Levobupivacaine

Absorption

The plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean Cmax levels of up to 1.2 μg/mL.

Toxicity

LD50: 5.1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous (Archives Internationales de Pharmacodynamie et de Therapie. Vol. 200, Pg. 359, 1972.) Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations.

Chemical properties

White Solid

Originator

Chirocaine,Abbott Laboratories

The Uses of Levobupivacaine

Local anaesthetic used for epidural and intrathecal anaesthesia.

Background

Levobupivacaine is an amino-amide local anaesthetic drug belonging to the family of n-alkylsubstituted pipecoloxylidide. It is the S-enantiomer of bupivacaine. Levobupivacaine hydrochloride is commonly marketed by AstraZeneca under the trade name Chirocaine. In particular, the specific levobupivacaine enantiomer is a worthwhile pursuit because it demonstrates less vasodilation and possesses a greater length of action in comparison to bupivacaine. It is approximately 13 per cent less potent (by molarity) than racemic bupivacaine.Levobupivacaine is indicated for local anaesthesia including infiltration, nerve block, ophthalmic, epidural and intrathecal anaesthesia in adults; and infiltration analgesia in children. When administered appropriately, the occurrence of adverse effects is not anticipated much if at all. In general, the majority of potential adverse effects are predominantly associated with inappropriate administration methods that may cause systemic exposure and/or toxicity associated with overexposure to an anesthetic. Regardless, allergic reactions may also occur - although only rarely.

Indications

For the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management

Definition

ChEBI: Levobupivacaine is the (S)-(-)-enantiomer of bupivacaine. It has a role as a local anaesthetic, an adrenergic antagonist, an amphiphile, an EC 3.1.1.8 (cholinesterase) inhibitor and an EC 3.6.3.8 (Ca(2+)-transporting ATPase) inhibitor. It is a conjugate base of a levobupivacaine(1+). It is an enantiomer of a dextrobupivacaine.

Manufacturing Process

Synthesis of L-pipecolic acid 2,6-xylidide (Patent US 4,695,576)
130 g of pipecolic acid and 158.6 g of Laevo (+)-tartaric acid are dissolved under stirring in 2 L 95% ethyl alcohol and 125 ml water at 80°C. The solution is allowed to cool to room temperature and after two days the crystallized D-pipecolic-tartrate is separated. The L-pipecolic-tartrate remains in solution. The filtrate is evaporated and dissolved in 5% acetic acid. Finally the solution is treated with Amberlite IR 45* in an ion exchanger. The eluate thus obtained is evaporated and the resulting crystalline residue is dried with potassium hydroxide in vacuo. The product obtained consists of L-pipecolic acid [α]D24 = -26.2°(C = 5, H2O).
4 g of phosphorus pentachloride was added to a suspension of 4 g of Lpipecolic acid hydrochloride in 40 ml acetylchloride. The initial reaction is effected at a temperature of about 35°C under stirring for 2 hours. The chlorination is completed by adding during a time period of about 10 minutes an additional two grams of phosphorus pentachloride and stirring over a further period of 4 hours while maintaining the suspension at a temperature of about 35°C. The resulting L-pipecolic acid chloride hydrochloride is filtered and washed with toluene and acetone. The crystalline residue is then dried in vacuo, m.p. 155°C.
A mixture of 2.7 ml 2,6-dimethylaniline, 4 ml acetone, and 4 ml Nmethylpyrrolidone is gradually added under stirring for 2 hours at 70°C to a suspension of 4 g of L-pipecolic acid chloride hydrochloride. This yields a crystalline product, which is filtered, washed with acetone and dried. This crystalline product is then dissolved in water and the base is precipitated by the addition of ammonia. The base is then extracted by the use of toluene and is recovered by evaporation. The base is recrystallized from a mixture of hexane and ethanol to yield L-pipecolic acid 2,6-xylidide. The melting point of this compound is 129-130°C.
Preparation of L-N-n-butylpipecilic acid 2,6-xylidide may de carried out by analogy with the preparation of L-N-n-propylpipecolic acid 2,6-xylidide (Patent US 5,777,124).
n-Butylbromide and potassium carbonate are added to a solution of L-pipecolic acid 2,6-xylidide dissolved in isopropyl alcohol. Thereafter, 5 ml of water is added to the mixture and the reaction is carried out for 4 hours at 72°C.
To complete the reaction, a further 0.8 ml n-butylbromide are added under continuous stirring and heating for 4 hours. The residue is treated with a mixture of 250 ml toluene and an equal amount of water at 50°C. The toluene layer is separated and washed three times with 100 ml warm water (40°C). A 175 ml portion of the toluene is removed by evaporation and the remainder is stored at +5°C for 6 hours to achieve crude crystalline L-N-n-butylpipecilic acid 2,6-xylidide. The crystalline product is separated by filtration, washed with some cooled toluene and dried at 70°C. Recrystallization may be carried from toluene. This product is dissolved in 100 ml ethanol and neutralized with concentrated hydrochloric acid. Ethanol is removed by evaporation and the hydrochloride product obtained is vacuum dried. Finally the latter is recrystallized from isopropyl alcohol.

Therapeutic Function

Local anesthetic

General Description

Levobupivacaine is the pure “S” enantiomer of bupivacaineand in vivo and in vitro studies confirm that it does notundergo metabolic inversion to R(+) bupivacaine. The pKaof the tertiary nitrogen is 8.09, the same as bupivacaine’s pKa. Levobupivacaine is available in solution for epiduraladministration, peripheral nerve block administration, andinfiltration anesthesia. Clinical trials have shown thatlevobupivacaine and bupivacaine have similar anestheticeffects. Levobupivacaine has lower CNS and cardiotoxicitythan bupivacaine although unintended intravenousinjection when performing nerve blocks may result intoxicity. Racemic bupivacaine is metabolized extensivelywith no unchanged drug found in the urine or feces. Liverenzymes including the CYP3A4 and CYP1A2 isoforms areresponsible for N-dealkylation and 3-hydroxylation oflevobupivacaine followed by glucuronidation or sulfation.

Pharmacokinetics

Levobupivacaine, a local anesthetic agent, is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures.

Pharmacology

This is the laevo (S–) enantiomer of bupivacaine, with similar properties to the racemic mixture, though it has slightly higher protein binding and clearance and hence a lower potential for cardiac and CNS toxicity. In practice, several other factors contribute to local anaesthetic toxicity, and the recommended maximum doses remain the same. Its formulation is expressed as percentage weight per unit volume of free base; racemic bupivacaine is expressed as percentage weight per unit volume of hydrochloride salt. Levobupivacaine therefore contains 13% more active molecules for a given dose.

Metabolism

Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo.