Respiratory tract drugs Respiratory tract drugs
Lu-Tai Tien, Ph.D.
Lu-Tai Tien, Ph.D.
School of Medicine School of Medicine
Fu-Jen Catholic University
Fu-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 drugs Classification of drugs
Drugs used to treat asthma
Drugs used to treat asthma
Drugs used to treat allergic rhinitisDrugs used to treat allergic rhinitis
Drugs used to threat chronic Drugs used to threat chronicobstruction pulmonary diseases obstruction pulmonary diseases
(COPD) (COPD)
Drugs used to treat cough Drugs used to treat coughStimuli / Other Factors Stimuli / Other Factors
allergens allergens
– not all atopic have asthma not all atopic have asthma – dust mites, pollen dust mites, pollen
pollutants pollutants
– SOx SOx
food additives food additives
– bisulfite antioxidants bisulfite antioxidants
cold air cold air
drugs drugs
– aspirin aspirin
exercise exercise
industrial chemicals and industrial chemicals and byproducts
byproducts
– aluminum smelters aluminum smelters – cedar dust cedar dust
lung infection lung infection
– predisposing before age of predisposing before age of two two
genetic predisposition genetic predisposition
– more boys than girls in more boys than girls in childhood
childhood
– more women than men more women than men from 2nd decade onwards.
from 2nd decade onwards.
– Familial risk of allergies Familial risk of allergies
Control of Airway Diameter Control of Airway Diameter
Parasympathetic Parasympathetic
– ACh is the neurotransmitter at airway smooth muscle ACh is the neurotransmitter at airway smooth muscle – it acts at M it acts at M
33receptors- activation causes formation of IP receptors- activation causes formation of IP
33(increasing Ca
(increasing Ca
2+2+) and diacylglycerol ) and diacylglycerol tension is the result tension is the result
No sympathetic innervation No sympathetic innervation
● β β
22adrenoceptors are present in airway smooth muscle adrenoceptors are present in airway smooth muscle
● normally epinephrine released from adrenal medulla activa normally epinephrine released from adrenal medulla activa tes tes
Other nerves - bradykinin, neurokinins Other nerves - bradykinin, neurokinins
Therapies for Asthma Therapies for Asthma
Treatments that mitigate an Treatments that mitigate an asthma attackasthma attack
Treatments that relax airway Treatments that relax airway smooth musclesmooth muscle
Treatments that mitigate chronic Treatments that mitigate chronic inflammationinflammation
Relaxing airway contraction Relaxing airway contraction
Inhibition of BronchoconstrictionInhibition of Bronchoconstriction– Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors
– Muscarinic receptor antagonistsMuscarinic receptor antagonists – β-adrenoceptor agonistsβ-adrenoceptor agonists
Phosphodiesterase Inhibitors Phosphodiesterase Inhibitors
Methylxanthine (caffeine is in this group)Methylxanthine (caffeine is in this group)– Theophylline Theophylline (aminophylline is the ethylenediamine comple (aminophylline is the ethylenediamine comple x) x)
– The therapeutic index of The therapeutic index of Theophylline Theophylline 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 ph Inhibits the breakdown of cyclic AMP by inhibiting ph osphodiesterase
osphodiesterase
– cAMP produced by cAMP produced by
ββ22-adrenoceptor activation initiates a pho -adrenoceptor activation initiates a pho sphorylation cascade causing relaxation of airway smooth m sphorylation cascade causing relaxation of airway smooth m
uscle uscle
They are adenosine receptor antagonists They are adenosine receptor antagonists
Clinical Use of
Clinical Use of Phosphodiestera Phosphodiestera se Inhibitors
se Inhibitors
Given orallyGiven orally
Sustained release preparations are availableSustained release preparations are available
Blood levels should be controlledBlood levels should be controlled– therapeutic range 5-20 mg/L therapeutic range 5-20 mg/L – below 5 no therapeutic effect below 5 no therapeutic effect
– above 20 side effects become a problem above 20 side effects become a problem
anorexia, headache, abdominal discomfort, anorexia, headache, abdominal discomfort, anxiety
anxiety
seizures and arrhythmias occur at high seizures and arrhythmias occur at high concentrations (>40 mg/L)
concentrations (>40 mg/L)
Muscarinic antagonists Muscarinic 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. Ipratropium Ipratropium
– 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 now Atropine is not used now
– dries mucus membranes, too many side effects dries mucus membranes, too many side effects – doesn’t reverse bronchoconstriction doesn’t reverse bronchoconstriction
in asthma bronchoconstriction is mostly due to leukotrien in asthma bronchoconstriction is mostly due to leukotrien es and other substances not muscarinic receptor stimulat es and other substances not muscarinic receptor stimulat ion ion
