Lecture 13 Pulmonary Arterial Hypertension Flashcards
What is type 5 PH
Type 5 is unclear/multifactorial pulmonary hypertension. This is where the cause of the disease is allusive or the result of a combination of factors
What is the issue of prostanoid delivery
Due to their rapid half-life prostanoids need to either be delivered by inhalation or continuous infusion which as the added problem that they need to be continuously cooled. This is really inconvenient for patients
How does systolic pressure in the aorta and pulmonary artery differ
Aortic systolic blood pressure is much higher at 100-140mmHg compared to the pulmonary artery pressure which is around 15-30mmHg
Tolerance is also a big issue with prostanoid usage T or F
T
What is the key difference between PH and PAH
PAH is PH but driven solely by vascular changes
What intervention is carried out when a patient is suspected of having PH
Right heart cardiac catheterisation. A catheter is inserted into the jugular vein and tracks back to the right atria and right ventricles where it records the blood pressure. The attached balloon then directs the catheter to the pulmonary artery where it takes another recording. These pressures can be used to determine if the patient indeed has PH
What is the clinical definition of pulmonary hypertension
A mean pulmonary artery pressure (PAP) over 25mmHg
What are the five classes of drugs used to treat PH
Endothelin receptor antagonists (ERAs) Ca2+ channel blocker (CCBs) soluble guanylate cyclase stimulators PDE5 inhibitors and prostanoids
Give an example of a sGC stimulator drug
Riociguat
How can the prostaglandin pathway be targeted in the treatment of PH
PGI2 analogues and IP-R agonists can be administered in order to trigger vasodilation
What is type 2 PH
Type 2 is pulmonary hypertension due to left heart disease. This often means patients will have problems with left ventricular function but can also be due to problems with the heart valves. This is the most mild form of the disease and as such there are no specific treatments
How can PDE5 be targeted in the treatment of PH
PDE5 inhibitors prevent cGMP breakdown effectively increasing levels of the signalling compound. This acts to decrease Ca2+ levels and increase the activity of PKG. PKG phosphorylates and increases the activity of MLCP which in turn dephosphorylates myosin. These two mechanisms act together to prevent vasoconstriction and promote vasodilation hence reducing PAP
What side effects are associated with PDE5 inhibition
Headache flushing epistaxis altered colour vision non-ischaemic optic neuropathy and priaprism
How might a patient with PH present
Progressive exertional breathlessness and chest pain as well as syncopal episodes after exertion
PH patients often can have low cardiac output T or F
T
What is the biggest problem with prostanoid usage
Prostanoids aren’t very stable as the PGI2 half-life is 2mins and hence analogues of this compound will also be broken down quickly. Even the best PGI2 analogues have a half-life of only 3 – 4.5 hours. This effects the way in which the drugs can be delivered
What is meant by pulmonary capillary wedge pressure
PCWP is essential an estimation of left atrial pressure and is also equivalent to the left ventricular end diastolic pressure
What is the clinical definition of pulmonary arterial hypertension
This is where there is a mean PAP over 25mmHg but the hypertension is driven by vascular changes. These patients will have a LVEDP below 15mmHg and a pulmonary vascular resistance over 240dyn s-1 cm-5
Recall the equation for peripheral vascular resistance
PVR = (Mean PAP – PCWP) / CO
What are the unique problems associated with inhaled prostanoid use
Inhalation is required 6-9 times daily and is not without side effects. It can often cause syncopal episodes as well as a cough
What is type 4 PH
Type 4 is known as chronic thromboembolic pulmonary hypertension (CTEPH) and is the only curable form of pulmonary hypertension. This is where blood clots lodge into the pulmonary circulation blocking the flow of blood to a region of the lung. Usually surgical removal of the clot resolves the condition
What are the side effective associated with CCBs
Systemic hypotension bradycardia and peripheral oedema
