Drugs for bronchial asthma

1. DRUGS FOR BRONCHIALASTHMA
PRESENTED BY :- TANYA SHARMA
MODERATOR :- DR. REENA SHERIN PARVEEN

2. OBJECTIVES
 INTRODUCTION
 HISTORY OF ASTHMA
 RISK FACTORS/TRIGGERS
 PATHOPHYSIOLOGY
 ROUTES AND DELIVERY DEVICES
 PHARMACOLOGICAL GOALS AND MANAGEMENT
 RECENT ADVANCES

3. HISTORY
• The earliest recorded reference to respiratory
distress – a disorder characterized by “noisy
breathing” (wheezing?) is found in China in 2600
BC
• Hippocrates (~400 BC)
first to use the term “Asthma” (Greek for “wind” or
“to blow”) for panting and respiratory distress.

4.  Roman doctors described asthma as:-
gasping and the inability to breathe without making noise. They noted “if from running or any other work, the
breath becomes difficult, it is called asthma.
 Pliny the elder( 50 AD) :-
• Pollen : as a source of respiratory difficulty
• Recommended the use of ephedra in red wine
Suggested drinking the blood of wild horses & eating 21 millipedes soaked in honey
 Maimonides(1135-1204 AD) :-
“Treatise on Asthma”
Rest, good personal hygiene, avoidance of opium, small quantity of wine and special diet.

5. • Rene Laennec, using the stethoscope he invented
• For the 1st time asthma wheezes could be heard
Asthma cigarettes
Herbal preparation containing Atropine like
alkaloids

6. 1905:-
Epinephrine referred for treatment
1950-1960:-
Oral corticosteroids, inhaled corticosteroids &
selective β2 agonist
1969:-
“Allergy & Asthma Medical Group & Research
Centre” leading to therapeutic advancements

7. INTRODUCTION
 Asthma is a chronic inflammatory disorder of the airway,
characterised:-
Clinically by :
 Recurrent episodes of wheezing
 Breathlessness
 Chest tightness
 Coughing(particularly at night/early
morning)
Physiologically by :
 Widespread, reversible narrowing
of the bronchial airways
 Marked increase in bronchial
responsiveness

8. Wheezing
Whistling or rattling sound
- result of airway
obstruction
Chest tightness
Dyspnoea
coughing
Early warning Signs:-
• Frequent cough, especially at night
• Shortness of breath
• Feeling very tired or weak while
exercising.
• Wheezing or coughing after exercise
• Feeling tired easily upset, grouchy or
moody.
• Signs of cold or allergies(sneezing,
runny nose, cough, nasal congestion,
sore throat and headache.
• Trouble sleeping.
CLINICAL
MANIFESTATIONS

9. RISK FACTORS & TRIGGERS INVOLVED
ENDOGENOUS FACTORS
• Atopy
• Airway hyper responsiveness
• Ethnicity
• Gender
• Genetic predisposition
ENVIRONMENTAL FACTORS
• Allergens-indoor
• Allergens-outdoor
• Obesity
• Occupational sensitizers
• Respiratory infection (early childhood, viral)
• Tobacco smoking (active & passive)

11. CLASSIFICATION
ACCORDING TO ETIOLOGY:-
1. Allergic or extrinsic asthma
2. Non-allergic or intrinsic asthma
ACCORDING TO DEGREE OF SEVERITY:-
1. Intermittent
2. persistent, mild
3. persistent, moderate
4. Persistent, severe

12. CHARACTERSTICS EXTRINSIC ASTHMA INTRINSIC ASTHMA
DEFINITION
Linked with exposure of specific
allergens. Eg., pollen, house dust
Linked with some nonspecific
stimulants. Eg.,chemical irritants
NATURE
Atopy (Type 1 hypersensitivity reaction)
due to exposure of exogenous non-
bacterial antigens.
IgE mediated.
Non immune mediated, due to increased
airway reactivity to vagal stimulation
AGE GROUP AFFECTED Children Adults
FAMILY HISTORY Usually present Usually absent
TRIGGERED Environment Infection

