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Asthma 2.pptx
1. Investigations :
There is no single satisfactory diagnostic test for all
asthmatic patients.
I. Respiratory function tests:
Measurements of peak expiratory flow (PEF) on waking,
prior to taking a bronchodilator and before bed after a
bronchodilator, are particularly useful in demonstrating
the variable airflow limitation that characterizes the
disease. The diurnal variation in PEF is a good measure
of asthma activity and is of help in the longer-term
assessment of the patient's disease and its response to
treatment.
To assess possible occupational asthma, peak flows
need to be measured for at least 2 weeks at work and 2
weeks off work.
2. Blood and sputum tests:
Patients with asthma may have an increase in the number of
eosinophils in peripheral blood (> 0.4 × 109/L).
The presence of large numbers of eosinophils in the sputum
a more useful diagnostic tool.
Chest X-ray:
There are no diagnostic features of asthma on the chest X-
although over inflation is characteristic during an acute
episode or in chronic severe disease.
A chest X-ray may be helpful in excluding a pneumothorax,
which can occur as a complication.
Skin tests:
Skin-prick tests should be performed in all cases of asthma to
help identify allergic causes.
3. Management
includes:
1. Avoiding the contact with allergen. If it is impossible, the specific hyposensitization
with standard allergens should be performed. It is rather effective in case of
monoallergy, in intermittent and mild persistent asthma, in remission phase.
2. Elimination of trigger factors (rational job placement, changing the residence,
psychological and physical adaptation, careful drug using) is the second
condition for successful asthma treatment.
3. Optimally selected medical care is the base of
asthma management.
4. Drug therapy
Antiinflammatory drugs
(basic)
Bronchodilators
2 drug categories are used:
Are divided into:
hormone-containing
(corticosteroids)
nonhormone-containing
(cromones, leukotriene
receptor antagonists)
3 groups:
anticholinergic drugs
b2-agonists
methylxanthines
8. Classification of bagonists
Table 1. Beta Agonists
Short acting
Generic name Duration of action b2-selectivity
Albuterol 4-6 h +++
Levalbuterol 8 h +++
Metaproterenol 4-6 h ++
Isoproterenol 3-4 h ++
Epinephrine 2-3 h -
Long acting
Salmeterol 12+ h +++
Formoterol 12+ h +++
10. Theophylline
The methylxantine theophylline share a similar structure to
the dietary xanthine caffeine.
Many salts of theophylline have been marketed, the most
common being aminophylline, which is the ethylenediamine
salt.
Theophylline has been in clinical use since the 1930s. It is a
weak, non-selective inhibitor of phosphodiesterase (PDE).
There are at least 10 PDE family members, all of which
catabolize cyclic nucleotides in the cell.
PDE inhibition results in an increased in cAMP and cGMP.
Another hypothesize mechanism of action is adenosine
receptor inhibition, which may prevent the release of
mediators from mast cells.
11.
12. Pharmacology of
Theophylline
ADME
Absorption: oral. The dose of theophylline required to yield
therapeutic concentrations varies among subjects, largely
because of differences in clearance.
Metabolism. Concurrent administration of phenobarbitol or
phenytoin increases activity of cytochrome P-450 (CYP), which
results in increased metabolic breakdown.
Elimination. Increased clearance is seen in children and in
cigarette and marijuana smokers. Reduced clearance is also
seen with the common drugs that interfere with the CYP system,
such as cimetidine, erythromycin, ciprofloxacin, allopurinol,
zileuton, and zafirlukast. Viral infections and vaccinations may
also reduce clearance.
13. Anticholinergic Drugs
Human airways are innervated by a supply of
efferent, cholinergic, parasympathetic autonomic
nerves.
Motor nerves derived from the vagus form ganglia
within and around the walls of the airways. This
vagally derived innervation extends along the length of
the bronchial tree, but predominates in the large and
medium-sized airways.
