Update on local anesthetic pharmacology

Update on local anesthetic pharmacology John Butterworth, MD Professor & Section-Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina Update on local anesthetic pharmacology  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA cardiovascular toxicity See:  Summary http://www1.wfubmc.edu/anesthesiology/ research/faculty_presentations.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  Koller and Gartner report local anesthesia (1884) 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 Early history of regional anesthesia  Koller and Gartner report local anesthesia (1884)  1884 Halsted injects cocaine directly into mandibular nerve and brachial plexus William S. Halsted 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  Koller and Gartner report local anesthesia (1884)  1884 Halsted injects cocaine directly into mandibular nerve and brachial plexus  1904 Einhorn discovers procaine (Novocaine) 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 Early history of regional anesthesia  Koller and Gartner report local anesthesia (1884)  1884 Halsted injects cocaine directly into mandibular nerve and brachial plexus  1904 Einhorn discovers procaine (Novocaine)  1943 Lofgren discovers lidocaine (Xylocaine) 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 Lidocaine M E D I C I N E Chronology of local anesthetics Cocaine Benzocaine Procaine Tetracaine Lidocaine Chloroprocaine Mepivacaine Bupivacaine Ropivacaine Niemann Salkowski Einhorn Eisler Lofgren Marks, Rubin Ekenstam Ekenstam Sandberg 1860 1895 1904 1928 1943 1949 1956 1957 1989 Ester Ester Ester Ester Amide Ester Amide Amide Amide After: Cartwright & Fyhr. Reg Anesth 1988;13:1-12 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: amides vs. esters  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 Update on local anesthetic pharmacology  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA cardiovascular 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 Voltage-gated Na (Nav) channels  Propagate action potentials in nerve and muscle  Shape, filter synaptic inputs  Initiate, maintain cellular oscillations (sinus node) and burst generation (brain cells)  Mutations lead to muscle, cardiac, & neural diseases and stillbirth  Bind local anesthetics to produce regional anesthesia, necessitating ASRAPM meeting! 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 Nav channels  1 larger  subunit (260 kD) (has ion conducting path)  1 or 2 smaller  subunits (30 kD)  All subunits heavily glycosylated From: Physiol Rev 1992;72:S15-S48 Ann Rev Biochem 1995;6:493-531 Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84 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 Nav channels  1 larger  subunit (260 kD) (has ion conducting path)  1 or 2 smaller  subunits (30 kD)  All subunits heavily glycosylated From: Physiol Rev 1992;72:S15-S48 Ann Rev Biochem 1995;6:493-531 Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84 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 Nav channels  1 larger  subunit (260 kD) (has ion conducting path)  1 or 2 smaller  subunits (30 kD)  All subunits heavily glycosylated From: Physiol Rev 1992;72:S15-S48 Ann Rev Biochem 1995;6:493-531 Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84 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 Nav channels  4 domains have 6 membranespanning α-helical segments (S1-S6)  S5-S6 P-loop part of ion-conducting pore Cytoplasm Plummer, Meisler. Genomics 1999;57:323-31 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 Nav channels  4 domains have 6 membranespanning α-helical segments (S1-S6)  S5-S6 P-loop part of ion-conducting pore Cytoplasm Plummer, Meisler. Genomics 1999;57:323-31 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 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  Membrane potential (or voltage) determines the conformation W A K E F O R E S T U N I V E R S I T Y AL Hodgkin AF Huxley 19171914-1998 Nobel Prize 1963 S C H O O L O F M E D I C I N E Latest model for voltage-gating of ion channels  S1-S4 segments form voltage sensor  “Conventional” models assume S4 moves in and out of lipid membrane  Xray diffraction: S4S3 hairpin loop, supports “paddle” Århem. Lancet 2004;363:1221-3 Jiang. Nature 2003;423:33-41 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 How LAs inhibit Na currents  Weidman (1955) shows that LAs reduce Na flux during impulses in Purkinje cells  Taylor (1959) shows that procaine inhibits Na currents in squid axons  No effect on resting membrane potential  No effect on Na equilibrium potential  Strichartz (1973) reports use-dependent block  Blocking and unblocking need open channels  Drug approaches binding site from inside cell  Ragsdale (1994) shows point mutations to D4S6 alter LA block of Nav1.2a channels 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 currents 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 How LAs inhibit Na currents  Weidman (1955) shows that LAs reduce Na flux during impulses in Purkinje cells  Taylor (1958) shows that procaine inhibits Na currents in squid axons  No effect on resting membrane potential  No effect on Na equilibrium potential  Strichartz (1973) reports use-dependent block  Blocking and unblocking need open channels  Drug approaches binding site from inside cell  Ragsdale (1994) shows point mutations to D4S6 alter LA block of Nav1.2a channels 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 binding to D4S6  D4S6 point mutations reduce LA binding to Nav1.2, 1.4  Binding between F1479 & Y1586 Godwin. Biophys Chem 2005;113:1-7 Ragsdale. Science 1994;265:1724-8 Wang. Pflugers Arch 1998;435:293302 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 binding to D4S6  D4S6 point mutations reduce LA binding to Nav1.2, 1.4  Binding between F1479 & Y1586 Godwin. Biophys Chem 2005;113:1-7 Ragsdale. Science 1994;265:1724-8 Wang. Pflugers Arch 1998;435:293302 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 binding to D4S6  Increasing hydrophobicity permits better “fit” in binding cavity for neutral LAs Godwin. Biophys Chem 2005;113:1-7 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 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 Use-dependent block of frog sciatic axons by halothane 1% Strichartz. Acta Anaesth Scand 1980;24:402-6 