PAH

• mPAP: > 25mmHg (at rest)
• LVEDP: < 15mmHg ( measured by cardiac catheterization)

• IPAH
• connective tissue disease
• congenital heart disease
• portal hypertension
• familial PAH

• 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

• low resistance
• high compliance
• low pressure

elastin which provides elasticity

smooth muscles

• 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

• scleroderma
• systemic lupus erythematosus
• mixed connective tissue disease
• lung fibrosis
• HIV
• portal hypertension

• Anorexic: aminorex, fenfluramine, dexfenfluramine
• amphetamine
• L-tryptophan
• cocaine
• chemotherapy agents: mitomycin C, bleomycin, carmustine, etoposide, cyclophosphamide

• 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

• 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

• vasoconstriction
• smooth muscles
• endothelial cell proliferation (the earliest abnormality in PAH)
• thrombosis

• BMPR-2: mutations
• ALK1: mutations
• SHTT: polymorphism
• ec-NOD: polymorphism
• CPS: polymorphism

• PGI₂: Prostacyclin
• TXA₂: Thromboxane
• Endothelin-1
• NO: Nitric Oxide
• Others: serotonin, adrenomedullin
• vasoactive intestinal peptide, vascular endothelial growth factor, coagulation, proinflammatory cytokines

• increase in TXA₂
• prostacyclin synthase: produces PGI₂ (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

• levels increased in PAH pts
• is a potent vasoconstrictor
• stimulates proliferation of pulmonary artery smooth muscles cells
• produced by endothelial cells
• acts via ET_A and ET_B receptors

• 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

• 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

• Right-heart catheterization
• positive response: reduced mPAP by 10mmHg to a value of 40mmHg or less

• alleviation of symptoms
• improve in QOL
• prevention of disease progression
• improvement in survival

• supplementing endogenous vasodilators
• inhibiting endogenous vasoconstrictors
• reducing endothelial platelet interaction and limiting thrombosis

• atrial septostomy
• pulmonary thromboendarterectomy for CETPH
• lung or heart-lung transplantation (when disease is not responsive to meds)

• 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)

diuretics

anticoagulants

• 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

• 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

• a solution to be given by inhalation
• class III, IV: indicated
• adverse effects: same as other prostacyclin and infectious complications due to catheter use

• competitive antagonist at both ET_A and ET_B receptors, but higher for ET_A
• inhibiting ET_A 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

• 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

• 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

• 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

• 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

• 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

• 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

• anticoagulants
• diuretics
• oxygen
• digoxin

based on presence of traditional risk factors for VTE, heart failure and sedentary lifestyle

for pts w/decompensated right-heart failure w/ ass. findings of increased central venous pressure, abdominal organ congestion, peripheral edema, ascites

oxygen saturation should be maintained at 90% 

• 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

• 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

• 6-minute walk distane
• echocardiography (ECHO)
• right heart catheterization: gold standard