Respiratory tract drugsRespiratory tract drugs

Lu-Tai Tien, Ph.D.Lu-Tai Tien, Ph.D.

School of MedicineSchool of Medicine

Fu-Jen Catholic UniversityFu-Jen Catholic University

藥物投予方式藥物投予方式

吸入吸入– 藥物可直接運送至呼吸道上藥物可直接運送至呼吸道上，，而其吸入劑而其吸入劑又不致造成全身性副作用又不致造成全身性副作用

– 較為普遍較為普遍 口服口服 靜脈注射靜脈注射

Classification of drugsClassification of drugs

Drugs used to treat asthmaDrugs used to treat asthma Drugs used to treat allergic Drugs used to treat allergic

rhinitisrhinitis Drugs used to threat chronic Drugs used to threat chronic

obstruction pulmonary diseases obstruction pulmonary diseases (COPD)(COPD)

Drugs used to treat cough Drugs used to treat cough

From Lippincott’s 3nd edition

Stimuli / Other FactorsStimuli / Other Factors

allergensallergens– not all atopic have asthmnot all atopic have asthm

aa– dust mites, pollendust mites, pollen

pollutantspollutants– SOxSOx

food additivesfood additives– bisulfite antioxidantsbisulfite antioxidants

cold aircold air drugsdrugs

– aspirinaspirin

exerciseexercise industrial chemicals and industrial chemicals and

byproductsbyproducts– aluminum smeltersaluminum smelters– cedar dustcedar dust

lung infectionlung infection– predisposing before predisposing before

age of twoage of two genetic predispositiongenetic predisposition

– more boys than girls in more boys than girls in childhood childhood

– more women than men more women than men from 2nd decade from 2nd decade onwards.onwards.

– Familial risk of allergiesFamilial risk of allergies

Control of Airway Control of Airway DiameterDiameter ParasympatheticParasympathetic

– ACh is the neurotransmitter at airway smooth muscleACh is the neurotransmitter at airway smooth muscle– it acts at Mit acts at M33 receptors- activation causes formation of IP receptors- activation causes formation of IP

33 (increasing Ca (increasing Ca2+2+) and diacylglycerol ) and diacylglycerol tension is the res tension is the resultult

No sympathetic innervationNo sympathetic innervation● ββ22 adrenoceptors are present in airway smooth muscle adrenoceptors are present in airway smooth muscle● normally epinephrine released from adrenal medulla acnormally epinephrine released from adrenal medulla ac

tivatestivates Other nerves - bradykinin, neurokininsOther nerves - bradykinin, neurokinins

Therapies for AsthmaTherapies for Asthma

Treatments that mitigate an asthma attackTreatments that mitigate an asthma attack Treatments that relax airway smooth muscleTreatments that relax airway smooth muscle Treatments that mitigate chronic inflammationTreatments that mitigate chronic inflammation

Relaxing airway Relaxing airway contractioncontraction

Inhibition of BronchoconstrictionInhibition of Bronchoconstriction– Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors– Muscarinic receptor antagonistsMuscarinic receptor antagonists– β-adrenoceptor agonistsβ-adrenoceptor agonists

Phosphodiesterase Phosphodiesterase InhibitorsInhibitors

Methylxanthine (caffeine is in this group)Methylxanthine (caffeine is in this group)– TheophyllineTheophylline (aminophylline is the ethylenediamine com (aminophylline is the ethylenediamine com

plex)plex)– The therapeutic index of The therapeutic index of TheophyllineTheophylline is slow is slow– Causing severe toxicity (the conc. > 20 μg/mL in blood)Causing severe toxicity (the conc. > 20 μg/mL in blood)

Inhibits the breakdown of cyclic AMP by inhibiting Inhibits the breakdown of cyclic AMP by inhibiting phosphodiesterasephosphodiesterase– cAMP produced by cAMP produced by ββ22-adrenoceptor activation initiates a -adrenoceptor activation initiates a

phosphorylation cascade causing relaxation of airway smphosphorylation cascade causing relaxation of airway smooth muscleooth muscle

They are adenosine receptor antagonistsThey are adenosine receptor antagonists

Clinical Use of Clinical Use of PhosphodiesteraPhosphodiesterase Inhibitorsse Inhibitors Given orallyGiven orally Sustained release preparations are Sustained release preparations are

availableavailable Blood levels should be controlledBlood levels should be controlled

– therapeutic range 5-20 mg/Ltherapeutic range 5-20 mg/L– below 5 no therapeutic effectbelow 5 no therapeutic effect– above 20 side effects become a problemabove 20 side effects become a problem

anorexia, headache, abdominal discomfort, anorexia, headache, abdominal discomfort, anxietyanxiety

seizures and arrhythmias occur at high seizures and arrhythmias occur at high concentrations (>40 mg/L)concentrations (>40 mg/L)

