BRONCHI A L AST H MA Ph arma c ol o g y a nd C linic al A spe c t s

1. MUDr. M. Laššánová BRONCHIAL ASTHMA Pharmacology andClinicalAspects Cvičenie č. 7

2. DEFINITION AB Asthma bronchiale is chronic inflammatory disease of airways connected with bronchial hyperreactivity andtotally or partiallyreversible obstruction of airways, which in the most casesdissapears spontaneously or with treatment.

3. ASTHMA BRONCHIALE • reversible obstruction • daily symptom variability • family history • beginning at any age, most often • 10-15% children • 5-10% adults • no smoking • allergy, rinitis, eczema - may / may not

4. Celosvetová iniciatíva pre astmu GINA 1995, 2002, 2006

5. ETIOPATOGENESIS •  INFLAMMATION activation of mastocytes, macrophages, eosinophils, helper Th-lymfocytes => formed and released inflammatory mediators: histamine, leucotriens, prostaglandins, bradykinin bronchoconstriction, mucus secretion, plasma exudation and bronchial hyperreactivity, airway remodelation  insufficient anti-inflammatory therapy => progressive destructive changes fixing of airway obstruction to emphysematous changes

6. Triggers of Symptoms and Exacerbations • allergens • factors of air pollution (including cigarette smoke) • respiratory infections, particularly viral (RSV, rhinoviruses, influenza viruses, chlamydia) • physical activity and hyperventilation (by osmotic processes) • wheather changes • food and drugs (ASA, NSAID, -blockers) • emotional stress • gastroesophageal reflux

7. KLINICAL SYMPTOMS OF AB • Emphasis on early diagnosis management begins with right analysis of symptoms • to them belong: • dyspnoe • cough • chest distress • wheezing

8. Clasification of Asthma according to clinical symptoms and lung function: GINA 2002

9. GINA 2006

10. KLINICAL SIGNS OF AB • depends on the stage of asthma • intermittent attacks of expiration type dyspnoe, ich worsening at night and at dawn • wheezing: intermittent, more significant at expiration • cough: usually not productive, can be basic sign • anxiety, pressure, chest tightness, dyspnoe • sputum production usually little, if than väzký mucus • prodromal signs prior attack: itching under the chin, discomfort between shoulder blades, fear, anxiety • typical is vanishing of signs after b-dilatances or antiinflammatory therapy, unsuccessful ATB th.

11. DIAGNOSTIC • PRINCIPLE:simple examinations made repeatedly are more usefull than complete examinations made at one time or during long intervals limitation of expiratory flow at asthma has variable character  findings may vary from completely normal to absolutely pathological • Functional diagnostics • Allergologic diagnostics • Specifying of inflammation markers

12. EXAMINATIONS AT AB • SPIROMETRIA • BRONCHODILATION TESTS (BDT) • it verifies the degree of obstruction reversibility • BRONCHOPROVOKING TEST (BKT) • BKT with histamine, ACh, adenosine, excercise, cold... • negative BKT excludes dg. of AB (absence of bronchial hyperreactivity...) • PEF variability by výdychomerom(self monitoring) • ARTERIAL BLOOD GASES(at exacerbation) • Determination of NO in exhaled air(early marker of asthmatic inflammation) • SPUTUM EXAMINATION • eosinophils and their effective products, Curshmann´s spirals, Charcot-Leyden´s crystalls

13. SPIROMETRIA • simple, reproductible • gives informations about restriction of air flow • – FVC(forced vital capacity) • FEV1(sec. vital cap.) • FEV3(forced expiratory flow at 50% expiration) • FEV1/VC– Tiffaneau´s index (FEV3/VC) • PEF (peak expiratory flow in l/min)

14. DIFERENTIAL DIAGNOSIS • chronic obstructive pulmonary disease • asthma cardiale at older adults • viral bronchiolitis at children • hyperventilatory syndrom • fixed obstacles in the airways (tumors, extramural compression, foreign particles) • diffuse interstitial lung processes • pneumothorax • chest wall diseases (kyphoscoliosis, neuromuscular diseases)

