Pharmacology of Asthma Flashcards
What perecentage of asthma deaths are thought to be preventable?
2/3
Every day how many people die from asthma?
3 people
What are the goals of asthma treatment?
- No daytime symptoms
- No night-time waking due to asthma
- No need for rescue medication
- No asthma attacks
- No limitations on activity including exercise
- Normal lung function FEV1 and/or PEF > 80% predicted or best
- Minimal side-effects from medication
What are the basic inhaler devices?
- MDI = Metered dose inhaler
- Breath-actuated
- Accuhaler - dry powder
- Via spacer/reservoir
What is the 5 step programme (up and down)?
- Intermittent reliever therapy
- Regular preventer therapy
- Initial add-on therapy
- Additional controller therapy
- Specialist therapy
What drugs are involved in step 1 therapy and how long do they work for?
- Salbutamol, terbutaline
- Short acting Beta2 agonist
- Fast-acting, lasts up to 5 hrs
- Used as required for breathlessness - rescue remedy / reliever
What are the side-effects of B2 agonists? (if given orally/I.V or high dose inhaled)
- Sympathomimetic effects (tachycardia, tremor, heaadache)
- Muscle pain/cramps
- Electrolyte disturbances (e.g hypokalaemia)
- Hyperglycaemia
- Paradoxical bronchospasm (v. rare)
What are the mechanisms of action of B2 agonists?
- Stimulate bronchial smooth muscle B2 receptors, relax muscles, dilate airwyas, reducing breathlessness
- Inhibit mediator release from mast cells and infiltrating leucocytes
- Increase ciliary action of airway epithelial cells - aids mucus clearance
What is involved in step 3 “initial add-on therapy”?
- Long acting B2 agonist (LABA)
- Salmeterol, Forrmoterol
- Given regularly (combined with inhaled steroid)
- Lasts longer (up to 12 hrs)
- Given to prevent bronchospasm (at night or during exercise) in patients requiring long-term therapy
What long acting B2 agonist is slower to act? salmeterol or formoterol
Salmeterol (formoterol can be used as a reliever therapy salmeterol cannot be)
When are step 2 drugs (inhaled corticosteroids) added?
- If has symptoms or using SABA more than 3 times per week
- If walking at night with wheeze
- If asthma attack in last 2 years
- Adherence vital
- Slower onset of action
- Longer term effects over months - reduction in airways responsiveness to allergens and irritants (including exercise)
Describe the inhaled corticosteroid mechanism of action
- They bind to glucocorticoid receptor, modify immune response
- Inhibit formation of cytokines (includes interleukins) produced by Th2
- Inhibit activation and recruitment to airways of inflammatory cells
- Inhibit generation of inflammatory prostaglandins and leukotrienes, thus reducing mucosal oedema
- Decrease mucosal inflammation, widen airway and reduces mucus secretion
Give some examples of inhaled corticosteroids which are used in asthma
- Beclometasone
- Budesonide
- Fluticasone
Give examples of corticosteroids which would be administered during an acute severe attack
- Oral route: prednisolone
- IV: hydrocortisone
What are the side-effects of corticosteroids?
- Oropharangeal candidiasis
- Dysphonia (hoarsness)
- Systemic (chronic high dose, inhaled and oral)
Osteoporosis
Adrenal insufficiency
Growth retardation
What are the drugs used in step 4 “Additional controller therapy”?
Leukotriene receptor antagonists (LTRA)
- Motelukast, Zafirlukast
- For prophylaxis therefore must be taken daily, no good for acute attacks
Desribe the step 4 additional controller therapy leukotriene receptor antagonists mechanism of action
- Block effects of bronchoconstricting cysteinyl leukotrienes (specifically CysLT1) in the airways, resulting in bronchodilation
- Reduce eosinophil recruitment to airways, reducing inflammation, epithelial damage and airway hyper-reactivity
What is the mechanism by which Montelukast and Zafirlukast are administered?
Orally (tablet form)
When are LTRAs usually indicated?
- Exercise induced asthma
- Reduce both early and late phase bronchoconstrictor responses to allergens
What are the side-effects of LTRAs?
- abdo pain
- Headache
- Hyperkinesia in children
What are the step 5 specialist therapies?
- Methylxanthines
Theophylline and Aminophylline - Monoclonal antibodies: omalizumab or mepolizumab
How do Methylxanthines work?
- Immunomodulatory and anti-inflammatory action (lower doses)
- Bronchodilator (at higher doses)
- Phosphodiesterase (PDE) inhibitors
- PDE implicated in inflammatory cells - therefore inhibition reduces inflammation
- Also PDE inhibition increases intracellular cAMP in bronchial smooth muscle, causing relaxation (bronchodilation)
- Also blocks adenosine receptors - results in brochodilation
- Activates histone deacetylase - immunomodulatory
What are the side-effects of methylxanthines?
- Narrow therapeutic index Side effects dose or rate related: - GI upset - Arrhythmias - CNS stimulation e.g seizures - Hypotension - Can possibly interact with antibiotics
Describe how an monoclonal antibody such as omalizumab is used to treat asthma
- “Preventer”
- Inject route (fortnightly/monthly)
- Slow to work - peaks at 3 to 4 months
- Reduces exacerbations and is steroid sparing
- Can cause anaphylaxis and increase risk of strokes/heart disease
- Expensive
How is asthma monitored?
- Peak expiratory flow
- If >50% predicted - severe asthma
- Nocturnal dip often present
What levels of peak flow indicate what level of asthma?
- Moderate acute asthma PEF >50-75%
- Acute severe asthma PEF 33-50%
- Life-threatening asthma < 33%
What indicates near-fatal asthma?
Raised PaCO2 &/or requires ventilation/NIV
What indicates acute severe asthma?
Any one of:
- PEF 33-50% best or predicted
- RR >= 25/min
- HR >= 110/min
- Inability to complete a sentence in one breath
What indicates life-threatening asthma?
Any one of the following
- Altered consciousness
- Exhaustion
- Arrythmia
- Hypertension
- Cyanosis
- Silent chest
- poor respiratory effort
- PEF < 33% best/predicted
- SpO2 < 92%
- PaO2 < 8 kPa
- “Normal” PaCO2 (4.6 - 6 kPa)
How is acute severe asthma managed immediately?
- Oxygen (to maintain a SpO2 at 94-98%)
- SABA (salbutamol or terbutaline) via nebuliser
- IV steroid = hydrocortisone…SWITCH to ORAL steroid = prednisolone
- +/- antibiotics
- +/- muscarinic agonist inhaled
If patient does not improve after steps are taken to treat severe asthma what should you consider?
- IV magnesium sulphate (bronchodilates, anti-inflammatory)
- Switch from nebulised to IV salbutamol or IV methylxanthine (aminophylline)
- Monitor blood gases and patient exhaustion/alertness
What are the first 3 basic treatments for asthma?
SOS
- Salbutamol
- Oxygen
- Steroid
When would an ICS be used in the treatment of COPD?
- limited benefit
- If FEV1<50% predicted and have 2 or more exacerbations in a year which require antibiotics or oral steroids
- High doses may increase risk of pneumonia and osteoperosis
What are muscarinic receptor antagonists used to treat?
COPD (not asthma)
What can muscarinic antagonists cause?
- Increased bronchodilation
- Decreased mucous secretion
- Increased mucociliary clearance
How long does it take for muscarinic antagonists take affect?
30 - 60 minutes
What muscarinic receptor is in the airways and is involved in brochoconstriction and mucous secretion?
M3
Give an example of a SAMA?
Ipratropium (acute - nebulised route), non selective
Give an example of a LAMA
Tiotropium, aclidinium, umeclidinium - more selective for M3 receptor
What are the side effects of muscarinic antagonists?
Uncommon
- Constipation
- Dry mouth
- Nausea
- Cough
- Urinary retention (men)
- Can worsen angle closure glaucoma
What other treatments can be used in the treatment of COPD?
- Methylxanthines
- Mucolytics - if chronic productive cough, reduce sputum viscosity, Carbocysteine
- Phosphodiesterase type 4 inhibitor - Roflumilast - if severe COPD, repeated exacerbations
- Longterm antibiotics - azirthromycin
- Anti-IgE monoclonal antibody
- Long term oxygen
How is COPD assessed?
- Primarily based on patient symptoms, ADL, exercise capacity, speed of symptom relief with SABA
- Changes in lung function - spirometry
- Risk of exacerbations
What are indicators of high risk?
Two exacerbations or more within the past year or FEV1 < 50% predicted are indicators of high risk
What indicates that a patient has ACOS - Asthma COPD Overlap Syndrome?
- Higher eosinophil count
- FEV1 swings
- Diurinal variation in PEFR
- Respond better to steroids (reducing exacerbation rate)
- More reversible to B2 agonists
How are exacerbations of acute, severe COPD treated?
- Nebulise SABA/SAMA (on air)
- oral prednisolone
- antibiotic if needed
- Physio
- 24-28% Oxygen (PaO2/PaCO2 needs to be monitored)
- Extreme - NIV - non-invasive ventilation , Intubation
