Local anesthetic
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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 an antiarrhythmic drug.
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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 thus inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel. Local anesthetic drugs selectively bind to activated and inactivated sodium channel (without binding to sodium channel in resting memebrane potential), and this is called state dependent blockade.
Local anesthetics are weak bases and are usually available as hydrochloride solutions. At physiologic pH the protonated and unprotonated forms of the molecule exist in an equilibrium. Only the unprotonated molecule diffuses readily across cell membranes, but only the protonated form is able to block sodium channels. It may be possible to enhance local anesthetic activity by altering the pH of a drug preparation. Besides, local acidosis caused by wound infection may defer the action of local anethetics.
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.