6. Despite all medicines and guidelines available,
there is still a big unmet need in asthma (Over
50% of patients poorly controlled in EU1)
1. Adamek L. et al. Poster presented at ATS Denver 2011
18. Aim of Asthma Therapy
CONTROL
Daytime symptoms None
( 0-2 / week)
Nocturnal symptoms
/ awakening
None
Limitations of
activities
None
Need for rescue /
“reliever” treatment
None
( 0-2 / week)
FEV1 or PEF Normal
Exacerbation None
19.
20. 1. In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school or
at home?
2. During the past 4 weeks, how often have you had shortness
of breath?
3. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath,
chest tightness or pain) wake you up at night, or earlier than usual in the morning?
4. During the past 4 weeks, how often have you used your rescue
inhaler or nebulizer medication (such as salbutamol)?
5. How would you rate your asthma control during the past
4 weeks?
Score
Patient Total Score
Copyright 2002, QualityMetric Incorporated.
Asthma Control Test Is a Trademark of QualityMetric Incorporated.
Asthma Control Test™ (ACT)
26. The WHO definition of severe asthma.
According to the
WHO definition,
severe asthma
is defined as:
‘uncontrolled asthma
which can result
in risk of frequent
severe exacerbations
(or death) and/or
adverse reactions to
medications and/or
chronic morbidity
Bousquet J, J Allergy Clin Immunol 2010;126:926–938.
27.
28.
29.
30. Difficult asthma
Asthma that is poorly controlled, despite prescription of
optimal asthma treatment Consider:
1. Poor adherence to treatment
2. Poor inhaler technique
3. Alternative diagnosis (?vocal cord dysfunction)
4. Persistent allergens exposure
5. Undertreated co-morbidities
31. Severe refractory asthma
Patients with asthma in whom:
Alternative diagnoses have been excluded
Co-morbidities have been treated
Trigger factors have been removed (if possible)
Compliance with treatment has been checked
But still have:
Poor asthma control, or
frequent (2) severe exacerbations per year
Despite :
The prescription of high-intensity treatment, or
Can only maintain adequate control when taking systemic corticosteroids
40. When a diagnosis of asthma is confirmed and comorbidities
addressed, severe asthma is defined as ‘‘asthma which requires
treatment with high dose ICS plus a second controller (and/or
systemic corticosteroids) to prevent it from becoming
‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy.’
These doses are likely to be on the relatively "flat" portion of the
corticosteroid dose-response relationship, above which the potential for
further therapeutic effect diminishes and the likelihood of systemic side-
effects is significant
ERS/ATS Guidelines 2014
42. Despite current treatment options, in particular ICS/LABA,
at least 40% of asthma patients still experience symptoms
and could benefit from new treatment options
Patients with severe refractory asthma represent small
subset of asthmatic patients (5-10% of all patients), but:
1. The greatest burden on health care system
2. The population most in need for new treatment approaches
43.
44.
45.
46. Step 2 Step 3 Step 4 Step 5Step 1
Asthma Education
Enviromental Control
As needed
rapid acting
2 agonists
As needed rapid acting 2 agonists
Controller
options
Select one Select one Add one or
more
Add one or
both
Low-dose ICS Low-dose ICS +
LABA
Medium or high
dose ICS+
LABA
Oral steroid
LTRA Medium or high
dose ICS
LTRA Anti-IgE
Low-dose ICS
+ LTRA
Theophylline
Low-dose ICS
+ Theophylline
INCREASEREDUCE TREATMENT STEPS
GINA 2013
As needed rapid acting B2-agonist
52. The neural supply to respiratory tract includes
parasympathetic supply through vagus, which is
more prominent, and sympathetic supply, which
is less prominent.
The sympathetic innervations to the respiratory
tract are very limited. However, they respond very
well to catecholamines and sympathomimetic
drugs .
The basic science
53. The basic science
The smooth muscle that surrounds the airways is innervated
by cholinergic, parasympathetic nerves which cause
bronchoconstriction and mucus secretion.
The acetylcholine released from these nerve fibres acts on
muscarinic receptors to mediate these effects in response to
activation of sensory nerves which are activated by irritants
and inflammatory mediators in the airways
Blocking muscarinic receptors with anti-muscarinic drugs
can ameliorate these effects. This has proven to be a
particularly effective therapeutic strategy in treating COPD,
and to a lesser extent asthma
56. The use of Short-acting anticholinergic agents, particularly
ipratropium bromide in patients with asthma has been
relegated primarily to the acute setting.
