Asthma Pharmacology

• Asthma Epidemiology

  • 5.4 million cases in the UK
  • 1.1 million children
  • 1 in 12 adults affected
  • 1 in 11 children affected
• Classification of asthma

  • extrinsic (allergic)
  • often seen in children
  • intrinsic (non-allergic)
  • usually later onset
  • no detectable serum IgE
  • negative skin prick test to common allergens
• Asthma triggers:

  • exercise
  • pollen
  • pets
  • stress
  • anger
  • pollution
  • strong odours
  • smoke
  • dust
  • fungus spores
  • cold air
  • chemical fumes
  • bugs in the home
• Immunological pathophysiology asthma

  • mediated by immunoglobulin E (IgE)
  • formed in response to an allergen
  • first exposure
  • sensitisation occurs
  • re-exposure
  • allergen binds to specific IgE molecule on mast cell surface
• Airway narrowing asthma

  • smooth muscle layer goes into spasm, narrowing the airway
  • lining of the lung becomes inflamed
  • mucus production is increased
  • in some parts of the airway, mucus can form plugs that nearly or completely block the airway
  • process takes about 20 minutes from initiation and can last up to three hours
• Early phase asthma

  • allergen or non-specific stimulus binds mast cell and causes degranulation
  • mast cell releases spasmogens leading to bronchospasm
• Late phase asthma

  • driven by chemokines e.g. interleukins
  • drives infiltration of Th2 cells and activation of inflammatory cells
  • release cysLTs and other mediators leading to
  • airway inflammation
  • airway hyperreactivity
  • bronchospasm and wheezing
  • also release toxic products e.g. EMBP, ECP leading to epithelial cell damage and further airway hyperreactivity
• Common signs and symptoms asthma

  • coughing (worse at night or early morning)
  • wheezing or whistling noise in chest (expiratory)
  • shortness of breath
  • tightness in chest (dyspnoea)
• Initial Assessment Asthma

  • clinical history
  • symptoms, duration of attack, trigger factors, family history
  • physical examination
  • pulse, respiration, auscultation of chest
  • lung function tests
  • spirometry, peak expiratory flow (PEF)
• What effect on the spirograph would you expect to see from a patient with asthma symptoms?

  • obstructive disease therefore increased resistance
  • harder to get rid of the air but there is the same amount of air
  • FVC stays similar
  • FEV1 decreases
  • Decreased ratio
  • decreased PEFR
• Moderate asthma

  • PEF > 50-75%
  • SpO2 > 92%
  • Speech normal
  • respiration < 25
  • Pulse < 110
• Acute severe asthma

  • PEF 33-50%
  • SpO2 > 92%
  • Can't complete sentences
  • Respiration > 25
  • Pulse > 110
• Life-threatening asthma

  • PEF < 33%
  • SpO2 < 92%
  • Silent chest, cyanosis or poor respiratory effort
  • Arrhythmia or hypotension
  • Exhaustion, altered consciousness
• Asthma treatment goals

  • minimise or eliminate symptoms
  • maximise lung function
  • prevent exacerbation
  • minimise need for medication
  • minimise adverse effects of treatment
  • promote adherence with medication
  • provide enough information and support to facilitate self-management
• Non-pharmacological measures

  • avoidance of triggers
  • desensitisation to specific antigen
  • house dust mite control measures
  • smoking cessation
  • weight reduction
• Relievers

  • beta-agonists
  • Antimuscarinics
  • methyxanthines
• Preventers

  • corticosteroids
  • leukotriene receptor antagonists
  • cromones
• Short-acting B2 agonists

  • e.g. salbutamol, terbutaline
  • stimulation of B2-receptors on airway smooth muscle
  • adverse effects
  • fine tremor (hands), nervous tension, headache, tachycardia
  • hypokalaemia at high doses
  • can develop tolerance
• Methyxanthines

  • e.g. theophylline
  • inhibits phosphodiesterase
  • additive effect when used in conjunction with small doses of b2-agonists
  • Given orally (usually slow-release) or by very slow IV infusion
  • hepatically metabolised (principally CYP1A2)
  • interactions with antibiotics/nicotine smoke etc. are problematic
  • Hyperkalaemia
  • narrow therapeutic range (10-20 mg/L)
• Adverse effects of methyxanthines

