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Calvin Coolidge 

John F. Kennedy Bob Hope

8 Marriages
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7 Men!!
2 Oscars Charles Dickens Beethoven

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

The outpouring of mucus from hypertrophied


submucosal glands, the bronchoconstriction, and
dehydration ,contribute to the formation of mucus
plugs that can block airways in asthmatic patients.
B.Asthma…Pathogenesis

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

Early And Late Reaction


B.Asthma…Pathogenesis-Chemical mediators

•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

Quick Relief Long Term Control


Medications Medications

• Short acting ß2 Agonists • Glucocorticoids

• Methylxanthines • Long-acting ß2 agonists


3. Anticholinergics
[Not alone] • Combined medications

• Mast cell stabilizers

• 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:

Pharmacological actions: Increase formation


b)Bronchodilatation
c)Inhibit mediator release
from mast cells ß2 Selective
d)Inhibit micro vasc.leakage
e)Increase ciliary activity •Salbutamol[Albuterol],
a) Tachycardia •Terbutaline,
d) Skeletal muscle •Metaproterenol,
tremor
•Pirbuterol
•Salmeterol,
•Formoterol
•Non-selective:
•Adrenaline, Ephidrene, Isoproterenol:
Not used because of CVS effects
ß2 Selective Sympathomimitics

Salbutamol[Albuterol], Terbutaline, Metaproterenol,


Pirbuterol

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 ?????

• Metabolism inhibitors-Erythro, Cipro,


Cimetidine, OCP
• DOSE of Theophylline??????

Preperations
Tablets, SR Tabs.
Aminophylline-Inj. ,
Why NSAIDs worsen Asthma?
Anti-inflammatory steroids
Glucocorticoids
Linoleic acid

Arachidonic acid Zileuton


NSAIDs
aspirin Cyclooxygenase
Lipoxygenase

Prostaglandins (PG) Leukotrienes (LT)

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

• Hypertrophy of smooth muscles


Management

[Rescue
medication]

?
Stepwise approach to asthma therapy
•ICS: Inhaled corticosteroid 5 Very
Severe
•LABA: Long acting β2 agonist Persistent

•OCS: Oral corticosteroid 4 Severe


Persistent OCS

3
Moderate LABA LABA
Persistent
2 Mild
LABA
Persistent
ICS ICS
High Dose High Dose
1 Mild ICS ICS
Intermittent Low Dose Low Dose

Short acting β2 agonist SOS for symptom relief


Harrison II Vol. Page 1605
Acute Severe asthma
• High flow OXYGEN via mask
• Nebulised high dose beta2- 9. Bolus IV magnesium 
agonists

sulphate - in those over 
Intermittent repeated doses 
(every 15-30 minutes) to  5 years with poorly 
continuous nebulisation  responsive
• +Nebulised ipratropium - 10. IV[Infusion?] 
• Steroid therapy - continue 
oral prednisolone therapy  aminophylline - only 
for 3 days (children) or 5  used in patients with 
days near-fatal or life 
•  Intravenous hydrocortisone  threatening asthma 
-Patients unable to take oral 
medication. with poor response
• IV fluids where dehydrated  11. Antibiotics are not 
• Correction of hypokalaemia  indicated routinely.
12. May require intubation. 
Aerosol Delivery of Drugs 
• Accomplishes topical application
• Most of Anti asthma drugs, Otherwise systemically
toxic
• Particles >10 mm – deposited in mouth and oropharynx,
• Particles smaller than 0.5 mm are inhaled to the
alveolae and subsequently exhaled without being
deposited in the lungs.
• Particles with a diameter of 1 to 5 mm deposited in
small airways hence the most effective.
• Unfortunately, no system in use produces
particles limited to the appropriate size
range.
Metered dose Inhaler
Step1:Shake the inhaler  Step 4: Continue breathing in slowly and 
well. steadily until the lungs are full.

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 

MDI Rotahaler Nebulizer


•Drug •Powder in a •Drug driven by
micronized capsule compressed
And under •Pt effort is air/oxygen
pressure •Required to •Motorized
•Sprayed draw the •Less pt effort
into the drug and •Emergencies
mouth inhale •Expensive
•Then
pt.inhales
Bronchial asthma
• Inflammatory disease
• NSAIDs not effective! But may worsen.
• Inflammation , secretions and
bronchospasm.
• Each is targeted by appropriate group of
drugs
• Severe asthma may be fatal
• Regular medication very important.
• Steroid phobia is ill placed.
• Children are also not spared
New drugs targeting Th2 lymphocytes in
asthma

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