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1、BRONCHODILATORS,林佳衡 新光吳火獅紀念醫院胸腔內科,Categories,-adrenergic receptor agonists Methylxanthines Anticholinergic agents Other bronchodilator agents,b-adrenergic Receptor Agonists,-adrenergic receptor agonists,First-line therapy for acute bronchospasm in the critically ill patient Parenteral infusion Promp
2、t bronchodilation Significant side effects including tachycardia, arrhythmias, hypotension, myocardial ischemia,b-adrenergic receptor agonists,Inhalation Reduced systemic doses Increased delivery to the active site Subcutaneous administration may be necessary when profound bronchospasm prevents adeq
3、uate drug delivery by aerosol,b-adrenergic receptor agonists,Subcutaneous route Decreased tachycardia compared to parenteral infusion Concern with increased myocardial oxygen demand Direct endotracheal instillation Used in a resuscitation setting,AC,Gs,Gs,ATP,cAMP ,Protein kinase A activation,2-Agon
4、ist,KCa activation,PI hydrolysis,Na+/Ca 2+ exchange, Na+/K+ ATPase, MLCK,Blocked by charybdotoxin iberiotoxin,Maxi-K channel,KCa,2 -AR,Cell membrane,K+,( intracellular iCa),Beta-2 Agonists,Airway smooth muscle,Mast cell,Eosinophil,Cholinergic nerve,Acetylcholine,Histamine LTD4,Microvascular leak,b-a
5、drenergic receptor agonists,b-adrenergic receptor agonists,Tolerance Down-regulation of 2-receptors Corticosteroids prevent the development of tolerance, and prevent and reverse the fall in 2-receptor density Mortality when high dose of 2-agonists were used More severe and poorly controlled asthma M
6、ay inhibit the anti-inflammatory action of corticosteroids,b-adrenergic receptor agonists,Side effects Tremor Tachycardia or arrhythmia Hypokalemia,b-adrenergic receptor agonists,Drug interactions Combined use of several b-agonists aggravates side effects Aminophylline plus b-agonist increase incide
7、nce of arrythmias (mainly supraventricular),Short-acting inhaled 2-agonists,Rapid onset but short duration Less side effects Effective in protecting against various challenge: exercise, cold air and allergen The bronchodilators of choice in treating acute severe asthma Use on an “As needed” basis Or
8、al preparation: less effective and more side effects that inhaled form,Long-acting inhaled 2-agonist,Use as regular basis (Bid) Particularly useful in treating nocturnal asthma May be added to low-dose inhaled corticosteroids if asthma is not controlled Should only be used in patients who are also p
9、rescribed inhaled corticosteroids,Methylxanthines,Methylxanthines,Only theophylline in clinical use Second-line bronchodilator Given with b-agonists for severe airflow obstruction Narrow therapeutic window(10-20g/ml) Individual variation in clearance,Methylxanthines,No additional benefit to b-agonis
10、t in the first few hours Benefit seen by 24 hrs may be due to anti-inflammatory action and augmentation of diaphragmatic contractility,Agonist,Receptor,Adenyl cyclase,Agonist,Receptor,Adenyl cyclase,PDE3,4,PDE5,ATP,cAMP,AMP,GMP,cGMP,GTP,PKA,PKG,Inflammatory cell inhibition,Bronchodilatation,Theophyl
11、line,Theophylline, leak Migration of lymphocytes?,Airway smooth muscle,Mediators (PDE ),T-lymphocyte,Mast cell,Macrophage,Neuropeptides (PDE ),Mediators Cytokines (PDE ), Numbers Trafficking? Cytokines?,Bronchodilation (PDE ),Mediators (PDE ),Eosinophil,Endothelial cell,Bone marrow,Effects?,Sensory
12、nerve,Diaphragm,Strength,Methylxanthines,Pharmacokinetics Oral form peak at 1-2 hrs (4 hrs for slow release preparations) Pharmacokinetics in critically ill patients unpredictable Metabolized in liver Excreted by kidney Half-life in healthy adults 7-9 hrs,Methylxanthines,Methylxanthines,Pharmacokine
13、tics IV infusion requires determination of initial serum level and subsequent monitoring 1 mg of aminophylline = 0.8 mg of theophylline If no previous theophylline, load 6 mg/kg of aminophylline over 30 min Rough guideline of 1 mg/kg of theophylline for 2 mg/L rise in serum level Maintenance dose st
14、ill requires subsequent adjustment,Methylxanthines,Methylxanthines,Side effects Nausea/vomiting Headache Diarrhea Insomnia Hyperglycemia (usually from overdose) Seizures (usually from overdose) Arrhythmias (usually from overdose),Methylxanthines,Side effects Serum level monitoring the only reliable
15、means of preventing toxicity Incidence of serious side effects near zero below 15 mg/L Charcoal hemoperfusion considered above 40 mg/L with severe symptoms,Methylxanthines,Side effects Cardiac complications Tachycardia Exacerbation of existing supraventricular arrhythmias Multifocal atrial tachycard
16、ia Arrhythmias may be precipitated by infusion through a central line Ventricular arrhythmias respond to lidocaine Profound hypotension can occur with rapid infusion,Anticholinergic Agents,Anticholinergic Agents,Antimuscarinic Block cholinergic (vagal) innervation Inhibit the action of acetylcholine at parasympathetic cholinergic nerve ending Predominately large airway bronchodilation,
