EFFECTS OF ALBUMIN ON THE DISPOSITION OF MORPHINE AND MORPHINE-3-GLUCURONIDE IN THE RAT ISOLATED PERFUSED LIVER

1. The effect of albumin on the disposition of morphine and hepatically generated morphine-3-glucuronide (M3G) was investigated in the single-pass rat isolated perfused liver. 1. Interest in the pharmacokinetic and pharmacodynamic properties of the enantiomers of chiral drugs has greatly increased in recent years. This is particularly so for agents used in anaesthesia. 2. Chiral compounds are those that can exist in two non-superimposable forms. Each form is termed an enantiomer or stereoisomer. Two naming systems are in use: one uses the terms (+) and (–) to indicate the direction the compound will rotate polarized light, while the other system, based on the absolute three-dimensional structure of the enantiomers, uses the terms R and S. 3. Investigation of the stereoisomers of the volatile anaesthetic agent isoflurane is increasing our understanding of the mechanism of general anaesthesia. Current evidence suggests a protein, rather than a lipid, receptor site. 4. Investigation of the stereoisomers of local anaesthetics is increasing the safety of these drugs. 5. For bupivacaine, a widely used amide local anaesthetic, important enantiomeric differences can be found for toxicity, clinical effect and pharmacokinetics. In particular S-(–)-bupivacaine has an improved central nervous system and cardiac safety profile. This is partly explained by the pharmacokinetic differences. 6. Based on these differences, ropivacaine, a propyl homo-logue of bupivacaine, has been produced solely as the S-(–)-enantiomer. The available evidence suggests significantly improved safety for this agent over racemic bupivacaine.     

The enantiomers: revolution or evolution

The use of single stereoisomers are gaining popularity in the world of anesthesiology. The reduced costs of production have made these compounds available for clinical application. The majority of drugs used in anesthesiology such as ketamine, isoflurane, etomidate, atracurium, bupivacaine and ropivacaine have an asymmetric carbon, and are still used primarily as racemic mixtures (1:1 mixture of R and S enantiomers). Among local anesthetics, the S enantiomers often have favorable biological properties. This insight has led to the development of ropivacaine. Ropivacaine is the first local anesthetic marketed as pure S-(-) enantiomer. Its pharmacodynamic and pharmacokinetic profile is similar to that of bupivacaine, but in vitro and in vivo studies have shown that ropivacaine is less cardiotoxic. Clinical data suggests that ropivacaine has a greater margin of safety than bupivacaine, which is necessary for further expanding the application of regional anesthesia. The time has come for the use of single enantiomers in regional and general anesthesia     

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.     

Levobupivacaine: a new safer long acting local anaesthetic agent

The choice of local anaesthetic is influenced by several factors; it must provide effective anaesthesia and analgesia for the duration of the procedure and meet the expectations for post-operative pain management. Of primary concern is patient safety. Bupivacaine, currently the most widely used long acting local anaesthetic agent in both surgery and obstetrics, generally has a good safety record but its use has resulted in fatal cardiotoxicity, usually after accidental intravascular injection. Hence, for several years there has been a need for a long acting local anaesthetic, similar to bupivacaine, but with an improved cardiovascular safety profile. Levobupivacaine, the single enantiomer version of bupivacaine, offers a new long acting local anaesthetic, clinically equivalent in anaesthetic potency to bupivacaine, but with a reduced toxicity profile. Preclinical studies, from in vitro in single ion channels to whole large animal models, have unquestionably demonstrated that levobupivacaine is significantly less CNS toxic and cardiotoxic than bupivacaine. Cardiotoxicity is less easy to study in man, as the clinical signs are not usually seen until the CNS toxicity is marked, and well beyond that which is tolerable to volunteers or patients. Nevertheless, levobupivacaine has been shown to have less effect on myocardial contractility and QTc prolongation, early signs of cardiotoxicity, than bupivacaine in healthy subjects. In clinical use levobupivacaine has been shown to be equally efficacious as bupivacaine at comparable doses and concentrations, and has been found to produce similar anaesthetic characteristics (onset, duration and density of block). As levobupivacaine now becomes commercially available, the database available with which to make efficacy and safety comparisons with other local anaesthetics will increase, and the true value of this new long acting local anaesthetic should become even more apparent.     

