Local anesthetics agents actions and misconceptions

Local anesthetics: agents, actions, & misconceptions John Butterworth, MD Professor & Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina Local anesthetics: agents, actions, & misconceptions  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA toxicity  Summary W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-1  Cocaine = natural product Erythroxylon coca W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-1  Cocaine = natural product  Properties well-known to Incas Erythroxylon coca W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-1  Cocaine = natural product  Properties well-known to Incas  Chewed coca dripped on trepanning sites Skulls from trepanned patients www.epub.org.br/cm/n02/ historia/trepan6b.gif W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-1  Cocaine = natural product  Properties well-known to Incas  Chewed coca dripped on trepanning sites Trepanning knife From Renato Sabbatini, PhD W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-1  Cocaine = natural product  Properties well-known to Incas  Chewed coca dripped on trepanning sites  1500s: Spaniards seize plantations & pay workers with coca paste Spaniards and Native Slaves From: cocamuseum.com W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-1  Cocaine = natural product  Properties well-known to Incas  Chewed coca dripped on trepanning sites  1500s: Spaniards seize plantations & pay workers with coca paste  Mixed with corn starch, chewed with guano, CaCO3, or ash; first example of “free basing” Chewing coca From: cocamuseum.com W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-1  Cocaine = natural product  Properties well-known to Incas  Chewed coca dripped on trepanning sites  1500s: Spaniards seize plantations & pay workers with coca paste  Mixed with corn starch, chewed with guano, CaCO3, or ash; first example of “free basing”  Monardes brings coca back to Europe (1580); fails to achieve instant popularity of tobacco W A K E F O R E S T U N I V E R S I T Y S C H O O L Fresh coca leaves From Andy Graham of hobotraveler.com O F M E D I C I N E History of local anesthesia-2  Cocaine HCl isolated by Albert Niemann (1860) Cocaine HCl powder W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-2  Cocaine HCl isolated by Albert Niemann (1860)  Merck produces 100 g cocaine (1862) Cocaine HCl powder W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-2  Cocaine HCl isolated by Albert Niemann (1860)  Merck produces 100 g cocaine (1862)  Koller and Gartner report local anesthesia (1884) Cocaine HCl powder Carl Koller 1857 -1944 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-2  Cocaine HCl isolated by Albert Niemann (1860)  Merck produces 100 g cocaine (1862)  Koller and Gartner report local anesthesia (1884)  Merck produces 1450 kg (1884); 72,000 kg (1886) Cocaine HCl powder Carl Koller 1857 -1944 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-2  Cocaine HCl isolated by Albert Niemann (1860)  Merck produces 100 g cocaine (1862)  Koller and Gartner report local anesthesia (1884)  Merck produces 1450 kg (1884); 72,000 kg (1886)  Coca-Cola (1886) and many other products contain cocaine http://wings.buffalo.edu/ aru/preprohibition.htm W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E History of local anesthesia-2  Cocaine HCl isolated by Albert Niemann (1860)  Merck produces 100 g cocaine (1862)  Koller and Gartner report local anesthesia (1884)  Merck produces 1450 kg (1884); 72,000 kg (1886)  Coca-Cola (1886) and many other products contain cocaine http://wings.buffalo.edu/ aru/preprohibition.htm W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Early history of regional anesthesia  1884 Halsted injects cocaine directly into mandibular nerve William S. Halsted 1852-1922 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Early history of regional anesthesia  1884 Halsted injects cocaine directly into mandibular nerve  1885: Cocaine injected “near” spinal blood vessels of dog, producing probable epidural J. L. Corning Corning JL. NY Med J 1885:42:483-5 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Early