Drugs for Respiratory System 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. Learning Objectives At the end of this session, you will be able to: Introduction Symptoms of respiratory system: no sputum---antitussives no sputum---antitussives Cough sputum --- expectorants sputum --- expectorants wheeze antiasthmatic drugs Global Initiative for Asthma (GINA), 2014 Beethoven Asthma Global Initiative for Asthma (GINA), 2014 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 David Beckham Sharon Stone Gregory Louganis Asthma Pathophysiology: Asthma is a disease characterized by airway inflammation and episodic, reversible bronchospasm.Asthma is a disease characterized by airway inflammation and episodic, reversible bronchospasm. Two characteristic features:Two characteristic features: 1) Inflammatory changes in the airway; 2) Bronchial hyperreactivity to stimuli. Important mediators: histamine, Leukotrienes(LTs, e.g. LTC 4, LTD 4, etc.)Important mediators: histamine, Leukotrienes(LTs, e.g. LTC 4, LTD 4, etc.) Drug actions on bronchiolar smooth muscle Antiasthmatic Drugs I. Bronchodilators 1.-receptor agonists 2.Theophylline 3.Muscarinic (cholinergic) antagonists II. Anti-inflammatory agents 1.Steroids 2.Anti-leukotriene agents III. Anti-allergic agents 1.Stabilizer of inflammatory cell membrane 2.H 1 receptor blocker Bronchodilators Beta Adrenoceptor Agonists Epinephrine : , agonist Isoprenaline 1, 2 agonist Ephedrine ( : , agonist 2 selective agonist Beta Adrenoceptor Agonists 2 -selective agonists Salbutamol ( Albuterol ) :Salbutamol ( Albuterol ) : Terbutaline ( ) :Terbutaline ( ) : Bambuterol ( , )Bambuterol ( , ) Pirbuterol Pirbuterol Salmeterol( ):Salmeterol( ): Formoterol ( ):Formoterol ( ): long-acting Mechanism of action The stimulation of 2 -adrenoceptors leads to an increase production of cAMP by activating adenyl cyclase. Route of administration Inhaled. Inhaled. Oral administration is reserved for children and people unable to use inhalers. Oral administration is reserved for children and people unable to use inhalers. Intravenous administration for status asthmaticus. 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 2-selective agonists appear to interact with inhaled corticosteroids to improve asthma control. Adverse Reactions of 2 agonists: 1)Skeletal muscle tremor 2)Cardiac effect: tachycardia 3)Metabolism disturbance: ketone bodies , acidosis, hypokalemia ketone bodies , acidosis, hypokalemia Clenbuterol increases the muscle-to-fat body ratio makes its illegal use in livestock popular to obtain leaner meats. increases the muscle-to-fat body ratio makes its illegal use in livestock popular to obtain leaner meats. Mechanism of Action Mechanism of Action none has been firmly established. 1.Inhibit phosphodiesterase (PDE); 2.Block adenosine receptors; 3. Enhancement of histone deacetylation. 4. strengthen the contractions of isolated skeletal muscle in vitro and improve contractility and reverse fatigue of the diaphragm. Theophylline 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 ( ) lethal. rhabdomyolysis Muscarinic Antagonists There are M 1, M 2, M 3 receptor subtypes in the airway. Selectively blocking M 1, M 3 receptor is resulted in bronchodilating effect. Ipratropium bromide binds to all M-R subtypes (M 1, M 2 and M 3 ), 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 - adrenoceptors in the airway. Routes of administration: Systemic administration: including oral and injection. More severe toxicity.Systemic administration: including oral and injection. More severe toxicity. Reserved for patients who require urgent treatment. Reserved for patients who require urgent treatment. Inhalation: regular or controller therapy.Inhalation: regular or controller therapy. Common inhalant GCs:,beclomethasone, budesonidebeclomethasonebudesonide 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). 1995 5 8 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 2 -receptor. Anti-leukotriene agents Cysteinyl leukotrienes is an important inflammatory mediator: Bronchoconstriction, increased bronchial reactivity, mucosal edema, mucus hypersecretion, etc.Bronchoconstriction, increased bronchial reactivity, mucosal edema, mucus hypersecretion, etc. LTD4 receptor antagnist: zafirlukast and montelukastLTD4 receptor antagnist: zafirlukast and montelukast 5-lipoxygenase inhibitor: zileuton5-lipoxygenase inhibitor: zileuton Anti-leukotriene agents Used for the maintenance treatment of asthma it is not useful for the treatment of acute asthma attacks Ach M cGMP -- LT 5-HT ATPcAMP5AMP -- -- -- A NA 3. -- 4. 2. 1. 5. 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. 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. 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: Central antitussives 1. Dependent central antitussives 2. Independent central antitussives 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 morphineSuppression of cough: 1/4 of morphine Analgesia: 1/7 of morphineAnalgesia: 1/7 of morphine Respiratory depression, constipation, tolerance, dependence that of morphineRespiratory depression, constipation, tolerance, dependence that of morphine Pharmacokinetics: Well absorbed from oral and injection.Well absorbed from oral and injection. 10% converted to morphine through demethylation.10% converted to morphine through demethylation. Clinical Uses: Dry cough, a painful cough caused by pleurisy will be controlled with codeine- based cough syrupsDry cough, a painful cough caused by pleurisy will be controlled with codeine- based cough syrups Codeine Adverse Reactions: Respiratory suppression in high dose (asphyxiation);Respiratory suppression in high dose (asphyxiation); Tolerance and physical dependence with frequently repeated administration;Tolerance and physical dependence with frequently repeated administration; Suppress secretion of bronchial gland and movement of cilia.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 () dextromethorphan ( ) Stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability. Stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability. pentoxyverine ( pentoxyverine ( ; cloperastine () cloperastine ( ) Dextromethorphan Clinical Use: Dry cough. Often + Antihistamine drugDry cough. Often + Antihistamine drug Because administration of dextromethorphan can trigger a histamine release (an allergic reaction), its use in children is very limited.Because administration of dextromethorphan can trigger a histamine release (an allergic reaction), its use in atopic children is very limited. Pentoxyverine( Suppression of cough: 1/3 of codeine. Direct suppression of cough center Atropine-like action and local anesthetic action. Cloperastine Derivative of diphenhydramine ( ). Suppression of cough center Blocking H 1 -receptor Peripheral Antitussives Reduce the sensitivity of peripheral sensory cough receptors . 1.Local anesthesia action: narcotine ( ), benzonatate () ; 1.Local anesthesia action: narcotine ( ), benzonatate ( ) ; 2.Alleviative action: extractum glycyrrhiza liquidum ( ), Syrup ( ) Expectorants 1.Mucus secretagogue drugs: stimulating gastric mucosa reflex secretion of bronchial gland dilution of sputum. Ammonium chloride. Ammonium chloride. Guaifenesin ( Guaifenesin ( Expectorants 2.Mucolytic drugs: 1) Acetylcysteine (): reduce the viscosity of bronchial secretions by cleaving disulphide bonds cross-linking mucus glycoprotein molecules. 1) Acetylcysteine ( ): reduce the viscosity of bronchial secretions by cleaving disulphide bonds cross-linking mucus glycoprotein molecules. 2) Bromhexine(): break acid mucin: 2) Bromhexine( ; ): break acid mucin: 3) DNAase: Enzymolysis