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PubMed1986

Clonidine prolongs canine tetracaine spinal anaesthesia.

Using a randomized blind cross-over design, the comparative efficacy of clonidine in prolonging tetracaine spinal anaesthesia was studied in six mongrel dogs. Lumbar subarachnoid injections (1 ml) of: tetracaine 4 mg with clonidine 150 micrograms, tetracaine 4 mg with epinephrine 200 micrograms, tetracaine 4 mg, clonidine 150 micrograms, epinephrine 200 micrograms, and five per cent dextrose in H2O (vehicle) were administered randomly to each animal at 5-7 day intervals. Subarachnoid tetracaine produced a motor blockade of 186 +/- 58 (mean +/- SEM) min. Both clonidine and epinephrine produced a similar prolongation of tetracaine motor blockade, 135 per cent (p less than 0.01) and 116 per cent (p less than 0.05) respectively, compared with tetracaine alone. No motor blockade was observed in dogs receiving clonidine, epinephrine or five per cent dextrose in H2O. The addition of clonidine to tetracaine spinal anaesthesia produced a significant increase in duration of sensory blockade, 56 per cent (p less than 0.01) and 107 per cent (p less than 0.01) respectively, when compared to tetracaine with and without epinephrine. Subarachnoid clonidine alone produced a sensory blockade of 76 +/- 17 minutes, while only one animal receiving subarachnoid epinephrine had a sensory blockade (40 minutes). No neurologic deficits were observed in any of the animals. The study concludes that during spinal anaesthesia with tetracaine in dogs, clonidine is as effective as epinephrine in prolonging motor blockade, but is more effective in prolonging sensory blockade.

Anesthesia, Spinal↗
PubMed1983

Tetracaine modifies the fragmentation mode of heated human erythrocytes and can induce heated cell fusion.

It is known that human erythrocytes in saline fragment by development of an unstable surface wave on the cell rim when cells are heated through the denaturation temperature of the structural protein, spectrin. Here the influence of tetracaine on the fragmentation process has been recorded and analysed by video microscopy of cells heated in rectangular glass microcapillaries. The number of waves per cell rim decreases with increasing tetracaine concentration until, at 0.5 mM tetracaine, wave growth on the cell rim is suppressed on most cells and the cells internalize membrane at the cell dimple. The rate constant for the change in the number of waves per cell with increasing tetracaine concentration is 9.6 mM-1 at a heating rate of 0.5 K/s. 50% of heated cells internalize membrane at 0.14 mM tetracaine. When cells are heated rapidly in suspension in test tubes the presence of tetracaine reduces the temperature for 50% haemolysis from 66 degrees C for washed control cells to 60.5 degrees C for cells in 2 mMs tetracaine. Cells heat in microcapillaries in tetracaine concentrations of 3 mM and higher begin to swell before the spectrin denaturation temperature is reached. Cell fusion was observed at and above the spectrin denaturation temperature in cells heated in 3 and 4 mM tetracaine. It was also noted that the morphology of erythrocytes maintained in 3.6 mM tetracaine for times up to 30 min at 37 degrees C or 20 degrees C was strongly dependent on temperature and time.

Cell Fusion↗
PubMed1994

Charged tetracaine as an inactivation enhancer in batrachotoxin-modified Na+ channels.

