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MUDr. M. Laššánová. BRONCHI A L AST H MA Ph arma c ol o g y a nd C linic al A spe c t s. Cvičenie č. 7. DEFIN ITION AB.

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slide1

MUDr. M. Laššánová

BRONCHIAL ASTHMA Pharmacology andClinicalAspects

Cvičenie č. 7

defin ition ab
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.

asthma bronchiale
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
etiopatogenesis
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

triggers of symptoms and exacerbations
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
klinical symptoms of ab
KLINICAL SYMPTOMS OF AB
  • Emphasis on early diagnosis

management begins with right analysis of symptoms

  • to them belong:
  • dyspnoe
  • cough
  • chest distress
  • wheezing
slide9

GINA

2006

klinical signs of ab
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.
diagnostic
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
examinations at ab
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
spirometria
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)
diferential diagnosis
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)
slide15

CHOPD

Asthma Bronchiale

slide16

Symptoms

Pulmonary

functions

CH O P D

slide17

Pulmonary

functions

Symptoms

A S T H M A

goals of optimal ab control
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
therapy of ab
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
slide20

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
therapy of ab1
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...)
a controllers
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
b relievers
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)
inhalatory corticoids ics
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

slide27
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
slide28
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
principles of treatment with ics
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

ics in the treatment of ab stable disease
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)

ics in the treatment of ab exacerbations
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

2 sympat h omimeti cs
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
slide33

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

slide34

ß2- sympatho MIMETICS = SM

Anti M -cholinergic = PsL

activate sympathic NS

block parasympathic NS

dilate bronchi

dilate bronchi

lo c ali sation of r eceptor s
Localisation ofReceptors

cholinergic (parasympathic)

adrenergic

(sympathic)

slide36
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!

slide37

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

slide38
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)
laba in the treatment of ab conclusion
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 !!!

c ontrol of ab
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 !

fix ed c ombin ation ics laba advantages
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

antileukotriene drugs
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.

antileukotriene drugs1
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
methylxanthines
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
methylxanthines1
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)
slide46
SABA
  • basic relievers
  • usedad hocto relieve or to remove symptoms
  • noreason forregularadministration
  • salbutamol(Ventolin)
  • fenoterol/Australia – deregistered for AE KVS/
  • terbutaline
inhalatory anticholinergic drugs
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

slide48

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

inhalatory anticholinergic drugs1
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
slide50

FUTURE

CONVENTIONAL

LOGICAL

One inhaler: Maintenance & relief

Rapid adjustments in controller replacing SABA

Adjustable maintenance dose

No adjustment in controller

SUND

Maintenance

+ prn Bud/form

Maintenance

+ prn SABA

EVOLUTION IN ASTHMA THERAPY

FACET

OPTIMA

GOAL

SMART =

Single inhaler Maintenance

And Reliever Therapy

Medication Use

Bud/form

Flut/salm

Maintenance

+ prn SABA