Asthma therapeutics Flashcards
Extrinsic
Allergic
Intrinsic
Non-allergic
Triggers for asthma
Pets Exercise Pollen Bugs Chemicals Cold air Fungus Dust Smoke Odours Pollution
What antibody mediates asthma?
IgE
How does IgE provide longer protection?
First formed in response to allergen
First exposure = sensitisation
Re-exposure = allergen binds to IgE on mast cell
What happens when allergen binds to IgE on mast cell?
Calcium channels open = degranulation = histamines/prostaglandins
Why is asthma bad?
Smooth muscle spasms and narrows airway
Lining of the lung is inflamed
Mucus production increased
Early phase of asthma attack
Allergen
Mast cells
Spasmogens (bronchospasm) or chemotaxis and chemokine
Late phase of asthma attack
Chemotaxis and chemokines
Infiltration of TH2 cells
Activates inflammatory cells by cysts or EMBP/ECP
cystLTs cause airway inflammation, bronchospasm and wheezing
EMBP causes damage to epithelial cells = hyper-sensitive airways
Symptoms of asthma
Coughing, wheezing, shortness of breath, thight chest
Asthma symptoms on spirograph
Obstructive disease = increased resistance = air can’t escape lungs
FVC doesn’t change but FEV1 is reduced
Moderate asthma
SpO2 >92%
Speech normal
respiration <25/min
Pulse <110
Acute severe asthma
SpO2 >92%
Can’t complete sentences
Respiration >25
Pulse >110
Life-threatening asthma
SpO2 <92%
Silent chest, cyanosis or poor respiratory effort
Arrythmia or hypotension
Exhaustion, altered conscious
Treatment/monitoring of asthma
- Minimise/eliminate symptoms
- Maximum lung function
- Prevent exacerbations
- Minimise medication
- Minimise adverse effects
- Promote adherence
Asthma relievers
B2 agonists/ antimuscarinics/ methylxanthines
Asthma preventers
Corticosteroids, leukotrienes, receptor antagonists, croons
B2 agonists
Salbutamol/terbutaline
Stimulates B2 receptors on airway smooth muscle
Can cause tremor, tension, headache, tachycardia
Action of B2 agonists
Vascular tone mediated by parasympathetic action (ACh)
Via G-alpha-q
Salbutamol activates G-protein coupled receptor
G-alpha-S receptor means that AC makes cAMP from ATP
cAMP inhibits MLCK = relaxation
PDE breaks down cAMP
Methylxanthines
Theophylline
Inhibits phosphodiesterase
- Additive effect when used in conjunction with small doses of B2 agonists
- Given orally or by very slow IV infusion
- Hepatically metabolised (principally CYP1A2)
- Narrow therapeutic range
- Adverse effects: nausea, headaches, insomnia, abdominal discomfort, toxic effects in high amounts
Antimuscarinics
- Block muscarinic receptors
- E.g. ipratropium
- Administered by inhalation - maximal effect 30-60 mins after use but can act 3-6 hours
- Adverse effects: dry mouth, constipation, diarrhoea, cough, headache
- Caution needed in prostatic hyperplasia, bladder outflow obstruction, angle-closure glaucoma
Corticosteroids
- Reduce bronchial inflammatory reactions (e.g. oedema and mucous hypersecretion)
- E.g. beclametasone, budesonide, fluticasone
- Metered inhalation
- Must be used regularly for maximum benefit
- Fewer systemic effects but can cause hoarse voice, reflex cough (use spacer to relieve) and oral candidiasis
- Oral therapy (prednisolene)for acute/chronic attacks, associated with many serous adverse effects, taken as single dose in morning
- Hydrocortisone iv injection in emergency treatment of severe acute asthma
Leukotriene-receptor antagonists
- E.g. montelukast, zafirlukast
- Block effects of cysteinyl leukotrienes in airways
- Effective in reduced late phase response
- Effective alone or with inhaled corticosteroid
- Well tolerated
Cromones
Mechanism unclear Thought to stabilise mast cells Sodium cromoglicate, nedocromil sodium Phophylatic drug (no value for acute attacks)
Long B2 agonists
Salmeterol, formoterol
Use with regularly inhaled corticosteroid
Long term control of chronic asthma
Monoclonal antibodies
E.g. omalizumab
Selectively binds to IgE to form complex
Other MABs target inflammatory mediators
Well controlled asthma
- No daytime symptoms
- No night-time awakening due to asthma
- No need for rescue medication
- No limitations on activity, including exercise
- Normal lung function with minimal side effects
