Flashcards in *Pharmacology (1) Deck (58)
What neurotransmitter do all preganglionic fibres of the sympathetic and parasympathetic division use?
Where are cell bodies of the preganglionic fibres of the parasympathetic division located?
In the brainstem (this is where they synapse onto the post-synaptic fibre)
Where are the cell bodies of the postganglionic fibres located (parasympathetic) in the respiratory system?
In the walls of the bronchi and bronchioles
What does stimulation of postganglionic cholinergic fibres cause in terms of bronchial smooth muscle?
What is this mediated by?
Bronchial smooth muscle contraction
M3 muscarinic ACh receptors on airway smooth muscle cells
Increased mucus secretion mediated by M3 muscarinic ACh receptors on goblet cells
What does stimulation of postganglionic noncholinergic fibres cause (parasympathetic division)?
Bronchial smooth muscle relaxation mediated by NO and VIP (instead of ACh which would cause contraction)
What are nitric neurones?
nerve cells where transmission is mediated by NO
What 2 effects can the parasympathetic system have on airway smooth muscle and what is each mediated by?
Contraction = cholinergic post-synaptic neurone (uses ACh)
Relaxation = nitrergic post ganglionic neurone (uses NO and VIP)
Does the sympathetic nervous system supply the lungs?
Post-ganglionic fibres supply submucosal glands and smooth muscles of blood vessels
There is NO innervation of bronchial smooth muscle
What does stimulation of the sympathetic nervous system cause in terms of the lungs? (4)
what is each mediated by?
Bronchial smooth muscle relaxation via B2-adrenoceptors on airway smooth muscle cells activated by adrenaline released from the adrenal gland
Decreased mucus secretion mediated by B2 adrenoceptors on goblet cells
Increased mucociliary clearance (mediated by B2 adrenoceptors on epithelial cells)
Vascular smooth muscle contraction mediated by alpha1-adrenoceptors on vascular smooth muscle
How does airway smooth muscle contract at the cellular level - G-protein-coupled receptor mechanism?
The transmitter or hormone activated the G-protein coupled receptor (in lungs this is M3)
This activates the membrane bound enzyme PLC
PLC degrades PIP2 to IP3 which is a secondary messenger
IP3 diffuses through the cytoplasm until it encounters the IP3 receptor on the sacroplasmic reticulum
IP3 opens the channel and calcium diffuses out of the reticulum and into the cytoplasm which causes contraction
What is the sarcoplasmic reticulum?
The main calcium ion store in the cell
How many ways can smooth muscle be stimulated to contract (cellular level)?
Either by the activation of G protein coupled receptors (most important)
Depolarisation activating a calcium channel on the cell surface
How does airway smooth muscle contract at the cellular level - calcium channel mechanism?
Depolarisation activates a Ca2+ channel on the cell surface
Calcium moves down the concentration gradient into the cell
This is an amplification stop
Calcium binds to the calcium activated calcium channel (ryanodine receptor) on the sarcoplasmic reticulum membrane which causes the channel to open and calcium to leave the internal Ca2+ store causing contraction
How does the release of calcium from the sarcoplasmic reticulum initiate contraction of smooth muscle?
Increase in intercellular calcium concentration is sensed by a calcium binding molecule within the cytoplasm called Calmodulin (this is a regulatory protein - not an enzyme)
When Calmodulin binds to Ca2+, it undergoes a conformational change and becomes an active complex which can integrate with downstream targets
Ca2+-Calmodulin wraps itself around inactive MLCK activating it
Active mLCK tips the terminal phosphate from ATP = ADP and Pi
this Pi phosphorylates the myosin cross bridge forming an actin myosin cross bridge which can bind actin
What does MLCK stand for?
Myosin light chain kinase
In terms of the regulatory myosin light chain, what causes contraction of smooth muscle cells?
phosphorylation of MLC in the presence of elevated intracellular Ca2+
How does smooth muscle relax?
Due to dephosphorylation fo MLC by myosin phosphatase (MLCK and myosin phosphates activity opposes each other)
What does myosin light chain kinase do?
Phosphorylates (adds a phosphate) to the myosin light chain causing contraction
What does myosin phosphatase do?
Dephosphorylates the myosin light chain = relaxation
What happens to the enzymes in the presence of elevated intracellular Ca2+
the rate of phosphorylation exceeds the rate of dephosphorylation
Therefore for relaxation the intracellular Ca2+ concentration must return to basal level (achieved by primary and secondary active transport)
What happens when B2 adrenoceptor is stimulated by adrenaline in terms of phosphorylation?
B2 adrenoceptor is coupled to Gs which activates adenyl cyclase (AC)
AC causes the conversion of ATP to cAMP which binds to protein kinase A (PKA) activating it (cAMP is degraded by Phosphodiesterase (PDE))
PKA phosphorylates the myosin light chain kinase inhibiting it and phosphorylates myosin phosphatase stimulating it
This results in relaxation of bronchial smooth muscle
What happens to vascular smooth muscle due to release of adrenaline and through what receptors?
Activation of B2 = vasodilation at lungs
Activation of alpha 1 = vasoconstriction in rest of body
What is asthma?
Recurrent and reversible (in the short term) obstruction of the airways in response to substances (or stimuli) that are not necessarily noxious and normally do not affect non-asthmatic subjects
What is acute severe asthma?
