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PubMed2006

Is there a place for local anesthetics structurally different from classical amid or ester local anesthetics?

PURPOSE OF REVIEW: The aim of this review is to describe the pharmacology, toxicology and chemistry of the new group of local anesthetics of phenylcarbamic acid type. RECENT FINDINGS: Basic esters of alkoxy-substituted phenylcarbamic acid have shown high local anesthetic potency, while maintaining a relatively safe toxicity profile. Their potency uniquely increases with the decreasing pH of the external medium. This is of importance when using local anesthesics in inflamed tissues, where the action of common local anesthetics is often problematic. SUMMARY: The most potent phenylcarbamic anesthetics exceed the potency of the most common clinically used local anesthetics 100-300 times. Due to the unique pH dependency of these local anesthetics, further study of their action is required.

Amides↗
PubMed1981

Pharmacology of local anesthetic agents.

Local anesthetic agents may be classified according to their intrinsic anesthetic potency and duration of activity. Procaine and chloroprocaine are relatively weak, short-acting drugs. Lidocaine, mepivacaine, and prilocaine represent agents of intermediate potency and duration of action. Tetracaine, bupivacaine, and etidocaine are highly potent, long-acting agents. The toxicity of local anesthetic drugs is usually due to inadvertent rapid intravascular injection or extravascular administration of an excessive amount. Intravascular toxicity is correlated with intrinsic anesthetic potency, whereas toxicity following extravascular injections is a function of physiological disposition characteristics of the various agents, such as rate of vascular absorption, rate of tissue redistribution, and rate of metabolism. The central nervous system is most susceptible to the toxic effects of local anesthetic agents. Signs and symptoms of CNS excitation followed by depression are the most common manifestations of local anesthetic toxicity. Cardiovascular depression may also occur following administration of excessive doses of local anesthetic agents or following high spinal or epidural anesthesia.

Anesthetics, Local↗
PubMed1980

Structure-activity relations for frequency-dependent sodium channel block in nerve by local anesthetics.

Different local anesthetic drug structures differ significantly in their capabilities for producing frequency (f)-dependent sodium channel block. Voltage-clamped frog myelinated nerve preparations have been utilized in order to investigate structure-activity relations for several modes of local anesthetic drug action, including the kinetics of f-dependent excitability block. Lipid solubility has been shown to be an important determinant of closed channel blocking potency, at least within the amide-linked series of local anesthetics. The ester-linked (beta blockers) and ester-linked local anesthetics appear to be relatively more potent at closed channel block than drugs of the amide-linked series. In addition, f-dependent block increments are greater for drugs of lower lipid solubility, supporting the "modulated drug receptor" hypothesis that intracellular drug forms participate in the open channel binding involved in f-dependent blocking. Finally, molecular size has been shown to be a very important determinant of closed channel block escape rates with smaller drug structures showing faster escape rates from f-dependent increments in channel block.

Anesthetics, Local↗
PubMed1976

The local anesthetic activity of saxitoxin alone and with vasoconstrictor and local anesthetic agents.

STX (saxitoxin), alone and with various vasoconstrictor and local anesthetic agents, was evaluated for its ability to produce topical anesthesia on the rabbit cornea, peripheral nerve block in the rat, and epidural anesthesia in the dog. High frequency and long duration of block can be attained if sufficiently high concentrations of STX are used, although latency is long and the doses used may produce systemic toxicity. Frequency of satisfactory blocks and mean duration of block can be increased and systemic toxicity reduced if STX is administered with a vasoconstrictor agent. Conventional local anesthetic agents also enhance the nerve blocking activity of STX. When appropriate concentrations of STX, vasoconstrictor and local anesthetic agents are used, systemic toxic effects are not manifested and the blocks produced exhibit the rapid onset and high frequency of block characteristic of the local anesthetic agent and the remarkably long duration of STX.

Anesthesia, Epidural↗
PubMed2002

Inhibition of mammalian Gq protein function by local anesthetics.

BACKGROUND: Local anesthetics have been shown to selectively inhibit functioning of Xenopus laevis Gq proteins. It is not known whether a similar interaction exists with mammalian G proteins. The goal of this study was to determine whether mammalian Gq protein is inhibited by local anesthetics. METHODS: In Xenopus oocytes, the authors replaced endogenous Gq protein with mouse Gq (expressed in Sf9 cells using baculovirus vectors). Cells endogenously expressing lysophosphatidic acid or recombinantly expressing muscarinic m3 receptors were injected with phosphorothioate DNA antisense (or sense as control) oligonucleotides against Xenopus Gq. Forty-eight hours later, oocytes were injected with purified mouse Gq (5 x 10(-8) M) or solvent as control. Two hours later, the authors injected either lidocaine, its permanently charged analog QX314 (at IC50, 50 nl), or solvent (KCl 150 mM) as control and measured Ca-activated Cl currents in response to lysophosphatidic acid or methylcholine (one tenth of EC50). RESULTS: Injection of anti-Gq reduced the mean response size elicited by lysophosphatidic acid to 33 +/- 7% of the corresponding control response. In contrast, responses were unchanged (131 +/- 29% of control) in cells in addition injected with mouse Gq protein. Injection of mouse Gq protein "rescued" the inhibitory effect of intracellularly injected QX314: whereas QX314 was without effect on Gq-depleted oocytes, responses to lysophosphatidic acid after QX314 injection were inhibited to 44 +/- 10% of control response in cells in addition injected with mouse Gq protein (5 x 10(-8) M). Similar results were obtained for m3 signaling and intracellularly injected lidocaine. CONCLUSION: Inhibition of Gq function by local anesthetics is not restricted to Xenopus G proteins. Therefore, Gq should be considered as one additional intracellular target site for local anesthetics, especially relevant for those effects not explainable by sodium channel blockade (e.g., antiinflammatory effects).