15. CHOPD Asthma Bronchiale

16. Symptoms Pulmonary functions CH O P D

17. Pulmonary functions Symptoms A S T H M A

18. GOALS of Optimal AB Control • elimination or significant reduction of symptoms • prevention of exacerbations • maintaining lung functions closest to physiological values • maintaining normal physical and living activity • absence of treatment adverse effects • prevention of irreversiblebronchial obstruction (remodelation of lower airways) • preventing asthma mortality

19. THERAPY OF AB • Nonpharmacological • Patients´ education • avoiding risk factors and triggers- • Pharmacological • A N T I I N F L A M M A T O R Y • relieves inflammation and bronchial hyperreactivity • regular, long-term use • B R O N CH O D I L A T O R Y • eliminates the symptoms of expiratory flow limitation • rescue therapy in exacerbation

20. Administration of Drugs at AB • peroral • parenteral • by inhalation  • directly to the site of action • fast beginning of action • maximum efficacy • lower therapeutic doses = minimalise risk of AE • limitationsfrom the site of patient (technique of inhalation, cooperation...) • inspiratory resistance, needs to be overcomed

21. Inhalatory Systems Nowadays

23. THERAPY OF AB A: CONTROLLERS • preventive drugs, controlling inflammation • are taken regularly,long time to maintain control  antiinflammatory drugs  long acting inhalatory bronchodilators B: RELIEVERS substances releasing bronchospasm  relieving = fast acting bronchodilators C: OTHER ANTIASTHMATIC DRUGS • Monoclonal Ab against IgE = omalizumab (50 pat. in SR) • ketotifen • Imunosupressives (MTX, CysA...)

24. A: CONTROLLERS • inhalatory corticoidsICS • long-acting2-sympathomimetics (long-acting betaagonists )LABA, (8-15h.) • antileukotriensLTRAs • leukotriene receptor antagonists • inhibitors of 5-lipooxygenase(zileuton) • retard methylxanthines • cromones

25. B: RELIEVERS • inhalatory short-acting2-sympathomimetics(short-acting betaagonists ) SABA (do 4-6 h.) • inhalatory anticholinergicsshort-acting • systemiccorticoids p.o./i.v. („rescue“ treatment)

26. INHALATORY CORTICOIDS ICS the most effectiveantiinflammatory antiasthmatics • to long-term use at all forms of AB • Mechanism of action: 1.inhibition of cytokine transcription antiinflam. ef. 2.inhibition of mediators of inflam. release 3.decrease of airways reactivity 4.restriction of vasodilation antioedematic ef. 5.affect synthesis of eikosanoids 6.control activation of adhesive molecules 7.increase of susceptibilityresp. protection of 2 receptors against down-regulation at long-term treatment with 2 mimetics

27. ICS • AE locally can reduce with the use of attachments and rinsing the mouth with NaHCO3 • oropharyngeal candidosis • dysphonia   • seldomly irritation to cough • risk of systemic AE is, depends on dose ,efficacy andpharmacokinetic ofsteroid • inflammationin airways, bronchialhyperreactivity andobstruction of airways • risk ofAE(acute exacerbations) andcontrol symptomsof disease

28. ICS • beclomethasone • budesonide • fluticasone • ciclesonide – 1 times per day, minimal syst. AE, prodrug-activationdirrectly inlungs, the part resorbed is inactive=>  systemicef. !!! • mometasone • flunisolide •  dexamethasone •  triamcinolone

29. Principles of Treatment with ICS 1. ICS need to be administered at each new dg.AB 2. Treatment is essential to start early 3.We administerattack doses of ICS 4. Reduction of dose only after longer stabilisation (6 months) – than minimal effective dose 5. If not sufficient low doses of ICS, we don´t increase them, but add LABA, possibly with methylxanthines, antileucotriens 6. High doses of ICS we try to avoid  relativelly small therapeutic benefit compared to higher incidence of AE

