Educational and therapeutic topic on asthma for MBBS and MD pharmacology students. other students like BDS , BHMS, BAMS etc can use for knowledge. and academic purpose.
VarSeq 2.6.0: Advancing Pharmacogenomics and Genomic Analysis
Dr. Chandane's Presentation on Asthma Pathogenesis and Treatment
1. Dr. CHANDANE R. D.Dr. CHANDANE R. D.
Assistant ProfessorAssistant Professor
Dept. Of PharmacologyDept. Of Pharmacology
Lady Hardinge MedicalLady Hardinge Medical
College, New DelhiCollege, New Delhi
2. HISTORYHISTORY
• Greek- azzein- sharp breathGreek- azzein- sharp breath
• HippocratesHippocrates
• GalenGalen
• Bronchodilators- 1901Bronchodilators- 1901
• anti-inflammatory added in 1960anti-inflammatory added in 1960
Incidence- higher in low income populationIncidence- higher in low income population
3. ASTHMA DEFINATIONASTHMA DEFINATION
““Asthma is defined as a chronicAsthma is defined as a chronic
inflammatory disease of airway that isinflammatory disease of airway that is
characterized by increase responsiveness ofcharacterized by increase responsiveness of
tracheobronchial tree to a multiplicity oftracheobronchial tree to a multiplicity of
stimuli .”stimuli .”
Extrinsic: episodic, atopyExtrinsic: episodic, atopy
Intrinsic : perennial, status asthmaticusIntrinsic : perennial, status asthmaticus
4. Asthma is characterisedAsthma is characterised
CLINICALLYCLINICALLY- Recurrent bouts of coughing, shortness of
breath,chest tightness & wheezing
PHYSIOGICALLYPHYSIOGICALLY- Narrowing of bronchial airway & increase in
bronchial responsiveness
PATHOLOGICALLYPATHOLOGICALLY- Lymphocytic eosinophilic inflammation of
bronchial mucosa Remodelling of bronchial
mucosa & hyperplasia of all structural
elements
11. INVESTIGATIONSINVESTIGATIONS
1.1. Pulmonary Function Test – PEFR, FEV1 etc.Pulmonary Function Test – PEFR, FEV1 etc.
2.2. Absolute eosinophil countAbsolute eosinophil count
3.3. Chest X-rayChest X-ray
4.4. Allergy testAllergy test
12. Approaches to treatmentApproaches to treatment
1.1. Prevention of AG:AB reaction- AG avoidancePrevention of AG:AB reaction- AG avoidance
HyposensitizationHyposensitization
2.2. Neutralization of IgE- OmalizumabNeutralization of IgE- Omalizumab
3.3. Supression of inflammation & bronchial hyperreactivitivity-Supression of inflammation & bronchial hyperreactivitivity-
corticosteroidscorticosteroids
4.4. Prevention of release of mediators- mast cell stabilizersPrevention of release of mediators- mast cell stabilizers
5.5. Antagonism of related mediators- LT antagonist,Antagonism of related mediators- LT antagonist,
antihistamines, PAF antagonistantihistamines, PAF antagonist
6.6. Blockade of constrictor NT- AnticholinergicsBlockade of constrictor NT- Anticholinergics
7.7. Mimicking dilator NT- SympathomimeticsMimicking dilator NT- Sympathomimetics
8.8. Directly acting bronchodilator- Methyl xanthinesDirectly acting bronchodilator- Methyl xanthines
14. AEROSOL DELIVERY OF DRUGAEROSOL DELIVERY OF DRUG
• High local conc.-↓systemic side effects
• Delivery to Lung- Particle size 1-5µm
• Other factors- Rate of breathing & breath holding
• Maneuvers that ↑ drug deposition in lung
• Spacer - ↑ inhaled : swallow drug
15. INHALATION DELIVERY SYSTEMINHALATION DELIVERY SYSTEM
• MDI (Pressurized Metered Dose Inhaler) :-
-CFC propellants
- HFA propellants
- Cheap portable – Hand breathing co-ordination
• NEBULIZER :-
- two types – ultrasonic & jet
- not req. handbreathing co-ordination
- Severe asthma exacerbation
- face mask- children & older pt.
