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PubMed1985

Comparison of the vasoactivity of amide and ester local anaesthetics. An intradermal study.

The vascular effects and duration of action of two ester-linked local anaesthetics, procaine and amethocaine, and four amide-linked local anaesthetics, cinchocaine, lignocaine, mepivacaine and prilocaine, were investigated in 10 volunteers by intradermal injection using a double-blind technique. Procaine and amethocaine produced marked vasodilatation; weal formation was observed at 80% of the amethocaine injection sites. Mepivacaine had a marked vasoconstrictor effect; the other three agents produced more variable vasoactivity. Duration of action was concentration-dependent for all six drugs, the slopes of the log dose--duration plots reflecting the observed vasoactivity.

Adult↗
PubMed1995

In vitro and in vivo effects of cocaine and selected local anesthetics on the dopamine transporter.

The effects of selected local anesthetics on in vitro and in vivo measurements of dopamine transporter activity were determined to investigate the role of local anesthetic activity in the neuronal actions of cocaine. Cocaine inhibited [3H]2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1.5-naphthalenedisulfonate (CFT) binding and [3H]dopamine uptake with estimated Ki and IC50 values of 0.6 microM and 0.7 micorM, respectively. Of the local anesthetics tested, only dimethocaine showed full displacement of CFT binding (0-30 microM tested) and full inhibition of dopamine uptake (0-100 microM tested). Dimethocaine was only slightly less potent than cocaine with an estimated Ki of 1.4 micorM and an IC50 value of 1.2 microM for [3H]CFT binding and dopamine uptake. At a maximum concentration of 100 microM, the ester containing local anesthetics procaine, tetracaine, piperocaine and the amide containing local anesthetic dibucaine and bupivacaine partially inhibited dopamine uptake by 47-70%. The ester containing local anesthetic propoxycaine and the amide containing local anesthetics prilocaine, etidocaine, procainamide, and lidocaine inhibited dopamine uptake by 8-30% at 100 microM. A 10 min administration of cocaine, dimethocaine, or procaine in the dialysis solution produced dose-dependent, reversible increases in endogenous dopamine efflux from the striata of awake rats. Cocaine and dimethocaine produced similar 12-fold increases in dialysate dopamine at concentrations of 0.1 mM and 1 mM respectively. Procaine (10 mM) produced a 6-fold increase in dialysate dopamine while lidocaine (1 mM) produced a reproducible and reversible decrease (30%). These results show that the cocaine-like actions of certain local anesthetics such as dimethocaine and procaine result from their direct actions of dopamine uptake inhibitors.

Aminobenzoates↗
PubMed2001

Interaction of local anaesthetic agents with the endogenous norepinephrine transporter in SH-SY5Y human neuroblastoma cells.

Use of intravenous guanethidine for the treatment of complex regional pain syndrome type I is of variable efficacy. Guanethidine injection is painful, so local anaesthetic is co-administered. We hypothesize that local anaesthetic inhibits uptake of guanethidine and hence reduces its efficacy. In this study we have examined the effects of a range of local anaesthetic agents on the uptake of [3H]norepinephrine ([3H]NE) (as a surrogate for guanethidine) and the binding of [3H]nisoxetine to the NE transporter in cultured SH-SY5Y human neuroblastoma cells. All local anaesthetic agents inhibited NE uptake with a rank order cocaine>tetracaine>procaine(esters), dibucaine > bupivacaine > prilocaine > lidocaine (amides). In addition all anaesthetic agents displaced [3H]nisoxetine with a rank order cocaine > tetracaine > dibucaine > procaine > prilocaine > bupivacaine > lidocaine. There was a positive correlation between [3H]NE uptake and [3H]nisoxetine binding. Our data suggest that when local anaesthetic and guanethidine are co-administered the former may reduce uptake of the latter and hence reduce the clinical efficacy of guanethidine.

Anesthetics, Local↗
PubMed1997

Effects of aging on nerve conduction block induced by bupivacaine and procaine in rats.

