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capnhue
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PAH definition
- mPAP: > 25mmHg (at rest)
- LVEDP: < 15mmHg ( measured by cardiac catheterization)
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Most common causes for PAH in order
- IPAH
- connective tissue disease
- congenital heart disease
- portal hypertension
- familial PAH
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Three layers of arterial wall
- tunica intima: made of endothelial cells and has direct contact with blood
- tunica media: made of smooth muscle cells and elastin. controls diameter of lumen by sympathetic nerves and chemicals
- tunica externa (adventitia): made of collagen and elastin. protects and reinforce the wall, and anchors surrounding structures. Also contain fibroblast cells
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Pulmonary circulation is a system with?
- low resistance
- high compliance
- low pressure
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pulmonary arteries contain?
elastin which provides elasticity
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pulmonary arterioles contain?
smooth muscles
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Ventilation-perfusion coupling
- induces constriction of vessels to regions of the lungs with low oxygen levels reducing blood flow to poorly ventilated regions
- vasodilation of pulmonary arterioles occurs in areas of the lungs with good ventilation
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PAH can be a complication of what disorders
- scleroderma
- systemic lupus erythematosus
- mixed connective tissue disease
- lung fibrosis
- HIV
- portal hypertension
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Drugs that can cause PAH
- Anorexic: aminorex, fenfluramine, dexfenfluramine
- amphetamine
- L-tryptophan
- cocaine
- chemotherapy agents: mitomycin C, bleomycin, carmustine, etoposide, cyclophosphamide
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PAH classification
- PAH: idiopathic, drug-induced, HIV-associated, association with other disorders
- PH owing to left heart disease
- PH owing to lung disease, and/or hypoxia
- Chronic thromboembolic PH (CTEPH)
- PH with unclear multifactorial mechanisms
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WHO classification of PAH
- I: patients w/PAH w/ no limitations of usual physical activity. Physical activity does NOT cause dyspnea, fatigue, chest pain, presyncope
- II: pt w/PAH have MILD limitiation. NO discomfort at rest. activity causes increased dyspnea, fatigue, chest pain, presyncope
- III: pts w/ PAH have LIMITED physical activity. NO discomfort at rest. Less than normal activity causes increased dyspnea, fatigue, chest pain, presyncope
- IV: pts w/PAH unable to perform any physical activity at rest. have signs of right ventricular failure. dyspnea, fatigue present at rest. symptoms increased by physical activity
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PAH is a disease of pulmonary vasculature including:
- vasoconstriction
- smooth muscles
- endothelial cell proliferation (the earliest abnormality in PAH)
- thrombosis
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genetic predisposition for PAH
- BMPR-2: mutations
- ALK1: mutations
- SHTT: polymorphism
- ec-NOD: polymorphism
- CPS: polymorphism
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Vascular Modifiers
- PGI2: Prostacyclin
- TXA2: Thromboxane
- Endothelin-1
- NO: Nitric Oxide
- Others: serotonin, adrenomedullin
- vasoactive intestinal peptide, vascular endothelial growth factor, coagulation, proinflammatory cytokines
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PGI2 & TXA2 in PAH pts
- increase in TXA2
- TXA2: produced by platelets. activates platelets and form clots, promote vasoconstriction
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Endothelin-1 in PAH pts
- levels increased in PAH pts
- is a potent vasoconstrictor
- stimulates proliferation of pulmonary artery smooth muscles cells
- produced by endothelial cells
- acts via ETA and ETB receptors
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Nitric Oxide (NO) in PAH pts
- is an inhibitor of platelet activation and vascular smooth muscle proliferation
- promotes vasodilation
- is an activator of soluble guanylate cyclase enzymes (sGC) that synthesize cGMP (cyclic guanosine monophosphate)
- cGMP promotes relaxation of vasuclar smooth muscle
- decreses intracellular Ca - low levels of Ca associated with relaxation of smooth muscle cells
- produced by nitric oxide synthase and PAH pts have reduced levels of this synthase in endothelial cells
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The other vasular modifiers
- serotonin: increased in PAH, vasoconstrictor promoting smooth muscle hypertrophy/hyperplasia
- adrenomedullin: vasodilators increased in PAH (it is trying to counter balance all the other vasoconstrictors)
- vasoactive intestinal peptide: decreased in PAH, vasodilator, inhibits platelet activation and vasular smooth muscle proliferation
- vascular endothelial growth factor: increased in PAH, promotes endothelial cell proliferation
- coagulation mediators: increased in PAH, increases in von willebrand factor, plasminogen activator inhibitor-1, decrease in anticoagulants.