- ultrasonic- hypertonic saline
16. • DRY POWDER INHALER :- Spinhaler & RotahalerDRY POWDER INHALER :- Spinhaler & Rotahaler
- Lactose or Glucose- Lactose or Glucose
- High air flow req.- High air flow req.
- Irritating , Storage –humidity- Irritating , Storage –humidity
FATE OF DRUGFATE OF DRUG
- Only small % deposited 2-10%Only small % deposited 2-10%
- Swallowed drug –First pass metabolismSwallowed drug –First pass metabolism
18. I)I) BRONCHODILATORSBRONCHODILATORS
A}A} ββ-2 SYMPATHOMIMETICS-2 SYMPATHOMIMETICS
► SHORT ACTING - Symptomatic reliefSHORT ACTING - Symptomatic relief
► LONG ACTING - Prophylactic t/tLONG ACTING - Prophylactic t/t
MECHANISM OF ACTIONMECHANISM OF ACTION
► Stimulation ofStimulation of ββ-2 receptors-2 receptors →↑→↑c-AMP formation inc-AMP formation in
bronchial smooth muscle → relaxation of smoothbronchial smooth muscle → relaxation of smooth
muscle. ↑conductance of large Camuscle. ↑conductance of large Ca+2+2
sensitive Ksensitive K++
channels → membrane hyper polarization &channels → membrane hyper polarization &
relaxationrelaxation
► Stimulation ofStimulation of ββ-2 receptors on inflammatory cells →-2 receptors on inflammatory cells →
↑intracellular c-AMP → inhibit release of mediators↑intracellular c-AMP → inhibit release of mediators
& cytokines& cytokines
19. Receptor DesensitizationReceptor Desensitization:-:-
►chronic t/t ,chronic t/t ,
►Receptor on bronchial smooth muscles → resistantReceptor on bronchial smooth muscles → resistant
►Receptor on inflammatory cells → desensitized rapidly.Receptor on inflammatory cells → desensitized rapidly.
► Little effective in inhibiting airway inflammation.Little effective in inhibiting airway inflammation.
20. SHORT ACTINGSHORT ACTING ββ-2 ADRENERGIC AGONISTS-2 ADRENERGIC AGONISTS
Albuterol(salbutamol), Levoalbuterol,Albuterol(salbutamol), Levoalbuterol,
Metapreterenol, Terbutaline, Pirbuterol,Metapreterenol, Terbutaline, Pirbuterol,
Isoetharine, Bitolterol, Fenoterol, ProcaterolIsoetharine, Bitolterol, Fenoterol, Procaterol
Inhalation, onset action within 1-5 min.Inhalation, onset action within 1-5 min.
Bronchodilation for 2-6 hrs.Bronchodilation for 2-6 hrs.
Most effective drugMost effective drug → reversing→ reversing
BronchoconstictionBronchoconstiction
Rapid symptomatic relief; as needed basisRapid symptomatic relief; as needed basis
21. i]i] ALBUTEROL(SALBUTAMOL):-ALBUTEROL(SALBUTAMOL):-
- Attack of asthma- Attack of asthma
- S/E – Muscle tremors, palpitation restlessness,- S/E – Muscle tremors, palpitation restlessness,
nervousness, ankle edema, throat irritationnervousness, ankle edema, throat irritation
- Presystemic metabolism in gut wall- Presystemic metabolism in gut wall
- Dose- 2-4mg oral, 100-200µg inhalation,- Dose- 2-4mg oral, 100-200µg inhalation,
0.25-0.5mg im/s.c.0.25-0.5mg im/s.c.
ii]ii] LEVOALBUTEROL(LEVOSALBUTAMOL):-LEVOALBUTEROL(LEVOSALBUTAMOL):-
- R-enantiomer of albuterol- R-enantiomer of albuterol
- more potent Bronchodilator- more potent Bronchodilator
- less side effects: so used in pt with h/o SVT & other- less side effects: so used in pt with h/o SVT & other
arrhythmiasarrhythmias
iii]iii] TERBUTALINE:-TERBUTALINE:- Similar to albuterolSimilar to albuterol
- Dose- 5mg oral, 0.25mg sc, 250µg inhalation- Dose- 5mg oral, 0.25mg sc, 250µg inhalation
22. iv] METOPROTERENOL:-iv] METOPROTERENOL:-
- Less- Less ββ2 selective2 selective
- resistant to methylation by COMT- resistant to methylation by COMT
- More prone to cardiac stimulation- More prone to cardiac stimulation
v] ISOETHARINE:-v] ISOETHARINE:-
- First- First ββ2 selective widely used2 selective widely used
- resistant to metabolism by MAO- resistant to metabolism by MAO
- Inhalation- Inhalation
vi] FENOTEROL :-vi] FENOTEROL :- Association with increase deathAssociation with increase death
vii] BITOLTEROL:-vii] BITOLTEROL:- Prodrug - esterases hydrolyzes toProdrug - esterases hydrolyzes to
active Colterolactive Colterol
vii] PIRBUTEROL & ix] PROCATEROL :-vii] PIRBUTEROL & ix] PROCATEROL :- InhalationInhalation
23. LONG ACTINGLONG ACTING ββ-2 ADRENERGIC AGONISTS-2 ADRENERGIC AGONISTS
SALMETEROL, FORMOTEROL, BAMBUTEROL,SALMETEROL, FORMOTEROL, BAMBUTEROL,
CLENBUTEROLCLENBUTEROL
i)i) SALMETEROL:-SALMETEROL:-
- First long acting- First long acting ββ2 agonist2 agonist
- slow onset of action- slow onset of action
- duration is 12 hrs bronchodilation- duration is 12 hrs bronchodilation
- inhalation twice daily - nocturnal asthma- inhalation twice daily - nocturnal asthma
- 10,000 more lipophilic than albuterol- 10,000 more lipophilic than albuterol
- unbound salmeterol persist in membrane &- unbound salmeterol persist in membrane &
slowly dissociate from receptor environmentslowly dissociate from receptor environment
- DOSE: 50-100 µg BD by inhalation- DOSE: 50-100 µg BD by inhalation
24. ii) FORMOTEROL:-ii) FORMOTEROL:-
- Fast onset of action, duration 12 hrs- Fast onset of action, duration 12 hrs
- DOSE: 12-24 µg BD by inhalation- DOSE: 12-24 µg BD by inhalation
iii) BAMBUTEROL:-iii) BAMBUTEROL:-
- Prodrug of terbutaline- Prodrug of terbutaline
- Hydrolyzed by pseudo cholinesterase-release active drug- Hydrolyzed by pseudo cholinesterase-release active drug
- Chronic bronchial asthma- Chronic bronchial asthma
- DOSE: 10-20 mg OD in evening orally- DOSE: 10-20 mg OD in evening orally
iv) CLENBUTEROL:-iv) CLENBUTEROL:-
-- More potent, long acting & thermogenic drugMore potent, long acting & thermogenic drug
- ↑ aerobic capacity, ↑ BP, CNS Stimulation- ↑ aerobic capacity, ↑ BP, CNS Stimulation
- ↑ fat & protein use ↓ glycogen storage – wt. loss drug- ↑ fat & protein use ↓ glycogen storage – wt. loss drug
- banned for athletes & players- banned for athletes & players
- DOSE: 20-60µg/day max. 150µg- DOSE: 20-60µg/day max. 150µg
-T-T - 36-39 hrs - Pork meat poisoning- 36-39 hrs - Pork meat poisoning
25. ORAL THERAPY:-ORAL THERAPY:-
- Greater risk of side effects- Tremors, muscle cramps,- Greater risk of side effects- Tremors, muscle cramps,
cardiac tachyarrhythmia & metabolic disturbancescardiac tachyarrhythmia & metabolic disturbances
- two situations of oral therapy- two situations of oral therapy
1. Young children (syr.) -can not manipulate inhalers1. Young children (syr.) -can not manipulate inhalers
2. Severe asthma exacerbation - local irritation2. Severe asthma exacerbation - local irritation
COMBINATIONCOMBINATION ––
-- Long actingLong acting ββ2 agonist + Glucocorticoids2 agonist + Glucocorticoids
- Salmeterol + Fluticasone, Formoterol + Budesonide- Salmeterol + Fluticasone, Formoterol + Budesonide
- More effective than doubling steroid dose- More effective than doubling steroid dose
26. B} METHYL XANTHINESB} METHYL XANTHINES
--Theophylline - first extracted from tea leaves –Theophylline - first extracted from tea leaves –
1888 by German biologist Albrecht Kossel.1888 by German biologist Albrecht Kossel.
