Asthma treatments Flashcards by Louise Cave

Types of asthma

Acute or chronic
Chronic
recurrent attacks of reversible airway obstruction of air flow
controlled with drugs
Acute severe asthma (status asthmaticus)
not easily reversed with drugs
can be fatal

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Features of asthma

Characterised by 
inflammation in the airways
hyper-reactivity of bronchioles
   e.g. to
irritant chemicals
cold air
stimulant drugs
Results in
bronchoconstriction 
mucus secretion

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Aim of drug treatment

to reduce inflammation, prevent bronchoconstriction and restore airways calibre to normal

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Stimuli that trigger an attack

exercise (cold air), respiratory infection, atmospheric pollutants 
intrinsic trigger (non-atopic)
allergens in sensitised people
pollen 
dust mite proteins 
animal dander
allergic trigger (atopic)

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Development of asthma

When allergen first presents, B cells are activated (via T cell cascade) to make IgE, which recognises the antigen. Mast cells express a high-affinity receptor (FcεRI) for the Fc region of IgE. Very high affinity binding means that IgE is irreversibly bound, effectively coating the surface of Mast cells. Presentation of antigen to these Mast cells results in crosslinking of 2 IgE receptors, leading to degranulation.

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Immediate/ early phase of attack

Bronchospasm: bronchial muscle contracts
mast cells release spasmogens
histamine
leukotrienes (LTC4 and LTD4)
prostaglandin D2 
Mast cells release inflammatory mediators
interleukins (IL-4, IL-5, IL-13)
macrophage inflammatory protein-1a
tumour necrosis factor-a (TNF-a)
chemotaxins &amp; chemokines attract leukocytes to area
sets stage for late phase

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IgE

Immunoglobulin E (IgE) is a type of antibody that is present in minute amounts in the body but plays a major role in allergic diseases. IgE binds to allergens and triggers the release of substances from mast cells that can cause inflammation. When IgE binds to mast cells, a cascade of allergic reaction can begin.

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Late phase

Progressing inflammatory reaction
Th2 lymphocytes & eosinophils invade
Release cytokines, chemokine & toxic proteins

Agents from inflammatory cells cause
Damage to & loss of bronchial epithelium
smooth muscle cell hypertrophy & hyperplasia
hyper-reactivity to irritant stimuli

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Bronchodilators

Dilate bronchioles and increase air flow to alveoli

Relax smooth muscle cells around walls of bronchioles

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Types of bronchodilator

beta2 adrenergic receptor agonists
theophylline
muscarinic receptor antagonists
leukotriene receptor antagonists

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beta2 adrenergic receptor agonists

Direct action on beta2 adrenoceptors on bronchiole smooth muscle to relax muscle

Also
inhibit mediator release from mast cells & monocytes
may act on cilia to increase mucus clearance

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beta2 adrenergic receptor agonists - short acting

Short acting
salbutamol, terbutaline
Max effect within 30 min, last 4-6 hours
Used “as needed” to control symptoms

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beta2 adrenergic receptor agonists - longer acting

Longer acting
salmeterol
duration of action 12 hours
twice daily dose in patients not controlled with glucocorticoids

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Administration of beta2 agonists

By inhalation
to target action in lung
& minimise systemic effects

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Unwanted effects of beta2 agonists

result from absorption into systemic circulation
most common is tremor
some tolerance to beta2 agonists may develop - prevented by glucocorticoid

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Theophylline

xanthine (constituent of coffee & tea)
mechanism still unclear
Phosphodiesterase (PDE) inhibitor

PDE

Phosphodiesterase

Theophylline uses

second line drug (sustained-release tablet)
used with steroid when asthma response to beta2 agonist inadequate
given i.v. in acute severe asthma

Theophylline unwanted effects

Unwanted effects
CNS: stimulant (tremor, sleep disturbance)
Cardiovascular (stimulate heart, vasodilation)
GI tract (anorexia, nausea, vomiting)

Muscarinic receptor antagonists

main drug used – ipratropium
adjunct to beta2 agonists and steroid when these are insufficient
max effect in 30 min, lasts 3-5 hours
given by aerosol inhalation
poorly absorbed into systemic circulation
Few unwanted effects
Safe, well tolerated

