Neurons and Glia 2 Flashcards
Describe the glutamate-glutamine cycle. (4)
Astrocytes take up glutamate from synapse.
Glutamate converted to glutamine.
Glutamine transferred to presynaptic neurone.
Glutamine converted back to glutamate.
Name the enzyme which converts glutamate to glutamine. (1)
Glutamine synthetase
Name the enzyme which converts glutamine to glutamate. (1)
Glutaminase
Describe two reasons why it is important that astrocytes take up glutamate. (4)
To optimise neuronal function (by relieving metabolic burden of recycling NTs)
To prevent glutamate toxicity (by removing it from synaptic cleft)
How does glutamate cause excitotoxicity? (2)
Increased glutamate means more channels open
and more calcium enters cells and kills them.
Name the transporter that is involved in glutamate uptake by astrocytes. (1)
EAAT (excitatory amino acid transporter)
How do astrocytic membrane transporters take up glutamate against its concentration gradient? (3)
- Cotransport with Na
- Which is dependent on the Na/K pump maintaining the Na concentration gradient
- Using ATP
How does the uptake of glutamate into astrocytes affect the astrocytic membrane potential and why? (2)
Becomes more positive
Because of cotransport with positive ions moving into cell
Describe the relative glutamate concentrations inside and outside of astrocytes. (2)
Inside cell is high
Outside cell is low
What are ‘gliotransmitters’? (1)
Molecules which are released from glial cells and pass signals to other glial cells or neurones.
Name two examples of gliotransmitters. (2)
- Glutamate
- ATP
Describe how neuronal activity triggers the release of gliotransmitters from astrocytes. (4)
- Neurone releases neurotransmitter
- Neurotransmitter binds to metabotropic receptor on astrocyte
- Elevated intracellular calcium
- Release of gliotransmitter
What are the roles of gliotransmitters on pre/post-synaptic neurones. (2)
- Modify neuronal excitability
- Modify subsequent NT release
True or false? (1)
At a tripartite synapse, astrocytes contain receptors for 80% of the neurotransmitters which are released at the corresponding synapse.
False - astrocytes contain receptors for 100% of the NTs released
Name three methods of gliotransmitter release from astrocytes which are not vesicular. (3)
- Hemichannels
- P2X7 (ATP) receptors
- Volume sensitive chloride channels
What are two differences between intracellular increases in calcium in neurones and astrocytes? (2)
In neurones calcium rises rapidly and is a transient effect.
In astrocytes calcium rises slower but is more sustained.
Why does intracellular calcium rise rapidly in neurones but not astrocytes? (2)
In neurones, increased calcium is due to opening of voltage gated calcium channels.
In astrocytes, increased calcium is due to release from intracellular stores.
True or false? (1)
In addition to release from intracellular stores, calcium can also be increased in astrocytes due to movement through glutamatergic AMPA and kainate receptors.
True - in SOME subtypes, AMPA and kainate receptors are permeable to calcium, but this does not contribute much to the rise in calcium
Give the relative concentrations of calcium in:
a) extracellular space
b) astrocytic cytosol
c) astrocytic endoplasmic reticulum
(3)
Extracellular - high
Cytosol - low
ER - high
Give two reasons why it is important to keep the calcium concentrations low in the astrocytic cytoplasm. (2)
- Calcium kills cells
- So that calcium signals can be produced at low thresholds
Describe two methods of keeping cytosolic calcium concentrations low in astrocytes, and describe the ion channels used. (4)
Calcium moved to outside of cell
by plasma membrane Ca ATP-ase (PMCA).
Calcium moved into endoplasmic reticulum
by SarcoEndoplasmic reticulum Ca ATP-ase (SERCA).
Describe how the binding of glutamate to mGluRs leads to an increase in intracellular calcium concentration. (4)
- Second messenger cascade from GPCR
- IP2 converted to IP3
- by phospholipase C
- IP3 causes Ca to be released from ER
Describe how intracellular calcium waves are produced when glutamate binds to mGluRs. (3)
- Second messenger cascade causes IP3 to release calcium from ER
- Increased calcium augments IP3 action
- Positive feedback loop releasing more calcium throughout cell
What is an intercellular calcium wave? (1)
Localised increase in calcium which spreads between cells.
