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ASTHMA COMPANY!!
• B.Asthma
• ASTHMA IS DEFINED
• CHRONIC INFLAMMATORY DISEASE OF
AIRWAYS
• CHARACTERIZED BY INCREASED
RESPONSIVENESS OF THE
TRACHEOBRONCHIAL TREE, MULTIPLICITY
OF STIMULI.
• MANIFESTED PHYSIOLOGICALLY
• BY WIDESPREAD NARROWING OF THE AIR
PASSAGES
• RELIEVED SPONTANEOUSLY OR
AS A RESULT OF THERAPY.
• MANIFESTED CLINICALLY
• B.Asthma…..course
B.Asthma…Pathogenesis
INSPISSATED
MUCUS PLUG
COUGHED
UP BY A
PATIENT
DURING AN
ASTHMATIC
ATTACK
r a l
Neu
Bronchospasm
e n s
& e r g s t
i o n l l
A se d h u
m at ty u c
f l a m
c t i vi • H o r o a
r
In pera o c k d e
Hy •C d an
ns C a t lds
rge
•Mo ens
A l l e •
-
Non
t i o n o l l
ec e •P
•I nf
r c is
•Exe air
o l d a nts
•C l l u t
n .P o
•E
•Early Reaction •Late Reaction
Type I Type II
•Preformed •Inflammatory cell
mediator recruitment and activation
release •MAY LAST
WEEKS
1h 6h
Allergen challenge
•Eosinophil
Cationic protein
•E.Major Basic
Protein
Reversed by
βagonists
Theophyllin
e
Neural stimuli
Noxious stimuli
[Irritants]
B.Asthma…Pathogenesis
• Pharmacologic stimuli
Aspirin-Can be fatal [AIA]
ß-adrenergic antagonists-Can be
fatal
Sulfiting agents-Pot.metasulfite
[ pharmaceuticals as
preserving agents]
Tartarazine
Allergic inflammation of airways
Pharmacotherapy of Bronchial Asthma
2
1
Pharmacotherapy of Bronchial Asthma
• Leukotrine modifiers
• Methyl xanthines
Pharmacotherapy of Bronchial Asthma
1. Bronchodilators 1. Mast cell
• ß2 Agonists- stabilizers-
Salbutamol, Bambuterol,
Salmeterol,Formoterol, Nedocromil
Ephedrine Sod. Cromoglycate
B. Methylxanthines- [Cromonil ]
Theophylline,Aminiohylline,
Choline theophyllinate 4. Corticosteroids
C. Anticholinergics- E. Systemic-
Ipratropium bromide,
Triotropium bromide Hydrocortisone,-- i.v
2. Leukotrine modulators Prednisolone,--oral
Montelukast, Inhalational:
Zafirlukast,
Zileuton Beclamethasone
5. Anti-IgE Antibody:
Omalizumab
Sympathomimitecis[Bronchodilators]
MOA:
Route of Admin:
• MDI [Inhalation]: Peak15’ To 4-6h
• Nebulizer[Inhalation]: For emergency-More effective,[Less
co-ordination required]
Larger particles, hence dose is more
• Tablets [Salbutamol & Terbutaline] [Oral]:
• Not usually used.
