ChronicChronic Obstructive Obstructive

PulmonaryPulmonary disease disease 主講者主講者 :: 王瑞蓉王瑞蓉

2006/05/252006/05/25 DefinitionDefinition of of COPD COPD

 COPDCOPD is is a a disease disease state state characterized characterized by by airflowairflow limitation limitation that that is is notnot fully fully reversible reversible..  TheThe airflow airflow limitation limitation is is usually usually both both progressiveprogressive and and associated associated with with an an abnormalabnormal inflammatory inflammatory response response of of the the lungslungs to to noxiousnoxious particlesparticles or or gases. gases.

2005 GOLD AsthmaAsthma & & COPD COPD RiskRisk Factor Factor for for COPD COPD

Host Genes (eg : alpha-1 antitrypsin deficiency) factor Airway hyperresponsiveness Lung growth

Exposures Tobacco smoke Occupational Dusts And Chemicals Indoor and Outdoor Air pollution Infections Socioeconomic states DiagnosisDiagnosis of of COPD COPD

EXPOSURE TO RISK SYMPTOMS FACTORS cough tobacco sputum occupation

dyspnea indoor/outdoor pollution

SPIROMETRY SpirometrySpirometry

 Forced Vital Capacity (FVC) and  Forced Expiratory Volume in one second (FEV1)  Calculate the FEV1/FVC ratio .

Appropriate normal values for the person's sex, age ,and height .  Normal adults: FEV1/FVC is between 70%-80% ; less than 70% indicates airflow limitation and the possibility of COPD StagesStages of of COPD COPD GoalGoal of of therapy therapy

 Prevent disease progression  Relieve symptoms  Improve exercise tolerance  Improve health status  Prevent and treat complications  Prevent and treat exacerbations  Reduce mortality  Prevent or minimize side effects from treatment ManagementManagement of of COPD COPD

 AssessAssess and and Monitor Monitor Disease Disease  ReduceReduce Risk Risk Factors Factors

 ManageManage Stable Stable COPD COPD  ManageManage Exacerbations Exacerbations ManagementManagement of of COPD COPD

 Mild to Moderate COPD (Stages I and II) ： Involves the avoidance of risk factors to prevent disease progression and pharmacotherapy as needed to control symptoms.

 Severe (Stage III) and very Severe (Stage IV): Often require the integration of several different disciplines, a variety of treatment approaches, and a commitment of the clinician to the continued support of the patient as the illness progresses. AssessAssess and and Monitor Monitor Disease Disease-1

 InitialInitial Diagnosis Diagnosis : :  Chronic cough ；Chronic sputum； Dyspnea history of exposure to risk factors  MedicalMedical history history : :  Asthma；；Allergy ;sinusitis or nasal polypus； Respiratory infections in childhood； Other respiratory diseases  PhysicalPhysical Examination Examination : :  Considerations in Performing Spirometry DifferentialDifferential diagnosis diagnosis of of COPD COPD

DiagnosisDiagnosis SuggestiveSuggestive Features Features COPD Onset in mid-life Symptoms slowly progressive Long smoking history

Dyspnea during exercise Largely irreversible airflow limitation Asthma Onset early in life (often childhood) Symptoms vary from day to day Symptoms at night/early morning Allergy ,rhinitis ,and/or eczema also present Family history of asthma largely reversible airflow limitation DifferentialDifferential diagnosis diagnosis of of COPD COPD Tuberculosis Onset all ages Chest X-ray shows ling infiltrate or nodular lesions Microbiological confirmation .High local prevalence of tuberculosis Bronchiectasis Large volumes of purulent sputum Commonly associated with bacterial infection Coarse crackles/clubbing on auscultation Chest X-ray/CT shows bronchial dilation ,bronchial wall thickening Congestive Fine basilar crackies on auscultation Heart Failure Chest X-ray shows dilated heart ,pulmonary edema pulmonary function tests indicate volume restriction, not airflow limitation ReduceReduce risk risk factor factor-2

 SmokingSmoking cessation cessation isis the the single single mostmost effective effective and and cost cost effective effective wayway in in most most people people to to reduce reduce the the riskrisk of of developing developing COPD COPD and and stop stop itsits progression. progression. ReduceReduce risk risk factor factor-2 ManageManage Stable Stable COPD COPD-3

 Patient education  Pharmacologic therapy  Bronchodilator  Corticosteroids : FEV1<50% predicated and repeated exacerbations  Vaccines : Influenza vaccines reduce serious illness and death in COPD patients by 50%  Antibiotics : not recommended  Mucolytic agents ,water : not recommended  Antitussives : contraindicated to regularly in stable COPD  Respiratory stimulants agents : not recommended for regular use

