Anesth Analg 2006;102:473-477
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000189603.11216.c9
ANESTHETIC PHARMACOLOGY
The Effects of Local Anesthetics on Bile Flow, Potassium Equilibrium and Oxygen Consumption in the Perfused Rat Liver
Peter Felleiter, MD*,
Peter Lierz, MD
, and
Jürg Graf, MD
Department of *Intensive Care Medicine, Swiss Paraplegic-Centre Nottwil, Switzerland; Department of Anesthesiology and Intensive Care Medicine, Marienkrankenhaus Soest, Germany; and Department of Pathophysiology, Medical University of Vienna, Austria
Address correspondence and reprint requests to Peter Felleiter, MD, Swiss Paraplegic Centre Nottwil, CH-6207 Nottwil, Switzerland. Address e-mail to peter.felleiter{at}paranet.ch.
 |
Abstract
|
|---|
Amide local anesthetics mainly undergo hepatic metabolism. Specific applications, such as catheter application for long-term pain therapy, may result in large plasma concentrations. As it is unknown whether local anesthetics influence liver function, we examined the influence of lidocaine, bupivacaine, and ropivacaine in concentrations of 1 and 10 µg/mL on the metabolic activity of the perfused rat liver. At the large concentrations, all three local anesthetics caused an immediate increase of oxygen consumption. Bupivacaine and ropivacaine also transiently reduced potassium release. All drugs increased bile flow; this choleretic effect was also significant for bupivacaine and lidocaine in smaller concentrations. In the smaller concentration, only lidocaine significantly increased oxygen consumption. No significant changes in hepatic venous pH were observed. The results show that acute administration of all three local anesthetics results in significant changes of functional variables of the liver. The observed effects appear to result from mitochondrial uncoupling, uptake of the drugs, biliary secretion of their metabolites, and from inhibition of potassium channels. The data provide no evidence that these acute changes may result in enduring postoperative disturbances of liver function, such as cholestasis or jaundice.
|
Introduction
|
|---|
Research into the systemic effects of local anesthetics has been focused mainly on the cardiac and central nervous system (CNS). Severe side effects are dependent on the blood concentration of the drug and include seizures, decreases in myocardial contractility, arrhythmias, and hypertension. For the common use of these drugs, single or repeated bolus injections, these effects are of utmost importance.
Newer local anesthetics, such as ropivacaine, trigger cardiac and CNS side effects only at larger plasma concentrations (1). Their wider therapeutic range may lead to the acceptance of larger plasma concentrations, for example by using epidural and peripheral catheters for long-term pain therapy. Tachyphylaxis to local anesthetics, defined as a decrease in intensity or duration of the analgesic effect after repeated doses, is another possible reason for larger plasma concentrations resulting from increased dosages over time. Under these circumstances, other systemic effects of these drugs may become increasingly important.
Local anesthetics of the amide type undergo mainly hepatic metabolism. It is unknown whether local anesthetics influence liver function. Alterations of liver metabolism may be a direct effect of the local anesthetic or may result from decreased hepatic perfusion. For the most common types of local anesthetics in current use, there is a lack of data on the effects on the liver. Knowledge of the effects might influence both the indication for regional anesthesia and the choice of anesthetic. We therefore examined the influence of lidocaine, bupivacaine, and ropivacaine on the metabolic activity of the perfused rat liver. Our aim was to determine whether there are alterations on bile flow, potassium equilibrium, acid-base equilibrium, and oxygen consumption and whether these effects differ between the local anesthetics and different concentrations.
