Download 呼吸系统用药(汤慧芳2015V2)

Drugs for treatment of
respiratory diseases
Huifang Tang
Department of pharmacology
Zhejiang University, school of
medicine
[email protected]
Research building C422
Various
diseases of
respiratory
system
Common
symptoms:
cough
sputum
wheezing
Classification of drugs acting on
respiratory system
Ⅰ. Antitussive drugs:
1. Centrally acting: Codeine
2. Peripherally acting: Benzonatate
Ⅱ. Expectorant drugs:
1. Sputum-diluting drugs: NH4Cl、KI
2. Mucolytic drugs: Ambroxol
Ⅲ. Antiasthmatic drugs:
1. Bronchial dilators
(1) receptor agonists: Salbuterol
(2)theophyllines: Aminophylline
(3)muscarinic antagonists: Ipratropine
2. Anti-inflammatory drugs
(1)glucocorticosteroids: Budesonide
(2)mediator release inhibitors:
Disodium cromoglycate
A. Antitussives
物理、
化学
刺激
感受器（刺激感受器、牵张感
受器等）
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）
咳嗽反射示意图
咳嗽反射
Respiratory center
Centrally acting
antitussives
Sensory nerves
Motor nerves
Peripherally acting
antitussives
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
Narcotic Antitussives
Codeine
Clinical use:
可待因
Severe cough without sputum, such as cough induced by tumor,
pleurisy(胸膜炎) with pain
Narcotic Antitussives
Name
morphine
cough suppressant
effects
4
analgesic
effects
dependence
10
10
Codeine (可待因)
1
1
1
Dihydrocodeine
(双氢可待因)
1.5
1.5
0
Drotebanol（羟蒂巴酚）
10
<10
Pholcodine（福尔可定）
Clinical use:
Severe cough without sputum
0
less
Non-Narcotic Antitussives
Dextromethorphan(右美沙芬， DXM)
H3CO
O
N
HO
Dextromethorphan
Codeine
CH 3
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.
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.
Non-Narcotic Antitussives
Pentoxyverine(喷托维林, 咳必清)
(1)Pharmacological effects:
Depression of coughing center,
Local anesthetic effects, and
Muscarinic antagonism.
(2)Clinical uses:
Upper respiratory infection,
Cough without sputum.
(3)Adverse reaction:
Atropine-like side effects.
• Uses and adverse effects are similar to
dextromethorphan
Others
Non-Narcotic Antitussives
Pharmacological effects
Cloperastine
（氯哌斯汀）
Promolate（普
罗吗酯）
Fominoben
（福米诺苯）
Zipeprol
(齐培丙醇）
Side effects
a mild bronchorelaxant
antihistaminic activity
acting on the central nervous system
or the respiratory center
Sedative effect
bronchorelaxant effect
Depression of coughing center
Depression of coughing center
Act on respiratory center
a local anaesthetic
mucolytic
antihistamine properties
anticholinergic properties
hallucinations
(幻觉)
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)
Peripheral Antitussives
Pharmacological effects
antitussive
activity
side effects
1
constipation or
respiratory
depression
Codein
central action
Benproperine
（苯丙哌林）
peripheral and central action 1
Levodropropizine
（左羟丙哌嗪）
a peripheral action, without
action in the central nervous
system
sigma receptor agonist
similar to dextromethorphan
Narcodine
(那可丁)
Moguisteine
(莫吉司坦)
novel peripheral action
less
less
常用镇咳药比较表
药物
药效 镇痛 解痉 成瘾性
可待因
1
右美沙芬
1
喷托维林
1/3
+
+
临床应用
剧烈干咳，尤适
用于胸膜炎干咳
伴胸痛者
干咳
+
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
B. Mucoactive drugs
Hydration:
Sputum
dilution
Mucolysis
Mucous glycoprotein
network
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。
B. Mucoactive drugs
Mucolytic drugs(粘痰溶解药)