Describe two molecular mechanisms which may facilitate intercellular calcium waves. (2)
- IP3 and calcium diffuse to adjacent cells through gap junctions
- First cell releases ATP into extracellular space which acts as a messenger to stimulate IP3 production in adjacent cells
What is meant when astrocytes are described as a ‘syncytium’? (1)
Network of cells joined by gap junctions.
What would you expect the effect on neuronal mEPSCs to be after stimulating an astrocyte with increased intracellular calcium? (1)
Frequency would increase
Describe two potential mechanisms which may explain how increased calcium in astrocytes leads to modified neuronal activity. (4)
Increased calcium leads to glutamate release, which:
a) binds to NMDA receptors on neurones
AND/OR
b) binds to mGluRs on neurones
This leads to increased neuronal calcium which increased NT release.
Give two responses of astrocytes to increased glutamate in the synaptic cleft. (2)
- Uptake/recycling of glutamate
- Glutamate/calcium signalling to communicate with neurones
What percentage of the total cardiac output is received by the brain? (1)
20%
How is the distribution of blood in different areas of the brain varied? (1)
By the cerebral vasculature
True or false? (1)
Arterioles, venules, and capillaries all have multiple layers of endothelial cells and smooth muscle, making them contractile.
False - capillaries have no smooth muscle and only one layer of endothelial cells
It is likely that which types of cell help to control blood flow in capillaries? (1)
Pericytes
Describe what is meant by ‘neurovascular coupling’.
What structures are involved?
What is another name for neurovascular coupling? (3)
NVC describes the changes in local perfusion which occur as a result of changes in neuronal activity.
Occurs between neurones, astrocytes, and blood vessels.
Another name is ‘reactive hyperaemia’.
Describe how Poiseuille’s law relates to blood vessel radius and blood distribution in the brain. (2)
Flow rate is proportional to radius^4.
A very small increase in blood vessel radius will facilitate a large increase in blood flow.
Briefly describe the process of how astrocytes are able to cause dilation of cerebral arterioles. (5)
- Neural stimulation causes increased calcium in astrocytes
- via glutamate binding to mGluRs, or NA signalling
- Increased calcium leads to production of arachidonic acid
- COX enzymes convert AA to prostaglandins
- Which diffuse from astrocyte to blood vessel and cause vasodilation
What would the effect on blood vessel diameter be if mGluR receptor antagonists were applied to astrocytes? (1)
Astrocytes would not be able to affect blood vessel diameter.
What would the effect on blood vessel diameter be if mGluR receptor agonists were applied to astrocytes? (1)
Facilitation of change in blood vessel diameter
Describe how an increase in calcium facilitates increased production of arachidonic acid in astrocytes. (2)
- Calcium activates phospholipase A2
- Which converts phospholipids to arachidonic acid
Aspirin and indomethacin are COX inhibitors. How would they affect the production of prostaglandins in astrocytes? (1)
They would inhibit the production of prostaglandins.
What is the effect of NO on blood vessel diameter? (1)
Potent vasodilator
True or false? (1)
Neurones can occasionally be stimulated to release small amounts of NO to dilate blood vessels.
False - neurones constantly release NO in a sustained tonic pattern
True or false? (1)
Astrocytes are able to release NO in response to mGluR stimulation in order to enhance vasodilation.
Nobody really knows. Some suggest that this is true but others don’t.
Astrocytes are relatively large cells.
How does the local increase in calcium triggered by neuronal activity make its way to the end feet surrounding the blood vessels? (2)
Ca-induced Ca release.
Intracellular calcium waves produced by calcium and IP3.
True or false. (1)
As well as vasodilation, glutamate and NA released from neurones can also cause vasoconstriction.
True
True or false? (1)
The degree of vasoconstriction or vasodilation in cerebral arterioles is independent of the number of astrocytic end feet showing a rise in intracellular calcium.
