Local anaesthetics Flashcards
1
Q
what were the early medical uses of cocaine ?
A
- eye surgery
- spinal anaesthetic
2
Q
what was the first synthetic drug with ‘pure local’ anaesthetic’ properties ?
A
amylocaine
not in clinical uses today
3
Q
what is procaine ?
A
- second synthetic drug that was a ‘pure local anaesthetic’
- still used clinically in dentistry or to reduce pain of an antibiotic injection
4
Q
summarise signalling in the spinal cord .
A
- sensory and motor signals to and from the spinal cord and body are carried via spinal nerves
- spinal nerves divide into sensory and motor branches
- motor neurons pass through ventral roots
- sensory neurons enter spinal cord via dorsal root
5
Q
where are the cell bodies of sensory neurons ?
A
dorsal root ganglion
often called DRG neurons
6
Q
summary and classification of nerve fibre types
A
7
Q
what is the structure of DRG (sensory) neurons ?
compared to general neurons
A
- cell bodies in dorsal root ganglia
- single axon that splits with one branch to periphery and other to spinal cord (BIFURCATED AXON)
DRG neurons are unipolar (single axon)
8
Q
draw a labeled diagram of a DRG (sensory) neuron
4 marks
A
shows an Adelta fibre
9
Q
what are nociceptor ?
A
pain sensing neurons
10
Q
what is at the peripheral axon of nociceptive neurons ?
A
bare nerve ending with receptors for noxious stimuli
(or directly to mechanical stimulation)
11
Q
where do nociceptors send their signal ?
A
AP transmitted from periphery to spinal cord via DRG
12
Q
what are polymodal nociceptors ?
A
contain receptors for several types of stimuli
13
Q
draw a diagram for a polymodal noiciceptor
A
14
Q
what are the two main fibers responsible for transmitting pain signals ?
A
A delta and C fibers
15
Q
what are the cells that provide insulation around A alpha fibres ?
A
Schwann cells
16
Q
diagram of action potential time course
showing the importance of voltage gated sodium channels in genrating APs
A
17
Q
what is the relevance of sodium channels in local anaesthetics ?
A
- LAs block sodium channels
therefore.. - LAs block APs
therefore… - LAs block nociception
18
Q
what are VSSC’s ?
A
voltage sensitive sodium channels / same as voltage gated sodium channels
19
Q
what opens voltage-gated ion channels ?
A
MP depolarising
20
Q
how many subunits does the potassium channel have ?
A
4
it is a tetramer
21
Q
whatsi the structure of a potassium channel ?
A
transmembrane protein
- 6 TMDs
- channel lining between 5th and 6th TMD
22
Q
what are TPC channels ?
A
two pore channels
e.g. 2 copies of potassium channels that have then mutated so are no longer identical in structure
23
Q
where are CaV NaV and TPC channels thought to have evolved from ?
A
duplication of potassium channels which then mutates
- TPC as 2 copies
- CaV and NaV as 2 copies
24
Q
what is the structure of NaV (and CaV) channels ?
A
- pore forming subunit: alpha subunit
- alpha subunit is 4 similar copies of K+ channel structure strung together into a single peptide
- each segement of similar K+ channels is called a psudo subunit (4 pseudo subunits)
- alpha subunit folds so 4 pseudo subunits form the channel
25
how many NaV subunits are there ?
- alpha: 1.1-1.9 (9)
- 4 beta
- native channel: 1a and 1 beta
## Footnote
36 different types of sodium channels possible
26
what is a key feature of ion channels ?
- they have selective permeability (sort on basis of charge and size e.g. cation vs anion, Cl- or Na+)
- negative charge attract cations and vice versa
- does size based on hydration shell
27
what do we know about sodium channel activation and inactivation ?
they open rapidly but inactivate after ~1ms
28
how do voltage gated sodium channels work ?
- voltage sensor in 4th TMD, has charge
- as we depolarise membrane sensor moves and opens the channel allowing sodium ions to cross the membrane
- when membrane is depolraised, ball and chain structure blocks opening (inactivation gate)
29
what is the typical structure of a local anaesthetic ?
- aromatic group
- amine group
- ester OR amide group linking the two
30
what is the difference in the breakdown of amide linked local anaesthetics vs ester linked ones ?
- amide linked are broken down in the liver
- ester by plasma esterases
31
in what part of a local anaesthetic name indicates amide linkage ?
'i' in front of prefix (caine)
32
do amide or ester linked local anaesthetics have a longer duration of action ?
amide longer than ester
33
what is important about the amine group in LAs ?
allows them to become protonated, which gives them a positive charge
LA + H+ <-> LAH+
34
what does the amount of protonated forms of LAs depend on ?