Two distinct types of local anesthetics (LAs) have previously been found to block batrachotoxin (BTX)-modified Na+ channels: type 1 LAs such as cocaine and bupivacaine interact preferentially with open channels, whereas type 2 LAs, such as benzocaine and tricaine, with inactivated channels. Herein, we describe our studies of a third type of LA, represented by tetracaine as a dual blocker that binds strongly with closed channels but also binds to a lesser extent with open channels when the membrane is depolarized. Enhanced inactivation of BTX-modified Na+ channels by tetracaine was determined by steady-state inactivation measurement and by the dose-response curve. The 50% inhibitory concentration (IC50) was estimated to be 5.2 microM at -70 mV, where steady-state inactivation was maximal, with a Hill coefficient of 0.98 suggesting that one tetracaine molecule binds with one inactivated channel. Tetracaine also interacted efficiently with Na+ channels when the membrane was depolarized; the IC50 was estimated to be 39.5 microM at +50 mV with a Hill coefficient of 0.94. Unexpectedly, charged tetracaine was found to be the primary active form in the blocking of inactivated channels. In addition, external Na+ ions appeared to antagonize the tetracaine block of inactivated channels. Consistent with these results, N-butyl tetracaine quaternary ammonium, a permanently charged tetracaine derivative, remained a strong inactivation enhancer. Another derivative of tetracaine, 2-(di-methylamino) ethyl benzoate, which lacked a 4-butylamino functional group on the phenyl ring, elicited block that was approximately 100-fold weaker than that of tetracaine. We surmise that 1) the binding site for inactivation enhancers is within the Na+ permeation pathway, 2) external Na+ ions antagonize the block of inactivation enhancers by electrostatic repulsion, 3) the 4-butylamino functional group on the phenyl ring is critical for block and for the enhancement of inactivation, and 4) there are probably overlapping binding sites for both inactivation enhancers and open-channel blockers within the Na+ pore.

Animals↗
PubMed2001

The addition of epinephrine to tetracaine injected intrathecally sustains an increase in glutamate concentrations in the cerebrospinal fluid and worsens neuronal injury.

UNLABELLED: We have reported that large concentrations of intrathecal tetracaine increase glutamate concentrations in the cerebrospinal fluid (CSF) and cause neuronal injury in the spinal cord. In this study, we investigated whether the addition of epinephrine to tetracaine modulates these events. New Zealand white rabbits were assigned into five groups (six rabbits in each group) and intrathecally received 0.3 mL of epinephrine 0.1 mg/mL in NaCl solution (control), 1% tetracaine dissolved in saline (1%T), 1% tetracaine with epinephrine (1%TE), 2% tetracaine (2%T), or 2% tetracaine with epinephrine (2%TE). Glutamate concentrations in the lumbar CSF were monitored by microdialysis. Neurologic and histopathologic assessments were performed 1 wk after the administration. Glutamate concentrations significantly increased in all four groups that received tetracaine, whereas no change was observed in the Control group. The addition of epinephrine to tetracaine sustained large concentrations of glutamate. Sensory and motor dysfunction was observed in the 1%TE, 2%T, and 2%TE groups, and the dysfunction tended to be progressively exacerbated in this order. Characteristic histologic changes in animals with sensory and motor dysfunction were vacuolation in the dorsal funiculus and chromatolytic damage of motor neurons. The vacuolation of the dorsal funiculus in the 1%TE group was significantly worse than in the 1%T group. These results suggest that the addition of epinephrine to tetracaine may increase its neurotoxicity, which may possibly be related to a sustained increase of glutamate concentrations in the CSF. IMPLICATIONS: Sustained increase of glutamate concentrations produced by the addition of epinephrine to intrathecal tetracaine can cause neuronal injury.

Anesthetics, Local↗
PubMed1996

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 Na+ 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 Na+ channel blocker in vitro. It produced strong tonic and use-dependent inhibition of Na+ 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.

Anesthetics, Local↗
PubMed1998

The effect of tetracaine on stimulated contractions, sarcoplasmic reticulum Ca2+ content and membrane current in isolated rat ventricular myocytes.

