Enhancement of bupivacaine local anesthesia with the potassium channel blocker ibutilide.
In some clinical settings it is necessary to inject large volumes of local anesthetic--and consequently very high doses--in order to provide an adequate level of block. Subsequent absorption of these high doses, or inadvertent intravenous administration of even small doses, has led to systemic toxicity. Thus, it is desirable to develop adjuvants that are inert alone, but would enhance the potency and/or efficacy of local anesthetics to improve their safety. Adelta/C fibers possess K(+) channels identified as sustained delayed rectifier type K(DR) currents and transient A-type K(A) currents. In the heart, the class III antiarrhythmic drug ibutilide blocks the cardiac component of the rapid delayed rectifying K(+) current (IKr). Experiments were conducted to determine whether co-administration of the K(+) channel blocker ibutilide would enhance the local anesthetic bupivacaine in mice. After injecting bupivacaine mixed with vehicle or ibutilide in the popliteal region of mice, paw withdrawal latencies were determined by applying the plantar aspect of a single hind-paw to the surface a 55 degrees C hot-plate device. 0.5% Bupivacaine+ibutilide (7.8x10(-5) M) elicited significantly longer hot-plate latencies than 0.5% bupivacaine+vehicle. In addition, bupivacaine was 2.6-fold more potent when co-administered with ibutilide rather than vehicle. Epinephrine extends the tissue concentrations of local anesthetics by inducing localized vasoconstriction. Epinephrine augmented the enhancement by ibutilide of bupivacaine's potency by 6.8-fold. In summary, ibutilide may enhance the effects of bupivacaine by blocking K(+) channels on sensory nociceptive nerves.
Smith
Forrest L
FL
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, P.O. Box 980524, Richmond, VA 23298-0524, USA. flsmith1@vcu.edu
Lindsay
Raymond J
RJ
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000772:Anesthesia, Local / Q000379:methods*; D000779:Anesthetics, Local / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D002045:Bupivacaine / Q000494:pharmacology* / Q000627:therapeutic use; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004338:Drug Combinations; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D000316:Adrenergic alpha-Agonists; D000779:Anesthetics, Local; D000889:Anti-Arrhythmia Agents; D004338:Drug Combinations; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013449:Sulfonamides; C067192:ibutilide; D002045:Bupivacaine; D004837:Epinephrine