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Medical Management of Pulmonary Hypertension Dr. Christopher J Arendt, PharmD, RPh Assistant Professor of Pharmacy Mayo Clinic College of Medicine Rochester, Minnesota Disclosure • Nothing to disclose • No financial interests 2 Objectives • Describe the common mechanisms of action of 4 medication classes used to treat pulmonary hypertension. • Recognize common drug-drug and drug-herbal interactions with pulmonary hypertension management medications and what to expect. • Identify the most common adverse effects seen with medications used to manage pulmonary hypertension. 3 Pulmonary Arterial Hypertension What is it? Mean pulmonary Artery Pressure(mPAP) > 25 mmHg Normal to reduced Cardiac Output (CO) Normal capillary wedge pressure (PCWP) Characterized by : Vascular constriction Cellular proliferation Prothrombotic state Dyspnea, fatigue, weakness, inability to tolerate exertion 4 World Health Organization classification of functional status for Primary Pulmonary Hypertension Class Description I No limitations in physical activity, ordinary physical activity does not cause dyspnea or fatigue II Slight limitation in physical activity; ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest III Marked limitation of physical activity; less than ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest IV Unable to perform any physical activity without symptoms; dyspnea and/ or fatigue present at rest; discomfort increased by any physical activity 5 PAH Etiology 6 • Idiopathic Pulmonary Arterial Hypertension • Hereditary (Genetic) Pulmonary Arterial Hypertension • Associated Pulmonary Arterial Hypertension 7 Grouping of Disease Due to left heart failure (increased back pressure in the pulmonary vessels) • Left ventricular pump failure (heart attack, cardiomyopathy) • Left ventricular stiffness (hypertension, diabetes, metabolic syndrome) • Valve disease (mitral or aortic stenosis or regurgitation) Diseases affecting the whole lung (lung diseases obliterate blood vessels) • Chronic bronchitis and emphysema (combination of loss of lung plus hypoxia) • Interstitial lung diseases (destructive diseases that obliterate vessels, such as pulmonary fibrosis, sarcoidosis, and many others) Hypoxia related (decreased oxygen constricts pulmonary blood vessels) • High-altitude dwelling • Sleep apnea and other hypoventilation syndromes • Hypoxia of chronic bronchitis and emphysema (chronic obstructive pulmonary disease, or COPD) American Thoracic Society http://thoracic.org/education/breathing-inamerica/resources/chapter-17-pulmonaryhypertension.pdf 8 Grouping of Disease Pulmonary arterial hypertension (changes in the structure and function of the pulmonary arteries) • Idiopathic (formerly primary pulmonary hypertension) • Heritable (formerly familial, due to BMPR2 or Alk-1 mutations) • Drug- and toxin-induced (stimulants) • Connective tissue diseases (especially scleroderma) • HIV infection (rare occurrence <1%) • Portal hypertension (cirrhosis and other advanced liver diseases) • Congenital heart disease that allows blood to shunt around the lungs • Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (rare) Primarily obstructing diseases of the pulmonary vessels • Pulmonary thromboembolism • Schistosomiasis • Sickle cell anemia • Tumor emboli • Fibrosing mediastinitis (obstruction by fibrosis related to histoplasmosis) American Thoracic Society http://thoracic.org/education/breathing-inamerica/resources/chapter-17-pulmonary-hypertension.pdf 9 Pathological mechanisms in PAH. PDGF, platelet-derived growth factor; EGF, epidermalderived growth factor; FGF, fetal-derived growth factor; VEGF, vascular endothelial-derived growth factor; MCP-1, monocyte chemoattractant protein-1; IL, interleukin. Toshner M et al. Br Med Bull 2010;94:21-32 10 Cellular Mechanisms Am Heart J 2011;162:201-13 11 Classic vasodilator and vasoconstrictor systems and their translational therapies for pulmonary arterial hypertension (PAH). Yen-Chun Lai et al. Circulation Research. 