lecture on Asthma

1. BRONCHIAL ASTHMA
1

2. BRONCHIAL ASTHMA
• Definition
• Prevalence
• Etiology
• Pathogenesis
• Pharmacology of anti asthmatic drugs
• Management
2

3. Bronchial asthma
Bronchial asthma is a chronic inflammatory disorder of the
airways associated with airway hyper responsiveness
presents with:
• Wheezing
• Breathlessness
• Chest tightness
• Nighttime or early morning cough
Airway obstruction is reversible
either spontaneously or with treatment.
3

4. Bronchial asthma
• Bronchial asthma is a disease of the lungs in which
an obstructive ventilation disturbance of the
respiratory passages evokes a feeling of shortness of
breath.
• The cause is a sharply elevated resistance to airflow
in the airways.
• Despite its most strenuous efforts, the respiratory
musculature is unable to provide sufficient gas
exchange.
• The result is a characteristic asthma attack, with
spasms of the bronchial musculature, edematous
swelling of the bronchial wall and increased mucus
secretion.
4

5. WHO Definition of Asthma
• "A chronic inflammatory disorder of the airways in which
many cells play a role, in particular mast cells, eosinophils,
and T lymphocytes. In susceptible individuals this
inflammation causes recurrent episodes of wheezing,
breathlessness, chest tightness, and cough particularly at
night and/or in the early morning. These symptoms are
usually associated with widespread but variable airflow
limitation that is at least partly reversible either
spontaneously or with treatment. The inflammation also
causes an associated increase in airway responsiveness to a
variety of stimuli."
5

6. • 235-330 million affected individuals
• 1% -18% - global prevalence rate
• 2,50,000-3,45,000 people die per year from
the disease
• It is more common in developed than
developing countries
• Common in both gender
6

7. Asthma Prevalence and Mortality
Source: Masoli M et al. Allergy 2004
7

8. GENETICS
 Higher concordance in Monozygotic twins
 ↑ed incidence in primary relatives
• ADAM-33 1st gene identified as Asthma susceptibility gene
• 10 most common genes a/w Asthma
 Innate immunity (CD-14,HLA DRB1,DQB1)
 Th₂ cell signalling (IL-4,IL-13,IL-4Ra)
 Cellular inflammation (TNF,FCEDR1B)
 Lung development (ADAM33,ADRB2)
 Genome-wide association studies (GWAS) : 17 q 21,11 p 14,5
q 23,Chr 18
 Environment : Epigenetic modifications
8

9. ATOPIC ASTHMA
Begins in childhood.
A positive family history of atopy is common,
Asthmatic attacks are often preceded by allergic
rhinitis, urticaria, or eczema.
The disease is triggered by environmental
antigens, such as dusts, pollen, animal dander, and
foods, but potentially any antigen is implicated.
A skin test with the offending antigen results in an
immediate wheal-and-flare reaction, a classic
example of the type I IgE-mediated
hypersensitivity reaction .
9

10. NON ATOPIC ASTHMA
• The mechanism of bronchial inflammation and hyper-
responsiveness is much less clear in individuals with non-atopic
asthma.
• Viral infections of the respiratory tract (most common) and
inhaled air pollutants such as sulfur dioxide, ozone, and nitrogen
dioxide.
• In asthmatic subjects however, the bronchial response,
manifested as spasm, is much more severe and sustained.
• A positive family history is uncommon
• Serum IgE levels are normal
• There are no associated allergies
• Virus-induced inflammation of the respiratory mucosa lowers the
threshold of the subepithelial vagal receptors to irritants.
• The ultimate humoral and cellular mediators of airway
obstruction (e.g., eosinophils) are common to both atopic and
non-atopic variants of asthma. 10

11. Extrinsic (Allergic) Triggers:
Dust mites
Mould
Certain foods
Animal dander
Pollen
Intrinsic (Non-Allergic) Triggers:
Exercise
Infections (cold and flu)
Cold or humid air
Intense emotions (ex. Stress)
Medications (aspirin)
Hormones
Air pollution
Fragrances and chemicals
Occupational irritants 11

12. Pathophysiology of Asthma
• Asthma is a disease characterized by airway
inflammation and episodic, reversible
bronchospasm.
– Two characteristic features:
1) Inflammatory changes in the airway;
2) Bronchial hyperreactivity to stimuli.
12

