In the spinal dorsal horn, an area intimately associated with central sensitization, bupivacaine hydrochloride blocks NMDA receptor-mediated synaptic transmission [1]. Bupivacaine hydrochloride shifts the half-maximal activation/deactivation membrane potential toward a slightly more negative membrane potential, which has an impact on the voltage dependence of channel activation and steady-state inactivation. The SCN5A channel has an IC50 of 2.18±0.16 μM for bupivacaine hydrochloride, which indicates a slight sensitivity in the inactive state[2]. With an IC50 of 16.5 μM, bupivacaine hydrochloride dose-dependently and reversibly inhibits SK2 channels [3].

Bupivacaine does not only induce Ca2+ release from the sarcoplasmic reticulum (SR) in rats, but also inhibits Ca2+ uptake by the SR, which is mainly regulated by SR Ca2+ adenosine triphosphatase activity.

Cell Viability Assay[3]
Cell Types: HEK 293 cells transfected with the SK2 gene (transfected cells were named SK2 cells)
Tested Concentrations: 10, 100, 1000 µM
Incubation Duration:
Experimental Results: The IC50 value was 16.5 µM.

Absorption, Distribution and Excretion
Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with [meloxicam] produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a Cmax of 54 ± 33 ng/mL, a median Tmax of 3 h, and an AUC∞ of 1718 ± 1211 ng\*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng\*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng\*h/mL.
Only 6% of bupivacaine is excreted unchanged in the urine.
After absorption into the blood, bupivacaine hydrochloride is more highly bound to plasma proteins than are any other local anesthetics; bupivacaine is reportedly 82-96% bound. Bupivacaine hydrochloride has the lowest degree of placental transmission of parenteral local anesthetics and may cause the least fetal depression.
Pregnant rats received an intravenous infusion of bupivacaine at a rate of 0.33 mg. kg-1. min-1 over a period of 15 min. The fetuses were delivered either at the end of infusion or at 2 or 4 hr after dosing. Maternal and fetal blood and tissue samples were obtained for the assays of bupivacaine and its metabolites using capillary gas chromatography-mass spectrometry. The elimination half-life of bupivacaine was 37.7 min. The major metabolite was 3'-hydroxybupivacaine. Bupivacaine and 3'-hydroxybupivacaine were present in all samples at the end of administration. The fetal to maternal concentration ratio of bupivacaine in plasma was 0.29, and in the placenta was 0.63. The amnion contained the highest bupivacaine concentration: threefold higher in the maternal and 11-fold higher than in the fetal plasma. At 4 hr after dosing, bupivacaine was no longer detectable in any maternal and fetal samples, whereas 3'-hydroxybupivacaine was still present in all tissues except the fetal plasma and heart. These data indicate that a considerable amount of bupivacaine is taken up by both sides of the placenta, as well as the amnion and myometrium. 3'-Hydroxybupivacaine was present in all tissues except the fetal plasma and heart samples, even after the parent compound became no longer detectable.
After injection of Bupivacaine Hydrochloride for caudal, epidural, or peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours.
Pharmacokinetic studies on the plasma profile of Bupivacaine Hydrochloride after direct intravenous injection suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized.
For more Absorption, Distribution and Excretion (Complete) data for Bupivacaine (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4.
Pregnant rats received an intravenous infusion of bupivacaine at a rate of 0.33 mg. kg-1. min-1 over a period of 15 min. The fetuses were delivered either at the end of infusion or at 2 or 4 hr after dosing. Maternal and fetal blood and tissue samples were obtained for the assays of bupivacaine and its metabolites using capillary gas chromatography-mass spectrometry. The elimination half-life of bupivacaine was 37.7 min. The major metabolite was 3'-hydroxybupivacaine. Bupivacaine and 3'-hydroxybupivacaine were present in all samples at the end of administration. The fetal to maternal concentration ratio of bupivacaine in plasma was 0.29, and in the placenta was 0.63. The amnion contained the highest bupivacaine concentration: threefold higher in the maternal and 11-fold higher than in the fetal plasma. At 4 hr after dosing, bupivacaine was no longer detectable in any maternal and fetal samples, whereas 3'-hydroxybupivacaine was still present in all tissues except the fetal plasma and heart. These data indicate that a considerable amount of bupivacaine is taken up by both sides of the placenta, as well as the amnion and myometrium. 3'-Hydroxybupivacaine was present in all tissues except the fetal plasma and heart samples, even after the parent compound became no longer detectable.
Bupivacaine hydrochloride is principally metabolized to pipecolylxylidine (PPX) by N-dealkylation, probably in the liver. Bupivacaine is excreted in urine as small amounts of PPX, unchanged drug (5%), and other metabolites as yet unidentified.
Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4.
Route of Elimination: Only 6% of bupivacaine is excreted unchanged in the urine.
Half Life: 2.7 hours in adults and 8.1 hours in neonates

