Levobupivacaine is an amino-amide local anaesthetic drug belonging to the family of n-alkyl substitute pipecoloxylidide. Its molecular structure is 2– piperidinecarboxamide 1–Butyl–N– (2,6–dimethyl phenyl)– hydrochloride monohydrate. Its pKa is 8.1. Levobupivacaine is a non-pyrogenic, colourless solution (pH 4.0 - 6.5) with a water solubility of 0.0977 mg/mL [1].

Pharmacokinetics

Levobupicavaine is about 97% bound to plasma proteins. Half-life of levobupivacaine is 3.3 hours. Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or faeces [2].

Absorption 

The plasma concentration of levobupivacaine following therapeutic administration depends on dose and route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. 

Distribution 

The volume of distribution is estimated at 66.91 ± 18.23 L (after intravenous administration of 40 mg in healthy volunteers) [3]. Clearance of levobupicaiaine is 39.06 ±13.29 L/h (after intravenous administration of 40 mg in healthy volunteers). 

Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine and faeces. In CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. Levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates [4]. Metabolic inversion of levobupivacaine to R (+) - bupivacaine was not evident in both in vitro and in vivo.

Levobupivacaine exerts its pharmacological action through reversible blockade of neuronal sodium channels. Myelinated nerves are blocked through exposure at the nodes of ranvier more readily than unmyelinated nerves; and small nerves are blocked more easily than larger ones. In general, the progression of anaesthesia is related to the diameter, myelination and conduction velocity of the affected nerve fibres. Specifically, the drug binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. It blocks nerve conduction in sensory and motor nerves mainly by interacting with voltage sensitive sodium channels on the cell membrane. It also interferes with impulse transmission and conduction in other tissues [5].

Onset and Duration of Action

It depends upon the particular drug’s pKa and on lipophillic of its base and cation species. Levobupivacaine is long acting with a dose-dependent duration of anaesthesia. The onset of action is more than 15 minutes with various anaesthetic techniques. In studies of surgical anaesthesia in adults, levobupivacaine provided sensory block for up to 9 hours after epidural administration of less than 202.5 mg, 6.5 hours after intrathecal 15 mg and 17 hours after brachial plexus block with 2 mg/kg [6].

It is relatively free of adverse effects if administered in appropriated doses [7]. The clinical effects are following:

• Central Nervous System: CNS is more susceptible to levobupivacaine. The initial symptoms involve feeling of light headedness and dizziness followed by visual and auditory disturbances. Disorientation and occasional feeling of drowsiness may occur. Objective signs are usually excitatory in nature which includes shivering, muscular twitching and tremors; initially involving muscles of the face (perioral numbness) and part of extremities. At still higher doses cardiovascular or respiratory arrest may occur. Acidosis increases the risk of CNS toxicity from, since an elevation of PaCO2 enhances cerebral blood flow, so that more anaesthetic is delivered rapidly to the brain.

• Cardiovascular System: It depresses rapid phases of depolarization (Vmax) in purkinje fibres and ventricular musculature to a greater extent than lignocaine. It also decreases the rate of recovery from a dependent block than that of lignocaine. This leads to incomplete restoration of Vmax between action potential at high rates, in contrast to complete recovery by lignocaine.

• Respiratory System: Respiratory depression may be caused if excessive plasma level is reached which in turn results in depression of medullary respiratory center. Respiratory depression may also be caused by paralysis of respiratory muscles as may occur in high spinal or total spinal anaesthesia.

• Autonomic Nervous System: Myelinated preganglionic β fibres have a faster conduction time and are more sensitive to the action of local anaesthetic including levobupivacaine. Involvement of preganglionic sympathetic fibres is the cause of widespread vasodilation and consequent hypotension that occurs in epidural and paravertebral block. When used for conduction blockade all local anaesthetic particularly levobupivacaine produces higher incidence of sensory blockade than motor fibres.

Dosage 

Maximal dose is 2 mg/kg body weight (25-30 mL 0.5% solution) [8].

Availability 

Levobupivacaine is available in following concentration: 0.25% and 0.5% 0.25% and 0.5% in isotonic solution 0.125% - 0.75% used for nerve block and epidural anaesthesia or analgesia. 0.5% or 0.75% plus 80% of dextrose to make solution hyperbaric for subarachnoid block [9].

Adverse Effects 

Levobupivacaine produces the same adverse effects as seen with racemic bupivacaine and other local anaesthetics [10].

• The most common adverse drug reactions reported are: hypotension (31%), nausea (21%), vomiting (14%), headache (9%), procedural pain (8%), dizziness (6%). 

• The cardiac toxicity, neurological injury after peripheral nerve block and unwanted CNS effects, may be lower than bupivacaine.

Allergic type reactions are rare and range in severity from urticaria to anaphylactoid-like reaction.

1. Albrecht, E. Reynvoet M., Fournier N., Desmet M. "Dose–response relationship of perineural dexamethasone for interscalene brachial plexus block: A randomised, controlled, triple‐blind trial." Anaesthesia, vol. 74, no. 8, Aug. 2019, pp. 1001–08.

2. Bajwa, S.J. Kaur J. "Clinical profile of levobupivacaine in regional anesthesia: A systematic review." Journal of Anaesthesiology Clinical Pharmacology, vol. 29, no. 4, Oct. 2013, p. 530.

3. Leone, S. Di Cianni S., Casati A., Fanelli G. "Pharmacology, toxicology and clinical use of new long acting local anesthetics, ropivacaine and levobupivacaine." Acta Biomedica, vol. 79, no. 2, 1 Aug. 2008, pp. 92–105.

4. Burlacu, C.L. Buggy D.J. "Update on local anesthetics: Focus on levobupivacaine." Therapeutics and Clinical Risk Management, vol. 4, no. 2, Apr. 2008, p. 381.

5. Rachel, H. Foster A.M. "Levobupivacaine: A review of its pharmacology and use as a local anaesthetic." Drugs, vol. 59, no. 3, 2000, p. 551.

6. EL-Soudy, E.M. Atia A.M., Ali W.M., Abdel Sabour A.I. "The effect of ketamine as adjuvant in ultrasonic guided supraclavicular brachial plexus block." The Egyptian Journal of Hospital Medicine, vol. 76, no. 7, 1 July 2019, pp. 4643–48.

7. Abrahams, M.S. Aziz M.F., Fu R.F., Horn J.L. "Ultrasound guidance compared with electrical neurostimulation for peripheral nerve block: A systematic review and meta-analysis of randomized controlled trials." British Journal of Anaesthesia, vol. 102, no. 3, 1 Mar. 2009, pp. 408–17.

8. Williams, S.R. Chouinard P., Arcand G., Harris P., Ruel M., Boudreault D., Girard F. "Ultrasound guidance speeds execution and improves the quality of supraclavicular block." Anesthesia & Analgesia, vol. 97, no. 5, 1 Nov. 2003, pp. 1518–23.

9. Ilham, C. Bombaci E., Yurtlu S., Çolakoglu S. "Efficiency of levobupivacaine and bupivacaine for supraclavicular block: A randomized double-blind comparative study." Revista Brasileira de Anestesiologia, vol. 64, May 2014, pp. 177–82.

10. Abdelhamid, B.M. Omar H. "Nalbuphine as an adjuvant to 0.25% levobupivacaine in ultrasound-guided supraclavicular block provided prolonged sensory block and similar motor block durations (RCT)." Journal of Anesthesia, vol. 32, no. 4, Aug. 2018, pp. 551–57.