A power point presentation on drugs used in Bronchial asthma suitable for UG MBBS level students

1. DRUGS FOR BRONCHIAL
ASTHMA
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. Definition of Bronchial Asthma
• Bronchial asthma is chronic respiratory
condition characterized by
– Hyper-responsiveness
of tracheobronchial
smooth muscles to a
variety of stimuli ….

3. Results in …
Narrowing of
Air tubes …

4. … accompanied with ?
1. Increased secretion
2. Mucosal oedema
3. Mucus plugging
All are
Primarily due to
Inflammation!

5. … resulting clinically as
• Triad of asthma
– Dyspnoea (shortness of breath)
– Wheezing (additional sound)
– Cough (persistent)
– Additionally: limitation of activity
• Clinical definition: Bronchial asthma (also called reversible airway
obstruction) is a clinical syndrome characterized by recurrent bouts
Bronchospasm. There is increased responsiveness of the
tracheobronchial smooth muscles to various stimuli resulting in
widespread narrowing of the airway
• May be life threatening !!! - status asthmaticus
• Basis: Allergic basis and non-allergic basis (triggering factors)

6. Classification - Etiological
1. Extrinsic or allergic:
– History of `atopy` in childhood
– Family history of allergies
– Positive skin test
– Raised IgE level
– Below 30 years of age
– Less prone to status asthmaticus
1. Intrinsic or Idiosyncratic:
– No family history of allergy
– Negative skin test
– No rise in IgE level
– Middle age onset
– Prone to status asthmaticus
Pollens Dust mite
Mold Pet
danders

7. … contd.
What are the stimuli? (Triggers)
• Tobacco smoke
• Infections such as colds, flu, or pneumonia
• Allergens such as food, pollen, mold, dust mites, and 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

8. Airway Inflammation in asthma
• Airway inflammation presumably
is triggered by innate and/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

9. The inflammatory response
• Although there are subtypes of asthma (allergic vs. nonallergic),
certain features of airway inflammation are common to all asthmatic
airways
• Although Multiple Trigger for inflammation (mast cell secretion) -
there is consensus that a lymphocyte directed eosinophilic
bronchitis is a hallmark of asthma
• The lymphocytes that participate in asthma are of the T-helper type
2 (Th2) phenotype, leading to increases in production of interleukin
4 (IL- 4, IL-5, and IL-13).
– IL- 4 promotes IgE synthesis in B cells, while IL-5 supports eosinophil
survival
• The innate or adapted immune response triggers the production of
additional cytokines and chemokines, resulting in trafficking of
blood-borne cells (i.e., eosinophils, basophils, neutrophils, and
lymphocytes) into airway tissues; these cells further generate a
variety of autacoids and cytokines

10. Bronchial Asthma – Airway
Remodeling
Textbook of Goodman Gillman

11. What is COPD?
• COPD is characterized by airflow limitation caused by
chronic bronchitis or emphysema often associated with
long term tobacco smoking
• This is usually a slowly progressive and largely
irreversible process
• Consists of increased resistance to airflow, loss of elastic
recoil, decreased expiratory flow rate, and over inflation
of the lung
• COPD is clinically defined by a low FEV1 value that fails
to respond acutely to bronchodilators, a characteristic
that differentiates it from asthma - <15% in 1 sec FEV1

12. Pathology of Small Airways i.e. less
then 2 mm in diameter
Control Severe COPD

13. Treatment Strategy
• Neutralize IgE
• Prevent release of mediators
• Antagonize mediators

14. Antiasthmatics - Classification
1. Bronchodilators:
– ß2 sympathomimetics (agonists): salbutamol, salmeterol,
fometerol, rimeterol, bitolterol and terbutaline (non specific –
ephidrine, adrenaline and orciprenaline)
– Methylxanthines: theophylline and derivatives aminophylline etc.
– Anticholinergics: ipratropium bromide and tiotropium bromide
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, flunisolide etc.
2. Anti-IgE antibody: omalizumab

15. β-2 agonists – Recall
• All adrenergic drugs act via alpha/beta receptors
– Mainly, alpha -1 & 2 and Beta -1 & 2 (α1, α2 , ß1 and ß2)
• Type β1:
– These are present in heart tissue, JG cells - 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
• All β receptors activate adenylate cyclase, raising the
intracellular cAMP concentration

16. Results of β-2 activation
AND
Tocolytic

17. ß2-sympathomimetics (agonists) -
salbutamol and terbutaline etc.
1. Adrenergic drugs are mainstay in the treatment
of Bronchial asthma
• Bronchodilatation via beta-2 stimulation – increased
cAMP production
• Increased cAMP in mast cells – decreased mediator
release
1. Adrenaline and Isoprenaline – not used
frequently – WHY ? - (beta -1 receptor)
2. ß2-sympathomimetics are fastest acting
bronchodilators when inhaled (5 minutes) –
lasts 2 to 4 Hrs – hypertensives, digitalis & IHD