• Children,
• Severe asthma-Aerosol worsens cough
• No advantage, Over inhalation, More systemic
action
o S.C: Terbutaline is available
Long acting, accumulation on repeated
administration
ß2 Selective Sympathomimitics……
• Salmeterol & Formoterol[Long acting]
b) Long acting because highly lipid soluble
c) Combined with corticosteroids in long term therapy
d) Not used alone
ß2 Selective Sympathomimitics
Toxicity:
• Inhalational-Safe
• Oral-Cardiac toxicity,
tremors
ß2 Selective
Sympathomimitics…USES
Short acting-
• Rescue therapy
• Caution-Use of 2 or more cannisters /month
→Marker of risk of long term asthma
mortality
→Requires anti-inflammatory to prevent
loss of pulmonary function
Long acting
• Not for acute
• Long term-not controlled by low dose ICS
• May carry a risk of arrhythmia
Pharmacotherapy of Bronchial Asthma
C. Anticholinergics-
1. Bronchodilators
• ß2 Agonists-
Salbutamol, Bambuterol, 2.Leukotrine
Salmeterol,Formoterol modulators
Ephedrine
B. METHYLXANTHINES 6.Mast cell
stabilizers-
THEOPHYLLINE,
AMINIOHYLLINE, 4. Corticosteroids
CHOLINE 5. Anti-IgE
THEOPHYLLINATE Antibody:
Methyl xanthines-Theophylline
Source Alkaloid content
Tea Caffeine 50mg 1cup
leaves Theophylline 1 mg
Coffee Caffeine 75 mg 1 Cup
seeds
Cocoa, Theobromoine 24 mg 1Cup
Chocolate Caffeine 4mg
Cola Caffeine 30 mg 200ml
MOA:
•Inhibition of PDEs
•Competitive •Accumulation of cyclic
antagonist at
adenosine
AMP and cyclic GMP,
receptors •Increasing signal
transduction through
these pathways
Methyl xanthines-Theophylline
Pharmacological actions
• CVS:
• CNS;
• +ve chronotropic and
• Low and moderate inotropic effects
doses, caffeine— LOW
• Cortical arousal Block Adenosine receptors
Mod
• Increased alertness PDE inhibition-Accu.of
Deferral of fatigue. cAMP
High
• Nervousness and
Release of Ca at
tremor sarcoplasmic reticulum
• Very high doses, Increase blood flow-
Pentoxyfiilline
• Medullary Stimulation
– convulsions- death;
Methyl xanthines-Theophylline
Pharmacological actions…..
• GIT:
Stimulate secretion of gastric acid
and digestive enzymes. [Coffee . Not
caffeine]
• KIDNEY
Theophylline—weak diuretic. Not
useful
• SMOOTH MUSCLE
The bronchodilation
Adverse effects, limit the dose
Inhibit antigen-induced release of
histamine from lung tissue;
Methyl xanthines-Theophylline
Pharmacological USES
actions Not the first line
therapy in Asthma
• SKELETAL MUSCLE
[ADE]
• Improves-
contractility, Only when others fail
reverses fatigue of S.R. Tab in chronic
the diaphragm in TDM
patients –COPD Inexpensive
Apnoea in
premature infants
• PK?????
Theophylline toxicity and plasma concn
•Death,
B •Convulsions, Shock, Arrhythmias
R 30 μg •Delirium-Worsening CVS-
O Toxic
25 μg •VPBs- ↑ Muscle tone-Flashes of light
N •Tachypnioea-Agitation
C 20 μg 20 μg
H •Tremors-
O Therapeutic 15 μg 15
•Restlessness-
D Range •Palpitation
10 μg 10
L •Vomiting-Headache-Insomnia
A
5 μg 5 μg
T
I μ g/ml
O
N
Theophylline- Drug Interactions
• Metabolism Inducers: Smoking, Phenytoin,
Rifampicin, Phenobarbitone
• DOSE of Theophylline ?????
Preperations
Tablets, SR Tabs.
Aminophylline-Inj. ,
Why NSAIDs worsen Asthma?
Anti-inflammatory steroids
Glucocorticoids
Linoleic acid
Worsening of Asthma
Cox 1 Specific
Pharmacotherapy of Bronchial Asthma
1. Bronchodilators
• ß2 Agonists-
Salbutamol, Bambuterol,
Salmeterol,Formoterol,
Ephedrine
B. Methylxanthines-
Theophylline,
Aminiohylline, Choline
theophyllinate
C. ANTICHOLINERGICS-
• IPRATROPIUM 8. Mast cell
BROMIDE, stabilizers-
• TRIOTROPIUM 4. Corticosteroids
BROMIDE
2. Leukotrine
modulators 5. Anti-IgE Antibody:
Antimuscarinic Agents
Datura a source of
Effect of
Effect of ATROPINE
Vagal Tone
Vagal Tone Was in India from ages
[Ach Effect of
[Ach] Antimuscarinics
?????Receptors
•Ipratropium Bromide
•Tiotropium Bromide[longer acting]
•Inhalation
•As Rotacaps
• + Salbutamol
•More effective in COPD
•Not always effective-Other pathways?