Update on ropivacaine

Long-acting local anaesthetics are primarily used in the practice of anaesthesia, particularly in regional anaesthesia and analgesia. Ropivacaine is a new long-acting local anaesthetic that has been the focus of interest because of its increased cardiovascular safety compared with bupivacaine. Other advantages of ropivacaine over bupivacaine include a greater sensorimotor differential block and shorter elimination half-life (t(1/2)), with a lower potential for accumulation. The most important attribute of ropivacaine, however, is its increased margin of safety compared with bupivacaine when given in equal doses. Many post-marketing studies have focused on the comparisons of efficacy in blocks and toxicity profiles of bupivacaine versus ropivacaine. Recent animal toxicity studies confirm the results of original studies showing that ropivacaine has less cardiovascular toxicity than bupivacaine with respect to direct myocardial depression, success of resuscitation and arrhythmogenic potential when given in equal doses. Reduced cardiotoxicity may be a distinct characteristic of ropivacaine. A review of current literature suggests that, at clinically relevant doses, ropivacaine provides the lowest potential risk of cardiotoxicity for inadvertent intravascular injection. Studies are currently under way comparing ropivacaine with levobupivacaine, the latest addition to the group of long-acting local anaesthetics.     

Update on ropivacaine

Long-acting local anaesthetics are primarily used in the practice of anaesthesia, particularly in regional anaesthesia and analgesia. Ropivacaine is a new longacting local anaesthetic that has been the focus of interest because of its increased cardiovascular safety compared with bupivacaine. Other advantages of ropivacaine over bupivacaine include a greater sensorimotor differential block and shorter elimination half-life (t_1/2), with a lower potential for accumulation. The most important attribute of ropivacaine, however, is its increased margin of safety compared with bupivacaine when given in equal doses. Many post-marketing studies have focused on the comparisons of efficacy in blocks and toxicity profiles of bupivacaine versus ropivacaine. Recent animal toxicity studies confirm the results of original studies showing that ropivacaine has less cardiovascular toxicity than bupivacaine with respect to direct myocardial depression, success of resuscitation and arrhythmogenic potential when given in equal doses. Reduced cardiotoxicity may be a distinct characteristic of ropivacaine. A review of current literature suggests that, at clinically relevant doses, ropivacaine provides the lowest potential risk of cardiotoxicity for inadvertent intravascular injection. Studies are currently under way comparing ropivacaine with levobupivacaine, the latest addition to the group of long-acting local anaesthetics.     

Absorption of lignocaine and bupivacaine from the respiratory tract during fibreoptic bronchoscopy

Absorption of lignocaine and bupivacaine from the upper and lower respiratory tract was studied in patients undergoing fibreoptic bronchoscopy. No significant differences were found between the drugs and between the routes of administration in terms of the time taken to achieve maximum plasma concentrations. The relative availability of lignocaine was greater following administration via the upper respiratory tract, but bupivacaine availability did not differ. The apparent clearance of lignocaine was not affected by the route of administration but bupivacaine clearance was higher following administration via the lower respiratory tract. Bupivacaine, previously unreported as a topical agent in man, produced adequate anaesthesia at one-eighth of the dose of lignocaine. Plasma bupivacaine concentrations had a very wide safety margin.     

Cardiac and CNS toxicity of levobupivacaine: strengths of evidence for advantage over bupivacaine.

