Local anesthetic

A local anesthetic is a drug that reversibly inhibits the propagation of signals along nerves. When it is used on specific nerve pathways, effects such as analgesia (loss of pain sensation) and paralysis (loss of muscle power) can be achieved.

While many other drugs have some local anesthetic action as a side effect, all substances that are clinically used belong to two related classes: aminoamide and aminoester local anesthetics. These so-called synthetic local anesthetics are structurally related to cocaine. They differ from cocaine mainly in that they have no abuse potential and do not act on the sympathoadrenergic system, i.e. they do not produce hypertension or local vasoconstriction.

Local anesthetics vary in their pharmacological properties and they are used in various techniques of local anesthesia such as:

topical anesthesia (surface)
infiltration
plexus block
epidural (extradural) block
spinal anesthesia

The local anesthetic lidocaine is also used as a Class Ib antiarrhythmic drug.

Mechanism of action

Local anesthetic drugs act mainly by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell membrane, in particular the so-called voltage-gated sodium channels. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel. Local anesthetic drugs bind more readily to "open" sodium channels, thus onset of neuronal blockade is faster in neurons that are rapidly firing. This is referred to as state dependent blockade.

Local anesthetics are weak bases and are usually formulated as the hydrochloride salt to render them water-soluble. At physiologic pH the protonated (ionised) and unprotonated (unionised) forms of the molecule exist in an equilibrium but only the unprotonated molecule diffuses readily across cell membranes. Once inside the cell, the lower pH results in the molecule being protonated, thus inhibiting its passage back out of the cell. This is referred to as "ion-trapping". In the protonated form, the molecule binds to the local anaesthetic binding site on the inside of the ion channel near the cytoplasmic end.

It may be possible to enhance local anesthetic activity by altering the pH of a drug preparation to maximise the amount of drug in the unionised (unprotonated) form. It is well established that local acidosis such as caused by wound infection greatly reduces the action of local anesthetics. This is partly because most of the anaesthetic is ionised and therefore unable to cross the cell membrane.

Undesired effects

The conduction of electric impulses follows a similar mechanism in peripheral nerves, the central nervous system, and the heart. The effects of local anesthetics are therefore not specific for the signal conduction in peripheral nerves. Side effects on the central nervous system and the heart may be severe and potentially fatal. However, toxicity usually occurs only at blood plasma levels which are rarely reached if proper anesthetic techniques are adhered to.

Central nervous system

Depending on local tissue concentrations of local anesthetics, there may be excitatory or depressant effects on the central nervous system. At lower concentrations, a relatively selective depression of inhibitory neurons results in cerebral excitation, which may lead to generalized convulsions. A profound depression of brain functions occurs at higher concentrations which may lead to coma, respiratory arrest and death. Such tissue concentrations may be due to very high plasma levels after intravenous injection of a large dose. Another possibility is direct exposure of the central nervous system through the cerebrospinal fluid, i.e. overdose in spinal anesthesia or accidental injection into the subarachnoid space in epidural anesthesia.

Cardiovascular system

The conductive system of the heart is quite sensitive to the action of local anesthetics. Lidocaine is often used as an antiarrhythmic drug and has been studied extensively, but the effects of other local anesthetics are probably similar to those of Lidocaine. Lidocaine acts by blocking sodium channels, leading to slowed conduction of impulses. This may obviously result in bradycardia, but tachyarrhythmia can also occur. With high plasma levels of lidocaine there may be higher-degree atrioventricular block and severe bradycardia, leading to coma and possibly death.

Hypersensitivity/Allergy

Adverse reactions to local anesthetics are not infrequent, but true allergy is very rare. Non-allergic reactions may resemble allergy in their manifestations. In some cases, skin tests and provocative challenge may be necessary to establish a diagnosis of allergy. There are also cases of allergy to paraben derivatives, which are often added as preservatives to local anesthetic solutions.

Methemoglobinemia

The systemic toxicity of prilocaine is comparatively low, however its metabolite, o-toluidine, is known to cause methemoglobinemia. As methemoglobinemia reduces the amount of hemoglobin that is available for oxygen transport, this side effect is potentially life-threatening. Therefore dose limits for prilocaine should be strictly observed. Prilocaine is not recommended for use in infants.