1. Drugs for treatment of respiratory diseases
Huifang Tang
Department of pharmacology
Zhejiang University, school of medicine
Research building C422

2. Classification of drugs acting on respiratory system
Ⅰ. Antitussive drugs: Centrally acting: Codeine Peripherally acting: Benzonatate Ⅱ. Mucoactive drugs : Expectorants: Guaifenesin Mucoregulators:Carbocysteine
3. Mucolytics: N-Acetylcysteine
4. Mucokinetic drugs: Ambroxol Ⅲ. Antiasthmatic drugs: Bronchial dilators (1) receptor agonists: Salbuterol (2)theophyllines: Aminophylline (3)muscarinic antagonists: Ipratropine Anti-inflammatory drugs (1)glucocorticosteroids: Budesonide (2)mediator release inhibitors: Disodium cromoglycate

3. A. Antitussives 咳嗽反射示意图 物理、化学 感受器（刺激感受器、牵张感受器等） 刺激 传入神经（迷走、喉上神经）
咳嗽中枢（延髓）
传出神经（迷走、喉返、膈神经）
效应器（声门、
呼气肌）
咳嗽反射
咳嗽反射示意图

4. Clinical perspective - cough: an unmet need. Curr Opin Pharmacol
Clinical perspective - cough: an unmet need. Curr Opin Pharmacol. 2015 Jun;22:24-8

5. Multiple vagal afferent nerve subtypes innervate the airways and lungs
Antitussive drugs--past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):

6. A. Antitussives Central antitussives Narcotic drugs: codeine 可待因
pholcodine 福尔可定
Drotebanol 羟蒂巴酚
Non-Narcotic drugs:
dextromethorphan 右美沙芬
pentoxyverine 喷托维林(咳必清)
Peripheral antitussives
benzonatate 苯佐那酯

7. Narcotic Antitussives
Codeine 可待因
Clinical use:
Severe cough without sputum, such as cough induced by tumor, pleurisy(胸膜炎) with pain

8. Narcotic Antitussives
Name
cough suppressant effects
analgesic effects
dependence
morphine 4 10
Codeine (可待因) 1
Dihydrocodeine
(双氢可待因)
1.5
Drotebanol（羟蒂巴酚）
<10
Pholcodine（福尔可定）
less
Clinical use:
Severe cough without sputum

9. Non-Narcotic Antitussives Dextromethorphan(右美沙芬， DXM)
Codeine
Dextromethorphan

10. Metabolism of dextromethorphan.
3-methoxymorphinan
(3-甲氧基吗啡喃)
3-hydroxymorphinan
(3-羟基吗啡喃)
dextrorphan(右啡烷)
Antitussive drugs--past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):

11. Non-Narcotic Antitussives
Dextromethorphan
Mechanism of action
nonselective serotonin reuptake inhibitor
sigma-1 receptor agonist
Major metabolite dextrorphan(右啡烷) as an NMDA receptor antagonist, producing effects similar to ketamine and phencyclidine (PCP,苯环利啶,俗称天使尘),
Active metabolite 3-methoxymorphinan, which produces local anesthetic effects in rats with a potency above dextrorphan but below dextromethorphan itself.

12. Non-Narcotic Antitussives
(1)Pharmacological effects:
Depression of coughing center;
(2)Clinical uses:
Upper respiratory infection and dry cough.
(3)Adverse reaction:
Atropine-like side effects.
Contraindication:
In the patients with glaucoma,
pregnancy(< 3 months),
psychotic disorders, etc.

13. Pentoxyverine(喷托维林, 咳必清)
Non-Narcotic Antitussives
Pentoxyverine(喷托维林, 咳必清)
Also known as Carbetapentane
(1)Pharmacological effects:
Depression of coughing center,
Local anesthetic effects, and
Muscarinic antagonism.

