Lectures 12 and 13 Pulmonary Arterial Hypertension Flashcards
What is the average mean pulmonary arterial pressure (mPAP)?
25mmHg
What causes increases mPAP in pulmonary HT?
shunting of systemic blood pressure
thrombus formation
sustained pulmonary vasoconstriction
pulmonary vascular remodelling
What is the consequence of high mPAP in pulmonary HT?
right ventricular hypertrophy
right heart failure
high morbidity and death (~2.8 years)
What is the most common form of pulmonary HT?
schistosomiasis
What can other conditions have pulmonary HT as a secondary condition?
HIV and autoimmune diseases
diet pills
substance abuse
What are symptoms of increased PAH?
exertional breathlessness
chest pains
How is high PH diagnosed?
ECG - right heart in particular
hypertrophy of lungs, PAs and heart
lung function test
pulmonary artery systolic pressure
How is the mean pressure calculated?
2/3 diastolic pressure + 1/3 systolic pressure
How is the pulmonary vascular resistance calculated?
(mPAP-PAWP)/cardiac output
PAWP - pulmonary artery wedge pressure
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
What are the types of treatable pulmonary hypertension?
idiopathic PAH
PAH - pulmonary veno-occlusive disease; pulmonary capillary haemoglomatosis
chronic thromboembolic PH
What are the causes of idiopathic PAH?
heritable (genetic) drugs connective tissue disease HIV/autoimmune disease portal HT congenital heart disease schistosomiasis haemolytic anaemia
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
What are type of untreatable PH system disorders?
sarcoidosis Langerhans cell histiocytosis lymphangioleiomyomatosis neurofibromatosis vasculitis
What are type of untreatable PH metabolic disorders?
glycogen storage disease
Gaucher’s disease
thyroid disorder
Give examples of diet pills that led to PAH?
fenfluramine
phentamine
What are risk factors of PAH?
more common in females
What is the vascular pathology of PAH?
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?
BMPR2 endothelin 5-HT proteases elastases MMPs NOTCH and PPAR-gamma
What effect does pulmonary arteriole remodelling have on the heart?
increase resistance to blood flow
increased afterload - right ventricle hypertrophy
fall in cardiac output
What is the effect of elastic and ECM degradation?
increased vascular stiffness
promotion of SMC proliferation
EC apoptosis
loss of vascular integrity - vascular leakage
What initiates pulmonary arteriole remodelling in PAH?
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?
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?
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
