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
What are the side effects of glucocorticoids
Dysphonia
Oropharyngeal candidiasis
Explain the mechanism of cromones
A weak anti-inflamatory effect
Decrease in the sensitivity of irritant receptors and sensory C-fibres
Explain the mechanism of MABs
Bind to aspects of the asthma pathway
Omalizumab binds to IgE to stop FcE activation
Mepolizumab binds to IL-5 to reduce eosinophil activation
Explain the basic pathway leading to COPD.
The activation of neutrophils, CD8+ T cells and, macrophages by cytokines due to the repeated insult of alveolar resident macrophages causes a release of metalloproteases and free radicles.
This causes chronic bronchitis by chronic inflammation and eventual remodelling of the bronchioles.
This causes emphysema by distention and damage along with the destruction of acinial pouching in the alveolar sacs, along with the loss of the elastic recoil.
Explain the location and function of the 3 classes of muscarinic receptors within the airway
M1 receptors are present on the postganglion neurone and facilitate the fast neurotransmission from the preganglionic fibre
M2 receptors are present at the postpanglionic neurone terminals, these act as inhibiotry autoreceptors reducing the release of ACh (blockage of them increases ACh)
M3 present on the ASM cells themselves. M3 meidate the contraction of the airway by GPCR action.
(Hence why selective M3 receptor agonsits are used)
Explain the action of muscarinic receptor antagonists
Act as antagonists to M3 receptors (all but ipratroium) reducing the influx of Ca and inturn reducing the effect of MLCK to reduce the levels of contraction.
Which is the blockage of M2 receptors non-desirable in the management of COPD.
As M2 receptors act as auto-receptor antagonsits.
They reduce the release of ACh to act on M3 receptors
What are the 3 classifications of allergic rhinitis
Seasonal (related to seasons)
Perennial (present all year)
Episodic (related to a certain thing)
Explain the pathway leading to allergic rhinitic
An allergen increases levels of allergen-specific IgE
IgE binds to mast cells and basophil FcE receptors
Re-exposure causes mast cell and basophil degranulation
The products of degranulation leads to symptoms both immediate and delayed
Explain the main diffrence between allergic and non-allergic rhinitis
Allergic rhinits involves IgE, non-allergic does not this occurs by other mechanisms.
Explain the mechanism of glucocorticoids in reference to rhinitis
Reduce vascualar permiability
Reduce recruitment and activation of pro-inflamatory cells
Explain the mechanism of anti-histamines in reference to rhinitis
Act as competitive antagonists to H1 receptors to reduce the effect of mast cell-derived histamine
Better for allergic rhinitis
Give examples of H1 receptor antagonsits
Loratidine, fexofenadine and cetirizine (they end in “ine”)
Which anti-cholinergic drug is used in rhinnitis
Ipratropium
Explain the mechanism of sodium cromoglicate
Suspected to stablise mast cells and reduce degranualtion
Explain the mechanism of vasoconstirctors (rhinitis)
Give the name of the vasoconstirctor used in rhinitis
Act either directly or indirectly to mimic the efect of noradrenalin on a1-adrenoceptors to decreases swelling in th evascular mucosa
Oxymetazoline is a selective a1-adrenoceptor agonsit given for short term relief of allergic rhinitis
Explain why oxymetazoline (vasoconstirctor) isn’t recomended for more than a few days
Runs the risk of the development of a rebound increase in nasal congestion upon discontinuation
This is due to downregulation and desensitization of receptors in the nasal mucosa.
