Local anesthetics
Local anesthetics are drugs which, by inhibiting nerve conduction where they are administered, make the territory corresponding to this innervation insensitive to pain. The drug of reference of this group is lidocaine.
By reducing the membrane permeability to Na + ions, local anesthetics inhibit depolarization and nerve conduction. They do not block the external part of the channel but the intracellular part after penetration inside the cell.
The need for intracellular penetration of local anesthetics in order to be active explains why polar compounds with a quaternary ammonium group which do not cross membranes, applied outside the cells, are inactive, whereas, introduced inside the cell, they have local anesthetic properties. Local anesthetics must thus pass the membrane in neutral form which depends on their pK value and the extra and intracellular pH.
Local anesthetics have the same general chemical structure (see formulas of three of them).
Effects
Local anesthetic effect
Local anesthetics inhibit the nerve conduction in a reversible way without damaging the nerve. Inhibition appears quickly and has more or less duration according to the product and its concentration. The extent of the territory made insensitive to pain depends on the conditions of administration of the local anesthetic, either at the level of nerve terminations, or at the level of a nervous trunk, for example.
With sufficient concentration, local anesthetics inhibit all the nerve fibers, sensitive, motor, vegetative. They reach initially sensitive fibers because they have a smaller diameter than motor ones and, not being myelinated, are easier to reach by the anesthetic.
The order of disappearance of the feelings is as follows: painful feeling, temperature (cold, heat), tactile. The recovery occurs in the inverse order.
Present at the level of synapses, local anesthetics inhibit transmission.
Other properties
- Vasodilator effect: local anesthetics, except cocaine which is not used any more in therapeutics, have a vasodilator effect.
The simultaneous administration of a vasoconstrictor, generally adrenaline, is very important because it avoids the diffusion of the local anesthetic which remains at a high concentration at the level of its injection site. But one never should use the vasoconstrictive for local anesthesia of fingers, toes, ears, penis, because there is a risk of necrosis by ischemia.
- Other effects: the systemic diffusion of a local anesthetic can induce, in addition to vasodilation:
- cardiac effects: decrease of conduction and force of contraction, resulting in hypotension, even shock.
- neurological effects: tremors even seizures explained by the preferential inhibition of inhibiting cerebral areas, which induces a stimulation and finally respiratory arrest.
Metabolism
In theory, it is not wished that the anesthetics administered topically diffuse throughout the body. Actually, a diffusion of a local anesthetic exists always, even when combined with a vasoconstrictive, but it must be sufficiently slow to not have general adverse effects.
Local anesthetics, like the other drugs, are metabolized, i.e. undergo biotransformations. The principal reactions are hydrolysis by esterases like plasma or tissue cholinesterases for local anesthetics such as procaine and tetracaine, and dealkylation, at the hepatic level in particular, for amide type local anesthetics, i.e. the majority of them.
Therapeutic uses and presentations
The therapeutic uses of local anesthetics are very numerous: endoscopic explorations, surgical operations, small surgery, dental extractions.
Preparations are available for these various uses.
- Local anesthesia or regional: injectable forms
One distinguishes several kinds of local anesthesia:
- Surface, preparations for cutaneous and mucous applications
- Infiltration (the anesthetic is injected into the area to anesthetize)
- Conduction (the anesthetic is injected at the level of a nerve and the innerved territory is anesthetized)
- spinal the local anesthetic is injected either into the cerebrospinal fluid and the injection is called intraspinal, or in the epidural space and it is called epidural
The products used as local anesthetics are lidocaine (Xylocaine*), bupivacaine (Marcaine*, Marcain*), procaine (Novacain*), Etidocaine (Duranest*), mepivacain (Carbocaine*), ropivacaïne (Naropin*).
The preparations containing adrenaline should not be given by intravenous route nor used for the anesthesia of theextremities, fingers, penis, because of the vasoconstrictive effect of adrenaline.
Lidocaine is also used as a class Ib antiarrhythmic (see following page).
Adverse effects
Allergic accidents are exceptional but can be severe.
The accidents due to an overdose are much more frequent. They follow the administration of too high a dose or a too fast a delivery in the circulation. They result in cardiovascular and neurological disorders preceded by subjective signs: paresthesia, headache, faintness, nausea, visual disturbances.
The cardiovascular disorders are generally a fall of arterial pressure possibly causing collapse, arrhythmias, and even cardiac arrest
The neurological disorders are partial then generalized seizures with, very exceptionally, a respiratory arrest. These seizures are usually treated by the administration of an injectable benzodiazepine such as diazepam.
Notice
Cocaine was the first compound known to have local anesthetic properties. It is not used any more in therapeutics, because it induces psychic disorders and an extremely important addiction, related to its dopaminomimetic action resulting from inhibition of dopamine reuptake.
The stimulation of D2 receptors could be at the origin of the addiction whereas the stimulation of the D1 receptors could have the inverse effect and decrease it.
Cocaine is largely used by drug addicts by parenteral, nasal or pulmonary route. Introduced into cigarettes in the base form, cocaine is instantaneously absorbed by the smoker. In this form it is called “ace” because it makes a noise resembling the crystal crushing under the effect of heat, or “rock” because of its aspect. The intensity of the symptoms which it induces depends on the rate with which its concentration varies in the brain.
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