BronchodilatorBronchodilator BronchodilatorBronchodilator

 Bronchodilator medications are central to symptom management in COPD  Inhaled therapy is preferred  The choice between ß2-agonist ，anticholinergic， theophyllin，combination therapy depends on availability and individual response in terms of symptom relief and side effects。  Bronchodilators are prescribed on an as-needed or on a regular basis to prevent or reduce symptoms。  Long-acting inhaled bronchodilators are more effective and convenient, but more expensive。 BronchodilatorBronchodilator  Combining bronchodilators may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator。  The bronchodilating effect of short-acting inhaled anticholinergics lasts longer than that of short- acting β2-agonists, with some bronchodilator effect generally apparent up to 8 hours after administration。  Efficacy of theophylline in COPD were done with slow-release preparations. Theophylline is effective in COPD but, due to its potential toxicity, inhaled bronchodilators are preferred when available。 ββ22--agonistsagonists

 The principal action of β2--agonists is to relax airway smooth muscle by stimulating β2-- adrenergic receptors, which increases cyclic AMP and produces functional antagonism to

bronchoconstriction.

 Oral therapy is slower in onset and has more side effects than inhaled treatment. ββ22--agonistsagonists

 Adverse effects :

 resting sinus tachycardia (rare event with inhaled therapy)

 exaggerated somatic tremor

 hypokalemia ( especially when combined with thiazide diuretics and oxygen consumption ) ββ22--agonistsagonists Short-acting Drug Trade Inhaler Solution Oral Duration name (μg) for of action Nebulizer (hr) Fenoterol Berotec* 200 4-6 (MDI) Frandyl* 2.5 mg Salbutamol Buventol* 200 (DPI) 4-6 Easyhaler Ventolin* 5mg/2.5 2mg ml

 MDI = metered dose inhaler  DPI = dry power inhaler FenoterolFenoterol

 Fenoterol HBr 2.5mg Tab (Frandyl*) [B] 臻舒喘錠  Dosage:  Adult : PO, 5-10 mg tid  Pediatric : PO, 0.05-0.15mg/kg/day div. 3 dose or <1yr : PO, 1.25mg bid-tid 1-6yrs : PO,1.25-2.5mg tid 6-14yrs : PO, 2.5mg tid  P : Tab: 2.5mg(22062), Berotec MDI: 300puff/set(29073)  ADR : tachycardia, nervousness, palpitations, muscle tremor SalbutamolSalbutamol

 Ventolin* sulphate 2mg Tab [C]泛得林錠  Dosage:  Adult : PO, 2-4 mg tid-qid, Max. 32 mg/day  Pediatric : 2-6yrs: PO, 0.1 to 0.2 mg/kg/dose 3 times/day, Max. 12mg/day. 6-12 yrs: PO, 2 mg 3-4 times/day, Max. 24 mg/day  P : Tab: 2mg(22064), Combivent MDI: 200puff/B(29100), Nebuliser sol''n: 5mg/2.5mL(29086)  ADR:  Common : hypokalemia, nausea, nervousness, palpitations, tachycardia, tremor  Serious : erythema multiforme (in children), Stevens-Johnson syndrome SalbutamolSalbutamol

 Ventolin* nebules 5mg/2.5mL Amp [C]泛得林 呼吸溶液劑  Dosage:  Adult : Asthma: nebulization, 2.5 mg 3-4 times daily  Pediatric : Asthma: nebulization, 0.63or1.25 mg 3-4 times daily  P : Tab: 2mg(22064), Combivent MDI: 200puff/B(29100), Nebuliser soln: 5mg/2.5mL(29086)  ADR:  Common : hypokalemia , nausea, nervousness, palpitations, tachycardia, tremor  Serious : erythema multiforme (in children), Stevens-Johnson syndrome  NOTE : Nebulizer sol''n dilute with NS deliver over 5-15 min ββ22----agonistsagonists

Long-acting

Drug Trade name Inhaler Solution Oral Duration (μg) for of action Nebulizer (hr) Formoterol Oxis* 9 (DPI) 12+