13. Pathophysiology of Asthma
• Antigens (pollen and house-dust mites) sensitize patients
by eliciting the production of IgE type of antibodies, which
remain either circulating in the blood or become attached to
the mast cells of nasal or bronchial tissues and basophils.
• On re-exposure the same antigen, the resulting antigen-
antibody reaction in the early phase causes degranulation
of the lung mast cells and releasing of the powerful
bronchoconstrictors: histamine, 5-HT, PGD2 and
cysteinyl leucotriens (LTB4, LTC4 and LTD4).
13

14. • Lung mast cells also release ILs (IL-4, IL-5 and IL-13).
In the late (delayed) phase of asthma, these mediators
activate additional inflammatory cells (eosinophils,
basophils, and alveolar macrophages) which also release
LTs and ILs.
• Other mediators of inflammation, in delayed phase,
are: adenosine (causing bronchconstriction), neuropeptides
( causing mucus secretion and increase in vascular
permeability; neurokinin A, causing bronchoconstriction),
PAF etc.
•The normal tone of bronchial smooth muscle is influenced
by a balance between parasympathetic, sympathetic and
non-adrenergic–non-cholinergic (NANC) mediators
activity.
14

15. 15

16. 16

17. 17

18. http://link.brightcove.com/services/player/bcpid236059233?bctid=347806802
18

19. Lung Morphology in Asthma
• Bronchial inflammation
• Edema, Mucousplugging
• Bronchospasm
• Obstruction
• Over inflation

20. Lung Hyperinflation in Asthma

21. Thick bronchi with Mucous plugs

22. Airways Innervations
Afferent nerves (sensory)
 Irritant receptors in upper airways.
 C-fiber receptors in lower airways.
Stimulated by :
Exogenous chemicals
Physical stimuli (cold air)
Endogenous inflammatory mediators
22

23. Efferent nerves (motor)
 Parasympathetic supply
M3 receptors in smooth muscles and glands.
 No sympathetic supply but B2 receptors in
smooth muscles and glands
23

24. 24

25. 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 ).
25

26. Anti asthmatic drugs
Bronchodilators
(Quick relief medications)
treat acute episodic attack of
asthma
• Short acting 2-agonists
• Antimuscarinics
• Xanthine preparations
Anti-inflammatory Agents
(control medications or
prophylactic therapy)
reduce the frequency of attacks
• Corticosteroids
• Mast cell stabilizers
• Leukotrienes antagonists
• Anti-IgE monoclonal antibody
• Long acting ß2-agonists
26

27. Classification of Antiasthmatic Drugs
1. Bronchodilators
• Selective β2-agonists: Clenbuterol, Salbutamol,
Fenoterol, Indacaterol, Levosalbutamol, Salmeterol,
Terbutaline
• Nonselective β-agonists: Epinephrine, Isoprenaline,
Orciprenaline; Ephedrine
• M-cholinolytics: Ipratropium, Tiotropium, Oxitropium
• Methyl Xanthines: Theophylline, Aminophylline,
Theotard
2. Mast Cell Stabilizers: Sodium Cromoglycate,
Ketotifen, Nedocromil
27

28. 3. Glucocorticosteroids (GCS)
• Oral: Prednisone, Methylprednisolone
• Parenteral: Methylprednisolone, Betamethasone
• Inhalational: Beclomethasone, Budenoside,
Fluticasone, Triamcinolone
4. Inhalational β2-agonists/Glucocorticosteroids
Seretide® (fluticasone/salmeterol)
Symbicort® (budenoside/formoterol)
5. Leukotriene Modulators
• 5-Lipoxygenase Inhibitor: Zileuton
• LTD4-antgonists: Zafirlukast, Montelukast
6. Monoclonal Anti-IgE Antibody: Omalizumab
7. Miscellaneous: NO-donors, Calcium antagonists
28

29. 29

30. Sympathomimetics
- adrenoceptor agonists
Mechanism of Action
 direct 2 stimulation  stimulate adenyl
cyclase  Increase cAMP 
bronchodilation
 Inhibit mediators release from mast cells.
 Increase mucus clearance by (increasing
ciliary activity).
30

31. Classification of  agonists
 Non selective  agonists:
epinephrine - isoprenaline
 Selective 2 – agonists (Preferable).
Salbutamol (albuterol)
Terbutaline
Salmeterol
Formeterol
31

