These slides describe pharmacology of drugs used for treatment of asthma

1. Pharmacology of drugs affecting
the respiratory system
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2. Pharmacotherapy of Asthma
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3. Introduction
• Asthma is a chronic inflammatory condition of the
lung airways characterized by recurrent bouts of
shortness of breath, chest tightness, and wheezing,
often associated with coughing
• The chronic inflammation heightens the “twitchiness”
of the airways (airways hyperresponsiveness (AHR))
to provocative exposures
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4. Introduction …cont
• The reasons for the manifestations of asthma are;
– Widespread, reversible narrowing of the bronchial airways
and a marked increase in bronchial responsiveness to
inhaled stimuli;
– Lymphocytic, eosinophilic inflammation of the bronchial
mucosa
– Remodeling of the bronchial mucosa, with thickening of the
lamina reticularis beneath the airway epithelium and
hyperplasia of the cells of all structural elements of the
airway wall—vessels, smooth muscle, and secretory glands
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5. Pathogenesis of Asthma
• The classic immunologic model of asthma presents asthma as a
disease mediated by reaginic immuno globulin (IgE)
• Exposure to allergens ( e.g proteins from house dust mite,
cockroach, animal danders, molds, and pollens)causes synthesis
of IgE which binds to mast cells in the airway mucosa
– On reexposure to allergen, antigen-antibody interaction on
mast cell surfaces triggers release of mediators of anaphylaxis
like histamine, tryptase, prostaglandin D2 , leukotriene C4 ,
and platelet-activating factor (PAF)
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6. Pathogenesis…cont
• Reexposure to allergen also causes the synthesis and release of a
variety of cytokines: interleukins 4 and 5, granulocyte-
macrophage colony-stimulating factor (GM-CSF), tumor necrosis
factor (TNF), and tissue growth factor (TGF) from T cells and
mast cells
– These agents provoke contraction of airway smooth muscle,
causing the immediate fall in forced expiratory volume
(FEV1)
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7. Pathogenesis…cont
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8. Treatment of Asthma
• Optimal medical treatment of asthma includes the following key
components:
– Environmental control,
– Pharmacologic therapy, and
– Patient education including attainment of self-management skills
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9. Pharmacologic therapy
• Asthma medications can be divided into long-term control
medications and quick-relief medications
• The following are drug classes used for asthma treatment
– Sympathomimetic agents
– Methylxanthines (Theophylline)
– Anticholinergic Agents
– Corticosteroids
– Leukotriene Modifiers
– Miscellanous drugs
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10. Sympathomimetic Agents
• The adrenoceptor agonists relax airway smooth muscle,
inhibit release of bronchoconstricting mediators from
mast cells and may also inhibit microvascular leakage
and increase mucociliary transport by increasing ciliary
activity
• The β agonists stimulate adenylyl cyclase and increase the
formation of intracellular cAMP their by resulting
relaxation of airway smooth muscle
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11. Sympathomimetic Agents …cont
• Widely used drugs in asthma include epinephrine,
ephedrine, isoproterenol, and albuterol and other β2 -
selective agents
• Are best delivered by aerosol because this results in the
greatest local effect on airway smooth muscle with the
least systemic toxicity
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12. Bronchodilation is promoted by cAMP
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13. Epinephrine
• Is an effective rapidly acting bronchodilator when injected SC
or inhaled as a microaerosol from a pressurized canister
• Maximal bronchodilation is achieved 15 minutes after
inhalation and lasts 60–90 minutes
• Is non selective to different adrenoceptors
– Tachycardia, arrhythmias, and worsening of angina are
troublesome ADRs.
• As a result its use in asthma has been displaced by other more β2 -
selective agents mainly because of its CVS effects
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14. Ephedrine
• Has a longer duration, oral activity, more pronounced central
effects, and much lower potency in comparison to epinephrine
• Because of the development of more efficacious and β2 -
selective agonists, ephedrine is now used infrequently in
treating asthma
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15. Isoproterenol
• Is a potent bronchodilator when inhaled as a microaerosol
from a pressurized canister
• It causes maximal bronchodilation within 5 minutes
• It has a 60 to 90 minute duration of action
• High doses of inhaled isoproterenol attributed to cardiac
arrhythmias
• It is now rarely used for asthma
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16. β2 -Selective Drugs
• Drugs include: albuterol, terbutaline, metaproterenol,
pirbuterol, formoterol, salmeterol, and others
• Are the most widely used sympathomimetics for the
treatment of the bronchoconstriction of asthma
• They are effective after inhaled or oral administration and
have a long duration of action
• Used for rapid relief and long term management of
asthma
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17. Sympathomimetic Agents… ADR
• The use of sympathomimetic agents raised fears about possible
cardiac arrhythmias and about hypoxemia
• Tremor
• Hypokalaemia
• Tachycardia
• All ADRs are generally worse with oral use
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18. Methylxanthine Drugs
• The three important methylxanthines are theophylline,
theobromine, and caffeine
• Use of theophylline has reduced as the greater
effectiveness of inhaled adrenoceptor agents for acute
asthma and of inhaled antiinflammatory agents for
chronic asthma has been established
• Still used in certain areas because of its very low cost
• A theophylline derivative commonly used for asthma is
aminophylline 18

