Drugs for treatment of respiratory diseases

Drugs for Drugs for treatment of treatment of respiratory respiratory

diseasesdiseases

2013-4-17

Global asthma rates

全球 3 亿中国 2 500 万（ 1 000 万儿童）

2

粘液分泌过多

嗜酸性细胞

肥大细胞

抗原

Th2 细胞

血管扩张新血管形成

血浆渗出水肿形成

中性粒细胞

粘液栓

巨噬细胞 /树突状细胞

平滑肌收缩肥大 / 增生

胆碱能反射

上皮脱落

上皮纤维化

感觉神经激活

神经激活

哮喘的现代观点 - 气道炎症

Barnes PJ

3

急性炎症

慢性炎症

气道重塑

炎症细胞数量增加

上皮损伤

支气管痉挛粘膜水肿

气道分泌增多

气道狭窄气道高反应性气道可逆性降低

症状哮喘恶化 /加重

细胞增生

细胞外基质增加

哮喘的病理学基础

4

疾病进程哮喘症状发作性呼吸困难喘憋胸闷咳嗽反复发作夜间加重季节性和家族史

5

哮喘成功治疗应该 :

控制症状预防发作保持正常的肺功能防止不可逆的气流受限维持正常的活动水平 ( 包括运动 )避免药物副作用减少死亡率

Global Initiative for Asthma

6

哮喘的治疗机制

舒张支气管平滑肌

消除支气管粘膜的炎症水肿

避免诱发因素

7

Antiasthmatic drugsAntiasthmatic drugs

Airway Airway inflammationinflammation

bronchoconstrictibronchoconstrictionon

Airway Airway hyperresponsivenesshyperresponsiveness

Immunological and non-Immunological and non-immunological stimuliimmunological stimuli

Wheezing (asthmatic Wheezing (asthmatic symptoms)symptoms)

glucocorticosteroidglucocorticosteroidss

disodium disodium cromoglycatecromoglycate

leukotriene leukotriene modifiersmodifiers

2 2 receptor receptor agonistsagonists

theophyllinetheophylline

muscerinic muscerinic antagonistsantagonists

Relievers - Bronchodilators 2 agonists short-acting: salbutamol, terbutaline long-acting: salmeterol, formoterol Anticholinergics (muscarinic antagonists):

ipratropine Xantines (theophyllines): aminophylline

Preventers - Anti-inflammatory drugs Glucocorticosteroids: Inhaled steroids: beclomethasone( 倍氯米松） ,

budesonide （布地奈德） , fluticasone （氟替卡松 ) oral steroids: hydrocortisone （氢化可的松） ,

prednisone（ , 强的松）， dexamethasone （地塞米松） Leukotriene (LT) receptor antagonists (leukotriene

modifiers): LT antagonists: montelukast ( 孟鲁司特 ), zafirlukast

( 扎鲁司特 ) 5-lipoxygenase inhibitors: zileuton ( 齐留通 ) Inhibitors of mediator release: cromolyn sodium( 色甘

酸钠） , nedocromil （奈多罗米 )

Antiasthmatic drugsGlucocorticosteroids Glucocorticosteroids Systemic:Systemic: hydrocortisone hydrocortisone 氢化可的松氢化可的松 prednisone prednisone 泼尼松泼尼松 dexamethasone dexamethasone 地塞米松地塞米松

Inhaled:Inhaled: beclomethasone dipropionate beclomethasone dipropionate 二丙酸倍二丙酸倍

氯米松氯米松 budesonide budesonide 布地奈德布地奈德 triamcinolone acetonide triamcinolone acetonide 曲安奈德曲安奈德 fluticasone propionate fluticasone propionate 丙酸氟替卡松丙酸氟替卡松 flunisolide flunisolide 氟尼缩松氟尼缩松

Adrenocorticoid drugs

Adrenocortical hormones Mineralocorticoids （球状带， 15% ） Glucocorticoids （束状带， 78% ）

(Glucocorticosteroids)

Sex hormones （网状带， 7% ）

1855 年， Addison’s 病 ( 肾上腺皮质功能低下） 1920s ，认识到肾上腺皮质对于维持功能的重要性 1936 ，自肾上腺皮质提取物制备了多种固醇化合物