Pharmacotherapy of Bronchial Asthma
1. Bronchodilators 1. Mast cell
• ß2 Agonists- stabilizers-
Salbutamol, Bambuterol,
Salmeterol,Formoterol, 4. Corticosteroids
Ephedrine 5. Anti-IgE
B. Methylxanthines- Antibody:
Theophylline,
Aminiohylline, Choline
theophyllinate
C. Anticholinergics-
Ipratropium bromide,
Triotropium bromide
2. LEUKOTRINE
MODULATORS
MONTELUKAST,
ZAFIRLUKAST,
ZILEUTON
:Leukotriene Modifiers:
1. Leukotriene Receptor Antagonists P
2. 5-Lipoxygenase Inhibitor
R
• Arachidonic acid P
5-Lipoxygenase Inhibitor •Efficacy and use H
same as below
Zileuton
• 5-Lipoxygenase •Short acting Y
•Hepatotoxic
L
• Leukotrines[LTB4, C4, D4]
Leukotriene Receptor •Food interferes
with absorption
A
Antagonists
Montelukast •Prophylactic
•Oral
C
Zafirlukast
•Safe
T
• LT Receptors Airway edema,
I
*Smooth muscle
*constriction,
*Inflammatory process
C
Pharmacotherapy of Bronchial Asthma
1. Bronchodilators 1. MAST CELL
• ß2 Agonists- STABILIZERS-
Salbutamol, Bambuterol,
Salmeterol,Formoterol, NEDOCROMIL
Ephedrine SOD.
B. Methylxanthines- CROMOGLYCATE
Theophylline,
Aminiohylline, Choline [CROMONIL ]
theophyllinate 4. Corticosteroids
C. Anticholinergics-
Ipratropium bromide, 5. Anti-IgE
Triotropium bromide Antibody:
2. Leukotrine modulators
Montelukast,
Zafirlukast,
Zileuton
Mast cell stabilizers P
R
P
H
Y
L
•Nedocromil] A
•Sod. Cromoglycate [Cromonil]C
•Inhibit degranulation
of mast cells
T
•Route-MDI I
•Uses-Asthma, Allergic rhinitis
Allergic conjuctivitis
C
Pharmacotherapy of Bronchial Asthma
1. Bronchodilators 1. Mast cell
• ß2 Agonists- stabilizers-
Salbutamol, Bambuterol,
Salmeterol,Formoterol, Nedocromil
Ephedrine Sod. Cromoglycate
B. Methylxanthines-
Theophylline,
[Cromonil ]
Aminiohylline, Choline 4. CORTICOSTEROIDS
theophyllinate
C. Anticholinergics- E. SYSTEMIC-
Ipratropium bromide,
Triotropium bromide
2. Leukotrine modulators HYDROCORTISONE
Montelukast, , PREDNISOLONE
Zafirlukast, INHALATIONAL:
Zileuton
BECLAMETHASONE
5. Anti-IgE Antibody:
Glucocorticoids
• • Profound and generalized
Asthma
antiinflammatory action
• Airway inflammation, • Very few mechanisms of
• Airway hyperreactivity, inflammation escape the
inhibitory effects
• Acute bronchoconstriction
3. Modulation of cytokine
• Glucocorticoids do and chemokine
not directly relax production;
4. ↓ of PG synthesis;
airway smooth
5. ↓ Accumulation of
muscle basophils, eosinophils,
• No effect on acute 6. ↓Vascular permeability
bronchoconstriction 7. Potentiate the effect of ß-
agonists
• Most effective drugs
Inhaled Glucocorticoids[Aerosol therapy]
1. Glucocorticoids are very PREPERATIONS
effective in controlling asthma,
• Beclomethasone
2. Systemic glucocorticoids
dipropionate
-serious adverse effects
3. Inhaled glucocorticoids - target • Triamcinolone
drug directly to the site of acetonide
inflammation-LUNG • Flunisolide
4. Enhance the therapeutic index
• Fluticasone
5. ↓number and propionate
degree of side • Budesonide
effects
• Mometasone
6. Without
sacrificing • Ciclesonide[Trial]
clinical utility
Glucocorticoids
Uses
• Acute asthma
• Persistent asthma
• ‘Status’-Acute severe
• Oral prednisone
• COPD-Exacerbations
Glucocorticoids-ADE
• ADE[Inhalation]
• ADE:Oral
• Cough, oral candidiasis
glucocorticoids
• Dysphonia
• Hypertension
• Abolished by rinsing the
mouth after use and • Diabetes
• Use of a spacer device. • Proximal myopathy
• Systemic effects can • Osteopenia/osteone
occur [Inhalation] :
crosis
• Increases with dose
• Central
• Growth retardation
(children) adiposity/purple
• Increased bone catabolism
striae/buffalo hump
(osteoporosis risk)
• Adrenal suppression
• Bruising
Glucocorticoids; Some facts
• Steroid phobia
• Inhaled is not=systemic Or =
Anabolic steroids
• Regular therapy is important
• If inadequately controlled,
Long-acting Beta agonist can
be combined-Combination
inhalers
• Fluticasone+Salmaterol
• Budesonide+Formeterol
Other Drugs
OMALIZUMAB
•Anti-IgE
Monoclonal AB
•Prophylactic
•Expensive
Future:
•MAB against cytokines
•Antagonists of cell
adhesion molecules
3. Protease inhibitors
4. Immunomodulators
•Macrolides[??Anti Chlamydial]
•PDE4 Specific inhibitors
Roflumilast, Cilomilast, Tofimilast
Pharmacotherapy
Causes of airway narrowing and Tt.
• Broncho constriction Easily reversed
• Mucosal edema
i n ed
• Cellular infiltration S u s ta
t w ith
• Hyperplasia of secretory cells T -infl.
i
Ant ired
u
• Hyperplasia of vessel wall req
[Rescue
medication]
?
Stepwise approach to asthma therapy
•ICS: Inhaled corticosteroid 5 Very
Severe
•LABA: Long acting β2 agonist Persistent
3
Moderate LABA LABA
Persistent
2 Mild
LABA
Persistent
ICS ICS
High Dose High Dose
1 Mild ICS ICS
Intermittent Low Dose Low Dose
Step 2: Breathe out gently, place the
Step 5: Hold your breath
mouthpiece in the mouth with lips curled
for 10 seconds or for as
around it.
long as comfortable.
Breathe out slowly.
Step 3: Begin breathing in slowly but at the
same time, press down on the inhaler
canister.
MDI
Rotahaler
Step 1: Insert a rotacap, transparent end
first, into the raised square hole of the
rotahaler
Step 2: Rotate the base of the Rotahaler in
order to separate the two halves of the
rotacap.
Step 3: Breathe in as deeply as you can*.
Hold your breath for 10 seconds. Breathe
out slowly.
*Note: If you are breathing correctly, you
will hear the soft rattling sound of the
rotacap.
How to use the Spacer
[Less cordination required]
Step 1: Assemble your Spacer by fitting the Step 4: Release a dose
two parts together of medicine into the
Spacer and breathe in
steadily and deeply through
your mouth.
Step 2: Shake the Inhaler. Fill the inhaler
into the slot opposite the mouthpiece.
Step 5: Remove the Spacer
and hold your breath for
as long as comfortable
. Breathe out slowly
Step 3: Close your lips firmly around the
mouthpiece. Zerostat Spacer
Nebulizer
http://www.pubmedcentral.nih.gov/articlerender.f
• J Occup Med Toxicol. 2008; 3(Suppl 1): S6.
• Gaetano Caramori,1 David Groneberg,2 Kazuhiro
Ito,3 Paolo Casolari,1 Ian M Adcock,3 and Alberto
Papi1