Pharmacology of airway diseases (Week 2) Flashcards
Explain the pathophysiology of early phase of asthma and how it sets up the late phase.
Early phase: 1) exposure to allergen, activation of Th2 lymphocytes and release of inflammatory cytokines
2) Chemoattraction of other inflammatory cells such as eosinophils and B plasma cells.
3) Activation of B cells to produce IgE against allergen/ non specific insult
4) Eosinophil activation and release of leukotrienes and toxic proteins. Leukotriene = bronchospasm Toxic protein= Damage to respiratory epithelium and airway hyperreactivity
5) Expression of IgE and receptors on mast cells and eosinophils
6) Rexposure to allergen/ stimulus, cross linking of IgE on mast cells, degranulation leading to release of histamine and leukotrienes. Bronchospasm.
7) Degranulation also leads to release of chemokines and chemotaxins-sets up delayed phase by attracting more inflammatory cells.
Explain the pathophysiology of the late phase of asthma
1) release of chemokines and chemoattractants by degranulation of mast cells after IgE crosslinking (exposure to allergen/ non specific stimulus) leads to more infiltration of T lymphocytes, eosinophils
2) More release of cysteinyl leukotrienes, interleukins, GF’s and toxic proteins from inflammatory cells
3) Release of toxic proteins by activated eosinophils destroys respiratory epithelium leading to exposure of C fibres and irritant receptors- AIRWAY HYPERRESPONSIVENESS
4) Release of growth factors leads to smooth muscle hypertrophy and hyperplasia - airway inflammation. Mucus overproduction.
4) Airway hyperreactivity and inflammation leads to bronchospasm, wheezing and coughing
What three things is asthma characterised by?
1) reversible airways obstruction
2) Airway hyperrepsonsiveness
3) Inflammation
What two conditions are encompassed by the term COPD?
Give a brief explanation of each
COPD= umbrella term for chronic and generally nonreversible airways obstuction, encompasses both emphysema and chronic bronchitis. Both diseases characterised by an increase in resistance. Causes: smoking and airway pollution which leads to oxidative stress and activation of inflammatory pathways in the lungs.
1) Chonic bronchitis
- obstruction generally affects larger airways (bronchii and bronchioles)
- due to mucosal gland hypertrophy and mucous overproduction
- Hypersecretion of mucus leads to decreased cilia action and increased infections
2) Emphysema
- Obstruction generally occurs in smaller airways (respiratory bronchioles and aleveolar acinus)
- Infilitration of inflammatory cells leading to oxidative stress and imbalance between proteases/ antiproteases.
- Destruction of alveolar walls and elastic tissue, airspace enlargement
- Increased compliance but increased resistance due to loss of airway tethering and elastic recoil.
State three strategies for treating airway diseases
1) target nervous system release of neurotransmitters and smooth muscle cell contraction- Bronchospasm/ airway constriction
2) Target acute inflammation in the lungs - airways hyperresponsiveness
3) Target chronic inflammation in lungs and airways remodelling - long term inflammation
What drugs can be used for bronchodilation?
Bronchodilation: BAM
B- Beta 2 adrenergic adrenoreceptor agonists (b2 agonists)
A- Anticholinergics
M- methylxanthines
What drugs can target inflammation in the airways?
LuGlu
Leukotriene receptor antagonists
Glucocorticoids (corticosteroids)
What is the treatment for an acute asthma attack?
OSHIT
Oxygen
Salbutamol (B2 adregnergic receptor agonist)
Hydrocortisone (glucocorticoid)
Ipatroprium (anticholinergic)
Theophyline (methylxanthine)
Explain the action of the autonomic nervous system on airway dilation/ constriction
1) Sympathetic NS (fight or flight)- stimulates BRONCHODILATION
Via adrenergic neurones and release of NORADRENALINE. Binds to B2 Adrenergic receptors on airway smooth muscle cells, stimulates RELAXATION and therefore BRONCHODILATION.