N-Acetylcysteine 乙酰半胱氨酸
Carbocisteine 羧甲司坦
Erdosteine 厄多司坦
Fudosteine 福多司坦
Lifusteine 立氟司坦
Mucokinetics drugs（痰液调节药）
 Bromhexine 溴己新
 Ambroxol 氨溴索
Expectorants
Ammonium chloride 氯化铵
• 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.
Expectorants
Guaifenesin 愈创木酚甘油醚
• 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
Mucolytic drugs
Bromhexine 溴己新
• 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.
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
Mucolytic drugs
N-Acetylcysteine
N乙酰半胱氨酸,NAC
• a derivative of cysteine;
• 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:
– Prevention of radiocontrast-induced nephropathy -Nephroprotective agent
Mucoregultor
Carbocysteine 羧甲司坦
• Mucolytic
• 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.
Mucolytic drugs
Erdosteine 厄多司坦
• it is a thiol derivative.
Action
• Mucolytic
• 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.
Mucokinetic drugs
Ambroxol ( 氨溴索,沐舒坦)
• 全肺动力型排痰剂
• a mucoactive drug with several properties including
•
– secretolytic and secretomotoric actions that restore the physiological
clearance mechanisms of the respiratory tract
– It stimulates synthesis and release of surfactant by type II
pneumocytes.
– It 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;
Mucokinetic drugs
Ambroxol Side Effects
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.
Mucoactive drugs
Fudosteine (福多司坦)
• 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.
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
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
口服
痰液粘稠难于咳
出
雾化吸入
粘痰阻塞气道
乙 酰 半 胱 氨 裂解粘蛋白
酸
气管滴入
Bronchodilators
(支气管扩张药)
Drugs acting on respiratory system
Cough
antitussive drugs
centrally acting
peripherally acting
Sputum expectorant drugs
sputum-diluting drugs
mucolytic drugs
Asthma antiasthmatic drugs
Bronchodilators
 receptor agonists
theophyllines
muscarinic antagonists
Anti-inflammatory drugs
glucocorticosteroids
mediator release inhibitors
Antiasthmatic drugs
Immunological and non-immunological stimuli
Airway inflammation
bronchoconstriction
glucocorticosteroids
2 receptor agonists
Disodium
cromoglycate
Muscerinic antagonists
Leukotriene
modifiers
Theophylline
Airway hyperresponsiveness
Wheezing (asthmatic symptoms)
Bronchodilators
  Receptor agonists


Non-selective：adrenaline, isoprenaline
2-selective: salbutamol, terbutaline,
salmeterol, formoterol
 Theophyllines: aminophylline
 Muscarinic antagonists: ipratropium bromide
 receptor agonists
non-selectivity
去甲肾上腺素
肾上腺素
异丙肾上腺素

沙丁胺醇
福莫特罗
2 receptor selective agonists
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)
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-610355
• 7. AZD3199.
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
Dysfunction of metabolism (ketoacidosis,raises blood sugar levels,
elevated blood levels of fatty acids and glyceroletc.)
mild appetite suppression, headache, nausea, and sleep disturbances
Side effect
• Increased heart rate and palpitations
• they should be used with caution in patients with
hyperthyroidism or cardiovascular disease (arrhythmias,
hypertension, QT-interval prolongation)
• transient decrease in partial pressure of oxygen in
arterial blood (PaO2) despite concomitant
bronchodilation.
• used with caution in patients with diabetes because of
the risk of ketoacidosis.
• 2-AR stimulation in the liver induces glycogenolysis and
therefore raises blood sugar levels
Selectivity of 2 agonists
Bronchial dilators
2 receptor selective agonists：
Long-acting 2 receptor agonists (LABA)
Formoterol
Salmeterol
福莫特罗
沙美特罗
Bronchial dilators
 Theophyllines
Aminophylline
--
--
O
H3C
N
O
--
.
NH
N
CH3
氨茶碱
CH2NH2
. 2H2O
CH2NH2
N
-- 2
Theophyllines:
One type of xanthine derivatives (甲基黄嘌呤类衍生物)
 Theophyllines history
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.
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;
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.
Muscarinic antagonists
Presynaptic mediator involved in ACh release (neurojunctional plaque).
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
1.Glycopyrronium bromide （格隆溴铵）
2. Aclidinium bromide （阿地溴铵）
3. Other muscarinic acetylcholine receptor antagonists under
development.
 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.
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.
Long-acting Muscarinic
antagonists(LAMA)
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.
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. Beta2adrenergic receptor agonists bind to beta2-adrenergic receptor and induce a
cascade of signal transduction events that ultimately lead to smooth muscle
relaxation.
Novel class of Brochodilators
Aerosol
inhalation
定量手控
气雾器
Spacer used for aerosol inhalation
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
Drugs for treatment
of respiratory
diseases
Huifang Tang
Department of pharmacology
Zhejiang University, school of medicine
[email protected]
Antiasthmatic drugs
Immunological and non-immunological
stimuli
Airway inflammation
bronchoconstriction
glucocorticosteroids
2 receptor agonists
disodium cromoglycate
theophylline
leukotriene modifiers
muscerinic antagonists
Airway hyperresponsiveness
Wheezing (asthmatic
symptoms)
Antiasthmatic drugs
Airway pathological changes in pathogenesis of bronchial asthma
 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)
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
A. Glucocorticoid drugs
 1. Pharmacological effects











