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asthma management
1. Dr. Bushra Hasan Khan
Deptt of Pharmacology
JNMC, AMU
Management of Bronchial Asthma
2. Introduction
Asthma is a chronic inflammatory disorder of the airways
that is characterized:
clinically by recurrent episodes of wheezing, breathlessness,
chest tightness, and cough, particularly at night / early
morning.
physiologically by reversible narrowing of the bronchial
airways and a marked increase in bronchial responsiveness.
3. 300 million people around the globe suffer from Asthma.
World-wide, deaths from this condition have reached over
180,000 annually.
In Western Europe as a whole, asthma has doubled in
ten years.
India has an estimated 15-20 million Asthmatics.
In India, rough estimates indicate a prevalence of
between 10% and 15% in 5-11 year old children.
The human and economic burden associated with this
condition is severe.
WHO
4. Classification
A heterogenous disorder, no universally accepted classification
Atopic /extrinsic /allergic (∼70%) – IgE mediated immune
responses to environmental antigens.
Non-atopic/ intrinsic /non-allergic(∼30%) –triggered by non
immune stimuli.
Patients have negative skin test to common inhalant
allergens and normal serum concentrations of IgE.
5. The ultimate humoral and cellular mediators of
airway obstruction are common to both atopic and
non-atopic variants of asthma, and hence they are
treated in a similar way.
12. Inflammation…
Exact cause of airway inflammation is unknown.
Thought to be an interplay between endogenous and
environmental factors.
Endogenous factors –
o Atopy –
o Genetic predisposition to IgE mediated type I hypersensitivity
o An excessive TH2 reaction against environmental antigens
o The major risk factor for asthma
o Asthma is commonly associated with other atopic diseases –
allergic rhinitis(80%), atopic dermatitis, urticaria, etc.
Genetics : Polymorphism of gene on chr. 5q , ADAM-33,
DPP-10 , GPRA gene .
14. Airway Hyper-responsiveness
Bronchial hyper-responsiveness is a state characterised by
easily triggered bronchospasm.
Bronchial hyper-responsiveness can be assessed with
a bronchial challenge test.
Concentration of a bronchial spasmogen
(methacholine/histamine), needed to produce
a 20% increase in airway resistance in asthmatics
is often only 1% to 2% of the equally effective
concentration in healthy control subjects.
15. Effects of inflammation
Airway epithelium – damage and shedding may lead to
AHR.
Mucus hypersecretion
Nerves –sensitization of nerve terminals and reflex
activation of cholinergic nerves.
Vessels – increased in number, blood flow is increased.
Smooth muscle – hyperplasia and hypertrophy
Fibrosis – subepithelial.
16.
17. Clinical presentation
Wheezing, dyspnea and cough.
Tenaceous mucus production.
Symptoms worse at night.
Limitation of activity.
Signs
↑ respiratory rate, use of accessory muscles
Hyper-resonant percussion note
Expiratory wheeze
May be SILENT CHEST
No findings when asthma is under control or b/w attacks
18. Investigations
Pulmonary function testsSpirometry
estimate degree of obstruction
↓FEV1, ↓FEV1/FVC, ↓PEF.
>12% increase in FEV1, 15 minutes after β2 agonist inhalation.
AHR – histamine / methacholine provocation test> 20% fall in FEV1
CXR – hyperinflated
Arterial blood-gas analysishypoxia & hypocarbia
(severe acute asthmahypercarbia)
Skin hypersensitivity test
Sputum & Blood eosinophilia
Elevated serum IgE levels
19. Aims of anti asthmatic drugs:
• To relieve acute episodic attacks of
asthma
(bronchodilators, quick relief
medications).
• To reduce the frequency of attacks, and
nocturnal awakenings
(anti-inflammatory drugs, prophylactic or
control therapy ).
20. Efferent nerves (motor)
Parasympathetic supply
M3 receptors in bronchial smooth muscles and
glands.