14. PATHOPHYSIOLOGY
BRONCHO
CONSTRICTION
AIRWAY
INFLAMMATION
AIRWAY HYPER
RESPONSIVENESS
AIRWAY
REMODELLING

15. Adapted from Barnes (2011).

17. AIRWAY
AIRWAY HYPERRESPONSIVENESS
MUCOUS HYPERSECRETION
AIRWAY NARROWING/BRONCHOSPASM
SYMPTOMS(WHEEZING,SHORTNESS OF BREATH)
MECHANISM OF AIRWAY NARROWING
Airway smooth muscle
(response to bronchoconstrictor)
Airway edema-inflammatory mediators
Airway thickening remodelling
Cholinergic nerves- activated by reflex triggers
Bronchoconstriction
TRIGGERS
Inflammatory mediators
Stimulation of : interleukins, IGE, Interferons
Activation of : Mast cells, Eosinophils
Histamines/Prostaglandins/Leukotrienes
INFLAMMATION

18. CHRONIC OBSTRUCTIVE PULMONARY DISEASE
• Common, preventable & treatable disease,
characterized by persistent airflow limitation that
is usually aggressive & associated with an
enhanced chronic inflammatory response in the
airway & the lung to noxious particles or gases
• Characterized by:
 progressive emphysema (alveolar destruction)
 bronchial fibrosis

20. LABORATORY DIAGNOSIS
Pulmonary function tests:-
Using Spirometry
Estimating degree of obstruction:-
o Decreased FEV1
o Normal / decreased FVC
o Increased RV & TLC
Chest X-ray:-
normal appearance to hyperinflammation
Flattening of the diaphragm
Arterial blood gas (ABG)

21. ROUTES OF DRUG DELIVERY TO THE
LUNGS
1. INHALED ROUTE:-
• Administration of the drug directly into the lung by aerosol inhalation.
• Particle size:-
› Size of the particle determines the site of deposition in the respiratory tract.
› Optimum size for the particles to settle in the airways :- 2-5 MMAD
› Large particles:- settle in the upper airways
› Smaller particles:- remain suspended & are exhaled

22. DRY POWDER METERED
DOSE INHALER
PRESSURIZED METERED
DOSE INHALER
SPACE
CHAMBER
JET NEBULIZER
ULTRASONIC NEBULIZER

23.  Of the total drug delivered - 10-20% enters the lower airways with conventional pMDI
 Drugs with higher molecular weights – retain to a greater extent in the airways.
 More extensive pulmonary distribution of a drug with a smaller MMAD –
• Increases alveolar deposition
• Likely to increase absorption from the lungs into the general circulation.

24. 2. ORAL ROUTE:-
• Reserved for the few patients unable to use inhalers (e.g., small children, patients with physical problems such
as severe arthritis of the hands).
• Theophylline:- ineffective by the inhaled route and therefore must be given systemically
• Corticosteroids may have to be given orally for parenchymal lung disease
3. PARENTERAL ROUTE:-
• Reserved for delivery of drugs in the severely ill patient who is unable to absorb drugs from the GI tract.

26. APPROACHES TO TREATMENT
Prevention of AG:AB reaction
Neutralization of IgE
Suppression of inflammation & bronchial hyper reactivity
Prevention of release of mediators
Antagonism of released mediators
Blockade of constrictor neurotransmitter
Mimicking dilator neurotransmitter
Directly acting bronchodilators

27. CONTROLLER MEDICATIONS RELIEVER MEDICATIONS
 Control/treat chronic inflammation & bring about
an improvement of overall asthma control
 Immediate reversal of bronchospasm but no effect on
underlying inflammation
 Taken regularly on a long term basis  Used at the time of acute attacks
 Inhaled glucocorticosteroids
 Leukotriene modifiers
 Long acting β2 agonists
 Low dose sustained release theophylline
 Short acting β2 agonists
 Anticholinergics
 Theophylline immediate release

