Transcript LABA

BRONCHIAL ASTHMA
Pharmacology and
Clinical Aspects
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
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
CLINICAL SYMPTOMS OF AB
• Emphasis on early diagnosis
management begins with right analysis of
symptoms
- to them belong:
•
•
•
•
dyspnoe
cough
chest tightness
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%
Levels of Asthma Control GINA 2011
Assessment of current clinical control (preferably over 4 weeks)
Characteristics
Controlled (all Partly Controlled (any
of the following)
measure presented)
Daytime symptoms
None (twice or
less / week)
More than twice / week
Limitations 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)
Uncontrolled
Three or more
features of partly
controlled asthma
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 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.
DIAGNOSIS
• 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
• SPIROMETRY
• 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
SPIROMETRY
• 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)
COPD
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
COPD
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)
Monoclonal Ab against IL-5 = mepolizumab
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 anticholinergics short-acting
• systemic corticoids p.o./i.v. („rescue“ treatment)
• some sources – controllers
• fast acting methylxantines
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
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 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 –
„exacerbations“
• the best to add high dose of ICS to regular
maintenance therapy ICS+LABA
• at severe AE  systemic CS
Adverse effects of systemically
administered corticosteroids
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•
•
•
•
•
•
•
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•
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
CONTROLLER
options
As needed SABA
Select one
Select one
Select one or more Add either
Low-dose ICS
Low-dose ICS +
LABA
Medium-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
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.
salbutamol, fenoterol
Fast beginning,
long duration
inhal. formoterol
Slow beginning,
short duration
oral
salbutamol rtd. cps.
Slow beginning,
long duration
inhal. salmeterol
SHORT
SABA
LONG
LABA
maintanance therapy
FAST
rescue treatment
duration of action
β2 –sympathomimetics
(LABA, SABA, ultraLABA)
SABA
LABA
ultraLABA
2x per day
1x per day
Fenoterol
Formoterol
Indacaterol
Levalbuterol
Salmeterol
Vilanterol
Salbutamol
Abediterol
Terbutaline
Olodaterol
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 lonely,
without ICS!
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
• formoterol
• salmeterol
LABA
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)
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:
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•
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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, 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 longlasting 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
SABA
basic 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 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 long-lasting effect: tiotropium bromide
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 β2– mimethics
and have a little slower beginning of action
• advantageous combinations v 1 inhalation
system:
• ipratropium
• ipratropium+fenoterol
INHALATORY ANTICHOLINERGIC DRUGS
SAMA
Ipratropium
LAMA
LAMA
2x per day
1x per day
Aclidinium
Tiotropium
Glycopyrronium
Umeclidinium
Is this patient with
asthma?
5th May, 2015