history of regional anesthesia  1884 Halsted injects cocaine directly into mandibular nerve  1885: Cocaine injected “near” spinal blood vessels of dog, producing probable epidural  1891 Quincke describes lumbar puncture Heinrich I. Quincke 1842-1922 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Early history of regional anesthesia  1884 Halsted injects cocaine directly into mandibular nerve  1885: Cocaine injected “near” spinal blood vessels of dog, producing probable epidural  1891 Quincke describes lumbar puncture  1898 Bier and Hildebrandt undergo spinal anesthesia Professor August Bier 1861-1949 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Early history of regional anesthesia  1884 Halsted injects cocaine directly into mandibular nerve  1885: Cocaine injected “near” spinal blood vessels of dog, producing probable epidural  1891 Quincke describes lumbar puncture  1898 Bier and Hildebrandt undergo spinal anesthesia  1902 Sicard and Cathelin perform caudal epidural Dr. Jean Sicard 1872-1929 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Early history of regional anesthesia  1884 Halsted injects cocaine directly into mandibular nerve  1885: Cocaine injected “near” spinal blood vessels of dog, producing probable epidural  1891 Quincke describes lumbar puncture  1898 Bier and Hildebrandt undergo spinal anesthesia  1902 Sicard and Cathelin perform caudal epidural  1904 Einhorn discovers procaine (Novocaine) W A K E F O R E S T U N I V E R S I T Y S C H O O L Procaine O F M E D I C I N E Early history of regional anesthesia  1884 Halsted injects cocaine directly into mandibular nerve  1885: Cocaine injected “near” spinal blood vessels of dog, producing probable epidural  1891 Quincke describes lumbar puncture  1898 Bier and Hildebrandt undergo spinal anesthesia  1902 Sicard and Cathelin perform caudal epidural  1904 Einhorn discovers procaine (Novocaine) W A K E F O R E S T U N I V E R S I T Y 1909 Bier describes IV regional anesthesia Professor August Bier 1861-1949 Procaine Professor August Bier 1861-1949 S C H O O L O F M E D I C I N E Early history of regional anesthesia  1884 Halsted injects cocaine directly into mandibular nerve  1885: Cocaine injected “near” spinal blood vessels of dog, producing probable epidural  1891 Quincke describes lumbar puncture  1898 Bier and Hildebrandt undergo spinal anesthesia  1902 Sicard and Cathelin perform caudal epidural  1904 Einhorn discovers procaine (Novocaine) W A K E F O R E S T U N I V E R S I T Y 1909 Bier describes IV regional anesthesia 1921 Pages describes lumbar epidural anesthesia for abdominal surgery Dr. Fidel Pages S C H O O L O F M E D I C I N E Early history of regional anesthesia  1884 Halsted injects cocaine directly into mandibular nerve  1885: Cocaine injected “near” spinal blood vessels of dog, producing probable epidural  1891 Quincke describes lumbar puncture  1898 Bier and Hildebrandt undergo spinal anesthesia  1902 Sicard and Cathelin perform caudal epidural  1904 Einhorn discovers procaine (Novocaine) W A K E F O R E S T U N I V E R S I T Y 1909 Bier describes IV regional anesthesia 1921 Pages describes lumbar epidural anesthesia for abdominal surgery 1943 Lofgren discovers lidocaine (Xylocaine) Lidocaine Dr. Fidel Pages S C H O O L O F M E D I C I N E Local anesthetics: agents, actions, & misconceptions  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA toxicity  Summary W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Functions of voltage-gated Na channels  Propagate action potentials in nerve and muscle over long distances  Shape and filter synaptic inputs  Initiate, maintain cellular oscillations (sinus node) and burst generation (brain cells)  Mutations lead to muscle, cardiac, & neural diseases  Bind local anesthetics to produce regional anesthesia Lopreato. Proc Natl Acad Sci 2001;98:7588-92 Viswanathan & Balser. Trends Cardiovasc Med 2004;14:28-35 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Structural characteristics of Na channels  1 larger  subunit (230270 kD) (has ion conducting path)  1 or 2 smaller  subunits (37-39 kD)  All subunits heavily