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 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 Pro 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 Many nerve toxins  Batrachotoxin From: www.bio.davidson.edu 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 Many nerve toxins  Batrachotoxin From: chemweb.calpoly.edu 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 Many nerve toxins  Batrachotoxin  Grayanotoxin From: www.currieecology.org.uk & vm.cfsan.fda.gov 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 Many classes of compounds bind and inhibit Na channels        Local anesthetics General anesthetics Ca channel blockers 2 agonists Tricyclic antidipressants Substance P antagonists Many nerve toxins  Batrachotoxin  Grayanotoxin  Tetrodotoxin (TTX) 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 Many nerve toxins  Batrachotoxin  Grayanotoxin  Tetrodotoxin (TTX) 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 Many nerve toxins anesthetics?  Batrachotoxin  Grayanotoxin  Tetrodotoxin (TTX) 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 Update on local anesthetic pharmacology  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA cardiovascular 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 EC50 LA concentrations (in M) for block of Na and K channels Xenopus laevis sciatic nerve fibers Lid Na K Eti 18 Mep Bup 149 27 92 Pro 60 Tet 0.7 204 1118 176 2305 6303 946 Observations 1. Potency at Na > K channel 2. Rank order the same as for clinical regional anesthesia 3. Larger, more lipid soluble agents are more potent W A K E F O R E S T U N I V E R S I T Y Brau et al. Anesth Analg 1998;87:885-9 Olschewski et al Anesthesiology 1998:88:172-9 O F M E D I C I N E S C H O O L LA characteristics that sort together: bupivacaine vs. mepivacaine  Physical and chemical  ↑lipid solubility  ↑protein binding  Pharmacological & toxicological     ↑potency ↑onset time ↑duration of action ↑tendency to produce severe CV toxicity 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 pKa and speed of onset: the facts vs. the textbooks of anesthesiology Strichartz. Anesth Analg 1990;71:158-70 Temp (oC) 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 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)  Selective Nav inhibitors in future? 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 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 Genomics of human Nav channels  Only 1 or 2 Nav channel genes in invertebrates  9 distinct Nav channel α-subunit genes in mammals (10th homologous gene doesn’t code for functional channel)  Cell-specific expression and localization of Nav channel 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 Chromosomes, distribution of neuronal Nav channels Nav1.1 Nav1.2 2 2 Nav1.3 2 Nav1.6 15 Nav1.7 2 Nav1.8 9 Nav1.9 9 Adult DRG DRG, DRG, CNS, DRG CNS, (80% (small), motor, CNS CNS DRG, Injured small, hippoc. motor CNS DRG 20% lg) 1. Nav1.8, Nav1.9 relatively TTX insensitive: related to neuropathic pain? 2. Nav1.3 TTX sensitive: related to ectopic discharges after axotomy? 3. Nav1.4 skeletal muscle, 1.5 cardiac muscle Lai et al. Curr Opin Neurobiol 2003;13:291-7 Wu, Pan. Brain Res 2004;1029:251-8 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 Update on local anesthetic pharmacology  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics and dosing  LA cardiovascular 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 Why do books and chapter persist in defining a maximal drug dose?      Depends on site of administration Altered by additives Depends on patient characteristics Altered by diseases Tolerable dose is small when given into the vertebral artery or into a vein!  Illogical to speak of one maximal “safe” dose of local anesthetic Rosenberg. Reg Anesth Pain Med 2004; 29:564-75 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 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 Effects of medical conditions & drugs on LA dosing & kinetics  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  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 Update on local anesthetic pharmacology  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA cardiovascular 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  Na, K, Ca channels  G-protein modulation of channels  Many enzymes  Many receptors  Nicotinic acetylcholine  NMDA  β2-adrenergic  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  Na, K, Ca channels  G-protein modulation of channels  Many enzymes  Many receptors  Nicotinic acetylcholine  NMDA  β2-adrenergic  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  Important for spinal, epidural, or systemic effects? 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 Cardiovascular toxicity from local anesthetics  Predisposition to cardiac arrest with bupivacaine & etidocaine (Albright, 1979)  S- isomers (levo-bupivacaine and ropivacaine) less potent at CV toxicity than R+ isomers or racemic mixes  Which is most important?  Increasing potency (increasing LA size)  R+ stereoisomer  Biochemical, electrophysiologic, negative inotropic, vascular actions 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. Anesth Analg 2000;91:1103-11 W A K E F O R E S T Ventricular arrhythmias after supraconvulsant (2x) doses of LAs 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 with B, LB than R, Li  More epi-induced VF (EpVF) & death with B than R or Li  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?     Arrhythmias (bupivacaine)? Left-ventricular depression (lidocaine)? Resuscitation drug failure (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 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  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 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 Update on local anesthetic pharmacology  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  LA pharmacokinetics  LA cardiovascular 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  LAs bind and inhibit Nav channels  Other drugs that inhibit Nav channels  Pharmacodynamic effects of medical conditions, additives  Differential block and specific Nav channel types  Toxicity: CNS vs. CV; neurotoxicity; allergy  Resuscitation See: 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 http://www1.wfubmc.edu/anesthesiology/ research/faculty_presentations.htm M E D I C I N E