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Physiology and pharmacology of local anesthetic agents.
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Mechanisms of toxicological interactions involving organophosphate insecticides.
Administration of apparently nontoxic doses of organophosphorus compounds can greatly alter the toxicity of other compounds. These might include other organophosphates, as well as other drug or nondrug xenobiotics. Mechanisms of toxicologic interactions are discussed. Emphasis is placed upon organophosphate inhibition of noncritical tissue esterases and alterations in the metabolism and toxicity of selected ester and amide containing xenobiotics.
Effect of local anaesthetics and pH: new aspects.
The pH dependence of the effect of local anaesthetics with ester, amide, or carbanilate structure on action potential conduction was studied in rat desheathed sciatic nerve and in single axon preparation in vitro. Not only different slopes but also different directions of this dependence were observed in the pH range 6.0-8.4. The effect of common local anaesthetics such as procaine, lidocaine, trimecaine, and bupivacaine kept decreasing with lower pH. New drugs with carbanilate structure, however (pentacaine, carbisocaine and heptacaine) displayed an opposite dependence. Further analysis showed that this phenomenon cannot be linked to the type of the intermediary chain of the drugs, to differences in pKa values, or to differences in potency of the drugs. Yet a relationship was found to exist between pH dependence and the lipophilicity of the drug. It is suggested that the current hypothesis concerning the pH dependence of the effect of local anaesthetics be complemented by the lipophilic properties of such drugs. This implies a pH dependent formation of micelles in highly lipophilic local anaesthetics which changes their bioavailability, as well as a diffusion of these drugs into and through the lipoid phase besides the base also in the form of an ion pair.
[Treatment of arrhythmia in myocardial infarct].
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[Clinical significance and treatment of disorders of the cardiac rhythm in patients with myocardial infarct].
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Inhibition of hepatic microsomal carboxylesterase activity by paraoxon.
A large number of therapeutic agents are esters of carboxylic acids and are thus substrates for microsomal carboxylesterase enzymes. These studies characterized the effects of the organophosphate compound, paraoxon, on the hydrolysis of several drug esters (procaine, chloramphenicol succinate, prednisolone succinate, lidocaine, procainamide and methylparaben) by microsomal preparations from guinea-pigs. These investigations demonstrate that carboxylesterase activity toward several drug esters is present in liver, lung and kidney. The liver is by far the major site of hydrolysis of these ester compounds. Since no hydrolysis was observed with the two amide esters, the hydrolysis of carboxylesters and amide esters appears to be mediated by different enzymes in the guinea-pig. At the substrate concentrations studied, the hydrolysis of methylparaben followed zero-order kinetics. When added to isolated microsomal preparations, paraoxon produced a dose-dependent inhibition of hydrolysis of all substrates. Administration of paraoxon to guinea-pigs prior to isolation of microsomes did not produce consistent effects with any substrate. Inhibition of ester hydrolysis was observed with some pretreatments, while either no change or increased hydrolysis was observed with other pretreatment regimens.
The reversal of experimental cardiac arrhythmias by indoramin (Wy 21901).
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Ionization and adsorption of a series of local anesthetics in detergent micelles: studies of drug fluorescence.
The goal of this study was to compare the behavior of structurally homologous local anesthetics (LAs) adsorbed to a simplified membrane model. Interactions of LAs with micelles made from negative and neutral detergents were assayed by drug fluorescence. Micellar:drug affinity, equivalent dielectric constant and pKa of bound LAs were assessed for procaine, tetracaine, procainamide, benzocaine and aminoparabenzyldiethylamine, a procaine homologue containing an alkyl chain instead of an ester bond. Shifts in maximum emission wavelength and changes in fluorescence intensity showed that 1) increased LA hydrophobicity (expressed as octanol:buffer partition coefficient) corresponded to increased affinity for all micelles; 2) protonated species of LA were bound more tightly than neutral species to negative micelles, but less tightly to unchanged micelles; 3) drugs with larger dipole moments (amide < ester < alkyl) bind less tightly to micelles than those with smaller dipoles; 4) Larger dipole moments of LAs also result in a larger equivalent dielectric constant around the micellar-bound LAs, meaning that the LA binds at a shallower depth from the micelle surface; and 5) binding the neutral micelles lowers the pKa but binding to negatively charged micelles raises the pKa (due to the concentrating effects of surface charge on H+). The results provide a picture of interfacial adsorption of LAs in a relatively simple system that should allow interrelation of the dipole field contributions to LA behavior in phospholipid bilayers.
Topical anesthesia versus retrobulbar block for cataract surgery: the patients' perspective.
