Local Anesthetics

Author: Maurizio Vono
Date: 17/01/2011



Lidocaine is known to be a common local anaesthetic drug, possibly chiefly answering three main purposes,that is:

  • Lidocaine, is used in dental surgery , coupled to epinephrine (adrenaline), whose vasoconstricting action causes blood vessels to narrow, hence both decreasing bleeding and increasing the duration of anaesthesia due to constriction of efferent vessels – which prevents the anaesthetic drug spreading away from the required area too quickly by delaying the resorption of Lidocaine - , is well known. Hence adding adrenaline allows the lidocaine effect to double, making it last from 60 up to 120 minutes.
  • On emergency circumstances, it is used intravenously,so as to allow dealing with severe ventricular heart arrhythmias (for acute myocardial infarction, digitalis poisoning, cardioversion or cardiac catherization).
  • For gastroenterologic purposes, it is administered as a topic anaesthetic drug, available under the form of a spray solution, and also owing to its possessing anti-inflammatory activity, so as to prevent gagging reflexes during intubation of the esophagus with the endoscope.

Lidocaine works by easily binding and blocking the fast voltage gated sodium (Na+) channels to be found both on the heart cardiomyocytes and in the neuronal cell membrane (at the instance of the axon, that is the thin extension sent out by each nerve cell within the ganglion; such an axon extending all the way from the ganglion into one of the nerve trunks that issue from the ganglion and/or into its target tooth - axons in their turn possibly branching multiple times making connections with numerous other neurons or somatic cells, even if each neuron in itself only has a single axon), held responsible for signal propagation. given that it alters signal conduction in neurons. With sufficient blockade, the membrane of the postsynaptic neuron will not depolarize and so fail to transmit an action potential, leading to its anaesthetic effects. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations will also affect other modalities of neuron signaling.
The mechanism by which lidocaine inhibits Na+ channels, that is the major generators of the upstroke of action potentials, is suggested to involve low-affinity binding to rested states and high-affinity binding to the inactivated state of the channel, implying either multiple receptor sites or allosteric modulation of receptor affinity. However as to the afore-mentioned receptors the lidocaine action mechanism acts in the very same way – by decreasing permeability to Na+ ions in such channels, hence causing the permeability as to the Na+ ions to decrease in such channels by depressing the phase 0 depolarization (i.e. reducing Vmax), which means it inhibiting the electrical impulse initiation and conduction. After a chemical viewpoint lidocaine is acknowledged to belong to the local-anaesthetic category of the amidic type – hence having to be ranked as an amino-amide, whose amphiphilic structure can be subdivided into three main sections:

  • A lipophilic portion, composed by a benzene ring bonding to two methyl groups – such a molecule portion allows lidocaine to display its rapid onset action given that it enables it to rather easily spread – and improving the lipid solubility of the compound, which evidencing that greater lipid solubility enhances diffusion through nerve sheaths, as well as the moelinic sheaths and neural membranes of individual axons comprising a nerve trunk.
  • A hydrophilic basic portion, consisting of an amine in its tertiary form (3 bonds) that is lipid soluble – which affects the molecule hydrosolubility given that it has to be held responsible for the lidocaine bonding to the sodium channel.
  • An intermediate aliphatic ester, or amide chain (or linkage) determining the pattern of biotransformation and to be found in between the two afore-mentioned portions.



Though according to a process that is both transitory and reversible, lidocaine blocks nerve conductivity by affecting the action potential propagation at the instant of the axon.
Under physiological resting circumstances (in which Na+ slowly leaks into the cells and K+ leaks out of the cell because of electrochemical driving forces), the axon membrane is characterized by a membrane potential corresponding to about –70mV – so that the potential energy level is kept stable by the activity of the Na+-K+-ATP-powered pumps located on the axon membrane and allowing each cycle to create a negative potential within the cell by pumping more positive changes out of the cell than into the cell. It means keeping a low concentration of sodium ions and high levels of potassium ions within the cell (intracellular), whereas. outside cell (extracellular) there are retraced high concentrations of sodium and low concentrations of potassium, so that diffusion occurs through ion channels in the membrane. In a word such an activity allows 3 sodium ions to get released outside the axon membrane due to its low affinity for sodium ions while also binding 2 extracellular K+ ions in their turn introduced there, the pump activity hence creating a negative potential within the cell. At the instant of the axon membrane several kinds of channel are to be found, among which are the voltage-gated sodium channels, as a rule closed on resting potential conditions; on the other side they get activated (opened) whenever an electrical impulse stimulation reaches the axon – which triggers both depolarizing and the action potential at first increasing and then peaking, abruptly shooting upward, at the instant of the membrane. As a matter of fact whenever the axon membrane is stimulated by an electrical impulse, the voltage-dependent sodium channels get opened so as to allow the sodium ions to diffuse into the axon cytosol, according to the concentration gradient, thus making the membrane potential shift from negative to positive. Voltage-gated sodium channels have three types of states: deactivated (closed), activated (open), and inactivated (closed). The remarkable level of membrane depolarization results in the sodium channel getting structurally modified – which works so as to hamper any further Na+ ion from diffusing. What ensues resides in the membrane excited state turning into the inactivated one.

