PHARMACOTHERAPY OF BRONCHIAL ASTHMA FOR MBBS

1. By
Dr. Manoj Kumar
Assistant Professor
Department of Pharmacology
Adesh Medical College & Hospital Ambala Can’t

2. Bronchial Asthma
 Bronchial asthma (also called reversible airway obstruction)
is a clinical syndrome characterized by increased Hyper-
responsiveness of the tracheobronchial smooth muscles to
various stimuli resulting in narrowing of the airway.
 May be life threatening.

3. What are the stimuli? (Triggers)
 Tobacco smoke.
 Infections such as colds, flu, or pneumonia.
 Allergens such as food, pollen, mold, dust mites & pet dander.
 Exercise.
 Air pollution and toxins.
 Weather, especially extreme changes in temperature.
 Drugs (such as aspirin, NSAID, and beta-blockers).
 Food additives.
 Emotional stress and anxiety.
 Singing, laughing, or crying.
 Smoking, perfumes, or sprays.
 Acid reflux.

5. Results in …
Narrowing of
Air tubes

6. Accompanied with ?
 Increased secretion
 Mucosal oedema
 Mucus plugging
All are
Primarily due to
Inflammation!

7. Resulting in (clinically)
 Triad of asthma
 Dyspnoea (shortness of breath).
 Wheezing (additional sound).
 Cough (persistent).
 Additionally: limitation of activity

8. Classification - Etiological
Extrinsic asthma or allergic:
 Start in an early age
 Mostly episodic.
 History of `atopy` in childhood
 Family history of allergies
 Raised IgE level
 Below 30 years of age
 Less prone to status asthmaticus
Intrinsic asthma or Idiosyncratic:
 No family history of allergy
 Middle age onset
 Prone to status asthmaticus

9. Airway Inflammation in asthma
 Triggered by innate or adaptive immune responses
Immediate release of mediators from granules:
Histamine, protease enzymes and TNF-alpha
Release of Mediators from cell membrane:
PG, LT and PAF etc.
Gene activation (delayed):
Interleukins and TNF-alpha

10. Antiasthmatics - Classification
1. Bronchodilators:
 sympathomimetics (agonists):
 Selective ß2- agonist
Short acting :- salbutamol, terbutaline and bambuterol.
Longer acting :- salmeterol, fometerol, rimeterol, bitolterol and fenoterol.
Non specific:– ephidrine, isoprenaline and adrenaline.
 Methylxanthines:
Theophylline and derivatives aminophylline, cholinetheophyllinate,
Hydroxyethyltheophylline etc.
 Anticholinergics:
Ipratropium bromide and tiotropium bromide

11. Antiasthmatics – Classification….
2. Mast cell stabilizers:
sodium chromoglycate and ketotifen
3. Leukotriene antagonists:
montelucast and zafirlucast
4. Corticosteroids:
Systemic: hydrocortisone and prednisolone.
Inhalation: beclmethasone dipropionate, budesonide, fluticasone propionate.
5. Anti-IgE antibody: omalizumab

12. What is a beta-2 agonist ?
 All adrenergic drugs act via alpha/beta receptors
Mainly (α1, α2 , ß1 and ß2)
 Type β1:
These are present in heart tissue, and cause an increased heart
rate by acting on the cardiac pacemaker cells
 Type β2:
These are in the Bronchial smooth muscles and vessels of
skeletal muscle and cause relaxation of smooth muscles and
cause vasodilation

13. Results of beta-2 activation
AND
Tocolytic

14. ß2-sympathomimetics (agonists)
salbutamol and salmeterol etc.
1. Adrenergic drugs are base in the treatment of Bronchial
asthma
2. Adrenaline and Isoprenaline – not used frequently – WHY ?
 (beta -1 receptor agonist)
3. ß2-sympathomimetics are fastest acting bronchodilators
when inhaled (5 minutes) – lasts 2 to 4 Hrs

15. ß2-sympathomimetics - MOA
MOA:
 Stimulation of β2 receptor in
bronchial smooth muscle cell
membrane activation of adenyl
cyclase → cAMP →Ca2+↓
→SM relaxation
 Also activate β-receptor on
mast cell membrane – decrease
in mediator release

16. Results of β2 stimulation

17. Salbutamol
 A highly selective β2 agonist.
 Cardiac side effects are less prominent.
 Inhaled salbutamol delivered mostly from pressurized
metered dose inhaler (pMDI).
 Produces bronchodilatation effect within 5 min.

