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Pharmacokinetics of Local Anesthetics

  • Chapter
Local Anesthetics

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 81))

Abstract

Utilizing the pharmacokinetics of local anesthetic agents has different emphasis than for most other drugs, as these agents are applied directly to the site of their action rather than being transported in the blood stream to this site. Toxic reactions to local anesthetics are usually associated with the accidental intravenous injection of drug, but toxic effects can occur in normal usage. A knowledge of how the body handles these agents will help in understanding why these reactions can occur and also their different pharmacological behaviour.

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References

  • Aberg G (1972) Toxicological and local anaesthetic effects of optically active isomers of two local anaesthetic compounds. Acta Pharmacol Toxicol 31:273–286

    CAS  Google Scholar 

  • Akerman B, Ross S (1970) Stereospecificity of the enzymatic biotransformation of the en-antiomers of prilocaine. Acta Pharmacol Toxicol 28:445–453

    CAS  Google Scholar 

  • Akerman B, Astrom A, Ross S, Telc A (1966 a) Studies on the absorption, distribution and metabolism of labelled prilocaine and lidocaine in some animal species. Acta Pharmacol Toxicol 24:389–403

    CAS  Google Scholar 

  • Akerman B, Petersson SA, Wistrand P (1966 b) Methemoglobin forming metabolites of prilocaine. Third International Pharmacological Congress: Abstracts of Communications, Lectures and Symposia, July 24–30, 1966, Sao Paolo, Brazil, p 237

    Google Scholar 

  • Arthur GR (1981) Distribution and elimination of local anesthetic agents: the role of lung, liver and kidneys Ph D thesis, University of Edinburgh

    Google Scholar 

  • Arthur GR, Scott DHT, Boyes RN, Scott DB (1979) Pharmacokinetic and clinical pharmacological studies with mepivacaine and prilocaine. Br J Anaesth 51:481–485

    PubMed  CAS  Google Scholar 

  • Bax ND, Tucker GT, Woods HF (1980) Lignocaine and indocyanine green kinetics in patients following myocardial infarction. Br J Clin Pharmacol 10:353–361

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Meister W (1978) Clinical pharmacokinetics of lignocaine. Clin Pharma-cokinet 3:177–201

    CAS  Google Scholar 

  • Benowitz N, Forsyth RP, Melmon KL, Rowland M (1974) Lidocaine disposition kinetics in monkey and man. I. Prediction by a perfusion model. Clin Pharmacol Ther 16: 87–98

    PubMed  CAS  Google Scholar 

  • Bertler A, Lewis DH, Lofstrom JB, Post C (1978) In vivo lung uptake of lidocaine in pigs. Acta Anaesthesiol Scand 22:530–536

    PubMed  CAS  Google Scholar 

  • Bloedow DC, Ralston DH, Hargrove JC (1980) Lidocaine pharmacokinetics in pregnant and nonpregnant sheep. J Pharm Sci 69:32–37

    PubMed  CAS  Google Scholar 

  • Boyes RN (1975) A review of the metabolism of amide local anaesthetic agents. Br J Anaesth 47:225–230

    PubMed  Google Scholar 

  • Brodie BB, Lief PA, Poet R (1948) The fate of procaine in man following its intravenous administration and methods for the estimation of procaine and diethylaminoethanol. J Pharmacol Exp Ther 94:359–366

    PubMed  CAS  Google Scholar 

  • Bromage PR, Gertel M (1972) Brachial plexus anaesthesia in chronic renal failure. Anesthesiology 36:488–493

    PubMed  CAS  Google Scholar 

  • Brown JE, Kitchell BB, Bjornsson TD, Shand DG (1981) The artifactual nature of heparin- induced drug protein binding alterations. Clin Pharmacol Ther 30:636–643

    PubMed  CAS  Google Scholar 

  • Burney RG, Difazio CA, Foster JA (1978) Effects of pH on protein binding of lidocaine. Anesth Analg 57:478–480

