Drugs Affecting the Respiratory System anjie Institute of Pharmacology, School of Medicine, Shandong University

introduction Cough, sputum and Asthma are main symptoms in respiratory systemic diseases. So we are going to learn agents used in therapy of Cough, sputum and Asthma..

Antiasthmatic drugs

Asthma Asthma Asthma is a chronic inflammatory pulmonary disorder that is characterized by reversible obstruction of the airways. Asthma affects 4 to 5% of the whole population.

recurrent dyspnea Shortness of breath Coughing Chest tightness Whistling Whistling Asthma SYMPTOMS

Asthma Most people have a mild form of the disease, with symptoms occurring only occasionally.( e.g, on exposure to allergens or certain pollutants, on exercise, or after a viral infection.)

Allergens –molds, dust mites, cockroaches, animal dander, pollens, foods Irritants –secondhand smoke, strong odors, aerosols, volatile organic compounds, ozone, particulate matter Other –Viral respiratory infections –Changes in weather (cold air, wind, humidity) –Exercise –Medication –Endocrine factors (menstrual period, pregnancy, thyroid disease) Common asthma Triggers * 5 major indoor asthma triggers

Pathogenesis of asthma 1.allergic reaction ( Ⅰ -type) : mediate d by IgE antibodies. mediate d by IgE antibodies.Symptoms: (1)mediators (HA, PGs) release (1)mediators (HA, PGs) release (2)broncho-constriction (2)broncho-constriction (3)vascular leakage. (3)vascular leakage.

Pathogenesis of asthma 2.inflammation of airway mucosa: nonspecific bronchial hyper-reactivity to some stimuli (eg. allergen inhalation, to some stimuli (eg. allergen inhalation, or infection with virus.) or infection with virus.) Neural mechanism:

Treatment of asthma Treatment should be directed toward reduction of inflammation, as well as to management of bronchoconstriction.

ClassificationBranchodilator 1.  2 – adrenoceptor agonists : salbutamol 1.  2 – adrenoceptor agonists : salbutamol 2.Theophylline : aminophylline 2.Theophylline : aminophylline 3.M – Receptor blockers: ipratropine 3.M – Receptor blockers: ipratropine Anti-inflamation agents 1.Glucocorticoids:beclomethasone 1.Glucocorticoids:beclomethasone 2.inhibitors of leukotirenes(LTs) 2.inhibitors of leukotirenes(LTs) Anti-hypersensitive agents 1. inhibitors of mediator release : cromolyn sodium 1. inhibitors of mediator release : cromolyn sodium

means of administration means of administration Drugs can be delivered to the lungs by inhalation, oral, or injection. Inhalation is often preferred because the drug is delivered directly to the target tissue and is effective in doses that do not cause significant systemic side effects.

Antiasthmatic Drugs The drugs most commonly used drugs for management of asthma are adrenoceptor agonists (used as “relievers” or broncho- dilators ) and inhaled corticosteroids (used as “controllers” or anti-inflamatory agents) The drugs most commonly used drugs for management of asthma are adrenoceptor agonists (used as “relievers” or broncho- dilators ) and inhaled corticosteroids (used as “controllers” or anti-inflamatory agents)

Bronchodilators Bronchodilators The major drugs used to treat bronchospasm are the The major drugs used to treat bronchospasm are the β 2 - adrenoceptor agonists and the theophylline.

adrenoline receptor agonists adrenoline receptor agonists

adrenaline pharmacological actions: AD is a nonselective adrenoceptor agonist which can activate all of the α, β-receptors nonselectively.

★ mechanism of anti-asthma actions 1. activate β2-R → ↑AC→↑cAMP→↑PKA →↓Ca2+ →relaxation of airway smooth muscle 2. activate α-R→vascular constriction of bronchial mucosa→edema lightened →airflow improved 3. inhibit mast cell degranulation →release of alergic mediators decreased

clinical use: S.C(subcutanous) : acute attacks of asthma side effects: stimulatesβ 1 as well asβ 2 receptors, can result in cardiac adverse reactions (eg. tachycardia, arrhythmias) can result in cardiac adverse reactions (eg. tachycardia, arrhythmias)

Ephedrine ★ characteristics (VS AD): slow onset; moderate effect; long duration; vasoconstriction and CNS excitation. slow onset; moderate effect; long duration; vasoconstriction and CNS excitation. ★ clinical use The oldest agents used to treat asthma, and can be used in prevention and treatment of mild asthma.

Isoprenaline (Isop) was introduced in the 1940s as a pure β- agonist. was introduced in the 1940s as a pure β- agonist. ★ anti-asthmatic action: ★ anti-asthmatic action: potent, quick-onset potent, quick-onset used in acute asthma used in acute asthma ★ severe toxicity on heart: ★ severe toxicity on heart: arrythmia arrythmia

Selectiveβ 2 - R agonists The most widely used adrenoceptor agonist for the treatment of asthma at the present time. They are effective after inhaled or oral administration and have a long duration of action and significant β 2 selectivity.

Selectiveβ 2 - R agonists Salbutamol( 沙丁胺醇 ), p.o. ＆ inhale ， ivd Clenbuterol( 克伦特罗）, potent effect Terbutaline ( 特布他林 ) p.o. ＆ s.c. long duration formaterol( 福莫特罗 ), sameterol( 沙美特罗 ) : long duration, also inhibit release of inflammatory mediator. Mainly used in chronic asthma and Chronic obstructive lung disease. long duration, also inhibit release of inflammatory mediator. Mainly used in chronic asthma and Chronic obstructive lung disease. Bambuterol( 班布特罗 ) P.O.

Selectiveβ 2 - R agonists Clinical use acute attacks of asthma. acute attacks of asthma. interact with inhaled corticosteroids to improve asthma control. Adverse effects: cardiac reaction cardiac reaction skeletal muscle tremor (β 2 - R) skeletal muscle tremor (β 2 - R) metabolic disorder metabolic disorder

Theophylline aminophylline( 氨茶碱 ), choline theophylline( 胆茶碱 ), glyphylline( 甘油茶碱, 喘定 )

※ Effects: relaxation of smooth muscle cardiac stimulation CNS stimulation Excitation of skeletal muscle diuresis

※ Mechanism 1) ↓PDE ( phosphodiesterase ) 1) ↓PDE ( phosphodiesterase ) 2) ↑Release of CA (catecholamine) 2) ↑Release of CA (catecholamine) 3) Block adenosine 3) Block adenosine (a bronchoconstrictor) (a bronchoconstrictor) 4) Anti-inflammatory effect 4) Anti-inflammatory effect

Therapeutic uses Chronic asthma Chronic obstructive lung disease

Theophylline ※ adverse reactions: gastrointestinal distress gastrointestinal distress CNS stimulation CNS stimulation Cardiovescular reaction: arrythmia, ↓ BP Acute nephridial failure

3. M-receptor blocker : ipratropium( 异丙阿托品 ) Slow onset Slow onset Oxitropium ( 氧托品 ) Tiotropium ( 泰乌托品 ) ： potent effect, long duation potent effect, long duation

Anti-inflammatory steroids Glucocorticoids Most effective anti-inflamatory drugs Used in continuous and severe asthma attack

Glucocorticoids Effect : Effect : effective in improving all index of asthma control and can improve quality of life. effective in improving all index of asthma control and can improve quality of life. (1) reduce bronchial reactivity; (1) reduce bronchial reactivity; (2) increase airway caliber; (2) increase airway caliber; (3) reduce the frequency of asthma ecurrence (3) reduce the frequency of asthma ecurrence

Mechanisms:  1) reduce microvascular leakage.  2) inhibit influx of inflammatory cells into the lungs.  3) inhibit of production of inflammatory cytokines.  4) increase the effect of β-R agonists

