Local anaesthetics L13

Question 1

what are anaesthetics

Answer 1

drugs that prevent localised pain and sensation for limited period of time during surgery
general anaesthetics induce loss of consciousness

Question 2

how do LA work

Answer 2

they block electrical activity in neurones

Question 3

what is the composition of ions in neurones

Answer 3

inside: K+ and A-
outside: Na+ and Cl-
outside is more positive than outside (-60mv to -90mv)

Question 4

what is an action potential and what causes it

Answer 4

rapid change in membrane potential
dependant on voltage gated ion channels

Question 5

describe an action potential

Answer 5

In response to depolarisation above (approx. -55mV)
Voltage gated Na channels open at -55 mV Na+ goes into the cell (concn gradient) Membrane potential rises and polarity changes
Na channels close and Na+/K+ATPase moves Na+ out
K+ pours out of the cell (concn gradient) via voltage gate K channels
Membrane potential falls again

Question 6

what do LA block in the action potential

Answer 6

voltage gated Na channels

Question 7

describe the composition of VG Na channels

Answer 7

it has 3 subunits
- Alpha: contains the ion channel
- single polypeptide. It contains extracellular domains, 4 transmembrane domains each comprising 6 A-helical regions
- Beta 1 and 2: anchor alpha to the membrane
- Beta 2 is covalently attached to alpha, beta 1 is not

Question 8

what does the alpha subunit contain in the hydrophobic domain

Answer 8

voltage sensors that change their orientation when voltage varies. Their orientation determines the configuration of the entire domain and controls the opening and closing of a pore.

Question 9

what do LA interact with

Answer 9

interact with the A subunit and physically ‘plug’ the transmembrane pore

Question 10

what form do LA have to be in to bind to binding site and where is the binding site
- why is this an issue

Answer 10

have to be in ionised/ hydrophilic form
the binding site is normally closer to intracellular domain in membrane
hydrophilic ions can not cross the membrane

Question 11

how do we deal with the ionisation issue

Answer 11

intra and extra cellular domains have slightly different pH’s
this property is exploited
Unionised form gains access through nerve sheath and axon membrane
Ionised form binds in channel

Question 12

what is the general structure of LA

Answer 12

aromatic group (left), ester or amide group (middle) and basic amine group (right).

Question 13

what does the basic amine group ensure

Answer 13

the molecules are ionised at physiological pH

Question 14

what does the aromatic group ensure

Answer 14

ensures lipid solubility.

Question 15

what does the ester or amide group determine

Answer 15

Duration of action is limited by the hydrolysis of the ester/amide bond and by the lipid solubility of the agent.
esters: Metabolised in plasma by esterases (except cocaine) Shorter T1/2
amide: Metabolised in liver by CYP3A4,1A2 -longer T1/2 consequences in individuals with liver failure

Question 16

describe the action of LA

Answer 16

The anaesthetic, a weak base, is injected as hydrochloride salt in an acid solution - suitable for injection (i.e. dissolves in solution).
Following injection, the pH increases (due to the higher pH of the tissues, which is usually 7.4) and the drug dissociates, the degree of which depends on pKa, and free base is released (lipid soluble).
Lipid soluble free base enters the axon. Inside the axon the pH is lower (the environment is more acidic, pH7), and re-ionization takes place.
The re-ionized portion enters the Na+ channels and blocks them, preventing depolarization

Question 17

how can we manipulate LA

Answer 17

1. Restrict site of action and prolong durations of action
   Coadmininster adrenaline (local vasocontriction via A1 adrenoreceptors
2. Accelerate the speed of onset of the anaesthetic
   Use slightly alkaline solution, this will assist in absorption of the anaesthetic into the nerve tissue

Question 18

how do all nerves respond to LA

Answer 18

they all have VG Na+ channels

Question 19

describe why some nerves may respond differently to LA

Answer 19

Block conduction in small diameter fibres more effectively than in large diameter fibres

Nosciceptive (pain) fibres are small diameter and particularly sensitive
Motor axons have a large diameter and are less sensitive

Question 20

what is use dependant block

Answer 20

depth of block increases with an increase in action potential frequency
Channels is in three states
Resting, open, inactive

Use dependent block occurs because the anaesthetic gains access to, and has higher affinity for the channels more readily when it is open and/or inactive

Question 21

what are the side effects of LA

Answer 21

occur due to escape of the local anaesthetic into the systemic circulation
- CNS, confusion and agitation
- Cardiovascular, hypotension
- Inhibition of sympathetic activity
- Inhibition of sodium conductance in cardiac tissue

doesnt work well on inflamed or infected tissue as this disrupts pH

Question 22

what would a drug target if it wanted to target chemical neurotransmission

Answer 22

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

Question 23

what would a drug target if it wanted to target electrical transmission

Answer 23

voltage gated channels

Question 24

what do antihypertensive and antiarrhythmic drugs target

Answer 24

L-type calcium channels

Question 25

what do antiepileptic or Anticonvulsant target

Answer 25

target voltage gated sodium channels
Exploit use dependence block
Block high frequency discharge that occurs during a siezure without effects the low frequency firing of neurones in their normal state

Question 26

what is Tetrodotoxin

Answer 26

produced by marine bacteria and defensively by a number of animals such as tropical rain forest frogs and newts and by puffer fish block voltage gated Na+ channels.
(different binding site to LAs)