    PubMed  CAS  Google Scholar 

  • Caldwell J, Moffatt JR, Smith RL, Lieberman BA, Cawston MO, Beard RW (1976) Pharmacokinetics of bupivacaine administered epidurally during childbirth. Br J Clin Pharmacol 3:956P-957P

    CAS  Google Scholar 

  • Collinsworth KA, Strong JM, Atkinson AJ, Winkle RA, Pelroth F, Harrison DC (1975) Pharmacokinetics and metabolism of lidocaine in patients with renal failure. Clin Pharmacol Ther 18:59–64

    PubMed  CAS  Google Scholar 

  • Covino BG, Vassallo HG (1976) Local anesthetics. Mechanisms of action and clinical use. Grune and Stratton, New York

    Google Scholar 

  • Coyle DE, Denson DD (1982) Plasma protein binding of bupivacaine in the dog. Anesthesiology 5:A209

    Google Scholar 

  • Cusack B, Kelly JG, Lavan J, Noel J, O’Malley K (1980) Pharmacokinetics of lignocaine in the elderly (Proceedings). Br J Clin Pharmacol 9:293–294

    Google Scholar 

  • De Boer AG, Breimer DD, Pronk J, Gubbens Stibbe JM (1980) Rectal bioavailability of lidocaine in rats. Absence of significant first pass elimination. J Pharm Sci 69:804–807

    PubMed  Google Scholar 

  • Denson DD, Ritschel WA, Turner PA, Ohlweiler DF, Bridenbaugh PO (1981) A comparison of the intravenous and subarachnoid lidocaine pharmacokinetics in the rhesus monkey. Biopharm Drug Dispos 2:367–380

    PubMed  CAS  Google Scholar 

  • DuSouich P, Erill P (1977) Altered metabolism of procainamide and procaine in patients with pulmonary and cardiac disease. Clin Pharmacol Ther 21:101–102

    Google Scholar 

  • Edwards DJ, Lalka D, Cerra F, Slaughter RL (1982) Alpha 1 - acid glycoprotein concentration and protein binding in trauma. Clin Pharmacol Ther 31:62–67

    PubMed  CAS  Google Scholar 

  • Effros RM, Chinard P (1969) The in vivo pH of the extravascular space of the lung. J Clin Invest 48:1983–1996

    PubMed  CAS  Google Scholar 

  • Elvin AT, Cole AF, Pieper JA, Rolbin SH, Lalka D (1981) Effect of food on lidocaine kinetics: mechanism of food-related alteration in high intrinsic clearance drug elimination. Clin Pharmacol Ther 30:455–460

    PubMed  CAS  Google Scholar 

  • Eriksson E (1966) Prilocaine. An experimental study in man of a new local anesthetic with special regard to efficacy, toxicity and excretion. Acta Chir Scand (Suppl) 358:1–82

    CAS  Google Scholar 

  • Esquivel M, Blaschke TF, Snidow GH, Meffin PJ (1978) Effect of phenobarbitone on the disposition of lignocaine and warfarin in the dog. J Pharm Pharmacol 30:804–805

    PubMed  CAS  Google Scholar 

  • Feely J, Wade D, McAllister CB, Wilkinson GR, Robertson D (1982 a) Effect of hypotension on liver blood flow and lidocaine disposition. N Engl J Med 307:866–868

    PubMed  CAS  Google Scholar 

  • Feely J, Wilkinson GR, McAllister CR, Wood AJJ (1982 b) Increased toxicity and reduced clearance of lidocaine by cimetidine. Ann Intern Med 96:592–594

    PubMed  CAS  Google Scholar 

  • Feinstein MB, Paimre M (1969) Pharmacological action of local anesthetics on excitation-contraction coupling in striated and smooth muscle. Fed Proc 28:1643–1648

    PubMed  CAS  Google Scholar 

  • Feldman HS, Covino BG (1981) A chronic model for investigation of experimental spinal anesthesia in the dog. Anesthesiology 54:148–152

    PubMed  CAS  Google Scholar 

  • Foldes FF, Davidson GM, Duncalf D, Kunabara S (1965) The intravenous toxicity of local anesthetic agents in man. Clin Pharmacol Ther 6:328–335

