Local Anaesthetics

Mechanism of Action

• Local anaethetic drugs reversibly interfere with action potential generation and conduction in the neurons around which they are administered. To reach the neuronal plasma membrane where they act, local anaethetic drugs must first enter the nerve sheath. Only molecules lacking ionic charge may do this, and so local anaesthetic agents work more effectively in an alkaline pH when charge is neutral. Once inside the sheath, the drug gains charge and can then bind to voltage-gated Na⁺ channels, preventing depolarisation of the cell. Local anaesthetics also infiltrate and change the composition of the cell membrane to take effect. However, they do NOT alter resting membrane potential.

• Small diameter nerve fibres are blocked before large fibres by local anaesthetics, and fibres which are myelinated are blocked before those which are unmyelinated. Therefore, A-delta fibres are blocked before C fibres, and so the sensation of pain is eliminated before that of gentle touch.

• The blocking effects of local anaethetics is more effective in neurons which are firing. This is because action potentials cause channels in the nerve sheath to cycle between open, resting inactive conformations. The drugspenetrate the sheath through open channels, and bind most readily to inactivated channels.

• Local anaesthetic drugs also cause vasodilation. To prevent this effect leading to increased systemic absorption of drug, vasoconstrictors (e.g. adrenaline) are commonly added to preparations.

Pharmacokinetic Considerations

Local anaesthetic agents consist of a lipid-soluble (hydrophobic) aromatic ring joined to a basic (hydrophilic) amide group. The two groups may be either:

• Ester linked
  • For example, procaine and cocaine.
  • Local anaesthetics linked in this way are less stable in solution.
  • Metabolism by tissue esterases, hepatic esterases and hydrolysis occurs. Products are subsequently excreted by the kidney. However, one product of metabolism is para-amino benzoic acid (PABA), which may cause allergic reactions.
• Amide linked
  • For example, lidocaine and bupivicaine.
  • Amide linked local anaesthetics can be stored longer than ester-linked drugs and are heat stable.
  • Metabolism is by hepatic amidases, and excretion occurs via the kidney.

Protein Binding

The degree of plasma protein binding of individual drugs affects their distribution within the body and the duration of their action. Drugs which have a higher degree of binding have effects for a longer period of time, and in hypoproteinaemic animals, local anaesthetics have a shorter duration of action. For example, bupivicaine is 95% protein bound, compared to 65% for lidocaine, and so its effects will persist longer.

Ionisation

Local anaesthetics are weak bases and so the degree of ionisation will be greatest at low pHs. Since only unionised drug can cross the nerve sheath to enter the nerve and take effect, local anaesthetics work best in alkaline surroundings where the unionised form predominates. Infected tissue has a lower pH, increasing the proportion of ionised molecules and causing poor uptake of drug. For more about the effect of pH on drugs, see the pharmacokinetics page.

Side Effects and Contraindications

Local anaesthetics may have undesirable effects on the CNS. These include termors, convulsions and respiratory depression. The cardiovasular system may also be adversely affected, with drug administration leasing to reduced cardiac contractility, vasodilation and hypotension. #Bupivicaine is particularly cardiotoxic, but stereoisomerism exists. The cardio- and neuro-toxic effects of dextrobupivicaine are greatly increased compared to that of levobupivicaine. Commercially available preparations of bupivicaine are a 50:50 mixture of the two forms of the drug.