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  1. PAH definition
    • mPAP: > 25mmHg (at rest)
    • LVEDP: < 15mmHg ( measured by cardiac catheterization)
  2. Most common causes for PAH in order
    • IPAH
    • connective tissue disease
    • congenital heart disease
    • portal hypertension
    • familial PAH
  3. 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
  4. Pulmonary circulation is a system with?
    • low resistance
    • high compliance
    • low pressure
  5. pulmonary arteries contain?
    elastin which provides elasticity
  6. pulmonary arterioles contain?
    smooth muscles
  7. 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
  8. PAH can be a complication of what disorders
    • scleroderma
    • systemic lupus erythematosus
    • mixed connective tissue disease
    • lung fibrosis
    • HIV
    • portal hypertension
  9. Drugs that can cause PAH
    • Anorexic: aminorex, fenfluramine, dexfenfluramine
    • amphetamine
    • L-tryptophan
    • cocaine
    • chemotherapy agents: mitomycin C, bleomycin, carmustine, etoposide, cyclophosphamide
  10. 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
  11. 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
  12. PAH is a disease of pulmonary vasculature including:
    • vasoconstriction
    • smooth muscles
    • endothelial cell proliferation (the earliest abnormality in PAH)
    • thrombosis
  13. genetic predisposition for PAH
    • BMPR-2: mutations
    • ALK1: mutations
    • SHTT: polymorphism
    • ec-NOD: polymorphism
    • CPS: polymorphism
  14. Vascular Modifiers
    • PGI2: Prostacyclin
    • TXA2: Thromboxane
    • Endothelin-1
    • NO: Nitric Oxide
    • Others: serotonin, adrenomedullin
    • vasoactive intestinal peptide, vascular endothelial growth factor, coagulation, proinflammatory cytokines
  15. PGI2 & TXA2 in PAH pts
    • increase in TXA2
    • prostacyclin synthase: produces PGI(PAH pt has less of the synthase therefore produces less PGI2
    • PGI2: is a potent vasodilator, inhibits platelet activation, and clot formation, contains antiproliferative props.
    • TXA2: produced by platelets. activates platelets and form clots, promote vasoconstriction
  16. 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
  17. 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
  18. 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
  19. Gold standard of diagnosis for PAH
    • Right-heart catheterization
    • positive response: reduced mPAP by 10mmHg to a value of 40mmHg or less
  20. Goals of treatment for PAH
    • alleviation of symptoms
    • improve in QOL
    • prevention of disease progression
    • improvement in survival
  21. Pharmco therapeutic targets for PAH
    • supplementing endogenous vasodilators
    • inhibiting endogenous vasoconstrictors
    • reducing endothelial platelet interaction and limiting thrombosis
  22. surgical therapy for PAH
    • atrial septostomy
    • pulmonary thromboendarterectomy for CETPH
    • lung or heart-lung transplantation (when disease is not responsive to meds)
  23. 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)
  24. Pulmonary hypertension that progresses to right heart failure treated initially with?
  25. What drug is indicated for pt w/ severe pulmonary hypertension secondary to chronic thromboemolic disease or those w/ increased risk for VTE?
  26. 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
  27. 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
  28. Iloprost - Prostacyclin
    • a solution to be given by inhalation
    • class III, IV: indicated
    • adverse effects: same as other prostacyclin and infectious complications due to catheter use
  29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. 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
  36. Conventional Pharmco treatment
    • anticoagulants
    • diuretics
    • oxygen
    • digoxin
  37. anticoagulants in PAH pts
    based on presence of traditional risk factors for VTE, heart failure and sedentary lifestyle
  38. 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
  39. oxygen for PAH pts
    oxygen saturation should be maintained at 90% 
  40. 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
  41. 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
  42. How to measure PAH
    • 6-minute walk distane
    • echocardiography (ECHO)
    • right heart catheterization: gold standard
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