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

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

BH+ B + H+

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

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

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

Mode of Action toxins, calcium channel blockers, α2-adrenergic agonists, volatile general anesthetics, and meperidine can also inhibit Na channels

Pore

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

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

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

H+

H+

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

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 [-HN-CO-C-] linkage

ESTERS

Amide Bupivacaine Analogues

Amide Lidocaine Analogues

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

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

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

AGENTS OF INTERMEDIATE POTENCY 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

AGENTS OF HIGH POTENCY AND LONG DURATION

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

COCAINE BENZOCAINE

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

LIPID SOLUBILITY = POTENCY

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

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.

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

PROTEIN BINDING = DURATION

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

DETERMINANTS OF LA DURATION MEP BUP TET ETID LIDO

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

pKa = ONSET

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

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

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

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

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

The increased duration with epinephrine depends on the type of block 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

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

Adding NaHC03 does not “carbonate” a LA

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

Adding sodium bicarbonate raises the pH of the local anesthetic solution

“ion trapping”

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

Comparison of pH-Adjusted Solutions for Epidural Anesthesia 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

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

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

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

In this study, 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

A eutectic mixture of local anesthetics (EMLA) that contains 2 A eutectic mixture of local anesthetics (EMLA) that contains 2.5% lidocaine and 2.5% prilocaine in an oil and water emulsion

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

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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.

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

Pharmacology of Local Anesthetics 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 Factors Influencing Anesthetic Activity Dosage Addition of Vasoconstritor Site of Injection Carbonation pH Adjustment Mixtures Pregnancy

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

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

Fetal Pharmacology

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

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

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

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