MUDr. M. Laššánová
BRONCHIAL ASTHMA
Pharmacology and
Clinical Aspects
Cvičenie č. 7
DEFINITION 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 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
Celosvetová iniciatíva pre astmu
GINA
1995, 2002, 2006
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








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
Emphasis on early diagnosis
management begins with right analysis of
symptoms

-
to them belong:
 dyspnoe
 cough
 chest
distress
 wheezing
Clasification of Asthma according to clinical symptoms and lung
function:
GINA
DEGREE OF
SERIOUSNESS
SYMPTOMS DURING DAY
2002
IV. severe
persistent
A
III. moderate
persistent
II. mild
persistent A
I. mild intermittent
A
sy. continuously, attacks
often, physical activity
limited
SYMPTOMS
DURING
NIGHT
Often
PEF  60%N
variability of PEF
30%
 1/week
PEF = 60-80%N
variability of PEF
30%
 2/month
PEF  80%N
variability of PEF =
20-30%
sy. daily, attacks
2/week, influencing activity
sy. 2/week  daily, attacks
2/week, changing activity
sy. 2/week, only mild or no
attacks, aktivity unchanged
LUNG FUNCTION
 2/month
PEF  80%N
variability of PEF
30%
GINA
2006
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

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


SPIROMETRIA
BRONCHODILATION TESTS (BDT)


BRONCHOPROVOKING TEST (BKT)





it verifies the degree of obstruction reversibility
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
• 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)

CHOPD
Asthma Bronchiale
Beginning in middle age
Beginning in younger age
Symptoms progress 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 Usually reversible restriction
of air flow
of air flow bmedzenie
Family history of asthma
CH O P D
Pulmonary
functions
Symptoms
ASTHMA
Symptoms
Pulmonary
functions
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 irreversible bronchial
obstruction (remodelation of lower airways)
preventing asthma mortality
THERAPY OF AB

Nonpharmacological

Patients´ education
 avoiding risk factors and triggers
Pharmacological

ANTIINFLAMMATORY



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
parenteral

by inhalation 







directly to the site of action
fast beginning of action
maximum efficacy
lower therapeutic doses = minimalise risk of AE
limitations from the site of patient (technique of
inhalation, cooperation...)
inspiratory resistance, needs to be overcomed
Inhalatory
Systems
Nowadays
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

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 (do 4-6 h.)

inhalatory anticholinergics short-acting

systemic corticoids p.o./i.v. („rescue“
treatment)
INHALATORY CORTICOIDS 
ICS
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. 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 susceptibility resp. protection of 2
receptors against down-regulation at long-term treatment
with 2 mimetics
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 and pharmacokinetic of steroid
 inflammation in airways, bronchial
hyperreactivity and obstruction of airways
 risk of AE (acute exacerbations)
and control symptoms of disease
ICS
beclomethasone
 budesonide
 fluticasone
 ciclesonide – 1 times per day, minimal syst.
AE, prodrug-activation dirrectly in lungs, the
part resorbed is inactive =>  systemic ef. !!!
 mometasone
 flunisolide
  dexamethasone
  triamcinolone

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 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 in the Treatment of AB –
„stable disease“

mild persistent asthma  monotherapy
with small doses of ICS
( 500µg BDP/d)
 addition
of LABA will not reduce the
symptoms unless they are deteriorated
pulmonary functions decrease

moderate persistent asthma  if
insufficient control  add LABA  at
failure in the next step  dose ICS (cca.
800µg BDP/d)
ICS in the Treatment of AB –
„exacerbations“

