Prilocaine's primary target is the voltage-gated sodium channel on neuronal cell membranes. It stabilizes the neuronal membrane by preferentially binding to and inhibiting depolarization of the sodium channel. This results in decreased membrane permeability and inhibition of ionic sodium influx required for impulse initiation and conduction. Prilocaine is also a Na/K-ATPase inhibitor, with neurotoxic effects.

Prlocaine has a greater inhibitory impact on the plasma membrane Na,K-ATPase of transformed fibroblasts (LM cells) at 37 °C (43.8 mM) than it does at 25 °C (28.2 mM) [2].
In vitro, Prilocaine acts on sodium channels on the neuronal membrane, limiting the spread of seizure activity and reducing seizure propagation. It displaces [³H]BTX-B from high-affinity sites on voltage-gated sodium channels, with IC50 values ranging from 53,700 nM to as low as 1.73 nM depending on assay conditions. Prilocaine is more potent in inhibiting Na,K-ATPase of plasma membranes at 37°C (43.8 mM) than at 25°C (28.2 mM).

In vivo, Prilocaine provides local anesthesia by blocking sodium channels on neuronal membranes. It is used for infiltration anesthesia in dentistry and has anticonvulsant effects. The compound limits the spread of seizure activity and reduces seizure propagation. Its effects are localized to the site of administration, and it is commonly used in combination with other local anesthetics.

The in vitro activity of Prilocaine is assessed using radioligand binding assays and electrophysiological techniques. For sodium channel binding, membrane preparations from neuronal cells are incubated with [³H]batrachotoxinin A 20-α-benzoate ([³H]BTX-B) in the presence of varying concentrations of Prilocaine, and the displacement of the radiolabeled ligand is measured. For Na/K-ATPase inhibition, the enzyme is incubated with ATP and varying concentrations of Prilocaine, and inorganic phosphate release is measured spectrophotometrically. IC50 values are determined from dose-response curves.

For cellular assays, neuronal cell lines or primary neurons are used. Cells are cultured in appropriate media and treated with various concentrations of Prilocaine (typically 0.1-1000 μM) for defined periods. Sodium channel function is assessed using patch-clamp electrophysiology to measure sodium currents. Cell viability is assessed using standard assays such as MTT or trypan blue exclusion. For neurotoxicity studies, neuronal cells are treated with Prilocaine, and cell death is assessed by LDH release or apoptosis assays.

In vivo, Prilocaine is administered by local injection for infiltration anesthesia in dental and other minor surgical procedures. In animal models, the compound is injected subcutaneously or intradermally, and the onset, duration, and intensity of anesthesia are assessed by the pinprick test or tail-flick test. For anticonvulsant studies, Prilocaine is administered systemically, and seizure activity is monitored. Pharmacokinetic studies involve plasma concentration measurement by HPLC or LC-MS/MS.

Absorption, Distribution and Excretion
Prilocaine is metabolized in the liver and kidneys and excreted via the kidneys. /About/ Hydrolysis of the amide bond in prilocaine… After intravenous injection in cats, the plasma concentration of the R-(-)-enantiomer was found to be lower than that of the S-(+)-enantiomer. In vitro studies using liver preparations from various mammals confirmed that the hydrolysis rate of the R-(-)-isomer was much higher than that of the S-(+)-isomer… The D-(-)-isomer is more likely to cause methemoglobinemia, possibly due to the higher blood concentration of its hydrolysis product, o-toluidine.
Primocaine fetal/maternal concentration ratio: 1.0 /From table/
Intravenous injection of 0.2 g primocaine resulted in a plasma concentration of 0.26 mg/dL after 0.3 hours and 0.14 mg/dL after 0.17 hours; intravenous injection of 0.4 g resulted in a plasma concentration of 0.15 mg/dL at 0.12 hours and 0.08 mg/dL at 0.33 hours; epidural block injection of 0.4 g resulted in a peak plasma concentration of 0.26 mg/dL at 0.25 hours; intercostal block injection resulted in a plasma concentration of 0.40 mg/dL at 0.25 hours. /From table/

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Metabolism/Metabolites
Amide local anesthetics are typically degraded in the hepatic endoplasmic reticulum, with initial reactions involving N-dealkylation and subsequent hydrolysis. However, for prilocaine, the initial step is hydrolysis, producing the o-toluidine metabolite, which can lead to methemoglobinemia.
Biotransformation of prilocaine… in rats administered o-toluidine and N-alanine.