14. (2)Clinical uses: (3)Adverse reaction:
Upper respiratory infection, Cough without sputum.
(3)Adverse reaction:
Atropine-like side effects.
Uses and adverse effects are similar to dextromethorphan
However, there is very little published clinical data to suggest clinical efficacy with carbetapentane leading the FDA (2007) to conclude that this drug should not be made available as an OTC treatment of cough in the
USA (2007).

15. Non-Narcotic Antitussives
Others
Pharmacological effects
Side effects
Cloperastine（氯哌斯汀）
a mild bronchorelaxant
antihistaminic activity
acting on the central nervous system or the respiratory center
Promolate（普罗吗酯）
Sedative effect
bronchorelaxant effect
Depression of coughing center
Fominoben（福米诺苯）
Act on respiratory center
Zipeprol
(齐培丙醇）
a local anaesthetic
mucolytic
antihistamine properties
anticholinergic properties
hallucinations
(幻觉)

16. Peripheral antitussives
A. Antitussives
Peripheral antitussives
Benzonatate 苯佐那酯 (退嗽)
Blocking cough reflex
Local anesthetic effects
CNS depression
Others:
Benproperine(苯丙哌林)
Dropropizine (羟丙哌嗪)
Noscapine (那可汀); moguisteine (莫吉司坦)
Prenoxdiazine (普诺地嗪)
Dioxopromethazine (二氧丙嗪)

17. 常用镇咳药比较表 + 药物 药效 镇痛 解痉 成瘾性 临床应用 可待因 剧烈干咳，尤适用于胸膜炎干咳伴胸痛者 右美沙芬 干咳 喷托维林1 +
剧烈干咳，尤适用于胸膜炎干咳伴胸痛者
右美沙芬 干咳
喷托维林
1/3
上呼吸道炎症引起的干咳
尤适用于小儿百日咳
苯丙哌林 3
刺激性干咳

18. Antitussive drugs--past, present, and future. Pharmacol Rev
Antitussive drugs--past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):

19. B. Mucoactive drugs Mucolysis Hydration: Sputum dilution
Mucous glycoprotein network

20. B. Mucoactive drugs
Expectorants （Stimulating bronchial secretion 痰液稀释药）
Ammonium chloride 氯化铵
Glyceryl guaiacolate (Guaifenesin )愈创木酚甘油醚
Potassium iodide 碘化钾
Ipecac syrup 吐根糖浆
酒石酸锑钾、桔梗、远志等。
Mucoregulators
Carbocisteine 羧甲司坦*
Anticholinergic agents
Glucocorticoids
Macrolide antibiotics

21. B. Mucoactive drugs Mucolytic drugs(粘痰溶解药) Mucokinetics drugs（痰液调节药）
N-Acetylcysteine 乙酰半胱氨酸
Erdosteine 厄多司坦
Dextran
Heparin
Mucokinetics drugs（痰液调节药）
Bromhexine 溴己新
Ambroxol 氨溴索
Surfactants

22. Ammonium chloride 氯化铵 Expectorants 恶心性祛痰药的代表药
This causes the production of excess respiratory tract fluid which presumably is easier to cough up.
Ammonium salts are an irritant to the gastric mucosa and may induce nausea and vomiting.

23. Guaifenesin 愈创木酚甘油醚 Expectorants 刺激性祛痰药的代表药
Effect and mechanism of action
increasing the volume and reducing the viscosity of secretions in the trachea and bronchi.
stimulates the flow of respiratory tract secretions,
allowing ciliary movement to carry the loosened secretions upward toward the pharynx
increase the efficiency of the cough reflex
facilitate removal of the secretions

24. Carbocysteine 羧甲司坦 Mucoregultor
Carbocisteine is produced by alkylation of cysteine with chloroacetic acid.
Pharmacological effect
Reduces the viscosity of sputum allowing the sufferer to bring up sputum more easily.
Carbocisteine should not be used with antitussives (cough suppressants) or medicines that dry up bronchial secretions.

