pulmonary arterial hypertensionpathophysiology 10 • pulmonary arterial hypertension (pah) is a...

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

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


• 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


• 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


• 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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Initial lower dose


60 mg TID 2.5 mg QD

Daily dose

120–240 mg 240–720 mg Up to 20 mg

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Initial lower dose


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

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• 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

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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



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30Endothelin receptor antagonists

Bosentan

Macitentan

30

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• 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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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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Sildenafil Tadalafil

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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


Guanylate cyclase stimulant - Riociguat

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Guanylate cyclase stimulant - Riociguat

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• 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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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


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

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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

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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

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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

pulmonary arterial hypertensionpathophysiology 10 • pulmonary arterial hypertension (pah) is a...

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