Pharmacological and Clinical Attributes of Levobupivacaine hydrochloride

Levobupivacaine hydrochloride is the hydrochloride salt of levobupivacaine, an amide derivative with anesthetic property. Levobupivacaine reversibly binds voltage-gated sodium channels to modulate ionic flux and prevent the initiation and transmission of nerve impulses (stabilizing neuronal membrane), thereby resulting in analgesia and anesthesia. In comparison with racemic bupivacaine, levobupivacaine is associated with less vasodilation and has a longer duration of action. A piperidinecarboxamide-based local anaesthetic, it has a slow onset and long duration of action. A piperidinecarboxamide-based local anaesthetic, it has a slow onset and long duration of action. It has a role as an adrenergic antagonist, an amphiphile, an EC 3.1.1.8 (cholinesterase) inhibitor, an EC 3.6.3.8 (Ca(2+)-transporting ATPase) inhibitor and a local anaesthetic. It contains a levobupivacaine hydrochloride (anhydrous). It is an enantiomer of a dextrobupivacaine hydrochloride hydrate.

Local anesthetics: focus on levobupivacaine

In recent years Levobupivacaine hydrochloride, the pure S (−)-enantiomer of bupivacaine, emerged as a safer alternative for regional anesthesia than its racemic parent. It demonstrated less affinity and strength of depressant effects onto myocardial and central nervous vital centers in pharmacodynamic studies, and a superior pharmacokinetic profile. Clinically, Levobupivacaine hydrochloride is well tolerated in a variety of regional anesthesia techniques both after bolus administration and continuous postoperative infusion. Reports of toxicity with Levobupivacaine hydrochloride are scarce and occasional toxic symptoms are usually reversible with minimal treatment with no fatal outcome. Yet, levobupivacaine has not entirely replaced bupivacaine in clinical practice. In anesthesia and analgesia practice, levobupivacaine and bupivacaine produce comparable surgical sensory block with similar adverse side effects, and equal labor pain control with comparable maternal and fetal outcome. The equipotency of the two drugs has been recently questioned, prompting clinicians to increase the dose of Levobupivacaine hydrochloride in an attempt to ensure adequate anesthesia and analgesia and offsetting, therefore, the advantages of less motor block with Levobupivacaine hydrochloride. In this review we aim to discuss the pharmacological essentials of the safer profile of levobupivacaine, and analyze the evidence regarding the current clinical indications.[1]

Pharmacology of Levobupivacaine hydrochloride

Levobupivacaine hydrochloride is a long acting, amide-type local anaesthetic that is the S(−) \3- isomer of the racemate bupivacaine. In general, in vitro, in vivo and human volunteer studies of nerve block indicate that levobupivacaine is as potent as bupivacaine and produces similar sensory and motor block. A trend towards a longer sensory block with levobupivacaine was seen in some studies, and may be related to the greater vasoconstrictive activity of levobupivacaine than that of the R(+)-enantiomer (dexbupivacaine) at lower doses. The minimum local analgesic concentration was 0.083% for epidural levobupivacaine 20ml and 0.081% for bupivacaine 20ml in women in the first stage of labour. Levobupivacaine hydrochloride has been consistently less toxic than bupivacaine in animal models. The lethal dose of levobupivacaine was 1.3- to 1.6-fold higher than that of bupivacaine in most animal studies, providing supportive evidence for a safety advantage over bupivacaine. In vitro findings indicating a lower risk of cardiotoxicity with Levobupivacaine hydrochloride compared with dexbupivacaine and/or bupivacaine have included lesser effects or lower potency in: blocking cardiac sodium channels in the inactivated state; blocking cardiac potassium channels; reducing the maximal rate of depolarisation; prolonging atrioventricular conduction; and prolonging QRS interval duration.[2]

Differences between the agents with regards to effects on contractility seem to be less consistent, but l Levobupivacaine hydrochloride also appears to be less detrimental in this regard. In animal studies, levobupivacaine was associated with fewer and less severe cardiac disturbances, especially ventricular arrhythmias. In human volunteers, intravenous levobupivacaine (mean dose 56mg) produced less of a negative inotropic effect than bupivacaine (48mg). In another study of intravenous administration, the mean maximum increase in QTc interval was significantly less with Levobupivacaine hydrochloride than with bupivacaine (3 vs 24 msec) in volunteers receiving >75mg. A lower risk of CNS toxicity with levobupivacaine compared with dexbupivacaine and/or bupivacaine has also been reported, including less propensity to cause apnoea and higher convulsive doses (levobupivacaine 103mg vs bupivacaine 85mg) in animal studies. In human volunteers, 64% of intravenous bupivacaine recipients (mean dose 65.5mg) compared with 36% of Levobupivacaine hydrochloride (67.7mg) recipients experienced central or peripheral nervous system disorders. Intravenous levobupivacaine 40mg produced fewer changes indicative of CNS depression on EEG than bupivacaine 40mg in volunteers.

