Clinical Pharmacology_of_Pulmonary_Hypertension
•Download as PPTX, PDF•
1 like•28 views
Clinical Pharmacology of Pulmonary arterial hypertension with Recent advances. Discusses pathobiology, symptomatology, diagnostics and pharmacotherapy of PAH
Recommended
Recommended
More Related Content
Similar to Clinical Pharmacology_of_Pulmonary_Hypertension
Similar to Clinical Pharmacology_of_Pulmonary_Hypertension (20)
More from Seth GSMC and KEM Municipal Hospital
More from Seth GSMC and KEM Municipal Hospital (20)
Recently uploaded
Recently uploaded (20)
Clinical Pharmacology_of_Pulmonary_Hypertension
- 1. Pathophysiology of PAH and Clinical Pharmacology of drugs (with recent advances) Dr. Shakeeb Dhorajiwala For DM Clinical Pharmacology
- 2. Meeting etiquettes: • Standard behavior expected during work meetings • It prompts you to behave professionally and respect others’ time and efforts 21-09-2022 2
- 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 21-09-2022 4
- 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 21-09-2022 *Harrisons- 22 ed. 5
- 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 21-09-2022 *GG 6
- 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 21-09-2022 8
- 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. 21-09-2022 9
- 11. Fig. 1 Swan Ganz Pulmonary Artery catheter 21-09-2022 11
- 12. 21-09-2022 12 Fig. 2 CXR
- 13. 21-09-2022 13
- 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 21-09-2022 17
- 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 21-09-2022 20
- 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 21-09-2022 21
- 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 21-09-2022 22
- 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 21-09-2022 23
- 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 21-09-2022 24
- 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 21-09-2022 25
- 24. 21-09-2022 26
- 25. 21-09-2022 27
- 26. Endothelin antagonists ROCs: Receptor operated Ca2+ channels coadministration with cyclosporine and glyburide is contraindicated 21-09-2022 28 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 21-09-2022 29
- 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 21-09-2022 30
- 29. 21-09-2022 31 No symptoms Fig. 4 Class based treatment- I
- 30. 21-09-2022 32 Slight limitation Fig. 5 Class based treatment- II
- 31. 21-09-2022 33 Marked limitation Fig. 6 Class based treatment- III
- 32. 21-09-2022 34 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); 21-09-2022 35
- 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 21-09-2022 37
- 37. 21-09-2022 39
- 39. 21-09-2022 41
- 40. 21-09-2022 42 Q& A- Presenter’s Grilling Time
Editor's Notes
- Plexogenic terms especially used for pulm. Arteriopathy Pathognomic of PAH