3. Donald H. Lambert Pharmacology of Local Anesthetics

4. Donald H. Lambert Boston, Massachusetts Pharmacology of Local Anesthetics Dannemiller - Chicago - May 10, 2007 http://dann2007.debunk-it.org http://www.debunk-it.org

5. Donald H. Lambert Boston, Massachusetts Pharmacology of Local Anesthetics Dannemiller – San Antonio - June 12, 2007 http://dann2007.debunk-it.org http://www.debunk-it.org

6. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

7. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

8. Nerve Muscle

9. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

11. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

12. Compound action potential = sum of individual AP Individual fibers blocked = decline in comp. AP

13. B + H + BH +

14. The Sodium Channel  Sub-unit l Four domains (D1-D4) l Six segments (S1-S6) l Na channel is organized as a pseudo-tetramer with the S6 segments possibly lining the internal vestibule of the pore l P designates the pore region within the S5-S6 extracellular linker l “+S4+” is believed to be the “voltage sensitive” segment l The arrows indicate the putative BTX binding site and the putative LA binding site at D1-S6, D3-S6, D4-S6 Wang SY, et al. Biophys J 79;2000:1379–1387

15. Pore

16. l Membrane potential influences Na channel conformations and LA affinity l LA inhibition of Na currents increases with repetitive depolarizations, i.e., use- dependent block l Use-dependent block result from open and inactivated channels having greater LA affinity than resting channels l Repetitive depolarizations increase the chance that a LA will encounter Na channels that are open or inactivated Mode of Action

17. H+

18. H+H+

20. Block Susceptibility Although there is great individual variation, for most patients treatment with local anesthetics causes the sensation of pain to disappear first, followed by loss of the sensations of temperature, touch, deep pressure, and finally motor function.

21. Block Susceptibility In general, autonomic fibers, small unmyelinated C fibers (mediating pain sensations), and small myelinated A  fibers (mediating pain and temperature sensations) are blocked before the larger myelinated A , A , and A  fibers (mediating postural, touch, pressure, and motor information)

22. Block Susceptibility In general, autonomic fibers, small unmyelinated C fibers (mediating pain sensations), and small myelinated A  fibers (mediating pain and temperature sensations) are blocked before the larger myelinated A , A , and A  fibers (mediating postural, touch, pressure, and motor information) Pain/temp then proprioception/touch/pressure/motor

23. Block Susceptibility In general, autonomic fibers, small unmyelinated C fibers (mediating pain sensations), and small myelinated A  fibers (mediating pain and temperature sensations) are blocked before the larger myelinated A , A , and A  fibers (mediating postural, touch, pressure, and motor information)

24. Block Susceptibility The spacing of nodes of Ranvier increases with the size of nerve fibers. Because a fixed number of nodes must be blocked to prevent conduction, small fibers with closely spaced nodes of Ranvier may be blocked more rapidly because the local anesthetic reaches a critical length of nerve more rapidly.

25. Block Susceptibility Small diameter non-myelinated C fibers (++++) > Small diameter myelinated B fibers (++++) > Small diameter myelinated A  fibers (+++) > Larger diameter myelinated A  and A  fibers (++) > Largest diameter myelinated A  fibers (+)

26. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

27. The Local Anesthetic Molecule l Local anesthetics consist of an aromatic ring and an amine, separated by a hydrocarbon chain l Two types of local anesthetics based on the hydrocarbon chain linkage l Esters have [-CO-O-] linkage l Amides have [-N-CO-] linkage Hydrophobic Hydrophilic

28. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

29. ESTERS

30. Amide Bupivacaine Analogues

31. Amide Lidocaine Analogues

32. Amides v. Esters ParameterAmidesEsters Stability Metabolism Allergy StableUnstable Liver/kidneyPlasma RareLess rare

33. COCA I NE BENZOCA I NE

34. AGENTS OF LOW POTENCY AND SHORT DURATION AGENT CHEMICALRELATIVE ONSETDURATION CLASSPOTENCY(MINUTES) PROCAINE ESTER 1 SLOW 60 - 90 CHLOROPROCAINE ESTER 1 FAST 30 - 60

35. AGENTS OF INTERMEDIATE POTENCY AND DURATION AGENT CHEMICALRELATIVE ONSETDURATION CLASSPOTENCY(MINUTES) LIDOCAINE AMIDE 2 FAST 90 -200 MEPIVACAINE AMIDE 2 FAST 120 - 240 PRILOCAINE AMIDE 2 FAST 120 - 240

36. AGENTS OF HIGH POTENCY AND LONG DURATION

37. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

38. Lipid Solubility = Potency (and Duration) Lipid Bi-layer

39. l The most lipid soluble agents (amethocaine and etidocaine) are the most potent (lowest ED 50 ). l The amino-esters may interact with a greater number receptor sites, which may explain their inherently greater potency. l The amino-esters are more potent than the amino-amides (most leftward curve).

40. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

41. Protein Binding = Duration Lipid Bi-layer Protein Na+ Channel

43. DETERMINANTS OF LA DURATION MEP LIDO BUPTETETID

44. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

45. pKa = ONSET

46. Relationship of pKa to Percent Base and Onset of Anesthesia l Agents with the largest amount of free base produce the fastest onset l Small decreases in pKa l Cause large changes in the amount of free base at physiologic pH

47. Pop-quiz on pharmacology LA In normal tissue, which property of drugs has the greatest effect on the speed of onset of a local anesthetic? (A)Amide structure (B)Degree of protein binding (C)Intrinsic vasoconstrictor activity (D)pKa (E)Potency

48. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

50. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

51. Effect of Dose on Onset, Duration, and Quality of Anesthesia As dose increases The more you inject the faster it comes on, the better the block, the longer it lasts, and the greater the toxicity Onset time decreases from 12 min. to 5 min. Adequacy increases from 40% to 100% Duration increases from 100 to 260 min.

52. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

54. l The increased duration with epinephrine depends on the type of block l Compared to brachial block, epidural block is prolonged less because of Greater vascularity Fewer diffusion barriers u Prilocaine has good diffusion characteristics More sequestration by fat u Especially etidocaine and bupivacaine

55. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

57. Neuron Types

58. 40 ml inj: Lido = 400 mg, Bup = 100 mg 20 ml inj: Lido = 400 mg, Bup = 100 mg

59. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

60. Adding NaHC03 does not “carbonate” a LA

61. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

62. Factors Influencing Local Anesthesia l pH of local anesthetic l Pregnancy l Site of injection

63. Adding sodium bicarbonate raises the pH of the local anesthetic solution

64. 1% Lido Rat Sciatic Nerve Block Sinnott, et al. Anesthesiology 2000;93:1045-52 Plain NaOH NaHCO3

65. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

66. Onset quicker, duration same with mixture

67. l In this study of epidural analgesia, the onset of anesthesia seen with bupivacaine alone was not hastened by a mixture of chloroprocaine and bupivacaine l Furthermore, the block duration seen with bupivacaine alone was shortened with the mixture

68. A E utectic M ixture of L ocal A nesthetics (EMLA) that contains 2.5% lidocaine and 2.5% prilocaine in an oil and water emulsion

69. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

70. ????

71. VEINS Smaller CSF volume Non-Pregnant Pregnant

72.  Epidural local anesthetic has a greater dermatomal spread in pregnancy. Non-pregnant Pregnant 1st TRIMESTER  The effect is apparent in the first trimester of pregnancy, when there is no epidural venous engorgement to mechanically exaggerate the distribution of local anesthetic in the epidural space.  It appears that the increased spread of local anesthetics in early pregnancy is due to non- mechanical factors.

73. Median Nerve Block in Pregnant and Non-Pregnat Women J Butterworth, et al. Anesthesiology 1990;72:962-5

76. Collection of data of local anesthetic blood levels (mainly plasma concentrations) from various sources indicating the pattern of order of peak concentrations associated with various regional anesthetic blocks. Rosenberg PH, Veering BT, Urmey WF: Reg Anesth Pain Med 2004; 29: 564-75 Intercostal > caudal > epidural > brachial plexus > subcutaneous

77. Metabolism l Please refer to your syllabus l Some key words Volume of distribution Clearance  -1-acid-glycoprotein Cytochrome P450 T1/2 (half life)

78. Fetal Pharmacology

79. Intervillous space Cm Uterine artery Umbilical vein Umbilical artery Uterine vein Maternal Shunt Fetal Shunt Maternal Cm = UtA conc free drug Fetal Cf = UmA conc free drug Intervillous space Cf Placenta Fick’s Law passive diffusion Determinants of UtA Cm: Total Dose Route of administration Epinephrine in solution Maternal metabolism and excretion Maternal protein binding Maternal pH and pKa of drug Determinants of UmA Cf: Umbilical vein concentration (input) Fetal pH Fetal protein binding Fetal tissue uptake Nonplacental elimination Fetal hepatic metabolism Fetal renal excretion Factors influencing fetal uptake of drugs

80. Maternal plasmaFetal plasma PlacentaPlacenta 80% binding 67% binding bound Free (20%) Free (33%) (4) + (1) 5 molecules (1) + (2) 3 molecules Effect of differential protein binding by maternal and fetal blood

81. Effect of pH on Fetal Lidocaine Concentration Continuous maternal lidocaine infusion 1.2 1.0 0.8 0.6 Normal fetus pH 7.30-7.35 Fetal acidemia pH 6.90-7.18 Fetal NaHCO3 Correction pH 7.22-7.40 FA to MA Lido Conc

82. Pharmacology of Local Anesthetics l Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy l Advantages of Local Anesthesia l Normal Nerve Physiology l Mechanism and Site of Action of Local Anesthetics l The Local Anesthetic Molecule l Classification of Local Anesthetics Esters vs. Amides l Structure Activity Relationships Potency u Lipid Solubility Duration u Protein Binding & Lipid Solubility Onset u pKa Differential Block

83. The Pharmacology of Local Anesthetics Important stuff for everyday practice! And for exams!!

84. The Pharmacology of Local Anesthetics Important stuff for everyday practice! And for exams!!