This document provides an overview of the management of bronchial asthma. It discusses the pathophysiology of asthma including chronic airway inflammation and hyperresponsiveness. It describes the clinical presentation of asthma and drug treatments including bronchodilators, corticosteroids, leukotriene inhibitors, and cromones. The document highlights the roles of these drugs in controlling inflammation and reducing exacerbations to manage asthma symptoms.
4. Introduction
īĸ Asthma is a chronic inflammatory disorder of the
airways that is characterized:
īĸ clinically by recurrent episodes of wheezing,
breathlessness, chest tightness, and cough,
particularly at night/early morning.
īĸ physiologically by widespread, reversible
narrowing of the bronchial airways and a marked
increase in bronchial responsiveness.
5. Classification
īĸ A heterogenous disorder.
īĸ Atopic /extrinsic /allergic ( 70%)âŧ â IgE
mediated immune responses to environmental
antigens.
īĸ Non-atopic/ intrinsic /non-allergic( 30%)âŧ â
triggered by non immune stimuli. Patients have
negative skin test to common inhalant allergens
and normal serum concentrations of IgE. Asthma
may be triggered by aspirin, pulmonary
infections, cold, exercise, psychological stress or
inhaled irritants.
6. īĸThe 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.
9. 1. Inflammation
īĸ Chronic inflammatory state
īĸ Involves respiratory mucosa from trachea to
terminal bronchioles, predominantly in the
bronchi.
īĸ Activation of mast cell,infiltration of eosinophils
& T-helper type 2 (Th2) lymphocytes
īĸ T-helper type 2 (Th2) response -interleukin 4 (IL-
4), IL-5, and IL-13.
10. InflammationâĻ
īĸ IL-4 â stimulates IgE production
īĸ IL-3,IL-4,IL-9 âactivate mast cells
īĸ IL-5 â activates eosinophils
īĸ IL-13 â stimulates mucus production
īĸ Inflammatory mediators
īMany different mediators involved.
īRecent clinical studies with antileukotrienes
suggest that cysteinyl-leukotrienes have a
clinically important effect.
13. InflammationâĻ
īĸ Exact cause of airway inflammation is unknown.
īĸ Thought to be an interplay between endogenous and
environmental factors.
īĸ Endogenous factors â
īĸ Atopy â
ī Genetic predisposition to IgE mediated type I hypersensitivity
ī An excessive TH2 reaction against environmental antigens
ī The major risk factor for asthma
ī Asthma is commonly associated with other atopic diseases â allergic
rhinitis(80%), atopic dermatitis, urticaria, etc.
īĸ Genetics
ī Polymorphism of gene on chr. 5q
ī ADAM-33,DPP-10 ,GPRA gene
14. InflammationâĻ
īĸ Environmental factors
ī Viral infections â RSV, Mycoplasma, Chlamydia
ī Hygeine hypothesis - proposes that lack of
infections in early childhood preserves the TH2 cell ,
whereas exposure to infections and endotoxin results
in a shift toward a predominant protective TH1
response.
ī Air pollution
ī Allergens â house dust mite
15. 2. Airway Hyperresponsiveness (AHR)
īĸ The excessive bronchoconstrictor response to
multiple inhaled triggers that would have no
effect on normal airways.
īĸ Characteristic physiologic abnormality of
asthma.
īĸ e.g. 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.
20. Clinical presentation
īĸ Wheezing, dyspnea and cough.
īĸ Variable â both spontaneously and with therapy.
īĸ Tenaceous mucus production.
īĸ Symptoms worse at night.
īĸ Nonproductive cough
īĸ Limitation of activity
Signsī
īĸ â respiratory rate,with use of accessory muscles
īĸ Hyper-resonant percussion note
īĸ Expiratory rhonchi,expiration>inspiration.
īĸ During very severe attacks,airflow may be insufficient to produce
rhonchiī SILENT CHEST
īĸ No findings when asthma is under control or b/w attacks
21. Investigations
īĸ Pulmonary function testsī Spirometry
â estimate degree of obstuction
â âFEV1, âFEV1/FVC, âPEF.
â >12% increase in FEV1, 15 minutes after β2 agonist inhalation.