  • e.g. nausea, headaches, insomnia, abdominal discomfort
  • frequency and severity increase above 20 mg/L
  • toxic effects above 25 mg/L
  • start patient on low dose and slowly increase, monitoring for tolerance of side effects
• Molecular action of B2 agonists

  • smooth muscle tone in bronchi is mediated by parasympathetic action
  • acetylcholine drives bronchoconstriction or tone by contraction, by action of calcium on MLCK via G alpha Q receptors
  • b2 adrenoreceptor is G protein coupled (G alpha S coupled cyclic AMP second messenger)
  • cyclic AMP inhibits myosin light chain kinase, uncouples actin myosin interaction and leads to bronchodilation/relaxation of smooth muscle
• Phosphodiesterases break down cyclic AMP. Methyxanthines inhibit phosphodiesterase so more cAMP is available in cell - keep augmenting inhibition of MLCK driving broncho-relaxation. Unfortunately have narrow therapeutic range.
• Anti-muscarinics

  • e.g. ipratropium
  • block antimuscarinics
  • M3 main target
  • slower onset than b2 agonists
  • more use in patients over 40 not responding to beta agonists due to decrease in function of beta-receptors as we age
  • have to be specific about which antimuscarinic you use as can increase mucus production
  • administered by inhalation
  • maximal effect occurs 30-60 min after use, duration of action 3-6 hours
  • adverse effects
  • dry mouth, constipation, diarrhoea, cough, headache
  • caution needed in prostatic hyperplasia, bladder outflow obstruction, angle-closure glaucoma
• Corticosteroids

  • e.g. beclomethasone, budesonide, fluticasone
  • reduce bronchial inflammatory reactions (e.g. oedema and mucus hypersecretion)
  • metered inhalation
  • act via manipulating nuclear actions e.g. transcription of proteins etc. and mediators
  • must be used regularly for maximum benefit
  • fewer systemic effects however:
  • hoarse voice (dysphonia), reflex cough following inhalation (can be reduced by using spacer)
  • oral candidiasis
  • takes 3-7 days to become therapeutic but can be given at relatively low dose
• Oral corticosteroids (prednisolone)

  • acute attacks
  • chronic asthma
  • associated with many serious adverse effects
  • diabetes
  • gastric ulcers
  • osteoporosis
  • hypertension etc.
  • taken as a single dose in the morning
• Hydrocortisone IV injection can be given in emergency treatment of severe acute asthma
• Leukotriene-receptor antagonists

  • e.g. montelukast, zafirlukast
  • block effects of cysteinyl leukotrienes in airways
  • anti-inflammatory action
  • bronchodilation can occur within an hour of administration
  • effective in decreasing late phase response
  • Th2 driven activation of cysteinyl leukotrienes
  • effective alone or with inhaled corticosteroid
  • well tolerated
  • low side effect profile
• Cromones

  • e.g. sodium cromoglicate
  • mechanism of action is unclear
  • may be of value in allergic asthma, but difficult to predict who will have benefit
  • only used in patients where we are struggling to control the asthma
  • prophylactic drug - of no value in acute attacks
  • must be withdrawn gradually over 1 week - sudden withdrawal can lead to rebound sensitivity and make symptoms worse
  • adverse effects may be prohibitive - throat irritation, cough and bronchospasm
• Long-acting B2 agonists

  • e.g. salmeterol, formoterol
  • for use with regularly inhaled corticosteroid
  • role in long-term control of chronic asthma
  • not typically used for relief of asthma attack
  • combination inhalers available
  • e.g. symbicort (formoterol/budesonide), seretide (fluticasone/salmeterol)
• Monoclonal Antibodies

  • e.g. omalizumab
  • recombinant humanised monoclonal antibody
  • selectively binds to IgE forming a complex
  • recommended by NICE for use in adults and young people > 12 years with severe persistent allergic (IgE-mediated) asthma who meet specific criteria
  • expensive but may be more widely used as the price comes down
• 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 effect
  • FEV1 and/or PEF > 80% predicted or best
• Patient counselling

  • Knowledge of disease state
  • especially signs of worsening
  • Knowledge of medicines
  • different kinds
  • inhaler technique
  • spacer technique
  • side effects
  • knowledge of how to monitor condition
• Monitoring of asthma

  • compliance to treatment
  • nurse asthma reviews
  • symptoms
  • prescription frequency
  • lung function
  • pulmonary function
  • peak flow diaries
  • theophylline monitoring
  • hyperkalaemia
  • safe concentration range