Week 5 - Asthma Flashcards
What are the main first line drugs of asthma?
Glucocorticoids (steroids)
B2 adrenergic agonists
Where is the site of bronchodilator action?
Smooth muscle in the bronchiole walls
Name the types of bronchodilator
B2 adrenergic receptor agonists
Theophylline
Muscarinic receptor antagonists
Leukotriene receptor antagonists
What is the mechanism of action of B2 adrenergic receptor agonists?
Direct action on B2 adrenoreceptors on bronchiole smooth muscle to relax muscle
Also:
Inhibit mediator release from mast cells and monocytes
May act on cilia to increase mucus clearance
Name the shorter acting B2 adrenergic receptor agonists and what their duration of action is
Salbutamol
Terbutaline
- max effect within 30 mins
- lasts 4-6 hours
- used “as needed” to control symptoms
Name the longer acting B2 adrenergic receptor agonists and what their duration of action is
Salmeterol
- duration of action = 12 hours
- 2X daily in patients not controlled with glucocorticoids
How are B2 agonists administered and why?
Inhalation
- to target action in lung
- minimise systemic effects
What are the unwanted effects of B2 agonists?
- most common = tremor (activate B2 receptors in skeletal muscle)
- result from absorption in to systemic circulation
-some tolerance to them may be developed (receptors get desensitised) - prevent by use of a glucocorticoid
What is the mechanism of action of theophylline?
Phosphodiesterase (PDE) inhibitor
-mechanism still unclear
How is theophylline administered?
Orally (sustained release tablet)
IV in acute severe asthma (can’t inhale anything far enough)
When is theophylline used?
Second line drug
-used with steroid when asthma response to B2 agonist is inadequate
What are the side effects of theophylline?
- CNS - stimulant (tremor, sleep disturbance)
- CV (stimulates heart, vasodilation)
- GI tract (anorexia, N+V)
What are the actions of muscarinic antagonists?
Block action of endogenous acetylcholine at muscarinic receptors
- relax bronchial smooth muscle - bronchodilatoion
- inhibit elevated mucus secretion in asthma
- may increase clearance of bronchial secretions
What is the main muscarinic receptor antagonist used?
Ipratropium
When are muscarinic receptor antagonists used?
-adjunct to B2 agonists and steroid when these are insufficient
How are muscarinic receptor antagonists administered and what is their duration of action?
- aerosol inhalation
- max effect 30 mins, lasts 3-5 hours
- poorly absorbed in to systemic circulation
What are the side effects of muscarinic receptor antagonists?
Few unwanted effects - safe, well tolerated
What is the mechanism of action of leukotriene antagonists?
- act at cysteinyl-leukotriene receptors on bronchiole smooth muscle cells
- prevent actions of LTC4 and LTD4 which are bronchial spasmogens and stimulate mucus secretion
Name some leukotriene receptor antagonists
Montelukast (1X daily)
Zafirlukast (2X daily)
How are leukotriene receptor antagonists administered?
Orally
What are leukotriene receptor antagonists used for?
- prevent exercise induced and aspirin sensitive asthma
- action additive with B2 agonists
- main use as add on for uncontrolled, mild-moderate asthma
What does aspirin block in asthma?
The cyclooxygenase pathway
Therefore more leukotrienes are produced instead of prostaglandins because the pathway is sent to the right
What are the side effects of leukotriene antagonists?
Headache
GI disturbances
What is the mechanism of action of glucocorticoids?
- enter cells
- bind to intracellular receptors in cytoplasm - GRa and GRb
- receptor complex moves to nucleus
- binds to DNA in nucleus
- alters gene transcription (repression of IL-3)
What are the actions of glucocorticoids?
Reduce production of
- cytokines
- spasmogens (LTC4, LTD4)
- leukocyte chemotaxins (LTB4, PAF)
Therefore reduce:
- bronchospasm
- recruitment and activation of inflammatory cells
Name some glucocorticoids
Beclometasone diproprionate
Budesonide
Fluticasone propionate
Occasionally prednisolone or hydrocortisone
How are glucocorticoids administered and how long does it take for an effect to take place?
Usually given by inhalation (metered dose inhaler, localises effect in lung)
Full effect takes several days to develop
Which glucocorticoids are often given for acute exacerbations?
Hydrocortisone
Oral prednisolone
What are the side effects of glucocorticoids?
-uncommon with inhaled steroids
-oropharyngeal thrush and dysphonia
(Minimised using spacer)
- oral/regular large doses -serious effects
- e.g. Adrenal suppression - pts carry steroid card
What is the mechanism of action of cromoligate?
Not fully understood
-mast cell stabiliser (but not main action)
How is cromoligate administered?
Inhalation - aerosol, nebuliser solution or powder
Prophylactic use
- prevent both phases of attack
- most effective in children
- effects may take weeks to develop
What are the side effects of cromoligate?
- irritation of upper respiratory tract
- hypersensitivity reactions reported - rare
What is the drug related to cromoligate?
Nedocromil sodium
Who responds to chromoligate?
Not all asthmatics respond
- unpredictable
- children respond better than adults
What does cromoligate do?
- can reduce both early and late phase responses
- reduce bronchial hyper-reactivity
- effective in asthma caused by - antigen, exercise, irritants
What does lipocortin do?
Inhibitor of phospholipase A2
- lose production of leukotrienes
- reduced inflammation in tissue
What are biologic agents?
- new development
- recombinant DNA-derived humanised IgG1 monoclonal antibody
- binds to human IgE, inhibits binding of IgE to IgE receptor on the surface of mast cells and basophils
- inhibits IgE mediated cascade of asthma
Name a biologic agent
Omalizumab
How are biologic agents administered?
Sub cut injection every 2-3 weeks
- absorbed slowly
- peak plasma conc. in 7-8 days
What does the IgE antibody cause?
Inflammatory cell recruitment –> bronchoconstriction
What are the side effects of Omalizumab? (Biologic agent)
Few but can be severe
- anaphylaxis - allergic reaction to protein
- malignancies (slightly higher rate than normal)
What would be used to treat a mild asthmatic with rare attacks?
Inhaled B2 agonist when required
What would be used to treat a mild asthmatic with frequent attacks?
- glucocorticoid for prophylaxis
- B2 agonist when needed for acute attack
What would be used to treat moderate to severe asthma?
-drug combination preferred
- usually B2 agonist with glucocorticoid
- a combined inhaler
What are the aims of drug treatment in asthma?
- to reduce inflammation
- to prevent bronchoconstriction
- to restore airways calibre to normal
