Enhancement of bupivacaine local anesthesia with the potassium channel blocker ibutilide

Abstract

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.

Sustained release local anesthetics for pain management: relevance and formulation approaches

“…Though it has no analgesic effect when given alone, ibutilide is supposed to bind at a similar channel, sodium ion channels, with local anesthetics because it contains an amide-link characteristic of local anesthetics. Co-administration of ibutilide with bupivacaine and epinephrine combination further increased the potency of bupivacaine another 6.8-fold beyond the 2.3-fold enhancement elicited by the addition of epinephrine (57).…”

Beta-endorphin response to an acute pain stimulus

“…A hot-plate (15.9 × 15.9) insulated with polystyrene (Thermolyne Aluminum Type, Model HPA1915B, Dubuque, IA) was maintained at 55 ± 1 • C by a temperature controller (GlasCol, PowrTrol Model, Terre Haute, IN) and monitored using a thermo-coupled thermometer (Omega, Model HH11, Stamford, CT). In order to confirm that pain had been experienced by exposure to the hot-plate, the animal's paw-licking response was observed (Pierretti et al, 1993;Rubenstein et al, 1996;Liang et al, 2003;Rasmussen and Farr, 2003;Vermeirsch and Meert, 2004;Wesolowska et al, 2004;Suaudeau et al, 2005;Altug et al, 2006;Berrocoso et al, 2006;Smith and Lindsay, 2007;Hsieh et al, 2008;Milano et al, 2008). Exposure of a mouse to a 55 • C hot-plate induces the paw-licking response and the mouse begins to lick its front or hind paws.…”

Dual-Site Binding of Quaternary Ammonium Ions as Internal K+-Ion Channel Blockers: Nonclassical (C–H···O) H Bonding vs Dispersive (C–H···H–C) Interaction

“…A variety of molecules such as amiodarone (C 25 H 29 I 2 NO 3 ), − dronedarone (C 31 H 44 N 2 O 5 S), − ibutilide (C 20 H 36 N 2 O 3 S), , sotalol (C 12 H 20 N 2 O 3 S), ,,, and dofetilide (C 19 H 27 N 3 O 5 S 2 ) , are known to block the transport of potassium ions through the channel. However, quaternary ammonium (QA) ion-based molecules − have gained much attention due to their structural diversity (Scheme ).…”