结晶 1948 ，人工制备了可的松 1950 ，氢化可的松具有治疗作用 1958 ，地塞米松倍他米松，倍氯米松。。。

1. 1. Pharmacological effectsPharmacological effects

Mechanisms of glucocorticoid actionsMechanisms of glucocorticoid actions (1) Effects on metabolisms(1) Effects on metabolisms ：增加肝、肌糖原含量，：增加肝、肌糖原含量，

升高血糖升高血糖 (2) Permissive action(2) Permissive action ：可增加儿茶酚胺的缩血管效应：可增加儿茶酚胺的缩血管效应

和胰高血糖的升血糖作用和胰高血糖的升血糖作用 (3) Anti-inflammatory effects(3) Anti-inflammatory effects (4) Effects on immune and allergy(4) Effects on immune and allergy ：用于解除许多：用于解除许多

过敏性疾病的症状，抑制因过敏反应而产生的病理变化，抑过敏性疾病的症状，抑制因过敏反应而产生的病理变化，抑制排异反应制排异反应

(5) Anti-shock(5) Anti-shock ：广泛用于各种严重休克（内毒素和出血：广泛用于各种严重休克（内毒素和出血性休克）性休克）

(6) Other effects(6) Other effects effects on blood and blood-forming organseffects on blood and blood-forming organs

A. Glucocorticoid drugs

Mechanisms of glucocorticoid actions

binding to glucocorticoid receptor (GR) binding to glucocorticoid receptor (GR)

nuclear translocationnuclear translocation

binding to GR element binding to GR element

regulating related gene transcriptionregulating related gene transcription

biological effects (usually slow) biological effects (usually slow)


糖皮质激素 (GCS) 的作用机制

皮质激素受体

热休克蛋白 90

核膜

mRNA

nGRE +GRE激素反应靶基因

X

• 细胞因子• 诱导型一氧化氮

合成酶• 环氧酶－ 2 (COX-2)

• 磷脂酶 A2

• NK2- 受体• 内皮素 -1

• 脂皮素 -1- 受体• 内核酶• 中性肽链内切酶

GCS

GRE糖皮质激素

反应分子

Examples of glucocorticoid actions:Examples of glucocorticoid actions:

Inhibition of proinflammatory gene transcription (AP-1 and NFInhibition of proinflammatory gene transcription (AP-1 and NFBB))

(1) Effects on metabolisms(1) Effects on metabolisms

a) Carbohydrate:a) Carbohydrate: blood glucose ↑:blood glucose ↑: gluconeogenesis ↑, gluconeogenesis ↑, glucose glucose

utilization↓utilization↓ （用药期间少食高糖食物）（用药期间少食高糖食物）

b) Protein:b) Protein: synthesis ↓, degradation ↑synthesis ↓, degradation ↑ （用药期间多食高（用药期间多食高蛋白食物）蛋白食物）

c) Lipidc) Lipid （短期应用影响不大）（短期应用影响不大） :: plasma cholesterol ↑, fat plasma cholesterol ↑, fat redistribution (central obesity: moon face, buffalo redistribution (central obesity: moon face, buffalo hump)hump)

d) Water and electrolytic:d) Water and electrolytic: NaNa++ excretion ↓, excretion ↓,

KK+ + excretion ↑, Caexcretion ↑, Ca2+2+ excretion↑and absorption↓ excretion↑and absorption↓


(2) Permissive action(2) Permissive action Potentiating the effects of catecholamines Potentiating the effects of catecholamines

（儿茶酚胺）（儿茶酚胺） and glucagonand glucagon （胰高血糖素）（胰高血糖素） (3) Anti-inflammatory effects(3) Anti-inflammatory effects Acute: Acute: inhibiting microvascular leakageinhibiting microvascular leakage 减轻渗减轻渗

出和水肿出和水肿 leukocyte infiltration leukocyte infiltration 改善红肿热痛改善红肿热痛 Chronic:Chronic: inhibiting fibroblast proliferation inhibiting fibroblast proliferation deposition of collagendeposition of collagen cicatrization (cicatrization ( 瘢痕形成瘢痕形成 ))