The use of ipratropium results in fewer hospitalizations if
given in combination with a SABA to patients experiencing
exacerbations in the emergency department (EPR-3 2007).
56
57. Short-acting anticholinergics are generally
considered less effective acute bronchodilators
than SABAs, and their short duration of action
makes them broadly unsuitable as controller
medication
58.
59. Muscarinic receptors exist on smooth muscle and
submucosal glands. Acetylcholine (ACh) released from
postganglionic nerve endings in the airways activate these
receptors.
Five muscarinic receptor subtypes have been identified, of
which three subtypes—M1, M2, and M3—have been
identified in human airways. These receptor subtypes serve
different regulatory functions:
–Post-synaptic muscarinic receptors (M1) receptors facilitate
neurotransmission and enhance cholinergic reflex effects in
the airways.
60. –The pre-synaptic M2 receptors on postganglionic cholinergic
nerves have an auto inhibitory effect on acetylcholine
release.
–M3 receptors in airway smooth muscle mediate
bronchoconstrictor and mucus secretory response to
acetylcholine.
Inhaled anticholinergics exhibit kinetic receptor subtype
selectivity in that they dissociate more slowly from M3 than
from M2 and M1 receptors. M3 subtype selectivity of an
inhibitor has pharmacological advantages that may have useful
therapeutic implications. Dissociation from M1 is slower than
from M2
63. M2 receptors act as autoreceptors on postganglionic
nerve terminals and inhibit acetylcholine release.
Therefore, blocking these receptors selectively would
have the undesirable effect of increasing vagal excitation
of smooth muscle and glands.
Thus, it is preferable for antimuscarinic bronchodilators
to have a relatively high affinity for M1 and M3 receptors
and low affinity for the M2 receptor.
64. Ipratropium and oxitropium Currently available
short-acting anticholinergics are non-selective
antagonists of M1, M2 and M3 receptors, they
block all muscarinic receptors
In contrast, tiotropium has comparative selectivity
for the M1/M3, receptors, Dissociates very slowly
from M1 and M3 receptors but rapidly from M2
receptors
64
65.
66. The interesting property of tiotropium is that it binds
only briefly to M2 receptors, but dissociates from M3
receptors much more slowly (24 hours). Thus, by the
time the body has eliminated free tiotropium, the
remainder still bound to M3 receptors keep working
without affecting M2 receptors.
A long-acting anticholinergic which is M1- and M3-
selective (tiotropium) may have an advantage over
ipratropium, as M2-receptor blockade may limit
bronchodilation
78. Safety profile
comparable
to placebo
21%
risk reduction
for severe
asthma
exacerbation
68%
more likely
to improve
asthma
control
up to
154 mL
improvement
in lung function
Tiotropium Respimat® added on to at least ICS+LABA resulted in:
PrimoTinAasthmaTM studiesPHASE IIIConclusions…
79.
80.
81.
82.
83.
84.
85.
86.
87. Tiotropium add-on therapy offers advantages to adults
with severe asthma who are failing to gain control on
ICS and LABA combinations.
The benefit: risk ratio of ICS falls at high ICS doses,
suggests that addition of long-acting anticholinergic
bronchodilators to ICS plus a LABA is likely to be a
useful option for patients with poorly controlled severe
asthma, and an alternative to further increases in ICS
dose.
87
92. Potential for
tiotropium
Step 5Step 4Step 3Step 2Step 1
Asthma education, environmental control
As-needed rapid-
acting β2-agonists
As needed rapid-acting β2-agonist
Controller options***
Select one Select one
To Step 3 treatment,
select one or more
To Step 4 treatment,
add either
Low-dose ICS*
Low-dose ICS plus
LABA
Medium- or high-dose
ICS plus LABA
Oral
glucocorticosteroid
(lowest dose)
Leukotriene modifier**
Medium- or high-
dose ICS
Low-dose ICS plus
leukotriene modifier
Leukotriene modifier
Sustained-release
theophylline
Anti-IgE treatment
Low-dose ICS plus
sustained release
theophylline
GINA 2013
94. GINA 2015
Add-on tiotropium (softmist inhaler) now included
as a new ‘Other controller option’ for Steps 4 and
5 in adults and adolescents.
# Tiotropium by soft-mist inhaler is an add-on
treatment for patients with a history of
exacerbations; it is not indicated in children
<18 years.