What is another name for this?
an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators (inhalers) and steroids.
what can happen if chronic asthma is not treated?
It can develop into an obstruction of the airways which is only partially reversible
What pathological changes to the bronchioles can occur in chronic asthmatics due to long standing inflammation? (5)
Increased mass of smooth muscle (hyperplasia and hypertrophy)
Accumulation of interstitial fluid (oedema)
Increased mucus secretion
Epithelial damage (exposing sensory nerve endings)
(airway narrowing by inflammation and bronchoconstriction increases airway resistance decreasing FEV1 and PEFR)
What causes increased sensitivity of the airways to bronchoconstrictor influences in asthmatic?
Epithelial damage, exposing sensory nerve endings (C-fibres, irritant receptors) causes increased sensitivity of the airways to bronchoconsitrctor influences (may cause neurogenic inflammation due to release of various peptides)
what is hypersensitiviy?
having extreme physical sensitivity to particular substances or conditions.
What is hyper-reactivity?
a state characterised by easily triggered bronchospasm
What are the 2 components of bronchial hyper-responsivness in asthma?
What type of hyper-responsivness will a patient with mild asthma have?
What effect does this have on the curve of concentration of inhaled bronchoconstrictor against fall in FEV1 have?
Shifts it to the left
What type of hyper-responsivness will a patient with severe asthma have?
What effect does this have on the curve of concentration of inhaled bronchoconstrictor against fall in FEV1 have?
Hypersensitivity and hyperreactivity
Shifts the curve to the left and also increases the peak
What are the 2 phases of an asthma attack? What causes each phases?
What type of hypersensitivity reaction is each phase?
Immediate (mainly bronchospasm - some acute inflammation) - type I hypersensitivity reaction
Delayed (inflammatory reaction) - type IV hypersensitivity reaction
What are the 2 different types of T helper cells?
What type of T helper cell response leads to mild to moderate asthma?
What type of T helper cell response leads to severe asthma?
Th2 response predominates but Th1 response also contributes
What happens to nonatopic individuals when exposed to an allergen?
Phagocytosis by an antigen presenting (dendritic) cell causing a low level Th1 response (cell-mediated immune response involving IgG and macrophages)
What is a Th1 response?
Cell mediated immune reins involving IgG and macrophages
What is a Th2 response?
Antibody-medited immune response involving IgE
What happens to atopic individuals when exposed to an allergen?
Phagocytosis by antigen presenting (dendritic) cell causes a strong Th2 response
What is thought to favour a Th1 response when exposed to an allergen?
Exposure early in life to microbes favouring Th1 reponse
What is though to favour a Th2 response when exposed to an allergen?
A hygienic "western lifestyle"
What causes the initiation phase of the development of allergic asthma?
Initial presentation of an antigen (e.g. dust mite protein or pollen) initiates an adaptive immune response
What is another name for CD4+ cells?
Helper T cells
what is involved, in terms of cells, with the induction phase of the development of allergic asthma?
Antigen presenting cell (dendrite) in the airway epithelium presents an aeroallergen to T CD4+ cells (T helper cells)
This causes Th0 cells to preferentially mature to Th2 cells (instead of Th1 cells)
Th2 cells activate B cells by binding to them and by IL-4 production
B cells mature to IgE secreting plasma cells
What is another name for CD8+ cells?
Cytotoxic T cells
What can Th0 cells do?
Mature to Th1 or tH2 cells
What are interleukins?
any of a group of naturally occurring proteins that mediate communication between cells
what are cytokines?
any of a number of substances, such as interferon, interleukin, and growth factors, which are secreted by certain cells of the immune system and have an effect on other cells.
What is involved, in terms of cells, with the effector phase of the development of allergic asthma?
The IgE produced during the induction phase can attach to a number of inflammatory cells in the airways (in particular eosinophils and mast cells)
Eosinophils differentiate and activate in response to Il-5 released from Th2 cells allowing IgE receptors to be expressed on their membrane
Mast cells in the airway tissue express IgE receptors in response to il-4 and IL-13 released from Th2 cells
What happens when asthmatics are subsequently presented with the aeroallergen antigen?
The antigen crosslinks IgE receptors stimulating calcium entry into the mast cells and release of Ca2+ from intracellular stores causing:
-release of secretory granules containing preformed histamines and the production and release of other agents e.g. leukotrienes causing airway smooth muscle contraction
-release of substances (e.g. prostaglandins) which attract cells causing inflammation (e.g. eosinophils) into the area
What 2 phases does the development of allergic asthma involve?
What interleukin produced by Th2 cells activates B cells causing them to mature to IgE secreting plasma cells?
What interleukin released by Th2 causes eosinophils to differentiate and activate?
What interleukins released by Th2 cells causes mast cells to express IgE receptors?
IL-4 and IL-13
What cells are involved in the immediate stage of an asthma attack?
What does this lead to the late phase?
Allergen activates mast cells and other mononuclear cells = release of histamine, etc. which leads to bronchospasm and early inflammation
Release of chemotaxins and chemokines leads to the late phase
What does cytokine released in the immediate phase lead to (what happens in the late phase) in terms of cells?
Infiltration of cytokine releasing Th2 cells and monocytes and activation of inflammatory cells (particularly eosinophils)