Local Anaesthetics

Understanding of the pharmacology of local anaesthetic drugs, including their toxicity

Local anaesthetic drugs create a use-dependent temporary blockade of neuronal transmission by blocking the voltage-gated sodium channel in the cell membrane, preventing depolarisation.

Mechanism of Action

Action is dependent on blockade of the sodium channel. Two theories exist:

  • Unionised drug passes through the cell membrane, and then becomes ionised intracellularly
  • The ionised drug is then able to bind to the open sodium channel, and prevent conduction of sodium and therefore generation of an action potential
    • Local anaesthetics also display reduced affinity for K+ and L-type Ca2+ channels
    • This theory explains use-dependent blockade, as sodium channels can only be blocked in their open state
  • An alternative suggested mechanism of action is the drug enters the cell membrane and mechanically distorts the channel, rendering it ineffective
  • Onset is inversely proportional to the size of the fibre
    From fastest to slowest:
    • Pain
    • Temperature
    • Touch
    • Deep pressure
    • Motor

Chemical Structure of Local Anaesthetics

All local anaesthetics are weak bases consisting of:

  • A hydrophilic component
  • A lipophilic aromatic ring
  • An amide or ester link connecting the two

Chemical structure influences pharmacological behaviour:

  • Hydrophilic portion
    Typically the tertiary amine.
    • Determines ionisation
      • 3 bonds: Lipid soluble
      • 4 bonds: Water soluble
  • Lipophilic portion
    Typically aromatic ring.
    • Determines lipid solubility, and therefore potency, toxicity, and duration of action
  • Ester vs. amide
    • Amides
      • Hepatically metabolised (hydroxylation and N-de-alkylation)
        This is slower, therefore there is a greater risk of systemic toxicity.
      • Stable in solution
    • Esters
      • Heat-sensitive
        Cannot be autoclaved.
      • Rapidly hydrolysed in plasma
        Organ independent elimination.
      • Have a greater incidence of allergy
        Due to the inactive metabolite PABA.
  • Amine group length
    • Potency and toxicity increase as carbon-chain increases
    • Toxicity (but not potency) continues to increase beyond 10 carbons
  • Isomerism
    Alters behaviour:
    • Levobupivacaine is less toxic
    • R-ropivacaine is less potent and more toxic

Key Characteristics of Local Anaesthetics

Characteristics are related to chemical structure. These include:

  • Potency
    • Potency is expressed with the minimum effective concentration of local anaesthetic (Cm)
      This is the concentration of LA that results in complete block of a nerve fibre in 50% of subjects in standard conditions. More potent agents have a lower Cm.
    • Potency is a function of:
      • Lipid solubility
        Potency (and also toxicity) increases with greater lipid solubility.
      • Vasodilator properties
        In general, local anaesthetics cause vasodilation in low concentrations, and vasoconstriction at high concentrations (except cocaine, which causes vasoconstriction at all concentrations).
  • Duration of action
    Duration of action is a function of:
    • Drug factors
      • Vasodilator properties
        Vasoconstriction increases the duration of block.
      • Use of additives
        Addition of adrenaline to lignocaine increases duration of block.
      • Lipid solubility
        Increased lipid solubility increases duration of action, as agent remains in the nerve for longer.
        • Potency therefore has a positive correlation with duration of action
        • Duration of action is increased when pH increases, as the ionised portion falls
      • Protein binding
        Highly protein bound agents have an increased duration of action due to increased tissue binding.
        • Protein binding decreases with decreasing pH, increasing the fraction of unbound drug
          This is why agents such as bupivacaine are more cardiotoxic in acidotic patients.
        • Local anaesthetics are predominantly bound to α-1-acid glycoprotein (AAG)
          AAG is reduced in pregnancy, increasing the free drug fraction and therefore reducing the toxic dose of LA in pregnant patients.
    • Patient factors
      • Tissue pH
        Decreased duration of block when tissue pH is low.
      • Metabolic impairment
        • Hepatic failure increases duration of action of aminosteroids
        • Butylcholinesterase deficiency increases duration of ester local anaesthetics
      • Site of administration Well vascularised tissue (e.g. intercostal area) will have greater systemic uptake of drug than vessel poor tissue.
  • Onset
    Speed of onset is related to:
    • Drug factors
      • Dose
        Increasing the dose increases the speed of onset, as per Fick's Law.
        • Increased concentration will increase speed of onset and block density
        • Increased volume (without increasing dose, resulting in decreased concentration) will decrease speed of onset
      • Lipid solubility
        An increased lipid solubility increases the speed at which the local anaesthetic enters the nerve. However:
        • Lipid solubility also correlates with potency
        • Therefore, in practice, more lipid soluble agents are administered in lower doses, and so have a reduced speed of onset
          This is known as Bowman's Principle.
      • Ionised portion
        Only unionised drug can cross cell membranes. Ionisation is a function of:
        • pKa
        • Tissue pH
          • This is also why anaesthetics are ineffective in anaesthetising infected tissue, as the low pH makes the majority of the LA ionised and unable to cross the cell membrane.
    • Patient factors
      • Nerve activity
        Local anaesthetics produce a frequency dependent blockade, meaning nerves firing frequently will be blocked more rapidly than quiescent nerves
      • Nerve fibre size
        Larger nerves require an increased concentration of local anaesthetic to achieve blockade than smaller nerves.
      • Nerve type
        Different nerve fibres are affected at different speeds, which is mostly (though not entirely) a function of critical length.
        • Aγ (proprioceptive) are affected first
        • Small myelinated Aδ (sharp pain, cold) fibres are affected second
        • Large myelinated nerves are affected third These include Aα (motor) and Aβ (touch) fibres.
        • Unmyelinated nerves are affected last
          These include C (dull pain, heat) fibres.
      • Hyperkalaemia
        Reduces onset of action.

