Pulmonary arterial hypertension - 2

Question 1

Vasodilatory drug targets in PAH?

Answer 1

NO (key vasodilatory mediator) we want to stimulate, Endothelin receptors we want to inhibit, PGI2/Prostoglandins we want to stimulate

Question 2

Approved therapies - what are they and how do they work? What about vasoresponders?

Answer 2

Inhaled NO - in vasoresponders (individuals that respond well to catheterisation drugs) see a 10mmHg decrease in their blood pressure. 10% of individuals have this acute response.

Ca2+ channel blockers –> inhibit contraction of vascular smooth muscle cells. NIFEDIPINE

Question 3

Developing therapies?

Answer 3

PDE5 inhibitors
Prostanoids (typically IV but taken orally also)
IP receptor agonists (Prostanoid I2)
Endothelin receptor antagonist
IP receptor agonist
Prostanoids

Question 4

Approved therapies - adverse effects?

Answer 4

Peripheral hypotension
Decreased energy levels
Bradycardia 
Light headedness
Peripheral oedema

Question 5

Sildenafil - mechanism ? Adverse effect?

Answer 5

PDE inhibitor. Prevents inactivation of cGMP therefore prevents inactivation of PKG, maintaining vasodilation

ADVERSE EFFECTS - flushing, headaches, altered colour vision, Priapism (sustained painful erection), optic neuropathy, epistaxis

Question 6

ETr antagonists - BOSENTAN - mechanism?

Adverse effects

Answer 6

Prevents ET-1 from binding to receptors to induce IP3 release from the SR and therefore stimulate contraction
Good in combo with PDE–|

Adverse effects - headache, abnormal liver function, peripheral oedema, nasopharyngitis, headache

Question 7

Prostacyclins - the go-to therapy for treatment of PAH - mechanism and what is the main problem with them?

Answer 7

Go to therapy but least selective drugs!
Difficult to deliver
Cause vasodilation of the pulmonary and systemic arteries
Convert arachodonic acid to prostoglandin I2 to stimulate vasodilation

Reduces ventricular afterload, pulmonary arterial pressure and pulmonary vascular resistance

Question 8

Prostacyclin PGI2 analogue - what are the main problems?

Answer 8

PGI2 has a short half life/is unstable so continuous delivery is required.
This analogue is more stable with an extended half life –> the highest tolerable dose for each patient is best (PERSONALISATION)
also costs 100k per year per patient

Question 9

Prostocyclin analogue - adverse effect?

Answer 9

flushing, diarrhoea, headache, non-selectivity of the analogue means off target effects are seen (drug binds 3/4 other receptors)

Question 10

RIOCIGUAT - what is it used to treat, mechanism of action?

Answer 10

Chronic hypertension and CTEPH (chronic thromboembolic pulmonary hypertension)
Directly stimulates GC (via the cGMP pathway) to stimulate release of NO

Question 11

RIOCIGUAT - adverse effects?

Answer 11

Headache, dizziness, indigestion, diarrhoea, gut problems (gut is highly vascularised)

Question 12

How have the current treatments for PAH been effective?

Answer 12

Increased survival by 10% over the past decade

Question 13

Vascular remodelling - what are the causes and what gene is commonly mutated?

Answer 13

Heart failure, vascular injury of genetic factors can cause vascular remodelling
BMPrs are mutated in 80% of HPAH and 10% IPAH

Question 14

FK506 - what is its’ mechanism of action and what was shown in animal models?

Answer 14

FK506 is an anti-rejection drug that activates BMP at a low dose – drug is off patent so not commonly used or sold!
Was shown in animals models that vascular modelling could be reversed and lung pressure was lowered

Question 15

BMP9 - why is it a potential therapeutic target?

Answer 15

Inhibits EC permeability (prevents inflammation)
Stablises cell networks
inhibits EC proliferation and protects their apoptosis
Increases expression of BMPR||

Question 16

OPG/TRIAL axis - what is the relevance of this treatment ?

Answer 16

Elevated levels of these proteins in serum in PAH patients

Proposed anti-OPG therapy –> antibody used in rat models to prevent the action of this axis –> reduces PAH symptoms

Question 17

Elastase —-|s - therapetic target?

Answer 17

Breakdown of elastase is common in PAH - enzymes are responsible for this –> can we target elastase enzymes to allieve symptoms

Question 18

SEX HORMONES - relevance as a therapeutic target?

Answer 18

Aromatase enzyme (involved in oestrogen production) highly expressed in PAH –> cross talk between oestrogen and BMPR|| means that targeting the Aromatase enzyme may be beneficial

Question 19

O2, Anti-coagulants, diuretics – how could these be beneficial?

Answer 19

O2 - increases oxygen delivery to tissues
Anti coagulants - recommended for patients on IV therapies such as injected Prostanoids
Diuretics - used to tackle HT and reduce the circulating volume of the blood and oedema