- Synthesized by another German scientist,- Synthesized by another German scientist,
Wilhelm Traube.Wilhelm Traube.
- First clinical use in asthma t/t in 1950s.- First clinical use in asthma t/t in 1950s.
- Among Least expensive- Among Least expensive
- Three xanthine alkaloids: Caffeine, Theophylline &- Three xanthine alkaloids: Caffeine, Theophylline &
TheobromineTheobromine
31. Doxophylline:- Long acting,Doxophylline:- Long acting,
- Not interfere- sleep, G I secretion- Not interfere- sleep, G I secretion
- 400mg OD in evening- 400mg OD in evening
PDE4 Inhibitors- Cilomilast & RoflumilastPDE4 Inhibitors- Cilomilast & Roflumilast
In Asthma Theophyllines :In Asthma Theophyllines :
-Bronchodilatation,-Bronchodilatation,
- ↓ release of inflammatory mediators,
- improve mucociliary clearance,
- stimulate respiratory drive &
- ↑ diaphragmatic contractility
32. C} ANTICHOLINERGIC AGENTS
Atropinic drugs – block constrictor tone, large airway
IPRATROPIUM BROMIDE:-
- Muscarinic receptor antagonist
- M3 receptor – Bronchoconstriction
- Block all type of receptors
- Slow and less intense bronchodilatation
- Dose – 20-40 µg 6hrly inhalation
TIOTROPIUM BROMIDE:-
- Slow dissociation from muscarinic receptors
- High affinity
- OD doses
33. II) LEUKOTRIEN ANTAGONISTSII) LEUKOTRIEN ANTAGONISTS
Leukotrien receptor antagonist- Montelukast & ZafirlukastLeukotrien receptor antagonist- Montelukast & Zafirlukast
5 Lipoxygenase inhibitor- Zileuton5 Lipoxygenase inhibitor- Zileuton
History- 1930 Kellaway study leukotrienHistory- 1930 Kellaway study leukotrien
- 1990s three drugs released- 1990s three drugs released
Mechanism of Action-Mechanism of Action-
- Leukotrien receptor antagonist-- Leukotrien receptor antagonist-
Cysteinyl LT –bronchoconstrictor LTC4, LTD4, LTE4Cysteinyl LT –bronchoconstrictor LTC4, LTD4, LTE4
& LT1& LT1
Montelukast & Zafirlukast Pranlukast - high affinity competitiveMontelukast & Zafirlukast Pranlukast - high affinity competitive
antagonist - cys LT1 Receptor -antagonist - cys LT1 Receptor -
Leukotrien synthesis inhibitor- 5LOX InhibitedLeukotrien synthesis inhibitor- 5LOX Inhibited
arachidonic acid → Leukotrien by 5LOXarachidonic acid → Leukotrien by 5LOX
Inhibit formation of cys LTsInhibit formation of cys LTs
35. III) MAST CELL STABILIZERSIII) MAST CELL STABILIZERS
1) SODIUM CROMOGLYCATE ( Cromolyn Sod.):-1) SODIUM CROMOGLYCATE ( Cromolyn Sod.):-
- Synthesize-1965 , plant Amni visnaga ,- Synthesize-1965 , plant Amni visnaga ,
- use asthma 1973- use asthma 1973
Mechanism of Action:-Mechanism of Action:-
- Inhibit degranulation of mast cells and other- Inhibit degranulation of mast cells and other
inflammatory cells. Inhibit chemotaxisinflammatory cells. Inhibit chemotaxis
- ↓Bronchial hyperreactivity- ↓Bronchial hyperreactivity
Pharmacokinetics-Pharmacokinetics-
- not absorbed orally- not absorbed orally
