Lectures 12 and 13 Pulmonary Arterial Hypertension Flashcards by Charlotte Casey

What is the average mean pulmonary arterial pressure (mPAP)?

25mmHg

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What causes increases mPAP in pulmonary HT?

shunting of systemic blood pressure
thrombus formation
sustained pulmonary vasoconstriction
pulmonary vascular remodelling

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What is the consequence of high mPAP in pulmonary HT?

right ventricular hypertrophy
right heart failure
high morbidity and death (~2.8 years)

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What is the most common form of pulmonary HT?

schistosomiasis

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What can other conditions have pulmonary HT as a secondary condition?

HIV and autoimmune diseases
diet pills
substance abuse

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What are symptoms of increased PAH?

exertional breathlessness

chest pains

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How is high PH diagnosed?

ECG - right heart in particular
hypertrophy of lungs, PAs and heart
lung function test
pulmonary artery systolic pressure

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How is the mean pressure calculated?

2/3 diastolic pressure + 1/3 systolic pressure

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How is the pulmonary vascular resistance calculated?

(mPAP-PAWP)/cardiac output

PAWP - pulmonary artery wedge pressure

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What is the clinical thresholds for mPAP, PAWP and PVR (pulmonary vascular resistance)?

mPAP - 25mmHg
PAWP - 25mmHg (proposed lowered to 20mmHg)
PVR - 2 Woods Units

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What are the types of treatable pulmonary hypertension?

idiopathic PAH
PAH - pulmonary veno-occlusive disease; pulmonary capillary haemoglomatosis
chronic thromboembolic PH

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What are the causes of idiopathic PAH?

heritable (genetic)
drugs
connective tissue disease
HIV/autoimmune disease
portal HT 
congenital heart disease
schistosomiasis 
haemolytic anaemia

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What are the types of untreatable pulmonary hypertension?

PH-lung disease/hypoxia - COPD; interstitial lung disease; alveolar hypoventilation
PH-left heart - systolic dysfunction; diastolic dysfunction; valvular disease
haematological - myeloproliferative; splenectomy
system disorders - multifactorial/unclear
metabolic disorders - multifactorial/unclear
tumour obstruction
fibrosing mediastinitis
chronic renal failure

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What are type of untreatable PH system disorders?

sarcoidosis
Langerhans cell histiocytosis
lymphangioleiomyomatosis
neurofibromatosis
vasculitis

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What are type of untreatable PH metabolic disorders?

glycogen storage disease
Gaucher’s disease
thyroid disorder

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Give examples of diet pills that led to PAH?

fenfluramine

phentamine

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What are risk factors of PAH?

more common in females

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What is the vascular pathology of PAH?

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sustained pulmonary vasoconstriction
vasoconstrictive mediators - ET-1, TxA2, prostacyclin and NO-dysregulation
proliferation of pulmonary arteriole SMCs and myofibroblasts - narrowing of artery
mediators - chemokines, growth factors and cytokines
elastin and ECM degradation
estimated patient can lose up to 2/3 of vascular tree before becoming symptomatic

What growth factors mediate pulmonary arteriole narrowing?

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BMPR2
endothelin 
5-HT
proteases
elastases
MMPs
NOTCH and PPAR-gamma

What effect does pulmonary arteriole remodelling have on the heart?

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increase resistance to blood flow
increased afterload - right ventricle hypertrophy
fall in cardiac output

What is the effect of elastic and ECM degradation?

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increased vascular stiffness
promotion of SMC proliferation
EC apoptosis
loss of vascular integrity - vascular leakage

What initiates pulmonary arteriole remodelling in PAH?

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break in the endothelial cell layer
permits extravasation of serum factors into the sub-endothelium
stimulates CSMCs to produce endogenous vascular elastase

What is the mechanism of elastase in pulmonary arteriole remodelling in PAH?

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elastase has proteolytic action enhanced by activation of MMPs
results in liberation of matrix-bound growth factors (EGF) and upregulation of ECM glycoprotein TN
transcription and EC deposition of TN is associated with increased SMC proliferation in response to mitogens

elastase stimulates SMC migration through degradation of elastin
elastin peptides stimulate production of glycoprotein fibronectin
fibronectin critical for altering SMC shape - contractile to motile phenotype

What was the first genetic clue into PAH pathogenesis?

