2020B09 Discuss factors that influence the toxicity of local anaesthetics
when used for topical anaesthesia of skin and mucosa.

 

List:

·     Means of toxicity

·     Determinants of drug uptake

·     Determinants of LAST susceptibility

 

Means of toxicity:

LAST

·   Systemic blockade of voltage-gated Na+ channels (∝ dose)

·   CNS effects: e.g. seizure, coma

·   CVS effects: e.g. arrhythmia, arrest

Cocaine toxicity

·   Effects mostly ∝ dose

·   Effects ? additive ? synergistic with other local anesthetics (e.g. nasal surgery)

·   CVS: ↑↑noradrenaline -> ↑BP, ↑HR, coronary vasoconstriction,
Cardiomyopathy (? idiosyncratic)

·   CNS: ↑↑dopamine -> euphoria, risk-taking

·   Nasal: profound vasoconstriction -> ischaemic necrosis (∝ dose)

Prilocaine toxicity

·   ↑Methaemoglobin -> Hb unable to bind O2 (∝ dose)

·   ↑↑Risk of reductase deficiency: neonate, congenital

Hypersensitivity

·   i.e. allergy, anaphylaxis (dose-independent)

·   e.g. PABA metabolite of esters

·   e.g. sodium metabisulfite preservative with lignocaine

 

Determinants of drug uptake:

Diffusion rate:

Fick’s law:

    - ↑C1

·   ↑Drug concentration (e.g. 10% lignocaine for airway topicalisation)

·   Eutectic mixture: optimal ratio -> ↓melting point -> liquid state -> ↑C1 (cf. solution)

o EMLA: 2.5% lignocaine + 2.5% prilocaine, melting point 18°C

    - ↓C2

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

·   Regional variation: e.g. lower flow to foot cf. scalp

·   Drug effect: e.g. prolonged EMLA application -> vasodilation

·   Drug additive: adrenaline -> ↓rate of absorption (e.g. nasal lignocaine)

·   Pathology: hypothermia, shock, heart failure

    - ↑Area

·   ↑Area of application -> ↑total absorption but ↔ absorption per unit area
e.g. multiple patches

    - ↓Thickness

·   Extensor thicker than flexor

·   Lower limb thicker than upper limb

·   Mucous membrane -> ↓↓thickness, ↑↑rate of blood flow

o Contraindication for EMLA, topical amethocaine

o Risk of inadvertent overdose during topicalisation for AFOI

    - ↑Diffusion

       coefficient

·   ↑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)

Diffusion time:

·   Uptake ∝ application time

·   EMLA 30 mins for PIVC, 120 mins for skin graft

·   2% lignocaine viscous gargle < 1 minute for pharyngeal topicalisation

 

Determinants of LAST susceptibility:

Drug

Pharmacokinetics (PK):

·   Esters: rapid metabolism by BChE -> short t1/2β

·   Amides: slow metabolism by liver -> long t1/2β

Pharmacodynamics (PD):

·   Toxicity threshold: bupiv 1.5mcg/mL, ropiv 4mcg/mL, lignocaine 5mcg/mL

·   CC:CNS ratio – bupivacaine 3:1, ropivacaine 5:1, lignocaine 7:1

Patient

PK:

·   Absorption: see above

·   Distribution: Cachexia -> ↑plasma concentration -> ↑risk

·   Metabolism: liver disease -> ↓rate of amide removal -> ↑risk

PD:

·   Class 1 antiarrhythmics -> ↑Na+ channel blockade -> ↑risk

·   CVS

o ↑HR -> ↑channel cycling rate -> ↑risk

o ↓PaO2, ↓pH, ↑K+ -> ↑risk

o IHD, channelopathy -> ↑risk arrhythmias

o AV conduction delay -> ↑risk high grade block from lignocaine

·   CNS

o ↑PaCO2 (↑CBF), ↓PaO2, ↓pH -> ↑risk

o Pregnancy -> ↑local anaesthetic sensitivity

o Epilepsy, tramadol -> ↓seizure threshold

 

 

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