2002A09 Outline the toxicity of local anaesthetics.

↑Drug potency

·   ∝ Lipid solubility (i.e. bupivacaine >> lignocaine)

↑Peak plasma concentration

Main factors:

·   ↑Dose

·   ↑Rate of administration (bolus cf. infusion)

·   ↑Absorption rate (e.g. trachea, intercostal space)

·   ↓Metabolism rate (e.g. bupivacaine cf. lignocaine; liver disease)

↑CNS susceptibility

·   Pregnancy -> ↑sensitivity

·   Altered seizure threshold: epilepsy

·   Drug interactions: tramadol, cocaine, class 1 antiarrhythmics

·   ↑PaCO₂ (↑CBF), ↓PaO₂, ↓pH

↑CVS susceptibility

·   Cardiovascular disease e.g. ischaemia

·   Drug interactions: class 1 antiarrhythmics

·   ↑Heart rate -> ↑channel cycling rate

·   ↓PaO₂, ↓pH, ↑K⁺

↓CC:CNS ratio

(safety margin)

·   Dynamics: ↑Cardiac:CNS isoform affinity ratio for VDNaC

o e.g. D-bupiv > L-bupiv

·   Kinetics (e.g. ↓lipid solubility): less important

Threshold

CC:CNS ratio

Lignocaine

5mcg/mL

7:1

Ropivacaine

4mcg/mL

5:1

Bupivacaine

1.5mcg/mL

3:1

Mechanism

·  Inhibition of neuronal VDNaC

Effects

·  Initial excitatory effects

o Inhibition of inhibitory interneurons

o Peri-oral tingling, tinnitus, vertigo, slurred speech, inattention, twitching, seizures

·  Then inhibitory effects

o Inhibition of excitatory interneurons and others

o Coma, apnoea

Mechanism

·  Inhibition of cardiac VDNaC (very high affinity)

·  Inhibition of VDKC and VDCC (lower affinity)

·  ?↓cAMP

Effects

·  First phase: ↑HR, ↑mAP

·  Second phase: myocardial depression, ↓mAP

·  Terminal phase: peripheral vasodilatation, ↓↓mAP, re-entrant arrhythmia, arrest

ECG

·  “As if being pulled apart” ↑QT_C, ↑QRS duration

·  Arrhythmias: sinus bradycardia, AV block, ventricular tachyarrhythmia, asystole

Transient neurological symptoms

·  Associated with intrathecal lignocaine

·  Moderate to severe pain in buttocks and thighs

·  No objective neurological deficit

·  Onset: within 36 hours of complete recovery

·  Offset: 1-7 days

Neurotoxicity

·  Intra-neural injection

·  Intrathecal injection -> cauda equina syndrome to varying degree

·  Cause: ? ↑ICF [Ca²⁺]

Anterior spinal artery syndrome

·  Lower limb paralysis

·  Cause: ? thrombosis ?spasm ? hypotension ? vasoconstrictor

Total spinal anaesthesia

·  If ↑↑ intrathecal dose

·  Unconsciousness, apnoea, ↓↓mAP

Hypersensitivity

·  PABA metabolite of ester local anaesthetics

·  Sodium metabisulfite

Methaemo-globinaemia

·  Hb with Fe³⁺ is unable to bind O₂ or CO₂

·  Risk factors: dose >600mg, neonate (↓reductase activity)

·  Rx: methylene blue 1-2mg/kg IV over 5 mins

Cocaine toxicity

·  CVS: noradrenaline reuptake inhibition -> ↑ICF Ca²⁺ -> arrhythmias, coronary artery vasospasm -> ischaemia

·  CNS: dopamine and noradrenaline reuptake inhibition -> euphoria, delirium, seizure

Hepatotoxicity

·  Associated with continuous or repeat use of bupivacaine

Respiratory depression

·  Lignocaine depresses ventilatory response to ↓PaO₂

Weakness

·  Potentiates non-depolarising neuromuscular blockade
(inhibit VDNaC on sarcolemma pre-synaptic membrane)