Local Anaesthetics

Question 1

What are local anaesthetics?

Answer 1

Produce loss of pain sensation without affecting consciousness, they act locally by reducing conduction of APs by inhibiting VGNA⁺Cs

Question 2

What is the basic chemical structure of any local anaesthetic?

Answer 2

AROMATIC BENZYL GROUP - (ESTER or AMIDE bond) - BASIC GROUP

Question 3

What is the difference between procaine and lignocaine and which one is a better local anaesthetic?

Answer 3

Procaine has an ester bond whereas lignocaine has an amide bond.

Lignocaine is better as the amide bond present is less susceptible to hydrolysis, whereas the ester bond has a shorter half life due to high conc of esterases in the plasma, so procaine would be broken down quicker and not last as long.

Question 4

What is the action of local anaesthetics at physiological pH?

Answer 4

They act as weak bases (proton acceptors) - so more local anaesthetic is ionised as they accept more protons, becoming positive charged - this means they become less permeable to the membrane.

Question 5

Why is it beneficial for LAs to be dissolved in alkaline solution when administered?

Answer 5

When they are in alkaline conditions, they behave as weak ACIDS (proton donors) not bases, therefore they don’t become ionised and are more likely to cross the lipid membrane of the axon.

Once it crosses the membrane and enters physiological pH, it will become ionised and ionised LAs are more effective at blocking Na⁺ channels.

Question 6

What are the (3 main) mechanisms of blocking Na⁺ channels by local anaesthetics?

Answer 6

• some block closed sate - un-ionised state
• some block open state - ionised state
• substantial block channels in inactivated state - ionised state

Majority of LAs act on the inactivated state of a VGNa channel, this is where ionised local anaesthetic works best.

Question 7

What is meant by ‘use-dependence block’ in relation to LA action?

Answer 7

Some LAs only block Na⁺ channels in inactivated state - there is high activity/frequency of firing here as many Na⁺ channels enter inactivated state, especially in pain pathways.

This is useful as when you have a pain signal, they fire at high frequency whereas other neurones around won’t be firing at a high frequency so we don’t want to block those.

Question 8

What other types of drug follow the same principle of use-dependent action?

Answer 8

anti-epileptic, class I cardiac anti-arrthymic

Question 9

Why are pain fibres blocked before other sensory or motor nerves?

Answer 9

1. LAs block small diameter axons before large ones
2. LAs usually block un-myelinated before myelinated fibres

Nociceptive impulses (pain pathways) are conducted in Agamma fibres (small diameter myelinated axons) and C fibres (unmyelinated axons)

Pain sensation is lost first -> over inc conc/time LA starts to block all axonal conduction causing local paralysis (eg. dribbling/paralysis after dental injection)

Question 10

What are unwanted effects of local anaesthetics in the CNS?

Answer 10

Initial stimulation -> tremor, agitation, convulsions

Subsequent CNS depression -> respiratory problems

Question 11

What are unwanted effects of LAs in the CVS?

Answer 11

• decrease cardiac output - due to LAs blocking cardiac Na+ channels which leads to less Ca2+ influx and less force of contraction
• ­ increase vasodilatation – due to inhibition of sympathetic nerve activity innervating blood vessels -> less vascular tone

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Both these actions will cause low blood pressure -> potentially effect blood flow to vital organs

Question 12

Describe the 4 main routes of administration of local anaesthetic

Answer 12

1. Surface anaesthesia - applied to mucosal surface, eg. bronchial, nose, cornea - LAs do not cross skin very well
2. Nerve block - LA injected close to sensory nerve, eg. dentistry
3. Spinal anaesthesia - LA injected into subarachnoid space between 2^nd and 5^th lumbar verterbrae, enters CSF eg. surgery when inappropriate to use general anaesthetic, eg. hip replacement in elderly
4. Epidural - LA injected into epidural space - outside meninges, where it idffuses to and blocks nerve roots eg. childbirth

Question 13

Why is it useful to administer LAs with adrenaline?

Answer 13

• Adrenaline produces vasoconstriction by acting on a₁ adrenoreceptors on vascular smooth muscle cells within walls of vessels and vasoconstriction keeps LA localised to area of injection and inhibits absorption of LA from ECF to blood - reduces systemic toxicity
• Prevents bleeding
• Prolongs LA action

Question 14

What are risks of adminstration of adrenaline with LA?

Answer 14

• Local hypoxia - particularly extremities: fingers, toes, nose, penis
• Absorption of adrenaline -> arrthmia