2014;115:115-130 Medication Players Dec 2013 Treprostinil Oral • 390 Patients • Class II or III 2013 (Phosphodiesterase Inhibitor) (Endothelin Receptor )Antagonist Soluble Guanylate Cyclase (sGC) Stimulator 2013 Riociguat Oral • 443 Patients • Class II or III Adapted from Am Heart J 2011;162:201-13 13 Supportive Therapy • • • • Oxygen Diuretics Digoxin ( K channel and Calcium ) Anticoagulants (Warfarin) 14 Calcium Channel Blockers (CCB) • Use if a Positive response (Vasoreactivity test) – Decrease in mPAP ≥ 10 mmHg to a value ≤ 40 mmHg – Most beneficial in IPAH, FPAH, though limited Mechanism: Inhibits Fast Calcium Channels, Reduces intracellular calcium, thus inhibits vasoconstriction Diltiazem (Start 120 mg/day) Nifedipine (start 30 mg/day) Amlodipine (start 5 mg/day) Titrate Weekly. 3 month follow up. 1 year cath lab repeat. Adverse effects: Hypotension, constipation, edema PEARL: Frequent follow up ( 50% of pts see loss of benefit). Avoid verapamil Avoid CCB in severe PAH due to high short-term mortality. Start Stool softeners Multiple Drug Interactions Figure: Current Opinion in Anaesthesiology 2010, 23:49–56 15 Prostaglandins • Epoprostenol Mechanism: Direct vasodilation, inhibition of platelet aggregation – Epoprostenol IV (Central line) start at 2 ng/kg/min. Dose increase over 6 months. Range 25-40 ng/kg/min. Bag change every 8 hr. Refrigerated bag good for 28 hrs. Uses special diluent. Establish dosing weight. – Room Temp Stable (RTS) product can be changed daily. No Special Diluent needed Adverse Effects: Flushing, HA, jaw and lower extremity muscular pain, diarrhea, nausea, rash. PEARL: watch for line associated infection and catheter associated venous thrombosis, thrombocytopenia. Back-up bag is necessary. Rebound HTN noted with abrupt DC. RTS and original formulation are not interchangeable. 16 Prostaglandins • Treprostinil Mechanism: Direct vasodilation, inhibition of platelet aggregation – Treprostinil IV 1.25 ng/kg/min. BAG CHANGE Q48 HRS – Treprostinil SubQ 1.25 ng/kg/min: Change every 3 days. – Treprostinil Inhalation; 1 neb 4 times daily. 3 breath start. 9 max/dose. – Treprostinil Oral Extended Release Tab BID Adverse Effects: IV: Flushing, HA, jaw and lower extremity muscular pain, diarrhea, nausea, rash. SubQ: Injection site Pain ( 85%), with 8% stopping therapy. Inh: cough and throat irritation; headache, gastrointestinal effects, muscle, jaw or bone pain, flushing and syncope Oral; Diarrhea PEARL: IV/SubQ Back-up bag is NOT necessary due to the long half-life. No ice packs needed. Rebound HTN noted with abrupt DC. Neb uses 1 tube of drug/day, programming number of breathes on device.- 10 min pause between breaths is allowed. > 15 min pause resets the machine. 17 Prostaglandins $5,000 neb device • Illoprost Mechanism: Direct vasodilation, inhibition of platelet aggregation – Illoprost 2.5 mcg/mL initial. 6-9 times daily. Adverse Effects: Cough, flushing, HA PEARL: 10-15 min neb. Takes time to admin. Max dose 45 MG/DAY. 3RD OR 4TH Line PAH Agent 18 Endothelin Receptor Antagonist • Bosentan Mechanism: Blocks Both Endothelin A (ET A) and B (ET B) receptors, reducing exposure to vasoconstrictive and proliferative effects of Endothelin. – Bosentan 62.5 mg oral twice daily. Titrate to 125 mg oral twice daily. Adverse Effects: Liver toxicity (If 3x normal aminotransferases , hold therapy), HA, Dizziness, flushing PEARL: Monthly liver function tests are needed. CYP2C9 Interactions! Inhibited by fluconazole ( azoles), ginko biloba, St. Johns Wort, amidarone. Warfarin, Cyclosporine interactions. 