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.
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
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
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
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
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