Actions of muscarinic antagonists

relax bronchial smooth muscle
bronchodilation
inhibit elevated mucus secretion in asthma
may increase clearance of bronchial secretions

same mechanism for each effect
block action of endogenous acetylcholine at muscarinic receptors

Muscarinic system in airways

Low levels of Ach released from cholinergic nerves in airways
few muscarinic receptors activated
smooth muscle relaxed
airways open

Muscarinic system in asthma

Evidence for increased Ach release
Muscarinic receptors activated
Smooth muscle contracted
Narrowed airways

Leukotriene receptor antagonists

Examples
Montelucast (1x daily)
Zafirlukast (2x daily)
given orally
prevent exercise-induced and aspirin sensitive asthma
action additive with beta2 agonists
main use as add on for uncontrolled, mild-moderate asthma

Actions of leukotriene antagonists

``` act at cysteinyl-leukotriene receptors on bronchiole smooth muscle cells prevent actions of LTC4, LTD4, which are bronchial spasmogens stimulate mucus secretion ``` Unwanted actions – few Headache, GI disturbance

Anti-inflamatory drugs

``` glucocorticoids are main drugs beclometasone diproprionate budesonide fluticasone propionate occassionally prednisolone or hydrocortisone usually given by inhalation -metered dose inhaler -localises effect in lung full effect takes several days to develop ```

Actions of glucocorticoids

reduce production of cytokines spasmogens (LTC4, LTD4) leucocyte chemotaxins (LTB4, PAF) therefore reduce bronchospasm recruitment & activation of inflammatory cells

Mechanism of glucocorticoid action

Enter cells bind to intracellular receptors in cytoplasm GRalpha, GRbeta receptor complex moves to nucleus binds to DNA in nucleus alters gene transcription e.g. induction of lipocortin, repression of IL-3

Clinical use of glucocorticoids

for patients requiring regular bronchodilators to control attacks give inhaled steroid, with additional agent for severe asthma e.g. budesonide + b2 agonist or theophylline i.v. hydrocortisone + oral prednisolone for acute exacerbations short course oral prednisolone if deterioration prolonged oral predisolone needed for a few patients

Unwanted effects of glucocorticoids

``` Adverse effects uncommon with inhaled steroids oropharyngeal thrush & dysphonia minimised by using “spacer” devices reduce oropharyngeal drug deposition increase airways drug deposition Oral/ regular large doses – serious effects e.g. adrenal suppression patients carry ‘steroid card’ ```

Cromoglicate

``` Related drug - nedocromil sodium Can reduce both early and late phase responses Reduce bronchial hyper-reactivity Effective in asthma caused by antigen, exercise, irritants Not all asthmatics respond unpredictable children respond better than adults ```

Cromoglicate mechanisms

Not fully understood Mast cell stabiliser (but not main action) may reduce neuronal reflexes (desensitise to irritants) inhibit release of T-cell cytokines affect inflammatory cells and mediators Unwanted effects – few irritation of upper respiratory tract hypersensitivity reactions reported, but rare

Clinical use of cromoglicate

``` Given by inhalation by aerosol, nebulised solution or powder Prophylactic use to prevent both phases of attack most effective in children effects may take weeks to develop ```

Biologic agents

A new development omalizumab (Xolair) recombinant DNA-derived humanized IgG1 monoclonal antibody sub cutaneous injection every 2-3 weeks absorbed slowly peak plasma concentration in 7-8 days

Omalizumab mechanism

binds to human IgE inhibits binding of IgE to IgE receptor (Fc RI) on the surface of mast cells and basophils inhibits IgE-mediated cascade of asthma

Unwanted effects of omalizumab

Few, but can be severe anaphylaxis – allergic reaction to protein malignancies (slightly higher rate than normal)

Treatment of chronic asthma

``` Mild asthmatic with rare attacks Inhaled beta2 agonist when required Mild asthma with more frequent attacks glucocorticoid for prophylaxis beta2 agonist when needed for acute attack Moderate to severe asthma drug combination preferred, usually beta2 agonist with glucocorticoid in combined inhaler Other drugs added when this approach fails to control attacks ```