注意：在抑制炎症减轻症状的同时，也降低了机体防御功能，注意：在抑制炎症减轻症状的同时，也降低了机体防御功能，使用不当可使感染扩散，阻碍创伤愈合。使用不当可使感染扩散，阻碍创伤愈合。


a) Increasing inflammation related proteins or enzymes inducing lipocortin （炎症抑制蛋白脂皮素） , inhibiting

phospholipase A2 activity, decreasing mediators: PGs, LTs

inducing vasocortin （缩血管物质血管皮素） , decreasing microvascular permeability

inhibiting the expression of PLA2, COX-2, inducible NOS, etc.

b) Inhibiting cytokinins: decreasing the transcription and activities of TNFα, IL-1, IL-2, IL-5, IL-6, IL-8, etc.

c) Inhibiting adhesion molecules ： transcriptional inhibiting E-selectin and ICAM-1

d) Inducing the apoptosis of inflammatory cells: downregulating proliferative genes including c-myc and c-myb, activating apoptotic-related enzymes (GR-dependent)


糖皮质激素 (GCS) 的抗炎作用分子机制

对炎症抑制蛋白及某些靶酶的影响

增加脂皮素 -1 转录，抑制 PLA2 ，使 PGs 和 LTs 减少

抑制 NO 合酶和 Cox-2

诱导 ACE 生成对细胞因子和粘附因子影响抑制 TNF-a 等生成抑制 E- 选择素和 ICAM-1 表达增加 NF-kB 的抑制因子 IKB 表达对炎细胞凋亡的影响

基因效应基因效应非基因的受体介导效应细胞膜类固醇受体生化效应溶解于细胞膜，影响其生化特性，

对线粒体内膜影响直接导致例子通透性增加，进而致使氧化磷酸化偶联的解离。

特点：起效快对转录和蛋白质合成抑制剂

不敏感

非基因效应非基因效应

抗炎作用：抑制巨噬细胞和嗜酸粒细胞释放介质；抑制炎性细胞（主要是嗜酸细胞）进入肺内；诱导磷脂酶 A2 抑制蛋白的产生，抑制磷脂酶 A2 ，阻止膜磷脂分解为花生四烯酸，避免进一步转化为白三烯、前列腺素等；减轻炎症的渗出、水肿和毛细血管扩张，降低血管通透性。

抗过敏作用。舒张支气管：抑制细胞内磷酸二酯酶活性，另外对支气管平滑

肌有直接松驰作用。抑制支气管腺体的过度分泌，增强粘液－纤毛清除功能，参与

支气管上皮纤毛的形成，对受损的上皮起抗炎和再生作用。增加 β 受体的合成，并可增强 β 受体的功能，合用时可减少 β

受体激动剂耐药性的产生。

激素与激素与 22 受体激动剂之间的相互作用受体激动剂之间的相互作用

ß2-受体

• 激素对 ß2- 受体的作用

激素受体

激素

抗炎作用

• ß2- 激动剂对激素受体的作用，

ß2- 受体激动剂

支气管扩张作用

Barnes Nice 2001

(4) Effects on immune and allergy

Suppressing immunological functions and allergy

a) inducing apoptosis of T and B lymphocytes

b) inhibiting transcription factor － nuclear factor κB (NFκB) activity

应用：抑制组织器官的移植排异反应对自身免疫性疾病也发挥一定近期疗效


(5) Anti-shock(5) Anti-shock （大剂量）（大剂量） Septic shockSeptic shock a) improving cardiovascular functionsa) improving cardiovascular functions b) inhibiting the production of b) inhibiting the production of

inflammatory factorsinflammatory factors c) stabilizing lysosome membrane: c) stabilizing lysosome membrane:

decreasing the release of myocardial decreasing the release of myocardial depressant factor (MDF)depressant factor (MDF)

d) increasing the tolerance to endotoxin d) increasing the tolerance to endotoxin from bacteriafrom bacteria


(6) Other effects(6) Other effects a) antipyretica) antipyretic （退热）（退热） effectseffects b) effects on blood and blood-forming b) effects on blood and blood-forming

organsorgans red cell red cell ; lymphocytes ; lymphocytes ; neutrophils ; neutrophils

