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PulmonaryArterial
Hypertension
2017/05/02
陳詩涵
嘉義長庚紀念醫院藥劑科
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Outline• Introduction• Classification• Epidemiology• Diagnosis• Pathophysiology• Treatment• Medications
Introduction
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• Pulmonary hypertension (PH) is defined as an elevated mean arterial pressure ≥25 mmHg at rest.
• PH has several etiologies and can be a progressive, fatal disease, if untreated.
Pulmonary Hypertension Classification
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The WHO has classified PH based upon etiology into the 5 groups:
Group 1 – Pulmonary arterial hypertension (PAH)Group 2 – PH due to left heart diseaseGroup 3 – PH due to chronic lung disease and/or
hypoxemiaGroup 4 – PH due to chronic thromboembolic
pulmonary hypertension Group 5 – PH due to unclear multifactorial
mechanisms
Class WHO functional classification for PH
I
Patients with PH but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue or dyspnea, chest pain, or heart syncope.
II
Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in undue fatigue or dyspnea, chest pain, or heart syncope.
III
Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes undue fatigue or dyspnea, chest pain, or heart syncope.
IV
Patients with PH resulting in inability to carry on any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by physical activity. 5
1. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic PAH 1.2. Heritable
1.2.1. BMPR2 1.2.2. ALK1, endoglin, SMAD9, CAV1, KCNK3 1.2.3. Unknown
1.3. Drug- and toxin-induced 1.4. Associated with
1.4.1. Connective tissue diseases 1.4.2. HIV infection 1.4.3. Portal hypertension 1.4.4. Congenital heart diseases 1.4.5. Schistosomiasis
1′. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)
1′′. Persistent pulmonary hypertension of the newborn (PPHN)
PAH Classification
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Epidemiology
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Incidence/Prevalence: • reported prevalence 15-60 per 1,000,000
adults for PAH• reported incidence 5-10 per 1,000,000
adults for idiopathic PAH
Prevalence of disease-associated PAH
Congenital Heart
Disease
Systemic Sclerosis
Portal Hypertension
HIV
5%-10% 9% 2%-6% 0.5%
Diagnosis
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• Chest radiograph• Electrocardiography• Echocardiography• Pulmonary function tests• Overnight oximetry• Polysomnography• V/Q scan• Laboratory tests• Exercise testing• Right heart catheterization
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Right heart catheterization
Pathophysiology
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• Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy, characterized by vasoconstriction, cell proliferation, fibrosis, and thrombosis.
• Pathologic findings include hyperplasia and hypertrophy of all three layers of the vascular wall (intima, media, adventitia) in pulmonary arteries <50 microns.
• Fibrosis and in situ thrombi of the small pulmonary arteries and arterioles (plexiform lesions) can be seen.
• The pathologic appearance of the small pulmonary arteries and arterioles is qualitatively similar in all patients with group 1 PAH.
Pathophysiology
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• Given the proliferative nature of PAH, it is considered by some to be analogous to cancer and a multiple hit hypothesis has emerged.
• In other words, patients with PAH may have an underlying genetic predisposition to pulmonary vascular disease and a superimposed "second hit" or modifying factor activates the disease process.
Pathophysiology
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• The process may involve • increased endothelin levels
endothelin →vasoconstrictor and mitogen
• estrogen-induced growth• decreased nitric oxide levels
nitric oxide →vasodilator and antiproliferative
• and/or decreased prostacyclin levels prostacyclin → vasodilator, antiproliferative and inhibits platelet function
13Treatment診斷
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Vasoreactivity test斷
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• 分類(分級)
• Prior to the initiation of advanced therapy, it is recommended that patients with group 1 PAH undergo a vasoreactivity test, particularly patients with idiopathic PAH, heritable PAH, and anorexigen-induced PAH who are the groups of patients most likely to respond.