STUDY OBJECTIVES: To compare patients' perception of topical anesthesia (TA) with combined peribulbar and retrobulbar block (PRBB) for cataract surgery. DESIGN: Prospective, randomized, controlled, cross-over observational study. SETTING: Private clinic. PATIENTS: 98 ASA physical status I and II patients presenting for bilateral cataract surgery 1 week apart. INTERVENTIONS: Patients were prospectively randomized to receive either TA for surgery to one eye, followed by PRBB for surgery to the other eye 1 week later, or to receive PRBB first, followed by TA for the second operation the following week. Surgery, PRBB, and TA were standard for all cases. Interviews were conducted the day following surgery by an unbiased observer unaware of the technique used. Surgical pain was estimated on a visual analog scale of 0 to 10, and the surgeon judged the difficulty of surgery based on patient compliance and cooperation on a scale of 0 to 5. Means and variance of results were compared with analysis of variance. MEASUREMENTS AND MAIN RESULTS: Mean age was 71.45 +/- 9.76 years (mean +/- SD). Seventy patients (71.43%) preferred PRBB while 10 patients (10.20%) preferred TA (p = 0.0001). Eighteen patients (18.37%) reported no difference between the two techniques. Ninety-six patients (97.96%) were not aware of the PRBB being injected. Duration of surgery was similar for TA (11.92 +/- 3.43 min) and PRBB (10.78 +/- 3.00 min; p = 0.06). Surgery was more difficult during TA (p = 0.0004). Pain was worse during TA (p = 0.0001). Surgical and anaesthetic complications were unremarkable for both techniques. CONCLUSIONS: Patients who experienced both TA and PRBB preferred PRBB.
Effects of local anesthetics on fixed-interval responding in rhesus monkeys.
Several local anesthetics of both the ester and amide type were administered IM to rhesus monkeys trained to respond on a fixed-interval 5 min schedule of food delivery. With the exception of procainamide, all local anesthetics produced dose-related decreases in response rates. Effects on pattern of responding varied between local anesthetics. With some (cocaine, dimethocaine and lidocaine), rate-dependent effects were apparent. When control rates were low, these compounds increased rates; when control rates were high, they decreased rates. However, with others (procaine, chloroprocaine, tetracaine and propoxycaine) no rate-dependent effects were noted; i.e., these compounds had little or no effect on the pattern of responding, even at doses that substantially reduced response rates. Consistent with other experiments with these compounds, cocaine was the most potent of the group. In several instances, local anesthetics which had similar stimulus properties in other behavioral paradigms differed in terms of their effects on fixed-interval behavior.
Survey of local anesthetic toxicity in the families of patients with atypical plasma cholinesterase.
There have been reports of toxic reactions to ester-type local anesthetics in patients with genetic anomalies of plasma cholinesterase in so-called dibucaine-resistant homozygotes or heterozygotes. Because of these reports, 23 patients with prolonged apnea after administration of succinylcholine were studied with Kalow's method for abnormal dibucaine number (DN), which characterizes this condition, and for the history of local anesthetic toxicity. Thirty-eight relatives of abnormal individuals were studied in the same manner. Two atypical dibucaine-resistant homozygotes and the relative of one of these had toxic reactions to ester-type local anesthetics. Although low doses of ester-type local anesthetics may be tolerated by atypical homozygotes, these agents are best avoided and amide-type local anesthetics or tetracaine, which is hydrolyzed at a normal rate, should be used. Individuals with atypical plasma cholinesterase should wear a Medic-Alert bracelet or amulet so that complications and fatalities can be avoided.
Pharmacological and toxicological testing of the enantiomers of two chiral fomocaine alkylmorpholine derivatives in comparison to their in vitro interactions on drug metabolism in rats.
Between the stereoisomers of amide-type local anaesthetics differences have been noticed with respect to pharmacokinetics and side effects, but not regarding local anaesthetic capacity. Therefore, only S-(-)-ropivacaine has been introduced into clinical practice and with bupivacaine both the racemate and the S-(-)-enantiomer (levobupivacaine) are available by now. Based on this background, the aim of the present study was to evaluate if there are also dissimilarities to be found both in the toxicity and in the effectiveness of the enantiomers of two newly synthesized chiral fomocaine alkylmorpholine derivatives, OW3 and OW13, with an additional C2-chain in 2- or an additional C3-chain in 3-position at the morpholine ring, respectively. For this purpose, in vitro the interaction capacity with cytochrome P450 (CYP)-mediated monooxygenase and oxidase functions was investigated using rat liver 9000 g supernatants or microsomes. In vivo LD50, paresis of the N. ischiadicus and surface and conduction anaesthesia (cornea, N. ischiadicus) were tested in rats. The enantiomers of both OW3 and OW13 caused a concentration dependent inhibition of all CYP-mediated model reactions investigated. With all model reactions the (-)-enantiomer of OW3 was less effective than the (+)-form, whereas the opposite was the case with OW13. Also toxicity was lower with the (-)-enantiomer of OW3 and with the (+)-form of OW13 than with the respective counterparts. With both derivatives no clear-cut dissimilarities were noticed in the local anaesthetic capacity of the enantiomers. None of the four compounds caused paresis. Thus, similar to amide-type local anaesthetics, also with the enantiomers of chiral fomocaine alkylmorpholine derivatives differences in pharmacokinetic properties and toxicity could be demonstrated.
