Antitussives, expectorants, Antitussives, expectorants, and and

antiasmatic drugsantiasmatic drugs

Ximei WuXimei WuDept. of pharmacology,Dept. of pharmacology,

ZJUMSZJUMS

Drugs acting on respiratory systemDrugs acting on respiratory system

• Cough Cough antitussive drugsantitussive drugs• centrally actingcentrally acting• peripherally actingperipherally acting

• SputumSputum expectorant drugs expectorant drugs• sputum-diluting drugssputum-diluting drugs• mucolytic drugsmucolytic drugs

• AsthmaAsthma antiasthmatic drugs antiasthmatic drugs• bronchial dilatorsbronchial dilators• receptor agonistsreceptor agonists• theophyllinestheophyllines• muscarinic antagonistsmuscarinic antagonists• anti-inflammatory drugsanti-inflammatory drugs• glucocorticosteroidsglucocorticosteroids• mediator release inhibitorsmediator release inhibitors

1.1. AntitussivesAntitussives

• Centrally actingCentrally acting• Addictive drugs: Addictive drugs: • codeine codeine 可待因可待因• Non-addictive drugs: Non-addictive 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 ))

• Peripherally actingPeripherally acting• benzonatate benzonatate 苯佐那酯苯佐那酯

Codeine Codeine 可待因可待因

O

N CH3

HO

H3CO

• 1. 1. Pharmacological effectsPharmacological effects• suppression of coughsuppression of cough

• analgesiaanalgesia

• 2. 2. Clinical usesClinical uses• Cough without sputumCough without sputum

• 3. 3. Adverse effectsAdverse effects• Respiratory depression (at larger doses)Respiratory depression (at larger doses)

• AddictionAddiction• Contraindicated in patients with thick sputumContraindicated in patients with thick sputum

DextromethorphanDextromethorphan 右美沙芬右美沙芬

• 1. 1. Pharmacological effectsPharmacological effects• suppression of coughsuppression of cough• muscarinic and NMDA receptor antagonismmuscarinic and NMDA receptor antagonism

• 2. 2. Clinical usesClinical uses• Upper respiratory infection, cough without Upper respiratory infection, cough without

sputumsputum

• 3. 3. Adverse effectsAdverse effects• Atropine-like side effectsAtropine-like side effects• Contraindicated in patients with glaucoma, Contraindicated in patients with glaucoma,

pregnancy (< 3 m), psychotic disorders, pregnancy (< 3 m), psychotic disorders, etc.etc.

PentoxyverinePentoxyverine

喷托维林喷托维林 ((咳必清咳必清 ))

Pharmacological effectsPharmacological effects

• Suppression of coughSuppression of cough• Muscarinic antagonism and local Muscarinic antagonism and local

anesthetic effectsanesthetic effects• Uses and adverse effects are similar to Uses and adverse effects are similar to

dextromethorphandextromethorphan

BenzonatateBenzonatate

苯佐那酯苯佐那酯

Pharmacological effectsPharmacological effects

• Peripherally actingPeripherally acting• Blocking cough reflex Blocking cough reflex • Local anesthetic effectsLocal anesthetic effects• CNS depressionCNS depression

2.2. ExpectorantsExpectorants

Sputum-diluting drugsSputum-diluting drugs Stimulating bronchial secretionStimulating bronchial secretion Amonium chloride Amonium chloride 氯化铵氯化铵 Potassium iodide Potassium iodide 碘化钾碘化钾

Mucolytic drugsMucolytic drugs Bromhexine Bromhexine 溴己新溴己新 Ambroxol Ambroxol 氨溴索 氨溴索 Acetylcysteine Acetylcysteine 乙酰半胱氨酸乙酰半胱氨酸 Methylcysteine Methylcysteine 美司坦美司坦 Carbocisteine Carbocisteine 羧甲司坦羧甲司坦 Mesna Mesna 美司钠美司钠

3.3. Antiasthmatic Antiasthmatic

drugsdrugs

Asthma

• Asthma is physiologically characterized by increased responsiveness of the trachea and bronchi to various stimuli and by widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy.

• Its pathologic features are contraction of airway smooth muscle, mucosal thickening from edema and cellular infiltration, and inspiration in the airway lumen of abnormally thick, viscid plugs of mucus.