To test the hypothesis that the dose requirement for local anesthetics is changed in aged animals, the effects of two different local anesthetics on nerve conduction block were tested in young and old rats. Young (6 months) and old (27 months) male Fisher-344 rats were anesthetized with intraperitoneal pentobarbital and diazepam. Stimulating electrodes were placed in the sciatic notch and in the ankle and recording electrodes were placed distally in the ipsilateral foot to record evoked electrical activity of the interosseous muscles. Motor nerve conduction velocity was significantly less in old (48.8 +/- 3.9, mean +/- SD m.sec-1) than in young rats (56.4 +/- 10.3 m.sec-1) (P < 0.05). To test the effects of aging on conduction block, equipotent doses of bupivacaine (0.2%), an amide-linked local anesthetic, or procaine (0.6%), an ester-linked local anesthetic, were injected next to exposed sciatic nerves and evoked electrical activity was monitored following repeated stimulation at the sciatic notch. At 10 minutes after injection, bupivacaine produced significantly greater nerve block in old rats (100 +/- 0.0%) than young rats (29.8 +/- 41.6%) (P < 0.01); the difference for procaine (old 67.5 +/- 40.4% vs. young 30.4 +/- 35.3%) was not statistically significant. The lower dose requirement for bupivacaine, and the apparent differences compared to procaine, may have implications for the use of local anesthetics in an aging patient population.

Aging↗
PubMed1987

Inhibition of human serum and rabbit muscle cholinesterase by local anesthetics.

The effects of tertiary amine local anesthetics (procaine, mepivacaine, lidocaine, tetracaine, dibucaine, and bupivacaine) and chlorpromazine were investigated for rabbit muscle acetylcholinesterase and human serum cholinesterase. The muscle enzyme was poorly inhibited by local anesthetics containing an amide linkage. The serum cholinesterase was inhibited by all those compounds, their relative potencies being proportional to their octanol/water partition coefficients. The dissociation constants of tetracaine and procaine, ester anesthetics, were 1000-fold and 100-fold, respectively, that which would be expected from their partition coefficient basis respective to the other amide anesthetics. Procaine showed competitive inhibition of serum cholinesterase, whereas for most anesthetics a mixed type of inhibition was observed. Procaine probably binds at the main anionic site, while the other positively charged anesthetics bind to either the catalytic centre or to the peripheral or modulator anionic site, modifying the kinetic behaviour of cholinesterase as has been demonstrated by the appearance of negative cooperativity for binding to the substrate.

Acetylcholinesterase↗
PubMed1998

Epidermal iontophoresis: II. Application of the ionic mobility-pore model to the transport of local anesthetics.

PURPOSE: An in vitro study was carried out to determine the iontophoretic permeability of local anesthetics through human epidermis. The relationship between physicochemical structure and the permeability of these solutes was then examined using an ionic mobility-pore model developed to define quantitative relationships. METHODS: The iontophoretic permeability of both ester-type anesthetics (procaine, butacaine, tetracaine) and amide-type anesthetics (prilocaine, mepivacaine, lidocaine, bupivacaine, etidocaine, cinchocaine) were determined through excised human epidermis over 2 hrs using a constant d.c. current and Ag/AgCl electrodes. Individual ion mobilities were determined from conductivity measurements in aqueous solutions. Multiple stepwise regression was applied to interrelate the iontophoretic permeability of the solutes with their physical properties to examine the appropriateness of the ionic mobility-pore model and to determine the best predictor of iontophoretic permeability of the local anesthetics. RESULTS: The logarithm of the iontophoretic permeability coefficient (log PC(j,iont)) for local anesthetics was directly related to the log ionic mobility and MW for the free volume form of the model when other conditions are held constant. Multiple linear regressions confirmed that log PC(j,iont) was best defined by ionic mobility (and its determinants: conductivity, pKa and MW) and MW. CONCLUSIONS: Our results suggest that of the properties studied, the best predictors of iontophoretic transport of local anesthetics are ionic mobility (or pKa) and molecular size. These predictions are consistent with the ionic mobility pore model determined by the mobility of ions in the aqueous solution, the total current, epidermal permselectivity and other factors as defined by the model.

Anesthetics, Local↗
PubMed1983

Local anaesthetic induced turbidity increases: implications of interactions with intact bacterial cells and with subcellular fractions.

Four local anaesthetics (LAs), amethocaine and procaine (esters) and cinchocaine and lignocaine (amides) have been assessed in terms of their ability to induce turbidity increases in non-growing cells of Escherichia coli suspended in a carbohydrate free defined medium (CFM) or distilled water or in 0.2 M phosphate buffer. Procaine and lignocaine did not induce turbidity increases. The turbidity increase-LA concentration profiles for both amethocaine and cinchocaine are similar in all three systems. Slight variation are discussed in terms of the ionic content of the suspending media. Interactions between LAs and dispersed systems comprising: cell envelope preparations, cytoplasmic contents, lipid depleted cells and cell lipid dispersion, are also described. Transmission electron micrographs of LA treated cells are presented and the use of uranyl acetate as a 'vital' stain is illustrated. Results are discussed in terms of LA lipophilicity and the effectiveness of LAs in precipitating intracellular materials at high concentrations.

Anesthetics, Local↗
PubMed1983

Local anaesthetics as antimicrobial agents: structure-action considerations.

The antibacterial activity of four local anaesthetics (LAs), amethocaine and procaine (esters), and cinchocain and lignocaine (amides), has been studied. All four LAs inhibited cell growth but only amethocaine and cinchocain had significant effects on cell viability and on the leakage of cellular constituents. Effects on growth inhibition were reversible. Concentrations causing marked loss in viability also caused the leakage of cellular constituents. Uptake isotherms for all four LAs by E. coli are presented and an attempt made to relate derived intracellular LA levels with effects on growth inhibition. Cultures of E. coli grown in the presence of low levels of LAs effects reflecting the relative hydrophilic-lipophilic nature of the individual LAs.

Anesthetics, Local↗
PubMed1983

Local anaesthetics as antibacterial agents: effects on cellular respiration and the leakage of cytoplasmic constituents.

The effect of four local anaesthetics, amethocaine and procaine (esters) and cinchocaine and lignocaine (amides), on the respiration and dehydrogenase activity of E. coli has been studied. Cells were suspended in either a chemically defined medium or in 0.2 M phosphate buffer (pH 6.4). Substrates included: glucose, succinate, malate and lactate. Further studies on the release of cellular constituents (pentoses and inorganic phosphate) are included and indicated that some local anaesthetics, at high concentrations, inhibit autolysis. Results are discussed in terms of the action of local anaesthetics on membrane integrity and its significance in enzyme action. A novel method for the detection of inorganic phosphate by differential pulse voltammetry and its application to studies of drug induced leakage of intracellular materials is described.

Anesthetics, Local↗
PubMed1984

Pharmacodynamic and pharmacokinetic aspects of local anesthetics.

The clinically useful local anesthetic agents can be divided chemically into the amino-esters, e.g., procaine, chloroprocaine and tetracaine, and the amino-amides, e.g., lidocaine, mepivacaine, prilocaine, bupivacaine and etidocaine. Pharmacologically, these agents can be categorized as agents of low potency and short duration of action, e.g., procaine and chloroprocaine; agents of intermediate potency and duration of action, e.g., lidocaine, mepivacaine and prilocaine; and agents of high potency and long duration, e.g., tetracaine, bupivacaine and etidocaine. The blood level of local anesthetics is determined by the rate of uptake, tissue redistribution, metabolism and excretion. The rate of vascular absorption is a function of the site of injection, dosage, inclusion of a vasoconstrictor in the local anesthetic solution and the specific drug employed. The amino esters are eliminated by means of enzymatic hydrolysis in blood while the amino amides are metabolized primarily in the liver. Among the ester agents chloroprocaine is cleared most rapidly due to its fast rate of hydrolysis. Within the amide series, prilocaine is cleared most rapidly due to its fast rate of tissue redistribution and its rapid hepatic metabolism. Bupivacaine is cleared most slowly due primarily to its decreased rate of hepatic degradation.

