UNIVERSITÀ DEGLI STUDI DI SALERNO – DIPARTIMENTO CATTEDRA DI MALATTIE DELL’APPARATO Il razionale farmacologico della doppia broncodilatazione Alessandro Vatrella [email protected] RESPIRATORIO DI MEDICINA E CHIRURGIA Pharmacotherapeutic options for COPD LABA ULTRALABA LAMA (Indacaterol) LABA+LAMA ICS + LABA SABA (Salbutamol) 1930s 1968 1970s SAMA ICS Anticholinergics 1980s 1990s 2010 2011 2014 Selective PDE inhibitors (Roflumilast) XANTINEs Z. Diamant et al., New and existing pharmacotherapeutic options for persistent asthma and COPD, Nether J Med 2011 Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Bronchodilators Bronchodilator medications are central to the symptomatic management of COPD. Bronchodilators are prescribed on an as-needed or on a regular basis to prevent or reduce symptoms. The principal bronchodilator treatments are beta2agonists, anticholinergics, theophylline or combination therapy. The choice of treatment depends on the availability of medications and each patient’s individual response in terms of symptom relief and side effects © 2013 Global Initiative for Chronic Obstructive Lung Disease Moving from short-acting to ultra long-acting bronchodilators Salbutamol short Ipratropium Oxitropium Salmeterol Formoterol long Aclidinium Indacaterol ultra long Tiotropium Glycopyrronium Global Strategy for Diagnosis, Management and Prevention of COPD Therapeutic Options: Bronchodilators Long-acting inhaled bronchodilators are convenient and more effective for symptom relief than short-acting bronchodilators. Long-acting inhaled bronchodilators reduce exacerbations and related hospitalizations and improve symptoms and health status. Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator. © 2013 Global Initiative for Chronic Obstructive Lung Disease Cigarette smoke Environmental risk factors Airway Resistance Aiway Inflammation Bronchoconstriction Mucus hypersecretion Peribronchiolar fibrosis Genetic susceptibility I N F L A M M A T I O N COPD Airflow limitation Lung Elastic Recoil Alveolar wall destruction Loss of alveolar attachments Contrazione della muscolatura liscia delle vie aeree non voltage dependent calcium channels Mantenimento tensione Sviluppo tensione ASM contraction Giembycz MA and Newton R, Eur Respir J 2006 BRONCODILATAZIONE STRATEGIE FARMACOLOGICHE Antagonismo competitivo dei recettori degli agonisti contratturanti Antagonismo funzionale della contrazione della muscolatura liscia Antagonismo Recettoriale Competitivo LT SP PG ACh BR ET Acetylcholine concentration is increased in induced sputum from COPD patients Profita M et al. Biochim Biophys Acta 1822:1079-1089, 2012 ANTICHOLINERGICS IN COPD NORMAL COPD Vagus nerve Cholinergic = “tone” COPD: β2-agonists anticholinergics ACh ACh Asthma: β2-agonists >>> anticholinergics Resistance 1/r4 β2-Agonists: functional antagonists CHOLINERGIC TONE IS THE ONLY ASTHMA REVERSIBLE MECHANISM IN COPD ANTICHOLINERGIC (IN CONTRAST TO ASTHMA) β2-Agonists Histamine Cys-LTs PGD2 CHOLINERGIC CONTROL OF AIRWAYS Vagus nerve CNS M1 Ganglion Afferent nerves Smooth muscle M2 M3 M3 Mucous gland M1 Epithelium CHOLINERGIC CONTROL OF AIRWAYS Large airway Small airway Epithelial cells Inflammatory cells ACh BRONCHOCONSTRICTION Muscarinic receptors ACh Cholinergic nerve Wessler I & Kirkpatrick CJ: Br J Pharmacol 2008 Mode of action: High affinity for M3 muscarinic receptors and slow dissociation from them Parasympathetic nerve endings Released Ach Agonist Antagonist M3 muscarinic receptor (Airway smooth muscle) Bronchoconstriction short, long and ultralong-acting bronchodilators Type Onset of action Duration of action Salbutamol 3-5 min < 6 hrs Salmeterol 20-30 min < 12 hrs Formoterol 3-10 min < 12 hrs Indacaterol 3-10 min > 24 hrs Ipratropium 30-45 min 4-6 hrs Oxitropium 30-45 min 6-8 hrs Tiotropium 30-60 min 24 hrs 5 min 24 hrs 30-60 min 12 hrs Glycopyrronium Aclidiniium Half-life ratio for dissociation from M3 and M2 receptors t1/2 Ratio M3/M2 Ipratropium 7.3 Tiotropium 10.4 Glycopyrronium 16.5 Casarosa P, Bouyssou T, Germeyer S, Schnapp A, Gantner F, Pieper M. J Pharmacol Exp Ther 330:660-668, 2012 Bronchodilator activity of glycopyrronium and tiotropium in COPD 1.8 B Giorno 1 Glycopirronium (n=144) 1.8 Placebo (n=79) 1.7 1.6 Tiotropium (n=76) 1.6 FEV1 (L) 1.7 1.5 1.4 Placebo (n=79) Tiotropium (n=76) 1.4 1.3 1.2 1.2 0 Glycopirronium (n=144) settimana 12 1.5 1.3 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 0 1 Time post-dose (hours) C 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Time post-dose (hours) 1.8 Glycopirronium (n=144) 1.7 Settimana 52 Placebo (n=79) Tiotropium (n=76) 1.6 FEV1 (L) FEV1 (L) A 1.5 1.4 1.3 1.2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Time post-dose (hours) Kerwin E et al. GLOW 2 Eur Resp J 2012 Bronchodilator activity of glycopyrronium and tiotropium in COPD 1,8 *** 1,6 Glycopirronium 1,7 Tiotropium ††† Placebo FEV1 AUC5 min–4 h *** FEV1 1,6 1,5 1,4 1,5 1,4 1,3 1,2 1,3 0 1 2 3 4 Placebo Tiotropium Glycopirronium Time post-dose (h) At all time points: p<0.001 Glycopirronium vs placebo and tiotropium; p<0.01 tiotropium vs placebo ***p<0.001 versus placebo, †††p<0.001 versus tiotropium; data are LSMs±SE. AUC = area under curve Kerwin E et al. GLOW 2 Eur Resp J 2012 24-hour bronchodilatory efficacy of aclidinium and tiotropium on day 1 and week 6 BRONCODILATAZIONE STRATEGIE FARMACOLOGICHE Antagonismo competitivo dei recettori degli agonisti contratturanti Antagonismo funzionale della contrazione della muscolatura liscia Antagonismo Funzionale LT SP PG ACh BR b2 agonists ET A + - Caribdotossina b2-R b a s g AC K+ ATP cAMP Sensibilità al Ca++ della MLCK PKA PKG Attività fosfatasi della miosina Sequestrazione Ca++ nei depositi citosolici Rilascio Ca++ siti IP3 sensibili Marsico SA, Vatrella A, Pelaia G, Maselli R. In: Malattie dell’Apparato Respiratorio Piccin, 2008 b-Agonist History ma huang epinephrine (injection)1 epinephrine (aerosol)2 ephedrine (oral)3 isoproterenol (b selective)4 MDI b2 selective extended action long-acting single isomer Ultra-long acting 3,000 BC 1 1900 1920 1940 1960 Bullowa & Kaplan, 1903. 2 Burger & Dale, 1910. 3 Chen & Schmidt, 1924. 4 Konzett, 1941 1980 2000 2010 Indacaterol 300 µg od (n=66) 1,6 Salmeterol 50 µg bid (n=65) Placebo (n=66) FEV1 (l) 1,4 1,2 Long-acting bronchodilators maintain longer the improvement in airway calibre 1,0 -2 0 2 4 6 8 10 12 Time (h) 14 16 18 20 22 24 Mechanisms of bronchodilatory action of antimuscarinic agents and b2-adrenergic receptor agonists. b 2-agonist b2AR GS Cholinergic nerve Out GS In AC M2 (-) ACh Antimuscarinic cAMP ATP M3 (+) b 2AR PKA (active) PK (inactive) Smooth muscle Relaxation Relaxation Modified from Tashkin and Fabbri Respiratory Research 2010, 11:149 ANTICHOLINERGIC AND β2-AGONIST β2-Agonist Antcholinergic ACh β2 M3 PLCβ IP3 Ca2+ Gq PKC Diacylglycerol P P Gs AC ↑cAMP AMP Ca2+ Ca2+ Ca2+ Ca2+ BRONCHOCONSTRICTION BRONCHODILATATION LABA/LAMA COMBINATION Matera MG, Page CV, Cazzola M. Trends Pharmacol Sci 32:495-506, 2011 LABA/LAMA COMBINATION IN COPD FEV1 on day 7 1.7 P<0.05 at all points QVA-149 300/50 (n=142) (indacaterol + glycopyrronium) 1.6 FEV1 (L) >300mL 1.5 Indacaterol 300 µg (n=140) 1.4 Indacaterol 600 µg (n=142) 1.3 Placebo (n=140) 1.2 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (h) van Noord JA et al: Thorax 2010 Eur Respir J 2013; 42: 1484–1494 | Pharmacological lung volume reduction A=short-acting; B=twice daily; C=once-daily Correlation of Dyspnea with Hyperinflation and Neuromechanical Dissociation Bronchodilators O’Donnell D, 2002 MASSIMIZZAZIONE DELLA BRONCODILATAZIONE INTERAZIONE SINERGICA FRA ß2-AGONISTI ED ANTIMUSCARINICI I ß2-agonisti amplificano il rilasciamento della muscolatura liscia indotto dagli antimuscarinici riducendo il rilascio di ACh attraverso la modulazione della neurotrasmissione colinergica. Gli antimuscarinici aumentano la broncodilatazione indotta da ß2-agonisti riducendo l’effetto broncocostrittore dell’ACh. ß2-agonisti ed anticolinergici esplicano la loro azione broncodilatante sia a livello delle vie aeree di calibro maggiore che delle piccole vie aeree. Bronchodilators are essential to symptom management in COPD Air trapping Bronchoconstriction Smooth muscle relaxation Bronchodilators (LABA/LAMA) Increased mucociliary clearance Reduced hyperinflation Improved respiratory muscle function GOLD 2011 Airway pharmacological stenting Airway calibre 1xdaily 2xdaily 4xdaily “Trough” FEV1 AUC 0 6 12 Time (h) 18 24 Eur Respir J 2013; 42: 1484–1494 | Long-acting bronchodilators maintain longer the improvement in airway calibre Indacaterol vs salmeterol
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