- Inhalation Fraction absorbed excreted unchanged- Inhalation Fraction absorbed excreted unchanged
in urine & bilein urine & bile
- T- T1/21/2 – 45-100min– 45-100min
36. Adverse Effects- bronchospasm, cough, Throat irritation,Adverse Effects- bronchospasm, cough, Throat irritation,
Laryngeal edema, Headache, Bad tasteLaryngeal edema, Headache, Bad taste
Dose- 1 mg 4 times dailyDose- 1 mg 4 times daily
2) NEDOCROMIL:-2) NEDOCROMIL:-
1992 , similar to Cromolyn Sod. More effective1992 , similar to Cromolyn Sod. More effective
approvedapproved >> 12 yrs12 yrs
Dose - 4 mg qidDose - 4 mg qid
3) KETOTIFEN :-3) KETOTIFEN :-
Antihistaminic H1 with cromoglycate like actionAntihistaminic H1 with cromoglycate like action
Realease of mediator inhibitedRealease of mediator inhibited
orally absorbed Bioavai. 50% Torally absorbed Bioavai. 50% T1/21/2 – 22hrs– 22hrs
Adverse Effects:- Sedation, dry mouth, dizziness, wt gainAdverse Effects:- Sedation, dry mouth, dizziness, wt gain
Dose:- 1-2 mg BD Children 0.5 mg BDDose:- 1-2 mg BD Children 0.5 mg BD
37. IV) CORTICOSTEROIDSIV) CORTICOSTEROIDS
InhaledInhaled ββ2 agonist for 4 or more times wkly - start2 agonist for 4 or more times wkly - start
inhaled glucocorticoidsinhaled glucocorticoids
Mechanism of Action in Asthma:- -Mechanism of Action in Asthma:- -
inhibit airway inflammation -inhibit airway inflammation -
Anti-inflammatory effect-Anti-inflammatory effect-
*Modulation of cytokine chemokine production,*Modulation of cytokine chemokine production,
*Inhibition of eicosanoid production,*Inhibition of eicosanoid production,
*Inhibition of accumulation of inflammatory cells in*Inhibition of accumulation of inflammatory cells in
Lung tissue &Lung tissue &
*↓Vascular permeability*↓Vascular permeability
- ↓bronchial hyperreactivity, mucosal edema &- ↓bronchial hyperreactivity, mucosal edema &
supress inflammatory response by AG:AB reactionsupress inflammatory response by AG:AB reaction
38. INHALED STEROIDS
High topical & Low systemic activity
1) Beclomethasone dipropionate
2) Flunisolide
3) Fluticasone propionate
4) Budesonide
5) Triamcinolone acetonide
6) Mometasone
Newer steroids-
a) on site activated – Ciclesonide, Rofleponide
b) Soft steroids – improved local topical selectivity
Lactone GCS conjugate,
Loteprednol etabonate
40. CICLESONIDE-CICLESONIDE-
- Improved topical:Systemic activity ratio- Improved topical:Systemic activity ratio
- Prodrug- Prodrug
- esterases in bronchial epithelium- esterases in bronchial epithelium
- oral bioavailability <1% Extensively bindoral bioavailability <1% Extensively bind
to plasma proteinto plasma protein
- Dose- 80-160 µgOD in evening inhalation- Dose- 80-160 µgOD in evening inhalation
SYSTEMIC THERAPY-SYSTEMIC THERAPY-
Use – Chronic sever asthma & Acute asthma exacerbation.Use – Chronic sever asthma & Acute asthma exacerbation.
