Local Anaesthetics

Question 1

MOA of Local Anaesthetics

Answer 1

1) Block Na+ channels in the axonal membrane when applied locally in appropriate [ ],
- > Prevents Na+ ion entry, slowing down/blocking nerve conduction
- > Many LAs bind most strongly to the inactivated & activated states

2) Use-Dependency, depth of LA nerve block increases with action potential frequency ( works better when there is more pain! )
- Passage of train of action potentials causes Na+ channel to cycle through open & inactivated states
- LA gain access to channel more readily when the channel is open
- Higher affinity for inactivated than for resting (closed) channels

3) Non-selective modifiers of neuronal function
- Will block action potentials in all neurons
- -> Achieve selectivity by delivering LA to limited area

Question 2

Why are topical LAs less effective when the skin is inflammed?

Answer 2

• Tissues become acidic when inflammed
• pH drops, surplus of H+
• LA action becomes less effective as base becomes protonated (BH+) & cannot pass through membrane channel

Question 3

Factors affecting LA action

Answer 3

1) Lipid solubility
- > lipid soluble, > potent & act longer
- Eg. more hydrophobic: Tetracaine, etidocaine, bupivacaine
- less hydrophobic: lidocaine, procaine, mepivacaine

2) Nerves (Size, Frequency of firing, Position, Myelination)
- Smaller myelinated axons gets blocked > rapidly
- Nociceptive (pain) & sympathetic transmission is blocked first

3) pH dependency
- LA molecules are weak bases (pKa 8-9)
- Ionised at physiological pH
- Decreased LA activity at acidic pH as proportion of BH+ is high

• Plays critical role in LA penetrating nerve sheath & axon membrane to reach the inner end of the Na+ channel (LA binding site)

Question 4

Types of LA

Answer 4

1) Ester-type
- Cocaine, Procaine, Tetracaine, Benzocaine

2) Amide-type
- Lidocaine, Bupivacaine, Mepivacaine
- Others: Etidocaine, Prilocaine, Ropivacaine

Question 5

Methods of metabolism of the diff classifications of LA

Answer 5

Ester: Plasma/tissue non-specific esterases
Amide: Hepatic enzymes
- Not suitable if patient has hepatic failure

Question 6

Pharmacokinetics of LA (A,D,M + Onset)

Answer 6

Absorption: Mainly local (some still will get absorbed)
Distribution:
i) Phase I (alpha): Steep exponential decline in [LA]
Rapid distribution in blood & highly
perfused organs (brain heart, liver…)
ii) Phase II (beta): Slower decline in [LA] (nearly linear)
Distribute to less well perfused tissue
(muscles, gut…)
Onset:
- Most rapidly @ physiological pH
- LA penetrating axon most rapidly have fastest onset
–> Small, highly lipid soluble, low ionisation (@ tissue pH)

Metabolism:
Ester - Esterases in blood
Amide - Liver enzymes

Question 7

Adverse drug effects of LA

Answer 7

1) Systemic toxicity (b/c LA block all gated ion channels)
i) Accidentally injected IV/ Intra-arterial
ii) Overdose though injected locally
Management:
- Give with Epinephrine (cause vessels to constrict, decrease blood flow) to prevent LA systemic distribution from site of action

2) Cardiotoxicity as dose increases
- Bupivacaine > cardiotoxic than other LAs

3) Methaemoglobin (blueish blood, decrease O2 exchange)
- Bc of O-toluidine (metabolite of prilocaine)
Management:
- IV Methyleneblue/ascorbic acid to convert methaemoglobin -> Haemoglobin

4) Allergic reactions (cannot tolerate PABA)
- Ester LAs hydrolysed to PABA derivatives
Management:
- Give amide-LAs

5) Vasoconstriction & Hypertension
- Cocaine blocks NA re-uptake, increases NA in synapse (not widely used in SG anyways)

Question 8

Clinical applications of LA

Answer 8

To produce various forms of local anaesthesia

1) Topical (surface)
i) Skin - minor burns, inflamm, wounds
ii) Eye
iii) Dental - to gum before entry of inj needle
iv) Otorhinolaryngology - Endoscopy
v) Gynaecology (lidocaine) - Episiotomy cuts

2) Injected
i) Epidural anaesthetics (lidocaine, bupivacaine)
- Regional nerve block (analgesia)
- May combine with opioid fentanyl to reduce LA dose
ii) Dental anaesthesia (lidocaine (short), bupivacaine (long))
- May combine with Epinephrine to control bleeding + decrease blood flow (Decrease rate of bupivacaine getting into systemic circulation)

Question 9

How to decide choice of LA?

Answer 9

Based on duration of action!

• Surface anaesthesia requires rapid penetration of the skin (mucosa) & limited tendency to diffuse away
• -> Cocaine: Good penetration & vasoconstriction but not widely used clinically