Muscarinic antagonistsMuscarinic antagonists

阻斷迷走神經所傳導的呼吸道平滑肌收縮及黏液的分阻斷迷走神經所傳導的呼吸道平滑肌收縮及黏液的分泌泌

e.g. e.g. IpratropiumIpratropium– 病人無法忍受 病人無法忍受 β-adrenergic agonists β-adrenergic agonists 時可用此藥代替時可用此藥代替

Atropine is not used nowAtropine is not used now– dries mucus membranes, too many side effectsdries mucus membranes, too many side effects– doesn’t reverse bronchoconstrictiondoesn’t reverse bronchoconstriction

in asthma bronchoconstriction is mostly due to leukotrienin asthma bronchoconstriction is mostly due to leukotrienes and other substances not muscarinic receptor stimulates and other substances not muscarinic receptor stimulationion

– can cause viscid mucus plugs to formcan cause viscid mucus plugs to form

IpratropiumIpratropium Quaternary muscarinic antagonistQuaternary muscarinic antagonist Given by nebulization Given by nebulization (( 霧化霧化 )) so effects li so effects li

mited to airwaymited to airway Not routinely used as the only drug in the tNot routinely used as the only drug in the t

reatment of asthmareatment of asthma Has definite value in the treatment of acutHas definite value in the treatment of acut

e asthma exacerbation when used in addite asthma exacerbation when used in addition to ion to ββ-agonists-agonists

Used in the treatment of chronic obstructiUsed in the treatment of chronic obstructive pulmonary disease - COPDve pulmonary disease - COPD

Adrenergic agonists Adrenergic agonists

擬腎上腺素擬腎上腺素 ββ22-adrenergic agonist -adrenergic agonist 治療輕度氣喘治療輕度氣喘 直接作用在呼吸道平滑肌鬆弛直接作用在呼吸道平滑肌鬆弛，，為一有為一有效的支氣管擴張劑效的支氣管擴張劑

Short and long acting drugsShort and long acting drugs

Short acting drugsShort acting drugs

15-30 min15-30 min 可產生療效可產生療效 , , 可緩解症狀 可緩解症狀 4 – 6 hours4 – 6 hours 治療急性支氣管收縮治療急性支氣管收縮，，因不具抗發炎作用因不具抗發炎作用，，所以所以，，不不

可做為治療慢性氣喘的唯一藥物可做為治療慢性氣喘的唯一藥物 Metaproterenol, albuterol, terbutaline, bitolterol, Metaproterenol, albuterol, terbutaline, bitolterol,

pirbuterolpirbuterol– all can be given by inhalation – nebulizationall can be given by inhalation – nebulization– metaproterenol, terbutaline, albuterol can be given orallymetaproterenol, terbutaline, albuterol can be given orally– terbutaline injectable – subcutaneousterbutaline injectable – subcutaneous

若由吸入途徑給藥可能會降低全身性給藥所造成的 若由吸入途徑給藥可能會降低全身性給藥所造成的 心跳增快心跳增快，，血糖過高血糖過高，，血鉀過低血鉀過低，，血鎂過低等副作用血鎂過低等副作用

Long acting drugsLong acting drugs

SalmeterolSalmeterol, , formoterolformoterol– long acting - 12 hours or morelong acting - 12 hours or more– forms slow release depot in tissue (lipid soluble)forms slow release depot in tissue (lipid soluble)– long duration of action used to treat nocturnal astlong duration of action used to treat nocturnal ast

hmahma– not usednot used as monotherapy always with inhaled st as monotherapy always with inhaled st

eroidseroids 作為一般處方用藥作為一般處方用藥，，不用在急性症狀緩解治不用在急性症狀緩解治

療療

Other Other -Agonists-Agonists

EpinephrineEpinephrine– good bronchodilator - not selective (all good bronchodilator - not selective (all and and ))– short livedshort lived– used in emergencies, subcutaneous injection - severe asthma, used in emergencies, subcutaneous injection - severe asthma,

hypersensitivity reactions, anaphylaxishypersensitivity reactions, anaphylaxis– Available OTC (Over-The-Counter)Available OTC (Over-The-Counter)

Ephedrine (Ephedrine ( 麻黃素麻黃素 ))– long history of use in Chinalong history of use in China– ββ22 selective, not used much in asthma now selective, not used much in asthma now– Not as easily now available since methamphetamine can be maNot as easily now available since methamphetamine can be ma

de from this drugde from this drug CNS stimulant, amphetamine look-alike, “truck stop” pharmacologyCNS stimulant, amphetamine look-alike, “truck stop” pharmacology

