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Pharmacology of Local Anesthetics
Donald H. Lambert Boston, Massachusetts
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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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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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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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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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BH+ B + H+
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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
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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
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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
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Mode of Action toxins, calcium channel blockers, α2-adrenergic agonists, volatile general anesthetics, and meperidine can also inhibit Na channels
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Pore
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Mechanisms of Actions of Inhaled Anesthetics
JA Campagna KW Miller SA Forman NEJM 348: (2003)
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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
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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
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H+
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H+
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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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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
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ESTERS
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Amide Bupivacaine Analogues
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Amide Lidocaine Analogues
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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.
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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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AGENTS OF LOW POTENCY AND SHORT DURATION
AGENT CHEMICAL RELATIVE ONSET DURATION CLASS POTENCY (MINUTES) PROCAINE ESTER SLOW CHLOROPROCAINE ESTER FAST
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AGENTS OF INTERMEDIATE POTENCY AND DURATION
AGENT CHEMICAL RELATIVE ONSET DURATION CLASS POTENCY (MINUTES) LIDOCAINE AMIDE FAST MEPIVACAINE AMIDE FAST PRILOCAINE AMIDE FAST
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AGENTS OF HIGH POTENCY AND LONG DURATION
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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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COCAINE BENZOCAINE
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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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LIPID SOLUBILITY = POTENCY
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Lipid Solubility = Potency (and Duration)
Lipid Bi-layer
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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.
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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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PROTEIN BINDING = DURATION
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Protein Binding = Duration
Protein Na+ Channel Lipid Bi-layer
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DETERMINANTS OF LA DURATION
MEP BUP TET ETID LIDO
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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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pKa = ONSET
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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
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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
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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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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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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
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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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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
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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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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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Adding NaHC03 does not “carbonate” a LA
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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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Adding sodium bicarbonate raises the pH of the local anesthetic solution
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“ion trapping”
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0.5% Lido 1% Lido Sinnott, et al. Anesthesiology 2000;93:
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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 Epi Yes Yes Yes Yes No
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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
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1% Lido Rat Sciatic Nerve Block
NaHCO3 NaOH Plain Sinnott, et al. Anesthesiology 2000;93:
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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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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
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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
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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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????
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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.
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Median Nerve Block in Pregnant and Non-Pregnat Women
J Butterworth, et al. Anesthesiology 1990;72:962-5
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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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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:
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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)
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Fetal Pharmacology
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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
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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
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Effect of pH on Fetal Lidocaine Concentration
Continuous maternal lidocaine infusion Fetal NaHCO3 Correction pH Normal fetus pH FA to MA Lido Conc 1.2 1.0 0.8 Fetal acidemia pH 0.6
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The Pharmacology of Local Anesthetics
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