Local Anaesthetics

Question 1

What are local anaesthetics analogues of?

Answer 1

Cocaine

Question 2

Structure of local anaesthetics

Answer 2

consist of a hydrophobic group joint to an ionisable group (usually an amine) via an ester or amide linkage

Question 3

Potency definition

Answer 3

A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity

Question 4

potency of lidocaine, relative to what

Answer 4

4, relative to procaine 1

Question 5

Duration of action of lidocaine

Answer 5

medium

Question 6

Mechanism of action of local anaesthetics

Answer 6

Block sodium channels by plugging the transmembrane pore by interacting with many amino acid residues in the S6 helix

At low concentrations this increases the length of the action potential, thus increasing the length of the refractory period so less action potentials can be fired.

At high concentrations they prevent action potential firing

Question 7

Structure and basophilic tendency related to duration of action

Answer 7

• weak bases with a pKa value of 8-9, so that they are not completely ionised at the body’s pH- If completely ionised, cannot penetrate nerve sheath and membrane
• ester containing compounds are rapidly metabolised, thus have a short duration of action
• amines are more stable- longer duration of action

Question 8

Factors that affect the activity of local anasthetics

Answer 8

1. PKa
2. pH
3. Lipid solubility
4. intermediate chain
5. protein binding

Question 9

Explain pKa factor

Answer 9

PKa is the pH at which the number of ionised and unionised forms are equal

The lower the pKa the less ionised forms of the drug there are, therefore the better they are able to diffuse across the nerve sheath and thus the faster onset of action

Question 10

Explain pH factor

Answer 10

The lower the pH, the more acidic, the slower the onset of action because in acidic conditions the ionised form predominates, thus less available to cross bilayer and bind to sodium channel

Question 11

Explain lipid solubility

Answer 11

The more lipid soluble, the faster the diffusion through the membrane, greater depot of drug in axon

Question 12

explain intermediate chain

Answer 12

the longer the intermediate chain, the more potent the drug

Question 13

explain protein binding

Answer 13

The greater the affinity for protein binding, the longer the duration of action

Question 14

From which side to LAs block

Answer 14

Intracellular

Question 15

what form must the LA be?

Answer 15

ionised, unionised form has a low affinity for the voltage gated sodium channels

Question 16

Two pathways in which LAs work

Answer 16

Hydrophobic and hydrophilic

Question 17

Explain hydrophobic pathway

Answer 17

Uncharged LAs can bind and unbind even when the channel is closed

Question 18

Explain hydrophilic pathway

Answer 18

unionised form of LA diffuses through the lipid bilayer where it enters the slightly more acidic cytoplasm.

LA then become ionised and can block the channel

Move through channel

Question 19

Sequence of blockade

Answer 19

1. small fibres- such as nociceptors
2. myelinated - sympathetic
3. unmyelinated- motor fibres

Question 20

What does use dependence mean?

Answer 20

The more channels that are used, the more are blocked.

This is due to more channels being open thus more LAs being able to diffuse through

Question 21

What do most LAs bind to?

Answer 21

the channel in its inactivated state

Question 22

What are often added to LA?

Answer 22

Vasoconstrictors

Question 23

Function of vasoconstrictors

Answer 23

Narrow the blood vessels, to counteract the effect of LAs widening them

Absorption of LA into cardiovascular system is thus slowed, minimised the effect of local anaesthesia toxicity and increasing its duration of action