Toxicity

Local anaesthetics are:

  • Toxic to both the CNS and CVS
  • Toxicity occurs when there is an excess plasma concentration
    This occurs when the rate of drug entering the systemic circulation is greater than the drug leaving the systemic circulation due to redistribution and metabolism.

Toxicity is related to the:

  • Drug factors
    • Drug used
      Agents are compared using the CC/CNS ratio, which is the ratio of the dose of drug required to cause cardiovascular collapse (CC) compared to the dose required to cause seizure. It is a crude alternative to the therapeutic index.
    • Dose used
      Continuous infusions are more likely to cause a delayed onset of local anaesthetic toxicity.
  • Block factors
    • Site of administration
      This affects the rate of uptake into the systemic circulation, and the likelihood of inadvertent intravascular injection. Ranked (from highest to lowest):
      • Intravascular (obviously)
        This is the most common cause of LA toxicity.
        • Site is also relevant here: an injection into the carotid artery will cause toxicity at a lower dose than if injected into a peripheral vein.
      • Intercostal
      • Caudal
      • Epidural
      • Brachial plexus
      • Subcutaneous
    • Use of adjuncts
      • Adrenaline
        Vasoconstrictor properties reduce systemic absorption of LA.
    • Technique
      • Frequent aspiration
      • Test dose
      • Use of ultrasound
  • Patient factors
    Anything that increases peak [plasma] can lead to an increased risk of LA toxicity.
    • Blood flow to affected area
    • α1-acid glycoprotein
      Low levels of this protein increase free drug fraction.
      • Neonates and infants have half the level of AAG than adults.
    • Hepatic disease
      Reduces clearance of amides, which may cause toxicity with repeated doses or use of infusions.
    • Age
      Organ blood flow (and therefore clearance), as well as pharmacokinetic interactions may affect clearance of LA. Both children and the elderly have reduced clearance of LA.
    • Acidosis
      Increases unionised portion.
    • Hypercarbia
      Increases cerebral blood flow.

Cardiac Toxicity

Cardiac toxicity occurs due to:

  • Blocking of the cardiac Na+ channel (K+ and Ca2+ channels may also be involved)
    Severity of toxicity will vary depending on how long the agent binds to the channel, with less toxicity caused by agents spending less time bound:
    • Lignocaine
      Spends the shortest time bound to the channel, so causes the least amount of toxicity. This is also why lignocaine can be used as an antiarrhythmic, but other agents can not.
    • Bupivacaine
      Takes 10x as long to dissociate as lignocaine. This can lead to re-entrant arrhythmias, and then VF. The risk of this is increased in tachycardia due to use-dependent blockade.
    • Ropivacaine
      Dissociates more rapidly from cardiac channels than bupivacaine.
  • Direct myocardial depressant effects
    Reduces cAMP levels by disrupting metabotropic receptors.

Cardiac toxicity is triphasic:

  • Initial phase
    • Hypertension
    • Tachycardia
  • Intermediate phase:
    • Hypotension
    • Myocardial depression
  • Terminal phase:
    • Severe hypotension
    • Vasodilation
    • Various arrhythmias
      • Sinus bradycardia
      • Variable degree heart block
      • VT
      • VF
      • Asystole

CNS Toxicity

Local anaesthetics in their unionised state can cross the BBB and interfere with CNS conduction. CNS toxicity is biphasic:

  • Initially, inhibitory interneurons are blocked
    This causes excitatory effects:
    • Perioral tingling
    • Slurred speech
    • Visual disturbances
    • Tremulousness
    • Dizziness
    • Confusion
    • Convulsions
      Typically signifies the end of the excitatory phase.
  • Secondly, there is a general depression of all CNS neurons
    This causes inhibitory effects:
    • Coma
    • Apnoea

Treatment

Toxicity is managed with an ABC approach, though definitive management uses Intralipid emulsion:

  • Intralipid is an emulsion of soya oil, glycerol, and egg phospholipids.
    Mechanism of action in uncertain, but theories include:
    • Lipid sink
      ILE binds unionised LA, causing it to distribute off receptor sites.
    • Fatty acid metabolism
      Cardiac fatty acid metabolism is interrupted by LA. ILE provides a source of fatty acids to allow metabolism to continue.
    • Competitive antagonism
      ILE may directly inhibit LA binding.
  • Dosing of Intralipid 20%:
    • Bolus of 1.5ml.kg-1 over 1 minute
    • Infusion at 15ml.kg-1.hr-1

  • Complications include pancreatitis
    Note that ILE interferes with amylase and lipase assays, and so these will be unreliable.

  • Note that whilst propofol can be used to treat seizures, the amount of lipid contained in propofol is inadequate to bind LA

References

  1. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
  2. Christie LE, Picard J, Weinberg GL. Local anaesthetic systemic toxicity. Continuing Education in Anaesthesia Critical Care & Pain, Volume 15, Issue 3, 1 June 2015, Pages 136–142.
  3. Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
  4. Becker DE, Reed KL. Essentials of Local Anesthetic Pharmacology. Anesthesia Progress. 2006;53(3):98-109.
Last updated 2021-08-23

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