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Transcript
Drugs for Respiratory System Learning Objectives At the end of this session, you will be able to: 1.Classify the drugs and typical agents used in asthma 2.Analyse the mechanism of action, pharmacological effects, clinical use and adverse reactions of anti-asthmatic drugs 3.Demonstrate the pharmacological effects, clinical use and adverse reactions of antitussives 4.Analyse the pharmacological effects, clinical use and adverse reactions of Expectorants. Introduction ■ Symptoms of respiratory system: no sputum---antitussives ■ Cough 咳 ■ sputum --- expectorants 痰 wheeze ----- antiasthmatic drugs 喘 Global Initiative for Asthma (GINA), 2014 Asthma 由于哮喘和医 生的束手无策 而死于维也纳 Beethoven 1770-1827 Avoid troublesome symptoms during day and night Need little or no reliever medication Have productive, physically active lives Have normal or near normal lung function Global Initiative for Asthma (GINA), 2014 David Beckham 完 美 情 人 性 感 女 神 Sharon Stone Gregory Louganis 柯受良 谢霆锋 郑秀文 杜德伟 朱孝天 陆文夫 张敬轩 Asthma Pathophysiology: • Asthma is a disease characterized by airway inflammation and episodic, reversible bronchospasm. • Two characteristic features: 1) 2) Inflammatory changes in the airway; Bronchial hyperreactivity to stimuli. • Important mediators: histamine, Leukotrienes(LTs, e.g. LTC4, LTD4, etc.) Drug actions on bronchiolar smooth muscle Antiasthmatic Drugs Bronchodilators I. 1. 2. 3. β-receptor agonists Theophylline Muscarinic (cholinergic) antagonists Anti-inflammatory agents II. 1. 2. Steroids Anti-leukotriene agents Anti-allergic agents III. 1. 2. Stabilizer of inflammatory cell membrane H1 receptor blocker Bronchodilators Beta Adrenoceptor Agonists ■ ■ ■ ■ Epinephrine : α,β agonist Isoprenaline:β1 ,β2 agonist Ephedrine (麻黄碱) : α,β agonist β2 selective agonist 发汗散寒,宣肺平喘 Beta Adrenoceptor Agonists β2-selective agonists • Salbutamol(Albuterol ,舒喘灵): • Terbutaline(特布他林,博利康尼) : • Bambuterol (班布特罗, 帮备 ) • Pirbuterol 吡布特罗 • Salmeterol(沙美特罗): long-acting • Formoterol (福莫特罗): Mechanism of action The stimulation of β2-adrenoceptors leads to an increase production of cAMP by activating adenyl cyclase. Route of administration Inhaled. Oral administration is reserved for children and people unable to use inhalers. Intravenous administration for status asthmaticus. Clinical applications ■ ■ ■ ■ Acute asthma Symptom relief during maintenance therapy of asthma and other conditions with reversible airways obstruction (including COPD and bronchitis) Protection against exercise-induced asthma Long-acting β2-selective agonists appear to interact with inhaled corticosteroids to improve asthma control. Adverse Reactions of β2 agonists: 1) Skeletal muscle tremor 2) Cardiac effect: tachycardia 3) Metabolism disturbance: ketone bodies↑, acidosis, hypokalemia Clenbuterol increases the muscle-to-fat body ratio makes its illegal use in livestock popular to obtain leaner meats. Theophylline Mechanism of Action (none has been firmly established.) 1. 2. 3. 4. Inhibit phosphodiesterase (PDE); Block adenosine receptors; Enhancement of histone deacetylation. strengthen the contractions of isolated skeletal muscle in vitro and improve contractility and reverse fatigue of the diaphragm. ■ Clinical Use: 1. Asthma: maintenance treatment 2. Chronic obstructive pulmonary disease (COPD) 3. Central sleep apnea (CSA) ■ Adverse Reactions: Narrow margin of safety. Toxic effects are related to its plasma concentration. ■ • • Gastrointestinal distress, tremor, and CNS excitation. Acute toxicity: cardiac arrhythmias, convulsions(惊厥) → lethal. rhabdomyolysis Muscarinic Antagonists ■ ■ ■ There are M1, M2, M3 receptor subtypes in the airway. Selectively blocking M1, M3 receptor is resulted in bronchodilating effect. Ipratropium bromide binds to all M-R subtypes (M1, M2 and M3 ), and inhibits acetylcholine-mediated bronchospasm. Ipratropium bromide ■ ■ Inhalation for the treatment of obstructive lung diseases. Ipratropium is also combined with salbuterol for the management of chronic obstructive pulmonary disease (COPD) and asthma. Anti-inflammatory Agents Glucocorticoids (GCs) Mechanism of Action: 1. Broad anti-inflammatory efficacy 2. Increase the responsiveness of βadrenoceptors in the airway. Routes of administration: • Systemic administration: including oral and injection. More severe toxicity. Reserved for patients who require urgent treatment. • Inhalation: regular or “controller” therapy. Common inhalant GCs: • beclomethasone, budesonide Clinical applications GCs is limited to selected patients whose conditions cannot be controlled with bronchodilators and other nonsteroid medications. Adverse reaction ■ ■ Systemic reaction. Inhalaed corticosteroids may cause oropharyngeal candidiasis and hoarseness (effect on vocal cords). 