False - more calcium results in more change in blood vessel diameter
Describe the molecular mechanism which allows an increase in astrocytic calcium to result in vasoconstriction. (5)
- Calcium activates phospholipase A2
- PLA2 converts phospholipids to arachidonic acid
- AA diffuses from astrocyte and into vascular smooth muscle cell
- AA converted to 20-HETE by a CYP enzyme
- 20-HETE causes vasoconstriction
When there are low oxygen concentrations in a region of brain tissue, two molecules affect whether astrocytes cause vasoconstriction or vasodilation.
What are these molecules? (2)
- Adenosine
- Lactate
How does adenosine affect blood vessel diameter and blood flow in regions of low oxygen concentration? (3)
- Low ATP causes adenosine release from neurones
- Adenosine stops 20-HETE from causing vasoconstriction
- Increased blood flow
How does lactate affect blood vessel diameter and blood flow in regions of low oxygen concentration? (4)
Lactate produced due to anaerobic respiration.
Inhibits astrocytic reuptake of prostanoids.
Prostanoids persist in extracellular space, causing more vasodilation.
Increased blood flow.
What are pericytes and where are they found? (2)
Contractile cells that are spaced at intervals along capillaries,
mostly found where arterioles are becoming capillaries.
Name the three general types of pericyte found throughout the capillary network. (3)
- Ensheathing pericytes
- Mesh pericytes
- Thin-strand pericytes
True or false? (1)
In general, the further you move through the capillary network, the fewer pericytes are found.
True
Describe how neuronal activity affects the production and release of NO by neurones, and how this affects blood vessel diameter. (3)
- Glutamate (from increased neuronal activity) binds to NMDA receptors
- Increased NO production and release by neurones
- Vasodilation
Describe what is meant by a ‘passive axon’? (1)
An axon containing no voltage-gated ion channels, so all electrical activity is carried out through leak channels.
Name the three passive properties of an axon (and their symbols). (3)
- Membrane resistance (rm)
- Axoplasmic resistance (ri)
- Membrane capacitance (cm)
Describe the composition of the axoplasm and how this confers resistance. (2)
- Solution which contains salt ions
- More ions means lower resistance because there are more molecules able to carry the charge
Describe the composition of the passive neuronal membrane and how this confers resistance. (2)
Lipid bilayer with leak channels.
Increased leak channels means lower resistance because there are more pathways available for ions to exit.
Describe how the specific membrane capacitance of an unmyelinated axon changes as the properties of the axon change. (2)
It doesn’t change.
It tends to be fixed at about 1uF cm^-2
Give the definition of membrane resistance (rm). (1)
Membrane resistance of a 1cm length of axon (units = ohms.cm)
Give the definition of specific membrane resistance (Rm). (1)
Resistance of a 1cm^2 patch of membrane
(units = ohms.cm^2)
Give the equation linking rm with Rm. (1)
rm = Rm/(2 x pi x rad)
Give a simple equation which links rm with radius. (1)
rm = 1/radius
How does the number of ion channels in the membrane change if the radius of the axon is doubled?
How would this affect membrane resistance? (4)
Hint: use numbers
Doubled radius results in doubled membrane area.
Leak channels present in the membrane at a fixed density.
So double the number of ion channels.
rm decreases.
Define axoplasmic resistance (ri). (1)
Axoplasm (internal) resistance of a 1cm length of axon.
(units = ohms.cm^1)
Define specific internal resistance (Ri). (1)
Resistance of a 1cm length of a 1cm^2 cross-sectional area axon.
(units = ohms.cm)
Give an equation which links ri and Ri. (1)
ri = Ri/(pi x rad^2)
How does the number of ions in the axoplasm change if the radius of the axon is doubled?
How would this affect axoplasmic resistance? (4)
Hint: use numbers
Doubling the radius increases cross-sectional area by 4.
So number of ions will increase by 4 if the radius doubles.
Because the ions are present at a fixed concentration.
ri will decrease.
