Donald H. Lambert Boston, Massachusetts

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

3. 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

4. Nerve Muscle

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

7. BH+ B + H+

8. H+

9. H+

11. 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

12. ESTERS

13. AmideBupivacaine Analogues

14. AmideLidocaineAnalogues

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

16. COCAINE BENZOCAINE

17. 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

18. 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

19. AGENTS OF HIGH POTENCYAND LONG DURATION

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

21. 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.

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

23. pKa = ONSET

24. 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

26. 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

28. 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

30. 40 ml inj: Lido = 400 mg, Bup = 100 mg 20 ml inj: Lido = 400 mg, Bup = 100 mg

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

32. Onset quicker, duration same with mixture

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

34. ????

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

36. 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. Intercostal > caudal > epidural > brachial plexus > subcutaneous Rosenberg PH, Veering BT, Urmey WF: Reg Anesth Pain Med 2004; 29: 564-75

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