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.
Sodium channel drugs were used to modulate the anesthetic effects of bupivacaine in mice. Anesthesia was measured following perisciatic injection of bupivacaine with vehicle or neurotoxin in the popliteal region. The site 1 Na+ channel blocker tetrodotoxin alone was inactive, but increased the anesthetic effects of bupivacaine. We hypothesized that the site 2 and site 3 Na+ channel openers veratridine and anemone toxin II (ATXII), respectively, would antagonize bupivacaine. Paradoxically, both drugs enhanced bupivacaine. In bupivacaine-treated mice, a significant correlation was observed between limb weakness scores and paw withdrawal latencies. The correlation coefficients were higher when tetrodotoxin, veratridine, or ATXII was coadministered with bupivacaine. In conclusion, veratridine and ATXII may have increased the stimulus-dependent binding of bupivacaine to Na+ channels, thereby increasing the anesthetic effects of bupivacaine.
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