glycosylated  4 domains with 6 membrane-spanning regions  LA binding in D1-S6, D3S6 and D4-S6, not D2-S6 W A K E F O R E S T U N I V E R S I T Y From: Physiol Rev 1992;72:S15-S48 Ann Rev Biochem 1995;6:493-531 Biophys J 2000;79:1379-87 S C H O O L O F M E D I C I N E Structural characteristics of Na channels  1 larger  subunit (230270 kD) (has ion conducting path)  1 or 2 smaller  subunits (37-39 kD)  All subunits heavily glycosylated  4 domains with 6 membrane-spanning regions  LA binding in D1-S6, D3S6 and D4-S6, not D2-S6 W A K E F O R E S T U N I V E R S I T Y Outside Membrane Membrane From: Catterall & Mackie Ch 15, p334. Goodman & Gilman 9th Edition, 1996; Wang. Mol Pharm 2001;59:1100-7; Nau. Mol Pharm 1999;56:404-13 S C H O O L O F M E D I C I N E Inside Genomics of human Nav channels  Only 1 or 2 Nav genes in invertebrates  10 human genes on 4 chromosomes (5 on Chr 2 and 3 on Chr 3)  Cell-specific expression and localization of gene products Lopreato. Proc Natl Acad Sci 2001;98:7588-92 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E  Nav1.2 channels in axons of unmyelinated neurons  Nav1.6 channels in nodes of Ranvier  Nav1.8, Nav1.9 in small DRG nociceptors  Specific antagonists? Genomics of human Nav channels  Only 1 or 2 Nav genes in invertebrates  10 human genes on 4 chromosomes (5 on Chr 2 and 3 on Chr 3)  Cell-specific expression and localization of gene products Lopreato. Proc Natl Acad Sci 2001;98:7588-92 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E  Nav1.2 channels in axons of unmyelinated neurons  Nav1.6 channels in nodes of Ranvier  Nav1.8, Nav1.9 in small DRG nociceptors  Specific antagonists? Membrane potentials and ionic currents in neurons  Characteristic of living cells (-70 mV)  Na-K ATPase and K “leak” Potential (in mV)  Resting potential Squid axon, 16o  Action potential Time after stimulus (ms)  Na channels open, allow Na flux  Within milliseconds, Na channels return to nonconducting inactivated state W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Na channel conformations  3 channel forms: resting, open, & inactivated (1952)  Na+ ions pass only through open channels AL Hodgkin AF Huxley 1914-1998 1917Shared Nobel Prize in 1963 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Na channel conformations  3 channel forms: resting, open, & inactivated (1952)  Na+ ions pass only through open channels  No Na+ current through channels bound by LA GR Strichartz Brigham and Women’s Hospital  LA binding favored by: Harvard Medical School  Depolarization  Open or inactivated Na channels  Frequent impulses (use-dependence) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Use-dependent block of cardiac Na channels by LAs Control Control QX222 0.5 mM QX222 Hanck et al. J Gen Physiol 1994;103:19-43 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Many classes of compounds bind and inhibit Na channels  Local anesthetics Lidocaine Procaine W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Many classes of compounds bind and inhibit Na channels        Local anesthetics General anesthetics Ca channel blockers 2 agonists Halothane Tricyclic antidipressants Substance P antagonists Many nerve toxins  Tetrodotoxin  Batrachotoxin  Grayanotoxin W A K E F O R E S T U N I V E R S I T Y S C H O O L Threshold (µsec) Latency (msec) O F Butterworth et al J Physiol 1989;411:493516 M E D I C I N E Many classes of compounds bind and inhibit Na channels  Local anesthetics  General anesthetics  Ca channel blockers W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Many classes of compounds bind and inhibit Na channels % Inhibition of Action Potential     Local anesthetics General anesthetics Ca channel blockers 2 agonists Fiber types ○ Aα ●C 10-5 10-4 10-3 10-2 10-1 Clonidine Concentration (M) Anesth Analg. 1993;76:295-301 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Many classes of compounds bind and inhibit Na channels      Local anesthetics General anesthetics Ca channel blockers 2 agonists Tricyclic antidipressants Duration of sciatic block in rats (min) A. D. L. 250 200 150 100 Mot Noc 50 0 Bup Ami Imi Des Sudoh et al. Pain 2003;103:49-55 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Many classes of compounds bind and inhibit Na channels       Local anesthetics % block of action potential General anesthetics 100 Ca channel blockers A. D. L. 2 agonists 50 Tricyclic antidipressants Substance P antagonists A. SP D. D-Pro2, D-Trp7,9 SP L. Lidocaine Arg5, D-Trp7,9 0 .02 .1 .2 .4 (mM) 1 2 Post. Eur J Pharmacol 1985;117:347-54 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Many classes of compounds bind and inhibit Na channels        Local anesthetics General anesthetics Ca channel blockers 2 agonists Tricyclic antidipressants Substance P antagonists Nerve toxins (e.g. tetrodotoxin (TTX) and saxitoxin (STX)) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Many classes of compounds bind and inhibit Na channels        1.Might these other Local anesthetics compounds be used General anesthetics effectively for regional Ca channel blockers anesthesia or pain 2 agonists management? Tricyclic antidipressants Substance P antagonists Nerve toxins (e.g. tetrodotoxin (TTX) and saxitoxin (STX)) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Many classes of compounds bind and inhibit Na channels        1.Might these other Local anesthetics compounds be used General anesthetics effectively for regional Ca channel blockers anesthesia or pain 2 agonists management? Tricyclic antidipressants 2. Might they be Substance P antagonists “better”or safer than conventional local Nerve toxins (e.g. anesthetics? tetrodotoxin (TTX) and saxitoxin (STX)) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Local anesthetics: agents, actions, & misconceptions  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA toxicity  Summary W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E General characteristics of local anesthesia  Potency  Speed of onset  Duration of action  Tendency to produce differential block  Modifiers of local anesthetic activity W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E EC50 concentrations for Na channel block: Xenopus laevis sciatic nerve fibers vs rat dorsal root ganglia Lid Xenopus 204 Rat Constant rank order for potency across species and assays W A K E F O R E S T U N I V E R S I T Y Eti 18 Mep 149 324 Bup 27 26 Pro 60 Tet 0.7 Brau et al. Anesth Analg 1998;87:885-9 Olschewski et al. Anesthesiology 1998:88:172-9 S C H O O L O F M E D I C I N E Potency and protein binding increase with increasing lipid solubility: procaine vs. lidocaine vs. etidocaine  More potent (Pot) LAs tend to be more lipid soluble (Sol)  Greater lipid solubility also results in greater protein binding (Bdg) W A K E F O R E S T U N I V E R S I T Y Relative to procaine = 1 1000 100 10 1 Pr Li Et S C H O O L O F M E D I C I N E Pot Sol Bdg pKa and speed of onset: the facts vs. the textbooks of anesthesiology Strichartz. Anesth Analg 1990;71:158-70 Fastest Temp (oC) Slowest Slowest Fastest W A K E F O R E S T U N I V E R S I T Y pKa O O L S C H O F M E D I C I N E Characteristics of LAs  Physical and chemical  Increasing lipid solubility  Increased protein binding  Pharmacological & toxicological     Increasing potency Prolonged onset time Prolonged duration of action Increasing tendency to produce severe cardiovascular toxicity  In general, all tend to sort together W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Differential block  Goal = analgesia without motor block  Success in postoperative, labor analgesia  Differential onset of block with bupivacaine (versus mepivacaine)  No consistent differential block when the block fully “set up”  Smaller fibers of a given type more LAsensitive than larger (A fibers more LAsensitive than A fibers)  Antagonists to specific Na channel forms? W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Bupivacaine produces differential onset of block; mepivacaine does not Ririe et al. Br J Anaesth 1998;81:515-21 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Modifiers of LA activity  Increasing dose: ↓latency of onset; ↑duration, ↑block success, ↑[LA]  Vasoconstrictors: ↑duration, ↑block success, ↓[LA]  α2 agonists: ↑duration,↑[LA]  Opioids: ↑duration; permit ↓LA dose  Alkalinization (usually NaHCO3): ↓latency of onset, ↑potency  Pregnancy: ↑dermatomal spread, ↑LA potency, ↑free blood [LA] W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Local anesthetics: agents, actions, & misconceptions  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA toxicity  Summary W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Mepivacaine concentrations in blood after injection of the same dose in different sites Greatest to Least Intercostal Caudal Lumbar epidural Brachial plexus Sciatic-femoral Anesthesiology 1972;37:277 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Protein binding of LAs  All LAs are lipid soluble, so all are proteinbound to some extent  1-acid glycoprotein  albumin  Greater fraction of more potent LAs protein bound than less potent LAs  Protein binding declines during pregnancy (but not by much!) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Amides vs. esters: similarities and differences  Common structure  Aromatic ring  Tertiary amine  Alkyl chain Lidocaine  Linking bond  Amide bond (see lidocaine)  Ester bond (see procaine) W A K E F O R E S T U N I V E R S I T Y S C H O O L Procaine O F M E D I C I N E LA metabolism  Esters (half-lives in seconds to minutes)  Hydrolyzed by nonspecific esterases  Clearance independent of liver flow & function  Active metabolites (p-aminobenzoic acid (PABA) and allergy with procaine or benzocaine) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LA metabolism  Esters (half-lives in seconds to minutes)  Hydrolyzed by nonspecific esterases  Clearance independent of liver flow & function  Active metabolites (p-aminobenzoic acid (PABA) and allergy with procaine or benzocaine)  Amides (half-lives in hours)  N-dealkylation or hydroxylation (CYP450)  Clearance depends on liver blood flow, function  Active metabolite (prilocaine  o-toluidine and methemoglobinemia) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Effects of pregnancy, drugs, and organ failure on LA kinetics  Pregnancy: ↑hepatic blood flow; ↑amide clearance; ↓protein binding W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Effects of pregnancy, drugs, and organ failure on LA kinetics  Pregnancy: ↑hepatic blood flow; ↑amide clearance; ↓protein binding  Renal failure: ↑Vd; ↑accumulation of metabolic products W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Effects of pregnancy, drugs, and organ failure on LA kinetics  Pregnancy: ↑hepatic blood flow; ↑amide clearance; ↓protein binding  Renal failure: ↑Vd; ↑accumulation of metabolic products  Hepatic failure: ↑amide Vd, ↓amide clearance W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Effects of pregnancy, drugs, and organ failure on LA kinetics  Pregnancy: ↑hepatic blood flow; ↑amide clearance; ↓protein binding  Renal failure: ↑Vd; ↑accumulation of metabolic products  Hepatic failure: ↑amide Vd, ↓amide clearance  Cardiac failure; β and H2 blockers: ↓hepatic blood flow and ↓amide clearance W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Effects of pregnancy, drugs, and organ failure on LA kinetics  Pregnancy: ↑hepatic blood flow; ↑amide clearance; ↓protein binding  Renal failure: ↑Vd; ↑accumulation of metabolic products  Hepatic failure: ↑amide Vd, ↓amide clearance  Cardiac failure; β and H2 blockers: ↓hepatic blood flow and ↓amide clearance  Cholinesterase deficiency or inhibition: ↓ester clearance (presumably) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Local anesthetics: agents, actions, & misconceptions  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA toxicity  Summary W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LAs bind and inhibit many differing receptors and channels Do not assume LA toxic side effects arise from Na channel inhibition! Anesthesiology 1990; 72:711-34 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LAs bind and inhibit many differing receptors and channels  Channels  Na Control Control QX222 0.5 mM QX222 Hanck et al. J Gen Physiol 1994;103:19-43 Anesthesiology 1990; 72:711-34 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LAs bind and inhibit many differing receptors and channels  Channels  Na  Ca K Ca oscillations in rat neonatal cardiomyocytes McCaslin. Anesth Analg 2000; 91:82-8 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LAs bind and inhibit many differing receptors and channels  Channels  Na  Ca K Stereospecific inhibition of human TASK-2 currents Kindler. JPET 2003;306:84-92 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LAs bind and inhibit many differing receptors and channels  Channels  G-protein modulation of channels TRH 1 min Control TRH 3 min Xiong. Mol Pharmacol 1999;55:150-8 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LAs bind and inhibit many differing receptors and channels  Channels  G-protein modulation of channels No differences among control, lidocaine, or lidocaine + TRH Xiong. Mol Pharmacol 1999;55:150-8 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E TRH 1 min Control TRH 3 min LAs bind and inhibit many differing receptors and channels  Channels  G-protein modulation of channels  Enzymes  Adenylyl cyclase Butterworth. Anesthesiology 1993;79:88-95 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LAs bind and inhibit many differing receptors and channels  Channels  G-protein modulation of channels  Enzymes  Adenylyl cyclase  Guanylyl cyclase  Lipases Anesthesiology 1990; 72:711-34 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LAs bind and inhibit many differing receptors and channels  Channels  G-protein modulation of channels  Enzymes  Adenylyl cyclase  Guanylyl cyclase  Lipases Anesthesiology 1990; 72:711-34 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E  Receptors  Nicotinic acetylcholine  NMDA  β2-adrenergic LAs bind and inhibit many differing receptors and channels  Channels  G-protein modulation of channels  Enzymes  Adenylyl cyclase  Guanylyl cyclase  Lipases W A K E F O R E S T U N I V E R S I T Y  Receptors  Nicotinic acetylcholine  NMDA  β2-adrenergic  Important for spinal, epidural, or systemic effects? Anesthesiology 1990; 72:711-34 S C H O O L O F M E D I C I N E LAs bind and inhibit many differing receptors and channels Do not assume LA toxic side effects arise from Na channel inhibition! Anesthesiology 1990; 72:711-34 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Patterns of LA toxicity  Central nervous system  Excitation and depression  Direct cytotoxicity  Cardiovascular system  Arrhythmias and arrest  Contractile failure  Allergy W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E CNS toxicity from LAs  Progression of signs & symptoms with ↑LA  Vertigo  Tinnitus  Ominous feelings  Circumoral numbness  Garrulousness  Tremors  Myoclonic jerks  Convulsions  CNS depression  CV depression W A K E F O R E S T  Convulsive LA dose inversely related to LA potency  Acidosis, hypercarbia ↓ convulsive dose  Pregnancy lowers dose but not concentration producing convulsions  CV toxicity requires greater LA doses and concentrations than CNS toxicity U N I V E R S I T Y S C H O O L O F M E D I C I N E CNS toxicity from LAs  Progression of signs & symptoms with ↑LA  Vertigo  Tinnitus  Ominous feelings  Circumoral numbness  Garrulousness  Tremors  Myoclonic jerks  Convulsions  CNS depression  CV depression W A K E F O R E S T  Convulsive LA dose inversely related to LA potency  Acidosis, hypercarbia ↓ convulsive dose  Pregnancy lowers dose but not concentration producing convulsions  CV toxicity requires greater LA doses and concentrations than CNS toxicity U N I V E R S I T Y S C H O O L O F M E D I C I N E Cardiovascular toxicity from potent local anesthetics  Predisposition to cardiac arrest with bupivacaine & etidocaine (Albright, 1979) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Cardiovascular toxicity from potent local anesthetics  Predisposition to cardiac arrest with bupivacaine & etidocaine (Albright, 1979)  Electrophysiology  Bupivacaine vs. lidocaine: faster binding, delayed unbinding from cardiac Na channels  S- isomers less potent at cardiac Na channel block W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Cardiovascular toxicity from potent local anesthetics  Predisposition to cardiac arrest with bupivacaine & etidocaine (Albright, 1979)  Electrophysiology  Bupivacaine vs. lidocaine: faster binding, delayed unbinding from cardiac Na channels  S- isomers less potent at cardiac Na channel block  S- isomers (levo-bupivacaine and ropivacaine) less potent at producing cardiac arrest W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Cardiovascular toxicity from potent local anesthetics  Predisposition to cardiac arrest with bupivacaine & etidocaine (Albright, 1979)  Electrophysiology  Bupivacaine vs. lidocaine: faster binding, delayed unbinding from cardiac Na channels  S- isomers less potent at cardiac Na channel block  S- isomers (levo-bupivacaine and ropivacaine) less potent at producing cardiac arrest  Which is most important?  Increasing potency (increasing LA size)  R+ stereoisomer W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LA blood concentrations producing cardiac arrest in dogs: similar rank order as for potency 120 100 μg/mL 80 60 40 20 0 Bup Levo U N I V E R S I T Y Free Total Rop S C H O O L Lid O F M E D I C I N E Groban et al Anesth Analg 2000;91:1103-11 W A K E F O R E S T Ventricular arrhythmias after supraconvulsant (2x) doses of LAs: differing margins of safety 6 5 4 N 3 2 1 0 Bup Rop Lido V arr No V arr Feldman. Anesth Analg 1989;69:794-801 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LA infusions, cardiac arrest & resuscitation in dogs  More inducible arrhythmias, epiinduced VF with B, LB than R, Li 50 40 30 20 10 0 B R LB Li % of animals EpVF Groban. Anesth Analg 2000;91:1103; Anesth Analg 2001;92:37; RAPM 2002;27:460 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LA infusions, cardiac arrest & resuscitation in dogs  More inducible arrhythmias, epiinduced VF with B, LB than R, Li  Increased mortality with B 50 40 30 20 10 0 B R LB Li % of animals Death EpVF Groban. Anesth Analg 2000;91:1103; Anesth Analg 2001;92:37; RAPM 2002;27:460 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E LA infusions, cardiac arrest & resuscitation in dogs  More inducible arrhythmias, epiinduced VF with B, LB than R, Li  Increased mortality with B  Continued epi often needed for Li (86%) after arrest; rarely with B W A K E F O R E S T 50 40 30 20 10 0 % of animals Death EpVF B R LB Li Groban. Anesth Analg 2000;91:1103; Anesth Analg 2001;92:37; RAPM 2002;27:460 U N I V E R S I T Y S C H O O L O F M E D I C I N E Is there one common mechanism for LA-induced cardiac death?  LA-induced arrhythmias (bupivacaine)?  Left-ventricular depression (lidocaine)?  Resuscitation drug failure or complication (bupivacaine)?  Mechanism probably depends on specific drug! W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Levobupivacaine and ropivacaine  Less toxic than bupivacaine  Are they as potent as bupivacaine?  Confusing data: supramaximal doses; opioids, other additives  Onset time, motor block NOT substitutes for potency  Thus, potency ratios remain unknown W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Should we replace bupivacaine?  Not needed  Small doses (spinal, ankle, wrist)  Reduced concentration (cervical plexus)  Reasonable  Large doses (sciatic + femoral)  Multiple blocks  Unclear  Epidural  Brachial plexus W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Should we use lidocaine or 2-chloroprocaine? Spinal lidocaine  Deficits linked to microcatheters; later associate with lidocaine  Transient neurologic symptoms linked with arthroscopy, lithotomy position, and lidocaine spinal anesthesia  5% lidocaine (not other spinal LAs) in vitro produces irreversible nerve block W A K E F O R E S T 2-chloroprocaine  Large doses injected accidentally in CSF produce cauda equina syndrome  Metabisulfite, low pH  Toxicity disappeared when 2-CP reformulated  Toxicity returns when generic manufacturers use “old” formulation!  2-CP undergoing clinical trial for spinal anesthesia S C H O O L O F M E D I C I N E U N I V E R S I T Y Should we use lidocaine or 2-chloroprocaine? Spinal lidocaine  Deficits linked to microcatheters; later associate with lidocaine  Transient neurologic symptoms linked with arthroscopy, lithotomy position, and lidocaine spinal anesthesia  5% lidocaine (not other spinal LAs) in vitro produces irreversible nerve block W A K E F O R E S T 2-chloroprocaine  Large doses injected accidentally in CSF produce cauda equina syndrome  Metabisulfite, low pH  Toxicity disappeared when 2-CP reformulated  Toxicity returns when generic manufacturers use “old” formulation!  