28. BRONCHODILATORS

29. SYMPATHOMIMETICS
 β2 Agoinst:-
• Potent bronchodilator
• Usually given by inhalation route
• Effects:-
 Relaxation of airway smooth muscle
 Inhibition of mast cell mediator release
 Reduction in plasma exudate
 Increased mucociliary transport
 Inhibition of sensory nerve activation
• No effect on airway inflammation

30. SHORT ACTING β2 AGONIST (SABA)
Salbutamol, Terbutaline
• Inhaled SABAs :- most widely used and effective bronchodilators due to their functional
antagonism of bronchoconstriction.
• They are convenient, easy to use, rapid in onset, and without significant systemic side effects.
• Effective in protecting against various asthma triggers : exercise, cold air, and allergens.
• Bronchodilators of choice in treating acute severe asthma.
 Nebulized route

31. LONG ACTING β2 AGONIST (LABA)
Salmeterol, Formoterol, Arformoterol, Indacaterol, Vilanterol
12 hours 24 hours
• Improve asthma control (when given twice daily) compared with regular treatment with SABAs
(four to six times daily)
• Formoterol :- more rapid onset of action , almost full agonist
• Salmeterol :- partial agoinst, slower onset of action
 In COPD: Alone or in combination with anticholinergics or ICSs. LABAs improve symptoms
& exercise tolerance by reducing both air trapping & exacerbations.
 In asthma: Combination with an ICS in a fixed-dose combination inhaler

32. SIDE EFFECTS OF β2 AGOINSTS :-
• Muscle tremor (direct effect on skeletal muscle β2 receptors)
• Tachycardia (direct effect on atrial β2 receptors, reflex effect from increased
peripheral vasodilation via β2 receptors)
• Hypokalemia (direct β2 effect on skeletal muscle uptake of K+)
• Restlessness
• Hypoxemia (↑ V/Q mismatch due to reversal of hypoxic pulmonary vasoconstriction)
• Metabolic effects (↑ FFA, glucose, lactate, pyruvate, insulin)

33. METHYLXANTHINES
 Restricted to COPD & selected cases of asthma
as Adjuvant Medication
• Mechanism of action:-
1) Antagonism of adenosine receptors on the cell
membrane.
2) Inhibition of phosphodiesterases that
inactivate cAMP; and
3) Enhancement of deacetylation of histones
involved in the transcription of inflammatory
genes. Theophylline (oral), aminophylline (i.v.)

35. Absorption: well absorbed orally;
erratic rectal absorption
Distribution: all tissues; cross
BBM; 50% pp bound
Metabolism: by CYP1A2 by
demethylation & oxidation
Excretion: only 10 % excreted
unchanged in urine
1.Theophylline : narrow margin of
safety
2. Headache, nausea are early
symptoms
3. Gastric pain ( with oral ), rectal
inflammation (with suppositories)
& pain at the site of i.m injection
4. Rapid i.v injection:- precordial
pain, syncope & even sudden death
1.Bronchial asthma & COPD
2. Apnoea in premature infants
PHARMACOKINETICS ADVERSE EFFECTS USES

36. ANTICHOLINERGICS
 Blockade of M3 mediated cholinergic constrictor tone
 Acting primarily on Larger Airways
 Inhaled Ipratropium bromide:-
• Effective in asthmatic bronchitis & COPD
• Given by aerosol: No decrease in respiratory secretion
& impairment in mucociliary clearance
 Tiotropium bromide:-
• Longer acting
• Good for once daily maintenance therapy

37. NOVEL CLASSES OF BRONCHODILATORS
 MAGNESIUM SULFATE:-
• Reduces cystolic calcium in airway smooth muscle Bronchodilatation
Additional bronchodilator in children and adults with acute severe asthma
Benefits in serious severe exacerbations( FEV1˂ 30%)
Cheap and well tolerated treatment
• Side effects: flushing, nausea

38. POTASSIUM CHANNEL OPENERS:-
( cromakalim, levcromakalim )
• Open ATP dependent K channels in smooth muscles
Membrane hyperpolarization & relaxation of airway smooth muscle
 Maxi-K channel openers inhibits mucus secretion & cough
:- may be particular value in the treatment of COPD