How are PDE5 inhibitors used in combination to treat PH
Multiple PDE5 inhibitors are often together they can also have the addition of an ET-1 antagonist or used in combination with inhaled iloprost
What are the overall effects of prostanoid therapy
Vasodilatation of the pulmonary and systemic arterial vascular beds. Will also lower PAP and PVR and reduce right ventricular afterload. Finally prostanoids inhibit proliferation of human pulmonary artery smooth muscle cells
What mechanism can cause vascular remodelling in PH
Endothelial cells become dysfunctional and die by apoptosis. Serum factors released by the apoptotic endothelium then act on the smooth muscle to cause proliferation. Hence you get a narrowing of the vessel
What is the benefit of bosentan over other endothelin antagonists
Bosentan in ETA selective so doesn’t prevent the negative feedback loop that acts as a vasodilatory mechanism
What is type 1 PH
Type 1 is classical pulmonary arterial hypertension. Although rare most drugs target this form of the disease
Outline some of the new targets that drugs are being developed for in the treatment of PH
Receptor tyrosine kinase inhibitors that target PDGFR/VEGFR cytokines targeted by biologicals elastase inhibitors
Which growth factors and transcription factors are implicated in some of the vascular changes seen in PH
Growth factors - PDGF and VEGF. Transcription factors – PPARg and HIF
What are the three main features of PAH pathophysiology
Vasoconstriction vascular remodelling (increased thickness of the tunica media and vascular pruning) and right sided heart failure
What is the major caveat of using CCBs in the treatment of PH
The evidence for the effectiveness of CCBs is only in patients with acute vasodilator response. This is where inhaled NO is given during right heart catherization and if there is a drop in pulmonary arterial pressure that the patient will be responsive to CCBs
What is often seen on the chest X-ray in patients with PH
Normal lungs however there is often an increased pulmonary artery and heart size
Give an example of a PDE5 inhibitor that is used in the treatment of PH
Sildenafil tadalafil
Recall the equation for mean pulmonary artery pressure
Mean PAP = PVR x CO + PCWP
How can Type 2 pulmonary hypertension due to left heart disease be subclassified
Based on its route cause either due to systolic dysfunction diastolic dysfunction or valvular disease
What is the effect of drugs that stimulate soluble guanylate cyclase
Leads to an increase in cGMP levels which acts to decrease Ca2+ inside the cell and thus inhibit vascular smooth muscle contraction
If levels of ET-1 PGI2 and NO signalling components are altered in PH which main pathways are targets for drug treatment
ET-1 pathway antagonists NO pathway agonists and PGI2 agonists
Give some examples of drugs used in the treatment of PH that target the PGI2 pathway
Iloprost is a stable analogue of PGI2 that causes an increase in cAMP. Epoprostenol is an IP-R agonist that mimics the effect of PGI2
Using the graph below discuss the difference in prognosis in patients with PH
There is a massive difference in survival between the subgroups of pulmonary hypertension. Idiopathic pulmonary arterial hypertension (IPAH) has a 5-year survival of 50% yet PAH due to congenital heart disease has an 80% survival rate after 5 years. PAH due to connective tissue disorders has the worst prognosis with a 30% survival rate over 5 years
Which prostanoid is administered subcutaneously
Treprostinil
How can Ca2+ channel blockers be used to treat PH
Ca2+ channel blockers such as diltiazem and nifedipine prevent vascular smooth muscle contraction by inhibiting Ca2+ influx
How can the endothelin pathway be targeted in the treatment of PH
Antagonists of the ETA/B receptor will inhibit that activation of GαQ and thus the activation of PLC. This will prevent the production of IP3 and store release of Ca2+ hence preventing contraction of the vascular smooth muscle. The overall effect will be a vasodilation that will reduce the PAP
Why is the pressure in the pulmonary artery at the level it is
This low pressure is optimum for gas exchange to occur in the lungs. Flow needs to be high but the pressure must remain low
