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CDL301 Cardiovascular Pharmacology > Lecture 13 Pulmonary Arterial Hypertension > Flashcards

Lecture 13 Pulmonary Arterial Hypertension Flashcards

1
Q

How does systolic pressure in the aorta and pulmonary artery differ

A

Aortic systolic blood pressure is much higher at 100-140mmHg compared to the pulmonary artery pressure which is around 15-30mmHg

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2
Q

Why is the pressure in the pulmonary artery at the level it is

A

This low pressure is optimum for gas exchange to occur in the lungs. Flow needs to be high but the pressure must remain low

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3
Q

What is the clinical definition of pulmonary hypertension

A

A mean pulmonary artery pressure (PAP) over 25mmHg

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4
Q

What is the clinical definition of pulmonary arterial hypertension

A

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

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5
Q

What is the key difference between PH and PAH

A

PAH is PH but driven solely by vascular changes

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6
Q

What intervention is carried out when a patient is suspected of having PH

A

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

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7
Q

What is significant about the right atrial pressure

A

It is roughly the venous pressure between 2-5mmHg

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8
Q

What is the average pressure in the right ventricle during systole and diastole

A

Systolic – 20mmHg and diastolic – 1mmHg

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9
Q

What is significant about the pulmonary artery pressure

A

Systolic pressure is around the same at the right ventricle (20mmHg) but the diastolic pressure increases to around 15mmHg

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10
Q

How is mean arterial pressure calculated

A

Mean Pressure = 2/3 Diastolic Pressure + 1/3 Systolic Pressure

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11
Q

Recall the equation for peripheral vascular resistance

A

PVR = (Mean PAP – PCWP) / CO

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12
Q

Recall the equation for mean pulmonary artery pressure

A

Mean PAP = PVR x CO + PCWP

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13
Q

What is meant by pulmonary capillary wedge pressure

A

PCWP is essential an estimation of left atrial pressure and is also equivalent to the left ventricular end diastolic pressure

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14
Q

What is the significant of PCWP in regards to pulmonary hypertension

A

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

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15
Q

What oddity is seen in terms of the association of pulmonary hypertension with gender

A

PH is 4x more prevalent in women yet more severe in males

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16
Q

How might a patient with PH present

A

Progressive exertional breathlessness and chest pain as well as syncopal episodes after exertion

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17
Q

What is often seen on the chest X-ray in patients with PH

A

Normal lungs however there is often an increased pulmonary artery and heart size

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18
Q

What sorts of scans are carried out on patient suspected of having PH

A

Chest X-Ray CT pulmonary angiogram echocardiogram MRI and a Q scan to look at the blood flow

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19
Q

PH patients often can have low cardiac output T or F

A

T

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20
Q

What is type 1 PH

A

Type 1 is classical pulmonary arterial hypertension. Although rare most drugs target this form of the disease

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21
Q

What is type 2 PH

A

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

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22
Q

What is type 3 PH

A

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

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23
Q

What is type 4 PH

A

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

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24
Q

What is type 5 PH

A

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

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25
Q

How can type 1 PAH be subclassified

A

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

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26
Q

How can Type 2 pulmonary hypertension due to left heart disease be subclassified

A

Based on its route cause either due to systolic dysfunction diastolic dysfunction or valvular disease

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27
Q

What are some of the specific causes of Type 3 pulmonary hypertension

A

COPD ILD sleep-disordered breathing alveolar hypoventilation disorders chronic exposure to high altitude or developmental abnormalities

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28
Q

What are the most common forms of type 1 PH

A

Idiopathic and associated PH. These each account for 40% of cases with 10% being the heritable forms

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29
Q

What is significant about the drugs fentfluramine and phentamine and PH

A

These drugs are diet pills that lead to an epidemic of PH in the 1980s

30
Q

Using the graph below discuss the difference in prognosis in patients with PH

A

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

31
Q

What are the three main features of PAH pathophysiology

A

Vasoconstriction vascular remodelling (increased thickness of the tunica media and vascular pruning) and right sided heart failure

32
Q

What factors cause the vasoconstriction seen in PH

A

Increases levels of the vasoconstrictor ET-1. Decreased levels of the vasodilators PGI2 and NO signalling pathway components

33
Q

What mechanism can cause vascular remodelling in PH

A

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

34
Q

Which growth factors and transcription factors are implicated in some of the vascular changes seen in PH

A

Growth factors - PDGF and VEGF. Transcription factors – PPARg and HIF

35
Q

If levels of ET-1 PGI2 and NO signalling components are altered in PH which main pathways are targets for drug treatment

