1 / 52

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

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

mabyn
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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. 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. CLINICAL SYMPTOMS OF AB • Emphasis on earlydiagnosis managementbeginswithrightanalysisofsymptoms • to thembelong: • dyspnoe • cough • chesttightness • wheezing

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

  9. GINA 2006

  10. 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 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. 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

  12. 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

  13. 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)

  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. 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

  21. Inhalatory Systems Nowadays

  22. THERAPY OF AB A: CONTROLLERS • preventivedrugs, controllinginflammation • are takenregularly,longtimeto maintaincontrol  antiinflammatorydrugs  longactinginhalatorybronchodilators B: RELIEVERS substancesreleasingbronchospasm  relieving = fastactingbronchodilators C: OTHER ANTIASTHMATIC DRUGS • MonoclonalAbagainstIgE = omalizumab(50 pat. in SR) • ketotifen • Imunosupressives (MTX, CysA...)

  23. 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

  24. B: RELIEVERS • inhalatory short-acting2-sympathomimetics(short-acting betaagonists ) SABA (till 4-6 h.) • inhalatory anticholinergicsshort-acting • systemiccorticoids p.o./i.v. („rescue“ treatment) • some sources – controllers • fast acting methylxantines

  25. 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

  26. 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

  27. ICS • beclomethasone • budesonide • fluticasone • ciclesonide – 1times per day, minimalsyst. AE, prodrug-activationdirrectly inlungs, the part resorbedisinactive => systemicef. !!! • mometasone

  28. 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 ICS, we add as the drug of the first choice LABA, alternatives are leucotriene modifiers ( the first choice add-on therapy for children younger than 5 years), methylxanthines, slow release β2-agonists tablets 6. To adult patients are administered max. 200-800 mcg BDP/day and to children max. 400 mcg BDP/day, than you should start on with add-on therapy

  29. ICS in the Treatment ofAB – „exacerbations“ • thebesttoaddhighdoseof ICStoregularmaintenancetherapyICS+LABA • atsevere AEsystemicCS

  30. Adverse effects of systemically administered corticosteroids • Infections • The long-term use may increase blood pressure, cause fluid retention and salt retentionin the body (oedema), increasedexcretionofcalcium and potassium • Worse and longer wound healing • Rash and acne • Hyperglycaemia • They increase the risk of gastrointestinal perforation • Increased appetite and weightgain • Osteoporosis (↓ absorption of calcium, ↑ itsexcretion) • Muscle pain, muscleweakness and musclecramps (especially ↑ loss of potassium, ↓ calciumlevel in theblood) • Cataract, increased intraocular pressure, optic nerve damage, eye infections • CNS: irritability, mood and personality changes, depression, headaches, dizziness

  31. 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

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

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

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

  35. 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!

  36. 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

  37. 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)

  38. 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.

  39. 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.

  40. ANTILEUKOTRIENE DRUGS • controllers,forlong-termcontrolofsymptoms • antagonistsofleukotriene 1 (CysLT1)receptors •  montelukast, zafirlukast, pranlukast • inhibitorsof 5-lipooxygenase • zileuton • takenperorally • MA: -additiveantiinflam. effect to ICS -reducetissueeosinophilia -mildbronchodilationef. -bronchoprotectiveef.

  41. 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

  42. 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

  43. METHYLXANTHINES Provenbenefitbringonlydrugformsprovidinglong-lastingactionwithcontrolledrelease • withcontrolledrelease- p.o. • aminophylline, theophylline forusingduringdaytimealways + ICS – lesseffectivethan ICS+LABA • withshort-lastingef. - p.o., i.v. • aminophylline

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

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

  46. 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

  47. INHALATORY ANTICHOLINERGIC DRUGS • decrease n. vagus tonus • cause relaxation • but no bronchoprotective action • are in general less effective than β2– mimethics and have a little slower beginning of action • advantageous combinations v 1inhalation system: • ipratropium • ipratropium+fenoterol

More Related