|
Methods
|
|---|
The animal protocol was approved by the animal care and use committee of the University of Vienna. Twenty-one male Wistar rats (Forschungsinstitut für Versuchstierzucht und–haltung, Himberg, Austria), weighing 200 to 250 g, were used as liver donors. After cannulation of the common bile duct and of portal and hepatic veins the liver was placed on a Perspex support and perfused at 37°C with Krebs-Henseleit buffer equilibrated with 95% O2 and 5% CO2 at a rate of 3 to 3.5 mL/g liver/min (120 mM NaCl, 4.8 mM KCl, 2.6 mM CaCl2, 1.2 mM MgSO4, 1.2 mM KH2PO4, 25 mM HCO3, 5 mM glucose, pH adjusted to 7.4). Bile flow was measured by the weight of bile drops (approximately 8 mg) and the time interval between their falling from the bile duct cannula and interrupting an infrared light beam in a drop counter. Hepatic venous effluent perfusate was led through an array of electrodes composed of an amperometric Clark type oxygen electrode (PHM 71; Radiometer, Copenhagen, Denmark) and pH and potassium electrodes from a Nova 9 electrolyte analyzer (Nova Biomedical, Newton, MA). Data acquisition was by the FeliXTM software (Photon Technology International, Ford, West Sussex, UK) and bile flow, venous pH, K+ concentration, and oxygen tension were continuously monitored. Calibration values for the latter three variables were obtained after removal of the liver at the end of the experiment. Ropivacaine, bupivacaine, and lidocaine were obtained from AstraZeneca (Vienna, Austria) and applied to the portal perfusion medium at concentrations of 1 or 10 µg/mL beginning 30 min after the start of the experiment. Each concentration of the different local anesthetics was tested in at least three independent experiments; each liver was used for only one single experiment.
The data are expressed as mean ± sd and were analyzed by paired Student's t-test. Differences between values obtained 1 min before and during 2 to 3 min after application of the drugs were considered to be statistically significant at a P value of <0.05.
|
Results
|
|---|
Continuous measurements of bile flow and of venous effluent oxygen tension, pH, and potassium concentration revealed stable values after a perfusion period of 30 min. This time is required for the liver to recover from hypoxia during surgery and is characterized by large initial oxygen consumption and reuptake of potassium. Stable variables attained before application of the drugs were (n = 19) bile flow: 0.74 ± 0.18 mg/g liver/min, oxygen consumption: 1.35 ± 0.22 µmoles/g liver/min, and potassium release 0.50 ± 0.48 µmoles/g liver/min. Hepatic venous perfusate pH was 0.12 ± 0.04 U below 7.4, the value for portal venous perfusate pH. Figure 1 shows mean results obtained from 4 experiments with application of ropivacaine at a concentration of 10 µg/mL. The data show that ropivacaine causes an immediate increase of oxygen consumption, whereas potassium release was transiently reduced, or even reversed, to potassium uptake. Bile flow showed a more gradual increase and was nearly doubled 5 min after application of the drug. No significant changes in acid-base equilibrium (hepatic venous pH) were observed (data not shown). Similar effects on bile flow, oxygen consumption, and potassium release were seen for 10 µg/mL bupivacaine and lidocaine, except that the change in potassium release after application of lidocaine did not reach the level of significance (Figs. 2–4). The data obtained with small concentrations of 1 µg/mL also revealed a tendency towards an increase in bile flow and oxygen consumption after application of the drugs, but, at this smaller concentration, the choleretic effect was significant only for bupivacaine and lidocaine. Only lidocaine in small concentration significantly increased oxygen consumption.
View larger version (27K):
[in this window]
[in a new window]
|
Figure 1. Effects of 10 µg/mL ropivacaine in the perfused rat liver on oxygen consumption, bile flow, and potassium release.
|
|
View larger version (10K):
[in this window]
[in a new window]
|
Figure 2. Changes in bile flow after application of ropivacaine (R), bupivacaine (B), or lidocaine (L) at concentrations of 10 µg/mL or 1 µg/mL.
|
|
View larger version (12K):
[in this window]
[in a new window]
|
Figure 3. Changes in oxygen consumption after application of ropivacaine (R), bupivacaine (B), or lidocaine (L) at concentrations of 10 µg/mL or 1 µg/mL.
|
|
View larger version (11K):
[in this window]
[in a new window]
|
Figure 4. Changes in potassium release after application of ropivacaine (R), bupivacaine (B), or lidocaine (L) at concentrations of 10 µg/mL or 1 µg/mL.
