Pharmacology Flashcards
Where are the cell bodies of postganglionic fibres in the parasympathetic innervation to the airways
Embedded in the walls of the bronchi and bronchioles
How does the parasympathetic innervation to airway smooth muscle occur (Cholinergic)
ACh stimulates M3 receptors on the bronchial smooth muscle leading to contraction
How does parasympathetic innervation to the goblet cells work
ACh stimulates M3 receptors on gland cells leading to increased mucus secretion
How does the parasympathetic innervation to the airway smooth muscle occur (Non-cholinergic)
ACh stimulates the noncholinergic ganglion by NO and VIP to cause smooth muscle leading to relaxation
How does the sympathetic innervation of the airways occur
There is no direct innervation of bronchial smooth muscle in humans
The adrenal glands are stimulated by the sympathetic nervous system, this causes adrenaline release into the blood which stimulates beta-2 adrenoreceptors leading to smooth muscle relaxation, decreased mucus secretion and increased action of the mucociliary clearance
Explain the general mechanism of excitation-contraction coupling in smooth muscle
A GPCR (M3 for parasymapthetic) leads to formation of IP3 from PIP2. IP3 causes Ca release from IP3 receptor iron channels in the sarcoplasmic reticulum. Ca cause more Ca release by Ca-activated-Ca channels (ryanodine receptors) on the sarcoplasmic reticulum.
Ca can also be moved into the cell by voltage activated Ca channels.
How does Ca cause contraction of the smooth muscle
Ca binds to calmodulin.
Ca-Calmodulin causes activation of myosin light chain kinase.
Active MLCK causes phosphorylation of the myosin cross bridge.
How does relaxation of the smooth muscle occur.
Relaxation occurs by the dephosphorylation of myosin light chain by myosin phosphatase.
Reduced levels of intracellular Ca leads to increased myosin phosphatase activity.
How do extracellular signals affect the activity of myosin light chain kinase
Adrenalin stimulates GPCR (B2-adrenoceptors) to stimulate adenylyl cyclase to form cAMP.
Raised intracellular cAMP leads to increased activity of protein kinase A.
Protein kinase A phosphorylates MLCK to inhibit it.
Protein kinase A phosphorylates and stimulates myosin phosphatase to reduce phosphorylation of the myosin light chain
These 2 actions result in relaxation of the smooth muscle
What are the 5 pathophysiological hallmarks of long-standing inflammation due to asthma.
Smooth muscle hypertrophy & hyperplasia Interstitial oedema Increased mucosal secretion Epithelial damage Sub-epithelial fibrosis
Explain the mechanism of bronchial hyper-responsiveness in asthma
Epithelial damage leads to exposure of nerve endings
This leads to hypersensitivity in which low level stimulus will cause a bronchial constictive response.
This leads to hyper-reactivity in which a stimulus will produce a larger response than it would in a non asthmatic individual.
Which type of T cell dominantes the asthmatic reaction
TH2 which leads to a hyper immune response involving IgE
Explain the mechanism of B cell activation in asthma
A proccessed antigen is presented by MHC-II by epithelial cells.
This stimualtes a CD4+ T cell to form TH0 cells which preferntially form TH2 cells.
TH2 stimualte B cells by IL4
Stimualted B cellsmature to IgE plasma cells
Expalin the stimultion of mast cells in asthma
IgE from plasma cells binds to FcE receptors on the mast cells, this stimualtes Ca influx
TH2 cells produce IL-4&13 which stimulate the mast cells
Expalin the stimulation of eosinophils in asthma
IgE from plasma cells bind to FcE receptors on the eosinophils
TH2 cells produce IL-5 which stimualtes the eosinophils
Explain the effect of mast cells in asthma
Ca influx due to IgE binding to FcE receptors leads to release of secretory granules containing preformed histamines and other agents that cause airway smooth muscle contraction
These chemicals include chemotaxic agents and spasmogens
Explain the difference between the early and late stages of asthma exacerbation
Early stage: mast cell degranualtion of preformed products causing bronchospasm and early inflammation
Late stage: Infiltration of cytokine releasing TH2 cells and monocytes leads to activation of inflammatory cells in particular eosinophils
Explain the mechanism of B2-adrenoceptor agonists
Act as physiological antagonsits of all spasmogens.
Stimulate the B2 receptors (GPCR) leading to activation on adenyl cyclase and increased intracellualr concentrations of cAMP.
cAMP stimulates protein kinase A leading to phosphorylation of MLCK (inhibitory) and myosin phosphatase (stimulatory)
Which asthma drug must never be given as monotherapy
LABA’s must always be coadministered with a ICS
Explain the mechanism of action of CysLT1 receptor antagonsits
Act as antagonsits to the CysLT1 receptors which are stimualted by Cystic leukotrines (LTC4, LTD4 and LTE4) to reduce the bronchoconstircor effect of mast cell degranulation.
Explain the mechansim of methyxanthines
Mechanism not totally understood
Expected theory works off inhibition of phosphodiesterase leading to reduced cAMP breakdown and inturn increased intracellular cAMP concentrations
Explain the mechanism of corticosteorids (ICS)
These have no direct bronchodialtor action, thus innefective at relief of bronchospasm when given acutely.
Glucocorticoids are lipophilic molecules and enter cells by diffusion across the plasma membrane.
In the cytoplasm they bind to GRa to produce dissocaiton of inhibitory heat shock protiens and are imported to the nucleus by importins.
The monomers assemsble to homodimers and bind to the glucocorticoid response element of certain genes.
This switches on or off genes and modulates the release of proteins (reducing the immune effect)
What are the main side effects of B2-adrenoceptor agonists
Fine termor commonly
Tachycardia, cardiac dysrhythmia and hypokalaemia can occur less commonly
What are the side effects of methylxanthines
dysrhythmia, seizure and hypotention all possible if too high a dose
Nausea, vomitng, abdominal discomfort and headaches are common
