Asthma treatments Flashcards
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
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
Aim of drug treatment
to reduce inflammation, prevent bronchoconstriction and restore airways calibre to normal
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)
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.
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 & chemokines attract leukocytes to area sets stage for late phase
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.
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
Bronchodilators
Dilate bronchioles and increase air flow to alveoli
Relax smooth muscle cells around walls of bronchioles
Types of bronchodilator
beta2 adrenergic receptor agonists
theophylline
muscarinic receptor antagonists
leukotriene receptor antagonists
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
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
beta2 adrenergic receptor agonists - longer acting
Longer acting
salmeterol
duration of action 12 hours
twice daily dose in patients not controlled with glucocorticoids
Administration of beta2 agonists
By inhalation
to target action in lung
& minimise systemic effects
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
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