• Symptom: dyspnea, wheezing, stridor, coughing, an inability for physical exertion. The cough may sometimes produce clear sputum.

• Between episodes, most patients feel well but can have mild symptoms and they may remain short of breath after exercise for longer periods of time than the unaffected individual.

Asthma

inflammationinflammation bronchoconstrictionbronchoconstriction

Airway hyperresponsivenessAirway hyperresponsiveness

Immunological andImmunological and

non-immunological stimulinon-immunological stimuli

Wheezing (asthmatic Wheezing (asthmatic symptoms)symptoms)

glucocorticosteroidsglucocorticosteroids

disodium cromoglycate disodium cromoglycate

2 2 receptor agonistsreceptor agonists

TheophyllineTheophylline

muscerinic antagonistsmuscerinic antagonists

Receptor agonistsReceptor agonists Non-selectiveNon-selective ：： adrenaline, isoprotereroladrenaline, isoprotererol 22-selective: -selective: moderate-acting:moderate-acting: salbutamol, terbutalinesalbutamol, terbutaline long-acting:long-acting: salmeterol, formoterolsalmeterol, formoterol

Theophyllines:Theophyllines: aminophyllineaminophylline

Muscarinic antagonists:Muscarinic antagonists: ipratropine ipratropine

1. Bronchial dilators1. Bronchial dilators

Glucocorticosteroids:Glucocorticosteroids: Systemic: Systemic: hydrocortisone, dexamethasonehydrocortisone, dexamethasone Inhalation: Inhalation: beclomethasone, budesonidebeclomethasone, budesonide

Inhibitors of mediator release: Inhibitors of mediator release: cromolyn sodium, nedocromilcromolyn sodium, nedocromil

2. Anti-inflammatory drugs2. Anti-inflammatory drugs

Bronchial dilatorsBronchial dilators 22 receptor selective agonists receptor selective agonists

SalbuterolSalbuterol

沙丁胺醇沙丁胺醇

TerbutalineTerbutaline

特布他林特布他林

1. 1. Pharmacological effectsPharmacological effects Relaxing bronchial smooth musclesRelaxing bronchial smooth muscles

2. 2. Clinical usesClinical uses Controlling asthmatic symptomsControlling asthmatic symptoms Given by Given by inhalationinhalation, oral or injection, oral or injection

3. 3. Adverse effectsAdverse effects Skeletal muscle tremorSkeletal muscle tremor Cardiac stimulation (larger doses)Cardiac stimulation (larger doses) Dysfunction of metabolism (hypokalemia, etc.)Dysfunction of metabolism (hypokalemia, etc.)

Salbuterol Salbuterol 沙丁胺醇沙丁胺醇

Selectivity of Selectivity of 22 agonistsagonists

Aerosol Aerosol inhalationinhalation

less systemic toxicity

Spacer used for aerosol inhalationSpacer used for aerosol inhalation

定量手控定量手控

气雾器气雾器

Spacer will aid patients Spacer will aid patients inhale the aerosolized inhale the aerosolized drugs easierdrugs easier

22 receptor selective agonists receptor selective agonists

long-actinglong-acting

SalmeterolSalmeterol

FormoterolFormoterol

TheophyllinesTheophyllines

AminophyllineAminophylline

N

N N

NH3C H

CH2NH2

2H2OCH2NH2

O

O

CH3--

--

--

--

2

. .

Bronchial dilatorsBronchial dilators

1. 1. Pharmacological effectsPharmacological effectsBronchus dilationBronchus dilation

Inhibiting phosphodiesterase; Inhibiting phosphodiesterase;

Blocking adenosine receptors;Blocking adenosine receptors;

Increasing catecholamine release;Increasing catecholamine release;

Immunomodulation;Immunomodulation;

Increasing respiratory muscle contractility;Increasing respiratory muscle contractility;

CNS stimulation, diuretic, gastric acid CNS stimulation, diuretic, gastric acid secretion, etc.secretion, etc.

TheophyllinesTheophyllines

2. 2. Clinical usesClinical uses Bronchial asthma (Bronchial asthma (p.o.p.o., , i.v.i.v.)) Others: Others: acute pulmonary edema, acute pulmonary edema, etc.etc.

