Verapamil increases the toxicity of local anesthetics

The calcium channel blocker verapamil has, in addition to its other properties, been shown to be a local anesthetic. Its concurrent use in a patient undergoing regional anesthesia may, therefore, increase the potential risk for local anesthetic toxicity. To evaluate this possibility, the effect of verapamil on the median lethal dose (LD50) of lidocaine and bupivacaine in mice was determined. Immediate pretreatment with verapamil increased the mortality of mice given the LD50 dose of lidocaine to 74%, and in mice given the LD50 doses of bupivacaine, to 82%. In animals pretreated with verapamil and calcium chloride, the mortality associated with the administration of LD50 doses of lidocaine and bupivacaine decreased to 43% and 48%, respectively, thus returning the mortality rate back to the LD50 of the local anesthetics when administered alone. It seems that the combined administration of local anesthetic and verapamil results in a significant drug interaction: the resulting blockade of sodium and calcium channels apparently impairs membrane function to a greater degree than with either drug alone. Additional investigation is warranted, and caution should be exercised in giving verapamil to patients during regional anesthesia. Should an adverse drug interaction ensue, the administration of calcium may be beneficial.     

Locomotor effects of cocaine, cocaine congeners, and local anesthetics in mice

Spontaneous locomotor activity of mice was stimulated by IP administration of cocaine and its closely related phenyltropane analogs. In contrast, locomotion was inhibited by IP administration of cocaine congeners such as norcocaine, (+)-pseudococaine, and tropacocaine, and of isomers of phenyltropane analogs. Also inhibitory were the local anesthetics procaine, tetracaine, benzocaine, lidocaine, and prilocaine. The locomotor inhibition induced by IP norcocaine or tetracaine could be reversed by subsequent treatment with cocaine. Both cocaine and norcocaine were centrally stimulatory when injected intracerebroventricularly. The rank order of potencies of cocaine congeners and local anesthetics in depressing locomotion was similar to that of their potencies in interacting with sodium channels. From these results we infer that the locomotor depression induced by systemic administration of cocaine congeners results from a local anesthetic action involving inhibition of the ion conductance of sodium channels.     

The effect of carticain on mammalian non-myelinated nerve fibres

A study has been made of the effect of carticain, a drug structurally related to lidocaine and prilocaine, on non-myelinated nerve fibres of the desheathed rabbit vagus. Carticain did not affect the membrane potential, the membrane resistance, or the sodium pump activity. Carticain decreased the amplitude and rise time of the action potential and decreased the conduction velocity of the nerve. This indicates, that carticain diminished sodium influx during the action potential. It is concluded that carticain produces a specific local anesthetic effect in non-myelinated nerve fibres of the rabbit vagus, which is comparable to the action of lidocaine.     

Local anesthetic inhibits hyperpolarization-activated cationic currents

Systemic administration of local anesthetics has beneficial perioperative properties and an anesthetic-sparing and antiarrhythmic effect, although the detailed mechanisms of these actions remain unclear. In the present study, we investigated the effects of a local anesthetic, lidocaine, on hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels that contribute to the pacemaker currents in rhythmically oscillating cells of the heart and brain. Voltage-clamp recordings were used to examine the properties of cloned HCN subunit currents expressed in Xenopus laevis oocytes and human embryonic kidney (HEK) 293 cells under control condition and lidocaine administration. Lidocaine inhibited HCN1, HCN2, HCN1-HCN2, and HCN4 channel currents at 100 μM in both oocytes and/or HEK 293 cells; it caused a decrease in both tonic and maximal current (～30-50% inhibition) and slowed current activation kinetics for all subunits. In addition, lidocaine evoked a hyperpolarizing shift in half-activation voltage (ΔV(1/2) of ～-10 to -14 mV), but only for HCN1 and HCN1-HCN2 channels. By fitting concentration-response data to logistic functions, we estimated half-maximal (EC(50)) concentrations of lidocaine of ～30 to 40 μM for the shift in V(1/2) observed with HCN1 and HCN1-HCN2; for inhibition of current amplitude, calculated EC(50) values were ～50 to 70 μM for HCN1, HCN2, and HCN1-HCN2 channels. A lidocaine metabolite, monoethylglycinexylidide (100 μM), had similar inhibitory actions on HCN channels. These results indicate that lidocaine potently inhibits HCN channel subunits in dose-dependent manner over a concentration range relevant for systemic application. The ability of local anesthetics to modulate I(h) in central neurons may contribute to central nervous system depression, whereas effects on I(f) in cardiac pacemaker cells may contribute to the antiarrhythmic and/or cardiovascular toxic action.     