Side Effects of β-Side Effects of β-agonistsagonists Not completely selectiveNot completely selective

– Can increase heart rateCan increase heart rate– Can cause arrhythmiasCan cause arrhythmias

Headache - vasodilationHeadache - vasodilation

Anti-allergy agentsAnti-allergy agents- - OmalizumabOmalizumab Recombinant humanized antibody against the Cε3 doRecombinant humanized antibody against the Cε3 do

main of IgEmain of IgE– Complexes IgE preventing activation of mast cells Complexes IgE preventing activation of mast cells

and basophils thus prevents the release of inflamand basophils thus prevents the release of inflammatory mediatorsmatory mediators

Market name: Xolair Used only after primary treatments have failedUsed only after primary treatments have failed The drug is administered subcutaneously in 1 to 3 inj

ections every 2 or 4 weeks Not recommended when living in environments where

the presence of parasites is common

Inhibition of Inhibition of LeukotrienesLeukotrienes Inhibition of the formation of leukotrienesInhibition of the formation of leukotrienes

– 5-lipoxygenase inhibitor5-lipoxygenase inhibitor– ZileutonZileuton– Increases the lifetime of theophylline and drugs Increases the lifetime of theophylline and drugs

metabolized by CYP3A4metabolized by CYP3A4 Inhibition of the action of leukotrienesInhibition of the action of leukotrienes

– leukotriene receptor antagonists (LTRA)leukotriene receptor antagonists (LTRA)– ZafirlukastZafirlukast (LTD4), (LTD4), montelukastmontelukast (LTD4) (LTD4)

ZafirlukastZafirlukast (po), (po), montelukastmontelukast (po) (po)

Arachidonic acid

Cyclooxygenase

ProstaglandinsLeukotrienes

LTB4 LTC4

LTD4

LTE4

5-Lipoxygenase

Zileuton

LTC4

LTD4

+ CystLT1Contraction of airway smooth muscle cells

ZafirlukastMontelukast(CystLT1 antagonists)

-

Properties Leukotriene receptor antagonistsProperties Leukotriene receptor antagonists– Not all patients respondNot all patients respond– AspirinAspirin sensitivity results from LTD sensitivity results from LTD44 release release

Aspirin (or NSAID) sensitivity may be caused by inhibiting cAspirin (or NSAID) sensitivity may be caused by inhibiting cyclooxygenase and shunting of arachidonic acid metabolisyclooxygenase and shunting of arachidonic acid metabolism into the leukotriene pathwaym into the leukotriene pathway

– Takes 3-14 days to work - used for chronic therapTakes 3-14 days to work - used for chronic therapyy

– Contraindications - liver disease, pregnancy (crosContraindications - liver disease, pregnancy (crosses placenta), breast feeding (excreted)ses placenta), breast feeding (excreted)

– Fewer of the above concerns with Fewer of the above concerns with montelukastmontelukast as as compared to compared to zafirlukastzafirlukast or or zileutonzileuton

SteroidsSteroids

Systemic steroidsSystemic steroids– corticosteroidscorticosteroids (e.g., (e.g., prednisoneprednisone, , prednisoloneprednisolone))– used to treat severe persistent asthmaused to treat severe persistent asthma– significant side effectssignificant side effects

water retention - moon face (Cushingoid features)water retention - moon face (Cushingoid features) ImmunosuppressionImmunosuppression

Steroids reverse inflammation and reduce sensiSteroids reverse inflammation and reduce sensitivity of airway smooth muscle to stimulationtivity of airway smooth muscle to stimulation

adrenal suppression-must taper dose when discontinuing after adrenal suppression-must taper dose when discontinuing after prolonged therapyprolonged therapy

Inhaled SteroidsInhaled Steroids

BeclomethasoneBeclomethasone, , BudesonideBudesonide, , FlunisolideFlunisolide, , FlutiFluticasonecasone, , MometasoneMometasone and and TriamcinoloneTriamcinolone– given by inhaled routegiven by inhaled route– minimal systemic effects (better topical:systemic ratiminimal systemic effects (better topical:systemic rati

o)o)– reduces need for oral steroidsreduces need for oral steroids– Used as first line therapy for newly diagnosed cases - Used as first line therapy for newly diagnosed cases -

decreases chronic inflammation and might reverse redecreases chronic inflammation and might reverse remodeling of the airwaysmodeling of the airways

– Oral candidiasis - thrush - gargle and spit, use a spaceOral candidiasis - thrush - gargle and spit, use a spacerr