25. N-Acetylcysteine N乙酰半胱氨酸,NAC
Mucolytic drugs
N-Acetylcysteine N乙酰半胱氨酸,NAC
Pharmacological effect:
Antioxidant and liver protecting effects-- a dietary supplement :
Breaks disulfide bonds in mucus and liquefies it, making it easier to cough up.-- cough therapy:

26. Erdosteine 厄多司坦 Mucolytic drugs it is a thiol derivative. Action
free radical scavenging activity.
modulates mucus production and viscosity
increases mucociliary transport,
It also exhibits inhibitory activity against the effects of free radicals produced by cigarette smoke.
Clinical use:
chronic obstructive lung disease : reduced cough (both frequency and severity) and sputum viscosity more quickly and more effectively than placebo and reduced the adhesivity of sputum more effectively than bromhexine 30 mg twice daily.
Co-administration of erdosteine and amoxicillin in patients with acute infective exacerbation of chronic bronchitis resulted in higher concentrations of the antibiotic in the sputum, leading to earlier and more pronounced amelioration of clinical symptoms compared with placebo.
a low incidence of adverse events, most of which are gastrointestinal and generally mild.

27. Mucokinetic drugs
Ambroxol ( 氨溴索,沐舒坦)
全肺动力型排痰剂

28. Clinical use: Mucoactive action local anaesthetic effect
Mucokinetic drugs
Mucoactive action
secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract
stimulates synthesis and release of surfactant by type II pneumocytes.
promotes mucus clearance, facilitates expectoration and eases productive cough
local anaesthetic effect
a very potent inhibitor of the neuronal Na+ channels
anti-inflammatory properties
Clinical use:
upper respiratory tract infections and other lung problems, including chronic inflammatory pulmonary conditions;

29. Ambroxol Side Effects Mucokinetic drugs Gastrointestinal Side Effects
including diarrhea, heartburn, indigestion, and occasionally nausea and vomiting.
Allergic Reactions
rarely, mainly involve skin rashes, hives and dermatitis, as well as possible swelling.
Intravenous Side Effects
Intravenous ambroxol has been associated with chills, intense headaches, shortness of breath and weakness.

30. Bromhexine 溴己新 Mucolytic drugs
Bromhexine is a synthetic derivative of the herbal active ingredient vasicine(鸭嘴花碱)
used in the treatment of respiratory disorders associated with viscid or excessive mucus.

31. Pharmacological effect
Mucolytic drugs
Pharmacological effect
Bromhexine supports the body's own natural mechanisms for clearing mucus from the respiratory tract.
Secretolytic effect :
increases the production of serous mucus in the respiratory tract
enhances mucus transport by reducing mucus viscosity
secretomotoric effect:
enhances mucus transport by activating the ciliated epithelium
antioxidant effect

32. Fudosteine (福多司坦) Mucoactive drugs a cysteine derivative
Inhibit MUC5AC mucin hypersecretion by reducing MUC5AC gene expression
Iihibition of extracellular signal-relatedI kinase and p38 mitogen-activated protein kinase in vivo and extracellular signal-related kinase in vitro.

33. Myrtol (稀化黏素,桃金娘油) Pharmacological effects: Clinical use:
Mucoactive drugs
Myrtol (稀化黏素,桃金娘油)
an essential oil derived from the Myrtle plant (Myrtus communis)
consisting mainly of three monoterpenes:
(+)α-pinene（蒎烯 ）
d-limonene （柠檬烯 ）
1,8-cineole （桉叶素 ）
Pharmacological effects:
Increases mucociliar clearance
Mucosecretolytic effects.
Anti-inflammatory and antioxidative properties
Clinical use:
acute and chronic bronchitis and sinusitis

34. Mucoactive drugs.Eur Respir Rev 2010; 19: 116, 127–133

35. 祛痰药作用比较表 药物 作用机制 用法 临床应用 氯化铵 增加分泌物 口服 急、慢性呼吸道炎症痰多不易咳出者 溴己新 裂解粘多糖
痰液粘稠难于咳出
乙酰半胱氨酸
裂解粘蛋白
雾化吸入
气管滴入
粘痰阻塞气道