1. The effects of tetracaine were examined on rat ventricular myocytes. In both field-stimulated and voltage-clamped cells tetracaine (100-200 microM) produced an initial decrease of contraction before a recovery towards the control level. Removal of tetracaine produced a transient overshoot of contraction to levels greater than the control. 2. The transient decrease of contraction produced by tetracaine was accompanied by a small transient increase in the integral of the L-type Ca2+ current and a larger transient decrease of the Na+-Ca2+ exchange current on repolarization. These are attributed to decreased systolic release of Ca2+. On removal of tetracaine there was an increase of the Na+-Ca2+ exchange current. Before the addition of tetracaine, calculated Ca2+ influx and efflux across the sarcolemma were approximately equal. On adding tetracaine, efflux was transiently less than influx and, on removal of tetracaine, efflux was greater than influx. 3. These changes in Ca2+ fluxes result in an increase of cell Ca2+ during exposure to tetracaine. The calculated magnitude of this increase was equal to that measured directly by applying caffeine (20 mM) to release sarcoplasmic reticulum (SR) Ca2+ and integrating the resulting Na+-Ca2+ exchange current. 4. It is concluded that the effects of tetracaine can be accounted for by depression of calcium-induced Ca2+ release (CICR). The response is transient because the inhibition is compensated for by an increase of SR Ca2+ content such that there is no steady-state effect on the magnitude of the systolic Ca2+ transient. The consequences of this result for the effects of other modulators of CICR are discussed.

Animals↗
PubMed1975

Comparative study of the effects of propranolol and tetracaine on cation movements in resealed human red cell ghosts.

1. The effects of two positively charged local anaesthetic amines, tetracaine and propranolol, on cation permeability were studied in resealed human red cell ghosts prepared from metabolically depleted erythrocytes. 2. The K permeability was reduced by tetracaine but increased by propranolol. The effect of tetracaine was independent of extracellular Ca concentration but was raised to 2-5 x 10(-7) M. The effect of propranolol, which was enhanced when the external Ca concentration was raised, could be completely inhibited by lowering the internal free Ca to less than 10(-7) M. 3. Propranolol, but not tetracaine, increased the intracellular Ca ion concentration by releasing up to 20% of the membrane-bound Ca to the cell interior. This increase in intracellular Ca was sufficient to mediate the observed change in K permeability. 4. Tetracaine and propranolol reduced the Ca binding capacity of the ghost membrane by about 20 and 40% respectively. The Ca permeability was increased by propranolol and was slightly reduced by tetracaine. 5. In high concentrations (2-7 mM) propranolol by itself moderately increased K and Na permeability, but supressed completely the Ca-induced increase in K permeability. Tetracaine in concentrations up to 4 mM enhanced the Ca-induced increase in K permeability. Higher concentrations of the drug caused lysis of the cells. 6. Maximally effective concentrations of tetracaine and propranolol inhibited the ATP-dependent Ca outward transport by 30 and 70% respectively. 7. The effects of tetracaine on K permeability were shared by the local anaesthetics prilocaine and lidocaine, those of propranolol were shared by practolol, a beta-adrenergic antagonist and tetraethylammonium, a ganglionic blocking agent. 8. It is suggested that the differences in the effects of tetracaine and propranolol on cation permeability reflect qualitatively different interactions of the two drugs with Ca binding sites on the inner surface of the membrane.

Adenosine Triphosphate↗
PubMed1986

Spin label study of local anesthetic-lipid membrane interactions. Phase separation of the uncharged form and bilayer micellization by the charged form of tetracaine.

The interaction between tetracaine and egg phosphatidylcholine (egg PC) multibilayers was examined. ESR spectra of an ester spin label indicate that at low uncharged anesthetic: lipid ratios, membrane organization decreases. At higher ratios, saturation and phase separation occur, as suggested by a second spectral component which appears when the water solubility of tetracaine is reached. However, experiments with the drug in the absence and in the presence of membranes, making use of a phospholipid spin label, suggest that the new phase does not consist of solid tetracaine alone. Location of the new phase in the membrane would require a change in partition coefficient, while its location outside would imply a mechanism whereby the anesthetic would come off the membrane as an aggregate containing spin probe and phospholipid. Charged tetracaine forms micelles which disrupt-unilamellar egg PC vesicles (Fernandez, M.S. (1981) Biochim. Biophys. Acta 646, 27-30). Micellar tetracaine added to bilayers containing a PC spin probe changes the spectrum from one typical of a bilayer into one typical of micelles, indicating the formation of a tetracaine-egg PC mixed micelle. The effect is reversible upon dilution to concentrations below the critical micelle concentration of tetracaine. When membranes are prepared in the presence of a water-soluble spin label, TEMPOcholine, ascorbate destroys the signal of untrapped label; when mixed phospholipid-tetracaine are formed by addition of micellar tetracaine, this leads to a complete loss of the ESR signal. High drug concentrations are often used for anesthesia and could be related to morphological nerve damage caused by large doses of anesthetics.

