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

1. BRONCHIAL ASTHMA Pharmacology andClinicalAspects

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. AB • Extrinsic: oftenallergy and atopy • Intrinsic:non-alergic 10-30% (more severe, adult-onset) • dailysymptom variability • familyhistory • no smoking

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. CLINICAL SYMPTOMS OF AB • Emphasis on earlydiagnosis managementbeginswithrightanalysisofsymptoms • to thembelong: • dyspnoe • cough(in youngerpeoplemaybetheonlysymptom, mostly at night) • chesttightness • wheezing

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

10. GINA 2006

11. CLINICAL 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 deep mucus • prodromal signs prior attack: itching under the chin, discomfort between shoulder, fear, anxiety • typical is vanishing of signs after b-dilators or antiinflammatory therapy, unsuccessful ATB th.

12. DIAGNOSIS • 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

13. EXAMINATIONS AT AB • SPIROMETRY • BRONCHODILATION TESTS (BDT) • itverifiesthedegreeofobstructionreversibility • BRONCHOPROVOKING TEST (BKT) • BKT withhistamine, ACh, adenosine, excercise, cold... • negative BKT excludesdg. of AB (absenceofbronchialhyperreactivity...) • PEF variability by výdychomerom(self monitoring) • ARTERIAL BLOOD GASES(atexacerbation) • Determinationof NO in exhaledair(earlymarkerofasthmaticinflammation) • SPUTUM EXAMINATION • eosinophils and theireffectiveproducts, Curshmann´sspirals, Charcot-Leyden´scrystalls

14. SPIROMETRY • 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)

15. 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)

16. COPD • 95% are or have been cigarette smokers • less common causes: exposure to air polution, inherited alfa1-antiprotease deficiency • symptoms: persistent airflow obstruction, which can be reversible or irreversible and slowly progressive → progressive breathlessness and cough (often productive and worse in the morning), repeated respiratory infections, can lead to emphysema • particularly affects the peripheral airways

17. COPD Asthma Bronchiale

18. Symptoms Pulmonary functions C O P D

19. Pulmonary functions Symptoms A S T H M A

20. 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

21. 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

22. AdministrationofDrugsat AB • peroral • parenteral • by inhalation • directly to the site ofaction • fastbeginningofaction • maximum efficacy • lowertherapeuticdoses = minimalise risk of AE • limitationsfromthe site ofpatient(techniqueofinhalation, cooperation...) • inspiratoryresistance, needs to beovercomed

23. Device For Delivery of Drugs in AB • Pressurisedmetered-doseinhaler The most common device Theinhalershouldbeshaken beforeuse

25. Device For Delivery of Drugs in AB • Pressurisedmetered-doseinhalerwithspacer Spacer = plasticreservoir Removestheneed to coordinateaerosolactivation and inspiration (youngchildren)

26. Device For Delivery of Drugs in AB • Breath-actuatedmetered-doseinhaler Severaltypes; activated by inhalation Delivereitheranaerosol or drypowder Cannotbeusedwithspacer

27. Device For Delivery of Drugs in AB • Dry-powderinhaler Somedevicesuse a single dosecapsule, others are multidose (thesourseis a bulkpowderwiththe device meteringthedose)

29. Device For Delivery of Drugs in AB • Multi-doseliquidinhaler New delivery device Highdrugdelivery to thelungs

30. Device For Delivery of Drugs in AB • Nebulisers Are usedwithfacemask or mouthpiece to deliverdrugfromreservoirsolution Up to 10 timestheamount of drugisrequired in nebuliser to producethesameeffect as MDI • Jetnebulisers Usecompressedair or oxygen

31. Device For Delivery of Drugs in AB • Nebulisers 2. Ultrasonicnebulisers Produce more uniformparticlesize, but are more expensive Usepiezoelectriccrystalvibrating (do notrequiregassflow)

32. THERAPY OF AB A: Bronchodilators 1st choice: ß2- sympathomimetics 2nd choice: anticholinergics 3rd choice: methylxantines B: Anti-inflammatory drugs 1st choice: ICS 2nd choice: leukotriene receptor antagonists severe asthma: monoclonal antibodies