Give a simple equation linking ri with axon radius. (1)
ri = 1/radius^2
Complete the sentence. (1)
Membrane resistance can be thought of as a measure of ……………………………………………….
The number of leak channels in the membrane
Complete the sentence. (1)
Axonal resistance can be thought of as a measure of ……………………………………………..
The number of salt ions in the axoplasm.
Describe how resistance affects the amount of current which can move through a pathway. (1)
Decreased resistance means more current can move through that pathway.
Define membrane capacitance (cm). (1)
Membrane capacitance of a 1cm length of axon.
(units = F.cm^-1)
Define specific membrane capacitance (Cm). (1)
Capacitance of a 1cm^2 patch of membrane.
(units = uF.cm^-2)
Give an equation which links cm with Cm. (1)
cm = 2 x pi x rad x Cm
How does the membrane capacitance (cm) and specific membrane capacitance (Cm) change if the radius of the axon is doubled? (3)
Hint: use numbers
Increasing axon radius by 2 increases membrane area by 2.
cm will increase.
However Cm stays fixed.
Write Ohm’s law. (1)
V=IR
Give the definition of input resistance. (1)
Input resistance reflects the total resistance of an axon, made up of both membrane and axonal resistances.
Give an equation for input resistance. (1)
r(input) = 0.5(squareroot of (rm.ri))
(units = ohms)
How does input resistance affect how much voltage will be produced if a current is injected into an axon? (2)
If the axon has a high input resistance, a higher voltage will be produced when current is injected.
Because V=IR
Use the equation:
r(input) = 0.5(squareroot of (rm.ri))
to describe how axon radius affects input resistance. (2)
Hint: you will have to manipulate the equation
Manipulate the equation to 0.5(squareroot of (Rm.Ri/2Pi^2rad^3))
As axon radius increases r(input) decreases.
Describe the length constant (in words). (1)
The length constant is the distance over which voltage will spread.
Give an equation for the length constant. (1)
y = squareroot of (rm/ri)
To increase the length constant, would you have to increase or decrease rm? (1)
Increase
To increase the length constant, would you have to increase or decrease ri? (1)
Decrease
Use the equation:
y = squareroot of (rm/ri)
to describe how axon radius affects length constant. (2)
Hint: you will have to manipulate the equation
Manipulate and simplify the equation to y = squareroot of (rad)
As radius increases, length constant increases.
True or false? (1)
The relationship between axon radius and length constant is linear - increasing axon radius will always increase the length constant.
False - the length constant is limited so it will eventually not get any bigger, even with increasing radius
Describe the relationship between the length constant, and the distance that an injected current will spread down an axon. (1)
Increased length constant means that the current will spread for a longer distance down the axon.
Is the relationship between the current at a particular point on an axon (compared to an injected current further up the axon) and the length constant:
a) linear
b) exponential
c) there is no relationship
? (1)
Exponential
Complete the sentence. (1)
The voltage measured at any point along an axon (after a current has been injected) will be proportional to …………………………………
The current flow across the membrane
If a large amount of current flows across the membrane, describe the relative values of ri and rm. (2)
Low rm
High ri
Describe the time constant in words. (1)
The time constant is the time taken to reach 63% of the maximal voltage response to a current.
Give an equation for the time constant. (1)
T = Rm.Cm
Describe how the size of an axon affects the time constant, and explain the reasons for this. (2)
T is unaffected by axon size.
Increasing axon size causes rm to decrease to the same extent that cm increases.
How does the membrane resistance affect how rapidly the voltage across the membrane increases as a current is applied?
Explain the reason why, in terms of the time constant, T. (3)
- Increased membrane resistance means the voltage rises slower
- Because increased Rm results in increased time constant
Why does membrane capacitance cause a delay in the voltage response of an axon after current is applied? (2)
The ions which produce the current first charge the membrane (capacitor) before they charge the axon.
The ions charging the capacitor are tied up along the inside of the membrane so cannot contribute to the voltage charge.
Give an equation which describes change in voltage (conduction velocity) in relation to the passive properties of a membrane. (1)
Conduction velocity = 1/(ri.cm)
Give two ways by which conduction velocity of an axon can be increased.
