Donald H. Lambert Boston, Massachusetts Pharmacology of Local Anesthetics Dannemiller - Chicago - May 10,

Donald H. Lambert Boston, Massachusetts Pharmacology of Local Anesthetics Dannemiller – San Antonio - June 12,

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

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

Nerve Muscle

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

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

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

B + H + BH +

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

Pore

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

H+

H+H+

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

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 l Esters have [-CO-O-] linkage l Amides have [-N-CO-] linkage

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

ESTERS

Amide Bupivacaine Analogues

Amide Lidocaine Analogues

Amides v. Esters ParameterAmidesEsters Stability Metabolism Allergy StableUnstable Liver/kidneyPlasma RareLess rare

COCA I NE BENZOCA I NE

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

AGENTS OF INTERMEDIATE POTENCY AND DURATION AGENT CHEMICALRELATIVE ONSETDURATION CLASSPOTENCY(MINUTES) LIDOCAINE AMIDE 2 FAST MEPIVACAINE AMIDE 2 FAST PRILOCAINE AMIDE 2 FAST

AGENTS OF HIGH POTENCY AND LONG DURATION

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

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

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).

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

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

DETERMINANTS OF LA DURATION MEP LIDO BUPTETETID

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

pKa = ONSET

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

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 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

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

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

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

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

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

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

Adding NaHC03 does not “carbonate” a LA

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

Adding sodium bicarbonate raises the pH of the local anesthetic solution

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

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

Onset quicker, duration same with mixture

l In this study of epidural analgesia, 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

A E utectic M ixture of L ocal A nesthetics (EMLA) that contains 2.5% lidocaine and 2.5% prilocaine in an oil and water emulsion

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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VEINS Smaller CSF volume Non-Pregnant Pregnant

 Epidural local anesthetic has a greater dermatomal spread in pregnancy. Non-pregnant Pregnant 1st TRIMESTER  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

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: Intercostal > caudal > epidural > brachial plexus > subcutaneous

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

Fetal Pharmacology

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 Fick’s 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

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

Effect of pH on Fetal Lidocaine Concentration Continuous maternal lidocaine infusion Normal fetus pH Fetal acidemia pH Fetal NaHCO3 Correction pH FA to MA Lido Conc

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

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

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