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.
Department of Anesthesia Research Laboratories, Harvard Medical School, Boston, Massachusetts, USA.
G K
GK
Wang
C
C
Quan
M
M
Vladimirov
W M
WM
Mok
J G
JG
Thalhammer
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