- Prednisolone 20-60 mg/day (1-2mg/kg) Taper- Prednisolone 20-60 mg/day (1-2mg/kg) Taper
& start inhalation& start inhalation
- Acute asthma exacerbation- iv steroid then shift to- Acute asthma exacerbation- iv steroid then shift to
oral & tapperoral & tapper
41. ADVERSE EFFECTS OF INHALED STEROIDADVERSE EFFECTS OF INHALED STEROID
Horseness of voice, dysphonia, sore throat &Horseness of voice, dysphonia, sore throat &
Oropharyngeal candiasis- minimized by spacer, garglingOropharyngeal candiasis- minimized by spacer, gargling
& topical nystatin /clotrimazole& topical nystatin /clotrimazole
Hypothalamic adrenal supression-no risk ↑ with >1500Hypothalamic adrenal supression-no risk ↑ with >1500µgµg
Osteoporosis- female 500Osteoporosis- female 500 µg /dayµg /day
CHO & Lip[id metabolism - >1000µg /dayCHO & Lip[id metabolism - >1000µg /day
Cataract –Cataract –
Skin thinning- dose related 400-2000µg/day purpureaSkin thinning- dose related 400-2000µg/day purpurea
Growth retardation- no significant riskGrowth retardation- no significant risk
42. STEROID RESISTANT ASTHMA
Definition- It is defined as a failure to respond to high
doses of oral glucocorticoids
(2wk course of 40mg prednisolone/day)
Two types :-
• Type I:- 90% ↓binding affinity of GCS to T cell receptor
• Type II:- primary inactivity of steroid receptor /
abnormally low no. of GCS receptor binding
sites
43. MANAGEMENT OF STEROID RESISTANTMANAGEMENT OF STEROID RESISTANT
ASTHMAASTHMA :-:-
1)1) Methotrexate:Inhibit amidophosphoribosyltransferase-Methotrexate:Inhibit amidophosphoribosyltransferase-
inhibit T cell proliferation, ↓dose ↑sensitivity toinhibit T cell proliferation, ↓dose ↑sensitivity to
prednisoloneprednisolone
2)2) Cyclosporin: inhibit T cell proliferation, IL2 & otherCyclosporin: inhibit T cell proliferation, IL2 & other
cytokine productioncytokine production
3)3) Leflunomide: DMARDs Th cytokine expressionLeflunomide: DMARDs Th cytokine expression
suppresssuppress
4)4) Rapamycin: inhibit T cell proliferation, cytokine synthRapamycin: inhibit T cell proliferation, cytokine synth
5)5) IV Immunoglobulin: Steroid sparing, costlyIV Immunoglobulin: Steroid sparing, costly
6)6) Gold: ↓ steroid useGold: ↓ steroid use
44. V) ANTI IgE ANTIBODYV) ANTI IgE ANTIBODY
OMALIZUMABOMALIZUMAB
1921 Prausnitz & Kustner -reagin transfer allergic reaction1921 Prausnitz & Kustner -reagin transfer allergic reaction
1971 Ishizaka –IgE1971 Ishizaka –IgE
Omalizumab – DNA derived humanized monoclonalOmalizumab – DNA derived humanized monoclonal
antibody of IgG1k subclass. Cell culture (Chineseantibody of IgG1k subclass. Cell culture (Chinese
hamster ovary cells)hamster ovary cells)
Mechanism of Action:-Mechanism of Action:-
Fc-IgE ↔FcFc-IgE ↔FcεεRIRI
AGAG ↔ IgE ↔ Fc↔ IgE ↔ FcεεRIRI → activate mast cell.→→ activate mast cell.→
LTC4, PGD2, cytokinesLTC4, PGD2, cytokines
Omalizumab- IgG AB – AG is Fc-IgE (Anti- AB AB)Omalizumab- IgG AB – AG is Fc-IgE (Anti- AB AB)
Omalizumab + Free IgE → Omalizumab – IgE ComplexOmalizumab + Free IgE → Omalizumab – IgE Complex
complex- no affinity to Fccomplex- no affinity to FcεεRIRI
↓↓ FcFcεεRI expression on mast cells..RI expression on mast cells..
