Pharmacology Flashcards
What is the role of the parasympathetic division of the autonomic nervous system in the regulation of airway function and how does it do this?
causes bronchial smooth muscle contraction by M3 muscarinic ACh on ASM cells, increased mucus secretion by M3 ACh receptors on goblet cells
What is the role of the sympathetic division of the ANS in the regulation of airway function and how does it do this?
causes bronchial smooth muscle relaxation via beta 2 adrenoceptors on ASM activated by adrenaline, decreased mucus secretion by beta 2 adrenoceptoes on goblet cells and increased mucociliary clearance and vascular smooth muscle contraction by alpha 1 adrenoceptors
What is the principle transduction pathway that regulates airway smooth muscle tone?
a GPCR being activated to activate PLC which converts PIP2 to IP3 so Ca2+ ions are made, these bind to calmodulin and activate MLCK which causes myosin cross bridges to be phosphorylated so there is contraction
Under what conditions does contraction of airway smooth muscle occur?
after phosphorylation of the regulatory MLC in the presence of elevated Ca2+ and ATP
Under what conditions does relaxation of airway smooth muscle occur?
dephosphorylation of MLC by myosin phosphatase
What is the definition of asthma?
Asthma is a recurrent and reversible obstruction to the airways in response to substances that are not necessarily noxious
What is the incidence of asthma in the population?
5-10% in industrialised countries
What are the pathological changes in chronic asthma?
- increased smooth muscle so hypertrophy and hyperplasia
- accumulation of interstitial fluid
- increased mucus
- epithelial damage
- sub epithelial fibrosis
What is bronchial hyper-responsiveness?
bronchial hyper-responsiveness is when the airways have increased sensitivity to bronchoconstrictor due to epithelial damage and the exposing of sensory nerve endings
What changes will be seen with hypersensitivity and hyper-reactivity on a graph?
hyper-reactivity causes a vertical increase on a graph
hypersensitivity causes a left shift
What is the major cause of asthma? (immunologically)
in asthma, there is a strong Th2 repose involving IgE in response to an allergen instead of the normal mild Th1 response with IgG and macrophages
Describe in detail the events that occur after Th2 cell activation in asthma…
- Th2 cells activate B cells by binding and by IL4 production
- B cells then mature to P cells which secrete IgE
- mast cells then express IgE receptors in response to IL4 and IL13
- eosinophils differentiate and activate in response to IL5 from Th2
- calcium ions into mast cells and release of ions so histamine and leukotrienes
- platelet-activating factor and prostaglandins released causing inflammation
What events occur in the immediate phase of an asthma attack?
allergen stimulating mast cells to produce spasmogens for bronchospasm and chemotaxis which then stimulate the late phase
What events occur in the late phase of an asthma attack?
- infiltration of cytokine releasing Th2 cells and monocytes
- activation of inflammatory cells particularly eosinophils so epithelial damage
- airway hyper-responsiveness and inflammation so bronchospasm
- patient will present with wheezing and cough
What are the main pathological features of COPD?
- mucous gland hyperplasia leading to chronic bronchitis and small airway narrowing and obstruction
- bronchial thickening and fibrosis leading to small airway narrowing and obstruction
- alveolar destruction leading to emphysema, loss of elastic recoil and dynamic airway collapse
How does activation of M3 receptors cause contraction of airway smooth muscle?
M3 muscarinic receptors activate Gq11 which activates PLC to convert PIP2 to IP3 which causes Ca2+ to be released from the sarcoplasmic reticulum leading to contraction of the smooth muscle
What is the role of M3 muscarinic receptors?
they mediate contraction to ACh and evoke increased secretion on mucus-containing cells
What does Ipratropium do?
it is a non-selective blocker of M1-3 receptors
What do muscarinic antagonists do?
block activation by ACh so contraction is prevented
What do beta 2 agonists do?
they activate beta 2 adrenoceptors which causes relaxation
Who should you prescribe glucocovrticosteroids to?
patients with COPD that have frequent and severe exacerbations when given a LABA
What are phosphodiesterase inhibitors used for?
they prevent inflammation responses and immune cells
Why should you combine beta 2 adrenoceptors (LABAs) with LAMAs?
LAMAs prevent contraction and LABAs cause relaxation so FEV1 is increased
What are the three type of rhinitis?
allergic, non-allergic and mixed
What are the three types of allergic rhinitis?
seasonal, perennial or episodic
What is the pathology of allergic rhinitis?
- inhalation of allergen increases IgE levels
- IgE binds to receptors on mast cells and basophils
- re-exposure to allergen causes mast cell and basophil degranulation
- release of mediators including histamine, cysLT, tryptase and prostaglandins
- delayed response causes lymphocytes and eosinophils to be recruited to nasal mucosa
What are the results of the mediator release in allergic rhinitis?
acute itching, sneezing, rhinorrhoea and nasal congestion
What is non-allergic rhinitis?
any rhinitis that is acute or chronic but doesn’t involve IgE events
What are causes of non-allergic rhinitis?
infection, hormone imbalance, vasomotor disturbance, medication or cystic fibrosis
What is mixed rhinitis?
occupational rhinitis involving both allergic and non-allergic components
What are the similarities between allergic asthma and allergic rhinitis?
pathway is similar
What are the four treatments of rhinitis and examples of the drugs used?
- anti-inflammatory = glucocorticoids
- mediator receptos blockade = h1 receptor antagonist, cysLT receptor antagonists
- nasal blood flow = vasoconstrictors
- anti-allergic = sodium cromoglicate
What do glucocorticoids do?
hormone receptors that cross the cell membrane readily and bind to extracellular receptors that doubles as nuclear transmitter
What do glucocorticoids up-regulate and down-regulate?
- up-regulate the expression of anti-inflammatory mediators
- down-regulate pro-inflammatory mediators so less swelling
What is the effect of glucocorticoids?
- reduce vascular permeability
- increase expression of proteins that hold endothelial cells together so reduced leakiness
Which types are glucocorticoids used for?
SAR and PAR and in NARES
In what form do glucocorticoids come?
a nasal spray that works over several weeks
What are anti-histamines?
competitive antagonists that reduce effects of mast cell derived histamine
What are the effects of anti-histamines?
- reduce vasodilation and increase capillary permeability
- reduce activation and increase capillary permeability
- reduce mucus secretion from submucosal glands
What types are anti-histamines used for?
SAR, PAR and EAR but not used in non-allergic rhinitis
What do anti-cholinergic drugs do?
block the release of ACh from postganglionic parasympathetic fibres
What do anti-cholinergic drugs reduce?
rhinorrhoea
What types are anti-cholinergic drugs used for?
PAR and SAR
What is the main anti-cholinergic drug that is used?
ipratropium
What is sodium cromoglicate?
mast cell stabiliser and used for allergic rhinitis
What do cysteinyl leukotriene receptor antagonists do?
reduce the effects of cysts upon the nasal mucosa
What types are cysteinyl leukotriene receptor antagonists used to treat?
PAR and SAR so allergic rhinitis and asthma
What is the common cysteinyl leukotriene receptor antagonists that is used?
oral montelukast
What do vasoconstrictors do?
directly or indirectly act to mimic the effects of noradrenalin to produce vasoconstriction
What is the main vasoconstrictor used?
oxymetazoline which is a selective alpha 1 adrenoceptor agonist which reduces congestion in allergic rhinitis
