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Pharmacology of Local Anesthetics: Influencing Factors and Mechanisms

Explore the pharmacology of local anesthetics including dosage adjustments, site of injection, and mechanisms of action. Understand the factors influencing anesthetic activity and the advantages of using local anesthesia. Learn about the classification of local anesthetics, esters versus amides, and their structure-activity relationships.

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Pharmacology of Local Anesthetics: Influencing Factors and Mechanisms

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

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

  3. Nerve Muscle

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

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

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

  7. BH+ B + H+

  8. The Sodium Channel  Sub-unit Four domains (D1-D4) Six segments (S1-S6) Na channel is organized as a pseudo-tetramer with the S6 segments possibly lining the internal vestibule of the pore P designates the pore region within the S5-S6 extracellular linker “+S4+” is believed to be the “voltage sensitive” segment 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

  9. Pore

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

  11. H+

  12. H+

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

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

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

  16. ESTERS

  17. AmideBupivacaine Analogues

  18. AmideLidocaineAnalogues

  19. Amides v. Esters Parameter Amides Esters StabilityMetabolismAllergy Stable Unstable Liver/kidney Plasma Rare Less rare

  20. COCAINE BENZOCAINE

  21. AGENTS OF LOW POTENCYAND SHORT DURATION AGENT CHEMICAL RELATIVE ONSET DURATION CLASS POTENCY (MINUTES) PROCAINE ESTER 1 SLOW 60 - 90 CHLOROPROCAINE ESTER 1 FAST 30 - 60

  22. AGENTS OF INTERMEDIATEPOTENCY AND DURATION AGENT CHEMICAL RELATIVE ONSET DURATION CLASS POTENCY (MINUTES) LIDOCAINE AMIDE 2 FAST 90 -200 MEPIVACAINE AMIDE 2 FAST 120 - 240 PRILOCAINE AMIDE 2 FAST 120 - 240

  23. AGENTS OF HIGH POTENCYAND LONG DURATION

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

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

  26. The most lipid soluble agents (amethocaine and etidocaine) are the most potent (lowest ED50). • The amino-esters are more potent than the amino-amides (most leftward curve). • The amino-esters may interact with a greater number receptor sites, which may explain their inherently greater potency.

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

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

  29. DETERMINANTS OF LA DURATION MEP BUP TET ETID LIDO

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

  31. pKa = ONSET

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

  33. 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

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

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

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

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

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

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

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

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

  42. Adding NaHC03 does not “carbonate” a LA

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

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

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