Local anesthetic properties of a novel derivative, N-methyl doxepin, versus doxepin and bupivacaine.
Among various tricyclic antidepressants, doxepin and amitriptyline are also long-acting local anesthetics. We synthesized a new compound, N-methyl doxepin, and investigated whether this derivative possesses local anesthetic properties. N-methyl doxepin and doxepin were tested in a rat sciatic nerve model at 2.5, 5.0, and 10 mM. Proprioceptive, motor, and nociceptive blockade were evaluated and compared with those induced by 0.5% bupivacaine. Block of Na(+) channels by N-methyl doxepin and doxepin was assessed in cultured pituitary tumor cells under voltage clamp conditions. N-methyl doxepin elicited complete nociceptive blockade that generally lasted longer than that caused by doxepin (e.g., approximately 7.4 h versus 5.3 h at 10 mM). Significant differences were observed for full recovery of function at all concentrations and for the duration of complete blockade except at 2.5 mM. Bupivacaine at 0.5% (15.4 mM) was less effective in producing complete blockade (approximately 1.5 h) than N-methyl doxepin and doxepin. Both doxepin and N-methyl doxepin were potent Na(+) channel blockers, although N-methyl doxepin displayed a slower wash-in rate. No morphological alterations were detected in cross-sectioned sciatic nerve specimens with these three drugs. We conclude that N-methyl doxepin is a potent Na(+) channel blocker and a long-acting local anesthetic for rat sciatic nerve blockade.


CONCLUSIONS
N-methyl doxepin and doxepin are both potent Na(+) channel blockers; they elicit rat sciatic nerve block lasting longer than that induced by bupivacaine and seem to be nontoxic to peripheral nerves at concentrations up to 10 mM.
Sudoh
Yukari
Y
Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Cahoon
Elaine Elliott
EE
De Girolami
Umberto
U
Wang
Ging Kuo
GK
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002045:Bupivacaine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004316:Doxepin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D009619:Nociceptors / Q000187:drug effects; D010911:Pituitary Neoplasms / Q000473:pathology; D011434:Proprioception / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects
D000779:Anesthetics, Local; C483084:N-methyl doxepin; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D004316:Doxepin; D002045:Bupivacaine