Bupivacaine is currently the most widely used long-acting local anaesthetic. Its uses include surgery and obstetrics; however, it has been associated with potentially fatal cardiotoxicity, particularly when given intravascularly by accident. Levobupivacaine, a single enantiomer of bupivacaine, has recently been introduced as a new long-acting local anaesthetic with a potentially reduced toxicity compared with bupivacaine. Numerous preclinical and clinical studies have compared levobupivacaine with bupivacaine and in most but not all studies there is evidence that levobupivacaine is less toxic. Advantages for levobupivacaine are seen on cardiac sodium and potassium channels, on isolated animal hearts and in whole animals, anaesthetised or awake. In particular the intravascular dose of levobupivacaine required to cause lethality in animals is consistently higher compared with bupivacaine. In awake sheep, for example, almost 78% more levobupivacaine was required to cause death. In contrast, in anaesthetised dogs no differences were seen in the incidence of spontaneous or electrical stimulation- induced ventricular tachycardia and fibrillations among animals exposed to levobupivacaine or bupivacaine. The reversibility of levobupivacaine-induced cardiotoxicity has also been assessed. Some data point to an advantage of levobupivacaine over bupivacaine but this potential advantage was not confirmed in a recent study in anaesthetised dogs. Three clinical studies have been conducted using surrogate markers of both cardiac and CNS toxicity. In these studies levobupivacaine or bupivacaine were given by intravascular injection to healthy volunteers. Levobupivacaine was found to cause smaller changes in indices of cardiac contractility and the QTc interval of the electrocardiogram and also to have less depressant effect on the electroencephalogram. Assuming that levobupivacaine has the same local anaesthetic potency as bupivacaine, then, all things being equal, it is difficult to argue that levobupivacaine should not displace bupivacaine as the long-acting local anaesthetic of choice. It would appear, however, that levobupivacaine has not yet significantly displaced bupivacaine from the markets in which it is sold. This may be due to a lack of perceived safety benefit and/or consideration of the additional costs that are associated with switching to levobupivacaine, which is approximately 57% more expensive than bupivacaine. If the price of levobupivacaine were closer to bupivacaine then the argument to switch to levobupivacaine would undoubtedly be much stronger. With the continued clinical use of levobupivacaine the database available to make comparisons will increase and this may allow cost-benefit arguments to be made more forcefully for levobupivacaine in the future.     

Differences between gastric antiulcer effects of trapencaine enantiomers

The spatial arrangement of single stereoisomers may influence pharmacodynamic, pharmacokinetic and toxicological properties of a drug. Trapencaine (I. N. N.), (+/-)-trans-2-(pyrrolidin-1-yl)cyclohexylester of 3-(n)-pentyloxycarbanilic acid, was developed as an antiulcer drug with gastroprotective, local anaesthetic and spasmolytic effects. Limited information is available about the potential pharmacodynamic differences of the enantiomers of trapencaine. Therefore, the enantiomers of (+/-)-trans- or cis-2-(pyrrolidin-1-yl)cyclohexylester of 3-(n)-pentyloxy carbanilic acid were synthesised and tested on models of acute gastric damage induced by indomethacin and/or ethanol. A difference was found between their antiulcer effect, with the (+)-trans-enantiomer being the most effective and the (-)-cis-enantiomer the least effective in the models used.     

Clinical application of ropivacaine for the lower extremity

Ropivacaine is a new amide local anaesthetic, which is the first commercially available in its category as a pure S-(-) enantiomer. In most recent studies, ropivacaine exhibited a very close pharmacodynamic profile to equipotent doses of bupivacaine. Concentrations of 0.5%, 0.75% and 1% (5, 7.5 and 10 mg/mL, respectively) ropivacaine are used for intraoperative anaesthesia, while the concentration of 0.2% (2 mg/mL) is preferred for postoperative analgesia, either alone or in combination with opioids and/or clonidine. Ropivacaine is responsible for excellent postoperative analgesia following epidural and peripheral perineural injections, using single-shot injections and continuous infusions. Differential sensory/motor block is only apparent at low concentrations (0.2% and less). A significant amount of recent literature focuses on its use for peripheral blocks of the lower limbs, i.e. sciatic and femoral nerve blocks. The primary benefit of ropivacaine is its lower toxicity, mainly lower cardiotoxicity, following accidental intravascular injection. This higher therapeutic index leads to an improved safety profile as compared with potent local anaesthetics such as racemic bupivacaine. For that reason, ropivacaine is a good choice for both intraoperative and postoperative regional anaesthesia and analgesia.     

Ropivacaine: a review of its use in regional anaesthesia and acute pain management

Ropivacaine (Naropin) is the pure S(-)-enantiomer of propivacaine, and is a long-acting amide local anaesthetic agent, eliciting nerve block via reversible inhibition of sodium ion influx in nerve fibres.Ropivacaine is a well tolerated regional anaesthetic effective for surgical anaesthesia as well as the relief of postoperative and labour pain. The efficacy of ropivacaine is similar to that of bupivacaine and levobupivacaine for peripheral nerve blocks and, although it may be slightly less potent than bupivacaine when administered epidurally or intrathecally, equi-effective doses have been established. Clinically adequate doses of ropivacaine appear to be associated with a lower incidence or grade of motor block than bupivacaine. Thus ropivacaine, with its efficacy, lower propensity for motor block and reduced potential for CNS toxicity and cardiotoxicity, appears to be an important option for regional anaesthesia and for the management of postoperative and labour pain.     