|
|
|
Discussion
|
|---|
Local anesthetics are widely used in anesthesiology, especially to provide perioperative pain management for surgical patients and to relieve chronic pain. Long-term application of local anesthetics via an epidural or peripheral catheter is being used more frequently to prolong the analgesic effect of regional anesthesia postoperatively or for pain relief in chronic pain patients. Direct effects of local anesthetics on the liver might influence the choice of drug, especially for these indications. Although local anesthetics have been shown to provide protection both against hepatic dysfunction in murine septic peritonitis (2) and in hepatic ischemia/reperfusion injury (3), very little is known about their direct influence on the liver.
We monitored the alterations on bile flow, oxygen consumption, and potassium equilibrium in the rat liver perfused with 2 different concentrations of the commonly used local anesthetics lidocaine, bupivacaine, and ropivacaine. The concentrations of 1 µg/mL and 10 µg/mL were chosen because plasma concentrations of local anesthetics in this order of magnitude have been described for various procedures in regional anesthesia (Table 1). Because of the limited duration of experiments using the isolated perfused rat liver, this method is inapplicable to detect possible long-term effects of local anesthetics.
Bile flow was stimulated by all local anesthetics tested, especially in large concentrations. Bile flow in our model is bile salt-independent and it is mainly sustained by the secretion of endogenous organic anions such as glutathione. Multidrug resistance protein 2 (Mrp2), also called the "canalicular multispecific organic anion transporter" (cMOAT), is the canalicular efflux transporter that pumps, besides glutathione, a variety of glucuronide-, glutathione-, and sulfate-conjugates of xenobiotics into bile (5). Similar to other substrates of Mrp2, it is therefore tempting to speculate that the choleretic effect of the tested drugs results from secretion of their conjugated metabolites. All amide-type local anesthetics are metabolized in the liver via a variety of cytochrome P450 isoenzymes. Lidocaine, which is also used as a test substance for the efficacy of hepatic detoxification, is N-dealkylated to monoethylglycinexylidide (MEGX) and aryl-hydroxylated to form 3-OH-lidocaine, 3-OH-MEGX, and 4-OH-2,6-xylidine (6). Ropivacaine and bupivacaine are also N-dealkylated to form pipecolylxylidine and also aryl-hydroxylated to their 3- and 4-OH-derivatives (7,8). The hydroxylated metabolites of all three anesthetic compounds are prone to phase II biotransformation, and their sulfatation and glucuronidation have been demonstrated (9,10). Consistent with these metabolic modifications, substantial biliary secretion of lidocaine and bupivacaine and of their respective metabolites have been reported for the rat (11,12) and approximately 10% of ropivacaine (and metabolites) are excreted via the feces in humans (13). Further studies are needed, however, to identify the mechanism by which these local anesthetics produce choleresis and to show whether the rate of the biliary secretion of these compounds indeed directly correlates with the increase of bile flow.
All three local anesthetics markedly increased oxygen consumption of the perfused rat liver. Because stimulation of hepatobiliary transport accounts for only a very small fraction of hepatic energy metabolism, other mechanisms for the stimulation of oxygen consumption have to be considered (14). Extensive research has been devoted to studying the effects of local anesthetics on mitochondrial respiration and their interference with oxidative phosphorylation. Up to 1 mM lidocaine stimulated basal (state 4) and adenosine diphosphate-stimulated (state 3) respiration and exhibited an uncoupling effect on oxidative phosphorylation of liver mitochondria (15). Similar effects have been shown for bupivacaine (16) and, to a lesser degree, for ropivacaine (17). Although these effects may explain the increase in oxygen consumption of the perfused liver as seen here, it is noted though that, in isolated mitochondria, increases of respiration and inhibition of adenosine triphosphate (ATP) synthesis are observed for all 3 anesthetic drugs only at concentrations more than 0.2 to 0.5 mM (e.g., in heart mitochondria) whereas perfusate concentrations used here are in the range of 3 to 30 µM. However, concentrative uptake into liver cells, which may have taken place as transport of lidocaine by the electrogenic rat organic cation transporter 1 (rOCT1) of the sinusoidal plasma membrane has been demonstrated (18). In this case, a direct effect of the anesthetic drugs on liver mitochondria in the perfused liver with increased respiration and decreased ATP production could be a mechanism of possible liver damage.
