Quaternary ammonium derivative of lidocaine as a long-acting local anesthetic.
BACKGROUND
Use of long-acting local anesthetics that elicit complete neural blockade for more than 3 h often is desirable in pain management. Unfortunately, clinically available local anesthetics are in general not suitable for prolonged analgesia. This report describes the organic synthesis and functional testing of a lidocaine derivative that appears to fulfill the criteria of long-acting local anesthetics.


METHODS
A lidocaine derivative, N-beta-phenylethyl lidocaine quaternary ammonium bromide, was synthesized, and its ability to inhibit Na+ currents in cultured rat neuronal GH3 cells was tested in vitro under whole-cell voltage clamp conditions. Neurologic evaluation of sciatic nerve block of sensory and motor functions in vivo was subsequently performed in rats.


RESULTS
N-beta-phenylethyl lidocaine was found to be a potent Na+ channel blocker in vitro. It produced both tonic and use-dependent blocks of Na+ currents that exceeded lidocaine's effects by a factor of > 2 (P < 0.05). In vivo, N-beta-phenylethyl lidocaine elicited a prolonged and complete sciatic nerve block of the motor function and the withdrawal response to noxious pinch that was 3.6- and 9.3-fold longer than that of lidocaine (P < 0.001), respectively.


CONCLUSIONS
In an attempt to elicit prolonged local anesthesia, a quaternary ammonium derivative of lidocaine containing a permanent charge and an additional hydrophobic component was synthesized. Complete sciatic neural blockade of more than 3 h was achieved with this derivative. Of note, sensory blockade was prolonged to a greater extent than motor blockade. The approach used in this study may prove useful for developing new drugs applicable in pain management.
Wang
G K
GK
Department of Anesthesia Research Laboratories, Harvard Medical School, Boston, Massachusetts, USA.
Quan
C
C
Vladimirov
M
M
Mok
W M
WM
Thalhammer
J G
JG
D000779:Anesthetics, Local / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D015640:Ion Channel Gating / Q000187:drug effects; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects; D018408:Patch-Clamp Techniques; D000644:Quaternary Ammonium Compounds; D051381:Rats; D012964:Sodium / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors
D000779:Anesthetics, Local; D000644:Quaternary Ammonium Compounds; D015222:Sodium Channels; C097272:tonicaine; D008012:Lidocaine; D012964:Sodium