Mechanisms of glucocorticoid actions
(1) Effects on metabolisms
(2) Permissive action
(3) Anti-inflammatory effects
(4) Effects on immune and allergy
(5) Anti-shock
(6) Other effects
antipyretic effects
effects on blood and blood-forming organs
skeletal system
CNS effects
A. Glucocorticoid drugs
 Anti-inflammatory effects
 Acute: inhibiting microvascular leakage

leukocyte infiltration
 Chronic: inhibiting fibroblast proliferation

deposition of collagen

cicatrization (瘢痕形成)
• Mechanism of anti-inflammatory action of
corticosteroids in asthma.
Action mode of
glucocorticoid drugs
CBG: corticosteroid binding
globulin
S: glucocorticoid steroids
GR: glucocorticoid receptor
HSP: heat shock protein
IP: immunophilin
GRE: glucocorticoidresponse element
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
Non-genomic mechanisms of action of
glucocorticoids.
C. Boardman et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 129e143
• Effect of corticosteroids on inflammatory and structural cells
in the airways.
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.)
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
– 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
2017/5/23
Antiasthmatic drugs
Chemical structure of 4 kinds
inhalation glucocorticosteroids
二丙酸倍氯米松
(BDP)
HO
CH2OCOC2H5
C=O
OCOC2H5
CH3
布地奈德
(BUD)
CH2OH
C=O
HO
O
H
C
C3H7
O
Cl
O
O
H
丙酸氟替卡松
(FP)
HO
H
SCH2F
糠酸莫米他松
Cl
(MF)
C=O
OCOC2H5
CH3
HO
Cl
F
O
O
F
O
C=O
O CCH3
Receptor-binding affinity of inhaled
corticosteroids to the glucocorticoid receptor
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
布地奈德肺内酯化作用
O
=
-C-(CH2)nCH3
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
Atp,adenosine triphosphate;CoA,coenzyme A.
Tunek A et al.Drug Metob Dispos 1997;25:1311-1317;Miller-Larsson A et al.Drug Metab Dispos 1998;26:623-630.
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
高
中等/低
脂溶性
中等/高
高
低
分布容积(L)
183
318
20
气道滞留率
最高
高
低
经口吸收药物的首
过清除
高
较高
低
半衰期
2.8h
14.4h
0.1h
全身效应
低
中等
高
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.
Interaction with β2-adrenergic receptors
Clinical Reviews in Allergy & Immunology, 2006:231
Interactions and effects on gene expression that may occur between long-acting
b2-adrenoceptor agonists, or other cAMP-elevating agents, and glucocorticoids
4.Adverse effects
Adverse effects of
glucocorticoid drugs:
Effects resulting from
continued used of large
doses
B. PDE4 inhibitors
Roflumilast (罗氟司特)
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.
B. PDE4 inhibitors
Klaus F. Rabe, BJP,2011
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.
C. Leukotriene modifiers (LTM)
• CysLT1 receptor antagonist
– montelukast (孟鲁司特)
– zafirlukast (扎鲁司特)
• 5-lipoxygenase inhibitors
– zileuton (齐留通)
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.
C. Leukotriene modifiers (LTM)
Zafirlukast (Accolate, 扎鲁司特)
• an oral LTRA
• Reducing constriction of the airways and buildup 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 longacting bronchodilator.
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.
C. Leukotriene modifiers (LTM)
Adverse effects
• generic adverse reactions：
–
–
–
–
–
gastrointestinal disturbances
Headaches
hypersensitivity reactions
sleep disorders
increased bleeding tendency
• Churg–Strauss syndrome
• Drowsiness
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）
D. Inhibitors of mediator release
Disodium cromoglycate 色甘酸二钠
( cromolyn )
(色甘酸钠)
Sodium nedocromil
(萘多罗米钠)
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
Cromolyn Inhibits mediator
release from mast cells
D. Inhibitors of mediator release
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.
GINA stepwise approach for managing asthma in patients ≥ 5 years of age
with persistent mild or moderate disease, focus on step 3
World Allergy Organ J. 2010 Feb; 3(2): 16–22.
Expert Opin. Pharmacother. (2014) 15(1):85-96
Reference
Pharmacology and therapeutics of bronchodilators.
Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacol
Rev. 2012 Jul;64(3):450-504. doi: 10.1124/pr.111.004580. Review.