• Vasoreactivity testing facilitates agent selection by identifying those who may respond to calcium channel blockers (CCBs), which are less expensive and have fewer side effects than other forms of advanced therapy.
Vasoreactivity test斷17
• 分類(分級)
• Administration of a short-acting vasodilator followed by measurement of the hemodynamic response using a RHC.
• Agents commonly used for testing include:
Nitric Oxide
Epoprostenol Adenosine
Inhale infuse intravenous
10-20 ppm
1-2 ng/kg/min and increased by 2 ng/kg every 5-10 minutes
50 mcg/kg/min and increased every 2minutes
• clinically significant fall in BP• increase in HR• adverse symptoms(eg,
nausea, vomiting, headache)
• until uncomfortable symptoms develop
• maximal dose of 200-350 mcg/kg/min
Vasoreactivity test斷18
• 分類(分級)
• Administration of a short-acting vasodilator followed by measurement of the hemodynamic response using a RHC.
• Agents commonly used for testing include:
Nitric Oxide
Epoprostenol Adenosine
Inhale infuse intravenous
10-20 ppm
1-2 ng/kg/min and increased by 2 ng/kg every 5-10 minutes
50 mcg/kg/min and increased every 2minutes
• clinically significant fall in BP• increase in HR• adverse symptoms(eg,
nausea, vomiting, headache)
• until uncomfortable symptoms develop
• maximal dose of 200-350 mcg/kg/min
selective for the pulmonary vasculature with minimal systemic effects →better tolerated than the intravenous agents
Calcium Channel Blocker Therapy
• 分類(分級)
• The choice based on the patient’s heart rate• bradycardia → nifedipine and amlodipine• tachycardia → diltiazem
• The daily doses of these drugs that have shown efficacy in IPAH are relatively high.
• Limiting factors for dose increase are usually systemic hypotension and lower limb peripheral oedema.
CCBs Nifedipine Diltiazem Amlodipine
Initial lower dose
30 mg BID(Slow release)
60 mg TID 2.5 mg QD
Daily dose
120–240 mg 240–720 mg Up to 20 mg
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Calcium Channel Blocker Therapy
• 分類(分級)
• The choice based on the patient’s heart rate• bradycardia → nifedipine and amlodipine• tachycardia → diltiazem
• The daily doses of these drugs that have shown efficacy in IPAH are relatively high.
• Limiting factors for dose increase are usually systemic hypotension and lower limb peripheral oedema.
CCBs Nifedipine Diltiazem Amlodipine
Initial lower dose
30 mg BID(Slow release)
60 mg TID 2.5 mg QD
Daily dose
120–240 mg 240–720 mg Up to 20 mg
20
Calcium Channel Blocker Therapy
• 分類(分級)
• The choice based on the patient’s heart rate• bradycardia → nifedipine and amlodipine• tachycardia → diltiazem
• The daily doses of these drugs that have shown efficacy in IPAH are relatively high.
• Limiting factors for dose increase are usually systemic hypotension and lower limb peripheral oedema.
CCBs Nifedipine Diltiazem Amlodipine
Initial lower dose
30 mg BID(Slow release)
60 mg TID 2.5 mg QD
Daily dose
120–240 mg 240–720 mg Up to 20 mg
Patients who have notundergone a vasoreactivitystudy or those with a negative study should not be started on CCBs because of potential severe side effects(e.g. hypotension, syncope and RV failure).
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Treatment診斷
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Treatment診斷
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Medications
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Calcium channel blockers
Endothelin receptor antagonists
Phosphodiesterase type 5 (PDE5) inhibitors
Guanylate cyclase stimulant
Prostacyclin analogues
IP receptor agonists
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Calcium channel blockers
Nifedipine Diltiazem Amlodipine
28
Endothelin receptor antagonists
• Endothelin-1 (ET-1) is a potent vasoconstrictor and smooth muscle mitogen. High concentrations of ET-1 have been recorded in the lungs of patients with both idiopathic PAH and other etiologies of group 1 PAH, including scleroderma and congenital cardiac shunt lesions.