Intracellular potassium concentration is maintained by balanced K+ uptake by the activity of Na/K-ATPase and K+ release through K+ channels. In the perfused rat liver model, this pump-leak system is not precisely balanced and, after transient K+ uptake after the preparation of the organ, K+ is steadily released at a slow rate into the perfusion medium. Application of the local anesthetics inhibited this release or even reversed it into K+ uptake. In principle, this effect could be the result of both activation of K+ pumping and/or inhibition of K+ efflux through K+ channels. We find no indication in the literature that local anesthetics may activate Na/K-ATPase and, as noted above, fueling the pump may be even reduced by decreased ATP production. A number of K+ conducting channels have been described in rat liver cells, which include an inward rectifying K+ channel that is activated by cyclic AMP, a Ca2+-activated cell volume-sensitive channel and nonselective cation channels (19). No data are available on pharmacological effects on these channels that may pertain to the effects observed here. In contrast, besides their main effect on voltage gated Na+ channels, local anesthetic drugs inhibit various K+ channels in a number of other cells and tissues (20–22). We may, therefore, tentatively propose that the K+-sparing effect of local anesthetics as seen here results from inhibition of K+ channels in liver cells.
Postoperative cholestasis or jaundice is a frequent and significant clinical problem induced by a variety of different causes. It has also been proposed as a possible side effect of local anesthetics in rare cases (23), but this effect was not reproducible in a study by Wulf et al. (24). Because similar increases of hepatic microsomal enzyme activity are found after surgery under general or spinal anesthesia, the reason may be the surgical procedure itself (25). The results of our study demonstrate significant effects of local anesthetics on functional variables of the liver, but they provide no evidence that adverse effects on liver function, such as cholestasis, might be direct consequences of the local anesthetics lidocaine, bupivacaine, and ropivacaine, even in cases with very large plasma concentrations of the substances.
|
Footnotes
|
|---|
Supported, in part, by a grant of the Hochschuljubiläumsstiftung of the City of Vienna, Austria.
Accepted for publication August 31, 2005.
|
References
|
|---|
- Dony P, Dewinde V, Vanderick B, et al. The comparative toxicity of ropivacaine and bupivacaine at equipotent doses in rats. Anesth Analg 2000;91:1489–92.[Abstract/Free Full Text]
- Gallos G, Jones DR, Nasr SH, et al. Local anesthetics reduce mortality and protect against renal and hepatic dysfunction in murine septic peritonitis. Anesthesiology 2004;101:902–11.[ISI][Medline]
- Tomori H, Shiraishi M, Koga H, et al. Protective effects of lidocaine in hepatic ischemia/reperfusion injury in vitro. Transplant Proc 1998;30:3740–2.[ISI][Medline]
- Niesel HC. Klinische Pharmakologie und Toxikologie. In: Niesel HC, ed. Regionalanästhesie, Lokalanästhesie, regionale Schmerztherapie. Stuttgart, New York: Thieme, 1994:69–165.
