Local Anaesthetics

Question 1

What is the general mechanism of action of local anaesthetics?

Answer 1

Inhibit voltage-gated Na channels

Question 2

Procaine, a synthetic substitute for cocaine was superseded by what drug? What is the advantage of this drug over procaine?

Answer 2

Lignocaine; has an amide bond instead of an ester bond, therefore lignocaine is less susceptible to hydrolysis and so has a longer half-life (t_1/2)

Question 3

What is the pKa range of local anaesthetics?

Answer 3

pKa = 7-9; they are weak bases

Question 4

Local anaesthetic action is increased with alkaline pH, but local anaesthetics are more effective at blocking Na channels in acidic conditions. Explain what happens to local anaesthetics in an axon, and why this is referred to as ‘ion trapping’.

Answer 4

The extracellular pH is alkaline, therefore the local anaesthetic (LA) behaves as a weak acid: LAH⁺ + H₂O > LA + H₃O⁺. This means more LA is in the non-ionised form - LA. LA can freely cross the plasma membrane and enter the axon.

The intracellular pH is slightly acidic (7.2), therefore the LA behaves as a weak base: LA + H₃O⁺ > LAH⁺ + H₂O. More LA is in the ionised form, LAH⁺, thus the LA can block Na channels more effectively once inside the axon than they would otherwise if the pH was neutral or alkaline.

Question 5

Do local anaesthetics act on the extracellular membrane, intracellular membrane or both?

Answer 5

Intracellular

Question 6

What are use-dependent local anaesthetics?

Answer 6

Local anaesthetics that only work when activity is high, and do not affect low activity neurons. Thus, use-dependent drugs tend to have less side effects.

Note: other drugs such as anti-eplipetics and class I cardiac anti-arrhythmics use the same principle.

Question 7

Local anaesthetics first block axons with what characteristics?

Answer 7

Small diameter and unmyelinated

Question 8

Which 2 types of primary afferents are the first to be blocked by local anaesthetics, and which sensation is therefore lost first?

Answer 8

Aδ fibres are the first to be blocked as they are small diameter and unmyelinated, followed by the unmyelinated C fibres.

Thus, pain is the first sensation to be lost.

Question 9

Describe the possible unwanted effects of local anaesthetics on the CNS.

Answer 9

If LAs enter brain:

• Initial stimulation - tremor, agitation, convulsions.
• Subsequent CNS depression - respiratory problems.

Question 10

Name 2 possible effects of local anaesthetics on the CVS, and their consequences.

Answer 10

1. Blockage of cardiac Na channels > reduced Ca2+ influx > reduced force of contraction - result is decreased cardiac output.
2. Blockage of sympathetic nerves > decreased vascular tone - result is vasodilation.

Both of these effects lead to decreased blood pressure.

Question 11

Name 4 routes of administration of local anaesthetics.

Answer 11

1. Surface anaesthesia - applied to mucosal surfaces e.g. bronchial.
2. Nerve block - LA injected close to sensory nerve, e.g. in dentistry.
3. Spinal anaesthesia - LA injected into subarachnoid space between L2 and L5 - enters straight into CSF - e.g. in hip replacement.
4. Epidural - LA injected into epidural space - diffuse to and block nerve roots - e.g. in childbirth.

Question 12

Why are local anaesthetics adminstered with adrenaline? Explain why caution should be taken with this approach.

Answer 12

• Adrenaline produces vasoconstriction, which keeps the LA localised to the area of injection.
• Vasoconstriction inhibits absoprtion of LA from the extracellular space to the blood, preventing systemic toxicity.
• Adrenaline prolongs the action of the LA.
• Beware - local hypoxia of extremities - absorption of adrenaline > arrhythmia.