Anesthetics, Local↗
PubMed1979

Hydrolysis of ester-type drugs by the purified esterase from human intestinal mucosa.

Esterase from human intestinal mucosa was purified 210 fold by solubilization with Triton X-100, chromatography on DEAE-cellulose, Sephadex G-100 and hydroxylapatite, and isoelectric focusing. The purified esterase showed a single band by polyacrylamide gel electrophoresis. The molecular weight of the purified esterase was estimated to be about 55,000 by gel filtration on Sephadex G-150, and the isoelectric point was 5.02. The purified esterase was strongly inhibited by diethyl p-nitrophenyl phosphate (E-600) and diisopropyl fluorophosphate (DFP), and was not inhibited by eserine sulfate and p-chloromercuribenzoate. The purified esterase from human intestinal mucosa was found to be one of the carboxylesterases. The purified esterase hydrolyzed ester-type drugs, i.e., aspirin, clofibrate, indanyl carbenicillin and procaine, but did not hydrolyze amide-type drugs and choline-type drugs.

Aspirin↗
PubMedDate not supplied

Managing patients with local anesthetic complications using alternative methods.

This article discusses various alternative methods of treating the patient who encounters problems with local anesthetics. Those alternative methods include: acupuncture, hypnosis, sedation, general anesthesia, and antihistamines as a substitute for local anesthetics with more of a focus in using antihistamines as an effective local anesthetic agent. Although not frequently encountered in the clinical setting, allergic reactions to local anesthetics do occur. Various surveys indicate the number of deaths attributed to local anesthesia range from 1:1,500,000 to 1:4,000,000, with oral surgery offices having higher mortality rates than general dentistry offices. This occurs despite clinicians' attention to patient medical histories, aspiration of the local anesthetic syringe during injections, and minimizing the dosage of local anesthetic solutions. Generally speaking, local anesthetics can be divided into two groups: ester of benzoic and aminobenzoic derivatives (cocaine, benzocaine, procaine, tetracaine, butacaine, etc.) or amide-derivatives of xylidine and toluidine groups (lidocaine, mepivacaine, prilocaine a.k.a. Citanest, etc.). Adverse effects include allergic or toxic reactions, as well as negative effects of any vasoconstrictors contained within the local anesthetic solution. This article will concentrate on how to successfully manage patients who have previously encountered allergic reactions.

Acupuncture Analgesia↗
PubMed1998

Xylocain (lidocaine, lignocaine), its discovery and Gordh's contribution to its clinical use.

Hans v. Euler, while investigating how genes and enzymes were chemically related in some chlorofylldefective mutants of barley, isolated gramine, an indole. Erdtman synthetized isogramine and found it to have weak anesthetic properties. He then together with Löfgren synthetized other amino-amides, but no one of them could compete with the existing local anesthetics of the ester-type, derivatives of para-aminobenzoic acid, e.g. procaine. Later Löfgren and Lundqvist followed up these studies and found an amid compound lidocaine (2-dimethylaminoacet-2, 6-xylidide). Lidocaine represented such a significant advance over procaine in clinical tests preformed by T. Gordh that it was introduced for clinical use. It has now during a half century been the standard local anesthetic drug. All local anesthetics are neurotoxic in high enough doses. Xylocain, however, has had an excellent record of safety. Only during the last years have there been reports on possible toxic irritation and damage by Xylocain used for spinal anesthesia. The aetiology is still not clear In this connection two early observations by Gordh and his coworkers are discussed.

Alkaloids↗
PubMed1993

On the mechanisms of potentiation of local anesthetics by bicarbonate buffer: drug structure-activity studies on isolated peripheral nerve.

