3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
 3.1.3.4. Local anaesthetics 

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