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Pharmacology of Local Anesthetics Donald H. Lambert Boston, Massachusetts

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Presentation on theme: "Pharmacology of Local Anesthetics Donald H. Lambert Boston, Massachusetts"— Presentation transcript:

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2 Pharmacology of Local Anesthetics Donald H. Lambert Boston, Massachusetts http://www.debunk-it.org

3 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

4 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

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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

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8 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

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10 B + H + BH +

11 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

12 Mode of Action l LAs bind Na channels, inhibiting the Na permeability that underlies AP in neurons l Na channels can exist in at least 3 native conformations: resting, open, and inactivated l During an AP, Na channels open l Na ions flow into the cell depolarizing the cell l In millisecs, Na channels inactivate and Na current ceases

13 Mode of Action 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

14 Mode of Action l toxins, calcium channel blockers, α 2 - adrenergic agonists, volatile general anesthetics, and meperidine can also inhibit Na channels

15 Pore

16 Mechanisms of Actions of Inhaled Anesthetics JA Campagna KW Miller SA Forman NEJM 348:2110- 2124 (2003)

17 The Sodium Channel lThe sodium channel allows for the selective flow of Na+ from outside to inside of the cell lNa channels can exist in at least 3 native conformations: resting, open, and inactivated lDuring an AP, Na channels open lNa ions flow into the cell depolarizing the cell lIn milliseconds, Na channels inactivate and Na current ceases

18 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

19 H+

20 H+H+

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22 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

23 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 Esters have [-CO- O-] linkage Amides have [- HN-CO-C-] linkage

24 ESTERS

25 Amide Bupivacaine Analogues

26 Amide Lidocaine Analogues

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31 Comparison of Drugs and Chemical Groups l Ropivacaine and levobupivacaine are single (S- or levo) optical isomers. l Bupivacaine and mepivacaine are racemic mixtures and therefore consist of equal amounts of S- (levo) and R- (dextro) isomers.

32 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

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

34 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

35 AGENTS OF HIGH POTENCY AND LONG DURATION

36 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

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38 COCA I NE BENZOCA I NE

39 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

40 LIPID SOLUBILITY = POTENCY

41 Lipid Solubility = Potency (and Duration) Lipid Bi-layer

42 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).

43 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

44 PROTEIN BINDING = DURATION

45 Protein Binding = Duration Lipid Bi-layer Protein Na+ Channel

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47 DETERMINANTS OF LA DURATION MEP LIDO BUPTETETID

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

49 pKa = ONSET

50 Relationship of pKa to Percent Base and Onset of Anesthesia l Small changes in pKa cause large changes in the amount of free base at physiologic pH l Agents with the largest amount of free base produce the fastest onset and vice versa

51 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

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

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54 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

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

56 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

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58 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

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

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63 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

64 Adding NaHC03 does not carbonate a LA

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 Adding sodium bicarbonate raises the pH of the local anesthetic solution

67 ion trapping

68 0.5% Lido 1% Lido Sinnott, et al. Anesthesiology 2000;93:1045-52

69 Comparison of pH-Adjusted Solutions for Epidural Anesthesia l While the difference in onset times (3-4 min.) owing to pH adjustment are statistically significant, they are not clinically important pH 4.6 7.5 4.55 7.2 6.35 Epi Yes Yes Yes Yes No

70 Comparison of pH-Adjusted Solutions for Epidural Anesthesia l The plain (no Epi) solution produces nearly the same effect as does the pH adjustment of the Epi containing solution pH 4.55 7.2 6.35 Epi Yes Yes No

71 1% Lido Rat Sciatic Nerve Block Sinnott, et al. Anesthesiology 2000;93:1045-52 Plain NaOH NaHCO3

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74 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

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76 l In this study, 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

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78 A eutectic mixture of local anesthetics (EMLA) that contains 2.5% lidocaine and 2.5% prilocaine in an oil and water emulsion

79 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

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82 Epidural local anesthetic has a greater dermatomal spread in pregnancy. 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.

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

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86 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

87 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

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

89 Fetal Pharmacology

90 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 Ficks 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

91 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

92 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

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


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