39.  VASOACTIVE INTESTINAL POLYPEPTIDE ANALOGUES:-
• VIP binds to VPAC1 ( smooth muscles of blood vessels) & VPAC2 (airway
smooth muscle) couple to Gs adenylyl cyclase
stimulated smooth muscle relaxation
Potent bronchodilator in vitro studies
Produces rapid bronchodilator effect but is not prolonged

40.  BITTER TASTE RECEPTOR AGONISTS:-
(Denatonium, chloroquine)
• TAS2R agoinst
• Bronchodilation via G protein phosphatidylinositol pathway
activation of Ca dependent K channel & subsequent hyperpolarization of SM
• Bronchodilation in response to agonists such as quinine & chloroquine.

41. LEUKOTRIENE ANTAGONISTS
Montelukast, Zafirlukast, Zileuton
• Competitive antagonism of cysLT1 receptor mediated bronchoconstriction, airway mucus
secretion, increased vascular permeability & recruitment of eosinophils.
• Episodes of asthma exacerbations are reduced
Indicated for:- prophylactic therapy of mild-to-moderate asthma as alternatives to inhaled
glucocorticoids
Effective in aspirin induced asthma & exercise induced asthma
• Fewer side effects: abdominal pain, headache & rashes

42.  Monitoring of liver associated
enzymes required
 (zileuton, montelukast &
zafirlukast associated with rare
cases of hepatic dysfunction)
 Major Advantage: effectiveness
in tablet form
 Effective as once daily
preparation

43. MAST CELL STABILIZERS
 Inhibits degranulation of mast cell by
trigger stimuli
 Release of mediators like histamine,
LT, PAF, IL is Inhibited
 Bronchial hyperreactivity is reduced
 Bronchospasm due to various stimuli
( allergens, irritants, cold air &
exercise) is prevented.
Sodium cromoglycate, Ketotifen, Nedocromil

44. Sodium cromoglycate
• Synthetic chromone derivative
• Inhibits : degranulation of mast cells by trigger stimuli
• Restricts the release mediators of asthma- may involve a delayed Cl
channel in the membrane of these cells inhibiting activation.
• It is not a histamine antagonist/bronchodilator:- Ineffective in asthma
attack.
Administered as an aerosol through metered dose inhaler.
Minimal systemic toxicity.
A/E :- Bronchospasm, throat irritation & cough
Uses:-
1. Bronchial asthma:
prophylactic in mild to
moderate asthma
2. Allergic rhinitis: as a
nasal spray
3. Allergic conjunctivitis:
as eye drops

45. CORTICOSTEROIDS
• Acts by reducing :-
‣ Bronchial hypersensitivity
‣ Mucosal edema
‣ Inflammatory response to AG:AB reaction
More complete & sustained symptomatic relief
Improve airflow, reduce asthma exacerbations & may influence airway remodelling,
retarding disease progression
Increase airway smooth muscle responsiveness to β2 agonist

46. MECHANISM OF ACTION:-
• Binding to cytoplasmic receptor
(GR), this complex moves to
nucleus
• Increased transcription of anti-
inflammatory genes
• Supression of transcription of
proinflammatory genes

47. SYSTEMIC CORTICOSTEROID THERAPY
• Systemic steroid therapy is applied in the following cases:-
Severe chronic asthma Status asthmaticus
• Not controlled by bronchodilators & ICS
• Frequent recurrences of increasing severity
 Prednisolone 20-60mg daily
dose reduction after 1-2 weeks
 shifting patient to ICS
• Asthma attack not responding to intensive
bronchodilator therapy
 High dose of rapidly acting i.v. glucocorticoid
which generally acts in 6-24 hrs
 Shift to oral therapy for 5-7 days & the taper
rapidly

48. INHALED CORTICOSTEROID
Beclomethasone dipropionate, Budesonide, Fluticasone, Ciclesonide
• Inhaled corticosteroids are recommended as first-line therapy for patients with persistent asthma
• Prevent the episodes of acute asthma
Supress bronchial inflammation
Increase peak expiratory flow rate
Reduce need for rescue beta 2 agonist inhalation
• Peak effect seen after 4-7 days of instituting ICS & benefit persists for a few weeks after
discontinuation

