PED1003/L14 Local Anaesthetics

Question 1

What are anaesthetics?

Answer 1

Drugs used to prevent pain for a limited period of time for surgical or other procedures

Question 2

What is the difference between local and general anaesthetics?

Answer 2

Local - prevent localised pain or nociception and prevent tactile sensation
General - also induce loss of consciousness

Question 3

What is the mechanism of action in local anaesthetics?

Answer 3

Block electrical signalling in neurones by blocking VG Na+ channels

Question 4

What 3 subunits make up voltage-gated ion channels?

Answer 4

Alpha, beta1 and beta2

Question 5

Describe the structure of the alpha subunit in VG ion channels. (2)

Answer 5

One single polypeptide chain with extracellular domains
4 transmembrane domains each with 6 a-helical regions

Question 6

Where are the voltage sensors located on the VG ion channel?

Answer 6

Hydrophobic domain of a subunit

Question 7

Describe the linkage of the beta subunits to the alpha subunit in VG ion channels. (3)

Answer 7

B2 subunit linked covalently to a subunit
B1 not linked
2 B-units anchor a-subunit into lipid membrane

Question 8

How do local anaesthetics interact with the voltage-gated ion channel?

Answer 8

Plug the transmembrane pore

Question 9

What form do local anaesthetics bind in?

Answer 9

Ionised (hydrophilic) form

Question 10

How do local anaesthetics cross membranes if they can only bind to the site of action in an ionised form?

Answer 10

Exploit difference in pH outside and inside cell

Question 11

Describe the general structure of a local anaesthetic. (2)

Answer 11

Aromatic domain ensures lipid solubility
Basic side chain ensures molecules are ionised at physiological pH

Question 12

What is the duration of local anaesthetic action limited by?

Answer 12

Hydrolysis of ester/amide bond and lipid solubility of agent

Question 13

Describe the movement of local anaesthetic from outside to inside a cell. (3)

Answer 13

Lipid soluble base enters axon
pH lower inside axon
Ionisation occurs

Question 14

What is the difference between the esters and the amides?

Answer 14

Esters metabolised in plasma by esterases with shorter T1/2
Amides metabolised in liver by CYP3A4,1A2

Question 15

How can local anaesthetics be manipulated? (2)

Answer 15

Restrict site of action and prolong durations of action by coadministering adrenaline
Accelerate speed on onset of anaesthetic by using slightly alkaline solution

Question 16

Do all nerves show similar susceptibility to local anaesthetics?

Answer 16

Different types of axons show different sensitivity
Block conduction in small diameter fibres more than large

Question 17

Give an example of small and large diameter nerve fibres.

Answer 17

Nosciceptive (pain fibres) small
Motor axons large

Question 18

What is use-dependent block and why does it occur?

Answer 18

Depth of block increases with an increase in action potential frequency
Occurs because anaesthetic gains access to and has higher affinity for channels more readily when open and/or inactive

Question 19

Give a CNS and cardiovascular side effect of local anaesthetics.

Answer 19

CNS - confusion, agitation
CVS - hypotension

Question 20

Why do local anaesthetics cause cardiovascular side effects? (2)

Answer 20

Inhibition of sympathetic activity
Inhibition of sodium conductance in cardiac tissue

Question 21

Why is local anaesthetic not very effective in inflamed tissue?

Answer 21

Change in pH (more acidic) causes ionisation of drug before it crosses membrane

Question 22

Name 3 drug targets for chemical transmission.

Answer 22

G-protein coupled receptors
Ligand gated ion channels
Synthesis
Release
Uptake

Question 23

Give a drug target for electrical transmission.

Answer 23

Voltage-gated ion channels

Question 24

Give an example of other drugs targeting ion channels.

Answer 24

Anticonvulsant/antiepileptic drugs

Question 25

How do anticonvulsant/antiepileptic drugs exploit use dependent block?

Answer 25

Block high frequency discharge that occurs during a seizure without effects the low frequency firing of neurones in normal state

Question 26

Give an example of an anticonvulsant/antiepileptic drug.

Answer 26

Phenytoin
Carbamazepine