Anesthetics, Local↗
PubMed1987

Binding sites for [3H]tetracaine in synaptosomal sodium channel preparations from mouse brain.

The present study was an attempt to answer the question whether the local anesthetic [3H]tetracaine labels sodium channels in mouse brain synaptosomes. Binding of [3H]tetracaine had a Kd of 0.19 microM and a Bmax ranging from 3.7 to 5.2 pmol/mg of protein. Local anesthetics other than tetracaine and cocaine-related compounds inhibited [3H]tetracaine binding with Hill numbers between 0.3 and 0.6. Initiation of the dissociation of [3H]tetracaine binding by an excess of unlabeled tetracaine resulted in non-linear curves. These results are consonant with site heterogeneity, negative cooperativity, or complexities arising from the use of synaptosomal preparations instead of broken membranes. There were important differences between the absolute values of the potency of various local anesthetic drugs and cocaine-related compounds in inhibiting binding of [3H]tetracaine and those in inhibiting binding of [3H]batrachotoxinin A 20-alpha-benzoate. Although there were some effects of manipulating the state of the channel with activating toxins on the apparent rate of association and dissociation of [3H]tetracaine binding, the equilibrium binding was not much affected by the toxins. The results indicate that further characterization is necessary before accepting [3H]tetracaine binding as a valid tool for studying sodium channels.

Anesthetics, Local↗
PubMed2004

A Raman spectroscopic investigation of bioadhesive tetracaine local anaesthetic formulations.

Raman spectroscopy at 785 nm has been employed to characterise the properties of tetracaine in bioadhesive gel and patch formulations. In the first study, interactions between the drug and excipients in novel bioadhesive patch systems were characterised. It was determined that the drug did not interact with any of its formulation components, and that this was an important factor in its clinical performance, particularly the rapid onset of anaesthesia. Investigations of drug uptake in the stratum corneum from a gel formulation suggested that tetracaine rapidly undergoes a phase-change upon application to the skin. The intensity of the tetracaine Raman bands at approximately 1600 cm(-1) suggests that the local anaesthetic is rapidly absorbed into the skin. Decreases in Raman tetracaine band intensities, along with an absence in the concomitant alteration in the internal standard spectra, indicates an decrease in the tetracaine concentration present in the gel. Further, a baseline indicating complete tetracaine absorption appears to be reached after approximately 40 min of exposure. After this time little further absorption was observed, suggesting that the stratum corneum "reservoir" was saturated with tetracaine at this time. This is consistent with the optimum application time required for tetracaine gels to attain maximum clinical efficacy. This study has indicated the effectiveness of Raman spectroscopy in the analysis of gel-based pharmaceutical preparations, showing it to be a simple, rapid, virtually non-invasive technique for determination of tetracaine.

Adhesives↗
PubMedDate not supplied

Simultaneous determination of mepivacaine, tetracaine, and p-butylaminobenzoic acid by high-performance liquid chromatography.