– can cause viscid mucus plugs to form can cause viscid mucus plugs to form
Ipratropium Ipratropium
Quaternary muscarinic antagonistQuaternary muscarinic antagonist
Given by nebulization Given by nebulization (( 霧化霧化 )) so effects limi so effects limi ted to airwayted to airway
Not routinely used as the only drug in the trNot routinely used as the only drug in the tr eatment of asthmaeatment of asthma
Has definite value in the treatment of acute Has definite value in the treatment of acute asthma exacerbation when used in addition asthma exacerbation when used in addition to to ββ-agonists-agonists
Used in the treatment of chronic obstructive Used in the treatment of chronic obstructive pulmonary disease - COPDpulmonary disease - COPD
Adrenergic agonists Adrenergic agonists
擬腎上腺素擬腎上腺素
ββ2 2
-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 drugsShort acting drugs Short acting drugs
15-30 min 15-30 min 可產生療效 可產生療效 , , 可緩解症狀 可緩解症狀 4 – 6 hours 4 – 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, pir Metaproterenol, albuterol, terbutaline, bitolterol, pir buterol
buterol
– all can be given by inhalation – nebulization all can be given by inhalation – nebulization
– metaproterenol, terbutaline, albuterol can be given orally metaproterenol, terbutaline, albuterol can be given orally – terbutaline injectable – subcutaneous terbutaline 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 drugs Long acting drugs
Salmeterol Salmeterol
, ,formoterol formoterol
– long acting - 12 hours or more long 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 ast long duration of action used to treat nocturnal ast
hma hma
– not used not used as monotherapy always with inhaled st as monotherapy always with inhaled st eroids
eroids
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
Epinephrine Epinephrine
– good bronchodilator - not selective (all good bronchodilator - not selective (all and and ) ) – short lived short lived
– used in emergencies, subcutaneous injection - severe asthma, hyp used in emergencies, subcutaneous injection - severe asthma, hyp ersensitivity reactions, anaphylaxis
ersensitivity 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 China long history of use in China
– β β
22selective, not used much in asthma now selective, not used much in asthma now
– Not as easily now available since methamphetamine can be made Not as easily now available since methamphetamine can be made from this drug
from this drug
Side Effects of β-agonists Side Effects of β-agonists
Not completely selectiveNot completely selective– Can increase heart rateCan increase heart rate – Can cause arrhythmiasCan cause arrhythmias
Headache - vasodilationHeadache - vasodilationAnti-allergy agents Anti-allergy agents - - Omalizumab Omalizumab
Recombinant humanized antibody against the Cε3 do Recombinant humanized antibody against the Cε3 do main of IgE
main of IgE
– Complexes IgE preventing activation of mast cells Complexes IgE preventing activation of mast cells and basophils thus prevents the release of inflam and basophils thus prevents the release of inflam matory mediators
matory mediators
Market name: Xolair
Used only after primary treatments have failed Used 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 Leukotrienes Inhibition of Leukotrienes
Inhibition of the formation of leukotrienesInhibition of the formation of leukotrienes– 5-lipoxygenase inhibitor 5-lipoxygenase inhibitor – Zileuton Zileuton
– Increases the lifetime of theophylline and drugs me Increases the lifetime of theophylline and drugs me tabolized by CYP3A4
tabolized by CYP3A4
Inhibition of the action of leukotrienesInhibition of the action of leukotrienes– leukotriene receptor antagonists (LTRA) leukotriene receptor antagonists (LTRA) – Zafirlukast Zafirlukast (LTD4), (LTD4), montelukast montelukast (LTD4) (LTD4)
Zafirlukast Zafirlukast (po), (po), montelukast montelukast (po) (po)
Arachidonic acid
Cyclooxygenase
Prostaglandins Leukotrienes
LTB
4LTC
4LTD
4LTE
45-Lipoxygenase
Zileuton
LTC
4LTD
4+ CystLT
1Contraction of airway
smooth muscle cells
Zafirlukast
-
Properties Leukotriene receptor antagonistsProperties Leukotriene receptor antagonists– Not all patients respond Not all patients respond
– Aspirin Aspirin sensitivity results from LTD sensitivity results from LTD
44release release
Aspirin (or NSAID) sensitivity may be caused by inhibitin Aspirin (or NSAID) sensitivity may be caused by inhibitin g cyclooxygenase and shunting of arachidonic acid meta g cyclooxygenase and shunting of arachidonic acid meta bolism into the leukotriene pathway
bolism into the leukotriene pathway
– Takes 3-14 days to work - used for chronic therap Takes 3-14 days to work - used for chronic therap y y