3. 3. Adverse effectsAdverse effects GI reactionsGI reactions CNS stimulationCNS stimulation Acute toxication ( Acute toxication ( i.vi.v. injection too rapidly ). injection too rapidly )

tachycarida, arrhythmia, seizure, coma, deathtachycarida, arrhythmia, seizure, coma, death

TheophyllinesTheophyllines

Muscarinic antagonistsMuscarinic antagonists

IpratropineIpratropine

O

C

CH2

CH2 CH2

C6H5CHOCH

CH3

CH3

CH

NCH3

CH

OH

(CH3)2CH

Bronchial dilatorsBronchial dilators

• Relaxing bronchial smooth musclesRelaxing bronchial smooth muscles

• No effect on sputum secretionNo effect on sputum secretion

• Replaced with or combined with Replaced with or combined with 2 2 receptor selective agonistsreceptor selective agonists

Systemic (adverse effect):Systemic (adverse effect): hydrocortisonehydrocortisone prednisoneprednisone dexamethasonedexamethasone Inhalation:Inhalation: beclomethasone dipropionatebeclomethasone dipropionate budesonidebudesonide triamcinolone acetonide triamcinolone acetonide fluticasone propionate fluticasone propionate flunisolideflunisolide

Glucocorticosteroids Glucocorticosteroids

Beclomethasone dipropionateBeclomethasone dipropionate

O

HO

Cl

CH3

OCOC2H5

C O

CH2OCOC2H5

1. 1. Pharmacological effects Pharmacological effects ((Antiinflammation)Antiinflammation) Inhibiting inflammatory cell activities, Inhibiting inflammatory cell activities, Antibody production, mediator release, Antibody production, mediator release, Inhibit increased responsiveness of the trachea and Inhibit increased responsiveness of the trachea and

bronchibronchi

2. 2. Clinical usesClinical uses As first-line drugs, currentlyAs first-line drugs, currently Controlling chronic symptomsControlling chronic symptoms Ineffective for acute symptomsIneffective for acute symptoms

Beclomethasone dipropionateBeclomethasone dipropionate

Adverse effectsAdverse effects• Local:Local: oropharyngeal candidiasisoropharyngeal candidiasis －－ using spacerusing spacer

• Systemic effects Systemic effects • a) Hypercorticism-like syndrome: central obesity a) Hypercorticism-like syndrome: central obesity (moon face, buffalo hump, etc.); hypertension; (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; glycosuria, hypokalemia; etcetc..• b) Increasing susceptibility to infectionsb) Increasing susceptibility to infections• c) Ingestive system: peptic ulcers, c) Ingestive system: peptic ulcers, etcetc..• d) Cardiovascular system: hypertension, d) Cardiovascular system: hypertension, arteriosclerosisarteriosclerosis• e) Myopathy and osteoporosis: vertebral e) Myopathy and osteoporosis: vertebral compression fractures, spontaneous fractures, compression fractures, spontaneous fractures, especially in postmenopausal womenespecially in postmenopausal women• f) Adrenal suppressionf) Adrenal suppression

Inhibitors of mediator releaseInhibitors of mediator release

O ONaOOC COONa

OCH2CHCH2O

OH

O O

Disodium cromoglycateDisodium cromoglycate ( cromolyn )( cromolyn )

1. 1. Pharmacological effectsPharmacological effects Inhibiting mediator release from mast or other cellsInhibiting mediator release from mast or other cells Inhibiting sensory neuropeptide release and non-Inhibiting sensory neuropeptide release and non-

specific stimulus induced bronchus contractionspecific stimulus induced bronchus contraction

2. 2. Clinical uses (only inhalation)Clinical uses (only inhalation) Prevention of allergic asthmaPrevention of allergic asthma Acting slowly (2-4 weeks)Acting slowly (2-4 weeks)

3. 3. Adverse effectsAdverse effects Oropharyngeal irritationOropharyngeal irritation

Disodium cromoglycateDisodium cromoglycate

Other inhibitors of mediator releaseOther inhibitors of mediator release

• Nedocromil sodium: GI effectNedocromil sodium: GI effect

• TranilastTranilast

• KetotifenKetotifen (H(H11 receptor antagonist) receptor antagonist)

Leukotriene pathway inhibitors

• Airways

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

LTB4----chemoattractant for neutrophils

• Leukotriene pathway inhibitors

CysLT1 receptor antagonist (zafirlukast):

for mild or moderate asthma, but not use alone

for acute asthma

5-LOX inhibitor (zileuton)