Download Pulmonary Hypertension

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
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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.
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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
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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
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PAH Etiology
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• Idiopathic Pulmonary Arterial Hypertension
• Hereditary (Genetic) Pulmonary Arterial
Hypertension
• Associated Pulmonary Arterial Hypertension
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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
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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
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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
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Cellular Mechanisms
Am Heart J 2011;162:201-13
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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
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Supportive Therapy
•
•
•
•
Oxygen
Diuretics
Digoxin ( K channel and Calcium )
Anticoagulants (Warfarin)
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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
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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.
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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.
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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
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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
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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
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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
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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
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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
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Choice of therapy (PAH)
Riociguat
5th
5th
Adapted from : Lourenco
A et al. Int J Card 155
(2012) 350-361
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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
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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.
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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
[email protected]