- proinflammatory cytokines: last one
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Gold standard of diagnosis for PAH
- Right-heart catheterization
- positive response: reduced mPAP by 10mmHg to a value of 40mmHg or less
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Goals of treatment for PAH
- alleviation of symptoms
- improve in QOL
- prevention of disease progression
- improvement in survival
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Pharmco therapeutic targets for PAH
- supplementing endogenous vasodilators
- inhibiting endogenous vasoconstrictors
- reducing endothelial platelet interaction and limiting thrombosis
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surgical therapy for PAH
- atrial septostomy
- pulmonary thromboendarterectomy for CETPH
- lung or heart-lung transplantation (when disease is not responsive to meds)
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Nonpharmco therapy for PAH
- immunizations: against influenza, and pneumococcal
- supplemental oxygen: PAH pts flying
- sodium restriction: < 2400mg / day to avoid right heart failure
- drugs to avoid: drugs that interact w/ warfarin (IBU, ASA), ACEI, ARBs, beta-blockers (used in caution may cause hypotension)
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Pulmonary hypertension that progresses to right heart failure treated initially with?
diuretics
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What drug is indicated for pt w/ severe pulmonary hypertension secondary to chronic thromboemolic disease or those w/ increased risk for VTE?
anticoagulants
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Epoprostenol - Prostacyclin
- physiological pH results in dissipation of effects w/in 2-3 mins
- short-half life of 6mins
- class III, IV: indicated
- Side effects: flushing, HA, diarrhea, jaw pain, backache, abdominal cramping, foot/leg pain, hypotension
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Treprostinil - Prostacyclin
- solution for use in nebulizer allowing inhalation of drug (Tyvaso brand name for inhalation use)
- can be administered as SC (Remodulin brand name for SC use)
- vs epoprostenol: treprostinil (Remodulin) is easier to use, and has longer half-life
- Tyvaso (inhaled): used to improve exercise in class III pts. cautioned in acute pulmonary infections, or underlying lung disease.
- class III, IV: indicated
- Side effects (Tyvaso): throat irritation, cough, HA, nausea, dizziness, flushing
- Side effects (Remodulin): infusion site pain, and same as epoprostenol
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Iloprost - Prostacyclin
- a solution to be given by inhalation
- adverse effects: same as other prostacyclin and infectious complications due to catheter use
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Bosentan - Endothelin-1 receptor antagonist
- competitive antagonist at both ETA and ETB receptors, but higher for ETA
- inhibiting ETA decreases Ca leading to decreased contraction of smooth muscle
- the first ET-e antagonist oral treatment
- class II, III, IV: indicated
- metabolized: CYP2C9, CYP3A4
- adverse effects: can cause liver damage (if 3-5 times upper limit of normal, interrupt treatment), anemia
- category X: for pregnancy
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Ambrisentan - Endothelin-1 receptor antagonist
- can cause liver toxicity
- side effects: peripheral edema, nasal congestion, flushing and palpitations
- category X: for pregnancy
- class II, III, IV: indicated
- metabolized: CYP2C19, CYP3A4, glucoronidation
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Sildenafil (Revatio) - Phosphodiesterase inhibitor (PDE5 inhibitor)
- higher doseage than that of Viagra at 20mg tid for PAH
- side efects: changes in vision (blue tint, sudden loss of vision), HA, flushing, epistaxis (bleeding from nose), dyspepsia, diarrhea
- concurent nitrate therapy can lead to excessive blood pressure reduction
- class II, III, IV: indicated
- metabolized: CYP2C9, CYP3A4
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Tadalafil (Adcirtca) - Phosphodiesterase inhibitor (PDE5 inhibitor)
- 40mg tablets are used to treat pulmonary hypertension
- adverse effects: HA, myalgia, flushing
- concurrent use w/ nitrate therapy avoided w/tadalafil
- class II, III, IV: indicated
- metabolized: CYP3A4, and then glucoronidation
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MOA of Prostacyclin
- MOA: exert effects by activating the receptor (IP) for PGI2 on vascular smooth muscle cells and platelets, through cAMP synthesis.
- Relaxing smooth muscle cell, leading to vasodilation, and inhibition of platelet aggregation, leading to decreased blood viscosity
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MOA of Endothelin-1 antagonist
- MOA: endothelin-1 is a peptide produced in endothelial cells and has vasoconstrictive and mitogenic ( induce cell proliferation) properties.
- ET-1 (ETA and ETB)levels are elevated in plasma and lung tissue of PAH pts
- Type A mediates vasoconstriction
- Type B mediates both vasoconstriction and vasodilation
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MOA of Phosphodiesterase inhibitors (PDE5)
- inhibition of PDE5 enzymatic activity promotes an accumlation of cGMP and causes relaxation of vascular smooth muscle
- sildenafil and tadalafil are selective for binding to cGMP specific PDE enzymes. achieved by hydrogen bonding
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Conventional Pharmco treatment
- anticoagulants
- diuretics
- oxygen
- digoxin
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anticoagulants in PAH pts
based on presence of traditional risk factors for VTE, heart failure and sedentary lifestyle
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diuretics for PAH pts
for pts w/decompensated right-heart failure w/ ass. findings of increased central venous pressure, abdominal organ congestion, peripheral edema, ascites
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oxygen for PAH pts
oxygen saturation should be maintained at 90%
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Digoxin for PAH pts
- for pts w/ right-heart failure as adjunctive therapy alonw w/ diuretics
- for pts who have atrial flutter to slow ventricular rate
- monitor potassium if on this drug
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Calcium Channel Blocker CCB
- pts w/ PAH and a favorable response to acute vasodilator testing will do well w/ CCB
- preferrred drugs are dihydropyridine CCB they lack negative inotropic effects seen in Verapmil
- diltiazem: maybe used in pts w/ tachycardia. if left ventricular systolic dysfunction is present, diltiazem should NOT be used
- CCB: SHOULD NOT be used empirically to treat PAH
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How to measure PAH
- 6-minute walk distane
- echocardiography (ECHO)
- right heart catheterization: gold standard
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