INTRODUCTION: The purpose of the present study was to develop a simple method for the simultaneous determination of mepivacaine, tetracaine, and p-butylaminobenzoic acid (BABA) in human plasma using high-performance liquid chromatography (HPLC) with a multiwavelength detector. METHODS: Human blood samples containing heparin, as an anticoagulant, and physostigmine (100 microg/ml), as an anticholinesterase, or human plasma containing physostigmine were spiked with various concentrations of mepivacaine, tetracaine and, in some cases, BABA. Blood samples were centrifuged and plasma was deproteinized with trifluoroacetic acid (TFA; 7%). After centrifugation, the pH was adjusted to 4.5 and an aliquot of 20, 50 or 100 microl was injected into the HPLC apparatus. The detection was done simultaneously at wavelengths of 214 and 300 nm. Analytical chromatography was done on a Waters microBondapak C(18) reverse-phase column (3.9 x 300 mm; particle size 10 microm) with a 30-min increasing linear gradient of 20-40% acetonitrile+0.05% TFA in H(2)O+0.05% TFA at a flow rate of 1 ml/min. The Waters HPLC system included two pumps, an automatic injector, a column oven, and a M490 multiwavelength detector. Quantification was done using integration of peak areas with peaks of authentic mepivacaine, tetracaine, and BABA standards. RESULTS: Calibration curves for standards of mepivacaine, tetracaine, and BABA were linear in the concentration ranges from 0.1 to 100 microg/ml, and the correlation coefficients exceeded.99 for all compounds. The lower limits of detection were 100 ng/ml for mepivacaine and 50 ng/ml for tetracaine and BABA. The yields for mepivacaine, tetracaine, and BABA were 91+/-2.1%, 82+/-3.3%, and 88+/-2.0% (mean+/-S.E.M., n=6), respectively. Degradation of tetracaine by human plasma at 37 degrees C was inhibited by physostigmine. DISCUSSION: The method is sensitive enough to allow blood concentration determinations of mepivacaine and tetracaine or its metabolite, BABA, following local anesthesia induced by these two drugs, especially when their toxic effect may be present. This method also may be useful in forensic medicine for determination of the cause of death after local anesthesia with mepivacaine and/or tetracaine.

4-Aminobenzoic Acid↗
PubMed2003

Effects of tetracaine and bupivacaine on chemiluminescence generated by formyl-methionyl-leucyl-phenylalanine-stimulated human leukocytes and cell-free systems.

We investigated the abilities of an ester-type local anesthetic tetracaine and an amide-type local anesthetic bupivacaine to inhibit reactive oxygen and/or nitrogen species generated by either human leukocytes or cell-free systems via luminol- and lucigenin-enhanced chemiluminescence (CL). Tetracaine (96+/-1%, n=6, 1 mM) and bupivacaine (97+/-0.4%, n=5, 1 mM) significantly inhibited FMLP-induced-CL in leukocyte assay. In cell-free experiments, CL due to superoxide production was significantly inhibited by tetracaine (23+/-2%, n=6) and bupivacaine (25+/-4%, n=6) at 1 mM. Although bupivacaine was ineffective on H(2)O(2)-induced CL, tetracaine activated H(2)O(2)-induced luminol CL. Additionally, tetracaine inhibited FeSO(4)-induced CL (42+/-2%, n=6, 1 mM). In hypochlorous acid (HOCl)-induced CL assay, 70+/-10% (n=5) and 57+/-4% (n=15) inhibitions were observed by tetracaine and bupivacaine, respectively. Peroxynitrite-induced luminol (54+/-7%, n=7, tetracaine, and 26+/-5%, n=8, bupivacaine, at 1 mM) and lucigenin CL (58+/-3%, n=6, tetracaine, and 22+/-14%, n=9, bupivacaine, at 1 mM) were markedly inhibited. Tetracaine interacted with superoxide, hydroxyl radical, HOCl and peroxynitrite, while bupivacaine scavenged superoxide, HOCl and peroxynitrite. These direct scavenging properties of these drugs might be involved in the inhibition observed in leukocyte free radical release. In general, a decrease in CL-response was seen with higher concentrations (0.1-1 mM) of the local anesthetics, it is likely that tetracine and bupivacaine at therapeutic concentrations do not suppress leukocyte function in vivo.

Acridines↗
PubMed2000

Sensitive and selective determination of tetracaine and its metabolite in human samples by gas chromatography-mass spectrometry.

