BS42025 L7

Question 1

what are the different classifications of anaesthetics? (3)

Answer 1

Local anaesthetics- provide analgesia close to the source of the pain.

Central analgesia- provide analgesia through central/spinal sites (e.g. opioids)

General anaesthesia- provides loss of consciousness and (some but not all of these anaesthetics provide) analgesia.

Question 2

describe the pain pathway (5)

Answer 2

• peripheral nociceptive neurons receive a pain stimulus from the skin.
• This will evoke a response in the primary afferent nociceptive neurons.
• This will evoke an AP that will travel towards the spinal cord via Dorsal root ganglion neurons
• the AP will travel up the spinal cord to the thalamus
• thalamic neurons relay the signal to the cortex which registers the pain

Question 3

what can activate the pain sensitive ion channels? (2)

Answer 3

stretch (mechanoreceptors)

heat (TRPV1)

Question 4

how to Na+ and K+ channels react to APs? (4)

Answer 4

• membrane depolarises slightly and at -50mV Na+ channels open (m gate)
• this depolarising stage carries on till +50mV but the K+ channels are activated and open (n gate) at +20mV
• this is the repolarising phase where Na+ channels are inactivated (h gate close) and the membrane potential decreases to ~-80mV.
• this is called the undershoot and K+ channels are still open but re close when resting potential is maintained again (-70mV)

Question 5

describe Ad and C-fibres conduction properties

Answer 5

Ad-fibres are myelinated; fast conduction

C-fibres are unmyelinated; slow conduction

Question 6

what are Ad-fibres myelinated with?

Answer 6

Schwann cells

Question 7

what is fast and slow pain mediated by?

Answer 7

fast pain- Ad-fibres

slow pain- C-fibres

Question 8

how does slow and fast pain respond to NSAIDs and LAs?

Answer 8

fast pain- blocked by LAs but not NSAIDs

slow pain- blocked by both

Question 9

what channels do LAs work on?

Answer 9

Nav channels

Question 10

what are some important properties of the Nav channel? (4)

Answer 10

• voltage sensor on TM4 in all subunits
• re-entrant loop between TM5 and TM6 (lines channel pore)
• loop contains negative AAs so attracts positive ions (allows selectivity)
• TM4 has positively charged AAs to respond to membrane potential

Question 11

how do LAs interact with Nav channels?

Answer 11

• First, when a Na+ channel becomes activated, sodium flows into the cell
• LA cant gain access to the channel until it becomes activated.
• LA enters the cell through the Nav channel pore and blocks it from the intracellular side

Question 12

what state is the Nav channel when LAs show the highest affinity for it?

Answer 12

inactivated state

Question 13

what is the difference between TTX and LAs?

Answer 13

TTX blocks the influx of sodium extracellularly so is use independent (doesn’t need sodium to activate channel)
LAs block the influx of sodium intracellularly so are use dependent

Question 14

what are the different structures of LAs?

Answer 14

amides and esters

Question 15

give examples of ester LAs and amide LAs (4,6)

Answer 15

Ester- cocaine, procaine, tetracaine, benzocaine

Amides- lidocaine, mepivacaine, bupivacaine, etidocaine, prilocaine, ropivacaine.

Question 16

why is it important to know what type of LA you are using? (ester vs amide)

Answer 16

it dictates the route through which the LA will become metabolised.

Question 17

describe the main differences in metabolism between esters and amides

Answer 17

Esters- have a short duration of action as they are metabolised by plasma and liver pseudocholinesterase’s. allergies: most likely for esters-PABA (para-aminobenzoic acid) metabolites produced by metabolism through pseudocholinesterase’s.

Amides- metabolised more slowly, they have a longer duration of action as they are metabolised in the liver: CYP3A4. These are used much more widely. When administered correctly local anaesthetics do not have behavioural effects.

Question 18

what form of amide LA can cross the membrane? (cross membrane= block Nav channel)

Answer 18

basic (uncharged)

Question 19

what form of amide LA blocks the Nav channel?

Answer 19

cationic (charged) form

Question 20

why are unmyelinated fibres more susceptible to block by LAs?

Answer 20

as they have a smaller diameter

Question 21

why are myelinated fibres easier to block than unmyelinated fibres of the same diameter?

Answer 21

because of the nodes of ranvier

Question 22

how can LAs cause systemic toxicity and reduced heart function?

Answer 22

by binding to Nav1.5 channels (in the heart, they potently inhibit this channel)

Question 23

why is it important to administer LA close to the neuronal channels you are trying to block?

Answer 23

because LAs can interact well with any Nav channel

Question 24

what disorders does loss/gain of function of Nav1.7 cause?

Answer 24

loss of function- CIP

gain of function- erythromelalgia, PEPD