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Biological half-life
Intravenous infusion of 250 mg mepivacaine hydrochloride (I-HCl) and prilocaine hydrochloride (II-HCl) into healthy volunteers. The half-life of I is generally longer than that of II; the systemic clearance of II is consistently higher than that of I. The clearance of II exceeds normal hepatic blood flow: presumably an extrahepatic metabolic site exists.
Prilocaine has a molecular weight of 220.31 g/mol and a molecular formula of C13H20N2O. Its IUPAC name is N-(2-methylphenyl)-2-(propylamino)propanamide. The compound is an amino acid amide. It is commonly used in combination with epinephrine to prolong its anesthetic effect. Prilocaine can be formulated as a hydrochloride salt for clinical use. The compound should be stored under appropriate conditions to maintain stability.

Interactions
...Mouse studies have shown increased toxicity when co-administered with tetracaine. ...Primocaine has been reported to interact with succinylcholine, leading to an increase in the intensity and duration of succinylcholine-induced neuromuscular blockade and respiratory depression; other depolarizing muscle relaxants (e.g., decylamine) and non-depolarizing muscle relaxants (e.g., gallium triiodide and pancuronium bromide) may have similar effects. ...Primocaine slightly enhances the neuromuscular blocking intensity of acuronium chloride. A significant decrease in tidal volume was observed, indicating respiratory depression... ...Adrenaline prolongs the duration of action of primocaine. /Primocaine Hydrochloride/ ...For more complete data on interactions of primocaine (15 in total), please visit the HSDB records page.
Prilocaine can cause methemoglobinemia, a condition where hemoglobin is oxidized to methemoglobin, which cannot carry oxygen effectively. This is a dose-dependent side effect that is more common with Prilocaine than with other local anesthetics. Other side effects may include local reactions at the injection site, allergic reactions, and systemic toxicity at high doses (including CNS effects and cardiovascular depression). The compound should be used with caution in patients with methemoglobin reductase deficiency or those taking other drugs that cause methemoglobinemia.

[1]. Neurotoxic effects of local anesthetics on the mouse neuroblastoma NB2a cell line. Biotech Histochem. 2015 Apr;90(3):216-22.

[2]. Effects of local anaesthetics on the activity of the Na,K-ATPase of canine renal medulla. Pharmacol Res. 2000 Jan;41(1):1-7.

Prilocaine is an amino acid amide composed of an amide bond formed by the combination of N-propyl-DL-alanine and 2-methylaniline, and is used as a local anesthetic. It has dual effects of local anesthesia and anticonvulsant action. Prilocaine is an amino acid amide and a monocarboxylic acid amide. It is a local anesthetic with pharmacological effects similar to lidocaine. Currently, it is most commonly used for infiltration anesthesia in dentistry. (Excerpt from JAMA Drug Evaluation Yearbook, 1992, p. 165) Prilocaine is an amide-type local anesthetic. The physiological effect of prilocaine is achieved through local anesthesia. Prilocaine is a toluidine derivative, a medium-acting aminoamide with local anesthetic properties. Prilocaine stabilizes neuronal membranes by preferentially binding to and inhibiting the depolarization of voltage-gated sodium channels. This leads to decreased cell membrane permeability, thereby inhibiting the sodium ion influx required for the initiation and conduction of nerve impulses. A local anesthetic with pharmacological effects similar to lidocaine. Currently, it is most commonly used for infiltration anesthesia in dentistry. See also: Primacaine Hydrochloride (salt form)... See more...

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Drug Indications
Used as a local anesthetic, commonly used in dentistry.