â Morning dipping in PEF(chronic bronchitis)
īĸ AHR â histamine / methacholine provocation testī > 20% fall in
FEV1
īĸ CXR â hyperinflation, pneumothorax,emphysema
īĸ Arterial blood-gas analysisī hypoxia & hypocarbia(severe acute
asthmaī hypercarbia)
īĸ Skin hypersensitivity test
īĸ Sputum & blood eosinophilia
īĸ Elevated serum IgE levels
23. Classification of drugs
īĸ Bronchodilators â rapid relief, by relaxation of
airway smooth muscle
īĸ β2 Agonists
īĸ Anticholinergic Agents
īĸ Methylxanthines
īĸ Controllers â inhibit the inflammatory process
īĸ Glucocorticoids
īĸ Leukotrienes pathway inhibitors
īĸ Cromones
īĸ Anti-IgE therapy
24. β2 Agonists in asthma
īĸ Potent bronchodilators.(TOC)
īĸ Usually given by inhalation route.
īĸ MOA:
īĸ Relaxation of airway smooth muscle
īĸ Non-bronchodilator effects
ī Inhibition of mast cell mediator release
ī Reduction in plasma exudation
ī Increased mucociliary transport
ī Inhibition of sensory nerve activation
īĸ Inflammatory cells express β2 receptors but these are rapidly
downregulated.
īĸ No effect on airway inflammation and AHR.
27. Short-Acting β2 Agonists
īĸ Duration of action - 3-6hrs.
īĸ Convenient,rapid onset,without significant systemic side
effect
īĸ Bronchodil. of choice in acute severe asthma
īĸ Used for symptomatic relief on as required basis.
īĸ Only treatment required for mild, intermittent asthma.
īĸ Use >2 times a week indicates need of a regular controller
therapy.
28. Long-Acting β2Agonists
īĸ Duration of action - >12 hrs.
īĸ Used in combination with inhaled corticosteroid (ICS)therapy.
īĸ Improve asthma control and reduce frequency of exacerbations.
īĸ Allow asthma to be controlled at lower dose of ICS.
īĸ Fixed dose combination of corticosteroid with long acting β2 agonist
have proved to be highly effective.
īĸ e.g. salmeterol+fluticasone, formoterol + budesonide.
29. Long-Acting β2Agonists
īĸ Should not be used as monotherapy (increased
mortality).
īĸ Combination has complementary synergistic action
īĸ Not effective for acute bronchospasm.
īĸ Salmeterol ī slow onset,2 puffs of 25Îŧg 2-3 a day
īĸ Formoterol ī rapid onset,2 puffs of 6Îŧg 2-3 a day
30. ADRs â β2 agonists
īĸ Muscle tremors(direct effect on skeletal muscle β2
receptors)(mc)
īĸ Tachycardia(direct effect on atrial β2 receptors)
īĸ Hypokalemia(direct β2 effect on skeletal muscle uptake of
K+)
īĸ Hypoxemia
īĸ Restlessness
īĸ Cautious use â
ī Hypertension
ī Ischemic heart disease
31. Anticholinergic agents
īĸ Ipratropium bromide, tiotropium.
īĸ Prevent cholinergic nerve induced
bronchoconstriction.
īĸ Block M3 receptor on bronchial smooth muscles.
īĸ Less effective than β2 agonists.
īĸ Response varies with existing vagal tone.
32. Anticholinergic agents
īĸ Use in asthma
ī Intolerance to inhaled β2 agonist.
ī Status asthmaticus âadditive effect with β2 agonist.
īĸ Ipratropium-slow,bitter taste,precipitate
glaucoma,paradoxical broncho -constriction(hypotonic
nebulizer sol. & antibacterial additive)
īĸ Tiotropium âlonger acting, approved for treatment
of COPD.Dryness of mouth
33. Methylxanthines
īĸ Medium potency bronchodilator
īĸ Theophylline, theobromine, caffeine
īĸ Recently interest has declined in this class of drugs:
īSide effects
īNeed for plasma drug levels
īPharmacokinetics
īAvailability of other effective drugs
īĸ Still widely used drugs especially in developing countries due to
their lower cost.
īĸ Availability of slow release tablets â stable plasma levels
34. Methylxanthines
īĸ Mechanism of action
a) Inhibition of several members of the phosphodiesterase (PDE)
enzyme family
b) Inhibition of cell-surface receptors for adenosine
c) IL-10 release-anti inflammatory action
d) Prevents translocation of NF-kB into nucleus
e) Activation of histone deacetylation. (HDAC2)
39. â clearance
īĸ Enzyme induction(mainly CYP1A2) by co-administered
drugs(e.g.rifampicin,ethanol)
īĸ Smoking via CYP1A2 induction
īĸ High âprotein,low âcarbohydrate diet
īĸ Childhood
â clearance
īĸ CYPinhibition(cimetidine,erythromycin,allopurinol,ciprofloxacin,zileut
on,zafirlukast)
īĸ CHF
īĸ Liver ds.