36. Bronchodilators (支气管扩张药)

37. Antiasthmatic drugs Immunological and non-immunological stimuli
Airway inflammation
bronchoconstriction
2 receptor agonists
Theophylline
Muscerinic antagonists
glucocorticosteroids
Disodium cromoglycate
Leukotriene modifiers
Airway hyperresponsiveness
Wheezing (asthmatic symptoms)

39. Bronchodilators  Receptor agonists
Non-selective：adrenaline, isoprenaline
2-selective: salbutamol, terbutaline, salmeterol, formoterol
Theophyllines: aminophylline
Muscarinic antagonists: ipratropium bromide

41.  receptor agonists 去甲肾上腺素 肾上腺素 异丙肾上腺素 2 receptor selective agonists
non-selectivity
去甲肾上腺素
肾上腺素
异丙肾上腺素
2 receptor selective agonists
沙丁胺醇
福莫特罗

43. β2-AR agonists Short-acting β2-adrenergic receptor agonists(SABAs)
1. Albuterol (Salbuterol 沙丁胺醇 )
2. Fenoterol（菲诺特罗，酚间羟异丙肾上腺素）
3. Terbutaline (特布他林)
Long-acting β2-adrenergic receptor (LABAs)
1. Formoterol (福莫特罗)
2. Salmeterol (沙美特罗)

44. Ultra-long-acting β2-adrenergic receptor agonists
(ultra-LABA)
1. Indacaterol (茚达特罗)
2. Olodaterol (奥达特罗 )
3. Vilanterol (维兰特罗 )
4. Carmoterol (卡莫特罗)
5. LAS100977
6. PF
7. AZD3199.

45. Short-acting β2-AR agonists (SABAs)
Salbuterol 沙丁胺醇
1. Pharmacological effects
Relaxing bronchial smooth muscles
2. Clinical uses
Controlling asthmatic symptoms
Given by inhalation, oral or injection

46. Dysfunction of metabolism (ketoacidosis,raises blood sugar levels, elevated blood levels of fatty acids and glyceroletc.)
mild appetite suppression, headache, nausea, and sleep disturbances

47. Selectivity of 2 agonists

48. Bronchial dilators 2 receptor selective agonists：
Long-acting 2 receptor agonists (LABA)
Formoterol 福莫特罗
Salmeterol 沙美特罗

49. Aminophylline 氨茶碱 Bronchial dilators Theophyllines Theophyllines:
One type of xanthine derivatives (甲基黄嘌呤类衍生物)

50. Theophyllines

51. Bronchial dilators 1. Pharmacological effects
Inhibiting phosphodiesterase(PDE);
Blocking adenosine receptors;
Increasing catecholamine release;
Immunomodulation;
Increasing contractility of respiratory muscle(diaphragm muscle);
Diuretic,
CNS stimulation,
Gastric acid secretion, etc.

52. Bronchial dilators 2. Clinical uses Bronchial asthma (p.o., i.v.)
Others: acute pulmonary edema, etc.
Slow-release theophylline (for control of nocturnal asthma) is the most commonly used methylxanthine.
Aminophylline
pentoxifylline, is promoted as a remedy for intermittent claudication;

53. Common adverse effects:
Gastrointestinal distress, tremor, and insomnia.
Severe nausea and vomiting, hypotension, cardiac arrhythmias, Seizures
Very large overdoses (eg, in suicide attempts) are potentially lethal because of arrhythmias and seizures.
Beta blockers are useful in reversing severe cardiovascular toxicity from theophylline.

54. Presynaptic mediator involved in ACh release (neurojunctional plaque).
Muscarinic antagonists
Presynaptic mediator involved in ACh release (neurojunctional plaque).