Rational use of local anaesthetics

The judicious use of local anaesthetic agents requires knowledge of the pharmacological properties of the various drugs, technical skill in the performance of the different nerve blocks, and a thorough evaluation of the patient's clinical status. Regional anaesthesia may be classified anatomically as follows: (a) infiltration anaesthesia (extravascular or intravascular); (b) peripheral nerve blockade (minor or major nerve block); and (c) central neural blockade (epidural or subarachnoid block). Anaesthetic potency, onset time and duration of action are the most important clinical properties of any local anaesthetic agent. In general, onset of anaesthesia occurs most rapidly during infiltration techniques and subarachnoid administration, followed in order of increasing onset time by minor nerve blockade, epidural block and major nerve blocks. Duration of anaesthesia is most prolonged when major nerve blockade is performed, followed in order of decreasing duration by epidural and infiltration procedures, minor nerve and subarachnoid blocks. The local anaesthetic agents commonly employed for regional anaesthesia may be classified according to their relative potency and duration of activity into: (1) agents of low potency and short duration, e.g. procaine and chloroprocaine; (2) agents of moderate potency and duration, e.g. lignocaine (lidocaine), mepivacaine and prilocaine; and (3) agents of high potency and long duration, e.g. amethocaine (tetracaine), bupivacaine and etidocaine. In general, the onset, duration and quality of regional anaesthesia are enhanced by an increase in dose achieved by either an increase in concentration or in the volume of anaesthetic solution, and by the concomitant use of a vasoconstrictor drug, adrenaline (epinephrine). However, the local anaesthetic properties of the intrinsically more potent and longer acting agents are influenced less by the addition of adrenaline, particularly when such agents are employed for central neural blockade of the epidural type.     

The local anaesthetic activity of levobupivacaine does not differ from racemic bupivacaine (Marcain): first clinical evidence

The local anaesthetic efficacy of levobupivacaine was compared with racemic bupivacaine (Marcain) in healthy male volunteers who were undergoing ulnar nerve blockade. Levobupivacaine, like racemic bupivacaine, produced blockade of nerve function with evidence of a dose response relationship for levobupivacaine. There were no statistically significant differences with respect to duration of sensory pain, sensory touch or motor block when the adjusted mean for the levobupivacaine groups (0.125, 0.25 and 0.5%) were compared with the 0.25% racemic bupivacaine control group. It is concluded that levobupivacaine is an effective local anaesthetic in humans with a dose-related duration of effect. Its local anaesthetic effect did not differ from that of racemic bupivacaine.     

Cardiotoxicity with modern local anaesthetics: is there a safer choice?

The recognition that long-acting local anaesthetics, particularly bupivacaine the de facto standard long-acting local anaesthetic, were disproportionately more cardiotoxic than their shorter-acting counterparts stimulated the development of the bupivacaine congeners, ropivacaine and levobupivacaine. These agents, like all local anaesthetics, can produce cardiotoxic sequelae by direct and indirect mechanisms that derive from their mode of local anaesthetic actions, i.e. inhibition of voltage-gated ion channels. While all local anaesthetics can cause direct negative inotropic effects, ropivacaine and levobupivacaine are less cardiotoxic than bupivacaine judging by the larger doses tolerated in laboratory animal preparations before the onset of serious cardiotoxicity (particularly electro-mechanical dissociation or malignant ventricular arrhythmias). Additionally, they are less toxic to the CNS than bupivacaine judging by the larger doses tolerated before the onset of seizures. This may be clinically important because CNS effects may be involved in the production of serious cardiotoxicity. Preclinical studies in humans are a 'blunt instrument' in their ability to distinguish significant differences between these drugs because of the relatively small doses that can be used. Nevertheless, available evidence from human studies corroborates the preclinical laboratory animal studies. Because clinically significant differences between these drugs are more quantitative than qualitative, i.e. toleration of a larger dose before manifestation of toxicity, we have concluded that these newer agents have a lower risk of causing serious cardiotoxicity than bupivacaine. Thus, compared with bupivacaine, the newer agents may be seen as 'safer', but they must not be regarded as 'safe'.     