18. Clinical benefits of Beta-2
stimulation
• Bronchodilatation without tachycardia (beta-1)
• Inhibition of release of chemical mediators by
stabilization of mast cell membrane (beta
receptors)
• Prevention of mucosal edema (vessels)
• Increased ventilatory response to
chemoreceptor stimuli (better exchange)
• Restoration of mucocilliary transport mechanism
in respiratory tract (result of reduction in
secretion)

19. ß2-sympathomimetics - MOA
MOA:
 Stimulation of β2 receptor in
bronchial smooth muscle cell
membrane activation of
adenyl cyclase →cAMP
→Ca2+↓ →SM relaxation
Drawbacks:
• To abort or terminate attacks
only
• Not suitable for round-the
clock prophylaxis – does not
reduce bronchial
hyperactivity - worsens
• Down regulation of beta-2
receptors

20. Results of β2 stimulation

21. Salbutamol
• Pharmacokinetics:
– Undergoes metabolism in gut wall
– Bioavailability is 50%
– Duration of action: 4-6 Hrs
• Salbutamol: preparation and doses
– Available as 2, 4 and 8 mg tablets – reserved for patients who cannot
correctly use inhalers
– Syr. as 2 mg/5 ml
– As metered dose inhaler – 100 μg – Preferred route
– 200 μg as rotacaps
• Adverse effects:
– Muscle tremor, restlessness, palpitation and nervousness
– Vasodilatation – reduction in mean arterial pressure with tachycardia
and also exacerbate pulmonary hypoxia due to mismatched of
ventilation and perfusion
– Hyperglycaemia and hyperlacticacidemia
– Worsening of asthma on prolong inhalation

22. Salmeterol
• 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 –
maintenance therapy – twice daily
• Usually combined with steroids
• Bambuterol: Prodrug of terbutalin – hydrolysed in
plasma by pseudocholinesterase to release active
product – long acting – used in chronic bronchial asthma
• Formeterol: Long acting and lasts for 12 Hrs

23. Metylxanthines
• 3 Naturally occurring methylxanthines – caffeine,
theophylline and theobromine
• Theophylline and its derivatives are used in asthma – 3rd
line --- in COPD
• Chemically, they are purine structure and close to
adenine and uric acid
• Sources:
– Thea sinensis: Caffeine (50 mg) & Theophylline (1 mg)
– Coffea arabica: Caffeine (75 mg)
– Theobroma cacao: Theobromine (200 mg) and caffeine (4mg)
– Cola acuminata: caffeine (30 mg)

24. Metylxanthines - structures

25. Metylxanthines – Pharmacological
actions
• CNS:
– Stimulation: improves performance, sense of well being and allays
fatigue – thinking become clearer (caffeine:150-200 mg)
– Higher doses – nervousness, insomnia and restlessness
– High doses – tremor, convulsion
• CVS:
– Stimulation of heart – increase in heart rate, cardiac output
• Vagal stimulation – TOTAL VARIABLE EFFECTS
– Tachycardia – Theophylline, Caffeine – bradycardia
– Cardiac output and Cardiac workload - increase
– Higher doses – cardiac arrhythmia (above 9 cups); moderate drinking -
beneficial
– Dilatation of blood vessels including coronary – reduced
peripheral resistance
– But, constriction of cerebral vessels – migraine use

26. … contd.
• BP:
– Direct cardiac action – increased BP
– Vagal action & vasodilatation – decreased BP
– Overall: Rise in SBP and decrease in DBP
• Kidney: mild diuretic (decrease in tubular reabsorption of Na+ and
also increase in renal blood flow)
• Stomach: increase in acid-pepsin secretion – even parenteral dose
– gastric irritant
• Smooth muscles: relaxed (theo – more potent) – all SM;
bronchodilatation in asthmatics
– Slow and sustained bronchodilatation
– Biliary spasm relieved but no effect on intestine and urinary tract
• Metabolic: Increase in BMR – plasma fatty acid level raised -
release of endogenous catecholamines

27. Theophylline action - contd.
• Skeletal muscles:
– Caffeine increases contractile power
– High doses – direct release of Ca++ from
sercoplasmic reticulum
– Facilitates NM transmission by increasing Ach
release
– Decreased fatigue by CNS action – relieves
fatigue and increased muscular work
– Enhanced diaphragmatic contraction

28. 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
PDE

29. Bronchodilation is promoted by cAMP. Intracellular levels of cAMP can be increased
by - adrenoceptor agonists, which increase the rate of its synthesis by adenylyl
cyclase (AC); or by phosphodiesterase (PDE) inhibitors such as theophylline, which
slow the rate of its degradation. Bronchoconstriction can be inhibited by muscarinic
antagonists and possibly by adenosine antagonists.