55. Muscarinic antagonists
Short-acting muscarinic acetylcholine receptor (mAChR) antagonists(SAMAs)
1. Atropine methonitrate
2. Ipratropium bromide （异丙托溴铵）
3. Oxitropium bromide （氧托溴铵）
Long-acting long mAChR antagonists （LAMAs）
Tiotropium bromide （噻托溴铵）
Novel long-acting mAChR antagonists
Glycopyrronium bromide （格隆溴铵）
Aclidinium bromide （阿地溴铵）
3. Other muscarinic acetylcholine receptor antagonists under development.

56. Muscarinic acetylcholine receptor (mAChR) antagonists
ipratropium bromide (异丙托溴铵);
oxitropium bromide (氧托溴铵);
tiotropium bromide (噻托溴铵).
气道松弛作用强度: 异丙托溴铵＜氧托溴铵＜噻托溴铵;
作用持续时间: 异丙托溴铵＜氧托溴铵＜噻托溴铵.

57. Mechanism of Action and Effects
When given by aerosol, ipratropium and tiotropium competitively block muscarinic receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge.
Muscarinic antagonists reverse bronchoconstriction in some asthma patients (especially children) and in many patients with COPD.
They have no effect on the chronic inflammatory aspects of asthma.

58. Clinical Use and Toxicity
Ipratropium and tiotropium are useful in one third to two thirds of asthmatic patients; β2 agonists are effective in almost all.
For acute bronchospasm, therefore, the β agonists are usually preferred.
However, in COPD, which is often associated with acute episodes of bronchospasm, the antimuscarinic agents may be more effective and less toxic than β agonists.

59. Mechanisms of bronchodilatory action of antimuscarinic agents and beta2-adrenergic receptor agonists. Antimuscarinics block the binding of acetilcholine (ACh) to M3 muscarinic receptor, thereby inhibiting smooth muscle cell contraction. Beta2-adrenergic receptor agonists bind to beta2-adrenergic receptor and induce a cascade of signal transduction events that ultimately lead to smooth muscle relaxation.

60. Novel class of Brochodilators

61. Aerosol inhalation

62. Spacer used for aerosol inhalation
定量手控
气雾器
Spacer used for aerosol inhalation

63. Spacer will aid patients to inhale the aerosolized drugs easier
Outcome of different sized particles:
> 10μm: mouth and oropharynx
< 0.5μm: inhaled to the alveoli and subsequently exhaled without being deposited in the lung
1-5μm: the most effective

64. Anti-inflammatory drugs
抗炎平喘药
Glucocorticosteroids:
Inhaled steroids: beclomethasone(倍氯米松）, budesonide（布地奈德）, fluticasone（氟替卡松)
Systemic steroids: hydrocortisone（氢化可的松）, prednisone（强的松）， dexamethasone（地塞米松）
PDE4 inhibitors: Roflumilast (罗氟司特)
Leukotriene (LT) modifiers:
LT receptor antagonists: montelukast (孟鲁司特), zafirlukast (扎鲁司特)
5-lipoxygenase inhibitors: zileuton (齐留通)
抗过敏平喘药
Inhibitors of mediator release: cromolyn sodium(色甘酸钠）, nedocromil（奈多罗米)
H1 receptor antagonists: ketotifen (酮替芬)

65. Structure and function of adrenal cortex.
Zona
Faseciculata
Zona
Reticularis
Androgens
Adrenaline
Structure and function of adrenal cortex.

66. 甾 H 甾体结构 C D A B Basic structure of glucocorticoid drugs: 14 1 19 1213 18 16 15 14 1 9 2 A B 10 8
甾体结构 3 5 7 4 6

67. Mechanisms of glucocorticoid actions
CBG: corticosteroid binding globulin; S: glucocorticoid steroids; R: glucocorticoid receptor; GRE: glucocorticoid response element; HSP90: heat shock protein 90
2013 Basic_and_Clinical_Pharmacology_13th_Edition