- charged and uncharged forms in equilibrium
- but number of protonated (charged) depends on concentration of protons, so** pH dependent**
35
what is important about the unprotonated form of LAs ?
they are lipid soluble, so can cross cell membranes
- means equilibrium between charged and uncharged forms exist on both sides of the membrane
36
what did early experiments demonstrate about LAs and pH levels ?
- lower pH meant LAs didn't block NaVs as well
- means it could be either the uncharged or charged form that binds to NaV channels, but has to be from inside the cell (has to cross the membrane first)
37
what was the compound used to determine whether it was the charged or uncharged form of the LA that binds to NaVs and what did this reveal?
- QX314
- QX: tertiary amine (4 nitrogen groups), permenant postiive charge
- did not block NaV channels when applied to outside of cells (inactive extracellularly), but when innjected into cell it did (inhibition intracellularly)
## Footnote
QX is structurally related to lidocaine but no LA properties
38
what did the experiments with QX314 show ?
- LAs e.g. lidocaine block sodium channels from INSIDE and that it is the CHARGED form that acts on the channels
(uncharged is still important as allow it to cross membrane, but once inside the cell become protonated again and blocks channel)
39
what is the phenomenon of 'use dependence' ?
channels that are more active (either open or becoming inactivated) are blocked more strongly than resting channels
## Footnote
applies to hydrophillic pathway
40
what is the hydrophillic pathway for LAs ?
- extracellular LA is uncharged
- LA dissolves in membrane/ lipid bilayer
- LA enters cytoplasm
- LA become protonated
- channel opens, binding site for LA uncovered by opening of activation gate
- LA blocks open channel
OR
- channel inactivates, activation gate is still open so LA can bind
- LA can also block inactivated state
41
what is the hydrophobic pathway for LAs ?
- LA extracellular
- LA dissolves in membrane
- LA enters channel and is protonated
42
what is the difference between the hydrophillic and hydrophobic pathways ?
- in hydrophobic, channel activation gate does not need to open for LA to access binding site
- mechanism is use-INDEPENDENT
43
what does a lowered pH in inflammed tissue mean for LAs ?
- pH is lower (more acidic, more H+) thus LAs are less potent as will be harder to cross cell membranes
44
what are the psychotropic effects of cocaine on the CNS due to ?
block of noradrenaline reuptake
45
what are 7 methods that can be used to deliver local anaesthetics ?
- intravenous lidocaine
- epidural anaesthesia
- spinal anaesthesia
- intravenous regional anaesthesia
- nerve block
- infiltration anaesthesia
- topical anaesthesia
46
what are topical anaesthesias ?
- LAs as a cream, drops or spray
- applied to body surface e.g. nose, thraot or eyes
- block transmission of signals at peripheral nerve terminal
47
when are topical anaesthesias used ?
- pain relief from minor conditions e.g. sore throats, mouth ulcers, haemorrhoids
- minor prodecures to reduce pain of insertion of hypodermic needle
48
what is infiltration anaesthesia ?
- LAs injected into tissue around area that needs to be numbed
- only affects distal parts of the nerve/ terminal branches
49
what can be added to injected LAs/ infiltration anaesthesia and nerve block anaesthesia ?
- vasoconstrictors e.g. adrenaline
- prolongs duration of anaesthesia
50
when can infiltration anaesthesia be used ?
minor procedures e.g. suturing a wound or in dentistry
51
what is nerve block anaesthesia ?
- LAs injected around a spinal nerve trunk, everything distal (away from body) will be numbed
- needle often needs imagine e.g. ultrasound to help guide needle
52
why is nerve block anaesthesia better than topical or infiltration ?
gives better pain relief so can be used for more complicated surgeries e.g. knee replacement
53
what is intravenous regional anaesthesia ?
- pressure cuff cuts off blood supply to the limb, LA injected inravenously, 20 minutes later cuff can be removed and surgery can begin
54
why is there a period of waiting before removing the cuff after LA injection in intravenous regional anaesthesia ?
allows anaesthesia to develope and to reduce conc. of LA in blood vessels, avoiding toxicity
55
when are intravenous regional anaesthetics used and why ?
short procedures on the limbs, safe and simple
56
what is spinal anaesthesia ?
- LA injected into subarachnoid space above spinal cord
- pain sensation lost from all regions supplied by nerves emerging from SC at level of injection
57
when is spinal anaesthesia used ?
surgery on the lower body
58
why can spinal anaesthesia on be used on the bottom part of the spinal cord (and therefore in surgery for the lower body) ?
the bottom part of the spinal cord is where the subarachnoid space is large enough to avoid damage to spinal cord when placing needle
59
what some differences between spinal anaesthesia compared to an epidural one ?
