Assessment of differential blockade by amitriptyline and its N-methyl derivative in different species by different routes.
BACKGROUND
Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep.


METHODS
The Na+ channel-blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH(3) cells. Various functions (motor, nociception, proprioception-ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data).


RESULTS
In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mM N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data.


CONCLUSIONS
Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.
Gerner
Peter
P
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. pgerner@partners.org
Haderer
Anna E
AE
Mujtaba
Mustafa
M
Sudoh
Yukari
Y
Narang
Sanjeet
S
Abdi
Salahadin
S
Srinivasa
Venkatesh
V
Pertl
Christof
C
Wang
Ging Kuo
GK
D000639:Amitriptyline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000775:Anesthesia, Spinal; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D004594:Electrophysiology; D005260:Female; D008012:Lidocaine / Q000494:pharmacology; D009407:Nerve Block; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology; D012756:Sheep; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects; D013045:Species Specificity
D000779:Anesthetics, Local; D000929:Antidepressive Agents, Tricyclic; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000639:Amitriptyline; C007479:dimethylprotriptyline; D008012:Lidocaine