Clinical and economic factors important to anaesthetic choice for day-case surgery

Clinical and economic factors that are important to consider when selecting anaesthesia for day-case surgery can differ from those for inpatient anaesthesia. Patients undergoing day-case surgery tend to be healthier and have shorter durations of surgery. They expect less anxiety before surgery, amnesia for the surgical experience, a rapid return to normal (normal mentation with minimal pain and nausea) after surgery, and lower expenses. However, the latter 2 expectations can conflict; older generic drugs have lower acquisition costs but often impose longer recovery times. Longer recovery periods can increase costs by prolonging the time to discharge from labour-intensive areas such as the operating suite or the post-anaesthesia recovery unit. The challenge for today's anaesthetist is to use newer drugs judiciously to minimise their expense without compromising the rate or quality of recovery. Several approaches can secure these aims. Most apply the least anaesthetic needed. 'Least anaesthetic' may mean the particular form of anaesthetic (e.g. local infiltration with monitored anaesthesia care versus a general anaesthetic), or may mean the delivery of the smallest effective dose, perhaps guided by anaesthetic monitors such as end-tidal analysers or the bispectral index. For patients requiring general anaesthesia, a combination of several drugs usually secures the closest approach to the ideal. Drug combinations used usually include a short-acting properative anxiolytic (e.g. midazolam), intravenous propofol (a short-acting potent anxiolytic and amnestic agent) for induction of anaesthesia (and sometimes for maintenance) and primary maintenance of anaesthesia with inhaled nitrous oxide combined with a poorly soluble (low solubility produces rapid recovery; the least soluble is desflurane) potent inhaled anaesthetic delivered at a low inflow rate (to minimise cost). Although old, nitrous oxide is inexpensive and has favourable pharmacokinetic and cardiovascular advantages; however, it is limited in its anaesthetic/amnestic potency, and has the capacity to increase nausea. In children, induction of anaesthesia is often accomplished with sevoflurane rather than desflurane; although sevoflurane is modestly more soluble than desflurane, it is non-pungent whereas desflurane is pungent. Moderate- or short-acting opioids (fentanyl is popular) or nonsteroidal anti-inflammatory agents (especially ketorolac), or local anaesthetics are added to secure analgesia during and after surgery. Similarly, when needed, moderate- or short-acting muscle relaxants are selected. Before the end of anaesthesia, an intravenous antiemetic may be given. With this drug combination, patients usually awaken within minutes after anaesthesia and can often move themselves to the vehicle for transport to the recovery unit. These combinations of anaesthetics and techniques minimise use of expensive drugs while expediting recovery (again minimising cost) with minimal or no compromise in the quality of recovery.     

Levobupivacaine: a review of its pharmacology and use as a local anaesthetic

Based on findings that the cardiotoxicity infrequently observed with racemic bupivacaine shows enantioselectivity, i.e. it is more pronounced with the R(+)-enantiomer, the S(-)-enantiomer (levobupivacaine) has been developed for clinical use as a long acting local anaesthetic. The majority of in vitro, in vivo and human pharmacodynamic studies of nerve block indicate that levobupivacaine has similar potency to bupivacaine. However, levobupivacaine had a lower risk of cardiovascular and CNS toxicity than bupivacaine in animal studies. In human volunteers, levobupivacaine had less of a negative inotropic effect and, at intravenous doses >75 mg, produced less prolongation of the QTc interval than bupivacaine. Fewer changes indicative of CNS depression on EEG were evident with levobupivacaine. Levobupivacaine is long acting with a dose-dependent duration of anaesthesia. The onset of action is < or = 15 minutes with various anaesthetic techniques. In studies of surgical anaesthesia in adults, levobupivacaine provided sensory block for up to 9 hours after epidural administration of < or = 202.5 mg, 6.5 hours after intrathecal 15 mg, and 17 hours after brachial plexus block with 2 mg/kg. Randomised, double-blind clinical studies established that the anaesthetic and/or analgesic effects of levobupivacaine were largely similar to those of bupivacaine at the same dose. Sensory block tended to be longer with levobupivacaine than bupivacaine, amounting to a difference of 23 to 45 minutes with epidural administration and approximately 2 hours with peripheral nerve block. With epidural administration, levobupivacaine produced less prolonged motor block than sensory block. This differential was not seen with peripheral nerve block. Conditions satisfactory for surgery and good pain management were achieved by use of local infiltration or peribulbar administration of levobupivacaine. Levobupivacaine was generally as effective as bupivacaine for pain management during labour, and was effective for the management of postoperative pain, especially when combined with clonidine, morphine or fentanyl. The tolerability profiles of levobupivacaine and bupivacaine were very similar in clinical trials. No clinically significant ECG abnormalities or serious CNS events occurred with the doses used. The most common adverse event associated with levobupivacaine treatment was hypotension (31%). Conclusions: Levobupivacaine is a long acting local anaesthetic with a clinical profile closely resembling that of bupivacaine. However, current preclinical safety and toxicity data show an advantage for levobupivacaine over bupivacaine. Clinical data comparing levobupivacaine with ropivacaine are needed before the role of the drug can be fully established. Excluding pharmacoeconomic considerations, levobupivacaine is an appropriate choice for use in place of bupivacaine.     

