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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.

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

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Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

BRONCHIAL ASTHMA Pharmacology andClinicalAspects

Defin ition 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


  • reversible obstruction

  • daily symptom variability

  • family history

  • beginning at any age, most often

    • 10-15% children

    • 5-10% adults

  • no smoking

  • allergy, rhinitis, eczema - may / may not

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

Celosvetová iniciatíva pre astmu


1995, 2002, 2006



  •  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

Clinical symptoms of ab


  • Emphasis on earlydiagnosis


  • to thembelong:

  • dyspnoe

  • cough

  • chesttightness

  • wheezing

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

Clasification of Asthma according to clinical symptoms and lung function:



Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s



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.



  • 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




    • itverifiesthedegreeofobstructionreversibility


    • 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)


    • eosinophils and theireffectiveproducts, Curshmann´sspirals, Charcot-Leyden´scrystalls



  • 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


  • 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)

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s


Asthma Bronchiale

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





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


  • 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

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

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

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

Inhalatory Systems Nowadays

Therapy of ab1



  • preventivedrugs, controllinginflammation

  • are takenregularly,longtimeto maintaincontrol

     antiinflammatorydrugs

     longactinginhalatorybronchodilators



     relieving = fastactingbronchodilators


  • MonoclonalAbagainstIgE = omalizumab(50 pat. in SR)

  • ketotifen

  • Imunosupressives (MTX, CysA...)

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


  • 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

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

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s


  • 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

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s


  • beclomethasone

  • budesonide

  • fluticasone

  • ciclesonide – 1times per day, minimalsyst. AE, prodrug-activationdirrectly inlungs, the part resorbedisinactive => systemicef. !!!

  • mometasone

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 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

Ics in the treatment of ab stable disease according to british guidelines

ICS in theTreatmentofAB – „stable disease“according to Britishguidelines

  • mildintermittentasthma

  • inhaled short-acting β2-agonists as needed

  • mild persistentasthmamonotherapy withsmalldosesof ICS( 500µg BDP/d)

    • additionofLABAwillnotreducethesymptomsunlesstheyaredeteriorated resp. pulmonaryfunctions are decreased

      *BDP = Beclomethasonedipropionate CFC

Ics in the treatment of ab stable disease

ICS in theTreatmentofAB – „stable disease“

  • moderate persistentasthma

  • inhalated short-acting β2-agonists regularly

  • iflack of control by ICS → add LABA:

  • good response to LABA → continue combination therapy LABA + ICS

  • LABA effective, but inadequate control → increase the dose of ICS to

    BDP 800 mcg/day

    3.LABA ineffective →quit LABA, increase the dose of ICS to

    BDP 800 mcg/day → ifstillinadequatecontrol→ add other anti-asthmatics (leucotrienemodifiers, methylxanthines)

  • persistent poor control

  • inhalaled short-acting β2-agonists regularly

  • increase the dose of ICS

  • adding a fourth drug

Ics in the treatment of ab exacerbations

ICS in the Treatment ofAB – „exacerbations“

  • thebesttoaddhighdoseof ICStoregularmaintenancetherapyICS+LABA

  • atsevere AEsystemicCS

Adverse effects of systemically administered corticosteroids

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

2 sympat h omimeti cs


  • 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

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

β2 –sympathomimetics(LABA and SABA)

speed of effect beginning

rescue treatment

Fast beginning,

short duration


salbutamol, fenoterol

Fast beginning,

long duration

inhal. formoterol


maintanance therapy

Slow beginning,

short duration


salbutamol rtd. cps.

Slow beginning,

long duration

inhal. salmeterol


duration of action





Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

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)



Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s


  • 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!

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

Molecular mechanism ofpositive interaction ICS and LABA



Anti-inflammatory effect





  • 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

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s


  • 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 airways (biopsia)

Fda laba drug safety communication 2011

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.

Fda laba drug safety communication 20111

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.

Antileukotriene drugs


  • controllers,forlong-termcontrolofsymptoms

  • antagonistsofleukotriene 1 (CysLT1)receptors

    •  montelukast, zafirlukast, pranlukast

  • inhibitorsof 5-lipooxygenase

    • zileuton

  • takenperorally

  • MA: -additiveantiinflam. effect to ICS -reducetissueeosinophilia



Antileukotriene drugs1


  • 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



  • 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




  • withcontrolledrelease- p.o.

    • aminophylline, theophylline forusingduringdaytimealways + ICS – lesseffectivethan ICS+LABA

  • withshort-lastingef. - p.o., i.v.

    • aminophylline

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s


  • basicrelievers

  • usedad hocto relieve or to remove symptoms

  • noreasonforregularadministration

  • salbutamol(Ventolin)

  • fenoterol/Australia – deregisteredfor AE CVS/

Inhalatory anticholinergic drugs


 Relieversofthesecondchoice, at AE

 competitiveantagonists on M1, M2 and M3receptorsofparasympathicus

 cholinergic tonus

 Division:

  • withshort-lastingeffect: ipratropiumbromide

  • withlong-lastingeffect: tiotropiumbromide (CHOPD)

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

Muscarinic receptorys in airways


Nicotinový receptor (+)

M1 receptor (+)



M2 receptor (–)

M3 receptor (+)


Hladký sval

Barnes PJ. Eur Respir Rev 1996

Inhalatory anticholinergic drugs1


  • 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

Bronchi a l ast h ma ph arma c ol o g y a nd c linic al a spe c t s

Is this patient with asthma?

1 st may 2012

1st May, 2012

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