33. INFLUENCE OF AUTONOMIC NERVOUS SYSTEM IN THE TREATMENT OF ASTHMA • ß2- SYMPATHOMIMETICS • ANTICHOLINERGICS ADMINISTRATION BY INHALATION

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. ß2- SYMPATHOMIMETICS • Mechanism of action = agonistic, activatinginfluence on ß2 receptors ofsympathic NS 1. Long-actingß2SM (long-actingbetaagonists )= LABA • Controllers – to long-term,regularbronchodilation 2. Short-actingß2SM (short-actingbetaagonists )= SABA • Relievers– to short-term, acutemanagement ofexacerbation

37. ß2- SYMPATHOMIMETICS • Mechanism of action: Influence of ß2-receptors in lungs (↑cAMP, aktivation of PKA, phosphorylation of proteinsthatregulatesmoothmuscle tone) • TheregularusecanenhanceTh2 Inflammatorypathways and alsodown-regulate ß2-receptors (regularuse of ß2-sympathomimetics without ICS isnotadvised)

38. 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, indakaterol FAST maintanance therapy Slow beginning, short duration oral clenbuterol, salbutamol rtd. cps. Slow beginning, long duration inhal. salmeterol SLOW duration of action SHORT LONG SABA LABA

39. SABA • basicrelievers • usedad hocto relieve or to remove symptoms • noreasonforregularadministration • salbutamol(Ventolin) • fenoterol/Australia – deregisteredfor AE CVS/

40. LABA • thebest, fast and intenseacting b-dilatans duration ofaction>12 hours MA:Bronchodilationthroughβ2 => relaxation of smoothmuscle Improvemucociliarclearens Lowervascularpermeability Modulaterelease of mediatorsfrommastocytes a bazophils Providelong-term safetyagainstbronchoconstriction Length of thisbronchodilationeffect at long-term regularadministrationdecreasessign oftollerancefordownregulation of β2receptors => inhibition=concomitantadministration of ICS LABA in long-term therapy of asthma never canadministerlonely, without ICS!

41. β2 – SYMPATHOMIMETICS(LABA, SABA, ultraLABA)

42. 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

43. 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)

44. ß2- SYMPATHOMIMETICS - ADRs • Fine skeletal muscle tremor • Tachycardia and arrhythmias (high doses, oral or parenteral administration) • Hypokalaemia with high doses • Paradoxical bronchospasm • Headache • Tolerance (avoids use of ICS)

45. FDA – LABA drug safety communication 2011 • In February 2010, the agency announced it was requiring manufacturers to revise their drug labels because of an increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations, in pediatric and adult patients, as well as death in some patients using LABAs for the treatment of asthma.

46. FDA – LABA drug safety communication 2011 • The new recommendations in the updated labels state: • Use  of a LABA alone without use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated (absolutely advised against) in the treatment of asthma. • LABAs should not be used in patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. • LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. • Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an inhaled corticosteroid. • Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure adherence with both medications.

47. INHALED ANTIMUSCARINIC DRUGS  Relieversofthesecondchoice, at AE  competitiveantagonists on M1, M2 and M3receptorsofparasympathicus  cholinergic tonus  Division: • withshort-lastingeffect: ipratropiumbromide • withlong-lastingeffect: tiotropiumbromide (CHOPD)

48. FDA – LABA drug safety communication 2011 • In February 2010, the agency announced it was requiring manufacturers to revise their drug labels because of an increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations, in pediatric and adult patients, as well as death in some patients using LABAs for the treatment of asthma.

49. FDA – LABA drug safety communication 2011 • The new recommendations in the updated labels state: • Use  of a LABA alone without use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated (absolutely advised against) in the treatment of asthma. • LABAs should not be used in patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. • LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. • Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an inhaled corticosteroid. • Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure adherence with both medications.

50. Muscarinic receptorys in airways Pre-ganglionicnerve Nicotinic receptor (+) M1 receptor (+) Parasympatheticganglion Post-ganglionicnerve M2 receptor (–) M3 receptor (+) ACh Smooth muscle Barnes PJ. Eur Respir Rev 1996