PULMONARY ARTERIAL HYPERTENSION:

Pulmonary arterial hypertsion is an increase in blood pressure in the artery due to the increased pulmonary vascular resistence and right ventricular failure. Puimonary artery carries the bloodfrom the right ventricles to lungs.
Breathlessnesss Dizziness Fainting Non-productive lough Hemoptysis (cough out blood) Swelling around the ankle,knees Chest pain palpitation

SYMPTOMS:

vascular obstruction and vasoconstriction

progressive increase

in pulmonary vascular resistance and right ventricular failure

Mean Pulmonary arterial pressure(PAPm)

Normal healthy adults : 12-16mmHg (at rest) Pulmonary arterial hypertension : 25mmHg(atrest) ,35mmHG(exercise)

Exertional dyspnea When right ventricular failure sets in, patients start having lower extremity edema from venous congestion. Angina Orthopnea and paroxysmal nocturnal dyspnea (PND) hepatomegaly

Normally PAH is regarded mainly as disease of excess vasoconstriction But these view was incomplete new concets have been developed: In the pathophysiology of PAH Uncheked incresed in the proliferation of smooth muscle cells Dysregulated control of endothelial cell with apoptosis Dysfunction of some areas and profuse proliferation PAH is disease of the precapillary pulmonary arterial blood PAH is panvasculopathy,serum seritonin levels are increased Hence decreasing the vasodilator /vasoconstrictor ratio Prothambic factors including tissue factors are increased

In PAH ,Pulmonary artery smooth muscle cell (PASMC) apoptosis is supressed and proliferation is enhanced Factors involved in PASMC proliferation includes; Mutation of bone morphogenetic protein receptor type2(BMPR2) Mitochondrial metabolic abnormolities De-novo expression of survivin protien Increased expression of seritonin levels Increased expression of platelet derived growth factor receptor Tyrosine kinase activation

BMP are part of the tronsforming growth factor super family(TGF-) TGF- controls vascular remodelling; Cell proliferation Apoptosis Cellular differentiation Collagen and extra cellular matrix turnover

IN FAMILIAL PAH:
A loss function mutation in the BMPR2 It results in Imbalence between the apposing effects TGF- ,BMP signalling, It favours in smooth muscle cell for propliferative and anti apoptopic response in edothelial cells it favours ati proliferativve ad pro apoptopic response These overall effect leads to smooth muscle cell proliferation and endothelial hyperplasia

In IPAH (IDIOPATHIC ARTERIAL PULMONARY HYPERTENSION):

Decreased levels of endothelial derived vasodilator prostacyclin and NO Increased levels of endothelin-1

Plexi form lesion:

Dysregulated control of endothelial cell with apoptosis ,and wide spread endothelial cells with apoptosis results in proliferation of apoptosis resistant endothelial precursor cells that proliferate and eventually forms flexi form lesions It is hall mark of advanced PAH

dysregulated control of endothelial cells with apoptosis leads to plexiform lesions and emboli

PLEXI FORM LESION REPRESENTS: Collection of proliferating endothelial cells Smooth muscle cells Fibroblasts Endothelial progenitor cells

ECG CHEST X-RAY ECHOCARDIOGRAM COMPLETE BLOOD PROFILE TEST BIOMARKERS IMMUNOLOGICAL TESTS SPIRAL CT CHEST PULMONARY ANGIOGRAPHY MRI RIGHT HEART CATHETERIZATION ACUTE VASODIALTING TEST 6 MINUTE WALK TEST

Digitalis Diuretics Anthiarrythmics Anticoagulants O2 therapy

PROSTACYCLINS:

(product of arachidonic acid metabolism) Potent vasodilator of pulmonary and systemic circulation) Inhibits the platelet aggregation In PAH patients these levels are low

Raise in thromboxane level

EX:
Epoprostenol Treprostinol Iloprost Beraprost

Route of aadministrtion
:IV :SC :Inhalation :Oral

The route of administration depends on the half life and mode of absorption.

Rapid onset of action Short half-life (6mins) dose 2ng/kg/min Adverse effects Flushing, headache, nausea, vomitting

USES IPAH and PAH

Longer half-life(4hrs) USES shows significant improvement in A) exercise capacity B) Pulmonary dynamics ADVERSE EFFECTS Erythema at infusion site, nausea, vommiting, flushing

Inhalation Has minimal side effects because of direct pulmonary deliveribility

Disadvantages Multiple doses required Absence of treatment during sleep

Endothelial cells produces endothelian-1 (vasoconstrictor) Receptors ETa and ETb ETa activation causes: increased arterial pressure, sodium retention, postive ionotropy, increases catecholamine release, systemic vasocontrictions. ETb activation causes opposite effects of ETa.

Bosentan: Blocks the ETa and ETb. Dose:125mg It improves the pulmonary heamodyanamics and functional capacity
Sitaxsentan: Blocks ETa. It is not hepatotoxic but a rise in prothrombin time is a frequent sideeffect This is because of inhibition of CYP2C9 P450 enzyme which is involved in the metabolism of warfarin Ambrisentan: Blocks ETa. Dose:5mg Use full in class and class Less hepatotoxicity Adverse effects: Teratogenic and hepatotoxic.

NO:
Potent vasodilator, Inhibits smooth muscle cell proliferation NO is produced by nitric oxide synthase In PAH patients NO levels are low NO effects are mediated by cGMP, which is degraded by phosphodiesterase Hence phosphodiesterase inhibitors are used

Sildenafil: selective PDE-5 ihibitors. Dose:20mg, 3times a day. ITS EFFECTIVE IN: In improving the pulmonary hemodynamics significantly to improve the six minute walk test Other drugs: Tadalafil verdanafil

To maximize efficacy and minimize the toxicity PDI-5 and Prosracyclins (Synergism) Sildinafil with Bosentan accenture the bosentan hepatotoxicity

INVASIVE TECHNIQUE;
ATRIAL SEPTOSTOMY LUNG AND COMBINED HEART LUNG TRANSPLANT PULMONARY THROMBOENDARTERECTOMY

CLINICAL REPONSE TO TREATMENT

Adequate clinical response:
Stable and satisfactory clinical state Absence of signs of RV failure Normal BNP levels WHO functional class with out syncope 6minute walk test,no pericardial purfusion,right arterial pressure8mmHg

Inadequate clinical reponse:

Future therapies; Vasoactive intestinal polypeptide

Potent systemic and circulatory vasodilator Improves the hemodynamics in PAH

Gene therapy:
BMPR2 replacement

Targeting pro-proliferative path ways

PAH is characterised by vasosonstriction and smooth muscle cell proliferation ,this is because of over activity of several growth factors Treatment with platelet derived growth factor (PDGF) inhibitor eg:imatinib improve the clinical condition

Conclusion:
PAH is a complex condition,and it is heamodynamic abnormalityseen in different disease states Different investigations are essential to diagnose the underlying etiology and to asses the severity Significant improvent in patients treated with: Endothelin receptors blockers Prostanoids PDE-5 inhibitors

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