Lack of effect of cimetidine on the pharmacokinetics of bupivacaine in healthy subjects.

1. The possibility of a pharmacokinetic interaction between the H2-receptor antagonist cimetidine and the long-acting local anaesthetic agent bupivacaine was studied in seven healthy, non-smoking volunteers. 2. The study consisted of two sessions at a minimum interval of 4 days. In a randomized, crossover fashion, the volunteers received bupivacaine HCl 1.4 mg kg-1 by i.m. injection at two occasions, once after no premedication, and once after two oral doses of 400 mg cimetidine. The concentrations of bupivacaine and its metabolites, 4'-hydroxybupivacaine and desbutylbupivacaine, were assayed by h.p.l.c., in serum up to 8 h and in urine fractions up to 24 h. 3. No influence of cimetidine on the pharmacokinetics of bupivacaine or on the serum cumulation of urinary recovery of its measured metabolites was detected. 4. These data suggest that cimetidine may be used safely as a premedication before local anaesthetic procedures with bupivacaine.     

Pharmacokinetic profile of epidurally injected bupivacaine in awake patients

In order to investigate the influence of general anaesthesia on the pharmacokinetics of bupivacaine 0.5% after a single, epidurally injected dose of 20ml (= 100mg), 5 patients, scheduled for surgical procedures appropriate for epidural anaesthesia without the need for combination with general anaesthesia, were studied. In all patients an arterial, central venous and intrathecal catheter were inserted for sampling of, respectively, arterial and central venous blood and cerebrospinal fluid (CSF), at regular intervals up to 12 hours after administration. Bupivacaine was analysed by gas chromatography. The drug appeared after 2 minutes in the plasma and CSF samples, and was still detectable after 12 hours. There were no significant differences between the bupivacaine concentrations in the arterial and central venous plasma samples at all times. The same applied for the calculated plasma pharmacokinetic parameters at all intervals. The bupivacaine concentrations in the CSF were many dozen times higher than in the plasma samples at all times. There was no clear evidence of a pulmonary retention of bupivacaine in this study. From a pharmacokinetic point of view the epidural anaesthesia was largely spinal anaesthesia.     

Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep

1. The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupivacaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis. 2. In previous preclinical studies of the safety of these drugs with intravenous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excito-toxicity reversed the cardiac depressant effects when doses approached the convulsant threshold and thus precluded accurate comparison of their cardiovascular system (CVS) effects. 3. To study CVS effects over a wide range of doses with minimal CNS and other influences, brief (3 min) infusions of bupivacaine, levobupivacaine or ropivacaine were administered into the left main coronary arteries of previously instrumented conscious ewes (approximately 50 Kg body weight). After dose-ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 micromol (approximately 2.5 mg) in 8 micromol increments, to either a fatal outcome or a 40 micromol (approximately 12.5 mg) maximum. 4. All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: four of six with bupivacaine (mean+/-s.e.mean actual fatal dose: 21.8+/-6.4 micromol), five of seven with levobupivacaine (22.9+/-3.5 micromol), four of six with ropivacaine (22.9+/-5.9 micromol). No significant differences in survival or in fatal doses between these drugs were found. 5. The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosage.