2010A01 Describe how the chemical structure of local anaesthetic drugs
 determines their efficacy and safety.

 

List:

·      Intro

·      Lipophilic part

·      Link

·      Hydrophilic part

·      Other: isomerism, ionisation

 

Intro:

Local anaesthetic structure

·  Lipophilic group

·  Chain: ester or amide bond and hydrocarbon chain

·  Hydrophilic group

Determinant of efficacy

·  Propensity for blockade of neuronal voltage-dependent Na+ channel (VDNaC)

Determinant of toxicity

·  Propensity for blockade of VDNaC in the

o  CNS (excitation then depression)

o  CVS (conduction delay, re-entrant arrhythmia, arrest)

 

Lipophilic part:

Purpose

·  For crossing axonal membrane

·  For local anaesthetic activity

Structure

·  Usually an aromatic ring

Factors influenced

·  Lipophilicity

·  Potency

·  Duration

Examples

·  Ester:

o  Metabolite PABA may cause hypersensitivity

o  Excreted unchanged in urine; could accumulate in renal failure

·  Prilocaine:

o  Metabolite O-toluidine may cause methaemoglobinaemia

o  Oxidises Fe2+ in Hb

o  Significant if >600mg prilocaine given to adult. PABA excreted in urine

·  Chlorprocaine:

o  Cl atom ↑rate of ester hydrolysis 3.5x -> ↓risk toxicity

 

Link:

Ester bond

·  O=COR

·  Metabolized rapidly in plasma/liver by pseudocholinesterase

·  ↓peak plasma [LA] -> ↓risk toxicity (hence prilocaine used for Bier’s block)

·  Products: aromatic acid + alcohol + tertiary amide

·  ↑Length alcohol -> ↑potency up to a critical length, then ↑toxicity

Amide bond

·  NHC=OR

·  Metabolized slowly in liver by amidases (CYP450)

·  ↑peak plasma [LA] -> ↑risk toxicity

·  Agent-specific metabolites

Hydrocarbon chain

·  ↑length of chain -> ↑potency

 

Hydrophilic part:

Purpose

·   For water dissolution

Structure

·   Usually tertiary amine e.g. diethylamine

Determinant of

·   Lipid solubility (LS) potency toxicity

Examples: pipecolyxylidides

Structure-activity relationships:

·   Chiral due to assymetric carbon (cf. lignocaine)

·   Length piperidine C-chain lipid solubility, potency, toxicity, % protein bound

Comparisons (reference: procaine)

·   Methyl (CH3) = mepiv

o LS 100x, potency 2x, 77% plasma protein bound (PPB))

·   Propyl (C3H7) = ropiv

o LS 300x, potency 8x, 94% PPB)

o S-ropiv more potent, less toxic, hence always enantiopure

·   Butyl (C4H9) = bupiv

o LS 1000x, potency 8x, 95% PPB

o L-bupiv more potent, less toxic, preferred in paeds (expensive)

 

Other:

Isomerism

·   e.g. S-ropivacaine more potent, less toxic than R-ropivacaine

Ionisation

·   Determines diffusability hence speed of onset

o e.g. lignocaine pKa 7.9, 25% unionised at pH 7.4 -> fast onset

o e.g. bupivacaine pKa 8.1, 15% unionised at pH 7.4 -> medium onset

 

 

 

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