Salmeterol Servent* 25 (MDI) 12+

Bambuterol Baburol* 10mg 24

Procaterol Meptin* 25μg 8-12

Meptin* 5μg/ml syrup HexoprenalineHexoprenaline

 Ipradol*: 5mcg/2ml Amp 利喘寶 注射液 [B]  Dosage:  Acute asthma :1amp  Severe Dyspnoea : 1.5amp-2amp(max.2mp)  Status asthmaticus:1amp tid-qid /day  Onset: 3 to 15 minutes  Duration : 34 to 37 minutes (IV)  Adverse Reactions:  Arrhythmias , muscle tremor FormoterolFormoterol  Oxis* Turbuhaler 9 mcg/dose, 60dose/B[C] 優吸舒 都保 定量粉狀吸入劑  Dosage:  Adult : Inhalation, 9mcg qd-bid, Max. 36mcg/day  Pediatric : Inhalation > 5 yrs: same as adult  P: Oxis Turbuhaler: 60dose/B(29093)  ADR :  Common : dizziness, headache, palpitations, restlessness, tremor  NOTE :  1.Each metered dose of Oxis Turbuhaler (12mcg) correspond to 9mcg formoterol fumarate dihydrate from the mouthpiece of the inhaler.  2.Contraindications: significantly worsening or acutely deteriorating asthma SalmeterolSalmeterol

 Serevent*Inhaler25mcg/puff 60puff/Bot [C] 使立穩吸入劑  Dosage:  Adult Inhalation, 2-4 puffs bid  Pediatric ≧4 yrs: Inhalation, 2 puffs bid  P: Seretide Evohalar: 120puff/B(29097), Serevent Inhaler: 60puff/B(29056)  ADR:  Common : dizziness, headache, tachycardia ,tremor, throat irritation  Serious : asthma-related death, worsening of asthma-related events in African Americans  NOTE  1. Not be used to relieve symptoms of acute asthma  2. Not a substitute for oral or inhaled corticosteroids  3. Exercise-induced bronchospasm (EIB) - do not used salmeterol for 12 hr after initial dose; patients using salmeterol twice daily should not use salmeterol for EIB BambuterolBambuterol

 Baburol* 10mg Tab [B] 喘平樂 錠  Dosage:  Adult : Asthma: 10-20mg qhs  Dosing adjustments in hepatic impairment : NDA

 Dosing adjustments in renal impairment : NDA  P : Tab: 10mg(22068)  ADR:  Tremor, headache, uneasiness  NOTE :  Prodrug of terbutaline ProcaterolProcaterol

 Procaterol (MEPTIN*)- 25mcg tab [UK]滅喘淨微錠  Procaterol (MEPTIN*)- 5mcg/ml 60ml/B [UK]滅喘淨液  Dosage:  Adult : Asthma: PO, 50-100mcg bid

 Pediatric : Asthma: PO, 25-50mcg bid 0.5 ml/kg/day bid P : Tab: 25mcg(22065), Syrup: 60mL/Bot(28687)  ADR : Tachycardia, arrhythmia (in higher dose), nervousness, headache, tremor DrugDrug Interaction Interaction

InteractionInteraction with with ßß--22 agonists agonists  ßß BlockerBlocker Propranolol has been associated with the exacerbation of asthmatic symptoms in known asthmatics ‧ Patients with asthma or chronic obstructive pulmonary disease may tolerate cardioselective beta blockers better than nonselective agents 。  cardioselective beta blockers： Acebutolol, Atenolol, Betaxolol, Bisoprolol。 DrugDrug Interaction Interaction

Interaction with ß-2 agonists  MAO-I Concurrent use of ß-2 Agonists and MAO-I may result in an increased risk of tachycardia， agitation， or hypomania。  Digoxin Concurrent use of Albuterol and digoxin may result in an decreased digoxin serum level。 DrugDrug Interaction Interaction

Interaction with ß-2 agonists

 Diuretics ECG changes and hypokalemia associated

with diuretics may worsen with co administrate of Albuterol and Salmeterol 。 AnticholinergicAnticholinergic AnticholinergicAnticholinergic

 bronchodilator effect :  獨特四級胺結構，不通過B.B.B.，無全身性副作用，安 全性高。  Onset 約五至十分鐘。

 Duration 可達五至六小時。  無耐藥性，長期使用下不會產生Tachyphylaxis。  Adverse effects :  poorly absorbed  dryness of the mouth AnticholinergicAnticholinergic AnticholinergicAnticholinergic

Short-acting

Drug Trade name Solution for Duration of Nebulizer action (hr) Nebulizer action (hr)

Ipratropium Ipratran* 0.5mg/2ml 6-8 IpratropiumIpratropium

 Ipratran* nebuliser sol‘n 0.5mg/2mLAmp[B] 益撲喘單一劑量吸入液  Dosage:  Adult : 500mcg tid-qid, Max. 2 mg/day  Pediatric : 125-250 mcg tid

 P: Combivent MDI: 200puff/B(29100), Nebuliser soln: 0.5mg/2mL(29077)  ADR :  Common : bitter taste, dry mouth, nasal congestion, nasal dryness  Serious : hypersensitivity reactions (angioedema, bronchospasm, urticaria, anaphylaxis, oropharyngeal edema), paralytic ileus CombinationCombination bronchodilator bronchodilator therapytherapy  Combining bronchodilators with different mechanisms and durations of action may increase the degree of bronchodilation for equivalent or lesser side effects.

