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Local anesthetic

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Structure

A local anesthetic is a drug that causes reversible local anesthesia and a loss of nociception. When it is used on specific nerve pathways (nerve block), effects such as analgesia (loss of pain sensation) and paralysis (loss of muscle power) can be achieved.

Clinical local anesthetics belong to one of two classes: aminoamide and aminoester local anesthetics. 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, with the exception of Ropivacaine and Mepivacaine that do produce weak vasoconstriction.

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

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

Mechanism of action

All local anesthetics are membrane stabilizing drugs; they reversibly decrease the rate of depolarization and repolarization of excitable membranes (like nociceptors). Though many other drugs also have membrane stabilizing properties, not all are used as local anesthetics (propranolol, for example). 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 sodium channels in activated state, 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 the chemical's pKa the protonated (ionized) and unprotonated (unionized) forms of the molecule exist in an equilibrium but only the unprotonated molecule diffuses readily across cell membranes. Once inside the cell the local anesthetic will be in equilibrium, with the formation of the protonated (ionized form), which does not readily pass back out of the cell. This is referred to as "ion-trapping". In the protonated form, the molecule binds to the local anesthetic binding site on the inside of the ion channel near the cytoplasmic end.

Acidosis such as caused by inflammation at a wound partly reduces the action of local anesthetics. This is partly because most of the anesthetic is ionized and therefore unable to cross the cell membrane to reach its cytoplasmic-facing site of action on the sodium channel.

All nerve fibers are sensitive to local anesthetics, but generally, those with a smaller diameter tend to be more sensitive than larger fibers. Local anesthetics block conduction in the following order: small myelinated axons (e.g. those carrying nociceptive impulses), non-myelinated axons, then large myelinated axons. Thus, a differential block can be achieved (i.e. pain sensation is blocked more readily than other sensory modalities).

Undesired effects

Localized adverse effects

The local adverse effects of anesthetic agents include neurovascular manifestations such as prolonged anesthesia (numbness) and paresthesia (tingling, feeling of "pins and needles", or strange sensations). These are symptoms of localized nerve impairment or nerve damage.

Risks

The risk of temporary or permanent nerve damage varies between different locations and types of nerve blocks.[1] //Death

Recovery

Permanent nerve damage after a peripheral nerve block is rare. Symptoms are very likely to resolve within a few weeks. The vast majority of those affected (92%–97%), recover within four to six weeks. 99% of these people have recovered within a year. It is estimated that between 1 in 5,000 and 1 in 30,000 nerve blocks result in some degree of permanent persistent nerve damage.[1]

It is suggested that symptoms may continue to improve for up to 18 months following injury.

Causes

Causes of localized symptoms include:

  1. neurotoxicity due to allergenic reaction,
  2. excessive fluid pressure in a confined space,
  3. severing of nerve fibers or support tissue with the needle/catheter,
  4. injection-site hematoma that puts pressure on the nerve, or
  5. injection-site infection that produces inflammatory pressure on the nerve and/or necrosis.

General adverse effects

(See also local anesthetic toxicity)

General systemic adverse affects are due to the pharmacological effects of the anesthetic agents used. 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 plasma levels which are rarely reached if proper anesthetic techniques are adhered to. Additionally, persons may exhibit allergenic reactions to the anesthetic compounds and may also exhibit cyanosis due to methemoglobinemia.

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 CSF, 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 anesthetic

Treatment of overdose: "Lipid rescue"

There is evidence that Intralipid, a commonly available intravenous lipid emulsion, can be effective in treating severe cardiotoxicity secondary to local anesthetic overdose, including human case reports of successful use in this way ('lipid rescue').[2] [3][4][5][6]

Hypersensitivity/allergy

Adverse reactions to local anesthetics (especially the esters) are not uncommon, but true allergy is very rare. Allergic reactions to the esters is usually due to a sensitivity to their metabolite, para-aminobenzoic acid (PABA), and does not result in cross-allergy to amides. Therefore, amides can be used as alternatives in those patients. 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.

Local anesthetics in clinical use

Esters are prone to producing allergic reactions, which may necessitate the use of an Amide. The names of each locally clinical anesthetic have the suffix "-caine".

Most ester local anesthetics are metabolized by pseudocholinesterases, while amide local anesthetics are metabolized in the liver. This can be a factor in choosing an agent in patients with liver failure.[7]

Esters

Procaine

Amides

Lidocaine

Combinations

Natural local anesthetics

Naturally occurring local anesthetics not derived from cocaine are usually neurotoxins, and have the suffix -toxin in their names. [1] Unlike cocaine produced local anesthetics which are intracellular in effect, saxitoxin & tetrodotoxin bind to the extracellular side of sodium channels.

See also

References

  1. ^ a b "Nerve damage associated with peripheral nerve block" (PDF). Risks associated with your anaesthetic,. Section 12. The Royal College of Anaesthetists. January 2006. Retrieved 2007-10-10.{{cite journal}}: CS1 maint: extra punctuation (link)
  2. ^ Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 1998; 88: 1071-5.
  3. ^ Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Regional Anesthesia and Pain Medicine 2003; 28: 198-202..
  4. ^ Picard J, Meek T. Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob. Anaesthesia 2006;61:107-9. PMID 16430560
  5. ^ Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful Use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 2006;105:217-8. PMID 16810015
  6. ^ Litz, RJ, Popp M, Stehr S N, Koch T. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia 2006;61:800-1.
  7. ^ Arnold Stern (2002). Pharmacology: PreTest self-assessment and review. New York: McGraw-Hill, Medical Pub. Division. ISBN 0-07-136704-7.
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