• There are two receptors (endothelin receptor A and B) that are targeted by endothelin receptor antagonists (ERAs). ERAs that have been tested in clinical trials include: Nonselective dual action receptor antagonists –
bosentan and macitentan Selective receptor antagonists of endothelin
receptor A – ambrisentan and sitaxsentan
several fatal cases of hepatoxicity
29
Drug(PO)
Initial Dose
Maximum Dose
Adverse Reactions
US Boxed Warning
Ambrisentan 5 mg QD 10 mg/day• Peripheral
edema• Headache
Pregnancy Risk Factor X
Bosentan
<40 kg: 62.5 mg BID≥40 kg: 62.5 BID for 4 weeks; increase to maintenance dose of 125 mg BID
• Edema • Headache • Hepatotoxicity
(ALT&AST↑)• Respiratory
tract infection
HepatotoxicityTeratogenicity
Macitentan 10 mg QD 10 mg/day
• Headache• Anemia• Respiratory
disease
Pregnancy Risk Factor X
Endothelin receptor antagonists
29
30Endothelin receptor antagonists
Bosentan
Macitentan
30
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Phosphodiesterase type 5 (PDE5) inhibitors
• Inhibition of the cGMP degrading enzyme PDE5 results in vasodilation through the NO/cGMP pathway at sites expressing this enzyme.
• Since the pulmonary vasculature contains substantial amounts of PDE5, the potential clinical benefit of PDE5 inhibitors (PDE-5is) has been investigated in PAH.
• In addition, PDE-5is exert antiproliferative effects. All three PDE-5is cause significant pulmonary vasodilation.
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Phosphodiesterase type 5 (PDE5) inhibitors
Drug DoseAdverse
Reactions
Sildenafil
IV 2.5 mg or 10 mg TID• Flushing • Headache • Dyspepsia • Visual
disturbance
PO
5 mg or 20 mg TID, administered 4-6 hours apart
Tadalafil PO 40 mg QD
Vardenafil PO5 mg QD for 4 weeks, then BID*Not approved by FDA!
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Phosphodiesterase type 5 (PDE5) inhibitors
Sildenafil Tadalafil
34
Guanylate cyclase stimulant
• Stimulators of the nitric oxide receptor, soluble guanylate cyclase (sGC) have a dual mode of action. 1. increase the sensitivity of sGC to
endogenous nitric oxide (NO), a pulmonary vasodilator
2. directly stimulate the receptor to mimic the action of NO
Riociguat
Dose(PO)
• Initial: 1 mg TID- who may not tolerate the hypotensive effects: 0.5mg TID
• If systolic blood pressure remains >95 mm Hg and the patient has no signs or symptoms of hypotension, increase the dose by 0.5 mg TID at intervals of ≥2 weeks to the highest tolerated dosage
• Maximum dose: 2.5 mg TID
Adverse Reactions
• Hypotension • Headache • Dizziness • Dyspepsia • GI: Dyspepsia, nausea, diarrhea, vomiting
US Boxed Warning
Pregnancy Risk Factor X
Guanylate cyclase stimulant - Riociguat
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Guanylate cyclase stimulant - Riociguat
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Prostacyclin analogues
• Prostacyclin is produced predominantly by endothelial cells and induces potent vasodilation of all vascular beds.
• This compound is the most potent endogenous inhibitor of platelet aggregation and also appears to have both cytoprotective and antiproliferative activities.
