1. Jiří Slíva Drugs affecting respiratory system

2. Absolute number of patients suffering from AB in CZ Period Number of patients http://issar.cenia.cz

3. Asthma in numbers… 100-150 million worldwide; 180 000 deaths/year total number of AB patients has doubled during last decade Australia: every 6th child suffers from AB Source: WHO

5. THE MOST IMPORTANT ALERGENES

6. JANUARY FEBRUARY MARCH APRIL MAY 1. DEC. 2. DEC. 3. DEC. Pollen situation of„Alnus glutinosa“ in the Europe

10. DIAGNOSIS 1. ANAMNESIS 3. LABORATORY TESTS 2. CLINICAL FEATURES 4. ALLERGOLOGICAL TESTS

11. pharmacoterapy life style specific imunotherapy (SCIT vs SLIT) symptomatic antiinflammatoric preventive

12. sympatomimetics anticholinergics corticosteroides methylxantines antileukotriens antihistamines MABs Groups of drugs:

14. Novolizer:

15. Ventodisk, Turbuhaler:

17. β-mimetics - nonselective - adrenaline, isoproterenol, orciprenaline, ephedrine - selective - metaproterenol, albuterol, salbutamol, terbutalin, fenoterol => more effective via inhalation then p.o. administration => increase of cAMP => SABA, LABA, RABA Parasympatolytics ipratropium Antiasthmatics with rapid effect:

18. β 2 -mimetics with long-term effect: via inhalation salmeterol via per os (tbl, susp) clenbuterol, procaterol

19. Rapid & short-term acting  2 - sympatomimetics (RABA) fast and short-term bronchodilation after inhalation for acute treatment onset of action in 5-10 min (inhal.), 15-90 min (p.o.) duration of action 4-6 hrs salbutamol /Ventolin/ fenoterol (Berotec) terbutalin (Bricanyl)

20. Long-term acting  2 - sympatomimetics (LABA) bronchodilation  12 hrs not suitable for acute treatment, for prophylaxis only ICS are prefered (20x higher eff. than p.o., +  systemic ADRs) commonly in combination with ICS moderate & severe BA in combination with ICS salmeterol /Serevent/ formoterol /Oxis/ procaterol /Lontermin/

21. ADRs of  2 -mimetics muscle tremor (higher doses) palpitation, tachycardia, arrhythmia, sudden death headache paradox bronchospasm (after inhalation) rarely allergy

22. Action of beta-mimetics… 1.Smooth muscle rec. 1.bronchodilation 2.Other receptors (epitelium, mastocytes etc.) 1.mastocytes stabilization 2.inhibition of release mediators from eo, macro, T-cells or neu 3.decreased plasma exsudation to airways 4.etc. Hanania, 2004

23. beclometasone budesonide flunisolide fluticasone triamcinolone  potent antiinflammatory effect  decrease of number of inflammatory potent cells  inhibition of bronchoconstrictory mechanisms  direct relaxation of smooth muscle cells Corticosteroids:

24. ICS & beta-mimetics Synergism: CS recover bronchial responsivity to beta-2 mimetics => mechanism (?) CS recover bronchial responsivity to beta-2 mimetics => mechanism (?) Mechanism (?): Mechanism (?): –increased affinity of agonists to receptors –decreased degradation of receptors –decreased activity of COMT –decreased up-take of mediators to presynaptic button …Pauwels, 1985

25. ADRs of ICS

26. Local ADRs Most frequent: oropharyngel candidosis dysphonia coughPrevention: mouth washing after admin. ciclesonide C21-des-methylpropionyl- ciclesonide use of prodrugs (activation in lungs: ciclesonide => C21-des-methylpropionyl- ciclesonide)

27. Systemic ADRs I. absorption from lung & GI no important ADRs after admin. of budesonide 400  g or its equivalent GINA, 2006

28. Frequently discussed: suprarenal supression decreased BMD glaucoma & cataracta Systemic ADRs II.

29. theophylline - myotropic influence via inhibition of phosphodiesterase and via antagonism on the adenosine receptors A 2 => bronchodilatation => prevention from bronchoconstriction caused by histamine, cholinergic agonists (metacholine) or exertion. Aminophylline = theophylline + ethylendiamine Methylxantines :

30. Antiinflammatory theophylline Watanabe S, 2008

31. Antiinflammatory theophylline Watanabe S, 2008 Note: aminoglutethimide = inhibitor of GC synthesis; mifepristone = anta GCR

32. Mechanism of action ??? SYNERGISM with ICS ??? -both in vitro & in vivo higher activity of HDAC (histon deacetylases) in epit. cells & macrophages => higher eff. of ICS on genes with antiinflammatory properties Ito K, 2002

33. Anticholinergics CNS bronchial epithelium bronchial muscle cells mucus producing cells parasympat. ganglion neurokinines rec. M2 a M3 rec. M1 & M3 n. vagus tiotropium rec. M1

34. Anticholinergics ipratropium /Atrovent, in comb. with  2 mimet. Berodual/ similar structure to atropine shorter eff. 4-8 hrs, rapid onset: 5 ‒ 15 min for acute use with RABA for long-term therapy with LABA tiotropium /Spiriva/ longer eff. up to 48 hrs, slower onset for long-term therapy of BA or COPD

35.  inhibition of degranulation of mastocytes after exposition to specific agents  full effect after 4-6 weeks Cromones cromoglycate sodium nedocromil similar to cromoglycate in mechanism of action

36. zafirlukast montelukast zileuton = inhib. of 5-lipooxygenase Antileukotriens & Leukotriene Receptor Antagonists (LTRAs):

37. Antihistamines:

38. Histamine receptors: H1H1H1H11966 smooth muscles, endothelium, dendritic cells, neu, mono, eo, T a B ly, hepato, chondrocytes, CNS H2H2H2H21972 gastric parietal cells, myocardium, uterus, CNS H3H3H3H31983 CNS, airways, GIT H4H4H4H42000 mast cells

39. = sedative antihistamines inverse agonists of H 1 receptor low selectivity = influence of other receptors short interaction with the receptor => a need of more frequent administration (b.i.d. or t.i.d.) ANTIHISTAMINES 1 st generation

40. Common ADRs: Common ADRs: –antimuscarine eff. –arrhythmia –sedation (cross via HEB) –potentiation of alcohol –adrenolytic & antiserotonergic eff. ANTIHISTAMINES 1 st generation

41. ORALBisulepine Bilastine Dimetinden Clemastine Promethazin Ketotifen PARENTERALBisulepinPromethazinClemastin TOPICALDimetindenKetotifen COMBINED PREPARATIONS – local Spersallerg – eye Sanorin-Analergin – eye, nose Vibrocil – nose

42. = higher selectivity = better safety profile = higher selectivity = better safety profile Substances for systemic administration: Substances for systemic administration: acrivastine, cetirizine, loratadine, mizolastine acrivastine, cetirizine, loratadine, mizolastine Substances for local administration: Substances for local administration: azelastine, emedastine, epinastine, levocabastine, olopatadine azelastine, emedastine, epinastine, levocabastine, olopatadine ANTIHISTAMINES 2 nd generation

43. = active enantiomers (levocetirizine) or metabolites (desloratadine or fexofenadine) = active enantiomers (levocetirizine) or metabolites (desloratadine or fexofenadine) higher selectivity => better tolerability & safety profile higher selectivity => better tolerability & safety profile For systemic administration: For systemic administration: levocetirizine, desloratadine, fexofenadine levocetirizine, desloratadine, fexofenadine ANTIHISTAMINES 3 rd generation

44. verapamile nifedipine etc.  inhibition of calcium influx => inhibition of contraction of smooth muscle cells  induction of bronchodilation  used experimentally Inhibitors of calcium channels

45. Asthma vs glaucoma

46. Asthma vs. glaucoma Concomitant glaucoma and AB BB -in glaucoma – BB = drug of choice (CI: in AB) CS -in AB – CS = drug of choice (CI: in glaucoma)

47. „News“ ULABA arformoterol, carmoterol, indacaterol, GSK-159797 „ULABA“ – „ultra-long acting beta-2 agonists“ - arformoterol, carmoterol, indacaterol, GSK-159797 …in clinical praxis from 2010 for AB & COPD (once daily) omalizumab omalizumab - anti IgE – effective in all. rhinitis as well bimosiamos bimosiamos – inhalatory pan-selectine anta => inhibition of rolling & extravasation of infl. cells

48. Comparison of numbers of drugs used in therapy of bronchial asthma

50. 1) peripheral sensors inhibition - benzonatate, dropropizine 2) afferent signals modulation - prenoxdiazine 3) cough centre inhibition - a) opioid – codein, dextromethorphan - b) non-opioid - butamirate, pipazetate - clobutinol – RC stimulation + cough centre inhibition 4) efferent signals modulation - myorelaxants 5) effector modulation - penthoxyverine - bronchodilation

52. Secretomotorics – plant etheric oils - ol. menthae piperitae Secretolytics - saponines & alcaloids - ipekakuana, primula, NaI, KI, NH 4 Cl Mucolytics - acetylcystein, carbocystein, mesna, bromhexin, ambroxol