[The effect of local anaesthetics on uterine blood flow and O2-consumption in pregnant sheep (author's transl)].
The local anesthetics bupivacaine, etidocaine, lignocaine and chloroprocaine were infused intravenously for 30 min to pregnant sheep, prepared for chronic studies. The amide compounds reached highere plasma concentrations than chloroprocaine. All local anaesthetics decreased uterine blood flow and O2 consumption without marked alterations of arterial or uterine venous blood gases. These changes were within the wide physiological range of variation, which was established in controls during 24 h. The findings may be of significance during paracervical block or pathological states of UBF or fetal homeostasis.
Ion-transfer voltammetry of local anesthetics at an organic solvent/water interface and pharmacological activity vs. ion partition coefficient relationship.
The ion-transfer reaction of local anesthetics at an organic solvent/water interface has been studied using cyclic voltammetry (CV) with a stationary nitrobenzene (NB)/water (W) interface. Procaine and seven other local anesthetics gave reversible or quasi-reversible voltammograms at the NB/W interface in the pH range between 0.9 and 9.6. These drugs are present in aqueous solution in either neutral or ionic form, or both forms. The half-wave potential, as determined by the midpoint potential in CV, vs. pH curves, were determined and analyzed to determine the partition coefficients of both neutral and ionic forms of the drugs between NB and W. The partition coefficients of the ionic forms were derived from their formal potential of transfer at an NB/W interface. The dissociation constants of ionic forms of the drugs in NB were also deduced. A high correlation between the pharmacological activity and the partition coefficient of the ionic form of amide-linked local anesthetics has been shown.
Anaesthetic agents for advanced regional anaesthesia: a North American perspective.
Interest in the use of regional anaesthesia, particularly peripheral nerve blocks (PNBs) and continuous PNBs, has increased in recent years. Accompanying this resurgence in interest has been the development of new local anaesthetics and additives designed to enhance block duration and quality. This manuscript provides a literature-based review on accepted uses of local anaesthetics and adjuncts for a variety of regional anaesthesia techniques. A brief review of local anaesthetic pharmacodynamics describes the action of these drugs in preventing nerve depolarisation, thus blocking nerve impulses. Toxic adverse effects of local anaesthetics, specifically CNS and cardiac manifestations of excessive local anaesthetic blood concentrations and the direct neurotoxic properties of local anaesthetics, are discussed generally and specifically for many commonly used local anaesthetics. Clinically useful ester and amide local anaesthetics are evaluated individually in terms of their physical properties and toxic potential. How these properties impact on the clinical uses of each local anaesthetic is explored. Particular emphasis is placed on the long-acting local anaesthetic toxic potential of racemic bupivacaine compared with levobupivacaine and ropivacaine, which are both levorotatory stereoisomers. Guidelines for using ropivacaine and mepivacaine, based on the authors' experience using advanced regional anaesthesia in a busy practice, is provided. Finally, epinephrine (adrenaline), clonidine and other local anaesthetic additives and their rationale for use is covered along with other future possibilities.
Sedative action of some substituted benzylamides.
Substituted benzylamide derivatives of amino acylamide (compound A,B,C, & D) were found to be less potent local anaesthetics than lignocaine and procaine. However, the four compounds exhibited sedation without ptosis and reduced spontaneous locomotor activity better than methaqualone. Compound A alone antagonised methylamphetamine induced hypermotor activity. The test compounds potentiated hexobarbitone induced hypnosis. Three compounds antagonised calcium induced stoppage of isolated heart of frog. Except compound C all caused a transitory fall of blood pressure in dog which was not blocked either by atropine or propranolol. These compounds showed neuromuscular blockade and possessed slight analgesic activity but were devoid of anticonvulsant and tranquillizing activity. LD 50 values were calculated to be 164.1 +/- 23.0, 229.1 +/- 51.0, 181.6 +/- 28.18 and 416+/-38.2 mg/kg for compounds A,B,C & D respectively.