Pharmacology of local anesthetics   correct choices and looking to the future

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Pharmacology of local anesthetics

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Pharmacology of local anesthetics correct choices and looking to the future

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1. Pharmacology of local anesthetics – correct choices and looking to the future John Butterworth, MD Professor & Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina

3. Pharmacology of local anesthetics – correct choices and looking to the future History Molecular mechanisms Characteristics of local anesthesia New agents and approaches Summary

4. 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 leaves back to Europe (1580); fail to achieve instant popularity of tobacco

5. 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 leaves back to Europe (1580); fail to achieve instant popularity of tobacco

6. 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 leaves back to Europe (1580); fail to achieve instant popularity of tobacco

7. 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 leaves back to Europe (1580); fail to achieve instant popularity of tobacco

8. 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 leaves back to Europe (1580); fail to achieve instant popularity of tobacco

9. 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 leaves back to Europe (1580); fail to achieve instant popularity of tobacco

10. 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

11. 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

12. 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

13. 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

14. 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

15. Chronology of local anesthetics

16. Local anesthetics: amides vs. esters Common structure Aromatic ring Tertiary amine Alkyl chain Linking bond Amide bond (see lidocaine) Ester bond (see procaine)

17. Pharmacology of local anesthetics – correct choices and looking to the future History Molecular mechanisms Characteristics of local anesthesia New agents and approaches Summary

18. Functions of Na currents Long distance propagation of action potentials in nerve and muscle Shape and filter synaptic inputs Back propagation of dendritic action potentials (associate synaptic plasticity) Initiate, maintain cellular oscillations (sinus node) and burst generation Developmental, regulatory plasticity Mutations lead to muscle, cardiac, neural diseases

19. Genomics of human Na channels Only 1 or 2 genes in invertebrates 10 distinct Na channel genes in mammals Cell-specific expression and localization of gene products 10 human genes on 4 chromosomes (5 on Chr 2 and 3 on Chr 3) Nav1.2 channels in axons of unmyelinated neurons Nav1.6 channels in nodes of Ranvier Nav1.8, Nav1.9 in small DRG nociceptors

20. 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 heavily glycosylated 4 domains with 6 membrane-spanning regions LA binding in D1-S6, D3-S6 and D4-S6, not D2-S6

21. 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 heavily glycosylated 4 domains with 6 membrane-spanning regions LA binding in D1-S6, D3-S6 and D4-S6, not D2-S6

22. Membrane potentials and ionic currents in neurons Resting potential Characteristic of living cells (-70 mV) Na-K ATPase and K “leak” Action potential Na channels open, allow Na flux Within milliseconds, Na channels return to nonconducting inactivated state

23. 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 LA binding favored by: Depolarization Open or inactivated Na channels Frequent impulses (use-dependence)

24. 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 LA binding favored by: Depolarization Open or inactivated Na channels Frequent impulses (use-dependence)

26. LAs bind and inhibit many differing receptors and channels Channels Na Ca (multiple types) K Enzymes Adenylyl cyclase Guanylyl cyclase Lipases Receptors Nicotinic acetylcholine NMDA ß2-adrenergic Important for spinal, epidural, or systemic effects?

27. Many classes of compounds bind and inhibit Na channels Local anesthetics

28. 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

29. Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers

30. Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers ?2 agonists

31. Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers ?2 agonists Tricyclic antidipressants

32. Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers ?2 agonists Tricyclic antidipressants Substance P antagonists

33. 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)

34. TTX binds Na channels selectively & with high affinity

35. Pharmacology of local anesthetics – correct choices and looking to the future History Molecular mechanisms Characteristics of local anesthesia New agents and approaches Summary

36. 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 Editor-in-Chief Regional Anesthesia

37. Pharmacology of local anesthetics: the clinician’s perspective LA potency LA speed of onset LA duration of action Tendency to produce cardiac toxicity Tendency to produce differential block

38. Potency and protein binding increase with increasing lipid solubility Potency: etidocaine > lidocaine > procaine More potent (Pot) LAs tend to be more lipid soluble (Sol) Greater lipid solubility also results in greater protein binding (Bdg)

40. 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

41. 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 LA-sensitive than larger (A? fibers more LA-sensitive than A? fibers)

43. Additives and modifiers of LA activity Increasing dose: ?latency of onset; ?duration, ?block success, ?[LA] Vasoconstrictors: ?duration, ?block success, ?[LA] a2 agonists: ?duration,?[LA] Opioids: ?duration; permit ?LA dose Alkalinization (usually NaHCO3): ?latency of onset, ?potency Pregnancy: ?dermatomal spread, ?LA potency, ?free blood [LA]

44. Pharmacology of local anesthetics – correct choices and looking to the future History Molecular mechanisms Characteristics of local anesthesia New agents and approaches Summary

46. 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 No “MAC” for LAs Thus, potency ratios remain unknown

52. Strategies to delay LA absorption and prolong duration

55. Pharmacology of local anesthetics – correct choices and looking to the future History Molecular mechanisms Characteristics of local anesthesia New agents and approaches Summary

56. Summary LAs bind and inhibit Na channels 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 appear to be safer than bupivacaine No obvious replacement for conventional local anesthetic preparations

57. Pharmacology of local anesthetics – correct choices and looking to the future John Butterworth, MD Professor & Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina

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