30. Metylxanthines – contd.
• Kinetics:
– Absorbed orally, crosses placenta and secreted in milk
– Protein bound, metabolized in liver - demethylation and oxidation
– T1/2 is 6-12 Hrs, but faster in children: 3-5 Hrs, and slow in
elderly & prematures; highly plasma protein bound
– Saturation of metabolizing enzymes – On prolonged and high
dose – elimination is zero order from first order
• 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
convulsion and shock death
– Nausea and vomiting – common

31. Methylxanthines - Preparation and
Dosage
• Interindividual variation in plasma concentration
• Rapid IV injection: Precordial pain, syncope and sudden death
• Theophylline: (Unicontin/Theolong)
– Poorly water soluble and cannot be injected
– Available as tablets 100/200 mg SR
• Aminophylline: 85% Theophylline
– 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

32. Signal transduction pathway for
Bronchodilatation

33. Anticholinergics –
Ipratropium bromide and
tiatropium bromide
• Distinct muscarinic receptors exist within the airways are M1and M3
receptors
• M1 – present in peribronchial ganglion cells where the preganglionic
nerves transmit to the postganglionic nerves
• M3 are present on smooth muscle larger airways
• Muscarinic receptor activation of these M3 receptors
intracellular cAMP levels contraction of airway
smooth muscle bronchoconstriction
• Postganglionic fibers supply the smooth muscle and submucosal
glands of the airways as well as the vascular structures
• Motor nerves derived from the vagus form ganglia predominate in
the large and medium-sized airways
• Atropinic drugs block these cholinergic innervations and
brings about bronchodilatation

34. Anticholinergics –
contd.
• Less efficacious than sympathomimetics
• COPD, asthmatic bronchitis, psychogenic
asthma – respond better
• Drug of choice in COPD
• Slower response – for prophylaxis (2-4 puffs 6
hrly)
• IB + sympathomimetics = marked longer lasting
bronchodilatation
• Nebulized IB and Salbutamol – refractory
asthma

35. Action of Bronchodilators
Selective β2 agonist
ATP
cAMP
Theophyline
5’-AMP
Relaxation
Ach
Ipratopium
Vagus nerve

36. Cromolyn sodium/Sodium
cromoglycate
• Synthetic compound and chemically benzopyrone
• Stabilizes mast cells – inhibits degranulation of mast cells and other
inflammatory cells
• Mediator release is restricted
• Also prevent chemotaxis of eosinophils and neutrophils – local
inflammation is prevented
• Basis of action may be due to delayed Cl- channel in the
membranes
• Long term use prevents hyperactivity of bronchial tree
• No bronchodilatation or antagonism of constriction – no action on
acute cases
• Not absorbed orally, given via MDI – 1 mg/dose – 2 puffs 4 times
daily
• Uses: Prophylaxis of asthma, allergic rhinitis and allergic
conjunctivitis (2%)

37. Leukotriene Antagonists
Montelucast and zafirlucast:
• Cysteinyl leukotrienes LT-C4, LT-D4 and LTE4 are important
mediators of human asthma - Competitive antagonist of cysLT1
• Benefits – bronchodilatation, reduced eosinophil count,
decreased vascular permeability 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
• Half life: montelucast (3-6 hrs), zafirlucast (8-12 Hrs)
• Uses: Mild to moderate asthma as alternative to steroids – need
of steroid is reduced and rescue with beta-2 reduced
– Not suitable for termination of attack – useful in NSAID induced asthma
• Safe drug, effective orally – only headache and rashes

38. Zileuton and Ketotifen
• Zileuton: 5- LOX inhibitor, blocks LT-C4, LT-D4 and LTB4
synthesis – prevents all LT induced responses
– Efficacy is similar to montelucast
– Short duration of action and hepatotoxic
• Ketotifen: H1 antihistaminic having Chromone like
actions
– Inhibits mediator release (mast cells, macrophages, eosinophils,
lymphocytes and eosinophils)
– Not bronchodilator – only sedation
– 6-12 weeks therapy benefits 50% of patiens
– Low improvement of lung function
– Also used in atopic dermatitis, perennial rhinitis, conjunctivitis,
urticaria and food allergy etc. – orally effective