    PubMed  CAS  Google Scholar 

  • Friedman GA, Rowlingson JC, Difazio CA, Donegan MF (1982) Evaluation of the analgesic effect and urinary excretion of systemic bupivacaine in man. Anesth Analg 61:23–27

    PubMed  CAS  Google Scholar 

  • Geddes IC (1965) Studies on the metabolism of Citanest 14C. Acta Anaesthesiol Scand (Suppl) 16:37–44

    CAS  Google Scholar 

  • Giasi RM, D’Agostino E, Covino BG (1980) Interaction of diazepam and epidurally administered local anesthetic agents. Reg Anesth 5:8–11

    Google Scholar 

  • Goehl TJ, Davenport JB, Stanley MJ (1973) Distribution, biotransformation and excretion of bupivacaine in the rat and the monkey. Xenobiotica 3:761–772

    PubMed  CAS  Google Scholar 

  • Goldberg MJ, Spector R, Johnson GF (1982) Racial background and lidocaine pharmacokinetics. J Clin Pharmacol 22:391–394

    PubMed  CAS  Google Scholar 

  • Greenblatt DJ, Sellers EM, Shader RI (1982) Drug disposition in old age. N Engl J Med 306:1081–1088

    PubMed  CAS  Google Scholar 

  • Grossman SH, Davis D, Kitchell BB, Shand DG, Routledge PA (1982) Diazepam and lidocaine plasma protein binding in renal disease. Clin Pharmacol Ther 31:350–357

    PubMed  CAS  Google Scholar 

  • Halkin H, Meffin P, Melmon KL, Rowland M (1975) Influence of congestive heart failure on blood levels of lidocaine and its active monodeethylated metabolite. Clin Pharmacol Ther 17:669–676

    PubMed  CAS  Google Scholar 

  • Hansson E (1971) Absorption, distribution and excretion of local anesthetics. Int Encycl Pharmacol Ther 8:239–260

    CAS  Google Scholar 

  • Hollunger G (1960) Some characteristics of an amide-hydrolysing microsomal enzyme before and after its solubilization. Acta Pharmacol Toxicol 17:384–389

    CAS  Google Scholar 

  • Irestedt L, Andreen M, Belfrage P, Fagerstrom T (1978) The elimination of bupivacaine (Marcaine(r)) after short intravenous infusion in the dog: with special reference to the role played by the liver and lungs. Acta Anaesthesiol Scand 22:413–422

    PubMed  CAS  Google Scholar 

  • Jackson PR, Tucker GT, Woods HF (1982) Altered plasma drug binding in cancer: role of α1-acid glycoprotein and albumin. Clin Pharmacol Ther 32:295–302

    PubMed  CAS  Google Scholar 

  • Jorfeldt L, Lewis DH, Lofstrom JB, Post C (1979) Lung uptake of lidocaine in healthy volunteers. Acta Anaesthesiol Scand 23:567–574

    PubMed  CAS  Google Scholar 

  • Keenaghan JB, Boyes RN (1972) The tissue distribution, metabolism and excretion of lidocaine in rats, guinea pigs, dogs and man. J Pharmacol Exp Ther 180:454–463

    PubMed  CAS  Google Scholar 

  • Ketterer SG, Wiegand BD, Rapaport E (1960) Hepatic uptake and biliary excretion of indocyanine green and its use in estimation of hepatic blood flow in dogs. Am J Physiol 199:481–484

    PubMed  CAS  Google Scholar 

  • Lalka D, Vicuna N, Burrow SR, Jones DJ, Ludden TM, Haegele KD, McNay JL (1978) Bupivacaine and other amide local anesthetics inhibit the hydrolysis of chloroprocaine by human serum. Anesth Analg 57:534–539

    PubMed  CAS  Google Scholar 

  • Lanks KW, Sklar GS (1980) Pseudocholinesterase levels and rates of chloroprocaine hydrolysis in patients receiving adequate doses of phospholine iodide. Anesthesiology 52:434–435