50% dose of sildenafil if given concurrently with bosentan 19 Endothelin Receptor Antagonist • Ambrisentan Mechanism: Endothelin A (ET A) to B (ET B) receptor selectivity of 77:1. Inhibiting vasoconstriction and proliferation. – Ambresentan 5 mg daily, may increase to 10 mg daily if tolerated Adverse Effects: Liver toxicity (watch for elevated aminotransferases , hold therapy), HA, Decreased hemoglobin (Check at baseline and 1 month) PEARL: Pregnancy Test initial and monthly. P-Glycoprotein interactions (Sildenafil, loperamide), possible CYP2C19 interactions ( Clopidogrel and omeprazole) Amiodaone and cyclosporine interactions 20 Phosphodiesterase Inhibitors • Sildenafil Mechanism: Inhibit phosphodiesterase-5 and acts to enhance cGMP levels, which will prolong cGMP vasodilating effects in the pulmonary vasculature. – Sildenafil 20 mg oral Three times daily Adverse Effects: HA, abd. Discomfort, constipation, back pain PEARL: APAP premed helps with HA. Interactions CYP3A4 , Itraconazole, Amiodarone, tacrolimus, cyclosporine, SIMVASTATIN(Myopathy) Avoid nitrate, and caution if SBP <90/60 or > 170/90 21 Phosphodiesterase Inhibitors • Tadalafil Mechanism: Inhibit phosphodiesterase-5 and acts to enhance cGMP levels, which will prolong cGMP vasodilating effects in the pulmonary vasculature. – Tadalafil 40 mg daily Adverse Effects: HA, abd. Discomfort, constipation, back pain, nasopharyngitis PEARL: APAP premed helps with HA. Interactions CYP3A4 , Itraconazole (Reduce tadalafil to 2.5 mg daily), Amiodarone, tacrolimus, cyclosporine, Simvastatin ( Myopathy) Avoid nitrate, and caution if SBP <90/60 or > 170/90 22 Soluble Guanylate Cyclase (sGC) Stimulator • Riociguat Mechanism: increase the sensitivity of sGC to endogenous nitric oxide (NO), a pulmonary vasodilator, and directly stimulate the receptor to mimic the action of NO -Riociguat 1 mg oral Three times daily ( May start as low as 0.5 mg), Max 2.5 mg three times daily. Adverse Effects: Headache, Hypotension, Dyspepsia, N/V, Anemia, Dizziness, reflux, constipation. PEARL: Major drug interaction with CYP2C8, CYP3A4 and P-glycoprotein. PPI’s decrease riociguat serum concentrations. Pregnancy Test pre-initiation and monthly 23 Choice of therapy (PAH) Riociguat 5th 5th Adapted from : Lourenco A et al. Int J Card 155 (2012) 350-361 24 PAH drug and Herbal Interactions • CYP P450 Enzyme interactions ( 2C8, 2C9, 3A4, 2C19) • Over 90 possible herbal interactions • Major Interactions: Epoprostenol + L-Arginine= HoTN – Treprostinil + Danshen or Dong Quai ir Evening Primrose, or Willow Bark or Policosanol =Bleed – Sildenafil + St. Johns Wort= reduced effectiveness of sildenafil – Tadalafil or sildenafil + Sweet Orange= reduced P-Glycop transport= lower sildenafil and tadalafil levels. • Others: – Epo +Licorice= less effectiveness (HTN) – Epo + Blue Cohosh= less effective (HTN) – Epo +European Mistletoe=HoTN 25 Wrapping it up • 3 recognized pathological contributors to pulmonary arterial hypertension… and more to come! • Recent advances in medical management have improved survival • Interactions are possible, with significant hypotension , bleeding and toxicity risks. 26 Medical Management of Pulmonary Hypertension Dr. Christopher J Arendt, PharmD, RPh Assistant Professor of Pharmacy Mayo Clinic College of Medicine Rochester, Minnesota [email protected]