Drugs for treatment of respiratory diseases Huifang Tang Department of pharmacology Zhejiang...

Drugs for Drugs for treatment of treatment of respiratory respiratory

diseasesdiseasesHuifang Tang

Department of pharmacologyZhejiang University, school of medicine

[email protected] building C422

2012-3-28

mailto:[email protected]

Various Various diseases diseases of of respiratorrespiratory systemy system

Common Common symptoms:symptoms:

coughcough

sputumsputum

wheezingwheezing

Classification of drugs Classification of drugs acting on respiratory acting on respiratory

systemsystem Cough: Ⅰ. Antitussive drugs

Sputum: Ⅱ. Expectorant drugsAsthma: Ⅲ. Antiasthmatic drugs

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

Classification of drugs acting on respiratory system

Central antitussivesCentral antitussives Narcotic drugs: Narcotic drugs: codeine codeine 可待因可待因 pholcodinepholcodine 福尔可定福尔可定 Drotebanol Drotebanol 羟蒂巴酚羟蒂巴酚 Non-Narcotic drugs: Non-Narcotic drugs: dextromethorphan dextromethorphan 右美沙芬右美沙芬 pentoxyverine pentoxyverine 喷托维林喷托维林 (( 咳必清咳必清 ))

Peripheral antitussivesPeripheral antitussives benzonatate benzonatate 苯佐那酯苯佐那酯

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

咳嗽反射示意图

Sensory Sensory nervesnerves

Respiratory Respiratory centercenter

Motor nerves

Centrally acting antitussives

Peripherally acting antitussives

Codeine Codeine 可待因可待因

Narcotic Antitussives Antitussives

O

N CH3

HO

H3CO

1. Pharmacological effects1. Pharmacological effects suppression of cough suppression of cough (1/4 of morphine)(1/4 of morphine)

analgesia analgesia (1/7~1/10 of morphine)(1/7~1/10 of morphine)

2. Clinical uses2. Clinical uses Cough without sputumCough without sputum

3. Adverse effects3. Adverse effects Respiratory depression (at larger doses)Respiratory depression (at larger doses)

AddictionAddiction

Contraindicated in patients with thick Contraindicated in patients with thick sputumsputum


Other narcotic antitussives: Dihydrocodeine （双氢可待因） ; Drotebanol （羟蒂巴酚） ; Pholcodine （福尔可定）


Drotebanol (Oxymethebanol)羟蒂巴酚

A morphinan derivative that acts as an opiod agonist


Drotebanol Pharmacological effectsPharmacological effects

cough suppressant effects : around 10x more potent than codeine.

analgesic effects : several times stronger than codeine, but weaker than morphine

In animal studies it was found to be moderately addictive and produced limited physical dependence, but not as severe as that seen with morphine or pethidine

It was previously marketed for human use under the brand name Metebanyl, although it is now no longer used in medicine.


Pholcodine （福尔可定）Narcotic Antitussives Antitussives

an opioid cough suppressant

Pholcodine Pharmacological effectsPharmacological effects

Its cough suppressant effects is similar with codeine mild sedative effect little or no analgesic effects lower potential for dependence

Mechanism of actionMechanism of action It acts primarily on the central nervous system (CNS), causing depression

of the cough reflex, partly by a direct effect on the cough centre in the medulla.

Side effects Side effects Dizziness Gastrointestinal disturbances such as nausea or vomiting. constipation, drowsiness, excitation, ataxia and respiratory depression ( a

fter large doses) Increased levels of IgE-antibodies, Increase the risk of anaphylaxis to neuromuscular blocking agents used d

uring anaesthesia.


Dextromethorphan(Dextromethorphan( 右美沙芬，右美沙芬， DXDXM)M)

O

N CH3

HO

H3CO

CodeineCodeineDextromethorphanDextromethorphan

Non-NarcoticNon-Narcotic Antitussives

Dextromethorphan Mechanism of action

nonselective serotonin reuptake inhibitor sigma-1 receptor agonist major metabolite dextrorphan( 右啡烷 ) as an NMDA r

eceptor 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.



(1)Pharmacological effects: Depression of coughing center; (2)Clinical uses: Upper respiratory infection and dry co

ugh. (3)Adverse reaction: Atropine-like side effects.

Contraindication: In the patients with glaucoma, pregnancy(< 3 months), psychotic disorders, etc.

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 dextroUses and adverse effects are similar to dextro

methorphanmethorphan


others

Cloperastine （氯哌斯汀） Promolate ( 普罗吗酯 ) Fominoben ( 福米诺苯 ) Zipeprol （齐培丙醇）


Cloperastine （氯哌斯汀）

(1)Pharmacological effects: a mild bronchorelaxant antihistaminic activity acting on the central nervous system or the respiratory c

enter.


Zipeprol （齐培丙醇） A centrally acting cough suppressant developed in 1970

sPharmacological effects: a local anaesthetic mucolytic antihistamine properties anticholinergic properties

Zipeprol has been misused mainly for the hallucinations( 幻觉 )


Levocloperastine Fendizoate （左旋氯哌斯汀 -联苯酰苯酸盐）

an antitussive agent that acts centrally action ： on the bulbar cough center peripherally action ： on the cough receptors in the t

racheobronchial tree. This dual mechanism of action makes levoclope

rastine fendizoate effective in the treatment of cough associated with many chronic and acute conditions in patients of all ages.