18. Pharmacokinetics:
 Metabolism in gut wall
 Bioavailability is 50%
 Duration of action: 4-6 Hrs
 Salbutamol:
 Available as 2, 4 and 8 mg tab.
 Syr. as 2 mg/5 ml
 As metered dose inhaler – 100 μg
 200 μg as rotacaps

19. Adverse effects:
 Muscle tremors are the dose related side effect.
 Palpitation, restlessness, nervousness,
 Throat irritation and ankle edema can also occur.
 Vasodilatation – reduction in mean arterial pressure with
tachycardia.
 Hyperglycaemia and hyperlacticacidemia
 Worsening of asthma on prolong inhalation.

20. Terbutaline
 It is similar to salbutamol in properties and use.
 Dose: 5 mg oral, 0.25 mg s.c., 250 μg by inhalation.

21. Salmeterol
 Fast long acting Beta-2 agonist (more lipophilic).
 Available as inhaler: MDI and rotacaps (25 μg)
 Weaker than salbutamol but more beta-2 selective.
 Duration of action is 3 hrs to 12 hrs.
 Not useful for acute attacks, only for prophylaxis.
 Usually combined with steroids.

22. Bambuterol
 Biscarbamate ester prodrug of terbutaline .
 Slowly hydrolyzed in plasma and lungs by pseudo cholinesterase.
 Release the active over 24 hours.
 Reversible inhibition of pseudo cholinesterase occurs in a dose
dependent manner.
 Use in nocturnal and chronic asthma as a single evening dose of
10–20 mg oral.

23. Formoterol
 Another long-acting selective β2 agonist.
 Acts for 12 hrs when inhaled.
 In comparison to salmeterol, it has a faster onset of action.
 It is used on a regular morning-evening schedule for
round-the-clock bronchodilatation.
 Dose: 12–24 μg by inhalation twice daily.

24. Ephedrine
 This oral sympathomimetic has α + β1 + β2 actions
 Slowly developing bronchodilatation action for 3–5 hours.
 Used for mild to moderate chronic asthma.
 Because of low efficacy and frequent side effects.
 it is not preferred now.

25. Metylxanthines
 3 Naturally occurring methylxanthines –
 caffeine, theophylline and theobromine
 All three are consumed as beverages.
 Many salts of theophylline have been marketed but the most
common one is aminophylline is highly water soluble and a
stable mixture of theophylline and ethylene diamine
 Uses: Bronchial asthma and COPD and also in
infantile apnoea

26. Metylxanthines – Pharmacological actions
CNS: Caffeine and theophylline are CNS stimulants.
 Caffeine 150–250 mg produces a sense of wellbeing, alertness,
beats boredom, allays fatigue,
 Thinking becomes clearer
 Improve performance and increase motor activity.
 Caffeine is more active than theophylline.

27. Higher doses
cause nervousness, restlessness, panic, insomnia
and excitement.
Still higher doses
produce tremors, delirium and convulsions.
stimulate medullary vagal, respiratory and vasomotor
centres.
Vomiting, gastric irritation and CTZ stimulation.

28. CVS:
 Methylxanthines directly stimulate heart – increase in
heart rate, cardiac output
 Dilatation of blood vessels including coronary – reduced
peripheral resistance
 But, constriction of cerebral vessels – It use in migraine
 Tachycardia is more common with theophylline Higher
doses – cardiac arrhythmia

29. Kidney:
Mild diuretic (decrease in tubular reabsorption of Na and
also increase in renal blood flow)
 Stomach:
Increase in acid-pepsin secretion
 Smooth muscles:
Relaxed – bronchodilatation, but no effect on intestine
and urinary tract
 Metabolic:
Increase in BMR – plasma fatty acid level raised