2) Parasympathetic NS (rest and digest)- Stimulates BRONCHOCONSTRICTION
Via Cholinergic fibres that release ACETYLCHOLINE. Binds to M3 Muscarinic Ach Receptors on SMC membranes. Stimulates CONTRACTION and therefore BRONCHOCONSTRICTION.
Describe the cell signalling pathway when B2 agonist binds B2 adrenergic receptors on airway smooth muscle cell membranes.
What effect does this have on airway dilation/ constriction?
- When a B2 binds to B2 Adrenergic receptor on airway smooth muscle cell it results in activation of the receptor (a GPCR) and activation of Adenylyl Cyclase
- Activation of AC leads to the production of cAMP from ATP
- Increase in cAMP in the cell leads to activation of protein kinase A (PKA)
- Activation of PKA leads to dephosphorylation of myosin light chain kinase (MLCK), which inactivates it.
- Inactivation of MLCK leads to decreased phosphorylation of myosin light chain, promotes relaxation.
- Activation of PKA also promotes uptake of Ca2+ into intracellular stores.
- Reduction of [Ca2+] in SMC cytoplasm also promotes relaxation.
- Bronchodilation occurs.
Name two short acting B2 agonists?
Salbutamol
Terbutaline
Name two long acting B2 agonists (F’s sake)
F’s sake
Formoterol
Salmeterol
What are the key side effects of B2 agonists?
Tremor
Tachycardia
Cardiac arrythmias
Describe the normal cell signalling pathway when M3 muscarinic receptors are activated on bronchial smooth muscle cell membranes?
What does this mean when an anticholinergic drug is used?
Under normal conditions:
- Binding of Ach to M3 muscarinic receptors leads to activation of the receptor (GCPR) and activation of phospholipase C.
- Activation of phospholipase C leads to production of IP3.
- IP3 normally leads to release of calcium from IC stores- contraction of bronchial SMC and Bronchoconstriction
In presence of anticholinergic drug:
- Antagonism of the M3 muscarinic receptor means no Ach can bind
- Inhibits activation of cell signalling pathway, no PLC activation/ IP3 production/ Ca2+ release.
- As no Ca2+ released inhibits muscle contraction
- Relaxation and BRONCHODILATION occurs.
Name two anticholinergic drugs
1) short acting
2) long acting
What are the key side effects of these drugs?
1) Short acting- Ipratroprium
2) Long acting- Tiotroprium
Key side effects: Dry mouth, constipation, urinary retention
Describe the role of the phosphodiesterase enzyme in bronchial smooth muscle cells under normal conditions
Describe the effect of methylxanthine and how this affects airway constriction/ dilation?
Under normal circumstances:
- PDE enzyme breaks down cAMP produced by Adenylate cyclase conversion of ATP to cAMP (following activation of the B2 adrenergic receptor which activates Adenylate cyclase)
- Reduction in cAMP would reduce PKA activation and effects
- PKA stimulates uptake of ca2+ into IC stores and inhibits phosphorylation of Myosin light chain kinase - therefore promotes SMC relaxation.
- Reduction in cAMP reduces PKA stimulation of relaxation and bronchodilation
- Therefore PDE action would lead to bronchoconstriction.
In presence of methylxanthine:
- Methylxanthine inhibits PDE enzyme breakdown of cAMP
- Sustains levels of cAMP, therefore potentiates activation of PKA and PKA action
- Promotes Ca2+ uptake and dephosphorylation of MLCK
- Promotes SMC relaxation and bronchodilation.
List some of the key side effects of glucocorticoids
1) Skin - Thinning skin, brusing, poor wound healing, increased susceptibilty to infections
2) Muscle wasting and osteoporosis
3) Facial: Moon face and reddening of cheeks
4) Cranial- euphoria/ depression
5) Hypertension
6) Abdominal: increased abdominal fat, appetite, obesity, tendency to hyperglycaemia
