Local anesthetic clinical pharmacology

Local anesthetic clinical pharmacology: do the new ones make any difference? John Butterworth, MD Professor & Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina Local anesthetic clinical pharmacology: do the new ones make any difference?  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  Levobupivacaine and ropivacaine  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 Benjamin G. Covino, PhD, MD   12 Sep1930 – 6 Apr 1991 Astra Pharmaceuticals 1962-1977 Professor, Vice Chairman, U Mass Anesthesiology Department, 1977-1979 Professor & Chairman, Brigham & Women’s Hospital Anesthesia Department, 1979-1991 A founder of ASRAPM Editor in Chief Regional Anesthesia 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  Indigenous plant in South America  Available only to Incan aristocracy  1500s: Spaniards seize plantations & pay workers with coca paste  Coca mixed with corn starch or guano, chewed with lime or ash; first example of “free basing”  Chewed coca dripped on trephination sites  Monardes brings coca leaves back to Europe (1580); fails to achieve instant popularity of tobacco 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-2 Cocaine HCl isolated by Albert Niemann (1860) Merck produces 0.25 lbs cocaine (1862) Koller and Gartner report local anesthesia (1884) Merck produces 3179 lbs (1884); 158,362 lbs (1886) Pemberton introduces Coca-Cola (1886) S C H O O L O F M E D I C I N E Cocaine HCl powder W A K E F O R E S T U N I V E R S I T Y History of local anesthesia-2 Cocaine HCl isolated by Albert Niemann (1860) Merck produces 0.25 lbs cocaine (1862) Koller and Gartner report local anesthesia (1884) Merck produces 3179 lbs (1884); 158,362 lbs (1886) Pemberton introduces Coca-Cola (1886) S C H O O L O F M E D I C I N E 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 History of local anesthesia-2 Cocaine HCl isolated by Albert Niemann (1860) Merck produces 0.25 lbs cocaine (1862) Koller and Gartner report local anesthesia (1884) Merck produces 3179 lbs (1884); 158,362 lbs (1886) Pemberton introduces Coca-Cola (1886) 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 Chronology of local anesthetics Cocaine Benzocaine Procaine Dibucaine Tetracaine Lidocaine Chloroprocaine Mepivacaine Bupivacaine Ropivacaine W A K E F O R E S T Niemann Salkowski Einhorn Meischer Eisler Lofgren Marks, Rubin Ekenstam Ekenstam Sandberg S C H O O L 1860 1895 1904 1925 1928 1943 1949 1956 1957 1989 O F M E D I C I N E After: Cartwright & Fyhr. Reg Anesth 1988;13:1-12 U N I V E R S I T Y 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 Local anesthetic clinical pharmacology: do the new ones make any difference?  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  Levobupivacaine and ropivacaine  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 Membrane potentials and ionic currents in neurons  Resting potential Characteristic of living cells (-70 mV); arises Squid axon, 16o from Na-K ATPase and K “leak” Time after stimulus (ms)  Action potential With sufficient depolarization Na channels activate, open, allow Na flux Within milliseconds, Na channels inactivate, return to nonconducting 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 Potential (in mV) O F M E D I C I N E Structural characteristics of Na channels  1 larger  subunit (230-270 kD) (has ion conducting path)  1 or 2 smaller  subunits (37-39 kD)  All subunits are heavily glycosylated  4 domains with 6 membrane spanning regions W A K E F O R E S T U N I V E R S I T Y 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 α-subunit has 4 domains, each has 6 membrane spanning αhelical segments (S1-S6). LA binding in D1-S6, D3-S6 and D4-S6, W A K not O R E S T U N I V E R S I T Y but E F D2-S6 From: Catterall & Mackie Ch 15, p334. Goodman & Gilman 9th Edition, 1996; Wang. Mol Pharm 2001;59:1100-7; Nau. Mol Pharm 1999;56:40413 S C H O O L O F M E D I C I N E Na channel conformations  3 Na channel forms: resting, open, & inactivated (Hodgkin& Huxley,1952)  Na currents when Na ions pass through open channels  No current through channels AL Hodgkin AF Huxley bound by LA 1914-1998 1917Shared Nobel Prize in 1963  LA binding favored by:  Depolarization (voltage-dependence)  Open or inactivated Na channels  Frequent impulses (use- or frequency-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 Na channel conformations  3 Na channel forms: resting, open, & inactivated (Hodgkin& Huxley,1952)  Na currents when Na ions pass through open channels GR Strichartz  No current through channels Brigham and Women’s Hospital bound by LA Harvard Medical School  LA binding favored by:  Depolarization (voltage-dependence)  Open or inactivated Na channels  Frequent impulses (use- or frequency-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  General anesthetics  Ca channel blockers: verapamil  2 agonists  Antidipressants: amitriptyline  Substance P antagonists  Toxins  TTX, STX  Batrachotoxin, grayanotoxin W A K E F O R E S T U N I V E R S I T Y % Inhibition of Action Potential Fiber types ○ Aα ●C 10-5 10-4 10-3 10-2 10-1 Clonidine Concentration (M) O F M E D I C I N E S C H O O L Tetrodotoxin (TTX) •Fugu (puffer fish) sushi a delicacy, but contains TTX •Chefs undergo a long apprenticeship to reduce fatalities •Nevertheless, 5-10 Japanese die each year from TTX after eating fugu 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 TTX binds Na channels selectively & with high affinity •Squid axons have both Na currents (early, inward) and K currents (later, outward) •TTX inhibits only Na (early, downward) current •TTX has greater affinity and selectivity for Na channels than LAs W A K E F O R E S T U N I V E R S I T Y (A) 0 Time (ms) 5 10 I(nA) 10 0 -10 Control (B) 300 nM TTX S C H O O L O F M E D I C I N E Local anesthetic clinical pharmacology: do the new ones make any difference?  