Postganglionic fibers derived from the vagal ganglia
supply the smooth muscle and submucosal glands of
the airways as well as the vascular structures.
Release of acetylcholine (ACh) at these sites results in
stimulation of muscarinic receptors and subsequent
airway smooth muscle contraction and release of
secretions from the submucosal airway glands.
14. Anticholinergic Drugs (cont)
Three pharmacologically distinct subtypes of muscarinic
receptors exist within the airways: M1, M2 and M3 receptors.
M1 receptors are present on prebronchial ganglion cells where
the preganglionic nerves transmit to the postganglionic
nerves. M2 receptors are present on the postganglionic
nerves; they are activated by the release of acetylcholine and
promote its reuptake into the nerve terminal. M3 receptors
are present on smooth muscle.
Muscarinic receptor activation of these M3 receptors leads
to a decrease in intracellular cAMP levels, resulting in
contraction of airway smooth muscle and bronchoconstriction.
15. Anticholinergic Drugs
(cont)
Atropine is the prototype anticholinergic
bronchodilator.
Ipratropium is a quaternary amine, which is
poorly absorbed across biologic membranes.
Atropine and ipratropium antagonize the actions
of Ach at parasympathetic, postganglionic,
effector cell junctions by competing with Ach
for M3 receptor sites.
This antagonism of Ach results in airway smooth
muscle relaxation and bronchodilation.
16. Anticholinergic Drugs (cont)
Ipratropium is given exclusively by inhalation from a metered-dose inhaler or
a nebulizer. Inhaled ipratropium has a slow onset ( ~30 min) and a relatively
long duration of action ( ~6 h).
Tiotropium, a structural analog of ipratropiem, has been approved
for treatment of COPD. Like iprotropiem, tiotropiem has high
affinity for all muscarinic receptor subtypes but it dissociates from
the receptors much more slowly than ipratropium, esp. M3 receptors.
This permits once a day dosing. It is formulated for use with an oral
inhalator.
Clinical trials of anticholinergic therapy have generally failed to show
significant benefit in asthma. This relative lack of efficacy in asthma
contrasts with COPD, in which anticholinergic agents are among the most
effective therapies.
N
O
O
OH
CH3
CH3
H3C
Br
Ipratopium
N
O
CH3
H3C
O
O
S
S
OH
Br
Tiotropium
N
CH3
O
OH
O
Atropine
17. Future Pharmacological Agents for Asthma & COPD
Vasoactive intestinal peptide (VIP) analogs. VIP is a potent
relaxant of constricted human airways in vitro but it is degraded too
quickly in the airway epithelium to be effective. A more stable cyclic
analog of VIP (Ro-25-1553) has a prolonged effect in asthmatic
patients by inhalation.
Phosphodiesterase 4 (PDE4) inhibitors. Because of theophylline,
other PDE4 inhibitors are being tested. The PDE4 inhibitor cilomilast
has been clinically tested for COPD but the drug causes emesis, a
common side effect with this class (this could be due to inhibition of
PDE4D). There is hope that selective inhibitors of PDE4B might have
more therapeutic potential.
19. The stepwise management of asthma
Treatment
PEFR
Step
As-required bronchodilators If
used more than once daily,
move to step 2
100% predicted
Occasional symptoms,
less frequent than daily
1
Anti-inflammatory drugs
Sodium cromoglicate or low-
dose inhaled corticosteroids
up to 800 μg If not controlled,
move to step 3
≤80% predicted
Daily symptoms
2
High-dose inhaled
corticosteroids up to 2000 μg
daily
50-80% predicted
Severe symptoms
3
Add regular long-acting β2
agonists (e.g. salmeterol
50-80% predicted
Severe symptoms
uncontrolled with high-
dose inhaled
corticosteroids
4
Add prednisolone 40 mg daily
≤50% predicted
Severe symptoms
deteriorating
5
Hospital admission
≤30% predicted
Severe symptoms
deteriorating in spite of
prednisolone
6
