Drug Targets for PAH

-a drug class that works in the nitric oxide pathway is stimulators of ___, which includes __

sGc, riociguat

Drug Targets for PAH

-in the nitric oxide pathway, cGMP is converted to its inactive form by ___ ___

PDE-5

Drug Targets for PAH

-a drug class that works in the nitric oxide pathway is PDE-5 ___, which includes __ and ____

inhibitors, sildenafil, tadalafil

Drug Targets for PAH

-in the prostacyclin pathway, binding of prostacyclin to its __ causes vasodilation and reduced proliferation of pulmonary arterial smooth muscle cells (good)

receptor

Drug Targets for PAH

-a drug class that works in the prostacyclin pathway is prostacyclin receptor agonists, which include ___, __, ___, and __

epoprostenol, treprostinil, iloprost, selexipag

Drug Targets for PAH

-in the endothelin pathway, binding of ET-1 to its receptor causes ____ and __ proliferation of pulmonary arterial smooth muscle cells (bad)

vasoconstriction, increased

Drug Targets for PAH

-a drug class that works in the endothelin pathway is endothelin receptor antagonists, which include ___, ___ and __

macitentan, bosentan, ambrisentan

What are the 3 CCBs approved for PAH?

____ (DHP)

____ (DHP)

_____ (non-DHP)

amlodipine, nifedipine, diltiazem

CCBs MOA

-block L-type Ca2+ channels primarily on pulmonary artery smooth muscle cells leading to decreased Ca2+ influx, which results in ____

vasodilation

CCBs

-___ disease-modifying effect on vascular remodeling

-pharmacologically ___ compared to other PAH drugs

no, mild

CCBs

-only for "___" (identified by right heart catheterization (RHC) testing)

-___ doses required

vasoresponders, high

CCBs

-avoid ____ (negative inotrope)

verapamil

Prostacyclin Pathway Agents MOA

-prostacyclin receptor agonists that cause ___, anti-___, and anti-___ effects

vasodilation, proliferation, platelet

Prostacyclin Pathway Agents

-____ anti-remodeling class

strongest

Prostacyclin Pathway Agents

-___ and ___ are modified analogs of PGI2 with improved stability and half life

treprostinil, iloprost

Prostacyclin Pathway Agents

-most potent PAH therapy, especially IV ___

-used for __-risk disease or inadequate response to oral therapy

-requires careful dose __ and adherence

epoprostenol, high, titration

Epoprostenol

-natural (endogenous)

-half life is about __ __

-IV (continuous)

5 min

Treprostinil

-half life is about __-__ hours

-IV, SC, inhaled, oral

4-12

Iloprost

-half life is about ___ minutes

-inhaled

25

Selexipag

-this is a __-__ with a long-acting active metabolite

non-prostanoid

Selexipag

-half life is about __-__ hours (long)

-oral

7-13

Endothelin Receptor Antagonists (ERAs) core mechanism is to bind to ETA/ETB receptors on the surface of pulmonary arterial smooth muscle cells and prevent ET-1 from binding as an ___

agonist

3 Endothelin Receptor Antagonists (ERAs) ?

bosentan, ambrisentan, macitentan

the foundation of oral combination therapy for PAH is usually an ___ + an ___ __

ERA, PDE-5 inhibitor

when ET-1 binds to and agonizes the ETA receptor, this is a major driver of ___ and vascular remodeling (bad)

vasoconstriction

-when ET-1 binds to and agonizes the ETA receptor, this is a major driver of vasoconstriction and vascular remodeling (bad).

-Therefore, we desire to selectively antagonize ____ with an endothelian receptor antagonist

ETA

when ET-1 binds to and agonizes the ETB receptor, this causes some vasoconstriction and increased ___ of ET-1 (good)

clearance

-when ET-1 binds to and agonizes the ETB receptor, this causes some vasoconstriction and increased clearance of ET-1 (good)

-Therefore, we do NOT desire to antagonize ___ with an endothelian receptor antagonist because it would increase ET1 levels

ETB

Bosentan is a dual ___ and ___ receptor antagonist

ETA, ETB

Bosentan has the highest risk for ___ toxicity !!!

liver

Bosentan is an ___ option/1st gen ERA that is being used less due to LFT concerns (also its dosed BID while the other options are only QD)

older

Ambrisentan is a selective ___ receptor antagonist that is dosed QD and has low liver toxicity risk

ETA

Ambrisentan is a good option when ETA selectivity preferred (it does not undesirably affect ET-1 ____)

clearance

Macitentan is a dual ___ and ___ receptor antagonist (but with tighter, more sustained binding) that is dosed QD and has low liver toxicity risk

ETA, ETB

Macitentan is _____ due to safety and efficacy balance, as well as the best in-class tissue penetration and receptor affinity

preferred

PDE-5 Inhibitors

-core mechanism is to bind to PDE-5 within pulmonary arterial smooth muscle cells and inhibit the conversion of active cGMP to inactive ___, thus amplifying the NO signal and producing vasodilation

GMP

PDE-5 Inhibitors

-___ line therapy for PAH (combined with an ERA)

first

PDE-5 Inhibitors

-avoid use with __ ___ and/or ___ (bc increases active CGMP and therefore causes severe hypotension)

organic nitrates, riociguat

PDE-5 Inhibitors

sildenafil half life is about __ hours

tadalafil half life is about ___ hours

4, 17.5

sildenafil

-has a lower half life, so is dosed TID, so has a ___ convenience/adherence rate

lower

tadalafil

-has a longer half life, so is dosed QD, so has a ___ convenience/adherence rate

high

sildenafil PK profile has __ and ___

tadalafil PK profile is __ and ___

peaks, valleys, smooth steady

sildenafil

-has ___ PDE-5 selectivity, so inhibition of PDE-6 in the retina can cause blue ___ disturbances

less, vision

tadalafil

-has ___ PDE-5 selectivity

high

sildenafil

-typically just used as an ___ choice when tadalafil not tolerated

alternative

tadalafil

-___ line choice for many PAH patients

first

Riociguat binds to soluble guanylate cyclase within pulmonary arterial smooth muscle cells and:

1) stimulates the enzyme to convert inactive GTP into active ___

cGMP

Riociguat binds to soluble guanylate cyclase within pulmonary arterial smooth muscle cells and:

2) improves the ___ of sGC to endogenous __

sensitization, NO

unlike PDE-5 inhibitors, riociguat works even when NO levels are ___

low

Riociguat is a viable alternative to ___-___ (especially with tx failure)

PDE-5 Inhibitors

Riociguat

-CANNOT be combined with PDE-5 inhibitors due to severe __ risk

hypotension

in addition to PAH, Riociguat is the only approved drug for ____ (chronic thromboembolism pulmonary hypertension)

CTEPH