YW - Local Anaesthetics

Question 1

What is the difference between analgesia and anaesthesia?

Answer 1

Analgesia refers to the reduction or relief of pain

• Analgesia implies pain relief - but does not imply that all sensation is taken away, analgesia does not mean numbness

Anaesthesia refers to lack of sensation

• This can be accomplished with local anaesthetics
• Almost always this also results in a lack of pain - therefore analgesia usually accompanies anaesthesia

Question 2

How do the chemical features of LAs affect localised mode of action? (2)

Answer 2

Hydrophobic: In their uncharged form, tetracyclic amines are hydrophobic, meaning they repel water and are attracted to nonpolar environments like cell membranes.

Charged at physiological pH: Due to the pKa of the tertiary amine group, at physiological pH (around 7.4), most of the molecules will be charged. This makes them more hydrophilic. Their efficacy is reduced in acidic environments, such as injured tissue.

Mode of action requires equilibrium between charged (hydrophilic) and uncharged form
hydrophobic). And their efficacy is reduced in injured tissue which has a more acidic pH

Question 3

How do local anesthetics work?

Answer 3

Local anesthetics block sodium currents in nerve cells, preventing the transmission of pain signals.

• Their effectiveness depends on a complex, use-dependent interaction with sodium channels
• This means the effect of LAs depends on whether the sodium channel is activated or not

Question 4

What is the efficacy of inhibition dependent on?

Answer 4

The inter-conversion of the tertiary amine

Question 5

Comparison (QX-314 vs Lidocaine):

Answer 5

QX-314:

• More effective when applied directly inside the neuron (internal block).
• Can also block even when the membrane is stimulated (suggests binding to different channel states).

Lidocaine:

• Effectiveness depends on the conversion between different forms of the molecule (tertiary amine).
• Doesn’t require the same specific conditions for blocking as QX-314.

Question 6

How do local anesthetics bind to sodium channels?

Answer 6

Local anaesthetic acts to fill the pore region at centre of the Na+ channel

Question 7

Uncharged vs Charged LAs?

Answer 7

Uncharged important for drug to enter binding site sitting in the centre of the neuron.

• Can access the binding site when open or closed
• Can partition in the membrane

Charged form important for repulse activity and for increased efficacy of action.

• Can only access the binding site when the channel is open.
• Has to be injected inside the neuron.

Question 8

What do structural insights into Na channels show? (2)

Answer 8

• Binding site is a very small opening and has restricted access to local anaesthetics
• LA binding can both occlude (block completely) and repulse sodium ions, preventing them from entering the channel

Question 9

What are the five main types of anaesthesia techniques, and which local anaesthetics are commonly used with each?

Answer 9

1) Surface anesthesia (creams/drops)

• Examples: Lidocaine, tetracaine, benzocaine

2) Infiltration anesthesia (injection into tissues)

• Can be combined with epinephrine to prolong action

3) Intravenous regional anesthesia (Injection into a vein distal to a blood flow cuff)

• Lidocaine and prilocaine are commonly used
• The anaesthetic effect lasts as long as blood flow is stopped

4) Nerve block anesthesia (near specific nerves)

• Reduces the amount of anaesthetic needed compared to infiltration

5) Spinal/epidural anesthesia

• Spinal: Injection into cerebrospinal fluid (CSF) surrounding the spinal cord
• Epidural: Injection into epidural space near the spinal cord
• Lidocaine is commonly used for spinal anesthesia