39. Corticosteroids
• 2 types - Glucocorticoids and Mineralocorticoids
• Glucocorticoids –
– In general: Suppress inflammatory responses to all noxious
stimuli: Pathogens, chemical, physical and immune mediated
stimuli, hypersensitivity
– Antiinflammatory action – reduction in mediators IL, TNF and
PAF etc. and reduction in exudate formation
• Bronchial asthma is an inflammatory disease
– Not Bronchodilator but - Reduce bronchial hyperactivity,
mucosal oedema and suppress AG:AB reaction or other trigger
stimuli
– Reduction in cardinal signs of inflammation
– Complete and sustained symptomatic relief than bronchodilators
and chromones – improves airflow, reduce exacerbations and
may retard airway remodeling and disease progression
• Steroids act best in asthma than any other group of drugs - inhaled
• But ??? remember – Adverse Effects of Prolonged therapy

40. Systemic corticosteroid therapy
• Steroids are used as – inhaled, systemic
(oral/parenteral)
• 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

41. Corticosteroids – contd.
• Inhalation steroids – beclomethasone dipropionate, budesonide,
fluticasone propionate and triamcinolone acetonide
• Inhalation: high topical and low systemic activity
– Due to poor absorption and marked 1st
pass metabolism
– Can be step one for all asthma cases – inflammation starts even in early
cases
– However, not used for mild and episodic asthma
– Indicated when beta-2 agonists are required daily or disease not only
episodic
– Low dose starting 100 to 200 mcg BD – 3-5 days with max 400 qid
– Suppress inflammation and prevents episodes of asthma – beta-2
agonist requirement lessens
– No Role in acute attack
– Peak effects starts after 4-7 days
• To whom inhalation steroids can be given ?
– Fresh patients as well as to those who had already required oral steroids
– To be switched over from oral steroids – 1-2 weeks before tapering (precipitation
of asthma, muscular pain, depression, hypotension)

42. Corticosteroids – contd.
• COPD: high doses are required
• Hoarseness of voice, soar throat, dysphonia and
Oropharyngeal candidiasis
• Minimized by use of spacer and gurgling
• Side effects: Hoarseness of voice, dysphonia,
sore throat, oropharyngeal candidiasis
– Minimized by using spacers, gargling after the
use
– Topical Nystatin and clotrimazole
• Systemic effects: Mood changes, osteoporosis,
growth retardation, bruisig, petechiae, pituitary-
adrenal- suppression etc.

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

44. Treatment - asthma
• Seasonal: Chromones or low dose steroids (200-400 mcg/day) –
plus beta-2 agonists if required
• Step I: 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 episodic asthma)
• Step II: (Symptoms once daily or so) Regular inhalation of low-dose
steroids. Alternatively, cromoglycates. Beta-2 agonist as and
whenever required (Mild chronic asthma)
• Step III: (Attack more than once a day) 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
(Moderate asthma with frequent exacerbations) - spacers
• Step IV: Higher dose of steroid (800 to 2000 mcg) + regular beta-2
agonist twice daily (long acting salmeterol)
Additional treatment with oral drugs – LT antagonist or SR
theophylline or oral beat-2 agonist (Severe asthma)
• Step V: Not controlled adequately – needing emergency care
frequently – Oral Steroid therapy

45. Status asthmaticus
• May be 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) intermittent inhalations with
oxygen and nebulization
• 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
sodibicarb if required

46. Aerosols
• Solid and liquid dispersed particles of 1 to 5
micron in size suspended in gas
• Do not coalesce and do not sink
• Aim – to deliver to the alveoli without settling in
bigger tubes
– Particles > 10 micron are deposited primarily in the
mouth & oropharynx.
– Particles < 0.5 micron are inhaled to the alveoli and
exhaled without being deposited in the lungs.
• Aerosols are produced
– In solution: MDI, nebulizers
– Dry powder: Rotahaler and spinhaler etc.

48. Devices - Definition
• A metered-dose inhaler (MDI) is a device that
delivers a specific amount of medication to the
lungs, in the form of a short burst of aerosolized
medicine that is inhaled by the patient. ...
• A Spinhaler/Rotahaler is a device used to
deliver fine dry powered medications that are
measured out in Rotacap capsules
• An asthma Spacer is an add-on device used to
increase the ease of administering aerosolized
medication from a "metered-dose inhaler" (MDI)

49. Questions ???
• SAQs:
– Bronchodilators
– Pharmacotherapy (management) of status
asthmaticus
– Mechanism of action and Adverse effects of –
Theophylline
– Role of Salbutamol/Salmeterol in broncial asthma
• Short Questions on:
– Salbutamol, Salmeterol, Sodium chromoglycate,
leukotriene antagonists and Ipratropium bromide

50. Thank You