30. ICS in the Treatment ofAB – „stable disease“ mild persistent asthmamonotherapy with small doses of ICS ( 500µg BDP/d) addition ofLABAwill not reduce the symptoms unless they are deteriorated pulmonary functions decrease moderate persistent asthmaifinsufficientcontrol add LABAatfailure in the next step dose ICS (cca. 800µg BDP/d)

31. ICS in the Treatment ofAB – „exacerbations“ doubledose ofICS attreatment of AE isn´t effective veryhigh doses ICS (2000-4000µg BDP) to 1-2 Wmay be effective the besttoaddhigh dose of ICStoregular maintenance therapy ICS+LABA atsevere AEsystemicCS

32. ß2- SYMPATHOMIMETICS • Mechanism of action = agonistic, activating influence on ß2 receptors of sympathic NS 1. Long-actingß2SM (long-acting betaagonists )= LABA • Controllers – to long-term,regular bronchodilation 2. Short-actingß2SM (short-acting betaagonists )= SABA • Relievers – to short-term, acutemanagement of exacerbation

33. β2 –sympathomimetics(LABA and SABA) speed of effect beginning rescue treatment Fast beginning, short duration inhal. terbutaline salbutamol, fenoterol Fast beginning, long duration inhal. formoterol FAST maintanance therapy Slow beginning, short duration oral terbutaline, salbutamol, formoterol Slow beginning, long duration inhal. salmeterol, oral bambuterol SLOW duration of action SHORT LONG SABA LABA

34. ß2- sympatho MIMETICS = SM Anti M -cholinergic = PsL activate sympathic NS block parasympathic NS dilate bronchi dilate bronchi

35. Localisation ofReceptors cholinergic (parasympathic) adrenergic (sympathic)

36. LABA • the best, fast and intense acting b-dilatans duration of action>12 hours MA:Bronchodilation through β2 => relaxation of smooth muscle Improvemucociliar clearens Lowervascular permeability Modulate release of mediators from mastocytes a bazophils Provide long-term safety against bronchoconstriction Length of this bronchodilation effect at long-term regular administration decreases  sign oftollerance for down regulation of β2 receptors => inhibition = concomitant administration of ICS LABA in long-term therapy of asthma never can administer lonely, without ICS!

37. Molecular mechanism ofpositive interaction ICS and LABA Corticosteroid ß2-Agonist Anti-inflammatory effect Bronchodilatation ß2-Adrenoceptor Glucocorticoid receptor • Effect of corticosteroids on ß2-adrenoceptors • Effect of ß2-agonists on glucocorticoid receptors LABA: zlepšenie utilizácie KS a internalizácie GR do jadra (translokácia GR) ICS: prevencia desenzitizácie a znižovania expresie β2 receptora

38. LABA • formoterol • salmeterol Monotherapy LABA: •  effectivity of LABA vs. ICS • improving sleeping, butwithout effect to pulmonary functions • discontinuation ICS andadding LABAat persistent asthmaloosingcontrol • goodcontrolled patient with asthma with persistent asthmaat low dose ICS replacement by LABAloosingcontrol ( eNo and Eo in sputum) • without effect on inflam.in airways (biopsia)

39. LABA in the Treatment ofAB - Conclusion the most effective bronchodilatorsat AB effective atchildren and also adults formoterolsuitable also forAE(since fast beginnig + long duration of action) clinicallywithoutantiinflam. effect most effectivellyincombination with ICS formoterolcan be as rescue bronchodilator more effective than SABA at pat. not responding to SABA !!! at AB always prescribe together with ICS !!!

40. CONTROL ofAB low doseICS ifno controlreached: high doseICScosts addLABAmost effective addlow-dose methylxanthinescheapest addLTRAs little effective, expensive 3.ICS+LABA = the best strategyof AB treatment 4.15 studies: adding LABAto ICS ismore effectivethandoubling of ICS dose !