Peripheral antitussivesPeripheral antitussives BenzonatateBenzonatate 苯佐那酯苯佐那酯 (( 退嗽退嗽 ))

Blocking Blocking cough reflex cough reflex Local anesthetic effectsLocal anesthetic effects CNS depressionCNS depression Others:Others:

Benproperine(Benproperine( 苯丙哌林苯丙哌林 )) Dropropizine (Dropropizine ( 羟丙哌嗪羟丙哌嗪 )) Noscapine (Noscapine ( 那可汀那可汀 ); moguisteine (); moguisteine ( 莫吉司坦莫吉司坦 )) Prenoxdiazine (Prenoxdiazine ( 普诺地嗪普诺地嗪 )) Dioxopromethazine (Dioxopromethazine ( 二氧丙嗪二氧丙嗪 ))

A. Antitussives

Benproperine （苯丙哌林） It has a peripheral and central action The antitussive activity is comparable to that of

codeine, but is devoid of the undesirable codeine’s side effects

widely used as a cough suppressant for non-productive coughs.

PeripheralPeripheral Antitussives

Levodropropizine （左羟丙哌嗪）

It is the levoisomer of Dropropizine. It acts as a peripheral antitussive, with no action

in the central nervous system. It does not cause side effects such as constipatio

n or respiratory depression which can be produced by opioid antitussives such as codeine and its derivatives.


Narcodine,Noscapine( 那可丁 )

a benzylisoquinoline alkaloid from plants of the Papaveraceae family, without significant painkilling properties.

Noscapine's antitussive mechanism: sigma receptor agonist .

The effects, beginning around 45 to 120 mins after consumption, are similar to dextromethorphan.

Unlike dextromethorphan, noscapine is not an NMDA receptor antagonist


Moguisteine 莫吉司坦

novel peripheral non-narcotic antitussive drug.


B. Mucoactive drugs

Mucous Mucous glycoprotein glycoprotein networknetwork

HydrationHydration::

Sputum Sputum dilutiondilution

MucolysisMucolysis

B. Mucoactive drugs Expectorants Expectorants （（ Stimulating bronchial sStimulating bronchial s

ecretionecretion 痰液稀释药）痰液稀释药） Ammonium chloride Ammonium chloride 氯化铵氯化铵 glyceryl guaiacolate (glyceryl guaiacolate (Guaifenesin Guaifenesin )) 愈创木愈创木酚甘油醚酚甘油醚

Potassium iodide Potassium iodide 碘化钾碘化钾 ipecac syrup ipecac syrup 吐根糖浆吐根糖浆酒石酸锑钾、桔梗、远志等。酒石酸锑钾、桔梗、远志等。

Mucoregulators Mucoregulators Carbocisteine Carbocisteine 羧甲司坦羧甲司坦

B. Mucoactive drugsMucolytic Mucolytic drugs(drugs( 粘痰溶解药粘痰溶解药 )) Bromhexine 溴己新 N-Acetylcysteine 乙酰半胱氨酸 Erdosteine 厄多司坦 Fudosteine 福多司坦 Lifusteine 立氟司坦

Mucokinetics drugsMucokinetics drugs Ambroxol 氨溴索

Ammonium chloride Ammonium chloride 氯化铵氯化铵

irritative action on the bronchial mucosa. This causes the production of excess respiratory tract flu

id which presumably is easier to cough up. Ammonium salts are an irritant to the gastric mucosa an

d may induce nausea and vomiting.

Expectorants

Guaifenesin 愈创木酚甘油醚愈创木酚甘油醚

Effect and mechanism of action increasing the volume and reducing the viscosit

y of secretions in the trachea and bronchi. stimulates the flow of respiratory tract secretion

s, allowing ciliary movement to carry the loosened

secretions upward toward the pharynx increase the efficiency of the cough reflex facilitate removal of the secretions

Expectorants

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 mechanis

ms 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

Mucolytic drugs

Carbocysteine 羧甲司坦

Mucolytic Carbocisteine is produced by alkylation of cystei

ne 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.

Mucoregultor

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 cigaret

te smoke.Clinical use: chronic obstructive lung disease : reduced cough (both frequency and severity) and spu

tum 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.

Mucolytic 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, includin

g chronic inflammatory pulmonary conditions;

Mucokinetic drugs

Ambroxol Side EffectsGastrointestinal Side Effects including diarrhea, heartburn, indigestion, and occasionally nausea

and vomiting.

Allergic Reactions rarely, mainly involve skin rashes, hives and dermatitis, as well as p

ossible swelling.

Intravenous Side Effects Intravenous ambroxol has been associated with chills, intense head

aches, shortness of breath and weakness.

Mucokinetic drugs

Fudosteine ( 福多司坦 )

a cysteine derivative inhibit MUC5AC mucin hypersecretion by r

educing MUC5AC gene expression Iihibition of extracellular signal-relatedI ki

nase 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

Mucoactive drugs

药物药效镇痛解痉成瘾性临床应用可待因 1 + + 剧烈干咳，尤

适用于胸膜炎干咳伴胸痛者

右美沙芬 1 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

常用镇咳药比较表常用镇咳药比较表

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

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

祛痰药作用比较表祛痰药作用比较表

推荐阅读中华医学会呼吸病学分会哮喘学组 2009 年版

咳嗽的诊断与治疗指南

Drugs for treatment of respiratory diseases Huifang Tang Department of pharmacology Zhejiang...

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