- Zsembery A, Thalhammer T, Graf J. Bile formation: a concerted action of membrane transporters in hepatocytes and cholangiocytes. News Physiol Sci 2000;15:6–11.[Abstract/Free Full Text]
- Wang JS, Backman JT, Taavitsainen P, et al. Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans. Drug Metab Dispos 2000;28:959–65.[Abstract/Free Full Text]
- Ekström G, Gunnarsson UB. Ropivacaine, a new amide-type local anesthetic agent, is metabolized by cytochrome P450 1A and 3A in human liver microsomes. Drug Metab Dispos 1996;24:955–61.[Abstract]
- Gantenbein M, Attolini L, Bruguerolle B, et al. Oxydative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A. Drug Metab Dispos 2000;28:383–5.[Abstract/Free Full Text]
- Falany CN, Falany JL, Wang J, et al. Studies on sulfation of synthesized metabolites from the local anesthetics ropivacaine and lidocaine using human cloned sulfotransferases. Drug Metab Dispos 1999;27:1057–63.[Abstract/Free Full Text]
- Harkins JD, Karpiesiuk W, Tobin T, et al. Identification of hydroxyropivacaine glucuronide in equine urine by ESI+/MS/MS. Can J Vet Res 2000;64:178–83.[ISI][Medline]
- Keenaghan JB, Boyes RN. The tissue distribution, metabolism and excretion of lidocaine in rats, guinea pigs, dogs and man. J Pharmacol Exp Ther 1972;180:454–63.[Abstract/Free Full Text]
- Goehl TJ, Davenport JB, Stanley MJ. Distribution, biotransformation and excretion of bupivacaine in the rat and the monkey. Xenobiotica 1973;3:761–72.[ISI][Medline]
- Halldin MM, Bredberg E, Angelin B, et al. Metabolism and excretion of ropivacaine in humans. Drug Metab Dispos 1996;24:962–8.[Abstract]
- Schölmerich J, Baumgartner U, Miyai K, Gerok W. Hepatic passage of bile acids increases oxygen uptake by perfused rat liver. Res Exp Med (Berl) 1990;190:69–75.
- Tarba C, Cracium C. A comparative study of the effects of procaine, lidocaine, tetracaine and dibucaine on the functions and ultrastructure of isolated rat liver mitochondria. Biochim Biophys Acta 1990;1019:19–28.[Medline]
- Sztark F, Ouhabi R, Dabadie P, Mazat JP. Effects of the local anesthetic bupivacaine on mitochondrial energy metabolism: change from uncoupling to decoupling depending on the respiration state. Biochem Mol Biol Int 1997;43:997–1003.[ISI][Medline]
- Floridi A, Di Padova M, Barbieri R, Arcuri E. Effect of local anesthetic ropivacaine on isolated rat liver mitochondria. Biochem Pharmacol 1999;58:1009–16.[ISI][Medline]
- van Montfoort JE, Hagenbuch B, Groothuis GMM, et al. Drug uptake systems in liver and kidney. Curr Drug Metab 2003;4:185–211.[ISI][Medline]
- Graf J, Häussinger D. Ion transport in hepatocytes: mechanisms and correlations to cell volume, hormone actions and metabolism. J Hepatol. 1996;24(Suppl 1):53–77.
- Gonzalez T, Longobardo M, Caballero R, et al. Effects of bupivacaine and a novel local anesthetic, IQB-9302, on human cardiac K+ channels. J Pharmacol Exp Ther 2001;296:573–83.[Abstract/Free Full Text]
- Brau ME, Vogel W, Hempelmann G. Fundamental properties of local anesthetics: half-maximal blocking concentrations for tonic block of Na+ and K+ channels in peripheral nerve. Anesth Analg 1998;87:885–9.[Abstract/Free Full Text]
- Komai H, McDowell TS. Local anesthetic inhibition of voltage-activated potassium currents in rat dorsal root ganglion neurons. Anesthesiology 2001;94:1089–95.[ISI][Medline]
- Billström R, Blomberg HMS. Cholestasis after interpleural bupivacaine for chronic upper limb pain. Anesth Analg 1993;76:1158–9.[Free Full Text]
- Wulf H, Leger R, Raetzell M, et al. Cholestasis as a side effect of bupivacaine? Reg Anesth Pain Med 1998;23:278–82.[ISI][Medline]
- Loft S, Boel J, Kyst A, et al. Increased hepatic microsomal enzyme activity after surgery under halothane or spinal anesthesia. Anesthesiology 1985;62:11–6.[ISI][Medline]
This article has been cited by other articles:
|
|
|
|
 
B. Mets and E. A. Walker
Local Anesthetic Effect on Liver Function
Anesth. Analg.,
October 1, 2006;
103(4):
1045 - 1046.
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