32. Non selective -agonists.
Epinephrine
• Potent bronchodilator
• rapid action (maximum effect within 15 min).
• S.C. or by inhalation (aerosol or nebulizer).
• Has short duration of action (60-90 min)
• Drug of choice for acute anaphylaxis
(hypersensitivity reactions).
32

33. Disadvantages
 Not effective orally.
 Hyperglycemia
 CVS side effects:
tachycardia, arrhythmia, hypertension
 Skeletal muscle tremor
 Not suitable for asthmatic patients with
hypertension or heart failure.
Contraindication:
CVS patients, diabetic patients
33

34. Selective 2 –agonists
 drugs of choice for acute attack of asthma
 Are mainly given by inhalation (metered dose
inhaler or nebulizer).
 Can be given orally, parenterally.
 Short acting ß2 agonists
e.g. salbutamol, terbutaline
 Long acting ß2 agonists
e.g. salmeterol, formeterol
34

35. • Beta agonists or adrenergic agents, can be thought of as
rescue medications because they provide rapid relief of
labored breathing during an asthma episode.
• All of the currently available beta agonists are superior
to both adrenaline and ephedrine for duration of action
and less-pronounced side effects.
• These potent , when inhaled, provide rapid relief of
bronchial obstruction. Duration of action varies from
four to six hours. An exception is salmeterol
(Serevent®) which works for up to twelve hours but has
a slower onset of action of about an hour.
35

36. • These agents are excellent for the prevention of
wheezing triggered by exercise or cold air if taken
before the activity or exposure.
• Individuals may prefer one agent to another for
reasons of taste, cost, or personal preference. Generic
agents are now available for albuterol.
• Users of generic substitutes should be aware of the
potential problem of dosage variability.Side effects
are mild affecting less than 10% of users.
36

37. Short acting ß2 agonists
Salbutamol, inhalation, orally, i.v.
Terbutaline, inhalation, orally, s.c.
 Have rapid onset of action (15-30
min).
 short duration of action (4-6 hr)
 used for symptomatic treatment of
acute
episodic attack of asthma.
37

38. • Salmeterol is a bronchodilator. It works
by relaxing muscles in the airways to
improve breathing.
• Salmeterol inhalation is used to prevent
asthma attacks. It will not treat an asthma
attack that has already begun.
Salmeterol inhalation is also used to treat
chronic obstructive pulmonary disease
(COPD) including emphysema and
chronic bronchitis.
LONG ACTING ß2 AGONIST
38

39. Adverse Reactions of β2 agonists:
1) Skeletal muscle tremor - which results from a
direct stimulation of 2-adrenoceptors in skeletal
muscle.
• This effect is most notable on the initiation of
therapy and gradually improves on continued
use.
2) Cardiac effect - 2-Agonists also cause tachycardia
and palpitations in some patients.
• When administered by inhalation, the 2-agonists
produce only minor side effects.
3) Metabolism disturbance - ketone bodies↑,
acidosis, [K+]o↓ 39

40. Theophylline
• Methylxanthine derivatives.
• Mechanism of Action:
1. Inhibit phosphdiesterase (PDE);
2. Block adenosine receptors;
3. Increase endogenous catecholamine (CA)
releasing;
4. Interfere with receptor-operated Ca2+ channels →
[Ca2+]i↓;
5. Anti-inflammatory action
40

41. • Clinical Use:
1. Asthma: maintenance treatment
2. Chronic obstructive pulmonary disease (COPD)
3. Central sleep apnea (CSA)
• Adverse Reactions:
– Narrow margin of safety. Toxic effects are
related to its plasma concentrations.
– Gastrointestinal distress, tremor, and insomnia.
– Cardiac arrhythmias, convulsions → lethal.
41

42. Muscarinic Antagonists
• There are M1, M2, M3 receptor subtype in the airway.
• Selectively blocking M1, M3 receptor is resulted in
bronchodilating effect.
• Ipratropium bromide binds to all M-R subtypes (M1,
M2 and M3 ), and inhibits acetylcholine-mediated
bronchospasm.
42