What are some of the specific causes of Type 3 pulmonary hypertension
COPD ILD sleep-disordered breathing alveolar hypoventilation disorders chronic exposure to high altitude or developmental abnormalities
What factors cause the vasoconstriction seen in PH
Increases levels of the vasoconstrictor ET-1. Decreased levels of the vasodilators PGI2 and NO signalling pathway components
When are PDE5 inhibitors contraindicated
In patients on nitrates due to potential marked hypotension
What are the potential side effects of ERAs
Abnormal liver function (bosentan) headache nasopharyngitis peripheral oedema and anaemia
cGC stimulators are also contraindicated in patients on PDE5 inhibitors T or F
T
What is significant about the drugs fentfluramine and phentamine and PH
These drugs are diet pills that lead to an epidemic of PH in the 1980s
When might anticoagulation be used to treat PH
Anticoagulation is a mainstay of treatment for CTEPH in order to prevent the microthrombi that are often found in PAH vascular lesions
Give some examples of drugs used to treat PH that target the endothelin pathway
Bosentan macitentan and amrisentan
How is mean arterial pressure calculated
Mean Pressure = 2/3 Diastolic Pressure + 1/3 Systolic Pressure
Which PH type are cGC stimulators licenced for
CTEPH
What is the average pressure in the right ventricle during systole and diastole
Systolic – 20mmHg and diastolic – 1mmHg
What oddity is seen in terms of the association of pulmonary hypertension with gender
PH is 4x more prevalent in women yet more severe in males
What is significant about the right atrial pressure
It is roughly the venous pressure between 2-5mmHg
How are endothelin receptor antagonists administered
Orally
What other treatments are given to patients with PH to minimise the secondary symptoms
Oxygen is often given to prevent hypoxia and diuretics are sometimes administered to treat any resultant right side heart failure that occurs as a result of PH
How can type 1 PAH be subclassified
Idiopathic – accounting for 40% of cases. Heritable – due to mutations in BMPR2 or Alk1. Drug/Toxin Induced – methamphetamine and diet pills. Associated PAH – occurs as a result of connective tissue disease (scleroderma) HIV portal hypertension congenital heart disease or schistosomiasis
What is type 3 PH
Type 3 is pulmonary hypertension due to lung disease/hypoxia. This is an often mild form of the disease usually seen in patients with COPD
What side effects are associated with subcutaneous prostanoid administration
Skin irritation and regions of saw skin
What sorts of scans are carried out on patient suspected of having PH
Chest X-Ray CT pulmonary angiogram echocardiogram MRI and a Q scan to look at the blood flow
What are the benefits of macitentan over other ERAs
Macitentan has a slower receptor dissociation rate and hence prolonged effect on the receptor. It also has enhanced tissue penetration due to greater lipid solubility
What are the most common forms of type 1 PH
Idiopathic and associated PH. These each account for 40% of cases with 10% being the heritable forms
How are PDE5 inhibitors delivered
Orally
Describe how PGI2 causes vasodilation
PGI2 released from the endothelium acts on the IP-R receptor which is a GαS receptor that leads to the simulation of adenylate cyclase and an increase in cAMP levels. This in turn leads to a decrease in Ca2+ levels and subsequent relaxation. In addition the rise in cAMP levels also lead to activation of PKA which then phosphorylates MLCP increasing its activity in promoting relaxation
What is significant about the pulmonary artery pressure
Systolic pressure is around the same at the right ventricle (20mmHg) but the diastolic pressure increases to around 15mmHg
What is the significant of PCWP in regards to pulmonary hypertension
If the PCWP goes above 15mmHg then a patient is not considered to have pulmonary artery hypertension but pulmonary hypertension due to left side heart disease
What are the potential side effects of riociguat
Headache dizziness indigestion diarrhoea
What is selexipag
The first oral non-prostanoid IP-R agonist that has been licenced for use in PH
What is the first line monotherapy in the treatment of PH
PDE5 inhibitors
