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

2. 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.

3. 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

4. Celosvetová iniciatíva pre astmu
GINA
1995, 2002, 2006

5. 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

6. 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

7. KLINICAL SYMPTOMS OF AB
Emphasis on early diagnosis
management begins with right analysis of symptoms
to them belong:
dyspnoe
cough
chest distress
wheezing

8. Clasification of Asthma according to clinical symptoms and lung 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%N
variability of PEF 30%
III. moderate persistent
sy. daily, attacks
2/week, influencing activity
 1/week
PEF = 60-80%N
II. mild persistent A
sy. 2/week  daily, attacks 2/week, changing activity
 2/month
PEF  80%N
variability of PEF =
20-30%
I. mild intermittent A
sy. 2/week, only mild or no attacks, aktivity unchanged
 2/month
PEF  80%N
variability of PEF 30%
GINA
2002

9. GINA
2006

10. 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.

11. 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

12. 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

13. 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)

14. 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)

15. 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 of air flow
Usually reversible restriction of air flow bmedzenie
Family history of asthma

16. CH O P D
Pulmonary
functions
Symptoms

17. A S T H M A
Symptoms
Pulmonary
functions

18. 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

19. THERAPY OF AB Nonpharmacological Pharmacological 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

20. 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

21. Inhalatory Systems Nowadays

23. THERAPY OF AB A: CONTROLLERS  antiinflammatory drugs
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...)

24. 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

25. 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)

26. 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

27. 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

28. 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

29. 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

30. 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)

31. ICS in the Treatment of AB – „exacerbations“
double dose of ICS at treatment of AE isn´t effective
very high doses ICS ( µg 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

32. ß2- SYMPATHOMIMETICS 1. Long-acting ß2SM 2. Short-acting ß2SM
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

33. β2 –sympathomimetics (LABA and SABA) salbutamol, formoterol
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

34. ß2- sympatho MIMETICS = SM
Anti M -cholinergic = PsL
activate sympathic NS
block parasympathic NS
dilate bronchi
dilate bronchi

35. Localisation of Receptors
cholinergic (parasympathic)
adrenergic
(sympathic)

36. 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 lonely, without ICS!

37. Molecular mechanism of positive interaction ICS and LABA
Corticosteroid
Anti-inflammatory effect
ß2-Agonist
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

38. 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)

39. 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 !!!

40. CONTROL of AB low dose ICS if no control reached:
high dose ICS   costs
add LABA  most effective
add low-dose methylxanthines  cheapest
add LTRAs  little effective, expensive
3. ICS+LABA = the best strategy of AB treatment
studies: adding LABA to ICS is more effective than doubling of ICS dose !

41. 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

42. 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 Feb 24.

43. 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.

44. 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

45. 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

46. METHYLXANTHINES with controlled release - p.o.
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)

47. SABA salbutamol (Ventolin)
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

48. 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

49. Parasympatické ganglion
Muscarinic receptorys in airways
Pre-gangliový nerv
Nicotinový receptor (+)
M1 receptor (+)
Parasympatické ganglion
Post-gangliový nerv
M2 receptor (–)
M3 receptor (+)
ACh
Hladký sval
Barnes PJ. Eur Respir Rev 1996

50. 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

51. EVOLUTION IN ASTHMA THERAPY
No adjustment in controller
CONVENTIONAL
Adjustable maintenance dose
LOGICAL
Maintenance
+ prn SABA
SUND
One inhaler: Maintenance & relief
Rapid adjustments in controller replacing SABA
FUTURE
Maintenance
+ prn Bud/form
FACET
OPTIMA
GOAL
SMART =
Single inhaler Maintenance
And Reliever Therapy
Medication Use
Bud/form
Flut/salm
Maintenance
+ prn SABA

52. Is this patient with asthma?