2004A03 Briefly describe the factors that determine skin penetration by local anaesthetics.
Briefly describe the formulation and pharmacology of EMLA cream.

Structure

·   Epidermis

o Outer stratum corneum is insensate

o Inner strata contain free nerve endings

·   Dermis

o Rich in nerves, blood vessels

Determinants of penetration

·   Time for diffusion

o 30 mins for PIVC

o 120 mins for skin graft

·   Rate of diffusion (see next)

Fick’s law

↑C₁

·   ↑Drug concentration

·   Eutectic mixture: mutual dissolution + liquid state -> ↑C₁

↓C₂

·   ↑Tissue blood flow -> ↓C₂ but also offset of local effect

·   Intrinsic: e.g. lower flow to foot cf. scalp

·   Pathology: hypothermia, shock, heart failure

↑Area

·   ↑Area of application -> ↑total absorption but ↔ absorption per unit area

↓Thickness

·   Extensor thicker than flexor

·   Lower limb thicker than upper limb

·   Mucous membrane -> ↓↓thickness -> ↑↑rate of absorption -> toxicity

↑Diffusion coeff

·   ↑Lipid solubility -(lignocaine 150x, prilocaine 50x procaine)

·   ↑% unionized

o Drug: lignocaine 25%, prilocaine 33%, higher than most

o Additive: NaOH in EMLA -> ↑pH

·   ↓Molecular weight (all LA drugs have similar MW 200-250g/mol)

Presentation

·   White cream

·   Oil-in-water emulsion

Storage

·   Room temp

Additives

·   Polyoxyethene fatty acid ester (emulsifier)

·   Carbopol (thickener)

·   NaOH -> pH 9 -> ↑↑unionised % lignocaine and prilocaine -> ↑rate of onset

·   H₂O

Eutectic mixture

·   Ratio producing lowest melting point (eutectic temperature)

·   Ratio: 2.5% lignocaine + 2.5% prilocaine (1:1)

·   Melting points: Lignocaine 68°C, prilocaine 37°C, EMLA only 18°C

·   Liquid oil at room temp -> higher concentrations than in solution -> ↑rate of onset

Administration

·   1-2g per 10cm² skin under occlusive dressing

·   30-60min pre-IVC, 120min pre-graft

Time course

·   Onset: 30mins

·   Max time on skin 60 mins

·   Duration: 2-4 hours

Lignocaine

Prilocaine

Distribution

-pKa

-% unionised at pH 7.4

-Lipid solubility

-% plasma prot bound

7.9

25%

150x

70%

7.7

33%

50x

55%

Metabolism

-Mode

-t_1/2β

-Metabolites

Hepatic CYP450. High HER.

100 mins

MEGX: 80% of antiarrhythmic effect

Xylidide: 10% of antiarrhythmic effect

Hepatic CYP450

100 mins

O-toluidine -> methaemoglobinaemia

Toxicity at 600mg total

Excretion

Metabolites -> urine

10% lignocaine -> urine

Metabolite -> urine

<5% prilocaine -> urine