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

BRONCHIAL ASTHMA Pharmacology and Clinical Aspects Cvičenie č. 7 MUDr. M. Laššánová

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BRONCHIBRONCHIAAL ASTL ASTHHMA MA PhPharmaarmaccololooggyy a andnd

CCliniclinicalal AAspespeccttss

Cvičenie č. 7Cvičenie č. 7

MUDr. M. LaššánováMUDr. M. Laššánová

DEFINDEFINITION ABITION AB

Asthma bronchiale is chronic inflammatory disease of airways connected with bronchial hyperreactivity and totally or partially reversible obstruction of airways, which in the most cases dissapears spontaneously or with treatment.

ASTHMA BRONCHIALEASTHMA 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

GINAGINA1995, 2002, 20061995, 2002, 2006

Celosvetová iniciatíva pre astmu

ETIOPATOGENESISETIOPATOGENESIS INFLAMMATIONINFLAMMATION 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 Triggers of Symptoms and Exacerbations 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 ABKLINICAL SYMPTOMS OF AB

Emphasis on early diagnosis Emphasis on early diagnosis management begins with right analysis of

symptoms

- to them belong: dyspnoe cough chest distress wheezing

CClasification of Asthma according to clinical symptoms and lung lasification of Asthma according to clinical symptoms and lung function:function:

DEGREE OF SERIOUSNESS

SYMPTOMS DURING DAY SYMPTOMS DURING NIGHT

LUNG FUNCTION

IV. severe persistent A

sy. continuously, attacks often, physical activity limited Often

PEF 60%Nvariability of PEF 30%

III. moderate persistent

sy. daily, attacks 2/week, influencing activity 1/week

PEF = 60-80%Nvariability of PEF 30%

II. mild persistent A

sy. 2/week daily, attacks 2/week, changing activity

2/month

PEF 80%Nvariability of PEF =20-30%

I. mild intermittent A

sy. 2/week, only mild or no attacks, aktivity unchanged

2/monthPEF 80%Nvariability of PEF 30%

GINA

2002

GINA

2006

KLINICAL SIGNS OF ABKLINICAL 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.

DIAGNOSTICDIAGNOSTIC 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

SPIROMETRIA BRONCHODILATION TESTS (BDT)

it verifies the degree of obstruction reversibility BRONCHOPROVOKING TEST (BKT)

BKT with histamine, ACh, adenosine, excercise, cold... negativenegative BKT excludes dg. of ABexcludes 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

EXAMINATIONS AT ABEXAMINATIONS AT AB

SPIROMETRIASPIROMETRIA• 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 DIAGNOSISDIFERENTIAL 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)

Beginning in middle age Beginning in younger age

Symptoms progress slowlyprogress slowly Symptoms from day to day changing

Long anamnesis of smoking Symptoms in the afternoon or early morning

Dyspnoe at excercise Also allergy, rhinitis, eczema

Larger irreversible restriction of air flow

Usually reversible restriction of air flow bmedzenie

Family history of asthma

CHOPDCHOPDCHOPDCHOPD Asthma BronchialeAsthma BronchialeAsthma BronchialeAsthma Bronchiale

PulmonaryPulmonaryfunctionsfunctions

SymptomsSymptoms

CH O P DCH O P DCH O P DCH O P D

SymptomsSymptoms PulmonaryPulmonaryfunctionsfunctions

A S T H M AA S T H M AA S T H M AA S T H M A

GOALS of Optimal AB ControlGOALS of Optimal AB Control

- elimination or significant reduction of reduction of symptomssymptoms

- prevention of exacerbationsprevention of exacerbations- maintaining lung functionslung functions closest to

physiological values - maintaining normal physical and living

activity - absence of treatment adverse effects - prevention of irreversibleirreversible bronchial

obstruction (remodelation of lower airways)- preventing asthma mortalitypreventing asthma mortality

THERAPY OF ABTHERAPY OF AB

NonpharmacologicalNonpharmacological Patients´ education avoiding risk factors and triggers-

PharmacologicalPharmacological 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