2-CP undergoing clinical trial for spinal anesthesia S C H O O L O F M E D I C I N E U N I V E R S I T Y Allergy to LAs: The dogma  Common misdiagnosis after accidental IV injections  True allergy more common with esters (particularly those related to PABA) than amides  Avoid PABA in sunscreens  Cross reactions between PABA and methylparaben (preservative sometimes added to amide LAs) W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E None of 90 patients referred for LA reactions have allergy!  0 of 90 reacted to 1:100 LA dilutions!  <15% respond to undiluted LA even among 14 referred for anaphylactoid reactions  Thus, almost no patients had “real” LA allergy W A K E F O R E S T % with allergic response 15 10 5 Anaph (N=14) Others (N=76) 0 1:100 Undiluted S C H O O L O F M E D I C I N E deShazo. J All Clin Immunol 1979;63:387-94 U N I V E R S I T Y Treatment of local anesthetic toxicity Apparent allergy  Steroids  Histamine blockers  With severe reactions  Intravenous fluid  Epinephrine CNS toxicity  Don’t treat minor reactions  Seizures: maintain airway, provide O2  Terminate seizure with thiopental, midazolam, or propofol  Intubate patients with full stomachs S C H O O L O F M E D I C I N E W A K E F O R E S T U N I V E R S I T Y Treatment of local anesthetic toxicity Apparent allergy  Steroids  Histamine blockers  With severe reactions  Intravenous fluid  Epinephrine CNS toxicity  Don’t treat minor reactions  Seizures: maintain airway, provide O2  Terminate seizure with thiopental, midazolam, or propofol  Intubate patients with full stomachs S C H O O L O F M E D I C I N E W A K E F O R E S T U N I V E R S I T Y Treatment of LA CV toxicity  Follow ACLS guidelines  Substitute amiodarone for lidocaine  Substitute vasopressin for epinephrine  Consider cardiopulmonary bypass or lipid infusion if standard drugs fail W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Lipid emulsion counteracts bupivacaine cardiac toxicity  Lipid pretreatment with increases toxic dose of bupivacaine  Animals not resuscitated using ACLS recovered when given lipid emulsion Weinberg. Anesthesiology 1998;88:1071-5 Weinberg. Reg Anesth Pain Med 2003;28:198-202 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Lipid emulsion vs. saline after bupivacaine in rats CPR BUPI 15 mg/kg CPR CPR Weinberg. Reg Anesth Pain Med 2002;27:568-75 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Lipid emulsion vs. saline after bupivacaine in rats BUPI 15 mg/kg LIPID BOLUS Weinberg. Reg Anesth Pain Med 2002;27:568-75 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Lipid emulsion counteracts bupivacaine cardiac toxicity  Lipid pretreatment with increases toxic dose of bupivacaine  Animals not resuscitated using ACLS recovered when given lipid emulsion  Lipid may draw bupivacaine into plasma from binding site(s) in the heart  No human data Weinberg. Anesthesiology 1998;88:1071-5 Weinberg. Reg Anesth Pain Med 2003;28:198-202 W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Local anesthetics: agents, actions, & misconceptions  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA toxicity  Summary W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Summary  History of LAs and regional anesthesia  LA mechanisms of action on Na channels: voltage-, state-, and use-dependent block  Potency, lipid solubility, protein binding, onset time, duration, CV toxicity tend to sort together  pKa association with onset time  Effects of dose, additives, pregnancy  Differential block  Pharmacokinetics and metabolites  Toxicity, allergy, and treatment W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Vote early and often! W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E Local anesthetics: agents, actions, & misconceptions John Butterworth, MD Professor & Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina