Drug treatment of Bronchial asthma

1. Pharmacotherapy of
Bronchial Asthma
Dr. Tabindah Hesam
Junior resident
Department of Pharmacology

2. Introduction
• Asthma is a chronic inflammatory disorder of the airways.
• clinically by recurrent episodes of wheezing, breathlessness, chest
tightness, and cough, particularly at night/early morning.
• pathologically by activation of mast cells, infiltration of eosinophils,
and T helper 2 (TH2) lymphocytes (Barnes, 2008b).

3. Classification
1. EXTRINSIC ASTHMA
-Atopic asthma
-Non atopic asthma
2. INTRINSIC ASTHMA

4. Pathophysiology
The hallmarks of the disease are:
• airway hyper-responsiveness,
• inflammation of the bronchial walls,
• and increased mucus secretion.

7. Routes of drug administration
Inhaled route
-Preferred mode of delivery.
-Drugs are effective at doses which carry least systemic side effects.
-Rapid onset of action.
- Optimum size of particles:2-5µm mass median aerodynamic diameter.

8. PHARMACOKINETICS

9. Delivery devices
Pressurised metered dose inhalers:
 CFC replaced by a HFA that is “ozone friendly”.
 Convenient, portable
 deliver 100-400 doses of drug.
 Coordination is important.

10. Spacer chamber:
 Between patient and pMDI- reduces velocity
of drug entering the upper airways and size of
particles by allowing evaporation of liquid
propellant.
 Prevents oropharyngeal deposition of drugs
and reduces systemic and local side effects.
 Useful in small children.

11. Nebulizers
1.JET NEBULIZERS
2.ULTRASONIC NEBULIZERS
 Drugs are delivered at higher dose as compared to pMDI.
 Useful in acute exacerbation.
 For delivering drugs to infant and small children.

12. Oral route:
 Oral dose is much higher than the inhaled dose required to achieve
the same effect(Oral:inhaled~20:1)
 Reserved for the patients unable to use inhalers or for the drugs
which can not be delivered by inhalational route.
Parenteral route:
 Iv route is reserved for severely ill patients.

13. Management of bronchial asthma

14. NON-PHARMACOLOGICAL MANAGEMENT
• Avoid triggering factors
• Appropriate support to stop smoking.
• Weight-loss interventions (including dietary and exercise-based
programmes).
• Breathing exercise programmes (including physiotherapist-taught
methods) - as an adjuvant to pharmacological treatment to improve
quality of life and reduce symptoms.

15. PHARMACOLOGICAL MANAGEMENT
• Before initiating a new drug therapy practitioners should check
adherence with existing therapies, check inhaler technique, and
eliminate trigger factors.
• Inhaled corticosteroids are the recommended preventer drug for
adults and children for achieving overall treatment goals.
• The first choice as add-on therapy to inhaled corticosteroids in adults
is an inhaled long-acting β2 agonist, which should be considered
before increasing the dose of inhaled corticosteroids.
• If asthma control remains suboptimal after the addition of an inhaled
long-acting β2 agonist then the dose of inhaled corticosteroids should
be increased from low dose to medium dose in adults or from very
low dose to low dose in children (5–12 years), if not already on these
doses.

16. Relievers
Controller
• Beta 2 agonists
• Anticholinergics
• Methylxanthines
• Corticosteroids
• Mast cell stabilizers
• Anti Leukotriens
• Biological Agents

17. βeta-2 Agonists
• Usually given by inhalation route.
• Most effective bronchodilator with minimal side effects.
• No effect on airway inflammation and AHR.
Mechanism of action
• Relaxation of airway smooth muscle
• Inhibition of mediator release from mast cells.
• Inhibits microvascular leakage.
• Enhanced mucociliary clearance

18. 1.Short acting beta -2 agonists(SABA)
 Inhaled SABA are most widely used and effective bronchodilators.
 Effective in protecting against various challenges, such as exercise, cold
air, and allergens.
 Bronchodilators of choice in treating acute severe asthma.
 Duration of action - 3-6hrs.
 Used for symptomatic relief on as needed basis(4-6 times a day).

19. • Albuterol /salbutamol
100 µg in single dose/ 2-4mg tds orally
• Terbutaline
-oral inhalation causes tooth enamel erosion
-250µg, 2.5-5 mg BD or TDS orally
-Only bronchodilator safe in pregnancy.
• Bambuterol- only in chronic asthma, 10-20 mg orally OD
• Levalbuterol, the (R)-enantiomer of albuterol
• Metaproterenol – lesser beta-2 selectivity

20. 2.Long-Acting β2Agonists
• Improve asthma control and reduce frequency of
exacerbations.
• Always used in combination with inhaled corticosteroid
(ICS)therapy.
• Allow asthma to be controlled at lower dose of ICS.
Salmeterol
• Slow onset of action, duration of action-12 hrs
• Dose- 25-100µg inhalation BD

21. Formeterol
• Faster onset of action
• Used for acute attacks of nocturnal asthma, prophylaxis of exercise
induced bronchospasm.
• Dose-12-24µg inhalation BD
Pirbuterol
• onset of action-10 min, lasts for 5 hrs.