 A combination of a short-acting β2-agonist and an anticholinergic produces greater and more sustained improvements in FEV1 than either drug alone and does not produce evidence of tachyphylaxis over 90 days of treatment. CombinationCombination bronchodilator bronchodilator therapytherapy

Combination Therapy in COPD

• 1 9 7 4 COPD patients from 196 centers in 25 countries, o f w h o m 1 4 6 5 re c e iv e d tre a tm e n t

L a n c e t 2 0 0 3 ; 3 6 1 : 4 4 9 – 5 6 . CombinationCombination therapytherapy Combination short-acting β2-agonist plus anticholinergic in one inhaler Drug Trade name Inhaler(μg) Duration of action (hr) Salbutamol/ Combivent* 120/20(MDI) 6-8 Ipratropium Combination long-acting β2-agonist plus glucocorticosteroids in one inhaler Formoterol/ Symbicort* 4.5/160(DPI) Budesonide Salmeterol/ Seretide*125 25/125(MDI) Fluticasone

MethylxanthinesMethylxanthines

 Controversy remains about the exact effects of xanthine derivatives. They may act as nonselective phosphodiesterase inhibitors，but have also been reported to have a range of non-bronchodilator actions， the significance of which is disputed。  Xanthine preparations are lacking in COPD. Changes in inspiratory muscle function have been reported in patients treated with theophylline，but whether this reflects changes in dynamic lung volumes or a primary effect on the muscle is not clear。  Efficacy of theophylline in COPD were done with slow- release preparations。  Theophylline is effective in COPD but，due to its potential toxicity，inhaled bronchodilators are preferred when available。 MethylxanthinesMethylxanthines Drug Trade name Oral Vial for Duration of (mg) injection (mg) action (hr)

Aminophyllin Aminophylline* 100 250mg/10ml Variable up to 24

Theophylline Nosma*-SRMC 125

Telin*-SR 200

Thoin*-SRMC 250

SR = sustained release SRMC= sustained release microsphere capsule AminophyllineAminophylline

 Aminophylline* 250mg/10 ml [C] 心安寧 注射液  Dosage: For Acute bronchospasm  Adult : slow IV (rate<20mg/min)LD6mg/kg (given over 20- 30 min)  Pediatric : >6M slow IV (rate<20mg/min)LD1mg/kg (given over 20-30 min)  anhydrous theophylline ≈aminophylline 78.9%  Aminophylline sol''n PH > 8 → crystal  IV adminstration is preferred for treatment of Acute bronchospasm AminophyllineAminophylline

 Aminophylline* 100mg 胺非林錠  Dosage: For Acute bronchospasm  Adult (smoker) :oral LD=7.5mg/kg,followed by 3.75mg/kg q4h*3 MD=3.75mg/kg q6h  Adult (nonsmoker) :LD=7.5mg/kg,followed by 3.75mg/kg q6h*2 MD=3.75mg/kg q8h  Pediatric(6M-9yrs) : oral LD=7.5mg/kg,followed by 5mg/kg q4h*3 MD=5mg/kg q6h  Pediatric(9-16yrs):oral LD=7.5mg/kg,followed by 3.75mg/kg q4h*3 MD=3.75mg/kg q6h TheophyllineTheophylline  For Asthma & COPD  Dosage:  Adult & Pediatric (>6 M , asthma) initial 12mg/kg/day (or 400mg/day) div into 2 dose at 12hr may be increased by 2-3mg/kg/day at 3-day

>16yrs Max : 13mg/kg/day or 900mg/day 12-16yrs Max : 18mg/kg/day 9-12yrs Max : 20mg/kg/day 1-9yrs Max : 24mg/kg/day TheophyllineTheophylline Agents that decrease theophylline levels

Aminoglutethimide Rifampin Carbamazepine1

Barbiturates Smoking Isonizide1

Charcoal Sulfinpyrazone Loop diuretic1

Hydantoins2 Sympathomimetics (β- agonist) Ketoconazole Thioamines3

 1.May increase or decrease theophylline leveals  2.Decreased hydantoin leveals may also occur  3.Increase theophylline clearance in hyperthyroid patients TheophyllineTheophylline