Describe how they work with reference to the passive properties of the axon. (4)
- Add myelin (decreases cm)
- Increase axon size (decreases ri)
If an axon has an increased diameter, explain which the increase in membrane capacitance will NOT slow down conduction velocity. (3)
Capacitance is increased in proportion to rad.
However ri is decreased in proportion to rad^2.
So the decreased internal resistance has a larger effect on conduction velocity.
Describe how the radius of an axon affects its threshold, with reference to the axon’s passive properties. (3)
Greater radius means lower ri.
So more current enters the axon.
And it is depolarised more efficiently.
Describe a hypothesis which explains why the greater number of ion channels in the membrane of a larger axon is considered not to have an affect on how easily threshold is met when a current is applied. (2)
It is counter-balanced by capacitance,
however if capacitance didn’t exist, the greater number of ion channels would logically allow more current to enter the axon and reach threshold quicker.
Why is rm not included in the equation for conduction velocity, when logically, it would have an effect? (4)
The way to increase rm physiologically would be to increase the axon diameter
however if increasing the diameter, ri is affected relative to rad^2
rm is affected relative to rad
so ri is more important
What is meant by the phrase ‘caged calcium’? (1)
Calcium ions which have been encapsulated by a photochemical protective group.
True or false? (1)
Caged calcium is still able to participate in cellular signalling.
False - Caged calcium is inert
How is caged calcium ‘released’? (1)
Laser flash (photolysis)
Describe what is meant by ‘encephalisation’. (2)
The idea that larger animals have larger brains,
but as animals increase in size the proportion of the body that the brain occupies gets smaller.
Complete the sentence. (1)
As an animal’s body size increases, brain size increases by a factor of ……………………
Less than one
Describe how the actual size of the human brain compares with the expected size for its body mass. (1)
Brain mass is much larger
Describe how the brain size would compare between a rodent and a primate of the same body size. (1)
Mammal brain would be larger
Describe how the actual density of neurones in the human brain compares to the expected density of neurones for a brain of that size. (1)
The density is as expected
Describe why for humans, more neurones means higher intelligence, but for another animal with the same number of neurones, they would not have the same intelligence. (3)
After neurones have been assigned roles for survival, any remaining neurones can be assigned to the cerebral cortex for intelligence.
Humans will have a smaller body size compared to an animal with the same number of neurones in their brain.
So humans need less neurones assigned for survival, so more neurones are available for intelligence.
Name a technique that could be used to measure the number of neurones in a brain compared to the total number of cells. (1)
Isotropic fractionator technique
Describe the isotropic fractionator technique for counting the number of neurones and glial cells in the brain. (6)
- Isolate and homogenise bits of brain
- Stain sample with DAPI (stains all nuclei of neurones + glia)
- Count total number of nuclei
- Stain sample with NeuN (stains only neuronal nuclei)
- Count number of neuronal nuclei
- Number of glia = DAPI - NeuN
Describe how the number of neurones would differ between rodents and primates which have the same brain mass. (1)
Primates would have more neurones
Describe how the relationship between the number of neurones in a rodent and primate brain of the same size changes as the size of their brains increases. (1)
The difference becomes more pronounced
If a rodent and a primate had the same number of neurones in their brain, how would you expect the sizes of their brains to compare? (1)
Rodent brain would be much bigger
Describe the kind of number you would expect to define the power relationship between the number of neurones in a rodent’s brain, and the size of that brain. (1)
Number more than 1
For primates, describe the relationship between brain size and neuronal density. (1)
Neuronal density doesn’t tend to change with increasing brain size.
For rodents, describe the relationship between brain size and neuronal density. (1)
As rodent brains get larger, the neuronal density decreases.
True or false? (1)
A rodent and a primate with the same brain size will have differing numbers of neurones, however the number of neurones in the cerebral cortex will actually be the same.
False - the difference in neurone number will also be seen in the cortex
Describe the number of neurones in the brain of a great ape compared to what you would expect it to be according to their body mass. (1)
Number of neurones is lower than expected.