22. • Tolerance to the drug develops over time- not progressive, doubtful
clinical significance.
• Formoterol- more rapid onset , almost full agonist,
• salmeterol- partial agonist, slower onset of action.
• However no significant clinical differences between salmeterol and
formoterol have been found in the treatment of patients with severe
asthma (Nightingale et al., 2002).

23. Side effects of beta-2 agonists:
• Muscle tremor
• Tachycardia
• Hypokalemia( concurrent use of GC or methylxanthines).
• Restlesness
• Hypoxemia
• Continued use can lead to rapid downregulation /desensitization
of β2 receptors on inflammatory cells.

24. Anticholinergic agents
-Ipratropium ,
-Tiotropium.
• Prevent cholinergic nerve induced bronchoconstriction.
• Less effective than β2 agonists.
• Response varies with existing vagal tone.

25. Use in Asthma
-Intolerance to beta-2 agonists
-As additional therapy to LABA in acute and chronic asthma
-Status asthmaticus –additive effect with β2 agonist.
Side effects
-Bad taste
-Dryness of mouth
• Acute attack precipitated by Sulphur di-oxide, inert dust, cold air and emotional
factors respond to these agents.
• Devoid of systemic side effects due to poor absorption from lungs mucosa.
• Long acting agents need to be cautiously used in patients with BPH.
• Blockade of M-2 receptors may reduce the efficacy of drug.

26. Methylxanthines
• Theophylline,
• Aminophylline,
• Diprophylline
• Doxophylline
• Bronchodilator, anti-inflammatory and immunomodulatory effect
• Used in combination with beta agonists for control of asthma.

27. Mechanism of action:
• Inhibition of PDE III(present in airway smooth muscles), PDE IV
(present in eosinophil and mast cells)
• Adenosine receptor antagonism (A-1and A-3)
• IL-10 release
• Effect on gene transcription.
• Effects on apoptosis of eosinophils.

28. • Narrow therapeutic window
• Therapeutic range 5–15 mg/L
• Dose-6mg/kg IV over20-30 minutes f/b 0.5mg/kg per hour
SIDE EFFECTS
• Anorexia, nausea, vomiting, abdominal discomfort, headache, and
anxiety – start at >20 mg/L.
• Seizures or arrhythmias at conc.>40 mg/L

29. • Metabolism- Hepatic(CYP1A2)
• Increased clearance-Children, smokers, enzyme inducers.
• Reduced clearance-liver disease, certain drugs( erythromycin,
ciprofloxacin, cimetidine,zileuton, zafirlukast),vaccination, viral
infection.

30. • Use of these drugs has been decreased
• Side effects
• Need for plasma drug levels.
• Availability of other effective drugs.

31. Corticosteroids
• With their use as an anti-asthmatic drug corticosteroids remain the most
effective controller therapy of asthma.
• Introduction of inhaled corticosteroids(ICS) was a major breakthrough in
the management of asthma.
• Greater therapeutic index and considerable decrease in side effects
because of high
topical : systemic ratio.
• ICS reduced the requirement of oral corticosteroids as well as rescue
beta-2 agonists therapy.
• ICS is considered as first line therapy in all patients of asthma including
those with mild disease.

32. Mechanism of action
Inflammatory
stimuli
Inflammatory genes
Cytokines,chemokines, adhesion
molecules, inflammatory receptors,
enzymes, proteins
Increased gene
transcription
Decreased gene
transcription
+
corticosteroid
--
Corticosteroid
receptor
Nucleus
Cytoplasm

33. Effects of corticosteroids
• 1. Upregulation of beta 2 receptors in lung cells and leukocytes
• 2.Inhibit the release of PGs and LTs
• 3.promotes apoptosis of eosinophils
• 4.Inhibit the release and formation of cytokines and chemical
mediators.

34. Beclomethasone dipropionate and Ciclesonide ( prodrugs)
Esterases in lung
Active corticosteroid
• Budesonide, fluticasone, mometasone, and ciclesonide - first-pass hepatic
metabolism;
• At high doses (>1000 µg), budesonide and fluticasone propionate - less
systemic effects
- preferred in patients who need high doses of ICS and in children.
• > 800µ g beclomethasone dipropionate or equivalent daily, a large volume
spacer is recommended( to minimize local side effects).
• The amount of drug absorbed does not appear to have clinical effects in doses
of <800 µg beclomethasone dipropionate equivalent.

