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Drugs affecting respiratory system Jiří Slíva Absolute number of patients suffering from AB in CZ Number of patients Period http://issar.cenia.cz 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 THE MOST IMPORTANT ALERGENES Pollen situation of„Alnus glutinosa“ in the Europe 1. DEC. 2. DEC. 3. DEC. JANUARY FEBRUARY MARCH APRIL MAY DIAGNOSIS 2. CLINICAL FEATURES 1. ANAMNESIS 3. LABORATORY TESTS 4. ALLERGOLOGICAL TESTS life style pharmacoterapy specific imunotherapy (SCIT vs SLIT) symptomatic preventive antiinflammatoric Groups of drugs: • sympatomimetics • anticholinergics • corticosteroides • methylxantines • antileukotriens • antihistamines • MABs Novolizer: Ventodisk, Turbuhaler: Antiasthmatics with rapid effect: 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 β2-mimetics with long-term effect: • via inhalation salmeterol • via per os (tbl, susp) clenbuterol, procaterol 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) 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/ ADRs of 2-mimetics • muscle tremor (higher doses) • palpitation, tachycardia, arrhythmia, sudden death • headache • paradox bronchospasm (after inhalation) • rarely allergy 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 Corticosteroids: 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 ICS & beta-mimetics Synergism: CS recover bronchial responsivity to beta-2 mimetics => 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 ADRs of ICS Local ADRs Most frequent: oropharyngel candidosis dysphonia cough Prevention: mouth washing after admin. use of prodrugs (activation in lungs: ciclesonide => C21-des-methylpropionylciclesonide) Systemic ADRs I. absorption from lung & GI no important ADRs after admin. of budesonide 400 mg or its equivalent GINA, 2006 Systemic ADRs II. Frequently discussed: suprarenal supression decreased BMD glaucoma & cataracta Methylxantines: theophylline - myotropic influence via inhibition of phosphodiesterase and via antagonism on the adenosine receptors A2 => bronchodilatation => prevention from bronchoconstriction caused by histamine, cholinergic agonists (metacholine) or exertion. Aminophylline = theophylline + ethylendiamine Antiinflammatory theophylline Watanabe S, 2008 Antiinflammatory theophylline Note: aminoglutethimide = inhibitor of GC synthesis; mifepristone = anta GCR Watanabe S, 2008 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 Anticholinergics CNS n. vagus bronchial epithelium rec. M1 parasympat. ganglion neurokinines rec. M1 & M3 mucus producing cells rec. M2 a M3 bronchial muscle cells tiotropium 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 Cromones cromoglycate sodium inhibition of degranulation of mastocytes after exposition to specific agents full effect after 4-6 weeks nedocromil • similar to cromoglycate in mechanism of action Antileukotriens & Leukotriene Receptor Antagonists (LTRAs): zafirlukast montelukast zileuton = inhib. of 5-lipooxygenase Antihistamines: Histamine receptors: H1 1966 smooth muscles, endothelium, dendritic cells, neu, mono, eo, T a B ly, hepato, chondrocytes, CNS gastric parietal cells, myocardium, uterus, CNS H2 1972 H3 1983 CNS, airways, GIT H4 2000 mast cells ANTIHISTAMINES 1st generation = sedative antihistamines inverse agonists of H1 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 1st generation Common ADRs: – antimuscarine eff. – arrhythmia – sedation (cross via HEB) – potentiation of alcohol – adrenolytic & antiserotonergic eff. ANTIHISTAMINES 1st generation ORAL PARENTERAL Bisulepine Bilastine Dimetinden Clemastine Promethazin Ketotifen Bisulepin Promethazin Clemastin TOPICAL COMBINED PREPARATIONS – local Dimetinden Ketotifen Spersallerg – eye Sanorin-Analergin – eye, nose Vibrocil – nose ANTIHISTAMINES 2nd generation = higher selectivity = better safety profile Substances for systemic administration: acrivastine, cetirizine, loratadine, mizolastine Substances for local administration: azelastine, emedastine, epinastine, levocabastine, olopatadine ANTIHISTAMINES 3rd generation = active enantiomers (levocetirizine) or metabolites (desloratadine or fexofenadine) higher selectivity => better tolerability & safety profile For systemic administration: levocetirizine, desloratadine, fexofenadine Inhibitors of calcium channels verapamile nifedipine etc. inhibition of calcium influx => inhibition of contraction of smooth muscle cells induction of bronchodilation used experimentally Asthma vs glaucoma Asthma vs. glaucoma Concomitant glaucoma and AB - in glaucoma – BB = drug of choice (CI: in AB) - in AB – CS = drug of choice (CI: in glaucoma) „News“ „ULABA“ – „ultra-long acting beta-2 agonists“ arformoterol, carmoterol, indacaterol, GSK-159797 …in clinical praxis from 2010 for AB & COPD (once daily) omalizumab - anti IgE – effective in all. rhinitis as well bimosiamos – inhalatory pan-selectine anta => inhibition of rolling & extravasation of infl. cells Comparison of numbers of drugs used in therapy of bronchial asthma 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 Secretolytics - saponines & alcaloids ipekakuana, primula, NaI, KI, NH4Cl Mucolytics - acetylcystein, carbocystein, mesna, bromhexin, ambroxol Secretomotorics – plant etheric oils - ol. menthae piperitae