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Mechanism of Action
Primacaine acts on sodium ion channels on the neuronal cell membrane, limiting the spread of epileptic activity and reducing the propagation of seizures. Its antiarrhythmic effect is achieved by affecting sodium channels in Purkinje fibers.
...Blocking nerve conduction may be achieved by competing with calcium ions (CA) for a site controlling membrane permeability... Calcium ions also participate in the effects of local anesthetics on smooth muscle and adrenal medulla... /Local Anesthetics/
...Inhibits the generation and conduction of nerve impulses. Their primary site of action is the cell membrane. ...Blocking conduction by reducing or preventing a transient, significant increase in the permeability of the excitatory membrane to sodium ions (Na+), an increase usually caused by slight membrane depolarization. Local Anesthetics: As the effect of the anesthetic in the nerve gradually increases, the electrical excitation threshold rises, and the conduction safety factor decreases; when this effect is fully realized, nerve conduction is blocked. Local anesthetics have two mechanisms of action: one is to achieve blockade by increasing the surface pressure of the lipid layer that makes up the nerve membrane, thereby closing the pores through which ions can pass. The other is to affect membrane permeability by increasing the degree of membrane disturbance. /Local Anesthetics/

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Therapeutic Uses
Local Anesthetics
A drug with a chemical structure similar to lidocaine and mepivacaine, used for local and regional block anesthesia. Its onset time and efficacy (1-3% solution) are comparable to those of lidocaine and mepivacaine at concentrations of 1%-2%. Its duration of action is between that of short-acting lidocaine and long-acting mepivacaine. /Primocaine Hydrochloride/
Primocaine hydrochloride…has been used for…spinal anesthesia. /Primocaine Hydrochloride/
...acts on any part of the nervous system and all types of nerve fibers. /Local Anesthetics/
For more complete data on the therapeutic uses of primocaine (10 in total), please visit the HSDB record page.

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Drug Warnings
As with other local anesthetics, prilocaine hydrochloride is contraindicated in patients with shock, severe cardiovascular disease, or cardiac conduction block. /Prilocaine Hydrochloride/
...It should not be given to patients with idiopathic or congenital methemoglobinemia, anemia, or heart failure or respiratory failure with hypoxia; due to the cumulative effect of hemoglobin elevation from a single dose, caution should be exercised when using it for continuous epidural anesthesia. /Prilocaine Hydrochloride/
In cases of bleeding, the sympathetic blockade caused by epidural anesthesia can become extremely pronounced and may lead to rapid and harmful circulatory changes. /Local Anesthetics/
The two main dangers of tail anesthesia are: (1) accidental needle insertion into the sacral venous plexus, resulting in intravascular injection of the drug; (2) needle penetration of the dura mater, resulting in high spinal anesthesia. /Local Anesthetics/
For more drug warnings (complete) data on prilocaine (16 in total), please visit the HSDB record page.

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Pharmacodynamics
Primacaine binds to the intracellular surface of sodium channels, blocking the influx of sodium ions into the cell. Therefore, action potential conduction and nerve function are inhibited. This blockade is reversible; once the drug diffuses out of the cell, sodium channel function and nerve conduction are restored.

Prilocaine is a clinically approved local anesthetic used in dentistry and other minor surgical procedures. It is available in combination with lidocaine (as a eutectic mixture) and with epinephrine. Its intermediate duration of action and relatively low toxicity make it a useful alternative to lidocaine in certain clinical situations. Prilocaine was first synthesized in the 1960s and has been widely used since then. It is available as a generic medication and is included on the World Health Organization's List of Essential Medicines in some formulations.

C13H20N2O

220.32

220.157

721-50-6

Prilocaine hydrochloride;1786-81-8;Prilocaine acetate

4906

White to off-white solid powder

1.0±0.1 g/cm3

361.6±25.0 °C at 760 mmHg

37-38ºC

134.3±23.3 °C

0.0±0.8 mmHg at 25°C

1.543

1.74

2

2

5

16

218

0

MVFGUOIZUNYYSO-UHFFFAOYSA-N

InChI=1S/C13H20N2O/c1-4-9-14-11(3)13(16)15-12-8-6-5-7-10(12)2/h5-8,11,14H,4,9H2,1-3H3,(H,15,16)

N-(2-methylphenyl)-2-(propylamino)propanamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~453.91 mM)
H2O : ~2.5 mg/mL (~11.35 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (11.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (11.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 50 mg/mL (226.95 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)