A sensitive and reliable method was developed for the determination of tetracaine and its metabolite, p-butylaminobenzoic acid, in human samples. Tetracaine and the metabolite, effectively extracted using a liquid-liquid extraction procedure from 0.5 g of sample, were analyzed by gas chromatography-mass spectrometry. Tetracaine was analyzed without derivatization, and the metabolite was analyzed after tert-butylolimethylsilyl derivatization. Dibucaine and p-dimethylaminobenzoic acid were used as internal standards for tetracaine and the metabolite, respectively. The calibration curve for each compound was linear in the concentration range from 10 to 1,000 ng/0.5 g, and the lower limits of detection were 10 ng/g for tetracaine and 0.6 ng/g for the metabolite in whole blood and tissues. The accuracy and precision of the method were evaluated in whole blood and brain at the concentrations of 50 ng/0.5 g and 500 ng/0.5 g for tetracaine and 10 ng/0.5 g and 100 ng/0.5 g for the metabolite. The coefficients of variation ranged from 0.8 to 3.0% for tetracaine and 2.4 to 9.8% for the metabolite. We used this method to determine tetracaine and its metabolite in human whole blood and tissues of an autopsied patient who died during spinal anesthesia induced by tetracaine.

4-Aminobenzoic Acid↗
PubMed1989

Epinephrine increases the effectiveness of tetracaine spinal anesthesia.

The effect of epinephrine on the need for supplementation of spinal anesthesia produced with hyperbaric tetracaine was assessed in 60 patients undergoing transurethral resection of the prostate. Patients were randomly assigned to receive either 6 mg tetracaine alone (n = 20), 6 mg tetracaine with 0.2 mg epinephrine (n = 20), 10 mg tetracaine alone (n = 10), or 10 mg tetracaine with 0.2 mg epinephrine (n = 10). Observers were blinded to the presence or absence of epinephrine. Sensory level of anesthesia was assessed by pin prick, and surgery did not start until the level reached T10. Anesthesia was considered successful if the patient had no pain at the operative site. The success rate of low-dose tetracaine (6 mg) with epinephrine was 95% compared with 65% in patients receiving low-dose tetracaine alone (P = 0.04). All patients receiving 10 mg had successful anesthesia. Compared with patients receiving 6 mg tetracaine, those given 10 mg had higher dermatomal levels of anesthesia (P = 0.0001) and a higher incidence of nausea (P = 0.04). Thus, epinephrine can increase the effectiveness of low-dose tetracaine.

Aged↗
PubMed1998

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+ 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+ 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.

Anesthetics, Local↗
PubMed1997

The effect of tetracaine on spontaneous Ca2+ release and sarcoplasmic reticulum calcium content in rat ventricular myocytes.

1. The effects of tetracaine were studied on voltage-clamped rat ventricular myocytes, which exhibited Ca2+ overload as identified by spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) as shown by the associated contractions. This Ca2+ release was initially abolished by tetracaine before returning at a lower frequency, but greater amplitude, than the control. On removal of tetracaine, there was a burst of spontaneous Ca2+ release activity. All these effects were dose dependent, from 25 to 200 microM tetracaine. 2. The spontaneous Ca2+ release activated an inward Na(+)-Ca2+ exchange current as Ca2+ was pumped out of the cell. The integral of this current (i.e. the Ca2+ efflux) was increased in the presence of tetracaine. The calcium efflux per unit time was unaffected by tetracaine. 3. The SR Ca2+ content was increased by tetracaine, as shown by the integral of the caffeine-evoked Na(+)-Ca2+ exchange current. The increase of SR Ca2+ content was equal to the extra Ca2+ lost from the cell during the burst on removal of tetracaine, and to estimates of the extra calcium gained over the quiescent period following addition of tetracaine. 4. It is concluded that partial inhibition of calcium-induced calcium release increases SR Ca2+ content. In the steady state, cell Ca2+ balance is maintained as the lower frequency of spontaneous release (that activates efflux) is compensated for by their greater size.