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Biological Half-Life
2.7 hours in adults and 8.1 hours in neonates. Bupivacaine applied together with [meloxicam] for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site.
Pregnant rats received an intravenous infusion of bupivacaine at a rate of 0.33 mg. kg-1. min-1 over a period of 15 min. The fetuses were delivered either at the end of infusion or at 2 or 4 hr after dosing. Maternal and fetal blood and tissue samples were obtained for the assays of bupivacaine and its metabolites using capillary gas chromatography-mass spectrometry. The elimination half-life of bupivacaine was 37.7 min.
The elimination half-life of bupivacaine hydrochloride is 1.5-5.5 hours in adults and 8.1 hours in neonates.

Toxicity Summary
Bupivacaine is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.

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Toxicity Data
The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL.
LD50: 6 to 8 mg/kg (intravenous, mice)
LD50: 38 to 54 mg/kg (subcutaneous, mice)

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Interactions
Solutions of Bupivacaine Hydrochloride containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result.
Bupivacaine Hydrochloride with epinephrine 1:200,000 or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur.

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Non-Human Toxicity Values
LD50 Mouse sc 38-54 mg/kg
LD50 Mouse iv 6-8 mg/kg

[1]. Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? Best Pract Res Clin Anaesthesiol. 2005 Jun;19(2):247-68.

[2]. Inhibition of gastric cancer by local anesthetic bupivacaine through multiple mechanisms independent of sodium channel blockade. Biomed Pharmacother. 2018 Jul;103:823-828.

Therapeutic Uses
Bupivacaine hydrochloride is used for infiltration anesthesia and for peripheral, sympathetic nerve, and epidural (including caudal) block anesthesia. A 0.75% solution of the drug in 8.25% dextrose is used for spinal anesthesia. Bupivacaine is not used for obstetric paracervical block or topical anesthesia. /Use Included in US product label/
Bupivacaine Hydrochloride is indicated for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Only the 0.25% and 0.5% concentrations are indicated for obstetrical anesthesia. /Use Included in US product label/

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Drug Warnings
The 0.75% solution of bupivacaine hydrochloride is no longer recommended for obstetric anesthesia, since use of this concentration for epidural anesthesia in obstetric patients has been associated with cardiac arrest with difficult resuscitation or death. Cardiac arrest has occurred after seizures resulting from systemic toxicity, apparently following inadvertent intravascular injection.
Local anesthetics should only be employed by clinicians who are well versed in diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. delay in proper management of dose-related toxicity, under ventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. /Local anesthetics/
Pending accumulation of further data on the use of the drug in pediatric patients, bupivacaine hydrochloride solutions should not be used in children younger than 12 years of age and the solution for spinal anesthesia should not be used in children younger than 18 years of age.
Some commercially available formulations of bupivacaine hydrochloride contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
For more Drug Warnings (Complete) data for Bupivacaine (18 total), please visit the HSDB record page.

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Pharmacodynamics
Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both.

C18H28N2O.HCL

324.89

324.196

18010-40-7

Bupivacaine;38396-39-3;Bupivacaine hydrochloride monohydrate;73360-54-0

2474

White to off-white solid powder

423.4ºC at 760 mmHg

107.5 to 108ºC

209.9ºC

4.709

1

2

5

21

321

0

SIEYLFHKZGLBNX-UHFFFAOYSA-N

InChI=1S/C18H28N2O.ClH/c1-4-5-12-20-13-7-6-11-16(20)18(21)19-17-14(2)9-8-10-15(17)3;/h8-10,16H,4-7,11-13H2,1-3H3,(H,19,21);1H

1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.69 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 (7.69 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 3: 13 mg/mL (40.01 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.)