īĸ Pneumonia
īĸ Viral infection & vaccination
īĸ High-carbohyrate diet
īĸ Old age
40. Adr of theophylline
īĸ Anorexia, nausea, vomiting, abdominal discomfort,
headache, and anxiety â start at >20 mg/L.(PDE4
inhibition)
īĸ Seizures or arrhythmias at conc.>40 mg/L(A1
receptor antagonism)
īĸ Diuresis(A1 receptor antagonism)
Doxyphyllineī long acting,oral
ī§ inhibit PDE
ī§ Adenosine A1 & A2 ī reduced affinityī safe
ī§ Inhibit PAF-bronchocostiction & release of TXA2
ī§ Dose -400mg OD
41. Methylxanthines
īĸ Roflumilast, cilomilast, and tofimilast- more
selective inhibitors of PDE4.
īĸ Effective for asthma control but not used at
present due to their toxicities of nausea,
headache, and diarrhea.
īĸ Administration of these compounds by inhalation
is being considered.
42. Corticosteroids â asthma
īĸ Effective drugs for treatment of asthma.
īĸ Development of inhaled corticosteroids is a major
advance in asthma therapy.
īĸ Used prophylactically as a controller therapy.
īĸ Reduce the need for rescue β2 agonist.
īĸ Benefit starts in 1week but continues upto
several months.
īĸ If asthma not controlled at low dose of ICS then
addition of long acting β2 agonist is more
effective than doubling steroid dose.
43. Corticosteroids â MOA in asthma
īĸ Broad antiinflammatory effects:
ī Marked inhibition of infiltration of airways by inflammatory
cells.
ī Modulation of cytokine and chemokine production
ī Inhibition of eicosanoid synthesis (by inhibiting PLA2)
ī Decreased vascular permeability.
ī Potentiate effect of β2 agonist.
īĸ They do not relax airway smooth muscle directly but
reduce bronchial reactivity and reduce the frequency of
asthma exacerbations if taken regularly.
46. Inhaled corticosteroids( ICS)
Use of β2Agonists >2 times a week indicates need of a ICS
ī Beclomethasone
ī Budesonide
ī Fluticasone
ī Triamcinolone
ī Flunisolide
ī Ciclesonide
īĸ greatly enhance the therapeutic index of the drugs.
47. ADR of inhaled corticosteroids
īĸ Oropharyngeal candidiasis, dysphonia â
frequent at high doses. Reduced by using spacer
device.
īĸ Decreased bone mineral density.
īĸ Hypothalamic-pituitary-adrenal axis
suppression- >2000Âĩg/d of beclomethasone.
īĸ Skin thinning, purpura- dose related effect.
īĸ Growth retardation in children
48. īĸ Ciclesonide - recently approved corticosteroid,
a prodrug activated by esterases in bronchial
epithelial cells. Claimed to have lesser systemic
side effects.
49. Systemic steroids in asthma
īĸ Indication
ī Acute exacerbation(lung function <30% predicted)
ī Chronic severe asthma
īĸ A 5-10 day course of prednisolone 30-45mg/d is
used.
īĸ 1% of patients may require regular maintenance
therapy.
īĸ Single morning dose
50. Leukotrienes pathway inhibitors
īĸ Two approaches to interrupt the leukotriene
pathway have been pursued
ī Inhibition of 5-lipoxygenase, thereby preventing
leukotriene synthesis. Zileuton.
ī Inhibition of the binding of LTD4 to its receptor on
target tissues, thereby preventing its action.
Zafirlukast, montelukast.
ī Oral route.
ADR
ī Liver toxicity
ī Churg âStrauss synd.(vasculitis with eosinophilia)
52. Leukotrienes pathway inhibitors
īĸ They are less effective than ICSs in controlling
asthma
īĸ Use in asthma
īĸ Patients unable to manipulate inhaler devices.
īĸ Aspirin induced asthma.
īĸ Mild asthma â alternative to ICS.
īĸ Moderate to severe asthma â may allow
reduction of ICS dose.
53. Cromones
īĸ Cromolyn sodium & nedocromil sodium
īĸ On chronic use (four times daily) reduce the
overall level of bronchial reactivity.
īĸ 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.