43. • In the treatment of asthma, anticholinergic drugs are both old
and new. One hundred years ago, atropine, the parent drug of
this class, was smoked as a cigarette for asthma.
• Its usefulness was limited by unacceptable side effects of rapid
heart rate, hot skin, and dry mucous membranes. Excessive
doses could even provoke delusions and irrational behavior.
• Ipratropium (Atrovent®) preserves the bronchodilator effects
while eliminating these adverse effects.
• Atrovent® is not as potent as the sympathomimetics and is not
considered a first choice medication. It has an additive effect
when beta agonists are insufficient for symptom relief. It can
serve as an acceptable alternate when sympathomimetics
aren’t tolerated.
43

44. Anticholinergic Drugs
• Atrovent® should be inhaled four
times daily for maximum
effectiveness.
• It's available in multidose inhaler
form and in unit dose ampoules for
nebulizer use.
• The only common side effect is dry
mouth.
• Combivent® is a convenient,
combination product composed of
albuterol and ipratropium.
44

45. 45

46. Typical Spirometric (FEV1) Tracings
1
Time (sec)
2 3 4 5
FEV1
Volume
Normal Subject
Asthmatic (After Bronchodilator)
Asthmatic (Before Bronchodilator)
Note: Each FEV1 curve represents the highest of three repeat measurements
46

47. Anti-inflammatory agents
• Act at several points in this process. Cromolyn and nedocromil
stabilize mast cells and nerve endings preventing initiation of the
inflammatory process.
• Leukotriene antagonists block the production of leukotrienes, a
potent mast cell messenger chemical, or block the transmission of
their message to receptor cells.
• Corticosteroids stabilize blood vessels reducing vascular leakiness.
They also restore sensitivity of receptor cells to beta-agonists and
down-regulate the production and release of inflammatory
chemicals. This results in decreased numbers of eosinophils in the
airway walls. Corticosteroids have considerably greater anti-
inflammatory activity than any of the other drugs. The result is a
gradual resolution of the asthmatic condition.
47

48. • Since these drugs do not relax bronchial muscle, they
don’t provide the immediate relief characteristic of
bronchodilators.
• With regular and continued use of anti-inflammatory
agents however, the need for bronchodilators is
gradually reduced.
• Inhaled corticosteroids may trigger cough during an
acute asthma attack. Oral prednisone may be substituted
at such times.
48

49. Glucocorticoids (GCs)
• Mechanism of Action:
1. Broad anti-inflammatory efficacy
① Block the synthesis of arachidonic acid by
phospholipase A2.
② Reduce bronchial reactivity.
2. Increase the responsiveness of β-adrenoceptors
in the airway.
49

50. • The anti-inflammatory actions of GCS are mediated by
stimulation of synthesis of lipocortin, which inhibits pathways
for production of PGs, LTs and PAF. These mediators
would normally contribute to increased vascular
permeability and subsequent changes including
oedema, leucocyte migration, fibrin deposition. 50

51. • Glucocorticosteroids provide long-term
stabilization of the symptoms due to their anti-inflammatory
effects. Inhaled GCS, along with beta-2-agonists are the
first choice drugs for chronic asthma.
• GCS inhibit the release of PGs and LTs and thus prevent
smooth muscle contraction, vascular permeability and
airway mucus secretion.
• GCS produce eosinopenia which prevents cytotoxic effects
of the mediators released from eosinophils.
• GCS enhance beta-2-adrenergic response by up-regulating
the beta-2-receptors in lung cells and leuckocytes.
•Several hours are required for DNA transcription and RNA
translation to occur after administering GCS.
51

52. 52

53. Corticosteroids
53

54. Routes of administration
 Inhalation:
e.g. Budesonide & Fluticasone, beclometasone
– Given by inhalation, given by metered-dose
inhaler
– Have first pass metabolism
– Best choice in asthma, less side effects
 Orally: Prednisone, methyl prednisolone
 Injection: Hydrocortisone, dexamethasone
54

55. Glucocorticoids in asthma
 Are not bronchodilators
 Reduce bronchial inflammation
 Reduce bronchial hyper-reactivity to stimuli
 Have delayed onset of action (effect usually
attained after 2-4 weeks).
 Maximum action at 9-12 months.
 Given as prophylactic medications, used alone or
combined with beta-agonists.
 Effective in allergic, exercise, antigen and
irritant-induced asthma,
55