    PubMed  CAS  Google Scholar 

  • Le Lorier J, Moisan R, Gagne J, Caille G (1977) Effect of the duration of infusion on the disposition of lidocaine in dogs. J Pharmacol Exp Ther 203:507–511

    Google Scholar 

  • Lebeaux MI (1973) Experimental epidural anesthesia in the dog with lignocaine and bupivacaine. Br J Anaesth 45:549–555

    PubMed  CAS  Google Scholar 

  • Lebeaux M (1975) Sheep: a model for testing spinal and epidural anesthetic agents. Lab Anim Sci 25:629–633

    PubMed  CAS  Google Scholar 

  • Lennard MS, Bax NDS, Tucker GT, Woods HF (1978) Product-inhibition of hepatic lignocaine metabolism. Clin Sci Mol Med 55:5p

    Google Scholar 

  • Magno R, Berlin A, Karlsson K, Kjellmer I (1976) Anesthesia for cesarean section IV. Placental transfer and neonatal elimination of bupivacaine following epidural analgesia for elective cesarean section. Acta Anaesthesiol Scand 20:141–146

    PubMed  CAS  Google Scholar 

  • Mather LE, Thomas J (1978) Bupivacaine binding to plasma protein fractions. J Pharm Pharmacol 30:653–654

    PubMed  CAS  Google Scholar 

  • Mather LE, Tucker GT (1978) Pharmacokinetics and biotransformation of local anesthetics. Anesthesiol Clin 16:23–51

    CAS  Google Scholar 

  • McNamara PJ, Slaughter RL, Visco JP, Elwood CM, Siegel JH, Lalka D (1980) Effect of smoking on binding of lidocaine to human serum proteins. J Pharm Sci 69:749–751

    PubMed  CAS  Google Scholar 

  • McNamara PJ, Slaughter RL, Pieper JA, Wyman MG, Lalka D (1981) Factors influencing serum protein binding of lidocaine in humans. Anesth Analg 60:395–400

    PubMed  CAS  Google Scholar 

  • Meffin P, Thomas J (1973) The relative rates of formation of the phenolic metabolites of mepivacaine in man. Xenobiotica 3:625–632

    PubMed  CAS  Google Scholar 

  • Meffin P, Robertson AV, Thomas J, Winkler J (1973) Neutral metabolites of mepivacaine in humans. Xenobiotica 3:191–196

    PubMed  CAS  Google Scholar 

  • Mihaly GW, Moore RG, Thomas J, Triggs EJ, Thomas D, Shanks CH (1978) The pharmacokinetics of the anilide type local anesthetics in neonates: I. Lignocaine. Eur J Clin Pharmacol 13:143–152

    PubMed  CAS  Google Scholar 

  • Moore RG, Thomas J, Triggs EJ, Thomas DB, Burnard ED, Shanks CA (1978) The pharmacokinetics and metabolism of the anilide local anesthetics in neonates: III. Mepivacaine. Eur J Clin Pharmacol 14:203–212

    PubMed  CAS  Google Scholar 

  • Morgan DH, McQuillan D, Thomas J (1978) Pharmacokinetics and metabolism of the anilide type local anesthetics in neonates: II. Etidocaine. Eur J Clin Pharmacol 13:365–371

    PubMed  CAS  Google Scholar 

  • Morgan DJ, Smyth MP, Thomas J, Vine J (1977) Cyclic metabolites of etidocaine in humans. Xenobiotica 7:365–375

    PubMed  CAS  Google Scholar 

  • Morgan DJ, Koay BB, Paull JD (1982) Plasma protein binding of etidocaine during pregnancy and labor. Eur J Clin Pharmacol 22:451–458

    PubMed  CAS  Google Scholar 

  • Morishima HO, Finster M, Pedersen AL, Fukunaga A, Ronfeld RA, Vassallo HG, Covino BG (1979) Pharmacokinetics of lidocaine in fetal and neonatal lambs and adult sheep. Anesthesiology 50:431–436

    PubMed  CAS  Google Scholar 

  • Nation RL, Triggs EJ, Selig M (1977) Lignocaine kinetics in cardiac patients and aged subjects. Br J Clin Pharmacol 4:439–448