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  Levobupivacaine and ropivacaine  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 my appreciation for LAs increased after 1 July 2002… 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  LA potency  LA speed of onset  LA duration of action  Tendency of LA to produce differential 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 Local anesthetic potency correlates with lipid solubility  Potency: etidocaine > Relative to procaine = 1 lidocaine > procaine 1000  More potent (Pot) LAs tend to be more lipid 100 Pot soluble (Sol) Sol 10  Greater lipid solubility Bdg also results in greater 1 protein binding (Bdg) Pr Li Et 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 increases with increasing lipid solubility 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 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 Factors influencing LA activity  Increasing dose: ↓latency of onset; ↑duration, ↑block success, ↑[LA]  Vasoconstrictors: ↑duration, block success; ↓[LA]  Site of injection: influences dose, onset, duration, success rate, [LA]  Alkalinization (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 Pregnancy and local anesthesia  Increased spread of neuraxial blocks in pregnancy (probably due to CSF volume)  Progesterone increases bupivacaine potency in animals  Lidocaine more potent at median nerve block in pregnant women W A K E F O R E S T 100 80 Pregnant Not preg % inhibition 60 40 20 0 5 10 15 20 Elapsed time (min) Butterworth. Anesthesiology 1990;72:962-5 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  Successful for postop and labor analgesia  Differential sensory block during onset of bupivacaine (contrast mepivacaine)  No intraoperative differential block at steady state when the block fully “set up”  Smaller fibers of a given type are more LA-sensitive than larger (A fibers more LA-sensitive than A or C fibers) 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 Local anesthetic clinical pharmacology: do the new ones make any difference?  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  Levobupivacaine and ropivacaine  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 Levobupivacaine and ropivacaine  Less toxic than bupivacaine?  As potent as bupivacaine?  Should we replace bupivacaine? 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 doses and blood concentrations with convulsions in sheep (45 kg) 120 100 80 60 40 20 0 LID W A K E F O R E S T Dose (mg) Conc (mg/L) ROP U N I V E R S I T Y BUP Rutten. Anesth Analg 1989;69:291-9 S C H O O L O F M E D I C I N E Local anesthetic concentrations and cardiac arrest in dogs 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 Bupivacaine more toxic than levo or ropivacane in rats  Rats infused LA at 2 mg/kg/min  Asystole treated with epi .01 mg/kg + CPR  Resuscitation success: SAP >100 mmHg  B more potent than LB or R at sz, arr, asystole  Less epi needed for ropiv than bup or levo Ohmura. Anesth Analg 2001;93:743-8 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 Cumulative dose mg/kg 120 100 80 60 40 20 0 Sz Arr Asy B LB Ro Relative potency of ropivacaine, levobupivacaine, and bupivacaine  No local anesthetic equivalent of mean alveolar concentration (MAC)  Available data are confusing; studies poorly designed  Supramaximal concentrations used in clinic  Opioids and other additives  Onset time and motor block are NOT substitutes for potency  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)  Multiples blocks  How much are you willing to spend? 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 anesthetic clinical pharmacology: do the new ones make any difference?  History and general considerations  Na channels, cellular electrophysiology, & local anesthetic actions  General characteristics of local anesthesia  Levobupivacaine and ropivacaine  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 and Na channels: voltage-, state-, and use-dependent block  Potency, lipid solubility, protein binding, onset time, duration, CV toxicity tend to sort together  No direct mechanistic action of pKa on onset or protein binding on duration of action  Pharmacodynamic effects of dose, pH, vasoconstrictors, pregnancy  Differential block  Ropivacaine and levobupivacaine vs bupivacaine 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 anesthetic clinical pharmacology: do the new ones make any difference? John Butterworth, MD Professor & Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina Bicarbonate reduces fraction of protonated LA; speeds onset  Protonated LA H+ N N less membrane + NaHCO + Cl3 O permeable than Lidocaine HCl uncharged LA  Generally faster N N onset of block + Na+ +H2O + O with bicarbonate CO2 + ClLidocaine  Particularly with LAs formulated with epinephrine by manufacturer (acidity promotes long shelf-life) 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 Alkaline pH increases procaine potency in frog sciatic axons 100 % inhibition 80 60 40 20 0 0.1 0.3 0.5 1 2 5 pH 9.2 7.4 mM Butterworth. Anesthesiology 1988;68:501-6 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-induced arrhythmias, LV depression, & mortality in dogs  LA infusion: more % of animals inducible arrhythmias 50 with B, LB than R,L 40  When MAP<45 mmHg, ACLS + epi used to 30 restore MAP>55 Death 20  Continued epi more EpVF often needed for Li 10 (86%) than others 0  More epi-induced VF B R LB Li (EpVF) & death with B than R or Li 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