56. Systemic corticosteroids are reserved for:
– Status asthmaticus (i.v.).
Inhaled steroids should be considered for adults,
children with any of the following features
• using inhaled β2 agonists three times/week
• symptomatic three times/ week or more;
• or waking one night/week.
56

57. • Cushing’s syndrome
• Osteoporosis
• Tendency to hyperglycaemia
• Negative nitrogen balance
• Increased appetite
• Increased susceptibility
to infections
• Obesity etc.
Adverse
effects
of GCS
Cushing’s
syndrome
57

58. Side effects due to systemic corticosteroids
– Adrenal suppression
– Growth retardation in children
– Osteoporosis
– Fluid retention, weight gain, hypertension
– Hyperglycemia
– Susceptibility to infections
– Glaucoma
– Cataract
– Fat distribution, wasting of the muscles
– Psychosis
58

59. Inhalation has very less side effects:
– Oropharyngeal candidiasis (thrush).
– Dysphonia (voice hoarseness).
Withdrawal
– Abrupt stop of corticosteroids should be
avoided and dose should be tapered (adrenal
insufficiency syndrome).
59

60. Leukotrienes antagonists
Leukotrienes
 produced by the action of 5-lipoxygenase on
arachidonic acid.
 Synthesized by inflammatory cells found in the
airways (eosinophils, macrophages, mast cells).
 Leukotriene B4: chemotaxis of neutrophils
 Cysteinyl leukotrienes C4, D4 & E4:
– bronchoconstriction
– increase bronchial hyper-reactivity
– mucosal edema, mucus hyper-secretion
60

61. Leukotriene receptor antagonists
e.g. zafirlukast, montelukast, pranlukast
 are selective, reversible antagonists of cysteinyl
leukotriene receptors (CysLT1receptors).
 Taken orally.
 Are bronchodilators
 Have anti-inflammatory action
 Less effective than inhaled corticosteroids
 Have glucocorticoids sparing effect (potentiate
corticosteroid actions).
61

62. 62

63. Uses of leukotriene receptor antagonists
 Are not effective to relieve acute attack of
asthma.
 Prophylaxis of mild to moderate asthma.
 Aspirin-induced asthma
 Antigen and exercise-induced asthma
 Can be combined with glucocorticoids (additive
effects, low dose of glucocorticoids can be
used).
Side effects:
Elevation of liver enzymes, headache, dyspepsia
63

64. 64

65. Mast cell stabilizers
e.g. Cromolyn (cromoglycate) - Nedocromil
 act by stabilization of mast cell membrane.
 given by inhalation (aerosol, microfine powder,
nebulizer).
Have poor oral absorption (10%)
65

66. Pharmacodynamics
These are Not bronchodilators.
Not effective in acute attack of asthma.
Prophylactic anti-inflammatory drug.
 Reduce bronchial hyper-reactivity.
 Effective in exercise, antigen and irritant-induced
asthma.
 Children respond better than adults.
66

67. Uses
 Prophylactic therapy in asthma especially in
children.
 Allergic rhinitis.
 Conjunctivitis.
Side effects
 Bitter taste
 minor upper respiratory tract irritation (burning
sensation, nasal congestion)
67

68. 68

69. Omalizumab
is a monoclonal antibody directed against
human IgE.
prevents IgE binding with its receptors on
mast cells & basophiles.
↓ release of allergic mediators.
used for treatment of allergic asthma.
Expensive-not first line therapy.
69

70. Summary
70

71. Antiinflammatory drugs
Bronchodilators
Antiinflammatory drugs
71

72. 72

73. 73

74. Medications to Treat Asthma:
How to Use a Spray Inhaler
The health-care
provider should
evaluate inhaler
technique at each visit.
Source: “What You and Your Family Can Do About Asthma” by the Global Initiative for Asthma Created
and funded by NIH/NHLBI
74

75. Used by some (usually
moderate or severe)
asthma patients to
monitor ongoing lung
function to detect changes
Also known as a
“spacer” or valved holding
chamber (VHC)
Delivery of medication
over 100% more effective
75

76. Medications to Treat Asthma:
Inhalers and Spacers
Spacers can help
patients who have
difficulty with inhaler
use and can reduce
potential for adverse
effects from
medication.
76

77. 77

78. Medications to Treat Asthma:
Nebulizer
• Machine produces a mist
of the medication
• Used for small children or
for severe asthma
episodes
• No evidence that it is
more effective than an
inhaler used with a
spacer
78