īĸ Inhalation route
54. Cromones
īĸ Exact mechanism of action unknown
īĸ Alteration in the function of delayed chloride
channels in the cell membrane, inhibiting cell
activation.
ī Mast cells - inhibition of mediator release
ī Eosinophils - inhibition of the inflammatory response
to inhalation of allergens.
ī Inhibits parasympathetic & cough reflex
55. Cromones
īĸ Uses
īĸ Asthma - Prevention of asthmatic attacks in mild
to moderate asthma
īĸ Adverse effects
īĸ Well tolerated drugs
īĸ Minor side effects- throat irritation, cough, and
mouth dryness, rarely, chest tightness, and
wheezing.
56. Anti-IgE therapy
īĸ Omalizumab - recombinant humanized
monoclonal antibody targeted against IgE.
īĸ MOA - IgE bound to omalizumab cannot bind to
IgE receptors on mast cells and basophils, thereby
preventing the allergic reaction at a very early step
in the process.
īĸ Pharmacokinetics
īĸ single subcutaneous injection every 2 to 4 weeks.
īĸ Peak serum levels after 7 to 8 days.
57.
58. Omalizumab
īĸ Use in asthma
īĸ Persons >12 years of age with moderate-to-severe
persistent asthma.
īĸ Omalizumab is not an acute bronchodilator and
should not be used as a rescue medication or as a
treatment of status asthmaticus.
īĸ Expensive drug
īĸ Has to be given under direct medical supervision
due to the risk of anaphylaxis.
59. Classificationī global initiative for asthma-
gina severity grades
Grade Symptoms Night-time Symptoms
Mild
intermittent
Symptoms ⤠2 times/week ⤠2 times/month
Mild
persistent
Symptoms âĨ 2 times/week
but ⤠1/day
âĨ 2 times/month
Moderate
persistent
Daily Symptoms âĨ 1/week
Severe
persistent
Continued Symptoms
Limited physical activity
Frequent
61. Aerosol delivery of drugs
īĸ Topical application of drugs to lungs.
īĸ Least systemic delivery
ī Poor absorbtion from GIT
ī High first pass metabolism
īĸ Therpeutic index of drugs is Increased.
īĸ Drug particles of 2-5Âĩ are produced.
īĸ Devices - Metered dose inhalers, nebulisers, dry
powder inhaler.
63. Status asthmaticus(severe acute asthma)
īĸ Severe airway obstuction
īĸ Symptoms persist despite initial standard acute
asthma therapy.
īĸ Severe dyspnoea & unproductive cough
īĸ Pt. adopts upright position fixing shoulder girdle to
assist accessory muscles of respiration
īĸ Sweating,central cyanosis ,tachycardia
īĸ URTIī mc precipitant
64. Treatment of Status asthmaticus
īĸ High conc. of oxygen through facemask
īĸ Nebulised salbutamol(5mg) in oxygen given
immediately
īĸ Ipratopium bromide(0.5mg) + salbutamol(5mg)
nebulised in oxygen,who donât respond within 15-30 min
īĸ Terbutaline ī s.c.(0.25-0.5mg) or i.v.
(0.1Îŧg/kg/min)ī excessive coughing or too weak to
inspire adequately.
īĸ Hydrocortisone hemisuccinate 100mg i.v.stat, followed
by 100-200mg 4-8 hrly infusion.
īĸ ET intubation & mechanical ventilation if above Tt fails
65. Recent advances
īĸ Ultra long acting β2 agonist â Indacaterol, Carmoterol (phase II).
īĸ New bronchodil.ī MgSO4,K+ channel opener
īĸ CRTh2 antagonist
īĸ Endothelin antagonist
īĸ Inducible NO synthase inhibitors
īĸ Inhibition of chemokine receptors( CCR3).
īĸ Antibodies for IL-4,5 and13.
īĸ Inhibition of IL-4,5 production- suplatast tosilate.
īĸ NF-ÎēB inhibitors.
īĸ Mitogen-Activated Protein Kinase Inhibitors
īĸ Lumiliximab âantibody against low affinity IgE receptor(CD
23). Phase I.
67. Effects of inflammation
īĸ Airway epithelium â damage and shedding may
lead to AHR.
īĸ Smooth muscle â hyperplasia and hypertrophy
īĸ Vessels â increased in number, blood flow is
increased.
īĸ Mucus hypersecretion
īĸ Nerves âsensitization of nerve terminals and
reflex activation of cholinergic nerves.
īĸ Fibrosis â subepithelial.