Impulse inhibition by local anesthetics (LAs) is potentiated by extracellular solutions containing HCO3-. CO2 (BC), relative to the inhibition in BC-free solutions at the same pH. We studied the mechanistic basis of this potentiation by assaying compound action potential amplitudes in desheathed frog sciatic nerves with the sucrose-gap method. We compared the potencies of 12 different impulse-blocking agents in Ringer's buffered with BC (BC-R) and in Ringer's containing only atmospheric CO2 and buffered by a zwitterionic compound (3-(N-morpholino)propanesulfonic acid-Ringer's). The relative inhibition produced by an agent in BC divided by the inhibition produced in 3-(N-morpholino)propanesulfonic acid, was defined as the potentiation factor (PF). The organic guanidinium blockers of sodium channels, tetrodotoxin and saxitoxin, which act at a different site from that for LAs, were, by our definition, nominally potentiated (PF = 1.33 +/- 0.04, mean +/- SEM, n = 4, and 1.24 +/- 0.07, n = 10, respectively), implying that BC induces a decrease in the safety margin for impulse conduction, a decrease that cannot itself alone account for the much larger potentiation (PF = 5-8) by BC observed with certain LAs. Only nominal potentiations occurred with charged LAs (PF = 1.15), showing that little direct potentiation of the cationic LA species per se occurs. Inhibition by the permanently neutral LA benzocaine had a significantly larger than nominal potentiation (PF = 1.8) showing that BC can potentiate neutral LAs. Among the tertiary amine LAs, potentiation of ester-linked drugs (procaine, RAG505; PF = 3.9, 5.4, respectively), exceeded that of their amide-linked homologues (procainamide, lidocaine; PF = 1.3, 2.8, respectively) which have higher pKa values. This result is consistent with an ion trapping mechanism whereby CO2 acidifies the axoplasm and thereby increases the concentration of protonated LA inside the nerve fibers. However, slight differences in the molecular structure of 3 degrees-amine LAs with similar pKa values resulted in significantly different potentiations (e.g., procaine, PF = 3.9; 2-chloroprocaine, PF = 8.7), suggesting that the HCO3- or CO2 molecules interact specifically with the LA molecule or with LA binding sites in the nerve membrane. Spectrophotometric measurements of the free [Ca2+] in Ringer's showed it to be similar (+/- 0.03 mM) for both buffers, obviating changes in extracellular Ca2+ as a mechanism of BC potentiation. The resting potential of the nerve was slightly more negative (approximately -4 mV) in BC-R, so membrane depolarization cannot explain the potentiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1996

Effect of the antiarrhythmic drug procainamide on the toxicity and antitumor activity of cis-diamminedichloroplatinum(II).

The class I antiarrhythmic drug procainamide (Pd) was tested on BDF1 mice for its chemoprotective activity against cis-diamminedichloroplatinum(II) (DDP) toxicity. Pd at the dose of 50 mg/kg protected mice against otherwise lethal doses of DDP (survivors at Day 14 after 25 mg/kg DDP or 25 mg/kg DDP-Pd treatment: 0% vs 100%) and greatly reduced the weight loss induced by DDP. Moreover, the increased plasma urea nitrogen levels caused by a single ip administration of DDP in water (8 or 16 mg/kg) as well as the tubular degenerative changes detected by light microscopy were prevented by Pd. Pd had no effect on the sensitivity of P388 leukemic cells to DDP in vitro, but the administration of DDP (16 mg/kg) and Pd (50 mg/kg) to BDF1 mice bearing P388 leukemic cells produced a significant increase in survivals compared to mice receiving ip DDP alone diluted in 0.9% NaCl solution. The increased efficacy of this combination therapy in P388 leukemic mice compared to a single DDP treatment at the same dose was observed both when the drugs were administered ip simultaneously (p = 0.042) and when DDP and Pd were given ip and iv, respectively (p = 0.018). Since procaine, which differs from Pd merely in the replacement of the amide by the ester linkage, has also been reported to significantly enhance DDP efficacy (M. Esposito et al., 1990, J. Natl. Cancer Inst. 82, 677-684.), a comparison of their effects in tumored mice exposed to DDP has been made. Although both drug combinations were superior to that of DDP alone, in terms of both survival time and numbers of cures, Pd treatment seems to offer better protection against DDP-induced lethality than did procaine.

Animals↗