79. 79

80. Establishing the diagnosis
Not all that wheezes is asthma
• The medical history!
• Pulmonary function testing with
bronchodilator
– Reversibility: 12% AND 200 cc change in FEV1
– Obstructive physiology on pulmonary function test (FEV1
reduced much more than FVC)
• Bronchoprovocation testing
– Methacholine, histamine, exercise
• Exhaled nitric oxide (NO)
80

81. Methods of investigation
• Objectively: Tachypnoe with prolonged expiration,
wheezing, dry rales
• Sputum analysis: eosinophils, Kurshman spirals
(mucus from small bronchi), Sharko-Leiden crystals
(enzymes of eosinophils)
• General blood analysis: mild leucocytosis,
eosinophilia
• Spyrometry: decreased FVC, FEV1, FEV1/FVC,
increased daily variability
81

82. Diagnosing Asthma:
Spirometry
Test lung function when diagnosing asthma
82

83. Nitric Oxide
Exhaled NO
• Exhaled nitric oxide is a biological marker
that correlates with eosinophilic
inflammation in asthma.
• Exhaled NO measurement can provide
diagnostic and predictive value for a
corticosteroid response.
• More longitudinal studies are required
to clarify the clinical significance of
exhaled NO in asthma.
Kim et al, Curr Opin Allergy Clin Immunol 2014,14:49–5483

84. Indicators of Severe Asthma
 Anxious and diaphoretic appearance, upright position
 Breathlessness at rest and inability to speak in full sentences
 Tachycardia (HR>120) and Tachypnoea (RR>30)
 Pulse oximetry <91% (on room air)
 PaCO2 normal or increased
 PEFR <150 L/min or <50% predicted
84

85. controlled
partly controlled
uncontrolled
exacerbation
LEVEL OF CONTROL
maintain and find lowest controlling
step
consider stepping up to
gain control
step up until controlled
treat as exacerbation
TREATMENT OF ACTION
TREATMENT STEPS
REDUCE INCREASE
STEP
1
STEP
2
STEP
3
STEP
4
STEP
5
REDUCEINCREASE
85

86. 86

87. 87

88. Step-wise approach to the treatment of asthma according to recent guidelines. LTRA, leukotriene
receptor antagonist; SR, slow release. The dose of inhaled corticosteroids refers to
beclomethasone dipropionate
88

89. PREVENTION
Primary
Secondary
Tertiary
89

90. Prevention: Primary
• Patient awareness/education
 Efficacy of patient education and parental awareness has also been shown to be
effective in individual studies from India
(Singh et al. 2002; Gupta et al. 1998; Ghosh et al. 1998; Lal et al. 1995).
• Lifestyle Modifications: Regular balanced diet and avoidance of obesity.
Short acting beta-2 agonists should be used prior to anticipated exercise, in a
patient with exercise-induced Asthma, to alleviate symptoms
(Consensus on Guidelines of Management of Clinical Asthma 2005).
• Alternative System of Medicine:
Yogic breathing exercise technique, Pranayama, was been shown to reduce in
histamine reactivity
(Singh et al. 1990).
90

91. Prevention: Secondary
 Avoidance of precipitating factors
 Avoid dusting when subject is around
 Avoid using carpets, stuffed toys, open bookshelves, smoking,
chemical sprays in house. Prefer mosquito nets to repellants
 Food containing allergen to be avoided
 Maintain record of daily symptoms
*Involves avoidance of allergens and nonspecific triggers when
Asthma is established.
(Custovic et al. 1998; Strachan and Cook 1998; Chalmers et al. 2002; Jindal et al.
1997) 91

92. The Reality 
• Asthma is not yet curable *
• Under diagnosis & Under management
• Therapy is still evolving
Hope 
• Better understanding of Pathology
• New line of Promising Drugs.
• Proper management  normal life.
92

93. REFRENCES
• Goodman & Gilman’s - pharmacological basis of
therapeutics 11th edition
• Katzung - Basic & Clinical pharmacology 12th edition
• K D Tripathi – Essentials of medical pharmacology
7th edition
• Lippincott – modern pharmacology with clinical
application
• Harrison’s principles of internal medicine 18th edition
• GINA guidelines 2014
93

94. THANK YOU
THANK YOU94