o o n 2 agonists n n Methylxanthines

호흡기약물의 종류 o o 기관지확장제 점액조절제 n 2 -agonists n 거담제 n Methylxanthines n 점액용해제 n Anticholinergics 염증조절제 n o o Glucocorticosteroids n Cromones n Leukotriene modifiers 기타 약물 n Antihistamines n Decongestants n Antiallergic agents o Respiratory stimulants n Doxapram n Almitrine n Naloxone

천식 치료제의 종류 1. 교감신경 자극제 : 2 -agonists 2. 부교감신경 차단제 : Ipratropium, Tiotropium 3. Methylxanthine 계 : Theophillne 4. Mast cell stabilizer : Cromolyn sodium 5. 항염증제 1) 부신피질 호르몬 2) Leukotrien 길항제 : Pranlulast (Onon) Montelukast (Singulair) Zafirlukast (Accolate) 3) 5 -lipooxygenase inhibitor : Zileuton

증상완화제 (Reliever Medications) n Rapid-acting inhaled 2 -agonists n Systemic glucocorticosteroids n Anticholinergics n Methylxanthines n Short-acting oral 2 -agonists

질병조절제 (Controller Medications) n Inhaled glucocorticosteroids n Systemic glucocorticosteroids n Cromones n Methylxanthines n Long-acting inhaled 2 -agonists n Long-acting oral 2 -agonists n Leukotriene modifiers

항콜린성 기관지확장제 o 무스카린 수용체를 길항 o 콜린성 신경 종말의 신경전달 물질인 아세틸콜린 분비를 억제 o o 이상적인 항콜린성 기관지확장제 : n High affinity for M 1 and M 3 receptors n No or low M 2 receptor affinity 지속형 항콜린제 - tiotropium n Kinetic selectivity for M 1 and M 3 receptors n Prolonged binding relative to binding at M 2 receptors

Muscarinic Receptor Subtypes in Airways Pre-ganglionic nerve Nicotinic receptors (+) Parasympathetic ganglion M 1 receptors (+) Post-ganglionic nerve M 2 receptors (–) ACh Airway smooth muscle Barnes PJ. Eur Respir Rev 1996 M 3 receptors (+)

흡입 항콜린제의 특징 Atropine Ipratropium, tiotropium • Easily absorbed (GI) • Not easily absorbed • Pass blood brain barrier • Not pass blood brain barrier • Inhibit mucus secretion • Inhibit mucociliary transport • Not inhibit mucociliary transport • Block nicotinic receptor • Not block nicotinic receptor • Frequent systemic side reaction (heart, bladder, eye, dry mouth and nose) • No significant systemic side reaction : dry mouth

Theophylline 작용기전 o Phosphodiesterase의 억제 o Adenosine 수용체의 길항제 o catecholamine 분비를 자극 o 면역조절 효과 o 칼슘이온 분비를 억제

Cellular Effect of Corticosteroids

Efficacy and Safety of Inhaled Corticosteroid (ICS) o Efficacy 1. Dose-response relationship 2. Comparision of different inhaled corticosteroids 3. Early intervention with inhaled corticosteroids 4. Duration of treatment 5. Changes in the use of inhaled corticosteroids - “start high - go low” o Safety 1. Systemic side effects 2. Local side effects

Dose-Response Relationships(1)

Dose-Response Relationships(2)

Clinical Comparison of Different Inhaled Steroids o Available inhaled steroids: Beclomethasone dipropionate(BDP) Budesonide(BUD: Pulmicort, Pulmicort Turbuhaler) Fluticasone propionate(FP: Flixotide, Flixotide Diskus) Triamcinolone acetonide(TAA: Azmacort) o Potency BUD Turbuhaler > BDP p. MDI FP > BUD FP p. MDI > BUD p. MDI FP p. MDI, FP Diskhaler > BUD Turbuhaler

Early Intervention with Inhaled Corticosteroids Black bar: Inhaled budesonide early after diagnosis of asthma Gray bar: Inhaled budesonide delayed by 2 years

Safety of Inhaled Steroids 1. Systemic side effects n Effect on HPA axis n Effect on bone n Growth in children n Cataract and glaucoma n Skin thinning and easy bruising 2. Local side effects n Oral candidiasis n Dysphonia

Fate of Inhaled Corticosteroid

o Long acting 2 -agonist • o Long-acting inhaled 2 -agonist ; salmeterol, formoterol • Decrease adhesion of bacteria to epithelial cells in the airway – reduce infective exacerbation • Bambuterol ; oral, terbutaline Tiotropium bromide • Long-acting anticholinergics • Very slow dissociation from M 1 and M 3 muscarinic receptors • Once daily, more effective than ipratropium bromide • Additive effects with long-acting 2 -agonist

Combination inhaler o Long-acting beta agonist(LABA) + inhaled corticosteroid(ICS) o n Seretide (salmeterol + fluticasone) n Symbicort (formoterol + budesonide) Short acting beta agonist + ipratropium n Combivent

Combination therapy : Complementary actions LABA Smooth muscle dysfunction l Bronchoconstriction l BHR l Hyperplasia l Inflammatory mediator release Airway inflammation l Inflammatory cell infiltration/activation l Mucosal oedema l Cellular proliferation l Epithelial damage l Basement membrane thickening Symptoms exacerbations CS

Combination therapy : Synergistic actions steroid molecules LABA Cell membrane tor p e c - re Inactive steroid receptor Active steroid-receptor complex transcription factor Primed steroid receptor (requires less FP for activation) Increased ß 2 -receptor synthesis DNA strand Barnes PJ 2002 Dimer formation Gene binding Increased antiinflammatory activity

Potential Sites and Effects of Cysteinyl Leukotrienes Relevant to a Pathophysiological Role in Asthma Increased Mucus Secretion Decreased Mucus Transport Cationic Proteins (Epithelial Cell Damage) Airway Epithelium Increased Release of Tachykinins Sensory C Fibres Blood Vessel Cysteinyl Leukotrienes Smooth Muscle Edema Inflammatory Cells (e. g. Mast Cells, Eosinophils) Contraction and Proliferation Adapted from Hay DWP, Torphy TJ, Undem BJ Trends Pharmacol Sci 16: 304 -309, 1995

Biochemical Pathways of the Formation and Action of the Leukotrienes

Drugs that act on the 5 -lipoxygenase pathway Drug class and name Trade name Recommended oral dose Other information Leukotriene-receptor antagonist Montelukast Pediatric dose is a adults; 5 mg each night children (6 -12 yr) Pranlukast Zafirlukast before or 2 hr Singulair 10 mg each night in chewable tablet in Onon, Ultair Accolate 225 mg twice daily 20 mg twice daily after eating 5 -Lipoxygenase inhibitor Zileuton Measure serum alanine Zyflo 600 mg 4 times daily aminotransferase before treatment, every month Take 1 hr

Combination therapy for COPD • Short acting 2 -agonist • Theophylline • Ipratropium bromide • Short-acting 2 -agonist + theophylline • Short-acting 2 -agonist + ipratropium • Inhaled corticosteroid (ICS) • Long-acting 2 -agonist (LABA) • Long-acting anticholinergics (Tiotropium) • Long-acting 2 -agonist + ICS

흡입장치의 종류 1. Metered dose inhaler (MDI) 2. Dry powder inhaler (DPI) - spinhaler, rotahaler, diskhaler, tubuhaler, diskus 3. Nebulizer - jet, ultrasonic

MDI

DPI

Nebulizer