BRONCHIBRONCHIAAL ASTL ASTHHMA MA PhPharmaarmaccololooggyy a andnd

CCliniclinicalal AAspespeccttss

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, rhinitis, 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 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 ABCLINICAL SYMPTOMS OF AB

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

symptoms

- to them belong:• dyspnoe• cough• chest tightness• 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

Levels of Asthma Control GINA 2011

Assessment of current clinical control (preferably over 4 weeks)Characteristics Controlled (all

of the following)Partly Controlled (any measure presented)

Uncontrolled

Daytime symptoms None (twice or less / week)

More than twice / week Three or more features of partly controlled asthmaLimitations of activities None Áno

Nocturnal symptoms / awaking

None Áno

Need for reliever / rescue inhaler

None (twice or less / week)

More than twice / week

Lung function / (PEF or FEV1)

Normal < 80 % predicted or personal best (if known)

Assessment of future risk (risk of exacerbation, instability, rapid decline in lung function, side effects)Poor clinical control, frequent exacerbations in past year, ever admission to critical care for asthma, low FEV1, exposure to cigarette smoke, high dose medications

GINA

2006

CLINICAL SIGNS OF ABCLINICAL 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.

DIAGNOSISDIAGNOSIS• 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 ABEXAMINATIONS AT AB• SPIROMETRY • 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

SPIROMETRYSPIROMETRY• 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 bronchodilators long acting inhalatory bronchodilators B: B: RELIEVERSRELIEVERS substances releasing bronchospasm relieving = fast acting bronchodilatorsC: OTHER ANTIASTHMATIC DRUGSC: OTHER ANTIASTHMATIC DRUGS

– Monoclonal Ab against IgE = omalizumab (50 pat. in SR)– ketotifen – Imunosupressives (MTX, CysA...)

A: A: CONTROLLERSCONTROLLERS

• 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 anticholinergics short-acting

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

• some sources – controllers

• fast acting methylxantines

INHALATORY CORTICOIDS INHALATORY CORTICOIDS ICSICS

the 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

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 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 ICS in the Treatment ofin the Treatment of ABAB – – „stable „stable disease“disease“

according to British guidelines

• mild intermittent asthmamild intermittent asthma• inhaled short-acting β2-agonists as needed

• mildmild per perssististentent ast asthhmama monotmonothheraperapy with small doses ofy with small doses of ICSICS ( 500µg BDP/d)– addition of LABALABA will not reduce the symptoms unless they are

deteriorated resp. pulmonary functions are decreased

*BDP = Beclomethasone dipropionate CFC

ICS ICS in the Treatment ofin the Treatment of ABAB – – „stable disease“„stable disease“

• moderatemoderate per perssististentent ast asthhmama• inhalated short-acting β2-agonists regularly• if lack of control by ICS → add LABA:

1. good response to LABA → continue combination therapy LABA + ICS2. LABA effective, but inadequate control → increase the dose of ICS to

BDP 800 mcg/day3. LABA ineffective → quit LABA, increase the dose of ICS to

BDP 800 mcg/day → if still inadequate control → add other anti-asthmatics (leucotriene modifiers, methylxanthines)

• persistent poor controlpersistent poor control• inhalaled short-acting β2-agonists regularly• increase the dose of ICS• adding a fourth drug

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

• 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

Adverse effects of systemically administered corticosteroids

• Infections• The long-term use may increase blood pressure, cause fluid retention and salt

retention in the body (oedema), increased excretion of calcium and potassium• Worse and longer wound healing• Rash and acne• Hyperglycaemia• They increase the risk of gastrointestinal perforation• Increased appetite and weight gain• Osteoporosis (↓ absorption of calcium, ↑ its excretion)• Muscle pain, muscle weakness and muscle cramps (especially ↑ loss of potassium,

↓ calcium level in the blood)• Cataract, increased intraocular pressure, optic nerve damage, eye infections• CNS: irritability, mood and personality changes, depression, headaches, dizziness

Management control of asthma GINA 2011 (adults and children older than 5 years)

STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

Asthma education. Enviromental control.As needed SABA As needed SABA

CONTROLLER options

Select one Select one Select one or more Add eitherLow-dose ICS Low-dose ICS +

LABAMedium-dose or high-dose ICS + LABA

Oral glucocorticosteroid (lowest dose)

Leukotriene modifier

Medium-dose or high-dose ICS

Leukotriene modifier Anti – IgE treatment

Low-dose ICS + leukotriene modifier

Sustained release theophylline

Low-dose ICS + sustained release theophylline

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. salbutamol, fenoterol

Fast beginning, long duration

inhal. formoterol

Slow beginning,short duration

oral salbutamol rtd. cps.

Slow beginning,long durationinhal. salmeterol

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 ICSLABA 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 p pulmonaryulmonary

funfunctionsctions • 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)

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 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 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

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 CVS/

INHALATORY ANTICHOLINERGIC DRUGSINHALATORY ANTICHOLINERGIC DRUGS

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 long-lastinglong-lasting effect: tiotropium bromide (CHOPD)tiotropium bromide (CHOPD)

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 DRUGSINHALATORY 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 1 inhalation

system:• ipratropium• ipratropium+fenoterol

Is this patient with asthma?

1st May, 2012