When the sodium potential gets removed an amount of potassium ions, to be equalled to the one of the Na+ ions having drifted inward during depolarization, to leave the cell, which restores the membrane resting potential. To sum up, channels in the deactivated state are thought to be blocked on their intracellular side by an "activation gate", in its turn removed in response to stimulation opening the channel, whose inside is blocked soon after activation by the inactivation gate. The inactivation short lapse, ensuing depolarization, is over, when the membrane potential of the cell repolarizes following the falling phase of the action potential - which allows the channels to be activated again during the next action potential. On an increasing membrane potential sodium ion channels get opened – which leads to the inward flow of sodium ions (whose increased concentration causes depolarization) – which is soon afterwards matched by the outward flow of potassium ions as a result of the opening of potassium ion channels, mentioned above. The channel closing results from the peaking action potential.


The local anaesthetic drug action makes the axolemma permeability to the sodium ion decrease, while also leading to either a decreased or a completely absent excitability of the nervous fibre being involved in treatment – which depends on the amount of dosing and which results in inhibiting nociception, that is the thermal perception and pain-sensing threshold only in a selective way, though not affecting the sense of touch – which however is introduced here just as an example. What ensues is that such local anaesthetic drugs, as is lidocaine, prevent the nervous impulse being either generated or propagated as a result of stimuli by keeping the levels of sodium conductance as to the voltage-gated channels reasonably low, given that whenever nerve endings are stimulated, sodium enters the neuron, causing the nerve to undergo depolarization in turn leading to subsequent initiation of an action potential, that by propagating down the nerve toward the central nervous system, triggers the latter perception of it as pain.
In former times the mechanism held responsible for the effect of local anaesthetic drugs was believed to be triggered by their lipophilic properties and to be likely to stabilize the axon membrane by binding to it, thus making its area expand so that it causes modifications in the sodium channel structure to occur. Nowadays the afore-mentioned mechanism is known as a nonspecific mechanism, given that it tends to be shared by several other lipophilic substances whenever taken in remarkable doses.
The only anaesthetic drug working elusively this way is benzocaine, thus rarely made use of nowadays.
Instead, as far as the specific mechanism is concerned, it can be described as a selective blocking of the sodium channels by means of the anaesthetic drug interacting with a site located in the S6 segment of the α -subunit 4 domain - in turn found within the aqueous pore in between the activation gate and the inactivation one. Whatever sodium channel block is acknowledged to be voltage-gated, given that it is actually enhanced by the membrane depolarization, whenever basic conditions are retraced - which means the sites held responsible for binding showing very little affinity towards anaesthetic drugs, whenever the channel is closed.
The sodium channel block is also acknowledged to be frequency-dependent, given that it gets enhanced by the channel functional condition being both opened and inactive .
The effectiveness of whatever anaesthetic drug is boosted by stimulating the fibre when the latter is fed to by high-frequency trains of impulses, given that on such conditions channels get configured as open or inactivated, thus making it easier for the medicine to bind to the suitable corresponding binding site, consisting of two amino acidic residues, in turn known as phenylalanine and tyrosine to be found within the sodium channel at the instant of S6 segment of the α -subunit 4 domain.

The binding site can be accessed within the membrane only – which means lidocaine having first to flow through the axolemma so as to be enabled to block the sodium channel. Such a lidocaine flow is allowed owing to the molecule lipophilic composing portion that makes the membrane twofold phospholipidic layer possibly crossed, whereas the binding with the site held responsible for action is allowed by the lidocaine molecule hydrophilic composing portion.