Pharmacological studies on droxicainide, a new antiarrhythmic agent

The antiarrhythmic, local anesthetic and acute local and systemic toxic effects of DL-N-(2-hydroxyethyl)-pipecolinyl-2,6-dimethylanilide (AL-S-1249, droxicainide) and lidocaine were compared in animals. When given intravenously both substances suppressed ouabain-induced arrhythmias in pentobarbital-anesthetized guinea pigs; they were equipotent in this regard and had the same duration of antiarrhythmic action. Both substances produced generally equivalent sensory anesthesia following intradermal administration in the guinea pig and corneal application in the rabbit and block of motor and sensory function when injected near the sciatic nerve in the rat. In these local anesthetic tests and following intradermal administration to rabbits, droxicainide produced less local tissue irritation than lidocaine. When given intravenously to unanesthetized mice and unanesthetized and pentobarbital-anesthetized rats, the LD50's for droxicainide were consistently higher than those for lidocaine. Since droxicainide has antiarrhythmic and local anesthetic properties that are quantitatively similar to lidocaine but local and systemic toxicity that is relatively weaker, its antiarrhythmic and local anesthetic actions merit further study.     

Comparison of 1% and 2% lidocaine hydrochloride used as single local anesthetic: effect on postoperative pain course after oral soft tissue surgery.

It is known that some local anesthetics may cause pain when the initial local anesthetic effect disappears. The aim of this trial was to compare the postoperative pain intensities after infiltration of plain lidocaine 1% and 2% used in gingivectomies. The trial was done as a controlled, randomized, double-blind, parallel group study involving 117 patients with mean age 48 years (range 29-71 years) allocated to two treatment groups. There was no statistically significant difference between the mean postoperative pain courses of lidocaine 1% and 2% after gingivectomies during an 11-h observation period. A numerical difference was seen from 7 to 11 h in favor of lidocaine 1%. There were more patients experiencing no pain, but more patients reporting higher pain scores in the lidocaine 2% group than in the lidocaine 1% group. These differences were not statistically significant. It can be concluded that there is apparently no difference between lidocaine 1% and 2% with respect to postoperative pain experience when using gingivectomy as a pain model.     

Effect of mexiletine on spontaneous sensory afferent activity in spontaneous diabetic rats (WBN/Kob rats)

In this study, we investigated the hypothesis that mexiletine has an inhibitory action on spontaneous sensory afferent activity caused by small fiber neuropathy in diabetic rats (WBN/Kob rats). Gastric administrations of mexiletine (10 mg in 0.3 ml saline) and the local anesthetic agent lidocaine (10 mg in 0.3 ml saline) were made in urethane-anesthetized rats. In 6 of 7 WBN/Kob rats (57-62 weeks of age), spontaneous afferent activity was observed and was significantly inhibited after administration of mexiletine, whereas it was not seen in either WBN/Kob rats (54 weeks of age) or Wistar SLC rats (31 and 35 weeks of age). This inhibitory action of mexiletine was sustained for more than 2 h after the administration. In contrast, lidocaine administration also inhibited the spontaneous nerve activity, but the magnitude of the inhibitory action was less than that of mexiletine. In another experiment, the afferent conductance velocity of the sural nerve was not affected after mexiletine was administrated in the WBN/Kob rats (62 weeks of age). The results suggest that pain mitigation of a diabetic prescribed with mexiletine may depend on the inhibitory effect of mexiletine on the generation of the spontaneous afferent action potentials by mexiletine in aged WBN/Kob rats, whereas mexiletine has no effect on the autonomic function of the afferent nerve.     

Mexiletine has a local anesthetic effect on sciatic nerve blockade in rats

Mexiletine is an antiarrhythmic drug that has a Na⁺ channel blocking activity. The aim of the present study was to evaluate whether mexiletine had a local anesthetic effect as assessed by sciatic nerve blockade. Thus, the potency and duration of action of mexiletine on sciatic nerve blockade in terms of motor function and nociception were evaluated. Two local anesthetics, bupivacaine and lidocaine, were used as controls. Mexiletine produced a dose‐related local anesthetic effect on sciatic nerve blockade. The rank potency was bupivacaine >lidocaine >mexiletine (P<0.05 for each comparison). On an equi‐potent basis, the rank duration of action was bupivacaine>mexiletine>lidocaine (P<0.05 for each comparison). Co‐administration of mexiletine with bupivacaine produced an additive effect on sciatic nerve blockade. In conclusion, mexiletine had a local anesthetic effect on sciatic nerve blockades of motor function and nociception. Co‐administration of mexiletine with bupivacaine produced an additive effect on sciatic nerve blockade. Drug Dev. Res. 67:905–909, 2006. © 2007 Wiley‐Liss, Inc.     