(function (function ); eosinophils ); eosinophils ; platelets; platelets c) skeletal system: c) skeletal system: osteoporosisosteoporosis d) CNS: d) CNS: increasing excitability (elevated increasing excitability (elevated

mood, euphoria, insomnia, restlessness, mood, euphoria, insomnia, restlessness, increased motor activity)increased motor activity)


皮质激素药代动力学－半衰期

皮质激素血浆半衰期 ( 分钟 ) 生物半衰期 (小时 )

氢化可的松 90 8-12

强的松强的松龙甲泼尼龙去炎松

60

200

180

300

12-36

12-36

12-36

24-48

倍他米松地塞米松

100-300

100-300

36-54

36-54

皮质激素抗炎作用比较激素等效抗炎剂量抗炎强度无氟激素氢化可的松 20 1

强的松 5 4

强的松龙 5 4

甲泼尼龙 4 5

含氟激素去炎松 4 5

地塞米松 0.75 25

**Data from PNU fileData from PNU file

吸入激素使用剂量换算表 (成人 )

药物

二丙酸倍氯米松

布地奈德

丙酸氟替卡松

低剂量中剂量

200–500 µg

200–400 µg

100–250µg

高剂量

500–1000µg

400–800 µg

250–500 µg

>1000 µg

>800 µg

>500 µg

应根据病人对治疗的反应来决定给予药物的剂量，这是最重要的。

全球哮喘防治创议 (GINA 2002年 )

2. 2. ADME and properties of ADME and properties of commonly used drugscommonly used drugs

Cortisone and prednisone are Cortisone and prednisone are reduced and transformed to reduced and transformed to hydrocortisone and prednisolone hydrocortisone and prednisolone (active forms) in the liver(active forms) in the liver

Metabolism will be increased by Metabolism will be increased by hepatic enzyme inductors hepatic enzyme inductors ((phenobarbital, phenytoin, phenobarbital, phenytoin, rifampine, rifampine, etc.etc.))


3. 3. Clinical usesClinical uses

(1) Immune diseases(1) Immune diseases a) autoimmune disorders:a) autoimmune disorders: reumatic fever, reumatic fever,

reumatic carditis, rhumatic arthritis, reumatic carditis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, polyarthritis nodosa, lupus erythematosus, polyarthritis nodosa, nephritic syndrome, nephritic syndrome, etc.etc.

b) rejection of organ transplantationb) rejection of organ transplantation c) allergic diseases:c) allergic diseases: urticaria, serum urticaria, serum

sickenss, contact dermatitis, drug allergic sickenss, contact dermatitis, drug allergic reactions, chronic severe asthma, status reactions, chronic severe asthma, status asthmaticus, angioneurotic edema, asthmaticus, angioneurotic edema, etcetc. .


(2) Severe infection and inflammation

a) acute severe infections: merely suppressing inflammatory manifestations but at times lifesaving

Causion: combination with effective antimicrobial drugs !

Usually be not used in viral and fungal infections except for those with cerebral edema or severe systemic symptoms

b) prevention of sequelae of some types of inflammation, such as in brain, heart, eye, joint, etc.


(3) Septic shock: larger dose, short-term, combined with antimicrobial drugs

(4) Hemological diseases: acute lymphocytic leukemia, lymphomas, aplastic anemia, hemolytic anemia, leukocytopenia, thrombocytopenia, etc.

(5) Topical applications: skin, eye, respiratory tract, joint (local injection)

(6) Some types of tumors: breast and prostatic cancers, acute lymphocytic leukemia, etc.


4. 4. Adverse effectsAdverse effects

(1) Effects resulting from continued (1) Effects resulting from continued used of large dosesused of large doses

a) Hypercorticisma) Hypercorticism （肾上腺功能亢进）（肾上腺功能亢进） -like -like syndrome:syndrome: central obesity (moon face, central obesity (moon face, buffalo hump, etc.); hypertension; glycosuriabuffalo hump, etc.); hypertension; glycosuria（糖尿病）（糖尿病） , hypokalemia, hypokalemia （低钾血症）（低钾血症） ; ; etcetc..