    PubMed  CAS  Google Scholar 

  • O’Brien JE, Abbey V, Hinsvark O, Perel J, Finster M (1979) Metabolism and measurement of chloroprocaine, an ester-type local anesthetic. J Pharm Sci 68:75–78

    PubMed  Google Scholar 

  • Ochs HR, Carstens G, Greenblatt DJ (1980) Reduction in lidocaine clearance during continuous infusion and by co-administration of propranolol. N Engl J Med 303:373–377

    PubMed  CAS  Google Scholar 

  • Pedersen H, Morishima HO, Finster M, Arthur GR, Covino BG (1982) Pharmacokinetics of etidocaine in fetal and neonatal lambs and adult sheep. Anesth Analg 61:104–108

    PubMed  CAS  Google Scholar 

  • Piafsky KM, Knoppert D (1978) Binding of local anesthetics to α1-acid glycoprotein. Clin Res 26:836 A

    Google Scholar 

  • Post C, Andersson RGG, Rynfeldt A, Nilsson E (1979) Physico-chemical modification of lidocaine uptake in rat lung tissue. Acta Pharmacol Toxicol 44:103–109

    CAS  Google Scholar 

  • Price HL, Kovnat PJ, Safer JM, Conner EH, Price ML (1960) The uptake of thiopental by body tissues and its relation to the duration of narcosis. Clin Pharmacol Ther 1:16–22

    CAS  Google Scholar 

  • Raj PP, Ohlweiler D, Hitt BA, Denson DD (1980) Kinetics of local anesthetic esters and the effects of adjuvant drugs on 2–chloroprocaine hydrolysis. Anesthesiology 53:307–314

    PubMed  CAS  Google Scholar 

  • Reidenberg MM, James M, Dring LG (1972) The rate of procaine hydrolysis in serum of normal subjects and diseased patients. Clin Pharmacol Ther 13:279–284

    PubMed  CAS  Google Scholar 

  • Reynolds F (1971) Metabolism and excretion of bupivacaine in man: a comparison with mepivacaine. Br J Anaesth 43:23–37

    Google Scholar 

  • Rothstein P, Arthur GR, Feldman H, Barash PG, Kopf G, Sudan N, Covino BG (1982) Pharmacokinetics of bupivacaine in children following intercostal block. Anesthesiology 5:A426

    Google Scholar 

  • Rothstein P, Arthur GR, Feldman HS, Covino BG (1983) The lung modifies arterial concentrations of bupivacaine in humans. Reg Anesth 8:44

    Google Scholar 

  • Routledge PA, Barchowsky A, Bjornsson TD, Kitchell BB, Shand DG (1980) Lidocaine plasma protein binding. Clin Pharmacol Ther 27:347–351

    PubMed  CAS  Google Scholar 

  • Routledge PA, Shand DG, Barchowsky A, Wagner G, Stargel WW (1981 a) Relationship between alpha 1-acid glycoprotein and lidocaine disposition in myocardial infarction. Clin Pharmacol Ther 30:154–157

    PubMed  CAS  Google Scholar 

  • Routledge PA, Stargel WW, Kitchell BB, Barchowsky A, Shand DG (1981 b) Sex-related differences in the plasma protein binding of lignocaine and diazepam. Br J Clin Pharmacol 11:245–250

    PubMed  CAS  Google Scholar 

  • Sawyer DR, Ludden TM, Crawford MH (1981) Continuous infusion of lidocaine in patients with cardiac arrhythmias. Unpredictability of plasma concentrations. Arch Intern Med 141:43–45

    PubMed  CAS  Google Scholar 

  • Scott DB, Jebson PJR, Braid DP, Ortengren B, Frisch P (1972) Factors affecting plasma levels of lignocaine and prilocaine. Br J Anaesth 44:1040–1049

    PubMed  CAS  Google Scholar 

  • Seifen AB, Ferrari AA, Seifen EE, Thompson DS, Chapman J (1979) Pharmacokinetics of intravenous procaine infusion in humans. Anesth Analg 58:382–386

