Recent Developments in the Treatment of Pulmonary Hypertension

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Recent Developments in the Treatment of Pulmonary
Hypertension

• Scott Twaddell
• Clinical Pharmacologist Toxicologist

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PATHOGENESIS

• Raised Pulmonary pressure
• gt 25mmHg at rest
• gt 30 mmHg with activity
• Multiple aetiologies -
• 10 PHT, CTD (esp. SSc)
• Evidence for efficacy of treatment is for these
  two conditions only
• Novel treatments PBS approved for above two only

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MEDIATORS OF PULMONARY HYPERTENSION

• Prostacycline
• Thromboxane A2
• Endothelin-1
• Nitric Oxide (NO)
• Serotonin
• Adrenomedullin
• Vasoactive Intestinal Peptide (VIP)
• Vascular Endothelial Growth Factor (VEGF)

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PROSTACYCLINE THROMBOXANE A2

• Prostacycline
• Vasodilator
• Inhibits platelet activation
• Antiproliferative properties
• Thromboxane A2
• Vasoconstrictor
• Platelet agonist
• BALANCE SHIFTED TOWARDS THROMBOXANE

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ENDOTHELIN-1

• Potent vasoconstrictor
• Stimulates proliferation of smooth muscle cells
  in PA
• Plasma levels increased in PHT
• Level inversely proportional to pulmonary blood
  flow CO - ? Direct effect

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NO SEROTONIN

• NO
• Vasodilator inhibitor of platelet activation
  vascular SM proliferation
• Serotonin
• Vasoconstrictor promoting SM hyperplasia
  hypertrophy
• Elevated plasma levels/ reduced platelet levels
  in PHT (dexfenfluramine)

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• Hypoxia
• Leads to pulmonary vasoconstriction
• Anorexigens
• Fenfluramine/ Phentermine (Fen-Phen)
• CNS stimulants
• Amphetamine, methamphetamine

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ANTICOAGULANTS

• Warfarin
• Recent guidelines suggest that it is not of
  benefit

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ANTI-PLATELET AGENTS

• L-arginine
• Little evidence to support its use

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VASODILATORS

• Oxygen
• CCBs
• Endothelin-receptor antagonists
• BNP
• Calcitonin gene-related peptide

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ANTI-INFLAMMATORIES

• Prostacycline analogues
• NO donors
• Endothelin-receptor antagonists
• Statins
• 5-lipoxygenase inhibitors
• Monocyte-macrophage chemoattractant protein-1

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REMODELLING AGENTS

• Nitric oxide donors
• Endothelin-receptor antagonists

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INHALATIONAL THERAPIES

• Oxygen
• Prostacycline analogues
• Nitric oxide donors
• Ethyl nitrite

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ENDOTHELIN RECEPTOR ANTAGONISTS

• Endothelin-1 overexpressed in PHT
• Improve pulmonary haemodynamics, exercise
  capacity, functional status, clinical outcomes
• Bosentan, sitaxentan and ambrisentan

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BOSENTAN

• Sulphonamide-based ETA ETB receptor blocker
• Inducer of
• CYP2C9 - Vori/ fluconazole, warfarin, digoxin,
  simvastatin, tac/ sirolimus, sildenafil, OCP
• CYP3A4 ketaconazole
• t½ 5.6 /- 1.6 hours

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SITAXENTAN

• Sulphonamide-based selective ETA antagonist
• t½ 5-7 hrs
• ETA ETB 65001
• CYP 2C9 metabolised
• Interaction with warfarin
• Can cause intermittent uncoupling of lipid bile
  salt excretion ? transaminitis

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AMBRISENTAN

• Non-sulphonamide ETA moderately selective (2601)
  ERA
• No significant interaction with coumarin based
  anticoagulants
• Actelion-1 in development

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PHOSPHODIESTERASE INHIBITORS

• Sildenafil
• PDE type5 inhibitor
• Reduce metabolism of cGMP
• t½ 3-5 hours
• CYP3A4 2C9 substrate
• Concentration increased by concurrent bosentan
  I/As nitrates
• Tadalafil
• t½ 17 hours
• CYP 3A4

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PROSTACYCLINE ANALOGUES

• Vasodilators
• Reduce R L afterload increase SV CO
• Platelet aggregation inhibitors
• Main ADRs
• H/A and dizziness (80)
• Nausea and jaw pain

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PROSTACYCLINE ANALOGUES

• Iloprost
• IV or Inhaled
• I/As with CCBs, BBs and ACEIs (animal data)
• NO PK STUDIES FOLLOWING INHALATION!!
• t½ 0.7 hours
• Treprostinol
• IV or s/c injection
• No CYP inhibition - ? induction
• t½ 2-4 hours

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• Epoprostenol
• Continuous IV infusion
• F 0.2/ t½ 2-6 mins
• Spontaneous B/D to 6-oxo-prostaglandin F1a

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WHERE TO NOW?

• Inhaled agents inconvenient/ PAs ineffective
• ERAs first line for 1oPHT
• PDE5 inhibitors have limited evidence
• Increasing evidence that combination therapies
  are more effective (theoretical)