Corticosteroid ActionsCorticosteroid Actions

Decrease the followingDecrease the following– Secretion from, and numbers of eosinophilsSecretion from, and numbers of eosinophils– Cytokines from T-lymphocytesCytokines from T-lymphocytes– Number of mast cellsNumber of mast cells– Secretion and production of cytokines by macroSecretion and production of cytokines by macro

phagesphages– Leakiness of endothelia (vasoconstriction)Leakiness of endothelia (vasoconstriction)– Mucus secretion and hypertrophy of mucus cellsMucus secretion and hypertrophy of mucus cells– Upregulation of Upregulation of ββ-adrenergic receptors-adrenergic receptors

CorticosteroidsCorticosteroids

中至重度氣喘患者中至重度氣喘患者，，凡每日由口吸入　 凡每日由口吸入　 ββ22 –adrenergic agonists –adrenergic agonists 一次以上的一次以上的患者患者，，吸入性的 吸入性的 corticosteroids corticosteroids 乃是乃是首選首選

嚴重的氣喘患者有時需短期使用全身性嚴重的氣喘患者有時需短期使用全身性的 的 glucocorticoideglucocorticoide

Corticosteroids on Corticosteroids on lunglung Steroids Steroids 對呼吸道平滑肌無直接作用對呼吸道平滑肌無直接作用 吸入性的 吸入性的 glucocorticoides glucocorticoides 可降低巨可降低巨噬 細胞噬 細胞，，嗜伊紅性白血球及 嗜伊紅性白血球及 T T 淋巴淋巴球參與發炎的數目及反應球參與發炎的數目及反應

長期吸入 長期吸入 steroids steroids 可降低呼吸道平滑可降低呼吸道平滑肌對許多刺激支氣管收縮的物質如過敏肌對許多刺激支氣管收縮的物質如過敏原原，，刺激物刺激物，，冷空氣及運動等的反應冷空氣及運動等的反應

Side effects of Side effects of corticosteroidscorticosteroids

Cromolyn/NedocromilCromolyn/Nedocromil MechanismMechanism

– inhibits the degranulation of inhibits the degranulation of mast cellsmast cells - by in - by inhibiting chloride conductance channels in thhibiting chloride conductance channels in the mast cell membranes which reduces intrace mast cell membranes which reduces intracellular calcium increasesellular calcium increases

– works only prophylactically (works only prophylactically ( 預防性的預防性的 ))– cannot terminate an attackcannot terminate an attack– Can reduce late phase response when given aCan reduce late phase response when given a

fter an initial attack - inhibits eosinophil degrfter an initial attack - inhibits eosinophil degranulationanulation

Given by nebulizationGiven by nebulization– solution that is nebulizedsolution that is nebulized– Microfine powder - SpinhalerMicrofine powder - Spinhaler

few side effects because it is poorly absorbed anfew side effects because it is poorly absorbed and not metabolizedd not metabolized

side effects primarily in airwayside effects primarily in airway– can induce bronchoconstriction, chest tightness, coughcan induce bronchoconstriction, chest tightness, cough

ing, xerostomiaing, xerostomia– effects minimized by taking βeffects minimized by taking β22-agonist concomitantly-agonist concomitantly

Used to treat allergic rhinitisUsed to treat allergic rhinitis– available OTCavailable OTC

Treatments by Treatments by CromolynCromolyn//NedocromilNedocromil

CromolynCromolyn and and nedocromilnedocromil

抗發炎藥物抗發炎藥物 非支氣管擴張劑非支氣管擴張劑，，所以所以，，不用於急性氣不用於急性氣喘治療喘治療

副作用小副作用小，，可用於小孩與孕婦可用於小孩與孕婦

Treatment of AsthmaTreatment of Asthma

Asthma Asthma 的治療的治療

氣喘不一定會導致慢性阻塞性肺部疾病 氣喘不一定會導致慢性阻塞性肺部疾病 (COPD)(COPD)

誤解和誤診而造成惡化誤解和誤診而造成惡化 罹病率造成可觀的入院和門診治療花費罹病率造成可觀的入院和門診治療花費 治療目的治療目的 : : 使症狀緩解使症狀緩解，，進一步避免氣進一步避免氣喘再發生喘再發生

Study questionStudy question

有關 有關 β-adrenergic receptor agonists β-adrenergic receptor agonists 的敘述何的敘述何者不正確 者不正確 ??

(A) (A) 為一有效之支氣管擴張劑為一有效之支氣管擴張劑 (B) (B) 可用於急性氣喘時症狀之治療例如可用於急性氣喘時症狀之治療例如 SalmeSalme

terolterol (C) (C) 會引起心跳過快及血鉀過低等副作用會引起心跳過快及血鉀過低等副作用 (D) (D) 不具抗發炎效用不具抗發炎效用 Answer: (B)Answer: (B)

THE ENDTHE END