Clinical Pharmacology of Pulmonary arterial hypertension with Recent advances. Discusses pathobiology, symptomatology, diagnostics and pharmacotherapy of PAH

1. Pathophysiology of PAH and
Clinical Pharmacology of drugs
(with recent advances)
Dr. Shakeeb
Dhorajiwala
For DM Clinical
Pharmacology

2. Meeting
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3. Outline
Summary
Conclusion
Pharmacotherapy
Case study
Pathobiology
Diagnostics
Symptomatology
Introduction
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4. Introduction (1/3)
Pulmonary arterial pressure (PAP)- mean PAP of 25 mm Hg or
greater at rest > 20 mm Hg
Function of CO & PVR
low-resistance and low-pressure circulatory system
PAH- mean > 25 mm hg- additional stress on the RV- RV
dysfunction and hypertrophy
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5. Intro(2/3)
Heterogenous disease
Pathogenic remodeling of the pulmonary vasculature
Increased pulmonary artery pressure & vascular resistance
M/c causes:
• left heart pathology
• 1o lung disease
• late complication of luminal pulmonary embolism
High mortality rate
• decompensated right heart failure
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*Harrisons- 22 ed.
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6. Intro(3/3)
mean pulmonary artery pressure (mPAP):
• lowered from ≥25 mmHg to >20 mmHg
expedition in diagnosis (2 yrs)
• common  important implications both QALY and life span
median survival in untreated disease is 2.8 years, with modern therapies, the
median survival has been estimated to be about 9 years*
no approved targeted therapies for PH
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Symptomatology

8. (1/2)
Dyspnea and/or fatigue, edema, chest pain, presyncope, and syncope associated with
more advanced disease
Right ventricular failure with elevated jugular venous pressure
Accentuated P2 component of the S2
Right-sided S3 or S4 and a holosystolic tricuspid regurgitant murmur
It is also important to seek signs of the diseases that are commonly concurrent with PH:
clubbing may be seen
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9. (2/2)
In some chronic lung diseases, sclerodactyly and telangiectasia may signify
scleroderma CREST
crackles on examination of the lungs and systemic
hypertension may be clues to left-sided systolic or diastolic heart failure.
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10. Diagnostics
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11. Fig. 1 Swan Ganz Pulmonary Artery catheter
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Fig. 2 CXR

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Pathobiology

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https://www.google.co.in/search?q=pulmonary+hypertension+classification&tbm=isch&hl=en&sa=X&ved=2ahUKEwjK89CK0eH5AhXpk9gFHfEeDFgQrNwCKAB6BQgBEOwB&biw=1349&bih=663#imgrc=uXAOXATQrTMfzM
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Fig. 3 Pathobiology

16. Patho (3/3)
Imp. Variant: vasoconstriction-dominant phenotype
Other variants: PAH, CTEPH
Genetic & molecular level:
• decreased expression of the voltage-regulated potassium channel
• mutations in bone morphogenetic protein receptor-2
• increased tissue factor expression
• overactivation of the serotonin transporter
• Hypoxia induced activation of hypoxia-inducible factor-1α
• activation of nuclear factor of activated T cells
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Pharmacotherapy