35. Adverse effects
Local side effects:
• Dysphonia (~40%)
• Oropharyngial candidiasis(~5%)
• Throat irritation and cough.
Systemic side effects:
• Dermal thinning( especially in elderly)
• Growth suppression
• Cataract, glaucoma.
• Osteoporosis.

36. Systemic steroids in asthma
Intravenous steroids are indicated
- In acute asthma if lung function is <30%
- In patients who show no significant improvement with nebulized beta- 2
agonist.
Hydrocortisone is the steroid of choice because it has the most rapid onset (5-6
hours after administration), compared with 8 hours with prednisolone.
Dose: Hydrocortisone 4 mg/kg initially, f/b 3 mg/kg every 6 hours.
-Intravenous therapy is usually given until a satisfactory response is obtained,
and then oral prednisolone may be substituted.
-Oral prednisolone (40-60 mg) has a similar effect to intravenous hydrocortisone
and is easier to administer.

37. Oral Corticosteroids:
• Short courses of oral steroids – after acute attack(30-40 mg
prednisolone daily for 1-2 weeks).
• Alternate-day treatment has the advantage of less adrenal
suppression, although in many patients control of asthma is not
optimal on this regimen.

38. Combination inhalers
• Fixed dose combination of corticosteroid with long acting β2 agonist
Complementary synergistic action(Barnes et al2002)
eg; fluticasone+salmetrol (ADVAIR) , budesonide+formoterol
(SYMBICORT)
• LABA are an effective add-on therapy to ICS and are more effective than
increasing the dose of ICS when asthma is not controlled at low doses.
• Recently, a combination inhaler that contains formoterol and budesonide
was shown to be more effective for relieving acute symptoms than either
terbutaline or formoterol alone, suggesting that the inhaled
corticosteroids may also be contributing to the benefit (Rabe et al.,
2006).
• both for maintenance and relief of symptoms.

39. Leukotrienes pathway inhibitors
1. 5-lipoxygenase inhibitor
Zileuton
2. Cysteinyl Leukotriene-Receptor antagonist
Zafirlukast
Montelukast
Pralukast
Iralukast

41. • They are less effective than ICSs in controlling asthma
• ‘Responders’ and ‘non responders’.
Use in asthma
• Patients unable to manipulate inhaler devices.
• Aspirin induced asthma.
• Mild asthma – alternative to ICS.
• Moderate to severe asthma –Reduce the dosage of ICS as well as of
beta-2 agonist

42. Zileuton:
• hepatotoxic
• Headache, nausea, GIT distress
• Interaction with theophylline, warfarin
Zafirlukast:
• Food hampers absorption
• Half life-10 hrs
• Metabolism-CYP2C9
• GIT distress, headache

43. Montelukast
• Bioavaibility not affected by meals.
Pranlukast
• Safest
• No significant side effects have been reported during 5 years
surveillanace of trials.
Rare cases of churg strauss syndrome was reported.

44. Mast cell stabilizers(Chromones)
• Cromolyn sodium(Sodium cromoglycate)
• Nedocromil sodium.
• Non bronchodilating, Non steroidal drugs.
• They are only of value when taken prophylactically.
• On chronic use (3-4 times daily) reduce the overall level of bronchial reactivity.
• Reduce the need of beta agonist and corticosteroid

45. • Mechanism of action:
Stabilize mast cell by preventing Ca2+ ion influx
(provoked by Ag-Ab interaction on mast cell surface)
Prevent degranulation of mast cells
-Also inhibit leukocyte activation and chemotaxis.

46. Adverse effects
• Well tolerated drugs
• Minor side effects- throat irritation, cough, and mouth dryness,
rarely, chest tightness, and wheezing.

47. Anti-IgE therapy

48. • Use in asthma
-not controlled by inhaled CS and
- who are sensitive to aeroallergens
• Persons >12 years of age with moderate-to-severe persistent
asthma.
• Omalizumab is not a bronchodilator and should not be used as a
rescue medication or as a treatment of status asthmaticus.
• Expensive drug
• Has to be given under direct medical supervision due to the risk of
anaphylaxis.

49. Miscellaneous drugs
Nitric oxide donors
Clarithromycin

50. Treatment of Status asthmaticus
• Oxygen inhalation(40-60%)
• Inhaled short acting beta-2 agonist
• Systemic corticosteroid:
-Prednisolone 30-60 mg oral
- Hydrocortisonesodium succinate-100-200 mg iv
• Ipratropium bromide-0.5mg via inhalational route
• Correction of dehydration and acidosis.

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