advances in pathophysiology and managament10

7/29/2019 Advances in Pathophysiology and Managament10

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PULMONARY ARTERIALHYPERTENSION:


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Pulmonary arterial hypertsion is an increase in blood pressure in theartery due to the increased pulmonary vascular resistence and right

ventricular failure.

Puimonary artery carries the bloodfrom the right ventricles to lungs.

SYMPTOMS: Breathlessnesss Dizziness Fainting Non-productive lough Hemoptysis (cough out blood) Swelling around the ankle,knees Chest pain

palpitation


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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)


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Exertional dyspnea

When right ventricular failure sets in, patients start

having lower extremity edema from venouscongestion.

Angina

Orthopnea and paroxysmal nocturnal dyspnea (PND)

hepatomegaly


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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


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In PAH ,Pulmonary artery smooth muscle cell (PASMC) apoptosis issupressed 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


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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


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In IPAH (IDIOPATHIC ARTERIAL PULMONARYHYPERTENSION):

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


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dysregulated control of endothelial cells with apoptosis leadsto plexiform lesions and emboli


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

Endothelial progenitor cells


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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


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Digitalis

DiureticsAnthiarrythmics

Anticoagulants

O2 therapy


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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: Route of aadministrtionEpoprostenol :IV

Treprostinol :SCIloprost :InhalationBeraprost :OralThe route of administration depends on the half life and mode ofabsorption.


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Rapid onset of action Short half-life (6mins) dose 2ng/kg/min

Adverse effects Flushing, headache, nausea, vomitting

USES IPAH and PAH


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Longer half-life(4hrs) USES shows significant improvement in A) exercise capacity B) Pulmonary dynamics

ADVERSE EFFECTS Erythema at infusionsite, nausea, vommiting, flushing


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Inhalation Has minimal side effects because of direct

pulmonary deliveribility

Disadvantages Multiple doses required Absence of treatment during sleep


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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.


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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 side-

effect 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.


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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


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Sildenafil: selective PDE-5 ihibitors.Dose:20mg, 3times a day.

ITS EFFECTIVE IN:

In improving the pulmonary hemodynamicssignificantly to improve the six minute walk

testOther drugs:

Tadalafilverdanafil


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

hepatotoxicity


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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:


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Future therapies; Vasoactive intestinal polypeptide Potent systemic and circulatory vasodilator Improves the hemodynamics in PAH

Gene therapy:BMPR2 replacement

Targeting pro-proliferative path ways PAHis 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


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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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THANK YOU

advances in pathophysiology and managament10

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