A

ET-1 pathway antagonists NO pathway agonists and PGI2 agonists

36
Q

What are the five classes of drugs used to treat PH

A

Endothelin receptor antagonists (ERAs) Ca2+ channel blocker (CCBs) soluble guanylate cyclase stimulators PDE5 inhibitors and prostanoids

37
Q

How can the endothelin pathway be targeted in the treatment of PH

A

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

38
Q

Give some examples of drugs used to treat PH that target the endothelin pathway

A

Bosentan macitentan and amrisentan

39
Q

What is the benefit of bosentan over other endothelin antagonists

A

Bosentan in ETA selective so doesn’t prevent the negative feedback loop that acts as a vasodilatory mechanism

40
Q

How can Ca2+ channel blockers be used to treat PH

A

Ca2+ channel blockers such as diltiazem and nifedipine prevent vascular smooth muscle contraction by inhibiting Ca2+ influx

41
Q

What is the effect of drugs that stimulate soluble guanylate cyclase

A

Leads to an increase in cGMP levels which acts to decrease Ca2+ inside the cell and thus inhibit vascular smooth muscle contraction

42
Q

Give an example of a sGC stimulator drug

A

Riociguat

43
Q

How can PDE5 be targeted in the treatment of PH

A

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

44
Q

Give an example of a PDE5 inhibitor that is used in the treatment of PH

A

Sildenafil tadalafil

45
Q

Describe how PGI2 causes vasodilation

A

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

46
Q

How can the prostaglandin pathway be targeted in the treatment of PH

A

PGI2 analogues and IP-R agonists can be administered in order to trigger vasodilation

47
Q

Give some examples of drugs used in the treatment of PH that target the PGI2 pathway

A

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

48
Q

What is the major caveat of using CCBs in the treatment of PH

A

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

49
Q

What are the side effective associated with CCBs

A

Systemic hypotension bradycardia and peripheral oedema

50
Q

What is the first line monotherapy in the treatment of PH

A

PDE5 inhibitors

51
Q

How are PDE5 inhibitors delivered

A

Orally

52
Q

How are PDE5 inhibitors used in combination to treat PH

A

Multiple PDE5 inhibitors are often together they can also have the addition of an ET-1 antagonist or used in combination with inhaled iloprost

53
Q

What side effects are associated with PDE5 inhibition

A

Headache flushing epistaxis altered colour vision non-ischaemic optic neuropathy and priaprism

54
Q

When are PDE5 inhibitors contraindicated

A

In patients on nitrates due to potential marked hypotension

55
Q

Which PH type are cGC stimulators licenced for

A

CTEPH

56
Q

cGC stimulators are also contraindicated in patients on PDE5 inhibitors T or F

A

T

57
Q

What are the potential side effects of riociguat

A

Headache dizziness indigestion diarrhoea

58
Q

How are endothelin receptor antagonists administered

A

Orally

59
Q

What are the potential side effects of ERAs

A

Abnormal liver function (bosentan) headache nasopharyngitis peripheral oedema and anaemia

60
Q

What are the benefits of macitentan over other ERAs

A

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

61
Q

What are the overall effects of prostanoid therapy

A

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

62
Q

What is the biggest problem with prostanoid usage

A

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

63
Q

What is the issue of prostanoid delivery

A

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

64
Q

Tolerance is also a big issue with prostanoid usage T or F

A

T

65
Q

What are the unique problems associated with inhaled prostanoid use

A

Inhalation is required 6-9 times daily and is not without side effects. It can often cause syncopal episodes as well as a cough

66
Q

Which prostanoid is administered subcutaneously

A

Treprostinil

67
Q

What side effects are associated with subcutaneous prostanoid administration

A

Skin irritation and regions of saw skin

68
Q

What is selexipag

A

The first oral non-prostanoid IP-R agonist that has been licenced for use in PH

69
Q

Outline some of the new targets that drugs are being developed for in the treatment of PH

A

Receptor tyrosine kinase inhibitors that target PDGFR/VEGFR cytokines targeted by biologicals elastase inhibitors

70
Q

When might anticoagulation be used to treat PH

A

Anticoagulation is a mainstay of treatment for CTEPH in order to prevent the microthrombi that are often found in PAH vascular lesions

71
Q

What other treatments are given to patients with PH to minimise the secondary symptoms

A

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

CDL301 Cardiovascular Pharmacology (17 decks)

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