L13 Respiratory Pharmocology Flashcards
Asthma
Chronic, intermittent and reversible airway disease causing obstruction and type 4 hypersensitivity to small airways
Features of asthma
Eosinophilic Mucosal oedema and plugging Bronchospasm - constriction of small airways Wheezing Coughing Atopy
Considerations before stepping up or down
Adherence
Inhaler technique
Eliminate triggers I.e. allergens
Uncontrolled asthma
3+ days a week with symptoms
3+ days a week with SABA required
1+ nights a week with awakening due to asthma
Stepwise treatment of asthma
- SABA throughout - salbutamol
- low dose ICS
- Regular preventer - low dose ICS
- Add LABA - salmeterol
- Increased dose of ICS or LTRA
- Specialist therapies
Inhaled corticosteroid examples
Beclometasone
Budesonide
Fluticasone
ICS mechanism of action
Regular preventer when reliever alone is not sufficient
- passes through the plasma membrane as liopophilic
- activates cytoplasmic receptors (glucocorticoid receptor in cytosol)
- forms complex and passes into the nucleus
- modifies transcription therefore controls gene expression
Effects of ICS
Reduces mucosal inflammation - activates genes for anti- inflammatory mediators and represses genes for inflammatory mediators
Widens airways - activates genes for Beta 2 agonists for bronchodilation
Reduces mucus - represses genes for inflammatory mediators
- Therefore reduces symptoms and exacerbations to prevent death
Side effects of ICS
Local immunosuppression - candidiasis (oral thrush) and hoarse voice
Pneumonia risk in COPD patients
Pharmacokinetics of ICS
- Poor oral bioavailability but inhaled
- large lipophilic side chain for slow dissolution in aqueous bronchial fluid
- adheres and acts locally
- high affinity for glucocorticoid receptors in the cytosol
If ICS taken orally
- Transported from stomach to the liver via the hepatic portal system quickly
- almost complete first pass metabolism - low risk of systemic side effects
Beta 2 agonists
SABA - short acting beta 2 agonist used when required - symptom relief via bronchodilation
LABA - add on to ICS used when required
- bronchodilation
- increases mucus clearance by cilia action
- prevents bronchoconstriction prior to exercise
Beta 2 agonists used regularly
Reduced tolerance
Quickly fixed in young adults
Beta 2 agonist examples
Fast:
SABA - salbutamol and terbutaline
LABA - formoterol (more potent and efficacious than salmeterol)
Slow:
LABA: salmeterol
Beta 2 agonist mechanism
- Beta 2 agonist bind to GPCR
- GDP is replaced by GTP
- G alpha S sub unit dissociates from the G beta and gamma sub unit
- G alpha S activates adenyl cyclase
- Which stimulates ATP to convert into cAMP
- cAMP activate protein kinase A
- Which causes bronchial smooth muscle relaxation
Beta 2 agonist ADR
Increases sympathetic activity - flight or flight effects e.g.
- tachycardia
- palpitations
- anxiety
- tremor
COPD patients:
- Supraventricular tachycardia - increased SAN activity, increases HR and decreased refractory period and the AVN
- increased risk of right sided HF And CVD
Increased glycogenolysis (liver) - increased blood glucose Increased renin (kidney) - due to increeas3d HR
Why is LABA used with ICS?
Increased risk of death when used alone
Masks airway inflammation and near fatal attacks
Contraindications of beta agonists
Beta blockers as antagonist
When is LABA added?
Asthma not controlled with ICS
Frequent asthma exacerbations
Advantages of combined inhaler
Increase adherence
Safer for the patient - as not taking LABA alone
Less prescriptions
Easier to take
Leukotriene receptor antagonist example
Montelukast
Leukotrienes
- Mast cells and eosinophils release LTC4
- leukotrienes which cause bronchoconstriction, increased mucus production and mucosal oedema as there is increased vascular permeability
- via CysLT1 - GPCR
LTRA mechanism of action
Block CysLT1 receptors preventing bronchoconstriction, increased mucous production and mucosal oedema
Only useful in 15% of asthmatic patients
ADRs of LTRA
Headache
GI disturbances
Dry mouth
Hyperactivity
Additional controller therapies
LAMA - long acting muscarinic antagonist - tiotropium
SAMA - short a timing muscarinic antagonist- ipratropium
Adenosine receptor antagonist - theophylline
Special maintenance therapy - prednisolone
LAMA mechanism of action
Use:
- in severe asthma and COPD
Mechanism:
- selective for M3
- inhibition of muscarinic receptors - anticholinergic
- prevents bronchoconstriction
Side effects of LAMA
Anticholinergic therefore:
- dry mouth
- urinary retention
- dry eyes
Adenosine receptor antagonist
Type of methylxanthine - found in coffee
Also acts as a phosphodiesterase inhibitor
Theophylline - oral
Aminophylline - IV in acute emergency asthma patients
ADRs of adenosine receptor antagonists
Narrow therapeutic index
Potentially life threatening arrhythmia
Interactions with CYP450 inhibitors - increases the concentration of theophylline as there is less metabolism
Prednisolone
Oral steroid for severe uncontrolled asthma
Prescribed by a specialist and given a steroid card (COPD)
Post acute exacerbation - short course for at least 5 days
Post acute COPD - 5-7 days after hospital discharge
Self management plan
For asthmatic patients
Written instruction of when and how to take inhalers
Acute severe asthma presentation
Struggling to complete sentences
Resp rate - 25 +
Heart rate - 110+
Peak flow - a third to half of best or predicted
Life threatening
Peak flow - less than a third of best or predicted
Arterial oxygen saturation - less than 92%
Silent chest
Cyanosis
Exhaustion
Hypotension
Altered conscious level
Treatment for acute severe or life threatening asthma
Oxygen - aim for 94-98%
High dose nebulised beta 2 agonist
Prednisolone for 7- 14 weeks along with ICS
Nebulised ipratropium bromide with B2 agonist - if beta 2 agonist response is poor
Aminophylline is life threatening with no success with other treatments
- caution if taking theophylline
COPD 5 tasks of management
Task 1 - confirm COPD diagnosis Task 2 - stop smoking Task 3 - record MRC dyspnoea score - pulmonary rehabilitation for score less than 2 Task 4 - offer vaccinations Task 5 - consider medication
How to treat COPD
Acute exacerbation requiring hospitalisation:
- nebulised salbutamol or ipratropium driven by air not oxygen if hypercapnic
- prednisolone (less effective than eosinophilic asthma as COPD is neutrophilic)
- antibiotics
- review of chronic treatment and action plan
Inhalers
Blue - salbutamol reliever SABA
Brown - beclometasone preventer - ICS
Green - Ipratropium - SAMA
Inhaler options
Pressurised metered dose inhalers - slow breath in and hold
- can be used with spacer
Breath actuated pMDI - when breathing in
Dry powder inhalers (DPI) - fast deep inhalation
Particle size
1-5 microns - perfect
Too small - inhaled to alveoli and exhaled without being deposited
Too big - deposited in mouth and oropharynx