30. Metylxanthines - MOA
 Blockade of adenosine receptors – no contraction of smooth muscles
 Inhibition of Phosphodiesterase enzyme:
ATP/GTP cAMP/cGMP 5-AMP/5-GMP
(inhibit activity of PDE cAMP Ca2+ bronchial relaxation)
 Higher doses - Release of Ca++ from sarcoplasmic reticulum

31. Metylxanthines – contd.
 Kinetics:
 Absorbed orally, crosses placenta and secreted in milk.
 Metabolized in liver by demethylation and oxidation
 T1/2 is 6-12 Hrs, but faster in children and slow in elderly
(premature – slow)
 On prolonged and high dose – elimination is zero order
from first order

32. ADRs:
Low therapeutic index:
Therapeutic range - 0.2 to 2 mg/100 ml, higher than 4 mg/100ml
may cause
arrhythmia, convulsion and coma
 Insomnia,
 headache and nervousness,
 Restlessness, palpitation vomiting etc.
 Tachycardia, flushing, hypotension Delirium, worsening of CVS
status, shock, death.
Nausea and vomiting - common

33. Methylxanthines - Preparation and Dosage
 Theophylline: (Unicontin/Theolong)
Theophylline is well absorbed orally.
Poorly water soluble and cannot be injected
Available as tablets 100/200 mg SR
 Metabolized in liver by demethylation and oxidation primarily by
CYP1A2
Adverse effects
 Headache, nervousness and nausea are early symptoms.
 Children are more liable to develop CNS toxicity

34. Aminophylline:
 Water soluble and can be injected IV
 Available as 100 mg tablets and 250 mg/ml injection
 Hydroxyethyl theophylline: (Derriphylline)
 Available as 100/300 mg tablets or 220 mg/2ml injection

35. Anti-cholinergics
Atropine, Ipratropium bromide and tiatropium bromide
 Atropinic cause bronchodilatation by blocking M3 receptor.
 Ipratropium bromide is a short acting (duration 4–6 hr).
 Tiotropium bromide is long acting (duration 24 hours).
 Tiotropium is more effective than ipratropium in COPD; more
suitable for severe cases.
 Inhaled anticholinergics produce slower response than inhaled
β2 sympathomimetics and better suited for regular
prophylactic use (ipratropium 2–4 puffs 6 hourly or tiotropium
1 rotacap OD)

36. MAST CELL STABILIZER
Cromolyn sodium/Sodium cromoglycate
 Synthetic compound and chemically
benzopyrone
 Stabilizes mast cells – inhibits degrannulation
of mast cells and other inflammatory cells
 Also prevent chemotaxis of eosinophils and
neutrophils – local inflammation action is
prevented
 Basis of action may be due to delayed Cl-
channel in the membranes
 Long term use prevents hyperactivity of
bronchial tree.

37. Pharmacokinetics
 Not absorbed orally, given via MDI – 1 mg/dose – 2 puffs 4
times daily
 Uses: Prophylaxis of asthma, allergic rhinitis and allergic
conjunctivitis (2%)
 Adverse effects poor aqueous solubility and absorption .
 Bronchospasm, throat irritation and cough occurs in some
patients, especially with fine powder inhalation.
 Rarely nasal congestion, headache, dizziness, arthralgia and
rashes have been reported.

38. Leukotriene Antagonists
Montelucast and zafirlucast:
 They are compile Antagonist of cysLT1 - cysteinyl leukotrienes
LT4, LTD4 and LTE4 are important mediators of human asthma.
 Benefits – bronchodilatation, reduced eosinophil count and
suppression of inflammation and hyperactivity.
 Used in mild to moderate asthma as alternative to inhaled
glucocoticoides.
 Useful in children – reduces dose of steroids and beta agonists
 Absorbed orally and highly plasma protein bound.
 Side effects:- abdominal pain, headache and rashes.
 Half life: montelucast (3-6 hrs), zafirlucast (8-12 Hrs)

39. Corticosteroids
2 types –
Glucocorticoids and Mineralocorticoids
Glucocorticoids – Suppress inflammatory response
to all noxious stimuli:
 Pathogens,
 Chemical ,
 Physical and immune mediated
 Hypersensitivity

40. MOA:
Anti-inflammatory action – reduction in mediators IL, TNF
and PAF etc. and reduction in exudates formation in the
bronchial tree.
 Bronchial asthma is an inflammatory disease.
 Steroids act best in asthma than any other group of drugs.