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Prostacyclin analogues
Drug DoseAdverse
Reactions
Epoprostenol IV
• Initial: 2 ng/kg/minute• Increase dose in
increments of 1 to 2 ng/kg/minute at intervals of ≥15 minutes until dose-limiting side effects are noted or response to epoprostenol plateaus
• Tachycardia • Flushing • Hypotension • Dizziness • Headache• GI symptoms
Prostacyclin analogues
Drug DoseAdverse
Reactions
Iloprost Inh
• Initial: 2.5 mcg/dosetolerated→5 mcg/dose
• Administer 6-9 times daily (dosing at intervals ≥2 hours while awake according to individual need and tolerability)
• Maintenance dose: 2.5-5 mcg/dose
• Maximum daily dose: 45 mcg (ie, 5 mcg/dose 9 times daily)
• Flushing • Hypotension• Headache • Nausea • Cough• Flu-like
symptoms
39
Prostacyclin analogues
Drug DoseAdverse
Reactions
Iloprost Inh
• Initial: 2.5 mcg/dosetolerated→5 mcg/dose
• Administer 6-9 times daily (dosing at intervals ≥2 hours while awake according to individual need and tolerability)
• Maintenance dose: 2.5-5 mcg/dose
• Maximum daily dose: 45 mcg (ie, 5 mcg/dose 9 times daily)
• Flushing • Hypotension• Headache • Nausea • Cough• Flu-like
symptoms
40
Prostacyclin analoguesProstacyclin analogues - Treprostinil
Dose
Inh
• 18 mcg (or 3 inhalations) QIDnot tolerated→1-2 inhalations
• Target dose and maximum dose: 54 mcg (or 9 inhalations) QID
PO
• Initial: 0.25 mg Q12H or 0.125 mg Q8H• Maximum dose is determined by tolerability• If intolerable effects occur, reduce the dose in
increments of 0.5 mg to 1 mg daily
SubQ(preferred)
or IV infusion
• Initial: 1.25 ng/kg/minutenot tolerated→0.625 ng/kg/minute
• Increase dose first 4 weeks: 1.25 ng/kg/minute per week→2.5 ng/kg/minute per week for remainder
• Limited experience with doses >40 ng/kg/minute
Adverse Reactions
• Flushing • Headache • Skin rash • Diarrhea & Nausea • Pain at injection site (Injection)• Cough (Inhalation) 41
Prostacyclin analoguesProstacyclin analogues - Treprostinil
Dose
Inh
• 18 mcg (or 3 inhalations) QIDnot tolerated→1-2 inhalations
• Target dose and maximum dose: 54 mcg (or 9 inhalations) QID
PO
• Initial: 0.25 mg Q12H or 0.125 mg Q8H• Maximum dose is determined by tolerability• If intolerable effects occur, reduce the dose in
increments of 0.5 mg to 1 mg daily
SubQ(preferred)
or IV infusion
• Initial: 1.25 ng/kg/minutenot tolerated→0.625 ng/kg/minute
• Increase dose first 4 weeks: 1.25 ng/kg/minute per week→2.5 ng/kg/minute per week for remainder
• Limited experience with doses >40 ng/kg/minute
Adverse Reactions
• Flushing • Headache • Skin rash • Diarrhea & Nausea • Pain at injection site (Injection)• Cough (Inhalation) 42
IP receptor agonists - Selexipag
• Selexipag is an orally available, selective non-prostanoid prostacyclin receptor (IP receptor) agonist.
• Although selexipag and its metabolite have modes of action similar to that of endogenous prostacyclin (IP receptor agonism), they are chemically distinct from prostacyclin with a different pharmacology
Selexipag
Dose(PO)
• Initial: 200 mcg BIDincrease by 200 mcg BID, usually at weekly intervals
• Maximum dose: 1,600 mcg BIDIf a dose is not tolerated, reduce dose to previously tolerated dose
Adverse Reactions
• Flushing • Headache • Diarrhea & nausea & vomiting• Jaw pain & limb pain & myalgia 43
44
Reference
• UpToDate• 2015 ESC/ERS Guidelines for the
diagnosis and treatment of pulmonary hypertension
• 中華民國肺動脈高血壓關心協會• 長庚醫院藥品綜合查詢
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