Paul (Pharmacology of asthma drugs) Flashcards
5 distinguishing features of asthma
Chronic
Inflammation
Airways hyper-responsiveness and bronchiconstriction
Reversibility
Trigger factors
Classification of asthma
Extrinsic (atopic)
- Early onset
- Episodic
- Most common
Intrinsic (non-atopic)
- Late onset
- Chronic
Aetiology of asthma
Genetic predispodition
Atopy
Airway hyper-responsiveness
Gender
Ethnicity
Environmental factors
Indoor and outdoor allergens
Occupational sensitisers
Tobacco smoke
Air pollution
Diet and drugs
Obesity
Early response- type 1 allergic response
Bronchoconstriction
Mucosal oedema
- vascular vasodilation/permeability
Hyper-secretion of mucus
Immediate onset
Lasts about 1 hour
How FEV1 varies with time when an allergen is inhaled.
FEV1 is at 100% before inhalation. At hour 1 there is an acute asthmatic response (AAR) which drops FEV1 to 75%. Increases back up to 100% at hour 2 and stays high til hour 4 where it starts to decrease. Late asthmatic response (LAR) reached at hour 6 where. the FEV1 is at its minimum value of 25% and slowly increases over the next 6+ hours back to 100%.
Late response (allergic and non-allergic asthma)
2-4 hours after exposure
Maximum after 6-8- hours
Attracts inflammatory cells
Infiltration of local area with eosinophils
Mediator release- Th2 lymphocytes and neutrophils
- inflammatory mediators e.g. cytokines
- tissue destruction
- tissue remodelling
- reflex neural bronchoconstriction
- via vagus
Pathophysiology
Asthma = Inflammation + Bronchoconstriction
Inflammation
- mucosal infiltration with inflammatory cells
- oedema of the bronchioles
- hypertrophy of the glands and of smooth muscle
- damaged epithelium
Bronchoconstriction
- mast cell mediator release
- vagal stimulation
Asthma triggers
Alcohol
Animals and pets
Colds and flu
Emotions
Exercise
Food
Hormones (females)
House dust mites
Moulds and fungi
Pollen
Pollution
Recreational drugs
Sex
Smoking
Stress
Weather
Pharmacological management
Bronchodilators (“relievers”)
- beta-agonists (short acting and long acting)
- Xanthines
- Anti-cholinergics
Anti-inflammatory drugs (“preventers”)
- corticosteroids
- leukotriene modifiers
- anti IgE antibody
- sodium chromoglycate
Non-pharmacological methods
Avoidance of allergens
Stop smoking
Lose weight
Homeopathy
Breathing and relaxation
Acupuncture
Food avoidance
Herbal medicines
Ephedra Sinica (Ma Huang)
Chinese herbal remedy for asthma
Used 5000 years ago
Ephedrine- acts as an alpha and beta agonist
Banned in some states and Canada
28 deaths in the last 6 years
Adrenergic agonist- stimulates ALL alpha and beta receptors in the body which causes side effects e.g. palpitations
The ‘Royal College of Physicians 3 questions’
Answering ‘no’ to all 3 questions is consistent with controlled asthma.
1- Have you had difficulty sleeping because of your asthma symptoms (including cough)?
2- Have you had your usual asthma symptoms during the day (e.g. cough, wheeze, chest tightness, or breathlessness)?
3- Has your asthma interfered with your usual activities (e.g. housework, work, school)?
Not yet been validated in children
Beta-2 adrenoceptors in the lung
Sparsely innervated (supplied with nerves) by ANS
High concentrations in the lung
Density is constant
70% b2
- airway and vascular smooth muscle (uterus is also a smooth muscle. Salbutamol can be used to treat premature childbirth as uterus also has beta receptors)
- epithelium and sub-mucosal glands
- mast cells
- pre-junctional on cholinergic nerves
- inflammatory cells
30% b1
- localised to sub-mucosal glands
Effects of b2 adrenoceptos stimulation
Functional antagonism of bronchoconstrictors.
- bronchodilator of ALL airways
Inhibition of release of histamine and leukotrienes.
Inhibit plasma exudation.
Inhibit cholinergic transmission.
Inhibit mediator release from inflammatory cells (short term effect).
Increase mucus clearance.
SABAs vs LABAs
SABA
- faster onset
- duration of 4 hours
- e.g. salbutamol, terbutaline
- used for rescue
LABA
- slower onset
- duration of 12 hours
- e.g. formoterol, salmeterol
- used for maintenance
Salmeterol and formoterol should be prescribed in conjunction with inhaled corticosteroids- results in improved pulmonary function than just increasing the dose. Data suggests that up to 30% of patients prescribed these were not taking inhaled corticosteroids.
SABAs and LABAs safety
Tremor (particularly in the hands)
Headache
Peripheral dilation
Palpitations
Tachycardia and arrhythmias
Hypokalaemia Na+/K+ ATPase (ONLY occurs in severe asthma when people are on nebulisers with high concentrations)
Theophylline
Aminophylline (theophylline ethylenediamine
- Phyllocontin Continus tablets
NOT inhaled- oral or IB
Various mechanism of action proposed
- inhibit phosphodiesterase (dose problem)
- increase in cAMP
- cGMP
- dose?
- isoenzymes PDE III and IV
- antagonise adenosine
Effect on late phase inflammatory response?
- Has an anti-inflammatory effect on cytokine produced by phagocytic cells
- Reduces the late response to allergen
Other effects of theophylline
CNS stimulants
Cardiovascular effects
- positive chronotopic and ionotropic effects
- vasodilation
Renal effects
- weak diuretics
GI effects
Safety of theophylline
Small therapeutic window
- therapeutic drug monitoring is important
- nausea/vomiting warning signs
Elderly
Metabolised
- Cytochrome P450
Half-life affected by
- liver disease
- cardiac failure
- heavy smoking
- heavy drinking
- drug interactions
Muscarinic receptor antagonists
Non-selective
Antagonises vagal bronchoconstriction
No effect against allergen challenge/late phase
Inhibits secretions
Combined with beta agonists
Severe or life-threatening asthma
Examples:
Ipratropium (SAMA)
- nebulas, aero-caps, inhaler
- maximum peak effect 30-60 mins
- duration 3-6 hours
Tiotropium (powder) (LAMA
- long acting
peak at 3-4 hours
- duration 24 hours
Use of corticosteroids in asthma
Suppress inflammation
- early and late phases
Prophylactically
- by inhalation
- oral
Acute severe asthma
- oral
- parenteral
Glucocorticosteroids for asthma e.g.
- beclomethasone
- budesonide
- fluticasone
Corticosteroids safety
Common with inhaled steroids
- Dysphonia- abnormal voice/hoarseness
- Fluticasone (extensive 1st pass)
- Oral thrush
- Increased risk of diabetes
Prolonged oral therapy (for inflammation)
- Suppression of response to infection
- Suppression of endogenous glucocorticoid synthesis
- Metabolic effects
- Ostroporosis
- Latogenic Cushings syndrome
Corticosteroids cautions/side effects
Infections/wound healing/ulcers
Sudden withdrawal (LONG TERM- steroid warning card)
Effects on water and electrolytes
Hyperglycaemia
Osteoporosis
Thinning skin
Cataracts
Glaucoma
Why are there so many asthma related deaths in the UK?
Under use of anti-inflammatory drugs.
Overuse of b2 agonists.
Failure to recognise symptoms.
Failure to recognise severity of attack.
Incorrect use of inhalers.
Underuse of monitoring devices.
Lack of supervision, education, and understanding.