    PubMed  CAS  Google Scholar 

  • Shand DG, Kornhawer DM, Wilkinson GR (1975) Effects of route of administration and blood flow on hepatic drug elimination. J Pharmacol Exp Ther 195:424–432

    PubMed  CAS  Google Scholar 

  • Thomas J, Meffin P (1972) Aromatic hydroxylation of lidocaine and mepivacaine in rats and humans. J Med Chem 15:1046–1049

    PubMed  CAS  Google Scholar 

  • Thomas J, Morgan D, Vine J (1976) Metabolism of etidocaine in man. Xenobiotica 6:39–48

    PubMed  CAS  Google Scholar 

  • Thompson PD, Rowland M, Melmon K (1971) Influence of heart failure, liver disease and renal failure on the disposition of lidocaine in man. Am Heart J 82:417–421

    Google Scholar 

  • Triggs EJ, Nation RL, Long A, Ashley JJ (1975) Pharmacokinetics in the elderly. Eur J Clin Pharmacol 8:55–62

    PubMed  CAS  Google Scholar 

  • Tucker GT, Boas RA (1971) Pharmacokinetic aspects of intravenous regional anesthesia. Anesthesiology 34:538–549

    PubMed  CAS  Google Scholar 

  • Tucker GT, Mather LE (1975) Pharmacokinetics of local anesthetic agents. Br J Anaesth 47:213–224

    PubMed  Google Scholar 

  • Tucker GT, Mather LE (1979) Clinical pharmacokinetics of local anesthetics. Clin Phar-macokinet 4:241–278

    CAS  Google Scholar 

  • Tucker GT, Boyes RN, Bridenbaugh PO, Moore DC (1970) Binding of anilide-type local anesthetics in humans plasma: I. Relationships between binding, physicochemical properties anesthetic activity. Anesthesiology 33:287–303

    PubMed  CAS  Google Scholar 

  • Tucker GT, Wiklund L, Berlin-Wahlen A, Mather LE (1977) Hepatic clearance of local anesthetics in man. J Pharmacokinet Biopharm 5:111–122

    PubMed  CAS  Google Scholar 

  • Vine J, Morgan D, Thomas D (1978) The identification of eight hydroxylated metabolites of etidocaine by chemical ionization mass spectrometry. Xenobiotica 8:509–513

    PubMed  CAS  Google Scholar 

  • Wiklund L (1977 a) Human hepatic blood flow and its relation to systemic circulation during intravenous infusion of lidocaine. Acta Anaesthesiol Scand 21:148–160

    PubMed  CAS  Google Scholar 

  • Wiklund L (1977) Human hepatic blood flow and its relation to systemic circulation during intravenous infusion of bupivacaine and etidocaine. Acta Anaesthesiol Scand 21:189–199

    PubMed  CAS  Google Scholar 

  • Wood M, Wood AJ (1981) Changes in plasma drug binding and alpha 1 acid glycoprotein in mother and newborn infant. Clin Pharmacol Ther 29:522–526

    PubMed  CAS  Google Scholar 

  • Wyler F (1974) Effect of general anesthesia on distribution of cardiac output and organ blood flow in the rabbit: halothane and chloralose-urethane. J Surg Res 17:381–386

    PubMed  CAS  Google Scholar 

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  1. G. R. Arthur
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Editors and Affiliations

  1. Anesthesia Research Laboratories, Brigham and Women’s Hospital, Boston, MA, 02115, USA

    Gary R. Strichartz Ph. D. (Associate Professor) (Associate Professor)

  2. Department of Pharmacology, Harvard Medical School, Boston, MA, 02115, USA

    Gary R. Strichartz Ph. D. (Associate Professor) (Associate Professor)

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© 1987 Springer-Verlag Berlin Heidelberg

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Arthur, G.R. (1987). Pharmacokinetics of Local Anesthetics. In: Strichartz, G.R. (eds) Local Anesthetics. Handbook of Experimental Pharmacology, vol 81. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-71110-7_5

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  • DOI: https://doi.org/10.1007/978-3-642-71110-7_5

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