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.

Local anaesthetic drugs are known to reduce epithelial repair, and so it it wise to administer them away from the site of surgical incision so that healing is not impaired. Inadvertent intravenous administration of these drugs can result in tissue irritation and allergic reactions.

Drugs in this Group

Lidocaine

Lidocaine is an amide-linked local anaesthetic, which aslo has anti-arrhythmic properties. The time to onset of action is 3-10mins, after which the drug's effects last 60-90mins. The duration of action may be prolonged by the addition of adrenaline to the preparation. Lidocaine is a very cheap drug, and is a component of EMLA cream.

Bupivicaine

Bupivicaine is also an amide-linked local anaesthetic, but with a duration of action of around 8 hours, it is longer acting than lidocaine. It also has a longer time to onset (20-30mins). It is very cardiotoxic, casuing asystole by decreasing the force of contraction, and therefore must NOT be given intravenously.

Mepivicaine

Another amide-linked drug, mepivicaine has the same potency as lidocaine but is less irritant and vasodilatory. The time to onset is only 5-10 mins, and the effects last 90-180 mins. However, the drug is expensive, and is not formulated with a preservative and so the vial must be discarded once the seal is broken.

Procaine

Procaine is ester-linked, and so may cause allergic reactions to the PABA metabolite. It has a short duration of action and may be added to penicillin to reduce pain on injection.