49. ICS
• Currently the most effective long term preventive medications
• Early diagnosis & treatment with ICS: important for prevention of airway remodelling
• Initial treatment: dosing guided by asthma severity
• Long term treatment: titration of the lowest effective dose
• COPD:- High dose ICS in advanced COPD with frequent exacerbations

50. ADVERSE EFFECTS
LOCAL SIDE EFFECTS SYSTEMIC SIDE EFFECTS
Hoarseness of voice
Dysphonia
Sore throat
Oropharyngeal candidiasis
(Clinically relevant only at doses ˃ 600 µg/day)
Adrenal suppression
Growth suppression
Osteoporosis
Cataracts
Glaucoma
Hyperglycaemia

51. COMBINATION THERAPY
Fluticasone propionate + salmetrol
Budesonide + formoterol
MAINTENANCE

52. ANTI IgE RECEPTOR THERAPY
• Omalizumab : humanized monoclonal antibody
• Blocks the binding of :
 IgE to high-affinity IgE receptors (FcεR1) on
mast cells
 IgE to low-affinity IgE receptors (FcεRII, CD23)
on T & B lymphocytes, macrophages &
eosinophils

53. • Administered by: s.c. injection every 2-4 weeks
• Reduces :
 levels of circulating IgE
 Requirement for oral & ICSs
 Asthma exacerbations
• HIGH COST!
• A/E : anaphylactic response (˂0.1%)

55. New Drugs in Development for Airway Disease
• CRTh2 ANTAGONISTS
• The chemotactic factor for Th2 cells :- Prostaglandin D2, (DP2 receptor)
• Several DP2/CRTh2 antagonists are now in development for asthma
• Promising initial results in patients with Eosinophilic Inflammation
• ANTIOXIDANTS
• Oxidative stress : contribute to corticosteroid resistance.
 Vitamins C and E and N-acetyl-cysteine.

56. • CYTOKINE MODIFIERS
• Interleukin 5:- pivotal role in eosinophilic inflammation
• Anti–IL-5 & anti–IL-5 receptor (IL-5Rα) antibodies : inhibit eosinophilic
inflammation & airway hyperresponsiveness (mild asthma).
• In severe asthma and persistent eosinophilia despite high doses of corticosteroids :
significant reduction in exacerbations and sparing of oral steroids with an anti–IL-5
antibody, Mepolizumab.

57. • CHEMOKINE RECEPTOR ANTAGONIST
• Key role in recruitment of inflammatory cells (eosinophils, neutrophils, macrophages,
and lymphocytes) into the lungs.
• CCR3 antagonists (block eosinophil recruitment) - most favored target

58. • PHOSPHODIESTERASE INHIBITORS
(Roflumilast, cilomilast)
• PDE4 inhibition elevate levels of intracellular cAMP
Supresses inflammatory cell function
Inhibition of mucin production
Alterations in airway smooth muscle tone

59. REFERENCES
1. Goodman L, Gilman A. The pharmacological basis of therapeutics. 13th ed. New York : McGraw-Hill;
2011. Chapter 40, pulmonary pharmacology; p.727-46
2. Tripathi KD. Essentials of medical pharmacology. 8th edition, New Delhi : Jaypee Brothers Medical
publications (P) Ltd; 2019. Chapter 16, Drugs for cough and bronchial asthma; p.237-53
3. Katzung G. basic and clinical pharmacology. 13th edition, Chennai : McGraw-Hill; 2018. Chapter 20, drugs
used in asthma; p. 346-361
4. Whalen K. Lippincott Illustrated reviews of pharmacology. South asian edition,. Wolters Kluwer India Pvt.
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management. Allergy Asthma Clin Immunol 16, 75 (2020). https://doi.org/10.1186/s13223-020-00472-8
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Available from www.ginasthma.org

60. THANK YOU