W5: Locl Anaesthetics

Question 1

What do local anaesthetics do?

Answer 1

Local anaesthetics reversibly block nerve conduction when applied to a restricted area of the body to enable a procedure to be carried out without loss of consciousness.

Question 2

What is nociception?

Answer 2

Sensory receptors that detect damage or harm to the body perceived as pain. Generates action potentials which are sent to the brain.

Question 3

How to prevent pain

Answer 3

Preventing signals being sent to the brain. Target of drugs = voltage gated sodium ion channels to stop generation of APs

Question 4

Naming local anaesthetics

Answer 4

They end in -caine

Question 5

Chemical structure of local anaesthetics

Answer 5

Aromatic ring, amine group, with an amide or ester bond linking them.

Question 6

Where do enzymes act to break down local anaesthetic molecules/where is the site of metabolism?

Answer 6

At the ester or amide bond

Question 7

Are esters or amides broken down faster?

Answer 7

Esters

Question 8

What might happen after local anaesthetics are broken down?

Answer 8

They might form potentially harmful metabolites.

Question 9

What are the implications for clinical use of producing harmful metabolites from breakdown?

Answer 9

We need a drug that will be available in the body for a certain period of time and do not want potentially allergic metabolites.

Question 10

Property of the aromatic ring

Answer 10

Lipid soluble

Thus will target neurones which have a phospholipid bilayer.

Question 11

Property of the amine group

Answer 11

Amine groups can exist charged or uncharged. Thus all local anaesthetic molecules are weak bases and can accept a proton when dissolved in water.

Question 12

Can the ionised or unionised version of LA block VGNa+ channels?

Answer 12

Ionised

Question 13

What does the LA do in the presence of an action potential at a nociceptive neurone?

Answer 13

• presence of LA will be outside the axon in the extracellular fluid and there will be an equilibrium of ionised and unionised versions.
• the aromatic ring allows the molecule to be lipid soluble if uncharged (unionised version)
• unionised version moves into the axon, creating a new equilibrium such that some become ionised

Question 14

What is a use-dependent block?

Answer 14

The degree of the block is dependent on whether the channels are being used. The ionised molecule blocks open channels. Channels are only open if there is a stimuli generating APs. Therefore if there is a more painful stimulus, we may expect more action potentials, thus more open channels and thus a better block.

Question 15

How can pH affect effectiveness of LA?

Answer 15

pH determines the ionisation states of the molecules. Tissue pH is normal stable but sometimes disrupted.

Question 16

What can cause lower tissue pH?

Answer 16

When there is lots of inflammation, e.g., due to bacterial infection, bacteria are multiplying and respiring producing acidic byproducts, lowering tissue pH.

Question 17

What affect does the lower pH have on LA effectiveness?

Answer 17

Increased acidity drives the ionisation reaction to the right, creating a greater proportion of ionised LA molecules, so it is less likely that there are unionised molecules to cross the membrane to bring about the action of blockage, hence poorer effect of anaesthetic. Thus best to clear infection first.

Question 18

Formula for amine ionisation and how pH affects it.

Answer 18

molecule + H2O <—> molecule+ + OH-
Increased acidity shifts reaction right
Increased alkalinity shifts reaction left

Question 19

How do neurones affect effectiveness or LA?

Answer 19

Axons with a small diameter are nocipetic (Adelta and C). The largest axons found are alpha motor neurones.
Large alpha motor neurones are definitely myelinated so have a thickened wall but the nociceptic neurones vary.
If LA is used to alleviate pain, we want it to target Adelta and C neurones since these are nociceptic. They have higher sensitivity to LA so will be more targeted, but other motor neurones can also be affected hence loss of sensation in the affected areas.

Question 20

General rule for the route of administration of LA

Answer 20

The more proximal (closest to the centre thus the spinal cord) the site of administration, the greater the area anaesthetised.

Question 21

5 routes of administration of LA (refer to image)

Answer 21

Topical anaesthesia
Infiltration anaesthesia
Nerve block anaesthesia
Epidural anaesthesia
Spinal anaesthesia

Question 22

Describe topical anaesthesia

Answer 22

Anaesthetising surfaces. Nerve terminals are branching to cover the skin area. Not very effective since skin is made up of many layers and is dense so it is difficult for the LA molecules to diffuse across the skin.

Question 23

Describe infiltration anaesthesia

Answer 23

LA is injected into the skin. Sometimes done as multiple injections so all of the neurones supplying that area are anaesthetised. Can be used in some forms of dental work for anaesthetising one tooth.

Question 24

Describe nerve block anaesthesia.

Answer 24

Injection given quite proximally so it is targeting quite a large mixed nerve so all of the axons are affected within that nerve.

Question 25

Describe epidural anaesthesia

Answer 25

Associated with childbirth. LA injected into the epidural space - within the vertebrae but outside the spinal cord. Allows the LA to bathe the nerve roots that are exiting from the spinal cord to innervate the structures of the lower part of the body.

Question 26

Describe spinal anaesthesia

Answer 26

LA goes into the CSF that is found in the subarachnoid space. Can affect any spinal nerve running through that space and the spinal cord. Can affect a large area of the body, but individual remains conscious.

Question 27

What happens if LAs are injected into vessels or are given at too high doses?

Answer 27

If it gets into the bloodstream it circulates around the body and can block all of the VGNa+ channels in the body, perhaps get into the heart and interfere and cause a heart attack. These are specific side effects, caused by the LA molecules.

Question 28

What happens if LA enters the CNS?

Answer 28

Can affect neurones in the brain causing tremor, convulsions, respiratory failure etc (easy to cross the blood brain barrier since they are lipid soluble).

Question 29

What happens if LA enters the cardiovascular system?

Answer 29

Entering the cardiac muscle means heart may not contract as well. Blood vessels (containing smooth muscle cells with VGNa+) might not be able to contract so might dilate, decreasing blood pressure.

Question 30

What else is in LAs?

Answer 30

Something neutral to prevent bacteria growing in the solution so it is sterile, e.g. saline.

Question 31

Why are vasoconstrictors administered with LAs?

Answer 31

LA will affect the blood vessels in that region. We want to keep LA in that region so constricting the blood vessels can reduce flow so stop it from being easily enterable into the circulation. This decreases unwanted effects in other regions and increases duration of action since it reduce rate at which LA is metabolised in the body, so a lower dose can be given.

Question 32

Why must we be cautious of the area of vasoconstrictor administration?

Answer 32

E.g. administering into an extremity could cut off blood flow from this area.

Question 33

Examples of vasoconstrictors

Answer 33

Adrenaline/felypressin

Question 34

Linkage and duration of procaine, lidocaine, prilocaine, bupivacaine

Answer 34

Procaine - E, short
Lidocaine - A, medium
Prilocaine - A, medium
Bupivicaine - A, long

Question 35

What can cause hypersensitivity from local anaesthetics?

Answer 35

A variety of other agents are in the solution to preserve it. Some can cause hypersensitivity reactions, e.g. redness around injection site. This is non-specific because it is not due to the LA molecules themselves.

Question 36

Are there more ionised or unionised molecules of LA (amine group) at physiological pH?

Answer 36

At physiological pH there are more ionised than unionised molecules.