19. Methylxanthine Drugs…cont
• MOA: Several mechanisms have been proposed for the
actions of methylxanthines
– Inhibition of phosphodiesterase enzyme leading to
accumulation of cyclic nucleotides
– Competitive antagonism to adinosine receptors
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20. Methylxanthine drugs…ADR
• Sudden death - if there is rapid intravenous administration
• Headache, palpitation, dizziness, nausea, hypotension,
precordial pain
• Tachycardia, severe restlessness, agitation, emesis
• Focal & generalized seizures
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21. Antimuscarinic Agents
• Competitively inhibits effect of acetylcholine at muscarinic
receptors (M3)
– Block contraction of airway smooth muscle and the increase in
secretion of mucus that occurs in response to vagal activity
• When given IV atropine causes bronchodilation at a lower dose
than that needed to cause an increase in heart rate
• The selectivity of atropine’s effect can be increased further by
administering the drug by inhalation or by use of a more selective
quaternary ammonium derivative of atropine
– Ipratropium bromide and its structural analogue Tiotropium
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22. Corticosteroids
• Effective in inhibiting airway inflammation
• Improve all indices of asthma like severity of symptoms, tests
of airway caliber, bronchial reactivity, frequency of exacerbation
and quality of life
• Inhibit airway inflammation by;
– Modulation of cytokine & chemokine production,
– Decreasing eicosanoid synthesis,
– Decreasing accumulation of basophils, eosinophils & other
leukocytes in lung tissue,
– Decreasing vascular permeability 22

23. Arachidonic acid
Phospholipase A2
Corticosteroids ⊕
Bradykinin
Angiotensin
Cyclooxygenase (COX)
PGG2
Prostacyclin(PGI2)
PGE2
PGF2α
Thromboxane A2
Dipyridamole
hydroperoxidase
NSAIDs
Leukotrienes
5-lipoxygenase
Phospholipid
PGH2
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24. Anti-inflammatory actions of
corticosteroids
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25. Corticosteroids…cont
Preparations:
a. Oral: e.g. prednisone
b. IV: e.g. methylprednisolone
c. Aerosol: e.g. beclomethasone, budesonide, ciclesonide, flunisolide,
fluticasone, mometasone, and triamcinolone
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26. Corticosteroids…cont
• Because of severe ADRs when given chronically, oral and
parenteral corticosteroids are reserved for patients who require
urgent treatment
– Those who have not improved adequately with bronchodilators
or who experience worsening symptoms despite maintenance
therapy
• Regular or “controller” therapy is maintained with aerosol
corticosteroids.
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27. Corticosteroids…ADR
• The main problem caused by inhaled topical corticosteroids is the
occurrence of oropharyngeal candidiasis
– The risk of this complication can be reduced by having patients
gargle water and spit after each inhaled treatment
• Hoarseness can also result from a direct local effect of inhaled
corticosteroids on the vocal cords.
• Inhalational agents are remarkably free of other short-term
complications in adults but may increase the risks of osteoporosis
and cataracts over the long term
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28. Corticosteroids…ADR cont
• In children, inhaled corticosteroid therapy has been shown
to slow the rate of growth by about 1 cm over the first
year of treatment, but not the rate of growth thereafter, so
that the effect on adult height is minimal
• Other undesired effects of corticosteroids include mood
disturbances,  appetite, hypertension, peptic ulcer &
impaired glucose control in diabetics
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29. Leukotriene Pathway Inhibitors
• Block the action of leukotrienes;
– By inhibition of 5-lipoxygenase, thereby preventing leukotriene
synthesis (zaleuton) or
– By inhibition of the binding of leukotriene C4, D4, E4 to its
receptor on target tissues, thereby preventing its action
(zafirlukast, montelukast )
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30. Leukotriene Pathway Inhibitors
• Have demonstrated an important role in aspirin-induced asthma
• Their effect on symptoms, airway caliber, bronchial reactivity and
airway inflammation are less marked than the effects of inhaled
corticosteroids, but they are almost equally effective in reducing
the frequency of exacerbations
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31. Leukotriene Pathway Inhibitors…ADR
• Dyspepsia is the most common side effect of zileuton
• Zileuton inhibits the metabolism of theophylline leading to toxicity
of the latter if used together
• Zileuton is contraindicated in patients with acute liver disease and
should be used with caution in patients who consume substantial
quantities of alcohol or have a history of liver disease
• Zafirlukast and montelukast are well tolerated
– In rare cases, treatment of patients with these drugs is associated
with the development of Churg-Strauss syndrome, a condition
marked by acute vasculitis, eosinophilia, and a worsening of 31

32. Cromolyn Sodium & Nedocromil
Mechanism of action
• The precise MOA for their anti-asthmatic activities is
unknown
• Are thought to alter the function of delayed chloride
channels in the cell membranes inhibiting cell activation
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33. Cromolyn Sodium & Nedocromil…cont
• Were once widely used for asthma management, especially in
children, but have now been supplanted by other therapies
• These drugs have no effect on airway smooth muscle tone and are
ineffective in reversing asthmatic bronchospasm
– They are only of value when taken prophylactic ally
ADR: throat irritation, mouth dryness, reversible dermatitis,
myositis, bad taste, pulmonary infiltration with eosinophils and
anaphylaxis
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34. Thank you
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