Anesthetics, Local↗
PubMed1997

Dual effects of tetracaine on spontaneous calcium release in rat ventricular myocytes.

1. Confocal microfluorometry was used to study the effects of tetracaine on spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) in isolated rat ventricular myocytes. 2. At low concentrations (0.25-1.25 mM), tetracaine caused an initial inhibition of spontaneous release events (Ca2+ sparks) and Ca2+ waves, which was followed by a gradual increase in Ca2+ release activity. The frequency and magnitude of sparks were first decreased and then increased with respect to control levels. At high concentrations (> 1.25 mM), tetracaine abolished all forms of spontaneous release. 3. Exposure of the myocytes to tetracaine resulted in a gradual increase in the SR Ca2+ load as indexed by changes in the magnitude of caffeine-induced Ca2+ transients. 4. In cardiac SR Ca(2+)-release channels incorporated into lipid bilayers, tetracaine (> 0.25 mM) induced a steady inhibition of channel activity. Addition of millimolar Ca2+ to the luminal side of the channel caused an increase in channel open probability under control conditions as well as in the presence of various concentrations of tetracaine. 5. We conclude that the primary effect of tetracaine on SR Ca(2+)-release channels is inhibition of channel activity both in vitro and in situ. The ability of tetracaine to reduce spark magnitude suggests that these events are not due to activation of single channels or non-reducible clusters of channels and, therefore, supports the multichannel origin of sparks. We propose that the paradoxical late potentiation of release by submaximal concentrations of tetracaine is caused by a gradual increase in SR Ca2+ load and subsequent activation of the Ca(2+)-release channels by Ca2+ inside the SR.

Anesthetics, Local↗
PubMed1994

Comparative toxicity of tetracaine, proparacaine and cocaine evaluated with primary cultures of rabbit corneal epithelial cells.

Cocaine was first used as a topical anesthetic for the eye by Dr Carl Koller in 1884. It became evident that this agent produced erosion of the corneal epithelium in high doses or with repeated use. Synthetic local anesthetics such as tetracaine and proparacaine were developed which were more potent and less toxic than cocaine, but still produced corneal epithelium defects if used chronically. This investigation was undertaken to compare and rank the cytotoxicity of the most commonly used ocular local anesthetics, tetracaine, proparacaine and cocaine, with primary cultures of rabbit corneal epithelial cells. Cultures were exposed to either low concentrations of local anesthetics for 4-24 hr or to higher concentrations of local anesthetics for 15-120 min. Plasma membrane integrity was evaluated by measuring leakage of the cytosolic enzyme, lactate dehydrogenase, into the medium. Cell shape changes were evaluated by observing morphological changes. Mitochondrial dehydrogenase activity and cell viability were assessed by measuring 3-(4,5-dimethythiazol-2yl)-2,5-diphenyl tetrazolium bromide reduction. The cytotoxicity of the local anesthetics as evaluated by the lactate dehydrogenase leakage cytotoxicity test was ranked as follows: tetracaine (EC50 = 0.96 mM) >> proparacaine (EC50 = 4.4 mM) > cocaine (EC50 = 9.7 mM). The mitochondrial reduction assay seemed to be more sensitive than the lactate dehydrogenase leakage test in predicting toxicity: tetracaine (EC50 = 0.81 mM) >> proparacaine (EC50 = 3.4 mM) > cocaine (EC50 = 7.1 mM). When corneal epithelial cells were treated with local anesthetics, marked morphological changes occurred at concentrations that did not cause a decrease in viability. This was especially true for cocaine-treated cells. Tetracaine and proparacaine have the same anesthetic potency in vivo, although tetracaine is considered to be more irritating than proparacaine. This in vitro study showed that tetracaine was approximately four times more toxic than proparacaine. Cocaine was less toxic in vitro than proparacaine and tetracaine when compared on an equimolar basis, but in vivo it may be more toxic because of the higher concentrations that must be used to obtain the same degree of anesthesia as well as its marked effects on cell morphology.

Anesthetics, Local↗