Agents that increase theophylline levels Allopurinol Disulfiram Quinolones β-blockers(non- Ephedrine Thiabendazole selective) Ca channal blockers Influenza virus Thyroid vaccine hormones4 Cimetidine Interferon Carbamazepine1 Contraceptives ,oral Macrolides Isonizid1 Corticosteroids Mexiletine Loop diuretics1

 4. Decrease theophylline clearance in hypothyroid patient TheophyllinTheophyllin level level range range

Year adult adult adult pediatric <60yr 60-80yr >80yr

Conc 10-20 8-15 6-11 6-11 mcg/mL mcg/mL mcg/mL mcg/mL ManageManage Exacerbations Exacerbations-4

 The most common causes of an exacerbation are infection of the tracheobronchial tree and air pollution， but the cause of about one-third of severe exacerbations cannot be identified。

 Inhaled bronchodilators (particularly inhaled ß2- agonists and/or anticholinergics) ，theophylline，and systemic， preferably oral，glucocorticosteroids are effective treatments for exacerbations of COPD。 InhaledInhaled GlucocorticosteroidsGlucocorticosteroids

Drug Trade name Inhaler(μg) Solution for Nebulizer Budesonide Dusma* 200(MDI)

Pulmicort* 200(DPI) terbuhaler Pulmicort* 1mg/2ml Respules Fluticasone Flixotide* Evohaler 50(MDI) SystemicSystemic GlucocorticosteroidsGlucocorticosteroids

Drug Trade name Oral

Prednisolone Compesolone* 5mg

Methyl-prednisolone Metisone* 4mg

NewNew Version Version of of COPD COPD guideline guideline in in Taiwan Taiwan

藥物 吸入型(微克) 霧化液 口服 注射型 作用時間 （毫克/毫升） （毫克） （小時） 抗膽鹼藥物 Tiotropium bromide (長效) 18 (DPI) (-) (-) (-) 超過24 Ipratropium bromide (短效) 20-40 (MDI) 0.25-0.5 (-) (-) 6-8 Oxitropium bromide (短效) 100 (MDI) 1.5 (-) (-) 7-9 長效型乙二型交感神經刺激劑 Formoterol 4.5-12 (MDI和DPI) 超過12 Salmeterol 25-50(MDI和DPI) 超過12 短效型乙二型交感神經刺激劑 Fenoterol 100-200(MDI) 1 0.05% (糖漿) (-) 4-6 Salbutamol 100, 200 (MDI和DPI) 5 5毫克錠劑 0.1, 0.5 4-6 0.024% (糖漿) Terbutaline 400,500 (DPI) (-) 2.5, 5毫克錠劑 0.2, 0.25 4-6 抗膽鹼藥物與短效乙二型交感刺激劑合併劑型 Fenoterol /Ipratropium 200/80 (MDI) 1.25/0.5 6-8 Salbutamol/Ipratropium 75/15 (MDI) 1.5 6-8

* 台灣胸腔暨重症加護醫學會出版 NewNew Version Version of of COPD COPD guideline guideline in in Taiwan Taiwan

藥物 吸入型(微克) 霧化液 口服 注射型 作用時間 （毫克/毫升） （毫克） （小時） 甲基茶鹼類 Aminophylline 200-600毫克錠劑 240 可達24小時 Theophylline（SR） 100-600毫克錠劑 可達24小時 吸入型類固醇 Beclomethasone 50-400 (MDI和DPI) 0.2-0.4 Budesonide 100, 200, 400 (DPI) 0.2, 0.25, 0.5 Fluticasone 50-500 (MDI和DPI) Triamcinolone 100(MDI) 40 40 長效乙二型交感神經刺激劑與類固醇合併於單一吸入器 Formoterol/Budesonide 4.5/80-160 9/320(DPI) Salmeterol/Fluticasone 50/100,250,500 (DPI) 25/50,125, 250 (MDI) 全身性類固醇 Prednisolone 5-60毫克錠劑 Methyl-prednisolone 10-2000 4,8,16毫克錠劑

* 台灣胸腔暨重症加護醫學會出版 ReferenceReference : :

1. Applied Pharmcotherapy 2. CCIS 3. Drug Facts & Comparisons 4. Drug Information Handbook 5. Mary Anne Koda-Kimble,et al. Applied therapeutics : the clinical use of drugs.8th ed. Lippincott Williams & Wilkins,2005