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heterozygous germline mutations in BMPR2 encoding a TGF-beta receptor causes familial primary pulmonary HT

What are KLK1/Kallikrein genes? | What are their clinical importance?

subgroup of serine proteases with diverse physiological functions implicated into carcinogenesis potential as novel cancer and disease biomarkers

What is the GGCX gene?

many different isoforms identified encodes an enzyme which catalyses post-translational modification of vitamin K-dependent protein many vitamin K-dependent proteins involved in coagulation - function of enzyme for haemostasis

What are mutations in the GGCX gene linked to?

vitamin K-dependent coagulation defect | PXE-like disorder with multiple coagulation factor deficiency

What are the approved therapied for IPAH? Give examples How are they administered?

CCBs diltiazem - oral nifedipine - oral PDEV-inhibitors sildenafil (revatio/viagra) - oral tadalafil (adcirca) - oral endothelin receptor antagonists bosentan (tracleer) - oral ambristentan (letairis) - oral ``` prostacyclin derivatives epoprostenol (flolan) - IV iloprost (ventavis) - inhaled treprostinil (remodulin) - SC or IV beraprost (Japan/Korea only) - oral ```

When would you prescribe CCBs for PAH patients?

when patient has acute vasodilator response (~10% PAH patients) tested using inhaled NO and see if drop in mPAP by 10mmHg

What are side effects of CCBs?

systemic hypotension bradycardia peripheral oedema

What are the multi-drug responses with PDEV-inhibitors?

avoid patients on nitrates - hypotension | useful in combination with inhaled Iloprost

What are the side effects of PDEV-inhibitors?

``` headache flushing epistaxis (nose bleed) altered colour vision non-ischaemic optic neuropathy - rare priapism - rare ```

What is the mechanism of Riociguat? What is it used to treat? Does it have any drug interactions? What are the adverse effects?

new class stimulates guanylate cyclase chronic thromboembolic pulmonary hypertension avoid combination with PDEV-inhibitors headache, dizziness, indigestion, diarrhoea

What is the effect of ET binding to ETA and ETB on VSMCs?

vasoconstriction

What is the effect of ET binding to ETB on endothelial cells?

vasodilation

Give examples of endothelial receptor antagonists (ERA) What are the multidrug interactions of ERAs? What are the side effects of ERAs?

bosentan, ambrisentan, macitentan added to PDEV-inhibitors or other combinations abnormal liver function test (bosentan), headache, nasopharyngitis, peripheral oedema (ambrisentan), anaemia (macitentan)

What is the pharmacokinetics of Macitentan?

slow dissociation rate high lipid solubility allows enhanced tissue penetration delayed clinical worsening receptor inhibition overcome by prolonged ET-1 stimulation

What is the therapy of choice for advanced cases of PAH? Why?

prostacyclin therapy potent pulmonary vasodilator - improve RV function, reduced pulmonary resistance and afterload antiproliferative agent - slow/reverse vascular remodelling

What are the disadvantages of prostacyclin therapy?

tolerance side effects - diarrhoea, flushing, headaches high cost - £100K/year/patient continuous delivery system required related line complications - infection, thrombosis, pump failure made daily and kept cold

What are the disadvantages of Iloprost?

6-9 inhalations daily side effects - headache, flushing, diarrhoea, cough, syncope compliance no therapy overnight

What are the disadvantages of Treprostinil (SC delivery)?

discontinuation due to site pain erythema - redness of skin through hyperaemia (infection, skin injury, inflammation) induration - sclerosis or hardening forming

What is a new drug in clinical trial development for PAH treatment?

selexipag - phase III clinical trial (GRIPHON) | novel oral non-prostanoid IP receptor agonist

When is anticoagulation therapy used in PAH?

treating chronic thromboembolic pulmonary hypertension (CTEPH) patients patients on IV therapies

What are other treatments that can be given to PAH patients?

oxygen - suffering COPD or low oxygen at rest | diuretics - treat oedema from right heart failure

Lectures 12 and 13 Pulmonary Arterial Hypertension Flashcards

(44 cards)