Download 藥物投予方式

Respiratory tract drugs
Lu-Tai Tien, Ph.D.
School of Medicine
Fu-Jen Catholic University
藥物投予方式
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吸入
– 藥物可直接運送至呼吸道上，而其吸入劑
又不致造成全身性副作用
– 較為普遍
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口服
靜脈注射
Classification of drugs
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Drugs used to treat asthma
Drugs used to treat allergic rhinitis
Drugs used to threat chronic
obstruction pulmonary diseases (COPD)
Drugs used to treat cough
From Lippincott’s 3nd edition
Stimuli / Other Factors
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allergens
– not all atopic have asthma
– dust mites, pollen
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– aluminum smelters
– cedar dust
pollutants
– SOx
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food additives
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cold air
drugs
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– aspirin
lung infection
– predisposing before age of
two
– bisulfite antioxidants
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exercise
industrial chemicals and
byproducts
genetic predisposition
– more boys than girls in
childhood
– more women than men
from 2nd decade onwards.
– Familial risk of allergies
Control of Airway Diameter
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Parasympathetic
– ACh is the neurotransmitter at airway smooth muscle
– it acts at M3 receptors- activation causes formation of IP3
(increasing Ca2+) and diacylglycerol F tension is the result
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No sympathetic innervation
● β2 adrenoceptors are present in airway smooth muscle
● normally epinephrine released from adrenal medulla
activates
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Other nerves - bradykinin, neurokinins
Therapies for Asthma
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Treatments that mitigate an asthma attack
Treatments that relax airway smooth muscle
Treatments that mitigate chronic inflammation
Relaxing airway contraction
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Inhibition of Bronchoconstriction
– Phosphodiesterase Inhibitors
– Muscarinic receptor antagonists
– β-adrenoceptor agonists
Phosphodiesterase Inhibitors
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Methylxanthine (caffeine is in this group)
– Theophylline (aminophylline is the ethylenediamine complex)
– The therapeutic index of Theophylline is slow
– Causing severe toxicity (the conc. > 20 μg/mL in blood)
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Inhibits the breakdown of cyclic AMP by inhibiting
phosphodiesterase
– cAMP produced by β2-adrenoceptor activation initiates a
phosphorylation cascade causing relaxation of airway
smooth muscle
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They are adenosine receptor antagonists
Clinical Use of
Phosphodiesterase Inhibitors
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Given orally
Sustained release preparations are available
Blood levels should be controlled
– therapeutic range 5-20 mg/L
– below 5 no therapeutic effect
– above 20 side effects become a problem
anorexia, headache, abdominal discomfort,
anxiety
 seizures and arrhythmias occur at high
concentrations (>40 mg/L)
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Muscarinic antagonists
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阻斷迷走神經所傳導的呼吸道平滑肌收縮及黏液的分
泌
e.g. Ipratropium
– 病人無法忍受 β-adrenergic agonists 時可用此藥代替
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Atropine is not used now
– dries mucus membranes, too many side effects
– doesn’t reverse bronchoconstriction
 in asthma bronchoconstriction is mostly due to
leukotrienes and other substances not muscarinic
receptor stimulation
– can cause viscid mucus plugs to form
Ipratropium
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Quaternary muscarinic antagonist
Given by nebulization (霧化) so effects
limited to airway
Not routinely used as the only drug in the
treatment of asthma
Has definite value in the treatment of acute
asthma exacerbation when used in addition
to β-agonists
Used in the treatment of chronic obstructive
pulmonary disease - COPD
Adrenergic agonists
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擬腎上腺素
β2-adrenergic agonist 治療輕度氣喘
直接作用在呼吸道平滑肌鬆弛，為一有
效的支氣管擴張劑
Short and long acting drugs
Short acting drugs
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15-30 min可產生療效, 可緩解症狀 4 – 6 hours
治療急性支氣管收縮，因不具抗發炎作用，所以，不
可做為治療慢性氣喘的唯一藥物
Metaproterenol, albuterol, terbutaline, bitolterol,
pirbuterol
– all can be given by inhalation – nebulization
– metaproterenol, terbutaline, albuterol can be given orally
– terbutaline injectable – subcutaneous
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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，血糖過高，血鉀過低，血鎂過低等副作用
Long acting drugs
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Salmeterol, formoterol
– long acting - 12 hours or more
– forms slow release depot in tissue (lipid soluble)
– long duration of action used to treat nocturnal
asthma
– not used as monotherapy always with inhaled
steroids
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作為一般處方用藥，不用在急性症狀緩解治
療
Other b-Agonists
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Epinephrine
– good bronchodilator - not selective (all a and b)
– short lived
– used in emergencies, subcutaneous injection - severe asthma,
hypersensitivity reactions, anaphylaxis
– Available OTC (Over-The-Counter)
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Ephedrine (麻黃素)
–
long history of use in China
– β2 selective, not used much in asthma now
– Not as easily now available since methamphetamine can be made
from this drug
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CNS stimulant, amphetamine look-alike, “truck stop” pharmacology
Side Effects of β-agonists
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Not completely selective
– Can increase heart rate
– Can cause arrhythmias
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Headache - vasodilation
Anti-allergy agents
- Omalizumab
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Recombinant humanized antibody against the Cε3
domain of IgE
– Complexes IgE preventing activation of mast cells
and basophils thus prevents the release of
inflammatory mediators
Market name: Xolair
Used only after primary treatments have failed
The drug is administered subcutaneously in 1 to 3
injections every 2 or 4 weeks
Not recommended when living in environments
where the presence of parasites is common
Inhibition of Leukotrienes
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Inhibition of the formation of leukotrienes
– 5-lipoxygenase inhibitor
– Zileuton
– Increases the lifetime of theophylline and drugs
metabolized by CYP3A4
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Inhibition of the action of leukotrienes
– leukotriene receptor antagonists (LTRA)
– Zafirlukast (LTD4), montelukast (LTD4)
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Zafirlukast (po), montelukast (po)
Zileuton
Arachidonic acid
-
5-Lipoxygenase
Leukotrienes
Cyclooxygenase
Prostaglandins
LTB4 LTC4
LTD4
LTE4
LTC4
LTD4
+ CystLT1
Contraction of airway
smooth muscle cells
Zafirlukast
(CystLT1 antagonists)
Montelukast
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Properties Leukotriene receptor antagonists
– Not all patients respond
– Aspirin sensitivity results from LTD4 release
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Aspirin (or NSAID) sensitivity may be caused by
inhibiting cyclooxygenase and shunting of arachidonic
acid metabolism into the leukotriene pathway
– Takes 3-14 days to work - used for chronic
therapy
– Contraindications - liver disease, pregnancy
(crosses placenta), breast feeding (excreted)
– Fewer of the above concerns with montelukast as
compared to zafirlukast or zileuton
Steroids
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Systemic steroids
– corticosteroids (e.g., prednisone, prednisolone)
– used to treat severe persistent asthma
– significant side effects
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water retention - moon face (Cushingoid features)
Immunosuppression
Steroids reverse inflammation and reduce
sensitivity of airway smooth muscle to stimulation
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adrenal suppression-must taper dose when discontinuing after
prolonged therapy
Inhaled Steroids
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Beclomethasone, Budesonide, Flunisolide,
Fluticasone, Mometasone and Triamcinolone
–
–
–
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given by inhaled route
minimal systemic effects (better topical:systemic ratio)
reduces need for oral steroids
Used as first line therapy for newly diagnosed cases decreases chronic inflammation and might reverse
remodeling of the airways
– Oral candidiasis - thrush - gargle and spit, use a spacer
Corticosteroid Actions
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Decrease the following
– Secretion from, and numbers of eosinophils
– Cytokines from T-lymphocytes
– Number of mast cells
– Secretion and production of cytokines by
macrophages
– Leakiness of endothelia (vasoconstriction)
– Mucus secretion and hypertrophy of mucus cells
– Upregulation of β-adrenergic receptors
Corticosteroids
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中至重度氣喘患者，凡每日由口吸入
β2 –adrenergic agonists 一次以上的患
者，吸入性的 corticosteroids 乃是首選
嚴重的氣喘患者有時需短期使用全身性
的 glucocorticoide
Corticosteroids on lung
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Steroids 對呼吸道平滑肌無直接作用
吸入性的 glucocorticoides 可降低巨噬
細胞，嗜伊紅性白血球及 T 淋巴球參與
發炎的數目及反應
長期吸入 steroids 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原，
刺激物，冷空氣及運動等的反應
Side effects of corticosteroids
Cromolyn/Nedocromil
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Mechanism
– inhibits the degranulation of mast cells - by
inhibiting chloride conductance channels in the
mast cell membranes which reduces
intracellular calcium increases
– works only prophylactically (預防性的)
– cannot terminate an attack
– Can reduce late phase response when given
after an initial attack - inhibits eosinophil
degranulation
Treatments by
Cromolyn/Nedocromil
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Given by nebulization
– solution that is nebulized
– Microfine powder - Spinhaler
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few side effects because it is poorly absorbed and
not metabolized
side effects primarily in airway
– can induce bronchoconstriction, chest tightness, coughing,
xerostomia
– effects minimized by taking β2-agonist concomitantly
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Used to treat allergic rhinitis
– available OTC
Cromolyn and nedocromil
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抗發炎藥物
非支氣管擴張劑，所以，不用於急性氣
喘治療
副作用小，可用於小孩與孕婦
Treatment of Asthma
Asthma 的治療
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氣喘不一定會導致慢性阻塞性肺部疾病
(COPD)
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
治療目的: 使症狀緩解，進一步避免氣
喘再發生
Study question
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有關 β-adrenergic receptor agonists 的敘述何者
不正確 ?
(A) 為一有效之支氣管擴張劑
(B) 可用於急性氣喘時症狀之治療例如
Salmeterol
(C) 會引起心跳過快及血鉀過低等副作用
(D) 不具抗發炎效用
Answer: (B)
THE END