Pharmacology of local anaesthesia

• Local anaesthetic agents


  Drugs used clinically to produce reversible loss of neuronal transmission
• Nerve fibres


  • Small fibres are blocked before large fibres, Hence the order of blockade is: pain, temperature, and lastly motor
• Cocaine isolated from erythroxylum coca

  1860
• Koller used cocaine for topical anesthesia

  1884
• Halsted performed peripheral nerve block with local


  1885
• Bier performed the first spinal anaesthesia


  1899
• Lofgren developed lidocaine


  1943
• Mepivacaine developed


  1957
• Prilocaine developed


  1960
• Bupivacaine developed


  1963
• Ropivacaine developed


  1997
• Levobupivacaine developed


  2000
• Local anaesthetic molecule


  Consists of three parts: Aromatic group - linking chain - Tertiary amine
• Classes of local anaesthetic drugs

  • Esters
  • Amides
• Ester local anaesthetics


  • Cocaine
  • Chloroprocaine
  • Procaine
  • Tetracaine
• Amide local anaesthetics


  • Bupivacaine
  • Lidocaine
  • Ropivacaine
  • Etidocaine
  • Mepivacaine
• Free base


  The active form of the local anaesthetic
• A decrease in pH (such as from inflammation, abscess) reduces the active free base, reducing the efficacy of a local anaesthetic if injected into an inflamed area
• Mode of action


  LAs cause reversible interruption of the conduction of impulses in peripheral nerves by causing a local decrease in the rate and degree of depolarisation of the nerve membrane, impairing sodium ion flux and preventing the electrical impulse from being propagated down the nerve
• Esters


  • Relatively unstable in solution, rapidly hydrolysed in the body by plasma cholinesterase (and other esterases), one of the main breakdown products is para-amino benzoate (PABA) which is associated with allergic phenomena and hypersensitivity reactions
• Amides


  • Are relatively stable in solution, slowly metabolised by hepatic amidases, hypersensitivity reactions are rare
• Potency


  Directly related to lipid solubility - more lipid soluble agents like bupivacaine, etidocaine or tetracain are more potent than less lipid soluble agents like procaine due to better penetration of the lipid nerve membrane
• Duration of action


  Related to protein binding - higher protein binding allows the drug to remain longer in the circulation
• Onset of action


  Related to pKa - the closer pKa is to body pH, the faster the onset of action (e.g. lidocaine pKa 7.74, tetracaine pKa 8.6)
• All local anaesthetics cross the blood brain barrier
• All local anaesthetics cross the placenta and enter the blood stream of the developing fetus
• Ester local anaesthetics


  • Allergic reactions are common, rapidly metabolized by plasma and liver cholinesterases, the rate of hydrolysis is related to the degree of toxicity (tetracaine is hydrolyzed the slowest making it 16 times more toxic than chloroprocaine which is hydrolyzed the fastest)
• Amide local anaesthetics


  • Primary site of metabolism is the liver, allergic reactions are rare, virtually the entire metabolic process occurs in the liver, liver function and hepatic perfusion greatly affect the rate of metabolism
• Metabolism of local anaesthetics

  • Esters - plasma and liver cholinesterases
  • Amides - liver
• Kidneys are the major excretory organs for both ester and amide local anaesthetics
• Lignocaine


  One of the most commonly used local anaesthetics, onset of action is immediate, duration of action is 60mins or 90mins with adrenalin
• Bupivacaine


  About 4 times more potent than lignocaine, onset of action is slow (abt 15mins) but has long duration of action (4hrs)
• Ropivacaine


  Similar in onset and duration of action to bupivacaine but less cardiotoxic, less potent (0.75% ropivacaine is equipotent to 0.5% bupivacaine)
• Chloroprocaine


  The least toxic local anaesthetic
• Clinical uses of local anaesthetics

  • Surface/topical anaesthesia
  • Infiltration anaesthesia
  • Nerve block
  • Epidural anaesthesia
  • Sympathetic block
  • Spinal anaesthesia
  • Anti-arrhythmic agents (e.g. lidocaine)
• Systemic toxicity


  Occurs when blood concentration of the anaesthetic is too high, may be due to accidental intravascular injection, injection into highly vascular tissue, or gross overdose
• Symptoms of CNS toxicity

  • Feelings of light-headedness, dizziness, circumoral paraesthesia, visual and/or auditory disturbances, disorientation, drowsiness
• Signs of CNS toxicity

  • Shivering, muscular twitching and tremors, generalised convulsions of a tonic-clonic nature
• Cardiovascular toxicity


  Usually occurs at doses and blood concentrations higher than those required to produce CNS toxicity, includes tachycardia, bradycardia, hypotension, direct effects on heart and peripheral blood vessels
• Respiratory system depression can also occur with local anaesthetic toxicity