68. Antiasthmatic drugs Glucocorticosteroids Systemic corticosteroids
hydrocortisone 氢化可的松
prednisone 泼尼松
dexamethasone 地塞米松
Inhaled corticosteroids (ICS)
beclomethasone dipropionate 二丙酸倍氯米松
budesonide 布地奈德
fluticasone propionate 丙酸氟替卡松
flunisolide 氟尼缩松

69. A. Glucocorticoid drugs
(1) Effects on metabolisms
a) Carbohydrate: blood glucose ↑: gluconeogenesis ↑, glucose utilization↓
b) Protein: synthesis ↓, degradation ↑
c) Lipid: plasma cholesterol ↑, fat redistribution (central obesity: moon face, buffalo hump)
d) Water and electrolytic: Na+ excretion ↓,
K+ excretion ↑, Ca2+ excretion↑and absorption↓

70. A. Glucocorticoid drugs
(2). Pharmacological effects
(1) Anti-inflammatory effects
(2) Effects on immune and allergy
(3) Anti-shock
(4) Permissive action
(5) Other effects
antipyretic effects
effects on blood and blood-forming organs
skeletal system
CNS effects

71. A. Glucocorticoid drugs
Anti-inflammatory effects
Acute: inhibiting microvascular leakage
leukocyte infiltration
Chronic: inhibiting fibroblast proliferation
deposition of collagen
cicatrization (瘢痕形成)

72. A. Glucocorticoid drugs
Anti-inflammatory effects
Acute: inhibiting microvascular leakage
leukocyte infiltration
Chronic: inhibiting fibroblast proliferation
deposition of collagen
cicatrization (瘢痕形成)

73. Effect of glucocorticoids on transcription of genes relevant to asthma
Increased transcription (trans-activation)
• Lipocortin-1
• β2-Adrenoceptors
• Secretory leukocyte inhibitory protein
• IkB-a (inhibitor of NF-kB)
• MKP1 (inhibits MAP kinase pathways)
• Glucocorticoid inducible leucine zipper (GILZ)
• Anti-inflammatory or inhibitory cytokines
IL-10, IL-12, IL-1 receptor antagonist
Decreased transcription (trans-repression)
• Inflammatory cytokines: IL-2, IL-3, IL-4, IL-5, IL-6, IL-13, IL-15, TNF-a, GM-CSF, SCF, TSLP
• Chemokines: CCL1, CCL5, CCL11, CXCL8
• Inflammatory enzymes: Inducible nitric oxide synthase (iNOS), inducible cyclo-oxygenase (COX-2)
Inducible phospholipase A2 (cPLA2)
• Inflammatory peptides: Endothelin-1
• Mediator Receptors: Neurokinin (NK1)-, bradykinin (B2)-receptors
• Adhesion molecules: ICAM-1,VCAM-1

74. Non-genomic mechanisms of action of glucocorticoids.
The non-genomic mechanisms of action of glucocorticoids can be initiated in a number of ways. The immunosuppressive effects can occur when the glucocorticoid becomes incorporated into the phospholipid bilayer of the cell membrane or the glucocorticoid binds to a G-protein-coupled receptor within the cell membrane. The glucocorticoid can also bind to a membrane glucocorticoid receptor, which initiates a secondary messenger-signaling cascade leading to apoptosis. Finally, the multi-protein complex, which is bound to, the inactive glucocorticoid receptor dissociates upon glucocorticoid binding and causes the MAPK cascade to be fire.
C. Boardman et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 129e143

75. Effect of corticosteroids on inflammatory and structural cells in the airways.

76. A. Glucocorticoid drugs
2. ADME and properties of commonly used drugs
Cortisone and prednisone are reduced and transformed to hydrocortisone and prednisolone (active forms) in the liver
Metabolism will be increased by hepatic enzyme inductors (phenobarbital, phenytoin, rifampine, etc.)