Beclomethasone （倍氯米松） Characteristics: 1) inhaled: potent local anti-inflammatory action (500 times than Dex). 1) inhaled: potent local anti-inflammatory action (500 times than Dex). 2)far fewer systemic adverse reaction 2)far fewer systemic adverse reaction 3) slow onset, used in prevention of attack of moderate or severe asthma 3) slow onset, used in prevention of attack of moderate or severe asthma flunisolide( 氟尼缩松 ), flunisolide( 氟尼缩松 ), budesonide( 布地萘德，布的松 )

leukotrienes (LTs) pathway inhibitors LTs: LTC4 and LTD4:  inflimatory reaction  increased bronchial reactivity  mucosal edema  mucus hypersecretion

 two approaches : 1) inhibition of 5-lipoxygenase: zileuton ( 齐留通 ) 1) inhibition of 5-lipoxygenase: zileuton ( 齐留通 ) 2) LTD 4 -receptor antagonists: 2) LTD 4 -receptor antagonists: zafirlukast( 扎鲁司特 ), zafirlukast( 扎鲁司特 ), montelukast( 孟鲁司特 ) montelukast( 孟鲁司特 )  Principle advantage can be taken orally can be taken orally  Clinical use : all kinds of asthma, especially aspirin-induced asthma. aspirin-induced asthma.

Drugs stabilizing cellular membrane

☆ Sodium cromoglycate Mechanism of action: stabilizing cellular membrane stabilizing cellular membrane 1)on mast cell: inhibits the early response to antigen challenge. 1)on mast cell: inhibits the early response to antigen challenge. 2) on eosinophils: inhibit the inflammatory response to inhalation of allergens. 2) on eosinophils: inhibit the inflammatory response to inhalation of allergens. 3) inhibit sensory nerve endings 3) inhibit sensory nerve endings

Clinical use: pretreatment of asthma caused by antigen inhalation, by exercise, by aspirin, etc. administrated shortly before exercise or before unavoidable exposure to an allergen. Adverse reactions: throat irritation

Nadocrimil sodium( 奈多罗米钠 ) Ketotifen( 酮替芬 )

Antitussives

Overview Coughing is a protective mechanism through which foreign materials and secretions are cleared from the respiratory tract. But severe and prolonged coughing can But severe and prolonged coughing can be painful and exhausting. be painful and exhausting.

Overiew Some drugs act at one or more sites within the respiratory tract; others act at the cough center to inhibit activation of the efferent limb of the response.

Classification Ⅰ Central antitussives ⅰ Dependence : Codeine （可待因）, ⅰ Dependence : Codeine （可待因）, Dihydrocodeine （二氢可待因 ） ⅱ Nondependence: Dextromethorpham, Dihydrocodeine （二氢可待因 ） ⅱ Nondependence: Dextromethorpham, Cloperastine, Pentoxyverine Cloperastine, Pentoxyverine Ⅱ Peripheral antitussives: Benzonatate （苯佐那酯）, narcotin( 那可丁） Benzonatate （苯佐那酯）, narcotin( 那可丁）

Central antitussives Codeine and dihydrocodeine: opium receptor agonists, mainly used in dry cough. Mechanism: Act on cough center to suppress cough. Dextromethorphan (a synthetic non- opium compound) Pentoxyverine:Act on cough center and sensory nerve ending in branchial tract

Peripherial antitussives Benzonatate Have a local anesthetic action Two mechanisms: (1)the selective anesthesia of stretch receptors within the lungs (2) central suppression of cough.

Section 3 Expectorants Section 3 Expectorants Ⅰ Agents promoting mucous secretion ammonium chloride ammonium chloride [ Effects] [ Effects] (1)Expectorant action (1)Expectorant action (2) Diuretic action (2) Diuretic action (3) Acidified urine and blood (3) Acidified urine and blood

[Uses ] [Uses ] (1) Expectoration (1) Expectoration (2) Alkalemia (2) Alkalemia (3) Influence on excretion of some drugs (3) Influence on excretion of some drugs

Ⅱ Mucolytics Ⅱ Mucolytics Acetylcysteine( 乙酰半胱氨酸 ) Acetylcysteine( 乙酰半胱氨酸 ) Bromhexine （溴己新） Bromhexine （溴己新） Ⅲ Hypertonic saline Ⅲ Hypertonic saline NaCl ( 1.8% ） solution, NaCl ( 1.8% ） solution, N a HCO 3 (2%-7.5%) solution N a HCO 3 (2%-7.5%) solution