Voltage-Gated Sodium Channels (NaV)

Mepivacaine inhibits sodium influx and membrane depolarization by binding to particular voltage-gated sodium ion channels in the membranes of neuronal cells. This causes a barrier in the initiation and conduction of nerve impulses, which causes a temporary loss of feeling. This drug acts more quickly and for a moderate amount of time when compared to other local anesthetics[2]. Mepivacaine acts for a medium amount of time, which is shorter than procaine's, and with a fairly quick start (faster than procaine's)[3]. S(-)-bupivacaine shows a selectivity for TTXs Na(+) channels while mepivacaine exhibits a preferential use-dependent block of Na(v)1.8[4].

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Mepivacaine binds to specific voltage-gated sodium ion channels in neuronal cell membranes, which inhibits both sodium influx and membrane depolarization. This leads to a blockage of nerve impulse initiation and conduction and results in a reversible loss of sensation.

Mepivacaine is clinically used for local anesthesia via infiltration, nerve block, and epidural anesthesia. It has a rapid onset and intermediate duration of action (90-180 minutes). It is chemically related to bupivacaine but pharmacologically related to lidocaine. It is often used in dental procedures and minor surgeries.

For receptor binding assays, purified voltage-gated sodium channels (e.g., from rat brain) are reconstituted into lipid vesicles or membranes. Radioligand binding assays are performed using [3H]batrachotoxin or [3H]saxitoxin. Mepivacaine is incubated with the membranes at varying concentrations (0.1-1000 uM). Specific binding is measured after filtration or centrifugation. IC50 values can be determined. Alternatively, electrophysiology with heterologously expressed NaV channels is used.

For electrophysiology, HEK293 cells expressing human NaV1.7 channels are cultured in DMEM with 10% FBS. Whole-cell patch-clamp recordings are performed. The external solution contains NaCl, KCl, CaCl2, MgCl2, HEPES, and glucose. The internal solution contains CsF, CsCl, and EGTA. Cells are held at -120 mV and stepped to -10 mV. Mepivacaine is applied at 0.1-1000 uM, and the reduction in peak sodium current is measured.

In vivo anesthetic activity is assessed in animal models such as the rat tail-flick test or guinea pig intradermal wheal test. Mepivacaine (0.5-2%) is injected subcutaneously or intradermally. The degree and duration of sensory blockade are measured by response to pinprick or thermal stimulus (e.g., hot plate). For nerve block models, the sciatic nerve is exposed and a local anesthetic solution is injected; motor and sensory function are assessed.

Absorption, Distribution and Excretion
Local absorption: The systemic absorption rate of local anesthetics depends on the total dose and concentration administered, the route of administration, the vascular distribution at the site of administration, and the presence of adrenaline in the anesthetic solution. It is rapidly metabolized; only a small portion (5% to 10%) of the anesthetic is excreted unchanged in the urine. The liver is the primary site of metabolism, with over 50% of the administered dose excreted as metabolites in the bile. Metabolism/Metabolites It is rapidly metabolized; only a small portion (5% to 10%) of the anesthetic is excreted unchanged in the urine. The liver is the primary site of metabolism, with over 50% of the administered dose excreted as metabolites in the bile. It is rapidly metabolized; only a small portion (5% to 10%) of the anesthetic is excreted unchanged in the urine. The liver is the primary site of metabolism, with over 50% of the administered dose excreted as metabolites in the bile. Elimination route: It is rapidly metabolized; only a small portion (5% to 10%) of the anesthetic is excreted unchanged in the urine. The liver is the primary site of metabolism, with over 50% of the administered dose excreted as metabolites via bile. Half-life: The half-life of mepivacaine in adults is 1.9 to 3.2 hours, and in newborns it is 8.7 to 9 hours.

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Mepivacaine is rapidly absorbed after local injection. Onset of action is 3-5 minutes with duration of 90-180 minutes (depending on dose and presence of vasoconstrictor). It is metabolized primarily in the liver by CYP1A2 and CYP3A4 to inactive metabolites. Half-life in adults is 1.9-3.2 hours. Plasma protein binding is approximately 75-80%. Excretion is renal. It crosses the placenta but has low CNS penetration.

Toxicity Summary
Local anesthetics work by blocking the generation and conduction of nerve impulses. The mechanism may involve increasing the electrical excitation threshold of nerves, slowing the propagation speed of nerve impulses, and reducing the rate of rise of action potentials. Generally, the progression of anesthesia is related to the diameter, degree of myelination, and conduction velocity of the affected nerve fibers. Clinically, the order of loss of nerve function is as follows: pain sensation, temperature sensation, touch sensation, proprioception, and skeletal muscle tone. Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of mepivacaine during lactation. Given the low secretion of other local anesthetics in breast milk, a single use of mepivacaine during lactation is unlikely to have adverse effects on breastfed infants. However, especially in breastfeeding newborns or premature infants, other medications may be preferred. It has been reported that the use of mepivacaine as a local anesthetic during delivery may affect initial breastfeeding behavior in some infants, but it does not affect weight gain in the first 5 days postpartum. Although research on mepivacaine is limited, it appears that with good breastfeeding support, epidural anesthesia, whether or not combined with fentanyl or its derivatives, has little or no adverse effect on breastfeeding success. Labor analgesia may delay the onset of lactation. More research is needed to clarify the impact of mepivacaine use during labor on breastfeeding outcomes.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
A study comparing the effects of epidural analgesia with mepivacaine, bupivacaine, and lidocaine during normal labor found no difference in weight change among the three groups of breastfed infants in the first 5 days postpartum. Overall weight gain was within the normal range in all groups.
Of the six infants who received mepivacaine pudendal nerve block within one hour of delivery, four started breastfeeding later and had fewer initial milk volumes than 10 infants who did not receive anesthesia during labor. The long-term consequences of these differences have not been reported. A nationwide survey of women and their infants from late pregnancy to 12 months postpartum compared the duration of lactation stage II in mothers who received and did not receive analgesics during labor. Drug classes included: spinal or epidural anesthesia alone, spinal or epidural anesthesia in combination with other drugs, and other analgesics alone. Women receiving any class of drugs had approximately twice the risk of delayed lactation stage II (>72 hours) compared to women who did not receive labor analgesia. Protein Binding: Mepivacaine binds to plasma proteins at approximately 75%. Generally, the lower the plasma concentration of the drug, the higher the binding rate to plasma. Toxicity Data: In rhesus monkeys, the mean epileptogenic dose of mepivacaine was 18.8 mg/kg, and the mean arterial plasma concentration was 24.4 μg/mL. LD50: 23-35 mg/kg (intravenous injection, mice) (A308) LD50: 280 mg/kg (subcutaneous injection, mice) (A308)