77. Pharmacokinetics of ICS
Antiasthmatic drugs
Pharmacokinetics of ICS
2011, Goodman & Gilman';s The Pharmacological Basis of Therapeutics 12th

78. Antiasthmatic drugs 理想的 ICS需具备药代动力学的特性 合适的粒径 适宜的油/水分布比值 适宜的表观分布容积
高受体亲和力：脂溶性
高气道滞留率：水溶性、酯化作用、脂溶性
适宜的表观分布容积
适宜的半衰期
肝脏首过效应强，生物利用度低
2018/11/15

79. Chemical structure of 4 kinds inhalation glucocorticosteroids
Antiasthmatic drugs
Chemical structure of 4 kinds inhalation glucocorticosteroids
二丙酸倍氯米松
(BDP)
CH2OCOC2H5
CH2OCOC2H5
布地奈德
(BUD)
CH2OH
C = O
C = O
C = O
OCOC2H5
OCOC2H5 O H HO HO C
CH3
CH3 O
C3H7 Cl O O H H
糠酸莫米他松
(MF)
丙酸氟替卡松
(FP)
SCH2F Cl O
C = O
C = O
OCOC2H5 O C- HO
CH3 HO
CH3 F Cl O O F

80. Receptor-binding affinity of inhaled corticosteroids to the glucocorticoid receptor

81. 布地奈德 布地奈德是新一代糖皮质激素，具有呼吸道选择性 16 α和17α位加入了亲脂基团 增加了糖皮质激素受体的亲和力
增加了摄取及局部的应用
全身吸收后快速代谢失活

82. 布地奈德肺内酯化作用 布地奈德酯化作用 延长了抗炎作用时间 增加了呼吸道的选择性 O = -C-(CH2)nCH3
Atp,adenosine triphosphate;CoA,coenzyme A.
Tunek A et al.Drug Metob Dispos 1997;25: ;Miller-Larsson A et al.Drug Metab Dispos 1998;26:

83. ICS药理学和药代动力学参数对全身效应的影响
布地奈德
氟替卡松
倍氯米松
糖皮质激素效应 高
中等/低
脂溶性
中等/高 低
分布容积(L)
183
318 20
气道滞留率 最高
经口吸收药物的首过清除 较高
半衰期
2.8h
14.4h
0.1h
全身效应 中等

84. A. Glucocorticoid drugs
3. Clinical uses
ICS are now recommended as first-line therapy for all patients with persistent asthma, including children.
Current guidelines suggest that high doses of ICS should be used only in patients with severe disease (FEV1 < 50% predicted) who have frequent exacerbations (≤2 per year) which would comprise about 10% of patients, whereas currently high-dose ICS are used in approximately 80% of patients with a clinical diagnosis of COPD.

85. Interaction with β2-adrenergic receptors
1.The steroid–GR complex enhances coupling of β2-receptor to G proteins and/or prevents downregulation following β2-receptor activation. 2. β-Agonists may activate GR independently of glucocorticoids. 3. Binding between the activated GR and CREB in the cytoplasm may inhibit translocation to the nucleus. 4. Synchronized activation of other nuclear transcription factors such as C/EBP-α. 5. “Crosstalk” between the GR and CREB in the nucleus. 6. The GR and CREB may compete for or synergistically bind cofactors such as CBP, which are required for coupling with RNA polymerase and activation of response elements in the promoter regions of target genes. 7. Direct phosphorylation of protein cofactors such as CBP may alter their activity. 8. The presence of both GREs and CREs in the promoter regions of target genes may mutually enhance or inhibit their effects on gene transcription. 9. The promoter region of the β2-receptor gene contains GREs, which may enhance or suppress synthesis of the β2-receptor protein. 10. The promoter region of the GR gene contains CREs, which may enhance or suppress synthesis of the GR protein. 11. A cAMP-dependent mechanism enhances the stability of messenger RNA for the GR increasing receptor levels. 12. Activated GRs may enhance stability of β2-receptor mRNA
Clinical Reviews in Allergy & Immunology, 2006:231

86. 4.Adverse effects

87. Adverse effects of glucocorticoid drugs:
Effects resulting from continued used of large doses

88. Roflumilast (罗氟司特) B. PDE4 inhibitors 1. Pharmacological effects
Inhibits inflammation
Bronchial dilating effect
Attenuates bronchial remodeling
2. Clinical uses
Approved for the treatment of asthma and COPD (2010), once daily
3. Adverse effects
Diarrhea, abdominal pain, nausea, weight loss, headache, insomnia, depression, etc.

