Antitussives, expectorants, and antiasmatic drugs Ximei Wu Dept. of pharmacology, ZJUMS

Drugs acting on respiratory system Cough antitussive drugs centrally acting peripherally acting Sputum expectorant drugs sputum-diluting drugs mucolytic drugs Asthma antiasthmatic drugs bronchial dilators  receptor agonists theophyllines muscarinic antagonists anti-inflammatory drugs glucocorticosteroids mediator release inhibitors

1. Antitussives

Centrally acting Peripherally acting Addictive drugs: codeine 可待因 Non-addictive drugs: dextromethorphan 右美沙芬 pentoxyverine 喷托维林(咳必清) Peripherally acting benzonatate 苯佐那酯

Codeine 可待因

1. Pharmacological effects suppression of cough analgesia 2. Clinical uses Cough without sputum 3. Adverse effects Respiratory depression (at larger doses) Addiction Contraindicated in patients with thick sputum

Dextromethorphan 右美沙芬

1. Pharmacological effects suppression of cough muscarinic and NMDA receptor antagonism 2. Clinical uses Upper respiratory infection, cough without sputum 3. Adverse effects Atropine-like side effects Contraindicated in patients with glaucoma, pregnancy (< 3 m), psychotic disorders, etc.

Pentoxyverine 喷托维林(咳必清)

Pharmacological effects Suppression of cough Muscarinic antagonism and local anesthetic effects Uses and adverse effects are similar to dextromethorphan

Benzonatate 苯佐那酯

Pharmacological effects Peripherally acting Blocking cough reflex Local anesthetic effects CNS depression

2. Expectorants

Sputum-diluting drugs Stimulating bronchial secretion Amonium chloride 氯化铵 Potassium iodide 碘化钾 Mucolytic drugs Bromhexine 溴己新 Ambroxol 氨溴索 Acetylcysteine 乙酰半胱氨酸 Methylcysteine 美司坦 Carbocisteine 羧甲司坦 Mesna 美司钠

3. Antiasthmatic drugs

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.

Asthma 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.

non-immunological stimuli Wheezing (asthmatic symptoms) Immunological and non-immunological stimuli inflammation bronchoconstriction 2 receptor agonists Theophylline muscerinic antagonists glucocorticosteroids disodium cromoglycate Airway hyperresponsiveness Wheezing (asthmatic symptoms)

1. Bronchial dilators  Receptor agonists Theophyllines: aminophylline Non-selective：adrenaline, isoprotererol 2-selective: moderate-acting: salbutamol, terbutaline long-acting: salmeterol, formoterol Theophyllines: aminophylline Muscarinic antagonists: ipratropine

2. Anti-inflammatory drugs Glucocorticosteroids: Systemic: hydrocortisone, dexamethasone Inhalation: beclomethasone, budesonide Inhibitors of mediator release: cromolyn sodium, nedocromil

Bronchial dilators Salbuterol 沙丁胺醇 Terbutaline 特布他林 2 receptor selective agonists Salbuterol 沙丁胺醇 Terbutaline 特布他林

Salbuterol 沙丁胺醇 1. Pharmacological effects Relaxing bronchial smooth muscles 2. Clinical uses Controlling asthmatic symptoms Given by inhalation, oral or injection 3. Adverse effects Skeletal muscle tremor Cardiac stimulation (larger doses) Dysfunction of metabolism (hypokalemia, etc.)

Selectivity of 2 agonists

Aerosol inhalation less systemic toxicity

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

Spacer will aid patients inhale the aerosolized drugs easier

2 receptor selective agonists long-acting Formoterol Salmeterol

Bronchial dilators Theophyllines Aminophylline

Theophyllines 1. Pharmacological effects Bronchus dilation Inhibiting phosphodiesterase; Blocking adenosine receptors; Increasing catecholamine release; Immunomodulation; Increasing respiratory muscle contractility; CNS stimulation, diuretic, gastric acid secretion, etc.

Theophyllines 2. Clinical uses 3. Adverse effects Bronchial asthma (p.o., i.v.) Others: acute pulmonary edema, etc. 3. Adverse effects GI reactions CNS stimulation Acute toxication ( i.v. injection too rapidly ) tachycarida, arrhythmia, seizure, coma, death

Muscarinic antagonists Bronchial dilators Muscarinic antagonists Ipratropine

Relaxing bronchial smooth muscles No effect on sputum secretion Replaced with or combined with 2 receptor selective agonists

Glucocorticosteroids Systemic (adverse effect): hydrocortisone prednisone dexamethasone Inhalation: beclomethasone dipropionate budesonide triamcinolone acetonide fluticasone propionate flunisolide

Beclomethasone dipropionate

Beclomethasone dipropionate 1. Pharmacological effects (Antiinflammation) Inhibiting inflammatory cell activities, Antibody production, mediator release, Inhibit increased responsiveness of the trachea and bronchi 2. Clinical uses As first-line drugs, currently Controlling chronic symptoms Ineffective for acute symptoms

Adverse effects Systemic effects Local: oropharyngeal candidiasis－using spacer Systemic effects a) Hypercorticism-like syndrome: central obesity (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; etc. b) Increasing susceptibility to infections c) Ingestive system: peptic ulcers, etc. d) Cardiovascular system: hypertension, arteriosclerosis e) Myopathy and osteoporosis: vertebral compression fractures, spontaneous fractures, especially in postmenopausal women f) Adrenal suppression

Disodium cromoglycate ( cromolyn ) Inhibitors of mediator release Disodium cromoglycate ( cromolyn )

Disodium cromoglycate 1. Pharmacological effects Inhibiting mediator release from mast or other cells Inhibiting sensory neuropeptide release and non-specific stimulus induced bronchus contraction 2. Clinical uses (only inhalation) Prevention of allergic asthma Acting slowly (2-4 weeks) 3. Adverse effects Oropharyngeal irritation

Other inhibitors of mediator release Nedocromil sodium: GI effect Tranilast Ketotifen (H1 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)