41. Corticosteroids – cont..
 Inhalation:
 Not bronchodilator but reduces airway inflammation –
anti inflammatory action
 Topical action in lungs but low systemic absorption.
 Not used in mild episodic asthma
 Used when regular beta-2 agonists are required 100 – 200
mcg BD is starting dose and increased upto 400 mcg qid
 Reduces the required dose of beta-2 agonists and prevents
episodes of asthma

42. Inhalation steroids are used
 Beclomethasone,
 Dipropionate,
 Budesonide,
 Fluticasone propionate and
 Triamcinolone acetonide.

43. Systemic steroid is useful in:
 Acute asthma (status asthmaticus) – not relieved or
worsening of obstruction in spite of bronchodilatator
and inhaled steroid – hydrocortisone and prednisolone
 Chronic asthma – failure of previously optimal regimen
– frequent symptoms of progressive severity.
COPD: high doses are required
 Minimized by use of spacer and gurgling.

44. Adverse effects of long term steroids:
Hoarseness of voice, soar throat, dysphonia and
Oropharyngeal candidiasis.
Mood changes, osteoporosis, growth retardation,
hyperglycaemia and adrenal crisis etc.
Doses:
 Beclomethasone: available as 50, 100 and 1200 mcg/ml
MDI – dose is 400 mcg/day
 Budesonide: available as 100, 200, 400 mcg/ml MDI –
dose is 200 mcg BD

45. Anti-IgE antibody - omalizumab
• Humanized monoclonal antibody
• Administered IV or SC
• Neutralizes free IgE in circulation
• Expensive
• Reserved for resistant cases

46. Chronic obstructive
pulmonary disease
COPD

47. Drugs used in COPD
COPD is a chronic irreversible airflow obstruction, lung damage and
inflammation of the air sacs (alveoli).
 Smoking is a high risk factor
 Treatment:
 Inhaled bronchodilators
 Inhaled glucocorticoids
 Oxygen therapy
 Antibiotics specifically macrolides such as azithromycin to reduce the
number of exacerbations.
 Lung transplantation

48. Treatment of COPD
Inhaled bronchodilators
 Inhaled antimuscarinics
 β2 agonists
 these drugs can be used either alone or
combined
 salbutamol + ipratropium
 salmeterol + Tiotropium (long acting-less dose frequency).

49. Treatment - asthma
Step I: (Mild episodic asthma)
 When symptoms are less than once daily - occasional
inhalation of a short acting Beta-2 agonist – salbutmol,
terbutaline. If used more than once daily.
Step II: (Mild chronic asthma)
 Regular inhalation of low-dose steroids. Alternatively,
cromoglycates. Beta-2 agonist as and whenever required.

50. Step III: (Moderate asthma with frequent exacerbations)
 Inhalation of high dose of steroids (800 mcg) + Beta-2
agonist. Sustained release theophylline may be added. LT
inhibitors may be tried instead of steroids– spacers.
Step IV: (Severe asthma)
 Higher dose of steroid (800 to 200 mcg) + regular beta-2
agonist (long acting salmeterol)
Additional treatment with oral drugs – LT antagonist or SR
theophylline or oral beat-2 agonist.

51. Status asthmaticus ( Refractory asthma)
 called acute severe asthma
 Hydrocortisone hemisuccinate 100 mg stat IV and followed
by 100-200 mg 4-8 hrly. Infusion.
 Nebulize Salbutamol (2.5 to 5 mg) + Ipratropium bromide
(0.5 mg) inhalations with oxygen and nebulization.
 High flow Humidified Oxygen inhalation.
 Salbutamol or terbutaline IM or SC (0.4 mg)
 Intubation and Mechanical ventilation, if required
 Antibiotics
 IV saline – for dehydration and acidosis and sod.
bicarb0nate if required