Anesthetics, Local↗
PubMed1975

[Relations between the physico-chemical properties, the chemical reactivity and the local-anesthetic activity/part 33: studies on the interactions of local-anesthetically active cinchocaine homologues with phospholipids (author's transl)].

The general part consists of a review on nerve stimulus mechanism as well as the nerve structure and the function of nerve membrane as the site of action of local anesthetics. Furthermore a possibility of interaction between local anesthetics and the membrane components especially phospholipids is discussed. These phospholipids show interesting properties with respect to ions as well as local-anesthetics, which allow us to suppose that they are important participants in nervous stimulus transmission. In the experimental part two methods are described. The first deals with the measurement of electrical resistance as function of time at cephalin and cholesterin impregnated filter membrane in solutions of cinchocain homologues. An increase in the resistance with the increase in concentration of test substances was observed. The same was the effect of increasing chain length in alkoxy group where after butoxy derivative, a deformation of membrane was observed. In the second method the drug binding capacity of cephalin dispersed in aqueous medium was measured. Here, too, the increase in the binding capacity with the increase in alkoxy chain was observed. The large difference in free binding energy between two subsequent homologues is explained as the effect of increase in van der Waals' forces and hydrophobic interactions on one hand, and a change in colloidal form of cephalin dispersion on the other hand.

Absorption↗
PubMedDate not supplied

Pleural permeability to local anesthetics--the influence of concentration, pH, and local anesthetic combinations.

The transpleural passage of lidocaine, bupivacaine-lidocaine mixtures, and of bupivacaine, with and without epinephrine, was studied in vitro using pleural from piglets. Our objective was to ascertain whether changing physical parameters of local anesthetics such as pH, concentration, and addition of epinephrine might influence the transfer. Rate of transfer is linearly related to concentration at a given pH, but raising the pH increases the rate for bupivacaine. No change in rate was detectable when the pH of lidocaine was increased or in the rate of transfer of bupivacaine when bupivacaine and lidocaine were mixed. The mixture did however facilitate lidocaine flux. Epinephrine [1:200,000] lowers the pH of the solution dramatically but does not statistically change the transpleural passage of bupivacaine. We conclude that the onset of interpleural blockade may be shortened by using more concentrated solutions of bupivacaine whose pH have been modified by the addition of alkali, by using the higher concentrations of lidocaine or by mixing lidocaine with bupivacaine.

Anesthetics, Local↗
PubMedDate not supplied

The local anesthetic activity of tetrodotoxin alone and in combination with vasoconstrictors and local anesthetics.

Tetrodotoxin (TTX), alone and in combination with various vasoconstrictors and local anesthetics, was evaluated for its ability to produce peripheral nerve blocks in the rat and central neural blocks in the cat and dog. High frequency and long duration of block can be attained if sufficiently high concentrations of TTX are used, although latency is long and high dosage may produce systemic toxicity. Frequency and mean duration of block can be increased and systemic toxicity reduced if TTX is administered with a vasoconstrictive agent. Conventional local anesthetics also enhance the nerve-blocking activity of TTX. When appropriate concentrations of TTX and local anesthetics are used, a high frequency of blocks characterized by short latency and long duration can be demonstrated. The studies present some indirect evidence that local anesthetics enhance TTX activity by reversibly increasing the permeability of various neural barriers to TTX.

Anesthesia, Epidural↗
PubMed2003

The site of action of epidural fentanyl infusions in the presence of local anesthetics: a minimum local analgesic concentration infusion study in nulliparous labor.

UNLABELLED: We have previously demonstrated that continuous epidural infusions of fentanyl without local anesthetics elicit analgesia by a systemic mechanism. In this study, we examined the hypothesis that, in the presence of epidural bupivacaine, continuous infusions of epidural fentanyl elicit analgesia by a spinal mechanism. Forty-eight nulliparous women in active labor participated in this prospective, randomized, double-blinded study. Women received lumbar epidural analgesia with 20-30 mL bupivacaine 0.125% until pain free. Subjects were then randomized to either IV or epidural (EPI) fentanyl infusion groups. Each infusion delivered fentanyl 30 microg/h. All women received an epidural infusion of bupivacaine at a rate of 20 mL/h, the concentration of which was determined by the response of the previous woman in the same group to the analgesic regimen used. Unlike previous studies that assessed the minimum local analgesic concentration (MLAC) for bolus administration at the initiation of analgesia, this study assessed MLAC(infusion) for the maintenance of analgesia throughout the first stage of labor. MLAC(infusion) was determined using the up-down sequential analysis described by Dixon and Massey. The MLAC(infusion) of epidural bupivacaine was 0.063% (95% confidence interval, 0.058-0.068) and 0.019% (95% confidence interval, 0.000-0.038) in the IV and EPI groups respectively. A continuous infusion of fentanyl was more than three times as potent when administered by the epidural than by the IV route. This marked increase in potency for the epidural route is highly suggestive for a predominantly spinal mechanism of action for infused epidural fentanyl under the conditions of this study. IMPLICATIONS: This study determined the median effective concentration for epidural infusions of bupivacaine during labor analgesia. Coadministered epidural fentanyl infusions were more than three times more potent than IV fentanyl infusions, suggesting a predominantly spinal mechanism of opioid action under these study conditions.

Adolescent↗