A comparative study of the action of tolperisone on seven different voltage dependent sodium channel isoforms

The specific, acute interaction of tolperisone, an agent used as a muscle relaxant and for the treatment of chronic pain conditions, with the Na(v1.2), Na(v1.3), Na(v1.4), Na(v1.5), Na(v1.6), Na(v1.7), and Na(v1.8) isoforms of voltage dependent sodium channels was investigated and compared to that of lidocaine. Voltage dependent sodium channels were expressed in the Xenopus laevis oocyte expression system and sodium currents were recorded with the two electrode voltage clamp technique. Cumulative dose response relations revealed marked differences in IC(50) values between the two drugs on identical isoforms, as well as between isoforms. A detailed kinetic analysis uncovered that tolperisone as well as lidocaine exhibited their blocking action not only via state dependent association/dissociation with voltage dependent sodium channels, but a considerable fraction of inhibition is tonic, i.e. permanent and basic in nature. Voltage dependent activation was affected to a minor extent only. A shift in steady-state inactivation to more negative potentials could be observed for most drug/isoform combinations. The contribution of this shift to overall block was, however, small at drug concentrations resulting in considerable overall block. Recovery from inactivation was affected notably by both drugs. Lidocaine application led to a pronounced prolongation of the time constant of the fast recovery process for the Na(v1.3), Na(v1.5), and Na(v1.7) isoforms, indicating common structural properties in the local anesthetic receptor site of these three proteins. Interestingly, this characteristic drug action was not observed for tolperisone.     

Interaction of alfaxalone with the neuronal and the skeletal muscle sodium channel

The neurosteroid alfaxalone exerts potent anesthetic activity in humans and animals. In former studies on myelinated axons, alfaxalone was assumed to produce a local anesthetic-like effect on the peripheral nervous system. Therefore,the present in vitro study aimed to characterize possible modulatory actions of alfaxalone on voltage-gated sodium channels. -Subunits of voltage-gated neuronal (Nav1.2)and skeletal muscle (Nav1.4) sodium channels were stably expressed in human embryonic kidney cells, and in vitro effects of alfaxalone were compared with lidocaine by means of the patch clamp technique. Alfaxalone preferentially blocked slow inactivated channels and therefore could provide membrane-stabilizing effects in ischemic/hypoxic tissues where slow inactivation is regarded to play a crucial role.     

Stimulation of beta-adrenoceptors inhibits lordosis behavior in the female rat

Existing reports on the effects of beta-adrenergic antagonists on lordosis behavior appear contradictory, with (+/-) propranolol being reported to inhibit, and (+/-) pindolol to facilitate this behavior. In the present study, both the (-) and (+) optical isomers of propranolol were effective in inhibiting lordosis behavior in ovariectomized rats treated with estrogen and progesterone. This finding suggests that the lordosis-inhibiting effects of propranolol were not due to blockade of beta-adrenergic activity, but rather to the membrane stabilizing effect of the drug. An observed inhibition of lordosis following the peripheral administration of the local anesthetic lidocaine is consistent with this possibility. (+/-) Propranolol had no effect 30 min after peripheral administration in estrogen-treated, ovariectomized rats with low baseline levels of lordosis behavior. (+/-) and (-) pindolol, but not (+) pindolol also inhibited lordosis 30 min after administration. However, in addition to its antagonist effects, pindolol acts as a partial agonist in some tissues. Centrally active doses of the pure beta-antagonist (+/-) metoprolol produced no inhibitory effects. Indeed, metoprolol reversed the inhibitory effect of the beta-agonist (+/-) salbutamol. This suggests that the lordosis-inhibiting effects of pindolol were due to its partial agonist effects. Taken together, the present data indicate that activity at central beta-adrenoceptors inhibits rather than facilitates lordosis behavior.     

Identification of a potent, state-dependent inhibitor of Nav1.7 with oral efficacy in the formalin model of persistent pain

Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.     

