Moles, weights and potencies: freedom of expression!

* E-mail: g.a.mcleod{at}dundee.ac.uk

Editor—Rosenberg and Schug correctly remind us that there are 12.6% more molecules of bupivacaine in similarly expressed %wt/vol preparations of levobupivacaine (Chirocaine®) when compared with the racemate.1 They also correctly acknowledge that this difference was first highlighted in the British Journal of Anaesthesia in 1998.2 In that paper, the issue of regulatory changes to expressed formulations was first addressed and that an adjustment, equivalent to a reduction of 11% in the potency for the %wt/vol preparations of levobupivacaine when compared with racemate preparations that predated these changes, would be required. Although the discovery of this by Columb led to some initial concern, it became clear that, as this ‘error’ was systematic in the conduct of clinical toxicity and efficacy studies, the interpretation of any therapeutic implications would remain unaffected. However, Rosenberg and Schug incorrectly state that all authors have failed to consider the molar concentrations of levobupivacaine, when comparing it with bupivacaine and ropivacaine (Naropin®). Lyons and colleagues,2 using minimum local analgesic concentrations (MLAC), showed that a 2% potency difference existed between bupivacaine and levobupivacaine when expressed on a %wt/vol basis (MLAC %wt/vol 0.081 vs 0.083). However, a 13% reduction in potency occurred when taking the molarity of solutions into account (MLAC mmol litre–1 2.47 vs 2.87). In fact, from the outset, the first MLAC study comparing bupivacaine and lidocaine presented molar potencies in addition to usual %wt/vol.3 More recent studies have tended away from formally addressing the formulation issue, perhaps related to limited clinical importance of this, although Camorcia4 does discuss the molar potency issues relating to ropivacaine and levobupivacaine. Furthermore, the paper by McLeod,5 measuring the densities of local anaesthetics, tabulated the molar concentrations (mmol litre–1) of commercially available ‘0.75%wt/vol’ solutions of bupivacaine, levobupivacaine and ropivacaine. Table 1, adapted from this paper, shows that the concentration of levobupivacaine 7.5 mg ml–1 is 26.0 mmol litre–1, and is indeed 12.6% greater than the concentration of bupivacaine (23.1 mmol litre–1). However, Rosenberg and Schug are not consistent when translating the molar differences between bupivacaine and levobupivacaine to studies comparing levobupivacaine and ropivacaine.4 6 Ropivacaine has a smaller propyl side chain and thus, a smaller molecular weight, compared with bupivacaine and levobupivacaine, which possess a larger butyl side chain. One mole of ropivacaine has a mass of 274 g and a mole of bupivacaine or levobupivacaine has a mass of 288 g. The difference of 14 g is accounted for by one carbon and two hydrogen atoms. Therefore, when taking molecular weights into consideration, a concentration of ropivacaine, expressed as %wt/vol or mg ml–1, will have ~4–5% more molecules than racemic bupivacaine, and therefore 7–8% less than levobupivacaine. Again, we hope Table 1 may be useful for other researchers when considering these issues. Therefore, we suggest that in studies comparing the commercial solutions of bupivacaine racemate, levobupivacaine and ropivacaine, account may need to be taken of the differences in molarity attributable to differences in both molecular weights and presentation as base or hydrochloride. We also suggest that whilst the issues of molar potencies are of pharmacological interest, the limited clinical relevance of these formulation issues remains unchanged from that first published2 in the British Journal of Anaesthesia in 1998.


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Table 1 Typical values for molecular weights and 0.75%wt/vol preparations

 
G. A. McLeod1,* and M. O. Columb2

1 Dundee, UK
2 Manchester, UK

References

1 Rosenberg PH, Schug SA. Levobupivacaine base and levobupivacaine hydrochloride. Br J Anaesth 2005; 94: 544[Free Full Text]

2 Lyons G, Columb M, Wilson RC, Johnson RV. Epidural pain relief in labour: potencies of levobupivacaine and racemic bupivacaine. Br J Anaesth 1998; 81: 899–901[Abstract/Free Full Text]

3 Columb MO, Lyons G. Determination of the minimum local analgesic concentrations of epidural bupivacaine and lidocaine in labor. Anesth Analg 1995; 81: 833–7[Abstract]

4 Camorcia M, Capogna G, Lyons G, Columb M. Epidural test dose with levobupivacaine and ropivacaine: determination of ED50 motor block after spinal administration. Br J Anaesth 2004; 92: 850–3[Abstract/Free Full Text]

5 McLeod GA. Density of spinal anaesthetic solutions of bupivacaine, levobupivacaine, and ropivacaine with and without dextrose. Br J Anaesth 2004; 92: 547–51[Abstract/Free Full Text]

6 Benhamou D, Ghosh C, Mercier FJ. A randomized sequential allocation study to determine the minimum effective analgesic concentration of levobupivacaine and ropivacaine in patients receiving epidural analgesia for labor. Anesthesiology 2003; 99: 1383–6[CrossRef][ISI][Medline]





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