b) Increasing susceptibility to b) Increasing susceptibility to infections:infections: specific antimicrobial drugs specific antimicrobial drugs should be administered with GCsshould be administered with GCs

c) Ingestive system:c) Ingestive system: peptic ulcerspeptic ulcers （胃、十二（胃、十二指肠溃疡）指肠溃疡） , , etcetc..


d) Cardiovascular system:d) Cardiovascular system: hypertension, arteriosclerosishypertension, arteriosclerosis （动脉硬化（动脉硬化 ))

e) Myopathy and osteoporosis:e) Myopathy and osteoporosis: vertebral compression fractures, vertebral compression fractures, spontaneous fractures, especially in spontaneous fractures, especially in postmenopausal womenpostmenopausal women

f) CNS:f) CNS: behavioral disturbances, behavioral disturbances, induction of epileptic seizuresinduction of epileptic seizures

g) Inhibition or arrest of growth in g) Inhibition or arrest of growth in childrenchildren


Adverse effects of Adverse effects of glucocorticoid drugs:glucocorticoid drugs:

Effects resulting from Effects resulting from continued used of continued used of large doseslarge doses

(2) Withdrawal syndrome(2) Withdrawal syndrome

a) Suppression of hypothalamic-a) Suppression of hypothalamic-

pituitary-adrenal axis(pituitary-adrenal axis(下丘脑下丘脑 -- 垂体垂体 -- 肾上肾上

腺皮质轴，腺皮质轴， HPAHPA ））

b) Exacerbation of the underlying b) Exacerbation of the underlying

diseases (rebound)diseases (rebound)


Antiasthmatic drugs

Chemical structure of 4 kinds inhalation glucocorticosteroids

FO

HO

C = O

SCH2F

OCOC2H5

CH3

F

丙酸氟替卡松丙酸氟替卡松(FP)(FP)

布地奈德布地奈德(BUD)(BUD)

O

HO

C = O

CH2OH

OO

H

C HC3H7

糠酸莫米他松糠酸莫米他松(MF)(MF)

ClO

HO

C = O

Cl

OCH3

C-

O

Cl

HO

C = O

CH2OCOC2H5

OCOC2H5

CH3

H

二丙酸倍氯米松二丙酸倍氯米松(BDP)(BDP)

O

C = O

CH2OCOC2H5

OCOC2H5

CH3

Beclomethasone dipropionate

二丙酸倍氯米松二丙酸倍氯米松

O

HO

Cl

CH3

OCOC2H5

C O

CH2OCOC2H5


1. 1. Pharmacological effectsPharmacological effects Antiinflammation:Antiinflammation: 抑制多种参与哮喘发病的炎症细胞及免疫细胞抑制多种参与哮喘发病的炎症细胞及免疫细胞抑制细胞因子与炎症介质的产生抑制细胞因子与炎症介质的产生抑制气管高反应性抑制气管高反应性增加支气管及血管平滑肌对儿茶酚胺的敏感性增加支气管及血管平滑肌对儿茶酚胺的敏感性 2. 2. Clinical usesClinical uses As first-line drugs, currentlyAs first-line drugs, currently Controlling chronic symptomsControlling chronic symptoms （用于扩张药不能（用于扩张药不能很好控制病情的慢性哮喘患者）很好控制病情的慢性哮喘患者）

Ineffective for acute symptoms!Ineffective for acute symptoms!


Adverse effects

Local:Local: 口咽部念珠菌感染口咽部念珠菌感染————用药后漱口可减少发生用药后漱口可减少发生

Systemic effects Systemic effects 治疗剂量作用不明显治疗剂量作用不明显肾上腺功能亢进肾上腺功能亢进

易感染易感染


B. Inhibitors of mediator release

O ONaOOC COONa

OCH2CHCH2O

OH

O O

Disodium cromoglycate 色甘酸钠

1. Pharmacological effects 抑制抗原引起的肥大细胞释放炎性介质抑制非特异性支气管痉挛2. Clinical uses Prevention of allergic asthma （外源性效

果好，内源性效果差） Acting slowly (2-4 weeks) 8 周无效可放弃3. Adverse effects 咽喉和器官刺激，胸部紧迫感，甚至诱发哮喘（β激动剂

可防止）


CromolynCromolyn Inhibits mediator Inhibits mediator release from mast cellsrelease from mast cells

Other inhibitors of mediator release:

Sodium nedocromil( 萘多罗米钠 ) Inhibiting mediators release from mast cell or other cells, the effect is better than disodium cromoglycate.