Nisoxetine produces local but not systemic analgesia against cutaneous nociceptive stimuli in the rat

The aim of this study was to evaluate the local anesthetic effect of nisoxetine as infiltrative cutaneous analgesic. After rats were injected subcutaneously with nisoxetine, dose-response curves were constructed. The cutaneous anesthetic effect of nisoxetine or MK-801 (dizocilpine) was compared with lidocaine, a traditional local anesthetic. We found that nisoxetine and MK-801 acted like lidocaine and elicited dose-related cutaneous (local) anesthesia. The relative potency was nisoxetine>MK-801>lidocaine (P<0.01) as infiltrative anesthesia of skin. On an equianesthetic doses (20% effective dose [ED??], ED??, and ED??), nisoxetine produced longer action of cutaneous anesthesia than that of lidocaine or MK-801 (P<0.01). Coadministration of nisoxetine or lidocaine with MK-801 showed an additive cutaneous anesthesia. Neither local injection of a large dose of nisoxetine, MK-801 nor lidocaine in the thigh area produced cutaneous anesthesia (data not shown). In conclusion, nisoxetine had a local anesthetic effect as infiltrative cutaneous analgesia with durations of actions longer than that of lidocaine or MK-801. That N-methyl-d-aspartate receptors may not contribute to the cutaneous (local) anesthetic effect of nisoxetine or lidocaine.     

Effect of yohimbine on action potentials recorded from isolated canine ventricular myocytes

Yohimbine is used extensively as an alpha 2-adrenoceptor antagonist. This drug also inhibits sodium channels in the squid axon. In this study we investigated the electrophysiological effects of yohimbine in isolated canine ventricular myocytes. Yohimbine produced a reversible and concentration-dependent decrease in the maximum upstroke velocity and a slight increase in the action potential duration. The maximum upstroke velocity was reduced by over 90% by 10(-4) M yohimbine. It did not effect the resting or plateau potentials in control or isoproterenol-treated cells. Delayed after-depolarizations were also inhibited. These data suggest that yohimbine can produce a local anesthetic effect which is primarily due to inhibition of sodium channels.     

Evidence for a common site of action of lidocaine and carbamazepine in voltage-dependent sodium channels

The finding that the development of lidocaine-kindled seizures is blocked by carbamazepine suggests an interaction of carbamazepine with local anesthetic mechanisms. To study the site of interaction, the effects of lidocaine, carbamazepine and another anticonvulsant drug, phenytoin on scorpion venom-enhanced specific binding of [3H]batrachotoxinin A 20-alpha-benzoate to the sodium channel gating complex were examined in vitro in a rat brain hippocampus preparation. Lidocaine shifted the concentration inhibition curve of carbamazepine to the right and vice versa. Carbamazepine shifted the concentration inhibition curve of phenytoin to the right and vice versa. The experimentally determined apparent dissociation constants were in a good agreement with the dissociation constants calculated for a one-site model, suggesting that the interaction occurs because lidocaine shares a common binding site with carbamazepine and phenytoin in the voltage-dependent sodium channels.     

Altered metabolism of progesterone by hepatic microsomes from rats following dietary exposure to polybrominated biphenyls

The local anesthetic mepivacaine and various other drugs known to perturb sarcoplasmic calcium metabolism and/or sarcolemmal sodium conductance were injected into the gastrocnemius or subcutaneously over the gracilis muscles of rats. After 48 hr, the tissues were examined histologically, and muscle damage was rated on a single-blind basis. Following im administration, all of the agents tested which are capable of increasing the intracellular concentration of free calcium—mepivacaine-HCl, quinidine gluconate, A23187, caffeine, and 2,4-dinitrophenol-produced extensive and qualitatively similar myonecrosis. Damage to skeletal muscle was absent or negligible after im injection of control saline solutions or tetrodotoxin, a drug that blocks sodium channels without directly influencing the intracellular calcium distribution. The sc administration of mepivacaine caused extensive damage to fibers approximating the muscle surface, while saline was without effect. To assess the influence of a calcium antagonist on local anesthetic-induced myonecrosis, verapamil-HCl was administered sc, both alone and in combination with mepivacaine. Although verapamil by itself resulted in some minor surface injury, it almost completely blocked the damage produced by mepivacaine. It is concluded that the myotoxicity of local anesthetics is related to a disturbance of intracellular calcium homeostasis rather than to an influence on sarcolemmal sodium conduction.     

利多卡因凝胶经皮吸收的动力学和药效学

目的研究利多卡因凝胶的经皮吸收动力学以及药效学。方法用经皮微渗析的方法测定大鼠真皮内药物浓度的变化,计算相关参数;用电刺激法考察药效,并与市售EMLA(eutectic mixture of local anesthetics)霜剂进行药效比较。结果持续用药1 h,利多卡因经皮吸收动力学曲线在1.25 h达到峰值;起效时间与EMLA霜剂相近,局麻作用维持时间和局麻强度优于EMLA。结论利多卡因凝胶具有良好的局麻作用;局部用药后,利多卡因产生局部麻醉作用的真皮中最低有效浓度为12 mg·L^-1。     

Lidocaine: a foot in the door of the inner vestibule prevents ultra-slow inactivation of a voltage-gated sodium channel