Levobupivacaine hydrochloride is long acting with an onset of action ≤15 minutes. The duration of action is dose-dependent and varies according to the anaesthetic technique. Adequate sensory and motor block for surgery was achieved in ≥90% of adult patients receiving adequate doses of levobupivacaine with satisfactory anaesthetic technique in most of the 10 available clinical trials. The anaesthetic and/or analgesic effects of levobupivacaine hydrochloride were largely similar to those with bupivacaine at the same dose in all comparative studies, including those of epidural, peripheral nerve block (supraclavicular or axillary brachial plexus nerve block), local infiltration and peribulbar administration. The duration of sensory block tended to be longer with levobupivacaine hydrochloride, although the difference was not statistically significant compared with bupivacaine in most cases.

Clinical profile of levobupivacaine hydrochloride

Different studies have compared levobupivacaine, ropivacaine and bupivacaine in brachial plexus block for upper limb surgery. Levobupivacaine hydrochloride is a good substitute for bupivacaine. Compared to ropivacaine, levobupivacaine provides a significantly longer duration of analgesia. The return of motor activity is earlier with ropivacaine. The long duration of sensory block associated with good analgesia and less toxicity of levobupivacaine makes it a better choice for upper extremity blocks. Levobupivacaine hydrochloride 0.5% provides a longer duration of sensory block after sciatic nerve block using the Labat approach than the same dose of ropivacaine in foot and ankle surgery. The use of a single dose of 0.5% levobupivacaine to block the tibial and peroneal nerves for hallux valgus surgery using popliteal approach is preferable over 0.5% ropivacaine for good anesthesia and better control of post-operative pain. Levobupivacaine hydrochloride 0.5% is as effective as bupivacaine 0.5% and is recommended for the 3-in-1 block.

Combined spinal-epidural (CSE) technique is widely used in obstetric practice to provide optimal analgesia. It offers effective, rapid-onset analgesia with minimal risk of toxicity or impaired motor block. Minimum effective local anesthetic concentration studies using a CSE analgesia technique (CSE) for labor confirm the potency hierarchy of bupivacaine < levobupivacaine < ropivacaine for spinal sensory block. The intrathecal minimum local analgesic doses were 2.73-3.16 mg for levobupivacaine and 3.33-3.96 mg for ropivacaine. The addition of fentanyl to Levobupivacaine hydrochloride prolongs the duration and increases the success rate of the sensory block after intrathecal administration in a CSE analgesia technique. The addition of fentanyl to intrathecal levobupivacaine provides a local anesthetic sparing effect with more effective analgesia and less motor block as compared with a double dose of each drug. The addition of epinephrine to a mixture of Levobupivacaine hydrochloride and opioid increase the success rate of sensory block, but also increases the frequency of motor blockade.

Levobupivacaine hydrochloride has a safety margin of 1.3, which means toxic effects are not seen until the concentration rises by 30%. The concentration necessary to produce cardiac and neurotoxicity is higher for Levobupivacaine hydrochloride than for racemic bupivacaine. There are three case reports of successful resuscitation after inadvertent intravenous injection. The presentations were severe hypotension and bradycardia after a drug error; loss of consciousness, convulsions, hypotension and changes in QRS pattern of ECG after presumed intravenous injection during lumbar plexus block and loss of consciousness and convulsions after (a) spinal (b) sciatic nerve and (c) continuous lumbar plexus blocks. Levobupivacaine is a long-acting local anesthetic with a clinical profile similar to that of bupivacaine. In an individual patient, the clinical anesthetic effect from the drug is indistinguishable from that of bupivacaine. The better safety profile of Levobupivacaine hydrochloride confers an advantage over its racemic parent, bupivacaine.

References

[1]Burlacu CL, Buggy DJ. Update on local anesthetics: focus on levobupivacaine. Ther Clin Risk Manag. 2008 Apr;4(2):381-92.

[2]Foster RH, Markham A. Levobupivacaine: a review of its pharmacology and use as a local anaesthetic. Drugs. 2000 Mar;59(3):551-79.

[3]Bajwa SJ, Kaur J. Clinical profile of levobupivacaine in regional anesthesia: A systematic review. J Anaesthesiol Clin Pharmacol. 2013 Oct;29(4):530-9.

You may like