double dose of ICS at treatment of AE
isn´t effective

very high doses ICS (2000-4000µg BDP)
to 1-2 W may be effective

the best to add high dose of ICS
to regular maintenance therapy
ICS+LABA

at severe AE  systemic CS
ß2- SYMPATHOMIMETICS

Mechanism of action = agonistic, activating
influence on
ß2 receptors of sympathic NS
1. Long-acting ß2SM
(long-acting betaagonists ) = LABA
 Controllers – to long-term,regular bronchodilation
2. Short-acting ß2SM
(short-acting betaagonists ) = SABA
 Relievers – to short-term, acute management of
exacerbation
β2 –sympathomimetics
(LABA and SABA)
speed of effect
beginning
SLOW
Fast beginning,
short duration
inhal. terbutaline
salbutamol, fenoterol
Fast beginning,
long duration
inhal. formoterol
Slow beginning,
short duration
oral terbutaline,
salbutamol, formoterol
Slow beginning,
long duration
inhal. salmeterol,
oral bambuterol
SHORT
SABA
LONG
LABA
maintanance therapy
FAST
rescue treatment
duration of action
ß2- sympatho
MIMETICS =
SM
activate
sympathic
NS
dilate
bronchi
Anti M cholinergic
= PsL
block
parasympa
thic NS
dilate
bronchi
Localisation of Receptors
cholinergic
(parasympathic)
adrenergic
(sympathic)
LABA

the best, fast and intense acting b-dilatans
duration of action >12 hours
MA: 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
Molecular mechanism of positive
interaction ICS and LABA
Corticosteroid
ß2-Agonist
ß2-Adrenoceptor
Glucocorticoid
receptor
Anti-inflammatory effect
•
•
Bronchodilatation
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
LABA


formoterol
salmeterol
Monotherapy LABA:
  effectivity of LABA vs. ICS
 improving sleeping, but without effect to
pulmonary functions
 discontinuation ICS and adding LABA at
persistent asthma  loosing control
 good controlled patient with asthma with persistent
asthma at low dose ICS  replacement by LABA
 loosing control ( eNo and Eo in sputum)
 without effect on inflam. in airways (biopsia)
LABA in the Treatment of AB Conclusion
the most effective bronchodilators at AB
 effective at children and also adults
 formoterol suitable also for AE (since fast
beginnig + long duration of action)
 clinically without antiinflam. effect
 most effectivelly in combination with ICS
 formoterol can be as rescue
bronchodilator more effective than SABA at
pat. not responding to SABA !!!
 at AB always prescribe together with
ICS !!!

CONTROL of AB
1.
low dose ICS
2.
if no control reached:
dose ICS   costs
 add LABA  most effective
 add low-dose methylxanthines  cheapest
 add LTRAs  little effective, expensive
 high
3. ICS+LABA = the best strategy of AB
treatment
4. 15 studies: adding LABA to ICS is more
effective than doubling of ICS dose !
Fixed combination ICS+LABA
– ADVANTAGES









 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
same place  can occur molecular interaction
ICS+LABA  frequency of AE more than  dose of ICS
formoterol + budesonide
salmeterol + fluticasone
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 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

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
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)
SABA
 basic
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
DRUGS
 Relievers of the second choice, at AE
 competitive antagonists 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
Muscarinic receptorys in
airways
Pre-gangliový
nerv
Parasympatické
ganglion
Nicotinový receptor (+)
M1 receptor (+)
Post-gangliový
nerv
M2 receptor (–)
ACh
M3 receptor (+)
Hladký sval
Barnes PJ. Eur Respir Rev 1996
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 1 inhalation
system:
 ipratropium
 ipratropium+salbutamol
ipratropium+fenoterol

EVOLUTION IN ASTHMA THERAPY
CONVENTIONAL
Medication Use
No adjustment in
controller
FACET
OPTIMA
GOAL
LOGICAL
Adjustable
maintenance dose
SUND
FUTURE
One inhaler:
Maintenance & relief
Rapid adjustments
in controller
replacing SABA
SMART =
Single inhaler Maintenance
And Reliever Therapy
Bud/form
Flut/salm
Maintenance
+ prn SABA
Maintenance
+ prn SABA
Maintenance
+ prn Bud/form
Is this patient with
asthma?