邓丽君因过分注意维护自己的完美形象,而没有 遵循哮喘的规范治疗,终因哮喘急性发作又正巧 用完了急性缓解药物于1995年5月8日,猝逝于 泰国清迈。(1953-1995) Anti-allergic Agents ■ ■ Madiators release inhibitors. Prevent bronchoconstriction caused by a challenge with antigen. Cromolyn Sodium Mechanism of Action: 1. Stabilizer of mass cell membrane: decreases the release of mediators from mast cells. 2. Decreases bronchial hyperreactivity induced by stimuli. ■ an inhaler for preventive management of asthma Ketotifen ▲ H1 receptor blocker. ▲ Prevent and inverse down-regulation of β2-receptor. Anti-leukotriene agents Cysteinyl leukotrienes is an important inflammatory mediator: • Bronchoconstriction, increased bronchial reactivity, mucosal edema, mucus hypersecretion, etc. • LTD4 receptor antagnist: zafirlukast and montelukast • 5-lipoxygenase inhibitor: zileuton Anti-leukotriene agents ■ ■ Used for the maintenance treatment of asthma it is not useful for the treatment of acute asthma attacks 迷走神经兴奋 Ach ( -) 3. 抗胆碱药 抗原 过敏 反应 ( -) 5. 抗过敏药 ATP M胆碱受体 cGMP 支气管 收缩 过敏 介质 喘 (LT、组胺、 5-HT) ( -) 腺苷酸 环化酶 cAMP 毛细血 管扩张 磷 酸 5’AMP 二酯酶 ( -) 受体 A,NA ( -) 4. 皮质激素 1. 受体激动药 2. 茶碱类 ANTITUSSIVES ▲ Antitussives are drugs that inhibit the cough reflex. Cough is usually a valuable protective reflex mechanism for clearing foreign material and secretions from the airway. In some conditions, such as inflammation or neoplasia, the cough reflex may become inappropriately stimulated and in such cases, antitussive drugs may be used. ANTITUSSIVES Classification: Ⅰ Central antitussives 1. 2. Dependent central antitussives Independent central antitussives Ⅱ Peripheral antitussives Dependent Central Antitussives ■ ■ ■ ■ Opioid alkaloids. Morphine is the most effective drug for the suppression of cough, but have addiction. Mechanism: suppressing of cough center Clinical use: analgesic,sever cough without sputum (lung cancer) . Codeine (Methylmorphine) ■ ■ Selectively suppress cough center in medulla oblongata. It is less potent than morphine and has a correspondingly lower dependence-liability than morphine Potency: • Suppression of cough: ≈1/4 of morphine • Analgesia: ≈1/7 of morphine • Respiratory depression, constipation, tolerance, dependence < that of morphine Pharmacokinetics: • Well absorbed from oral and injection. • 10% converted to morphine through demethylation. Clinical Uses: • Dry cough, a painful cough caused by pleurisy will be controlled with codeinebased cough syrups Codeine Adverse Reactions: • Respiratory suppression in high dose (asphyxiation); • Tolerance and physical dependence with frequently repeated administration; • Suppress secretion of bronchial gland and movement of cilia. Cough syrups and tablets containing codeine are available without prescription; Some potential recreational users are reported to buy codeine from multiple pharmacies Independent Central Antitussives dextromethorphan(右美沙芬) Stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability. pentoxyverine(喷托维林;咳必清) cloperastine(氯哌斯汀) Dextromethorphan(右美沙芬) Clinical Use: • Dry cough. Often + Antihistamine drug • Because administration of dextromethorphan can trigger a histamine release (an allergic reaction), its use in atopic children is very limited. Pentoxyverine(喷托韦林) ■ ■ ■ Suppression of cough: ≈1/3 of codeine. Direct suppression of cough center Atropine-like action and local anesthetic action. Cloperastine ■ ■ ■ Derivative of diphenhydramine(苯海拉 明). Suppression of cough center Blocking H1-receptor Peripheral Antitussives Reduce the sensitivity of peripheral sensory ‘cough receptors’. 1. Local anesthesia action: narcotine(那可 丁), benzonatate(苯佐那酯); 2. Alleviative action: extractum glycyrrhiza liquidum(甘草流浸膏), Syrup(糖浆) Expectorants 1. Mucus secretagogue drugs: stimulating gastric mucosa → reflex secretion of bronchial gland↑ → dilution of sputum. Ammonium chloride. Guaifenesin (愈创木酚甘油醚) Expectorants 2.Mucolytic drugs: 1) 2) 3) Acetylcysteine(乙酰半胱氨酸):reduce the viscosity of bronchial secretions by cleaving disulphide bonds cross-linking mucus glycoprotein molecules. Bromhexine(溴己新; 必嗽平): break acid mucin: DNAase: Enzymolysis