Ketotifen( 酮替芬 ) Inhibiting mediators release, and antagonizing H1 receptor.


Leukotriene receptor antagonists Leukotriene receptor antagonists (LTRA) (LTRA)

(CysLT1 receptor antagonist) (CysLT1 receptor antagonist) montelukast (montelukast (孟鲁司特孟鲁司特 )) zafirlukast (zafirlukast (扎鲁司特扎鲁司特 ))

5-lipoxygenase inhibitors5-lipoxygenase inhibitors zileuton (zileuton (齐留通齐留通 ))

C. Leukotriene modifiers

Leukotriene metabolism pathway

LTC4, LTD4, LTE4----CysLT1 receptor bronchoconstrictors, increase microvascular permeability, mucus secretion

LTB4----BLT receptor

chemoattractant for neutrophils


Zafirlukast (Accolate, (Accolate, 扎鲁司扎鲁司特特 ))

an oral LTRA Reducing constriction of the airways and

build-up of mucus in the lungs and inflammation of the breathing passages.

Clinical use: twice daily maintenance treatment of asthma, often

used in conjunction with an inhaled steroid and/or long-acting bronchodilator.


Montelukast Montelukast (Singulair and Montelo-10, (Singulair and Montelo-10, 孟鲁司特孟鲁司特 ))

it blocks the action of leukotriene D4 (and secondary it blocks the action of leukotriene D4 (and secondary ligands LTC4 and LTE4) on the cysteinyl leukotriene ligands LTC4 and LTE4) on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by receptor CysLT1 in the lungs and bronchial tubes by binding to it. binding to it.

reduces the bronchoconstrictionreduces the bronchoconstriction

Clinical use: once daily AsthmaAsthma ：： maintenance treatment of asthma and to relieve maintenance treatment of asthma and to relieve

symptoms of seasonal allergiessymptoms of seasonal allergies

it is not useful for the treatment of acute asthma it is not useful for the treatment of acute asthma attacks. attacks.


Adverse effects

generic adverse reactions ： gastrointestinal disturbances Headaches sleep disorders increased bleeding tendency

Churg–Strauss syndrome Drowsiness

Zileuton Zileuton (Zyflo, (Zyflo, 齐留通齐留通 ))

an orally active inhibitor of 5-lipoxygenase inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4)

formation. Clinical use: taken four times per daytaken four times per day

Zileuton is used for the maintenance treatment of asthma.

Adverse effects sinusitis （鼻窦炎） , nausea （反胃） ,

pharyngolaryngeal pain （咽喉疼痛）


治疗药物的选用

缓解药物速效 β2 激动剂按需吸入

控制药物 : 每天吸入皮质激素

控制药物 : 每天吸入皮质激素

每天吸入长效β2 激动剂

控制药物 : 每天吸入糖皮质激素

每天吸入长效β2 激动剂

当哮喘控制时，减少剂量

监护

1 级 :间歇发作

2 级 :轻度持续

3 级 :中度持续

4 级 :重度持续降级

结果：哮喘控制尽可能的最好结果

控制药物 :无

-缓释茶碱 - 白三烯调节剂 -口服皮质激素

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属于糖皮质激素类的药物是 ( )

A. 特布他林 Terbutaline

B ．乙酰半胱氨酸 Acetylcysteine

C ．布地奈德 Budesonide

D ．氨茶碱 Aminophylline

E ．酮替芬 Ketotifen

关于糖皮质激素治疗哮喘的叙述，错误是 ( )

A．局部抗炎作用

B．减少白三烯的生成

C．可吸入给药

D．对磷脂酶 A2有抑制作用

E．对磷酸二酯酶有抑制作用

下述哪个药物属于抗过敏平喘药？ ( )

A. 特布他林 Terbutaline

B ．异丙肾上腺素 Isoprenaline

C ．布地奈德 Budesonide

D. 异丙托溴胺 Ipratropium bromide

E ．色甘酸钠 Disodium cromoglycate

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