NeuroPharm – LA

Master answer

Background

• toxicity = unwanted harmful effect of a drug
• LA= drugs that reversibly inhibit transmission of neural impulses in the applied region without affecting consciousness
• Toxicity from LA can be classified into local or systemic
  • Local toxicity: mechanism of delivery + reaction to PABA
  • Systemic toxicity = due to excess plasma concentration determined by rate of drug entrance relative to its redistribution and clearance by metabolism

Maximum recommended doses:

Toxicity Mechanisms and Effects

Local toxicity

• High epidural or spinal blockade
  • β fibres = small myelinated fibres readily blocked by LAs
  • large doses of epidural/spinal LA can result in inappropriately high block
  • High SY chain block
    • Vaso + veno dilation → ↓SVR + ↑venous capacitance → ↓↓MAP
    • Venodilation → ↓VR → ↓RAP → ↓HR
    • Blockade of cardioaccelerator (T1-T4) fibres → ↓↓HR
  • o Brainstem block
    • Blockade of resp centre → profound resp depression
    • Blockade of autonomic centre → CVS collapse (↓↓MAP + ↓↓HR)
• Neurotoxicity
  • epidural/ intrathecal injection → neurotoxicity: mechanism: lignocaine ↑intracellular [Ca2+] → neurotoxic via unknown mechanism
  • radicular irritation → transient neurological symptoms that resolve over 1-7days
  • cauda equina syndrome → diffuse lumbosacral plexus injury → sensory, bladder + bowel dysfunction, paraparesis
  • anterior spinal artery syndrome → lower limb paresis + dysaesthesia ?2o
    anterior spinal artery spasm
    

Systemic toxicity

• CNS toxicity
  • Biphasic effect
    • Excitatory phenomena: depression of inhibitory interneurons → circumoral tingling, tongue numbness → restlessness, tinnitus, vertigo → skeletal + facial muscle twitching → seizure
    • CNS depression: depression of central neurons → coma, apnoea
  • Seizure ?2o inhibition of inhibitory GABAergic pathways → unopposed excitatory activities → seizure
• CVS toxicity
  • ↑↑dose required to produce CVS toxicity than CNS toxicity
  • Main effects: hypotension + bradyarrhythmias
  • Mechanism:
    • Cardiac Na channel blockade LAs → slow conduction of cardiac impulses → PR prolongation + QRS widening → VTs
    • Inhibit Ca2+ and K+ ion channels
    • Inhibit cAMP synthesis (minor)
    • Relaxation of arteriolar vascular smooth muscle
  • CC:CNS ratio: ratio of the dose required to cause CVS collapse and the dose required to cause CNS toxicity: indicates that CNS is ↑vulnerable to LA than CVS
• Hypersensitivity reaction
  • Rare
  • LA or additive can → hypersensitivity reaction
  • Ester LAs metabolised to para-aminobenzoate (↑rates allergy)
• Hepatotoxicity
  • Continuous epidural infusion of bupivacaine found to rarely cause hepatic enzyme derangement + hepatoxicity
  • Mechanism unclear
• Methaemoglobinaemia
  • Prilocaine metabolised in liver to o-toluidine → oxidises Fe2+ of haem to Fe3+ → ↑methaemoglobin (unable to carry O2) → tissue hypoxia

Factors affecting risk of toxicity

• Drug factors
  • Dose
  • Route + location of administration
  • Potency; pKa
  • Isomerism (R-enantiomer more toxic than S)
  • Rate of metabolism
  • PB (↑PB → ↓free drug → ↓toxicity)
  • Intrinsic vasodilator activity
• Patient factors
  • Acidosis → ↑ionised → ion trapping → ↑toxicity
  • Pregnancy → ↑progesterone → competitive binding to AAG → ↑unbound LA → ↑toxicity
  • Hepatic/renal dysfunction
  • Heart failure → ↓perfusion + ↓VD → ↓elimination
  • Plasma cholinesterase activity

Prevention of LA toxicity

• Frequent aspirations
• Slow injection
• Test dose
• Total dose administered < max recommended dose
• Awake patient
• Monitoring
• USS guided
• Vasoconstrictors

Kerr 2016

Answer by Kerr