Wai Man Mok

Quaternary Ammonium Derivative of Lidocaine as a Long-acting Local Anesthetic

Background Use of long‐acting local anesthetics that elicit complete neural blockade for more than 3 h often is desirable in pain management. Unfortunately, clinically available local anesthetics are in general not suitable for prolonged analgesia. This report describes the organic synthesis and functional testing of a lidocaine derivative that appears to fulfill the criteria of long‐acting local anesthetics.

Use-dependent inhibition of Na+ currents by benzocaine homologs

Most local anesthetics (LAs) elicit use-dependent inhibition of Na+ currents when excitable membranes are stimulated repetitively. One exception to this rule is benzocaine, a neutral LA that fails to produce appreciable use-dependent inhibition. In this study, we have examined the use-dependent phenomenon of three benzocaine homologs: ethyl 4-diethylaminobenzoate, ethyl 4-ethoxybenzoate, and ethyl 4-hydroxybenzoate. Ethyl 4-hydroxybenzoate at 1 mM, like benzocaine, elicited little use-dependent inhibition of Na+ currents, whereas ethyl 4-diethylaminobenzoate at 0.15 mM and ethyl 4-ethoxybenzoate at 0.5 mM elicited substantial use-dependent inhibition--up to 55% of peak Na+ currents were inhibited by repetitive depolarizations at 5 Hz. Each of these compounds produced significant tonic block of Na+ currents at rest and shifted the steady-state inactivation curve (h infinity) toward the hyperpolarizing direction. Kinetic analyses showed that the decaying phase of Na+ currents during a depolarizing pulse was significantly accelerated by all drugs, thus suggesting that these drugs also block the activated channel. The recovery time course for the use-dependent inhibition of Na+ currents was relatively slow, with time constants of 6.8 and 4.4 s for ethyl 4-diethylaminobenzoate and ethyl 4-ethoxybenzoate, respectively. We conclude that benzocaine and 4-hydroxybenzoate interact with the open and inactivated channels during repetitive pulses, but during the interpulse the complex dissociates too fast to accumulate sufficient use-dependent block of Na+ currents. In contrast, ethyl 4-diethylaminobenzoate and ethyl 4-ethoxybenzoate dissociate slowly from their binding site and consequently elicit significant use-dependent block. A common LA binding site suffices to explain the presence and absence of use-dependent block by benzocaine homologs during repetitive pulses.

N-Butyl Tetracaine as a Neurolytic Agent for Ultralong Sciatic Nerve Block

Background Neurolytic agents such as phenol (5% to 10%) and absolute alcohol have long been used clinically to destroy the pathogenic nerve regions that manifest pain. Both phenol and alcohol are highly destructive to nerve fibers. However, these agents exert only weak local anesthetic effects and therefore are difficult to administer to alert patients without pain. This report describes a tetracaine derivative that displays both local anesthetic and neurolytic properties. Studies with such a compound may lead to the design of neurolytic agents that are more effective and more easily administered than phenol and alcohol. Methods A tetracaine derivative, N-butyl tetracaine quaternary ammonium bromide, was synthesized, and its ability to elicit sciatic nerve block of sensory and motor functions in vivo was tested in rats. A single dose of 0.1 ml N-butyl tetracaine at 37 mM was injected into the sciatic notch. Transverse sections of treated sciatic nerves were subsequently examined to determine the neurolytic effect of this drug. Finally, the local anesthetic properties of N-butyl tetracaine were studied in vitro; both tonic inhibition and use-dependent inhibition of Sodium sup + currents in neuronal GH3 cells were characterized under whole-cell voltage-clamp conditions. Results N-butyl tetracaine at 37 mM (equivalent to 1.11% tetracaine-hydrochloric acid concentration) elicited prolonged sciatic nerve block of the withdrawal response to noxious pinch in rats for more than 2 weeks. The withdrawal response was fully restored after 9 weeks. Parallel to sensory block, motor functions of the hind legs were similarly blocked by this drug. Morphologic examinations 3 and 5 weeks after a single injection of drug revealed degeneration of many sciatic nerve fibers, consistent with the results of functional tests. Finally, N-butyl tetracaine was found to be a potent Sodium sup + channel blocker in vitro. It produced strong tonic and use-dependent inhibition of Sodium sup + currents with a potency comparable to that of tetracaine. Conclusions A single injection of N-butyl tetracaine produces ultralong sciatic nerve block in rats. This compound possesses both local anesthetic and neurolytic properties and may prove useful as a neurolytic agent in pain management.

Structure-activity relation of N-alkyl tetracaine derivatives as neurolytic agents for sciatic nerve lesions

Background N‐butyl tetracaine has local anesthetic and neurolytic properties. An injection of this drug at the rat sciatic notch produces rapid onset and nerve impairment lasting > 1 week. This study aimed to elucidate the structure‐activity relation of various tetracaine derivatives to design better neurolytic agents. Methods N‐alkyl tetracaine salts (n = 2–6) were synthesized, and their ability to elicit sciatic nerve impairment of sensory and motor functions in vivo was tested in rats. A single dose (0.1 ml at 37 mM) was administered close to the sciatic nerve at the sciatic notch. Regeneration was assessed morphologically in transverse sections of treated nerves. Finally, the drug potency in blocking Na sup + currents was studied under voltage‐clamp conditions. Results N‐ethyl and N‐propyl tetracaine derivatives were non‐neurolytic and elicited complete sciatic nerve block lasting 3–7 h. In contrast, N‐butyl, N‐pentyl, and N‐hexyl tetracaine derivatives were strong neurolytic agents and elicited functional impairment of sciatic nerve for > 1 week. All derivatives were strong Na sup + channel blockers, more potent than tetracaine if applied intracellularly. External drug application showed marked differences in their wash‐in rate: tetracaine > N‐hexyl > N‐butyl > N‐ethyl tetracaine. All derivatives were trapped within the cytoplasm and showed little washout within 7 min. Conclusions When n‐alkylation is 4–6, n‐alkyl tetracaine appeared as a strong neurolytic agent. Neurolytic derivatives retained their local anesthetic activity and elicited rapid onset of nerve block after injection. Such derivatives are potential local anesthetic‐neurolytic dual agents for chemical lesions of the sciatic nerve.