After opening, Na(+) channels may enter several kinetically distinct inactivated states. Whereas fast inactivation occurs by occlusion of the inner channel pore by the fast inactivation gate, the mechanistic basis of slower inactivated states is much less clear. We have recently suggested that the inner pore of the voltage-gated Na(+) channel may be involved in the process of ultra-slow inactivation (I(US)). The local anesthetic drug lidocaine is known to bind to the inner vestibule of the channel and to interact with slow inactivated states. We therefore sought to explore the effect of lidocaine binding on I(US). rNa(V) 1.4 channels carrying the mutation K1237E in the selectivity filter were driven into I(US) by long depolarizing pulses (-20 mV, 300 s). After repolarization to -120 mV, 53 +/- 5% of the channels recovered with a very slow time constant (tau(rec) = 171 +/- 19 s), typical for recovery from I(US). After exposure to 300 microM lidocaine, the fraction of channels recovering from I(US) was reduced to 13 +/- 4% (P < 0.01, n = 6). An additional mutation in the binding site of lidocaine (K1237E + F1579A) substantially reduced the effect of lidocaine on I(US), indicating that lidocaine has to bind to the inner vestibule of the channel to modulate I(US). We propose that I(US) involves a closure of the inner vestibule of the channel. Lidocaine may interfere with this pore motion by acting as a "foot in the door" in the inner vestibule.     

Mutations in Cardiac Sodium Channels

Voltage-gated sodium channels (VGSCs) are critical transmembrane proteins responsible for the rapid action potential upstroke in most excitable cells. Recently discovered mutations in VGSCs, which underlie idiopathic clinical disease, have emphasized the importance of these channels in tissues such as skeletal muscle, nervous system, and myocardium. Mutations in the gene encoding the cardiac sodium channel isoform (SCN5A) have been linked to at least three abnormal phenotypes: variant 3 of the Long QT syndrome (LQT-3); Brugada's syndrome (BrS); and isolated cardiac conduction disease (ICCD). Mutations in SCN5A manifest as one or more of these clinical phenotypes - the precise distinction between these diseases is increasingly subtle. Clinical management of LQT-3 and diagnosis of BrS with the local anesthetic flecainide has proven promising. Channels associated with LQT-3 (D1790G) and BrS (Y1795H) both show more sensitivity to flecainide than wild-type (WT) channels, while lidocaine sensitivity is unchanged. One plausible explanation for differential drug sensitivity is that mutant channels may allow more access to a receptor site compared with WT through altered protein allosteric changes during an action potential. The high affinity binding site for local anesthetic block has been identified in the pore region of the channel. This region is not water accessible during the closed state, thus requiring channel opening for charged drug (flecainide and mexiletine) access and block. Channel mutations which disrupt inactivation biophysics lead to increased drug binding by altering the time the binding site is accessible during an action potential. Neutral drugs (lidocaine) which are not dependent on channel opening for binding site access will not be sensitive to mutations that alter channel inactivation properties. Interestingly another LQT-3 mutant (Y1795C) shows no change in flecainide sensitivity, suggesting that although drug effects of SCN5A mutations cross disease boundaries, clinical management with flecainide will be beneficial to patients in a mutation-specific manner.     

Differential modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by the local anesthetic lidocaine

1 Voltage-gated Na+ channels are transmembrane proteins that are essential for the propagation of action potentials in excitable cells. Nav1.7 and Nav1.8 dorsal root ganglion Na+ channels exhibit different kinetics and sensitivities to tetrodotoxin (TTX). We investigated the properties of both channels in the presence of lidocaine, a local anesthetic (LA) and class I anti-arrhythmic drug. 2 Nav1.7 and Nav1.8 Na+ channels were coexpressed with the beta1-subunit in Xenopus oocytes. Na+ currents were recorded using the two-microelectrode voltage-clamp technique. 3 Dose-response curves for both channels had different EC50 (dose producing 50% maximum current inhibition) (450 microm for Nav1.7 and 104 microm for Nav1.8). Lidocaine enhanced current decrease in a frequency-dependent manner. Steady-state inactivation of both channels was also affected by lidocaine, Nav1.7 being the most sensitive. Only the steady-state activation of Nav1.8 was affected while the entry of both channels into slow inactivation was affected by lidocaine, Nav1.8 being affected to a larger degree. 4 Although the channels share homology at DIV S6, the LA binding site, they differ in their sensitivity to lidocaine. Recent studies suggest that other residues on DI and DII known to influence lidocaine binding may explain the differences in affinities between Nav1.7 and Nav1.8 Na+ channels. 5 Understanding the properties of these channels and their pharmacology is of critical importance to developing drugs and finding effective therapies to treat chronic pain.