45. OMALIZUMAB…..OMALIZUMAB…..
Pharmacokinetics- Single s.c. inj. every 2-4 wksPharmacokinetics- Single s.c. inj. every 2-4 wks
- Bioavai- 60%,- Bioavai- 60%,
- T- T1/21/2- 26 days- 26 days
Adverse Effects- well toleratedAdverse Effects- well tolerated
- Inj. Site reaction- redness, stinging, induration- Inj. Site reaction- redness, stinging, induration
- Anaphylaxis 0.1%- Anaphylaxis 0.1%
In Asthma- >12yrs allergy & mod to severe AsthmaIn Asthma- >12yrs allergy & mod to severe Asthma
- ↓ exacerbations & steroid req- ↓ exacerbations & steroid req
PAF ANTAGONIST-PAF ANTAGONIST-
- Gingkgolide & structural analogue of PAF- Gingkgolide & structural analogue of PAF
- PAF – bronchoconstriction & edema- PAF – bronchoconstriction & edema
46. GUIDELINE FOR TREATMENT OF ASTHMAGUIDELINE FOR TREATMENT OF ASTHMA
1) MILD EPISODIC ASTHMA –1) MILD EPISODIC ASTHMA –
♦♦ Symptoms < 1 daily & Normal between attacksSymptoms < 1 daily & Normal between attacks
♦♦ STEP 1:- Inhaled short actingSTEP 1:- Inhaled short acting ββ2 agonist - onset of2 agonist - onset of
attack. No prophylactic t/t.attack. No prophylactic t/t.
2) MILD CHRONIC ASTHMA –2) MILD CHRONIC ASTHMA –
♦♦ Symptoms once daily or soSymptoms once daily or so
♦♦ STEP 2:- Regular inhaled low dose steroids & episodeSTEP 2:- Regular inhaled low dose steroids & episode
t/t witht/t with Inhaled short actingInhaled short acting ββ2 agonist2 agonist
48. 4) SEVERE ASTHMA -4) SEVERE ASTHMA -
♦ Continuous symptoms Limitation of♦ Continuous symptoms Limitation of
activity . Frequentactivity . Frequent
exacerbations/Hospitalisationexacerbations/Hospitalisation
♦♦ STEP 4:- Regular inhaled High dose steroidsSTEP 4:- Regular inhaled High dose steroids
(800-2000µg/day) large vol spacer + Inhaled(800-2000µg/day) large vol spacer + Inhaled
long actinglong acting ββ2 agonist2 agonist twice dailytwice daily
- Additional t/t with 1 or more -- Additional t/t with 1 or more -
i) Leukotrien antagonist/ SR theophylline/ Orali) Leukotrien antagonist/ SR theophylline/ Oral ββ2 agonist /2 agonist /
Inhaled ipratropium bromideInhaled ipratropium bromide
ii) episode t/t with Inhaled short actingepisode t/t with Inhaled short acting ββ2 agonist2 agonist
♦♦ STEP 5:- pt not adequately controlled or needing frequentSTEP 5:- pt not adequately controlled or needing frequent
emergency careemergency care
- Oral steroid therapy- Oral steroid therapy
49. STATUS ASTHMATICUSSTATUS ASTHMATICUS (Severe Acute Asthma)(Severe Acute Asthma)
Acute asthmatic attack not responding to routine t/t &Acute asthmatic attack not responding to routine t/t & ββ22
agonist life threateningagonist life threatening
Precipitated byPrecipitated by
i) Acute respiratory infectioni) Acute respiratory infection
ii) Abrupt cessation of steroid therapyii) Abrupt cessation of steroid therapy
iii) Pharmacological stimuli/Allergensiii) Pharmacological stimuli/Allergens
iv) Acute emotional stressiv) Acute emotional stress
50. MANAGEMENT OF STATUS ASTHMATICUSMANAGEMENT OF STATUS ASTHMATICUS
1.1. Hydrocortisone hemisuccinate 100mg iv statHydrocortisone hemisuccinate 100mg iv stat
f/b 100-200mg 4-8hrly infusion ( take 6hrs to act)f/b 100-200mg 4-8hrly infusion ( take 6hrs to act)
2.2. Nebulized Salbutamol (2.5-5mg) + IpratropiumNebulized Salbutamol (2.5-5mg) + Ipratropium
bromide (0.5mg)bromide (0.5mg)
3.3. High flow humidified OHigh flow humidified O22
4.4. Salbutamol /Terbutaline 0.4mg s.c.Salbutamol /Terbutaline 0.4mg s.c.
5.5. Intubation & mechanical ventilationIntubation & mechanical ventilation
6.6. AntibioticsAntibiotics
7.7. Saline + Sod. BicarbonateSaline + Sod. Bicarbonate
Aminophylline 250-500mg dil in 20-30mlAminophylline 250-500mg dil in 20-30ml
5% Glucose iv over 20-30min5% Glucose iv over 20-30min
51. Emerging Asthma Therapies in
Clinical Development
Sr
No.