Why do great apes not conform to the primate model of body mass vs number of neurones? (3)
- Great apes are vegetarian (calorific intake limited by not eating meat and only being able to forage in the daytime)
- If great apes had bigger brains they would not be able to meet the energy requirements due to their limited calorific intake
- Evolution stopped them having huge brains
Describe the distribution of neurones in an elephant’s brain. (1)
Much higher proportion of neurones in the cerebellum than in other species.
Why do elephants have lots of neurones in their cerebellum? (1)
Large nerves in their trunk require large amounts of sensory input and motor output to allow them to communicate and sense their environment.
True or false? (1)
It seems that intelligence may depend on the number of neurones in the cerebral cortex.
True - if they have the same brain mass, primates would have more neurones in their cerebral cortex than rodents, which is why they are generally more intelligent
Describe the general ratio of neurones to glial cells in the human brain. (1)
1:1 - there are the same number of neurones and glial cells
Describe the correlation between brain size and number of glial cells.
How does this differ between rodents and primates? (2)
Strong correlation between brain mass and number of glia (bigger brain = more glial cells).
This applies to both rodents and primates - it doesn’t differ.
Describe the expected glia:neurone ratio in a rodent brain.
Why would you expect this? (3)
High glia:neurone ratio.
Because rodents have less neurones, but the same number of glial cells as a primate with a similar-sized brain.
So more glial cells compared to neurones.
How would you expect the size of neurones to differ between rodents and primates with brains of the same size? Why? (2)
Rodent neurones must be larger
because less neurones fill the same volume.
How would you expect the size of glial cells to differ between rodents and primates with the same brain size? Why? (2)
They would be the same size.
Because rodents and primates with the same-sized brain would have the same number of glial cells.
Why have humans evolved to have a larger brain size compared to their body size? (3)
- Cooking enables increased calorie intake from food, and less need for foraging
- When cooking was invented humans were able to take in more energy each day
- Evolution allowed humans to have bigger brains because humans could meet the increased energy demands
A bigger brain does not always result in increased intelligence.
So how have humans been able to use their big brains to develop high intelligence levels? (2)
Humans have been able to challenge their brains
due to increased materials and knowledge that have become available over time.
What compromise is made in the brain, given that the size is limited by energy intake? (1)
Axons only conduct at the speeds that they need to in order to do their jobs.
If larger animals have brains which take up a smaller proportion of their bodies than smaller animals, they are going to struggle to increase axonal conduction velocity to the extent that is required for their body size.
What is the consequence of this? (1)
Larger animals tend to have slower reflexes.
Can large or small axons conduct action potentials at higher frequencies?
Why? (3)
Large axons conduct at higher frequencies.
Because they have more mitochondria but less sodium ions per unit area (due to dilution of sodium).
So Na removed from axon quicker by Na/K pump after action potential.
If larger axons can conduct action potentials at higher frequencies, why are many axons in the human brain relatively small?
Surely it would be better to conduct information at higher frequencies to pass along more information? (4)
The size of the brain is limited.
Many small axons can fit into the same space as one large axon.
Although smaller axons conduct information at lower frequencies, in total more bits of information are conducted per unit area, and less energy is used.
Therefore many smaller axons are more efficient.
Do large axons or small axons use more energy? (1)
Large axons
What is local anaesthesia? (3)
A transient loss of sensation (pain/touch/temperature/pressure)
in a localised anatomical area
by blocking nerve conduction.
Describe the three structural components of a local anaesthetic molecule. (3)
- Lipophilic aromatic ring
- Intermediate ester or amide link
- Tertiary amine
Are local anaesthetics soluble in water?
Give an explanation. (4)
Yes and no.
The amine part of the local anaesthetic is not water soluble in its tertiary ‘standard’ form.
However the amine form can also exist in a quaternary form,
which is positively charged and soluble in water.
Why does a local anaesthetic molecule need to convert between both water soluble and water insoluble forms to perform its function? (2)
Needs to be water soluble to be injected into skin/tissue.