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Mepivacaine is generally well tolerated at therapeutic doses. Common side effects include dose-dependent CNS effects (dizziness, drowsiness, confusion, seizures) and cardiovascular effects (hypotension, bradycardia, cardiac arrest). High doses can cause methemoglobinemia. Allergic reactions are rare. Overdose can be fatal. Toxicity is similar to other amide local anesthetics.

[1]. ECMO for Cardiac Rescue after Accidental Intravenous Mepivacaine Application. Case Rep Pediatr. 2012;2012:491692.

[2]. mepivacaine hydrochloride.

[3]. Pharmacokinetics of the enantiomers of mepivacaine after intravenous administration of the racemate in volunteers. Anesth Analg, 1997. 84(1): p. 85-9.

[4]. Leffler, A., J. Reckzeh, and C. Nau, Block of sensory neuronal Na+ channels by the secreolytic ambroxol is associated with an interaction with local anesthetic binding sites. Eur J Pharmacol, 2010. 630(1-3): p. 19-28.

Mepivacaine is a piperidine carboxamide compound composed of an amide bond formed by the combination of N-methylpiperidinic acid and 2,6-dimethylaniline. It is a local amide anesthetic. Mepivacaine is both a local anesthetic and a drug allergen. It is a local anesthetic with a chemical structure related to bupivacaine but pharmacologically related to lidocaine. It is suitable for infiltration anesthesia, nerve blocks, and epidural anesthesia. Mepivacaine is only effective when used locally in large doses and therefore should not be used via this route. (Excerpt from JAMA Drug Evaluation, 1994, p. 168) Mepivacaine is an amide local anesthetic. The physiological action of mepivacaine is achieved through local anesthesia. Mepivacaine is an amide local anesthetic. At the injection site, mepivacaine binds to specific voltage-gated sodium ion channels on the neuronal cell membrane, inhibiting sodium ion influx and membrane depolarization. This leads to the blockage of nerve impulse initiation and conduction, resulting in reversible sensory loss. Compared to other local anesthetics, this drug has a faster onset of action and a moderate duration of action. Mepivacaine is a local anesthetic with a chemical structure related to bupivacaine but a pharmacological action related to lidocaine. It is suitable for infiltration anesthesia, nerve blocks, and epidural anesthesia. Mepivacaine is only effective when applied topically in large doses and should therefore not be used via this route. (From JAMA Drug Evaluation, 1994, p. 168) See also: Mepivacaine hydrochloride (salt form). Drug Indications This drug is used to produce local or regional analgesia and anesthesia through local infiltration, peripheral nerve block techniques, and central nervous system techniques including epidural and caudal blocks. FDA Label Mechanism of Action Local anesthetics work by blocking the generation and conduction of nerve impulses. The mechanism may involve increasing the electrical excitation threshold of the nerve, slowing the propagation of nerve impulses, and reducing the rate of rise of action potentials. Typically, the progression of anesthesia is related to the diameter, degree of myelination, and conduction velocity of the affected nerve fibers. Clinically, the order of loss of nerve function is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone. Pharmacodynamics Mepivacaine is an amide-type local anesthetic. Mepivacaine has a rapid onset of action and a moderate duration of action; its brand names are carbocaine and polocaine. Mepivacaine is used for local infiltration and regional anesthesia. Systemic absorption of local anesthetics can affect the cardiovascular and central nervous systems. The blood concentrations achieved at normal therapeutic doses have minimal impact on cardiac conduction, excitability, refractory period, contractility, and peripheral vascular resistance.

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Mepivacaine (CAS: 96-88-8) is an FDA-approved local anesthetic (Brand names: Carbocaine, Scandicaine). It is available as a racemic mixture. Unlike lidocaine, mepivacaine is not a vasodilator and can be used without epinephrine for procedures where vasoconstriction is undesirable. It is in the amide class, so cross-allergy with ester-type anesthetics is rare. Reference: DrugBank DB00961.

C15H22N2O

246.35

246.173

96-88-8

(+)-Mepivacaine;24358-84-7;Mepivacaine hydrochloride;1722-62-9;Mepivacaine-d3;1346597-90-7

4062

White to off-white solid powder

1.077 g/cm3

383.062ºC at 760 mmHg

150.5 °C

185.47ºC

2.737

1

2

2

18

282

0

CC1=C(C(=CC=C1)C)NC(=O)C2CCCCN2C

INWLQCZOYSRPNW-UHFFFAOYSA-N

InChI=1S/C15H22N2O/c1-11-7-6-8-12(2)14(11)16-15(18)13-9-4-5-10-17(13)3/h6-8,13H,4-5,9-10H2,1-3H3,(H,16,18)

N-(2,6-dimethylphenyl)-1-methylpiperidine-2-carboxamide

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: 33.33 mg/mL (135.30 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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