Administration of Drugs at AB

peroral parenteralby inhalation directly to the site of action fast beginning of actionmaximum efficacy lower therapeutic doses = minimalise risk of AE limitationslimitations from the site of patient from the site of patient (technique of

inhalation, cooperation...) inspiratory resistanceinspiratory resistance, needs to be overcomed

Administration of Drugs at AB

peroral parenteralby inhalation directly to the site of action fast beginning of actionmaximum efficacy lower therapeutic doses = minimalise risk of AE limitationslimitations from the site of patient from the site of patient (technique of

inhalation, cooperation...) inspiratory resistanceinspiratory resistance, needs to be overcomed

Inhalatory Systems

Nowadays

THERAPY OF ABTHERAPY OF ABA: A: CONTROLLERSCONTROLLERS

preventive drugs, controlling inflammationcontrolling inflammation are taken regularly,long timeregularly,long time to maintain control

antiinflammatory drugsantiinflammatory drugs

long acting inhalatory bronchodilatorslong acting inhalatory bronchodilators

B: B: RELIEVERSRELIEVERS

substances releasing bronchospasm

relieving = fast acting bronchodilators

C: OTHER ANTIASTHMATIC DRUGSC: OTHER ANTIASTHMATIC DRUGS Monoclonal Ab against IgE = omalizumab (50 pat. in SR) ketotifen Imunosupressives (MTX, CysA...)

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

A: A: CONTROLLERSCONTROLLERS

B: RELIEVERS

inhalatory short-acting 2-

sympathomimetics (short-acting

betaagonists ) SABA (do 4-6 h.)

inhalatory anticholinergics short-acting

systemic corticoids p.o./i.v. („rescue“

treatment)

INHALATORY CORTICOIDS INHALATORY CORTICOIDS ICSICSthe most effective antiinflammatory 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. release3. decrease of airways reactivity 4. restriction of vasodilation antioedematic ef.5. affect synthesis of eikosanoids 6. control activation of adhesive molecules

7. increase of susceptibilityincrease of susceptibility resp. protection of 2 receptors against down-regulation at long-term treatment with 2 mimetics

ICSICS AE locally can reduce with the use of attachments

and rinsing the mouth with NaHCO3

oropharyngeal candidosis dysphonia   seldomly irritation to cough

risk of systemicsystemic AE is , depends on dose ,efficacy and pharmacokinetic of steroid

inflammationinflammation in airways, bronchibronchialal hyperreahyperreacctivittivityy and obobsstrutruction ction of airways

risk of AEAE (acute exacerbations) and control symptsymptoommss of disease

ICSICS beclomethasone budesonide fluticasone ciclesonide – 1 times per day, minimal syst.

AE, prodrugprodrug-activation dirrectly in lungs, the part resorbed is inactive => systemic ef. !!!!!!

mometasone flunisolide dexamethasone triamcinolone

Principles of Treatment with Principles of Treatment with ICSICS

1. ICS need to be administered at each new dg. AB

2. Treatment is essential to start early

3. We administer attack 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 ICS in the Treatment ofin the Treatment of ABAB – – „stable disease“„stable disease“

mildmild per perssististentent ast asthhmama monotmonothheraperapy y with small doses ofwith small doses of ICS ICS

( 500µg BDP/d)addition of LABALABA will not reduce the

symptoms unless they are deteriorated pulmonary functions decrease

moderatemoderate per perssististentent ast asthhmama if insufficient control addadd LABA LABA at failure in the next step d doseose ICS ICS (cca. 800µg BDP/d)

ICS ICS in the Treatment ofin the Treatment of AB AB – – „exacerbations“„exacerbations“

ddoubleouble dose of ICSICS at treatment of AE iisnsn

´t´t ef efffeectivective

veveryry highhigh d dosesoses ICS ICS (2000-4000µg BDP)

to 1-2 W mmay be effectiveay be effective

the bestthe best to addadd high dose ofhigh dose of ICS ICS

toto regular maintenance therapy

ICS+LABAICS+LABA

at severesevere AE AE systsystemicemic CCSS

ßß22- SYMPAT- SYMPATHHOMIMETIOMIMETICSCS

Mechanism of action = agonistic, activating influence on ß2 receptors of sympathic NS

1. 1. Long-actingLong-acting ßß22SMSM (long-acting betaagonists ) = LABA

Controllers – to long-term,regular bronchodilation

2. 2. Short-actingShort-acting ßß22SMSM (short-acting betaagonists ) = SABA

Relievers – to short-term, acute management of exacerbation

ββ22 –sympathomimetics –sympathomimetics(LABA and SABA)(LABA and SABA)

Fast beginning,short duration

inhal. terbutalinesalbutamol, fenoterol

Fast beginning, long duration

inhal. formoterol

Slow beginning,short durationoral terbutaline,

salbutamol, formoterol

Slow beginning,long duration

inhal. salmeterol,oral bambuterol

speed of effect beginning

FAST

SLOW

SHORT LONGduration of action

rescue treatment

mai

nta

nan

ce t

her

apy

LABASABA

ß2- sympatho MIMETICS = SM

Anti M -cholinergic = PsL

activate sympathic NS

dilate bronchi

block parasympathic NS

dilate bronchi

LoLoccalialisation ofsation of RReceptoreceptorss

cholinergcholinergicic (parasympat(parasympathhic)ic)

aadrenergdrenergicic

(sympat(sympathhic)ic)

LABALABA the best, fast and intense acting b-dilatans

duration ofduration of action action >>12 hours12 hours

MMAA:: Bronchodilation through β2 => relaxation of smooth

muscle

Improve mucociliar clearens

Lower vascular 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 of tollerance for down regulation of β2 receptors => inhibition =

concomitant administration of ICS

LABA in long-term therapy of asthma never can administer lonely, without ICS!

MoleMoleccululaar mechanir mechanissmm of of positive positive interainteractionction ICS a ICS andnd LABA LABA

Glucocorticoid receptor

ß2-Adrenoceptor

Corticosteroid

Anti-inflammatory effect

• Effect of corticosteroids on ßEffect of corticosteroids on ß22-adrenoceptors -adrenoceptors • Effect of ßEffect of ß22-agonists on glucocorticoid receptors-agonists on glucocorticoid receptors

ß2-Agonist

Bronchodilatation

LABA: zlepšenie utilizácie KS a internalizácie GR do jadra (translokácia GR)ICS: prevencia desenzitizácie a znižovania expresie β2 receptora

LABA formoterol   salmeterol

MonotMonothheraperapyy LABA: LABA: effectivity of LABA vs. ICS improving sleeping, but withoutwithout ef efffeect toct to

ppulmonaryulmonary fun functionsctions discontinuationdiscontinuation ICS ICS and addingadding LABA LABA at

persistent asthma loosingloosing ccontrolontrol good controlled patient with asthma with persistent

asthma at low dose ICS replacement byreplacement by LABA LABA loosingloosing ccontrolontrol ( eNo and Eo in sputum)

withoutwithout e efffefect on inflam.ct on inflam. in airways (biopsia)

LABA LABA in the Treatment ofin the Treatment of ABAB - - ConclusionConclusion the most effectivethe most effective bronchodilat bronchodilatorsors at AB effective at children and also adults formoterolformoterol suitable also for AEAE (since fast

beginnig + long duration of action) clinically withoutwithout antiinflam.antiinflam. effect most effectivelly inin  ccombinombination withation with ICS ICS formoterol can be as rescue

bronchodilator more effective than SABA at pat. not responding to SABA !!!

atat AB AB alwaysalways pre prescribe together with scribe together with ICS !!!ICS !!!

CCONTROLONTROL of of ABAB 1.1. llooww dose ICS ICS

2. if nno controlo control reached: highhigh dose ICSICS costsadd LABALABA most effectivemost effectiveadd low-dose low-dose methylxanthinesmethylxanthines cheapestadd LTRAs LTRAs little effective, expensive

3. ICS+LABAICS+LABA = the best strategy of AB treatment

4. 15 studies: addingadding LABA LABA to ICS is more more eeffffeectivective than ddoubling of oubling of ICSICS dose dose !

FixFixeded ccombinombinationation ICS+LABA ICS+LABA – – ADVANTAGESADVANTAGES

compliance costs control of asthma faster control of asthma dose ICS to reach control in 1 inhalation divice deposition of ICS and LABA at the at the

same placesame place can occur molecular interaction ICS+LABAICS+LABA frequency of AEAE more than d dose ofose of ICS ICS

formoterol + budesonide salmeterol + fluticasone

Specific Label Changes for Long-Acting Beta-Agonists (LABAs).

1. Contraindicate the use of LABAs for asthma in patients of all ages without concomitant use of an asthma-controller medication such as an inhaled corticosteroid.

2. Stop use of the LABA, if possible, once asthma control is achieved and maintain the use of an asthma-controller medication, such as an inhaled corticosteroid.

3. Recommend against LABA use in patients whose asthma is adequately

controlled with a low- or medium-dose inhaled corticosteroid.

4. Recommend that a fixed-dose combination product containing a LABA and an inhaled corticosteroid be used to ensure compliance with concomitant therapy in pediatric and adolescent patients who 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.

ANTILEUKOTRIENE DRUGSANTILEUKOTRIENE DRUGS

controllers,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 DRUGSANTILEUKOTRIENE DRUGS role in therapy of AB - still unclear are less effective than low doses of ICS as additive drugs (in combination with ICS)

reduce the need of steroid dose at severe asthma

again less effective than standard ICS+LABA

advantageous – aspirin asthma, by excercise induced asthma, „preschool wheezing“

compliance at taking tablet form

METHYLXANTHINESMETHYLXANTHINES 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

METHYLXANTHINESMETHYLXANTHINES

Proven benefit bring only drug formsdrug forms providing long-lasting action with controlled releasewith 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.with short-lasting ef. - p.o., i.v. aminophylline, teophylline

others:others: doxophylline, cilomilast (select. inhibitor of PDE4)

SABASABA

basic relieversbasic relievers used ad hoc to relieve or to remove symptoms no reason for regular administration

salbutamol (Ventolin) fenoterol /Australia – deregistered for AE KVS/

terbutaline

INHALATORY ANTICHOLINERGIC INHALATORY ANTICHOLINERGIC DRUGSDRUGS

Relievers of the second choice, at AERelievers of the second choice, at AE

competitivecompetitive antagonists antagonists on M1, M2 and M3 on M1, M2 and M3

receptors of parasympathicus

cholinergic tonuscholinergic tonus

Division:Division:

with short-lastingshort-lasting effect: ipratropium bromideipratropium bromide with prolongedprolonged effect: oxitropium bromideoxitropium bromide

with long-lastinglong-lasting effect: tiotropium bromidetiotropium bromide CHOCHP

Pre-gangliovýnerv

Parasympatickéganglion

Post-gangliovýnerv

ACh

Hladký sval

Nicotinový receptor (+)

M1 receptor (+)

M2 receptor (–)

M3 receptor (+)

MusMusccarariinnicic receptory receptorys in s in airwaysairways

Barnes PJ. Eur Respir Rev 1996

INHALATORY ANTICHOLINERGIC INHALATORY ANTICHOLINERGIC DRUGSDRUGS

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 1 inhalation system:

ipratropium ipratropium+salbutamol

ipratropium+fenoterol

EVOLUTION IN ASTHMA THERAPYEVOLUTION IN ASTHMA THERAPY

No adjustment in No adjustment in controllercontroller

CONVENTIONALCONVENTIONAL

Med

icat

ion

Use

Med

icat

ion

Use

MaintenanceMaintenance+ prn+ prn SABA SABA

FACETFACETOPTIMAOPTIMAGOALGOAL

Adjustable Adjustable maintenance dosemaintenance dose

LOGICALLOGICAL

MaintenanceMaintenance+ prn+ prn SABA SABA

SUNDSUND

One inhaler: One inhaler: Maintenance Maintenance

& relief& relief

Rapid adjustments Rapid adjustments in controller in controller

replacing SABAreplacing SABA

FUTUREFUTURE

Maintenance Maintenance + prn+ prn Bud/form Bud/form

Bud/formBud/form

Flut/salmFlut/salm

Bud/formBud/form

Flut/salmFlut/salm

SMARTSMART = = SSingle inhaler ingle inhaler MMaintenance aintenance AAnd nd RReliever eliever TTherapyherapy

Is this patient with asthma?