However needs to be lipid soluble (water insoluble) to cross neuronal membrane.
True or false? (1)
A local anasthetic molecule is injected in its tertiary form.
False - it needs to be charged (water soluble) to be injected, so it has to be in its quaternary form
True or false? (1)
Once injected, a local anaesthetic is converted from its quaternary form to its tertiary form inside the neuronal axoplasm.
False - the local anaesthetic cannot cross the neuronal membrane until it is in its tertiary form, so it has to be converted in the extracellular space
The whole point of it being converted is so that it can cross into the axoplasm.
What property of an injected local anaesthetic determines the time to its onset of action? (1)
The proportion of the molecule which is converted from quaternary to tertiary form.
Give the general chemical definition of pKa. (1)
pKa is an equilibrium constant which describes the propensity of a molecule to reversibly separate into a number of smaller molecules.
Give the definition of pKa, in terms of local anaesthetics. (1)
pKa is the pH at which half of a local anaesthetic is ionised and half is unionised.
Describe the relationship between the body’s pH and the effectiveness of a local anaesthetic, with reasons. (4)
As the pH becomes more acidic (eg. in injured and elderly)
a lower proportion of anaesthetic molecules are uncharged
so less molecules are able to cross the neuronal membrane
so the local anaesthetic is less effective.
If an equal dose was given of two anaesthetics, one with pKa 7.4 and one with pKa 8.6, which one would be more effective at a body pH of 7.3? (1)
pKa 7.4
If an equal dose was given of two anaesthetics, one with pKa 7.4 and one with pKa 8.6, which one would be more effective at a body pH of 8? (1)
pKa 7.4 (I think)
Clinically, how are local anaesthetics prevented from getting into the systemic circulation? (1)
By using vasopressors
How do vasopressors stop local anaesthetics getting into the systemic circulation? (2)
Constrict blood vessels
reduce the perfusion of local anaesthetics into the venous drainage.
Give two reasons why we don’t want local anaesthetics getting into the systemic circulation. (2)
- LAs block sodium channels, which would be bad if it happened in all neurones or other organs such as the heart
- Limiting the systemic circulation also prolongs the effects of the local anaesthetic
What is meant by the dual action hypothesis of local anaesthetics? (1)
The suggestion that a local anaesthetic acts on the neurone via one of two different pathways.
Describe the hydrophobic pathway of local anaesthetic action. (2)
- Local anaesthetic blocks sodium channels via the neuronal membrane
- LA can move through the membrane or channel wall and can bind to open or closed channels
Describe the hydrophilic pathway of local anaesthetic action. (2)
- The local anaesthetic blocks the sodium channel via the inside of the cell
- LA can only block open channels
True or false? (1)
A local anaesthetic molecule has to be charged (quaternary form) to be able to block sodium channels.
True - it gains a hydrogen ion after crossing the neuronal membrane
Which pathway of local anaesthetic mechanism can be described as ‘use-dependent’? (1)
a) hydrophobic
b) hydrophilic
Hydrophilic
Describe what is meant by the term ‘use-dependent’ when discussing hydrophilic local anaesthetic action. (3)
- A neurone which is firing high frequency action potentials is blocked more by local anaesthetics
- because the LA molecule is more likely to encounter an open channel
- and more LA binds cumutively during successive action potentials.
Which exact part of the sodium channel do local anaesthetic molecules bind to? (1)
Domain 4, segment 6 (IVS6)
How do local anaesthetic molecules bind to the right region of the sodium channel? (1)
It binds to specific amino acids in the polypeptide chain.
Describe the proposed mechanism of how the local anaesthetic reduces sodium current after it has bound to sodium channels. (3)
Local anaesthetic hovers in the pore of the channel
held in place by hydrostatic bonds to the relevant amino acids
the LA molceule can then use its positive charge to repel sodium ions
List 6 ideal properties of a local anaesthetic. (6)
- Non-irritant to area of application
- No permanent effect on nerve structure
- Low systemic toxicity
- Effective regardless of route of application
- Rapid time of onset
- Limited duration (no extended recovery)