89. B. PDE4 inhibitors
Klaus F. Rabe, BJP,2011

90. B. PDE4 inhibitors Combination of PDE4 inhibitor with ICS:
Enhanced the glucocorticoid function, suggesting its use as a glucocorticoid –sensitising
Combination of PDE4 inhibitor with LABAs(long-acting β2-adrenoceptor agonist):
Enhance anti-inflammatory glucocorticoid activity above the level produced by an inhaled glucocorticoid/LABA combination therapy alone. because LABAs and PDE4 inhibitors act on the same signaling pathway (i.e. they increase cAMP synthesis and block cAMP degradation, respectively), they may act synergistically.
F1000Prime Rep. 2015 Feb 3;7:16. 

91. C. Leukotriene modifiers (LTM)
CysLT1 receptor antagonist
montelukast (孟鲁司特)
zafirlukast (扎鲁司特)
5-lipoxygenase inhibitors
zileuton (齐留通)

92. 5-lipoxygenase; LT, leukotriene; PAF, platelet-activating factor.
LTC4, LTD4, LTE4----CysLT1 receptor bronchoconstrictors, increase microvascular permeability, mucus secretion; LTB4----BLT receptor chemoattractant for neutrophils
Effects of cysteinyl-leukotrienes on the airways and their inhibition by anti-leukotrienes. AS, aspirin sensitive; 5-LO,
5-lipoxygenase; LT, leukotriene; PAF, platelet-activating factor.

93. Zafirlukast (Accolate, 扎鲁司特)
C. Leukotriene modifiers (LTM)
Zafirlukast (Accolate, 扎鲁司特)
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.

94. Montelukast (Singulair and Montelo-10, 孟鲁司特)
C. Leukotriene modifiers (LTM)
Montelukast (Singulair and Montelo-10, 孟鲁司特)
it blocks the action of leukotriene D4 (and secondary ligands LTC4 and LTE4) on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it.
reduces the bronchoconstriction
Clinical use: once daily
Asthma：maintenance treatment of asthma and to relieve symptoms of seasonal allergies
exercise induced bronchospasm
allergic rhinitis
urticaria
it is not useful for the treatment of acute asthma attacks.

95. C. Leukotriene modifiers (LTM)
Adverse effects
generic adverse reactions：
gastrointestinal disturbances
Headaches
hypersensitivity reactions
sleep disorders
increased bleeding tendency
Churg–Strauss syndrome
Drowsiness

96. C. Leukotriene modifiers
Zileuton (Zyflo, 齐留通)
an orally active inhibitor of 5-lipoxygenase
Inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation.
Clinical use: taken four times per day
Zileuton is used for the maintenance treatment of asthma.
Adverse effects
sinusitis（鼻窦炎）, nausea , pharyngolaryngeal pain（咽喉疼痛）

97. D. Inhibitors of mediator release
Disodium cromoglycate 色甘酸二钠
( cromolyn ) (色甘酸钠)
Sodium nedocromil
(萘多罗米钠)

98. D. Inhibitors of mediator release
1. Pharmacological effects
Inhibiting mediator release from mast or other cells
Inhibiting sensory neuropeptide release
2. Clinical uses
Prevention of allergic asthma
Acting slowly (2-4 weeks)
3. Adverse effects
Oropharyngeal irritation

99. Cromolyn Inhibits mediator release from mast cells

100. D. Inhibitors of mediator release Sodium nedocromil(萘多罗米钠)
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.

101. Stepwise approach to asthma treatment
2016 GINA pocket Guide

102. 2016 GOLD pocket Guide

103. Expert Opin. Pharmacother. (2014) 15(1):85-96