- Spinal is less versatile
- Spinal produces more motor block, which is not good for baginal child birth
- Spinal has faster onset
- Spinal requires lower dose
60
what is epidural anaesthesia ?
- LA injected into Epidural space below vertebral column
- done via catheter which can be left in place to administer more doses if needed
61
what is the difference between the epidural space and subarachnoid space, and what does this mean for LAs ?
- epidural space has a larger volume
- more anaesthetic needed and onset slower for epidural space
- but placement of needle is easier and can be performed anywhere alonng spinal column
62
when are low dose epidurals used alone?
for analgesia in childbirth or for the treatment of chronic pain
63
what is the advantage of epidural vs spinal anaesthesia in terms of childbirth ?
epidural does not affect motor function as much
64
when can epidurals be used at high doses ?
- surgical anaesthesia where it is desired to keep patient awake e.g. C-section or health makes general anasthetics too risk e.g. hip replacements in older people
65
when is intravenous lidocaine used ?
patients who do not have cardiovascular problems or don't have epilepsy as a post-operative pain mangement strategy
66
what is an advantage and disadvantage of using intravenous lidocaine ?
- allows use of opioids to be reduced
- patients need to be carefully monitored for LA toxicity
67
what is 'Differential Blockade' ?
LA's act in a selective manner:
- sympathetic NS function lost first
- pain senstion lost
- touch and motor function at higher doses or last
68
what are the three factors that explain the 'differential blockade' (affect the sensitivity of a nerve fibre to be blocked by LA) ?
## Footnote
nerve fibre in a nerve
- degree of myelination
- fibre diameter
- position with the nerve
69
as a factor that affects the sensitivity of a nerve fibre to be blocked by LA, what role does the degree of myelination play ?
- spinal nerve fibres differ in degree of myelination
- A fibres have the most myelin, C are unmyelinated
- myelinated transmit APs via saltatory conduction and have NaV's conc. at nodes of Ranvier
- blockage of only a few nodes can completley prevent AP transmission
- thus, **higher degree of myelination, the more sensitive** to LAs
70
in myelinated nerve fibres, where are sodium channels concentrated ?
nodes of Ranvier
71
as a factor that affects the sensitivity of a nerve fibre to be blocked by LA, what role does fibre diameter play ?
thin fibres are more sensitive to LAs than thicker ones due to SA:V ratio
72
as a factor that affects the sensitivity of a nerve fibre to be blocked by LA, what role does the position of the nerve play ?
- fibres close to the surface of the nerve are affected more strongly (more sensitive) than those towards the centre
- due to LAs diffusing from outside the nerve into its core
73
summary table for sensitivity of nerve fibres and their function
++++: C fibre sympathetic, B fibre, C fibre sensory
+++: A delta
++: A gamma, A beta
+: A alpha
74
what kind of tissues contain VGSC's ?
heart, brain, skeletal muscle, smooth muscle
75
what do LA's cause at different doses in the brain ?
## Footnote
systemic toxicity of LAs
- low dose: neuronal activity is depressed
- and still at low dose but as conc. increase: actviity of inhibitory nuerons is suppressed more than excitatory ones, can result in convulsions
- high dose: profound depression of CNS actvity; coma or death as excitatory neurons are blocked
76
how do LA's affect the heart and cardiovascular system ?
## Footnote
systemic toxicity of LAs
- slow HR
- reduce BP
- can disturb cardiac rhythm e.g. arrhythmias
- vasodilation
## Footnote
systemic effects of LAs can be usedtheraputicall in emergency situations to reduce HR
77
what does it mean when LA's cause vasodilation in the heart and cardiovascular system ?
## Footnote
systemic toxicity of LAs
- blood flow increases
- drug into systemic circulation
- diminishes analgesic effects
78
as LAs can induce vasodilation in the cardiovascular system, how can this be avoided ?
## Footnote
systemic toxicity of LAs
can be co-injected with adrenaline (vasoconstrictor)
- limits systemic effects
- prolongs duration of action
79
when can we not co-inject LAs with adrenaline ?
## Footnote
systemic toxicity of LAs
cannot be used in tissues with limited blood supply
80
what kind of LA can produce an allergy and why ?
ester linked drugs, can be metabolised to para-aminobenzoic acid
## Footnote
or due to preservative used in formulating the drug for injection
81
what is a low dose of local anaesthetic entering the brain is likely to cause and why ?
convulsion, because inhibitory brain neurons are blocked more than excitatory ones
82
what is a high dose of local anaesthetic entering the brain is likely to cause and why ?
coma/death due to excitatory neurons being blocked
83
summary table of some local anaesthetics and their pharmacokinetics