41. Fixedcombination ICS+LABA – ADVANTAGES  compliance costs controlof asthma fastercontrol of asthma  dose ICSto reachcontrol in 1 inhalation divice deposition of ICS and LABA at the same placecan occurmolecular interaction ICS+LABA frequency ofAEmore than dose of ICS formoterol + budesonide salmeterol + fluticasone

42. Specific Label Changes for Long-Acting Beta-Agonists (LABAs). 1. Contraindicate the use of LABAs for asthma in patients ofall ages without concomitant use of an asthma-controller medicationsuch as an inhaled corticosteroid. 2. Stop use of the LABA, if possible, once asthma control isachieved and maintain the use of an asthma-controller medication,such as an inhaled corticosteroid. 3. Recommend against LABA use in patients whose asthma is adequatelycontrolled with a low- or medium-dose inhaled corticosteroid. 4. Recommend that a fixed-dose combination product containinga LABA and an inhaled corticosteroid be used to ensure compliancewith concomitant therapy in pediatric and adolescent patientswho require the addition of a LABA to an inhaled corticosteroid. Chowdhury BA, Dal Pan G. The FDA and Safe Use of Long-Acting Beta-Agonists in the Treatment of Asthma. N Engl J Med. 2010 Feb 24.

43. ANTILEUKOTRIENE DRUGS • controllers, for long-term control of symptoms • antagonists of leukotriene 1 (CysLT1) receptors •  montelukast, zafirlukast, pranlukast • inhibitors of 5-lipooxygenase • zileuton • taken perorally • MA: - additive antiinflam. effect to ICS - reduce tissue eosinophilia - mild bronchodilation  ef. - bronchoprotective ef.

44. ANTILEUKOTRIENE DRUGS • role in therapy of AB - still unclear • are less effectivethan low doses of ICS • asadditivedrugs (incombinationwith ICS) reduce the need of steroid dose at severe asthma • againless effectivethanstandard ICS+LABA • advantageous – aspirin asthma, by excercise induced asthma, „preschool wheezing“ •  compliance at taking tablet form

45. METHYLXANTHINES • controllers, to long-lasting control of symptoms • Improvement of clinical symptomatology • bronchodilation - without signif. increase of FEV1/ improvement of lung function parameters  through inhibition of fosfodiesterase I. to IV. =>  cAMP • antiinflam., immunomodulatory effects • positive effect on phenomenon of „corticoid resist.“ • AE: cephalea, nausea, vomiting, tachycardia, palpitations,  plasm. conc. (TDM)  arrhytmias, epileptic spasms even death • potential toxicity, profile of AE bronchodilators of the third choice

46. METHYLXANTHINES Proven benefit bring only drug forms providing long-lasting action with controlled release • with controlled release - p.o. • aminophylline, theophylline for using during day time always + ICS – less effective than ICS+LABA • with short-lasting ef. - p.o., i.v. • aminophylline, teophylline • others:doxophylline, cilomilast (select. inhibitor of PDE4)

47. SABA • basic relievers • usedad hocto relieve or to remove symptoms • noreason forregularadministration • salbutamol(Ventolin) • fenoterol/Australia – deregistered for AE KVS/ • terbutaline

48. INHALATORY ANTICHOLINERGIC DRUGS  Relievers of the second choice, at AE  competitiveantagonists on M1, M2 and M3 receptors of parasympathicus   cholinergic tonus  Division: • with short-lasting effect: ipratropium bromide • with prolonged effect: oxitropium bromide • with long-lasting effect: tiotropium bromide CHOCHP

49. Muscarinic receptorys in airways Pre-gangliovýnerv Nicotinový receptor (+) M1 receptor (+) Parasympatickéganglion Post-gangliovýnerv M2 receptor (–) M3 receptor (+) ACh Hladký sval Barnes PJ. Eur Respir Rev 1996

50. INHALATORY ANTICHOLINERGIC DRUGS • decrease n. vagus tonus • cause relaxation • but no bronchoprotective action • are in general less effective than β– mimethics and have a little slower beginning of action • advantageous combinations v 1inhalation system: • ipratropium • ipratropium+salbutamolipratropium+fenoterol