– Contraindications - liver disease, pregnancy (cross Contraindications - liver disease, pregnancy (cross es placenta), breast feeding (excreted)
es placenta), breast feeding (excreted)
– Fewer of the above concerns with Fewer of the above concerns with montelukast montelukast as as compared to
compared to zafirlukast zafirlukast or or zileuton zileuton
Steroids Steroids
Systemic steroidsSystemic steroids– corticosteroids corticosteroids (e.g., (e.g., prednisone prednisone , , prednisolone prednisolone ) ) – used to treat severe persistent asthma used to treat severe persistent asthma
– significant side effects significant side effects
water retention - moon face (Cushingoid features) water retention - moon face (Cushingoid features)
Immunosuppression Immunosuppression
Steroids reverse inflammation and reduce sensitiviSteroids reverse inflammation and reduce sensitivi ty of airway smooth muscle to stimulationty of airway smooth muscle to stimulation
adrenal suppression-must taper dose when discontinuing after adrenal suppression-must taper dose when discontinuing after prolonged therapy
prolonged therapy
Inhaled Steroids Inhaled Steroids
Beclomethasone Beclomethasone
, ,Budesonide Budesonide
, ,Flunisolide Flunisolide
, ,Fluticas Fluticas one one
, ,Mometasone Mometasone
and andTriamcinolone Triamcinolone
– given by inhaled route given by inhaled route
– minimal systemic effects (better topical:systemic ratio) minimal systemic effects (better topical:systemic ratio) – reduces need for oral steroids reduces need for oral steroids
– Used as first line therapy for newly diagnosed cases - d Used as first line therapy for newly diagnosed cases - d ecreases chronic inflammation and might reverse remod ecreases chronic inflammation and might reverse remod eling of the airways
eling of the airways
– Oral candidiasis - thrush - gargle and spit, use a spacer Oral candidiasis - thrush - gargle and spit, use a spacer
Corticosteroid Actions Corticosteroid Actions
Decrease the following Decrease the following
– Secretion from, and numbers of eosinophils Secretion from, and numbers of eosinophils – Cytokines from T-lymphocytes Cytokines from T-lymphocytes
– Number of mast cells Number of mast cells
– Secretion and production of cytokines by macroph Secretion and production of cytokines by macroph ages ages
– Leakiness of endothelia (vasoconstriction) Leakiness of endothelia (vasoconstriction)
– Mucus secretion and hypertrophy of mucus cells Mucus secretion and hypertrophy of mucus cells
– Upregulation of Upregulation of β β -adrenergic receptors -adrenergic receptors
Corticosteroids Corticosteroids
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 ββ2 2
–adrenergic agonists –adrenergic agonists 一次以上的患一次以上的患 者者，，吸入性的 吸入性的 corticosteroids corticosteroids 乃是首乃是首 選選
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 glucocorticoideglucocorticoideCorticosteroids on lung Corticosteroids on lung
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 corticosteroids
Side effects of corticosteroids
Cromolyn/Nedocromil Cromolyn/Nedocromil
MechanismMechanism– inhibits the degranulation of inhibits the degranulation of mast cells - by inhi mast cells - by inhi biting chloride conductance channels in the ma biting chloride conductance channels in the ma st cell membranes which reduces intracellular c st cell membranes which reduces intracellular c alcium increases
alcium increases
– works only prophylactically ( works only prophylactically ( 預防性的 預防性的 ) ) – cannot terminate an attack cannot terminate an attack
– Can reduce late phase response when given aft Can reduce late phase response when given aft er an initial attack - inhibits eosinophil degranul er an initial attack - inhibits eosinophil degranul ation
ation
Given by nebulization Given by nebulization
– solution that is nebulized solution that is nebulized
– Microfine powder - Spinhaler Microfine powder - Spinhaler
few side effects because it is poorly absorbed and n few side effects because it is poorly absorbed and n ot metabolized
ot metabolized
side effects primarily in airway side effects primarily in airway
– can induce bronchoconstriction, chest tightness, coughing, can induce bronchoconstriction, chest tightness, coughing, xerostomia
xerostomia
– effects minimized by taking β effects minimized by taking β
22-agonist concomitantly -agonist concomitantly
Used to treat allergic rhinitis Used to treat allergic rhinitis
– available OTC available OTC
Treatments by
Treatments by Cromolyn Cromolyn / / Nedocromil
Nedocromil
Cromolyn
Cromolyn and and nedocromil nedocromil
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 Asthma
Treatment 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 question Study 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