No sympathetic supply but ß2 receptors in
bronchial smooth muscles and glands
21. Classification of drugs
RELIEVERS (RESCUE MEDICATIONS)
o β2 Agonists
o Anticholinergic Agents
o Methylxanthines
CONTROLLERS
o Glucocorticoids
o Leukotrienes pathway inhibitors
o Cromones
o Anti-IgE therapy
22. Drugs
Adenyl cyclase
cAMP
– Short acting
– main choice in acute
attack of Asthma
– Inhalation
B2 agonists
Salbutamol, Terbutaline
Long acting, Prophylaxis
Nocturnal Asthma
Salmeterol, Formoterol
•Blocks M3
receptors
Main drugs For COPD
Inhalation
Inhalation
Antimuscarinics
Ipratropium (Short)
Tiotropium (long)
•Inhibits
phosphodiesterase
• cAMP
(orally)
(parenterally)
Xanthine derivatives
Theophylline
Aminophylline
Bronchodilators (relievers for bronchospasm)
24. β2 Agonists in asthma
Bronchodilators, Usually given by inhalation route.
MOA:
Relaxation of airway smooth muscle
Non-bronchodilator effects
Inhibition of mast cell mediator release
Reduction in plasma exudation
Increased mucociliary transport
Inhibition of sensory nerve activation
Inflammatory cells express β2 receptors but these are
rapidly downregulated.
No effect on airway inflammation and AHR.
25.
26. β2 Agonists in asthma
Short-Acting β2 Agonists
o Salbutamol
o Terbutaline
o Bambuterol
o Pirbuterol
o Metaproterenol
Long-Acting β2Agonists
o Salmeterol
o Formoterol
27. Short-Acting β2 Agonists
Duration of action : 3-6 hrs.
Convenient, rapid onset, without significant systemic side effect
Bronchodilator of choice in acute severe asthma
Used for symptomatic relief on as required basis.
Only treatment required for mild, intermittent asthma.
Use >2 times a week indicates need of a regular
controller therapy.
28. Long-Acting β2Agonists
Duration of action >12 hrs.
Used in combination with inhaled corticosteroid (ICS) therapy.
Improve asthma control and reduce frequency of
exacerbations.
Allow asthma to be controlled at lower dose of ICS.
Fixed dose combination of corticosteroid with long acting β2
agonist :
e.g. Salmeterol + Fluticasone, Formoterol + Budesonide.
29. Long-Acting β2Agonists
Should not be used as monotherapy (increased mortality).
Combination shows synergistic action.
Not effective for acute bronchospasm.
Salmeterol : slow onset, 2 puffs of 25 μg twice a day
Formoterol : rapid onset, 2 puffs of 6 μg twice a day
30. Risks with LABA monotherapy
Meta-analyses have shown that LABAs are associated
with increased risk of overall death when used as
monotherapy.
The use of LABAs concomitantly with inhaled
corticosteroids significantly reduces asthma
hospitalizations and is not associated with life-threatening
events and asthma-related deaths.
The evidence appears to support the use of LABAs plus
inhaled steroids in a single inhaler device for patients with
moderate to severe asthma.
Thorax 2012;67:342-349
32. Anticholinergic agents
Ipratropium bromide, Tiotropium.
Prevent cholinergic nerve induced bronchoconstriction.
Block M3 receptor on bronchial smooth muscles.
Less effective than β2 agonists.
Response varies with existing vagal tone.
33. Anticholinergic agents
Use in asthma
Intolerance to inhaled β2 agonist.
Status asthmaticus – additive effect with β2 agonist.
Ipratropium -- bitter taste, precipitate glaucoma
Tiotropium – longer acting, approved for treatment of
COPD.
34. Methylxanthines
Theophylline, Theobromine, Caffeine
Recently interest has declined in this class of drugs:
Side effects
Need for plasma drug levels monitoring
Pharmacokinetics
Availability of other effective drugs
Still widely used in developing countries due to
their lower cost.
Availability of slow release tablets – stable plasma levels
35. Methylxanthines: MOA
a) Inhibition of several members of the
phosphodiesterase (PDE) enzyme family
b) Inhibition of cell-surface receptors for adenosine
c) Enhancement of histone deacetylation.
36.
37. Methylxanthines
Theophylline base is poorly soluble in water.
Soluble salts of theophylline:
Aminophylline -85%
Etophylline – 80%
Oxtriphylline -64%
38. ADRs of Theophylline
At conc >20 mg/L : Anorexia, nausea, vomiting,
abdominal discomfort, headache, and anxiety start
(PDE4 inhibition)
At conc.>40 mg/L : Seizures or arrhythmias
(A1 receptor antagonism)
40. Corticosteroids – asthma
Effective drugs for treatment of asthma.
Development of inhaled corticosteroids is a major advance
in asthma therapy.
Used prophylactically as a controller therapy.
Reduce the need for rescue β2 agonist.
Benefit starts in 1week but continues upto several months.
If asthma not controlled at low dose of ICS :-
addition of long acting β2 agonist is more effective than
doubling steroid dose.
41. Glucocorticoids
Mechanism of action
Inhibition of phospholipase A2
↓ prostaglandin and leukotrienes
↓ Number of inflammatory cells in airways.
Mast cell stabilization →↓ histamine release.
↓ capillary permeability and mucosal edema.
Inhibition of antigen-antibody reaction.
Upregulate β2 receptors (have additive effect to β2 agonists).
43. Budesonide, fluticasone, mometasone, and ciclesonide : lower
oral bioavailability than beclomethasone dipropionate
This results in reduced systemic absorption from the fraction
of the inhaled drug that is swallowed and thus reduced
adverse effects.
Ciclesonide is a prodrug - converted to the active metabolite
by esterases in the lung : low oral bioavailability and a high
therapeutic index.
When doses of inhaled steroid exceed 800 µg
beclomethasone dipropionate daily, a large volume spacer is
recommended to reduce oropharyngeal deposition and
systemic absorption.
44. ADRs of inhaled corticosteroids
Oropharyngeal candidiasis, dysphonia, cough – frequent at
high doses. Reduced by using spacer device.
Decreased bone mineral density.
Hypothalamic-pituitary-adrenal axis suppression-
>1500µg/d of budesonide.
Metabolic abnormalities
Skin thinning, purpura- dose related effect.
Growth retardation in children – controversial.
45. Systemic steroids in asthma
Indication
Acute exacerbation
Chronic severe asthma
A 5-10 day course of Prednisolone 30-40 mg/d is used.
1% of patients may require regular maintenance therapy.
Side effects of long-term oral corticosteroid therapy :
Fluid retention, increased appetite, weight gain,
osteoporosis, capillary fragility, hypertension,
peptic ulceration, diabetes, cataracts, and psychosis.
46. Leukotrienes pathway inhibitors
Two approaches to interrupt the leukotriene pathway :
Inhibition of 5-lipoxygenase, thereby preventing
leukotriene synthesis - Zileuton.
Inhibition of the binding of LTD4 to its receptor on
target tissues, thereby preventing its action -
Zafirlukast, Montelukast, Pranlukast.
Oral route.
Side effects :-
Hepatic dysfunction
Churg –Strauss synd.(vasculitis with eosinophilia)
47.
48.
49. Leukotrienes pathway inhibitors
They are less effective than ICSs in controlling asthma
Use in asthma
Patients unable to manipulate inhaler devices.
Aspirin induced asthma.
Mild asthma – alternative to ICS.
Moderate to severe asthma – may allow reduction of ICS
dose.
50. Montelukast is effective as a once-daily oral preparation
(10 mg in adults, 5 mg in children).
In addition, oral administration may treat Concomitant
allergic rhinitis.
51. Cromones
Cromolyn sodium & Nedocromil sodium
On chronic use (four times daily) reduce the bronchial
reactivity.
These drugs have no effect on airway smooth muscle tone
and are ineffective in reversing asthmatic bronchospasm;
they are only of value when taken prophylactically.
Inhalation route
52. Cromones
Exact mechanism of action unknown
Alteration in the function of delayed chloride channels in
the cell membrane, inhibiting cell activation.
Mast cells - inhibition of mediator release
Eosinophils - inhibition of the inflammatory response to
inhalation of allergens.
53. Cromones : Uses
Asthma - Prevention of asthmatic attacks in mild to
moderate asthma
Adverse effects
Well tolerated drugs
Minor side effects- Throat irritation, Nausea, Headache.
54. Anti-IgE therapy
Omalizumab - recombinant humanized monoclonal
antibody targeted against IgE.
MOA - IgE bound to Omalizumab cannot bind to IgE
receptors on mast cells and basophils :-
preventing the allergic reaction at a very early
step in the process.
Pharmacokinetics
Single subcutaneous injection every 2 to 4 weeks.
Peak serum levels after 7 to 8 days.
55.
56. Omalizumab Use in asthma
Persons >12 years of age with moderate-to-severe
persistent asthma.
