Local anaesthetics

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=== Unfinished ===

To be added later: Structure of Na+, binding sites for LA, saxitoxin

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Overview

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• Cocaine is introduced as the first local anaesthetic in 1884 by Kollar, for use in ophthalmology
• Procaine was the first synthetic local anaesthetics, introduced by Einhorn in 1905
• Lignocaine was synthesized as an amide local anaesthetic by Lofgren in 1943
  --> Became the benchmark

 

Structure

• Local anaesthetics consists of:
  * A lipophilic portion (usually an unsaturated aromatic ring, like paraaminobenzoic acid)
  * A hydrophilic portion (usually a tertiary amine)
  * A hydrocarbon chain connecting the two portions
• The hydrocarbon chain is connected to the lipophilic portion by:
  * Ester bond, OR
  * Amide bond
  --> Basis for classification
• Main differences between amide LA and ester LA are in:
  * Site of metabolism
  * Potential to cause allergic reaction

Classification

Ester

• Procaine
• Chloroprocaine
• Tetracaine (aka Amethocaine)
• Cocaine

Amide

• Lidocaine
• Etidocaine
• Prilocaine
• Mepivacaine
• Bupivacaine
• Ropivacaine

Pipecoloxylidides

Includes mepivacaine, bupivacaine (and levobupivacaine), and ropivacaine

• Similar chemical structures
• Has a chiral centre
• S enantiomers are less neurotoxic and cardiotoxic
• Mepivacaine has a CH3 group on tertiary amine group
• Ropivacaine has a C3H7 group on tertiary amine group
• Bupivacaine has a C4H9 group on tertiary amine group
• Bupivacaine and mepivacaine are available in racemic mixture
• Ropivacaine and levobupivacaine are available as pure S enantiomers

Structure-activity relationships

• Amethocaine vs procaine
  --> Amethocaine has a butyl (4C) group
  --> Greater lipid solubility and about 10 times more potent
• Chloroprocaine vs procaine
  --> Chloroprocaine has an extra Cl group on the benzene ring
  --> Greater rate of hydrolysis by plasma cholinesterase
• Etidocaine vs lignocaine
  --> Etidocaine has longer carbon chains on the hydrophilic portion and on the hydrocarbon chain
  --> 50 times more lipid soluble, and 2-3 fold increase in duration of action
• Bupivacaine vs mepivacaine
  --> Bupivacaine has longer carbon chain on the piperidine nitrogen (butyl vs methyl group)
  --> 35 times more lipid soluble, and 3-4 times the potency and duration of action

Pharmaceutical

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• Generally poorly soluble in water
  --> Marketed as water-soluble hydrochloride salts
  --> Acidic (pH 6)
• Epinephrine may be added to LA
  * Epinephrine is also more stable at acidic pH
  * Commercial preparations pH range from 3.9 to 6.5
• Sodium bisulfite may be added to prevent oxidative decomposition of epinephrine

Liposomal local anaesthetics

• Some LA are incorporated into liposomes
  --> Prolong duration of action and decrease toxicity
  * e.g. lidocaine, tetracaine, bupivacaine

Alkalinisation

• Alkalinsation of LA (by adding sodium bicarbonate)
  --> Increased non-ionised fraction
  --> Increased lipid-solubility

Thus, alkalinsation leads to:

• Faster onset of neural blockade
• Enhancing depth of sensory and moter blockade
• Increase spread of epidural blockade