Local Anaesthetics

Anaesthetic agents are administered to the patient in most present day operations in order to minimize pain and distress. There are two main classes of anaesthetic agents: general anaesthetics, which exert their action on the CNS and local anaesthetics, which act to block the transmission of sensation locally. Both types of anaesthetics have a substantial side-effect profile.

Local anaesthetics can be very dangerous if the drug spreads systemically, as they can cause a dramatic fall in blood pressure and affects on the CNS that range from tremor and convulsions to respiratory depression. Such effects are avoided by ensuring local anaesthetics are locally contained.

Local anaesthetics cause loss of sensation locally at the site of operation whilst allowing the patient to remain aware. Many patients are less distressed if they can remain conscious during surgery, and local anaesthetics have the added advantage of faster recovery and discharge. Local anaesthetics act to reduce the spread of action potentials in peripheral nerves by blocking voltage dependent Na+ channels. Thus Na+ influx into the neuron is inhibited and membrane depolarization can not occur. Due to the nature of nerve fibres, the small diameter pain fibres are blocked first, followed by myelinated touch and sensation fibres and finally by motor neurons.

The two groups of local anaesthetics that are used clinically are aminoamides and aminoesters. The drugs work indiscriminately on voltage-gated Na+ channels, therefore adverse reactions are caused by blockage of off-target Na+ channels. For example, if local anaesthetics get into the blood stream they can inhibit the Na+ currents in cardiac muscle and therefore reducing the conduction velocity of non-nodal cardiac tissue. This effect can be beneficial and small doses of lidocaine can be administered as an antidysrhythmic. However, when local anaesthetic agents reach the heart in excessively large quantities, this leads to myocardial depression, hypotension and cardiovascular collapse.

The fall in blood pressure associated with myocardial depression is further exacerbated by local anaesthetic induced vasodilation. Lidocaine has been shown to initially cause vasodilation, followed by vasoconstriction. The vasoconstriction is thought to be caused by lidocaine-induced release of calcium ions into the cytoplasm of vascular smooth muscles from the intracellular stores. An increase in cytoplasmic calcium causes muscular contraction, which reduces the size of the blood vessel lumen and causes vasoconstriction. The subsequent vasodilation is thought to be due to lidocaine interacting with the hydrophobic domain of calmodulin that is exposed upon the binding of calmodulin with calcium. The physiological role of calmodulin is to activate the myosin light chain kinase (MLCK). If lidocaine blocks the calmodulin-MLCK interaction, MLCK is not activated and the phosporylation of myosin light chain is inhibited. Thus muscular contraction is unable to occur, and the vasculature undergoes vasodilation.

Evidence that supports the interaction of lidocaine with calmodulin can be seen in an experiment by Nosaka et al in which the smooth muscle of a turkey gizzard was isolated and local anaesthetic was applied. The muscle was stimulated by electric probes, however no muscular contraction was observed. This inhibition of contraction was not reversed by addition of calcium ions, but was reversed by the addition of calmodulin. It is hypothesized that the supplementary calmodulin competitively antagonizes the inhibitive action of the anaesthetic.

Therefore, when local anaesthetics enter systemic circulation, a severe drop in blood pressure can be observed. Physiologically this can be seen when local anaesthetic is injected intravenously into a limb isolated from systemic circulation by a pressure cuff. If the cuff is removed before the aminoesters have been locally hydrolysed there is a significant risk of systemic toxicity.

Whilst the effects of local anaesthetics are very serious, measures are taken in administration to prevent systemic spread and therefore avoid such serious side effects. The drugs are often injected locally in combination with vasoconstrictors such as adrenaline to limit the spread. If local anaesthetics are administered into the spinal column, then the patient is tilted with their head up to prevent cranial spread. As such, signs of local anaesthetic toxicity are rarely observed in practice.