18. Strategy
Pulmonary vasodilation
Exert antiproliferative or proapoptotic effects on highly proliferative cells in the
pulmonary vascular wall (e.g., myofibroblasts)
Prevent/ resolve in situ thrombosis in small arteries and precapillary arterioles
Exert antifibrotic effects to attenuate extracellular matrix stiffness
Reduce pulmonary vascular wall stiffness due to myogenic tone and cholesterol-
associated membrane stiffness
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19. Pharmacotherapy
Rx strategy: Sequential combination therapy with addition of other class of drugs as ds. progresses:
• + NO & cGMP/ PKG signaling
• membrane receptor agonists/ antagonists
• ion channel blockers and openers
ERAs, PDE5 inhibitors or sGC stimulators-first-line agents
most severe PAH patients parenteral therapy with
• epoprostenol
• treprostinil
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20. Nitric Oxide
Preferentially vasodilating better-ventilated lung regions from poorly inflated lung areas
Inhaled NO is a selective pulmonary vasodilator
A/c and specific effect- Very short t1/2
E- 70% as NO3- Urine
Uses:
• Persistent pulm. HTN of newborn
• a/c hypoxemic resp. failure
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21. Recent advances
Riociguat- Oct
2013 US-FDA
• first-in-class
stimulator of sGC
ADME:
• excellent oral
absorption,
• Tmax: 1.5 hrs
• Vd- 30 L
• M: CYPs variants
1A1, 3A, 2C8
• Tb= 12 hrs
ADR
• Syncope &
hypotension
• Fetotoxic
• Bleeding
• GI s/e
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22. Prostaglandin I2 Analogues (1/2)
Epoprostenol
• first synthetic
• dose dependent effect
and ADR-PVR & SR
• t1/2 = 3–5 min- infusion
through pump
• Improves survival
• Reduces symptoms
• ADRs- myalgias, pain
in the extremities,
systemic hypotension
Treprostinil
• longer half-life
• Dosage forms- Tablets,
SC inj. Injectables for
continuous infusion
• most common adverse
effect- Cough
Iloprost
• first PgI2- Inhalational
form
• minimal systemic side
effects
•
• ADR- headache, jaw
pain, cough
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23. Prostaglandin I2 Analogues (2/2)-Selexipag
Salient features
• orally active
• selective IPR
agonist
• chemically distinct
• different pk
properties
compared to others
PK properties:
• A- Rapid
• M- Liver by
hydrolysis
• E- t1/2 – 1-2 hrs
• t1/2 of active
metabolite- 10-14
hrs
• Properties
facilitates BD
dosing
Clinical
Pharmacology:
• starting dose of
200 μg
• weekly to a
maximum dose
• Uptitration upto
1600 μg twice daily
• A/E- headache, jaw
pain, nausea,
dizziness, flushing,
nasopharyngitis, &
vomiting
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26. Endothelin antagonists
ROCs: Receptor operated Ca2+
channels
coadministration with cyclosporine
and glyburide is contraindicated
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Bosentan
• competitive antagonist of
ETA and ETB receptors
• mild-severe functional
impairment (functional
classes II–IV)
• Dose- Max upto125 mg
twice daily
• M= CYPs 2C9 and 3A4
• E= t1/2 = 5 h, in bile
Macitentan
• orally active, competitive
ETA and ETB receptor
antagonist
• Dose- 10 mg daily
• Relatively hepato-safe
• t 1/2 parent compound-16 h,
, active metabolite about 48
h
Ambrisentan
• ETa selective (4000x)
• maximum of 10 mg daily
• t1/2- 9 h
• Hepatosafe (<mac)
• Clinically relevant
interactions- not reported

27. Receptor Tyrosine Kinase Inhibitors
Imatinib- targeted treatment of chronic myelogenous leukemia
• Targets- ABL TKR
Proposed target in PAH- PDGF receptor- vasc. Smooth muscle
hypertrophy
Utility- Add-on therapy – refractory PAH
Utility limited by ADR- chief subdural hematoma
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28. Calcium Channel Blockers (CCBs)
Vasoreactivity testing
initiated with a low dose of long-acting nifedipine, amlodipine, diltiazem, or verapamil
increased to the maximal tolerated dose
SBP , HR & O2 saturation - carefully monitored during titration
Sustained-release preparations of nifedipine, verapamil, and diltiazem are available
ADR- hypotension, while pulmonary vasodilation may reduce HPV Loss or inhibition of HPV can
worsen V/Q mismatch and cause hypoxemia, deterioration of RV function
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No symptoms
Fig. 4 Class based treatment- I

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Slight limitation
Fig. 5 Class based treatment- II

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Marked limitation
Fig. 6 Class based treatment- III

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Symptoms at rest
Fig. 7 Class based treatment- IV

33. Recent Advances- Drugs in Pipeline
Antagonists of 5HT2B receptors and transporters (e.g., LY393558)
Inhibitors of the PI3K/Akt1/mTOR signaling cascades (e.g., perifosine, ipatasertib, and
rapamycin derivatives sirolimus, temsirolimus, everolimus, deforolimus)
Inhibitors of the Notch signaling pathway (e.g., DAPT and MK-0752)
Blockers of transient receptor potential cation channels (e.g., 2-APB, ML204, aniline-
thiazoles)
Rho kinase inhibitors (e.g., fasudil)
Extracellular elastase inhibitors (e.g., elafin and sivelestat);
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34. Other Modalities
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35. Conclusion
Imbalance of vasoactive mediators, mitogenic and
angiogenic factors& pro/antiapoptotic proteins plays an
important role in PAH development
Pharmacological agents employed in PAH are focused on
restoring the balance between contraction and
proliferation the one hand and relaxation and
antiproliferation on the other
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36. Summary
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38. Summary
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Q& A- Presenter’s Grilling Time