Omalizumab is not an acute bronchodilator and should not
be used as a rescue medication or as a treatment of status
asthmaticus.
Expensive drug
Has to be given under direct medical supervision due to
the risk of anaphylaxis.
59. Aerosol delivery of drugs
Topical application of drugs to lungs.
Least systemic delivery
Poor absorbtion from GIT
High first pass metaobolism
Therpeutic index of drugs is Increased.
Drug particles of 1-5µ are produced.
Devices - Metered dose inhalers, nebulisers, dry powder
inhaler.
61. Status asthmaticus
Severe airway obstruction
Symptoms persist despite initial standard acute asthma
therapy.
Severe dyspnoea & cough
Patient adopts upright position fixing shoulder girdle to
assist accessory muscles of respiration
Sweating, central cyanosis, tachycardia
URTI mc precipitant
62. Treatment of Status asthmaticus
High flow humidified Oxygen through facemask
Hydrocortisone hemisuccinate 100 mg i.v. stat,
followed by 100-200mg, 4-8 hrly infusion.
Nebulised Salbutamol (5mg) in Oxygen given immediately
Ipratopium bromide (0.5mg) + Salbutamol (5mg) nebulised
in oxygen,who don’t respond within 15-30 min
Terbutaline (0.25-0.5mg) s.c. or (0.1μg/kg/min) i.v.
excessive coughing or too weak to inspire adequately.
ET intubation & mechanical ventilation if
above Treatment fails
63. Asthma medicines and pregnancy
A review of the animal and human studies on the effects of asthma
medicines taken during pregnancy found few risks to the woman or
her fetus.
It is safer for a pregnant woman who has asthma to be treated with
asthma medicines than for her to have asthma symptoms and
asthma attacks.
Poor control of asthma is a greater risk to the fetus than asthma
medicines are.
Budesonide is labeled by the U.S. Food and Drug Administration
(FDA) as the safest inhaled corticosteroid to use during pregnancy.
One study found that low-dose inhaled budesonide in pregnant
women seemed to be safe for the mother and the fetus.
Cellular mechanisms of asthma. Myriad inflammatory cells are recruited and activated in the airways, where they release multiple inflammatory mediators, which can also arise from structural cells. These mediators lead to bronchoconstriction, plasma exudation and edema, vasodilation, mucus hypersecretion, and activation of sensory nerves. Chronic inflammation leads to structural changes, including subepithelial fibrosis (basement membrane thickening), airway smooth muscle hypertrophy and hyperplasia, angiogenesis, and hyperplasia of mucus-secreting cells.
ADAM-33 ::: a disintegrin and metalloprotease domain. Containinng protein 33. is an enzyme that in humans is encoded by the ADAM-33 gene.
RES
They do not relax airway smooth muscle directly but reduce bronchial reactivity and reduce the frequency of asthma exacerbations if taken regularly.
ICS may have local side effects due to the deposition of inhaled steroid in the oropharynx. The most common problem is hoarseness and weakness of the voice (dysphonia) due to atrophy of the vocal cords following laryngeal deposition of steroid; it may occur in up to 40% of patients and is noticed particularly by patients who need to use their voices during their work (lecturers, teachers, and singers). Throat irritation and coughing after inhalation are common with MDI and appear to be due to additives because these problems are not usually seen if the patient switches to a DPI. There is no evidence for atrophy of the lining of the airway. Oropharyngeal candidiasis occurs in 5% of patients.
Most studies have been reassuring that doses 400 g/day have not been associated with impaired growth; on the contrary, there may even be a growth spurt as asthma is better controlled.
Corticosteroid resistance is a major barrier to effective therapy in patients with severe asthma, in asthmatic patients who smoke, and in patients with COPD and cystic fibrosis (Barnes and Adcock, 2009). "Steroid-resistant" asthma is thought to be due to reduced anti-inflammatory actions of corticosteroids.
Immunoglobulin (Ig)E plays a central role in allergic diseases. Blocking IgE using an antibody, such as omalizumab, is a rational therapeutic approach.
IgE may activate high-affinity receptors (FcRI) on mast cells as well as low-affinity receptors (FcRII, CD23) on other inflammatory cells. Omalizumab prevents these interactions and the resulting inflammation.
Omalizumab also reduces levels of circulating IgE.