There exist two neurotoxins exerting their action upon the receptors of voltage-gated sodium channels in ways to be paralleled to the lidocaine action, both of them as a rule triggering off noxious if not downright lethal effects; they are in turn known as tetradotoxin (acting more likely affects the Nav 1.1 Nav 1.2 Nav 1.3 Nav 1.7 sodium channels) produced by pufferfish and other similar Tetraodontidae, and saxitoxin, naturally produced by certain species of marine dinoflagellates such as “Gonyaulax” and cyanobacteria. As mentioned above, such poisoning agents acts by binding to the nerve voltage-gated sodium channels thus preventing activating potentials to be produced as usual.


  • pufferfish consumption (either as an incorrectly prepared puffer soup or as raw puffer meat, known as, sashimi fugu) is quite widespread in Japan; whatever the dish it has to be prepared by very skilled cooks, experienced as to the choice of its meat, taking into account that some parts of this fish contain so concentrated amounts of tetradotoxin to be lethal if ingested.
  • In turn shellfish accumulate saxitoxin at the instant of their muscles, which makes their poisoning highly dangerous for the consuming beings whose thropic level resides above theirs in the food chain.


  • On the other side a toxin antagonizing lidocaine is known as Veratridine, a steroid-derived alkaloid from the family of Liliaceae (especially retraced in the seeds of “Schoenocaulon officinalis”) and working as a neurotoxin by activating sodium ion channels. Veratridine preferentially binds to activated Na+ channels causing persistent activation that leads to increase nerve excitability.
  • Lidocaine in its turn is widely used in Mexico as antagonizing the beta toxin resulting from the envenomation of the scorpion known as Centruroides limpidus limpidus(01)00255-7/abstract - whose effect consists in keeping the sodium channels persistently opened hence triggering off such a long-lasting depolarization that it results in cardiac failure.


Lidocaine, whose elimination half-life is approximately 1.5–2 hours in most patients, gets rapidly metabolized (dealkylated) in the liver due to the action of the cytochrome P450 enzymes – answering to the purpose of catalysing the oxidation of organic substances and referred to as CYP3A4 and CYP1A2, whose transcription is mediated thanks to the intracellular receptor PXR (pregnane X receptor). Owing to such enzymes the liver is enabled to metabolize about 90% of the lidocaine flowing through the higly permeable liver sinusoids. The remaining 10% is cleared under the form of intact molecule. Hence the lidocaine clearance – just as it also occurs for several other xenobiotic substances – relies on both the hepatic blood flow rate and the liver function (clearance may take up to 136 in case of congestive heart failure, and as long as average 343 minutes in case of hepatic impairment). The system of such cytochromes does not undergo saturation – which means it not being dependent on dosing.

Drugs that inhibits CYP3A4

The lidocaine metabolism time may however be prolonged by taking such drugs inhibiting the CYP3A4 enzyme as:

Drugs that induces CYP3A4

The lidocaine metabolisn time may however be reduced by taking such drugs inducing the CYP3A4 enzyme as:

The lidocaine clearance gets decreased by whatever drug triggering a decreased hepatic blood flow rate. Beta blockers, such as propranolol, trigger a decreased lidocaine effect by both inhibiting CYP3A4 and keeping both heart sinus rhythm and hepatic flow at low rates.
The P450cytochromes known as CYP3A4 and CYP1A2 retraced in the microsomes of hepatocytes (making up 70-80% of the liver's cytoplasmic mass) lead to lidocaine modification, by producing such a pharmacologically-active metabolite as MEGX (monoethylglycinexylidide), having a longer half life than lidocaine but also being a less potent sodium channel blocker, by means of a chemical reaction known as oxidative deetilation 1. In its turn MEGX gets subsequently transformed into inactive GX (glyine xylidide) as a result of a latter chemical reaction known as oxidative deetilation 2.

Both MEGX e GX are acknowledged to be far les lipophilic but far more hydrophilic than lidocaine is – which results in their being excreted via urine. In pregnancy cases lidocaine paracervical anaesthesia may involve fetal acidosis (increased acidity in the blood, or loss of alkali, lowers the pH of the blood and tissue) and bradycardia (defined as a resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min). Further would-be risks consist in the newborn baby showing alterations in behaviour at birth.
Lab tests have been performer, aiming at evaluating potential mutagenesis and cancer genesis as far as one of lidocaine minor metabolites, that is the aromatic amine 2,6 xylidine, is concerned.

  • Lidocaine metabolites have proven not to be mutagenic on the ground of the Ames Test (a biological assay, whose positive result test indicates that the chemical might act as a carcinogen, to assess the mutagenic potential of chemical compounds).
  • Such a metabolite has also been proven to bring about tumours on the ground of the cancer long-run genesis tests performed on mice.

Maurizio Vono
Luca Valpreda

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