Classification Experimental
Agents
Mechanism Efficacy/Safet
y
Anticipate
d Benefit
1 Oligonucleoti
de agents
ASM8
1018 ISS
AVE 0675
HYB 2093
CYT 003-
QbG10
AIR 645
Promotes Th1
over Th2
response.
Inhibits IgE
production
Decreases
allergen-
induced early
and late
asthmatic
response
Sympto
matic
patients
already
receiving
immunot
herapy
2 Toll-like
receptor
agents
GSK 2245035
AZD8818
AVE 0675
IMO-2134
SAR 21609
Modulates T-
helper cells to a
Th1 over the
Th2 phenotype
Theoretical risk
of over-
stimulating the
immune system
and inducing
autoimmune
diseases
Not yet
known
52. Emerging Asthma Therapies in
Clinical Development
Sr
No.
Classification Experimental
Agents
Mechanism Efficacy/Safet
y
Anticipate
d Benefit
3 CRTH2
antagonists
MK-7246
OC0000459
ARRY-005
ACT-129968
AMG 85
CRTH2 is a
marker for Th2
cells
Improvement in
FEV1, reduction in
total IgE, and
trend for
reduction of
sputum
eosinophils
Not yet
known
4 Monoclonal
antibodies
targeting IL-5
Mepolizumab
Reslizumab
Benralizumab
(MEDI-563)
Reduces
production,
activation, and
proliferation of
eosinophils
Reduces
exacerbation
rates and
eosinophil
counts in both
blood and
sputum
Patients
still
symptoma
tic on
conventio
nal
therapy &
chronic
oral
corticoste
roids
53. Emerging Asthma Therapies in
Clinical Development
Sr
No.
Classification Experimental
Agents
Mechanism Efficacy/Safet
y
Anticipate
d Benefit
5 Monoclonal
antibodies
targeting IL-4
Alrakincept
Pascolizumab
(SB240683)
Pitrakinra
(Aerovant or
AER 001)
AMG 317
Blocking IL-4
decreases IgE
production,
mucus
hypersecretion,
airway
hyperresponsiven
ess, and
inflammatory
cellular influx
patients
receiving
highest-dose
pitrakinra
experienced
fewer
exacerbations
vs. placebo
Symptomati
c patients
with atopic
disease
Patients
with higher
reversibility
appear to
have better
responses
6 Monoclonal
antibodies
targeting IL-9
MEDI-528 Theoretically,
decreases mast cell
infiltration of the
lung, up-regulation
of IL-13 and IL-5,
eosinophil
infiltration, AHR,
and mucus
production
Small, phase 2
study showed
no effect on
FeNO or the
late asthmatic
response
Not yet
known
54. Emerging Asthma Therapies in
Clinical Development
Sr
No.
Classificatio
n
Experimental
Agents
Mechanism Efficacy/Safety Anticipate
d Benefit
7 Monoclonal
antibodies
targeting IL-
13
Tralokinumab
(CAT-354)
Anrukinzumab
(IMA-638)
QAX576
IMA-026
Lebrikizumab
(MILR1444A)
Theoretically
blocks AHR,
eosinophilic
inflammation,
and mucus
hypersecretion
Small, phase 1
study showed a
T1/2 of 12 to 17
days and can be
safely
administered to
patients with
asthma
Not yet
known
8 Drugs
targeting
TNF-α
Infliximab
Etanercept
Golimumab
(CNTO-148)
Reduction of
TNF-α can lead
to reduction in
BHR and
sputum
neutrophils
Short-term efficacy
seen in severe
disease. oral cortico-
steroids dose may be
reduced after
initiation. Safety
concerns with
golimumab include
malignancies &
pneumonia
Pt FEV1
<60%
predicted,
49 years or
older, and
onset of
asthma at
age 12
years or
older