Pharmacology of Local Pharmacology of Local AnestheticsAnesthetics
Donald H. Lambert
Boston, Massachusetts
http://www.debunk-it.org
Pharmacology of Local AnestheticsPharmacology of Local Anesthetics 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 AnestheticsPharmacology of Local Anesthetics 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 AnestheticsPharmacology of Local Anesthetics 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 AnestheticsPharmacology of Local Anesthetics 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
The Sodium Channel The Sodium Channel Sub-unit 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 poreP designates the pore region within the S5-S6 extracellular linker“+S4+” is believed to be the “voltage sensitive” segmentThe 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
Membrane potential influences Na channel conformations and LA affinityLA inhibition of Na currents increases with repetitive depolarizations, i.e., use-dependent blockUse-dependent block result from open and inactivated channels having greater LA affinity than resting channelsRepetitive depolarizations increase the chance that a LA will encounter Na channels that are open or inactivated
Mode of ActionMode of Action
Pharmacology of Local AnestheticsPharmacology of Local Anesthetics 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
The Local Anesthetic MoleculeThe 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
N C
O
O C C NCH3
CH3
H9C4
NH2 C
O
O C C N
C2H5
C2H5
NH2 C
O
O C C N
Cl
C2H5
C2H5
Procaine
Chloroprocaine
Tetracaine
ESTERS
Comparison of Drugs and Comparison of Drugs and Chemical GroupsChemical 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 AnestheticsPharmacology of Local Anesthetics 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
AGENTS OF LOW POTENCYAGENTS OF LOW POTENCYAND SHORT DURATIONAND SHORT DURATION
AGENT CHEMICAL RELATIVE ONSET DURATION CLASS POTENCY (MINUTES)
PROCAINE ESTER 1 SLOW 60 - 90
CHLOROPROCAINE ESTER 1 FAST 30 - 60
AGENTS OF INTERMEDIATEAGENTS OF INTERMEDIATEPOTENCY AND DURATIONPOTENCY 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 POTENCYAGENTS OF HIGH POTENCYAND LONG DURATIONAND LONG DURATION
AGENT CHEMICALCLASS
RELATIVEPOTENCY
ONSET DURATION(MIN)
ROPIVACAINE AMIDE 4 INTERMED. 180-600
TETRACAINE ESTER 6 SLOW 180-600
BUPIVACAINE AMIDE 6 INTERMED. 180-600
LEVOBUPIV. AMIDE 6 INTERMED. 180-600
ETIDOCAINE AMIDE 6 FAST 180-600
Pharmacology of Local AnestheticsPharmacology of Local Anesthetics 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 AnestheticsPharmacology of Local Anesthetics 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
The most lipid soluble agents (amethocaine and etidocaine) are the most potent (lowest ED50).
The amino-esters may interact with a greater number receptor sites, which may explain their inherently greater potency.
The amino-esters are more potent than the amino-amides (most leftward curve).
Pharmacology of Local AnestheticsPharmacology of Local Anesthetics 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
DETERMINANTS OF LA DETERMINANTS OF LA DURATIONDURATION
0
20
40
60
80
100
0 10 20 30 40 50
LIPID SOLUBILITY
% P
RO
TE
IN B
IND
ING MEP
LIDO
BUP TET ETID
Pharmacology of Local AnestheticsPharmacology of Local Anesthetics 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
Relationship of pKa to Percent BaseRelationship of pKa to Percent Base
and Onset of Anesthesia and Onset of Anesthesia
7.8 8.1 8.6 8.9
0
5
10
15
20
25
30
35
40L
ido
Bu
piv
Tet
ra
Pro
c
pKa
% Base
Onset(min)
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 LAPop-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 AnestheticsPharmacology of Local Anesthetics 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 AnestheticsPharmacology of Local Anesthetics 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
Effect of Dose on Onset, Duration, and Quality of Effect of Dose on Onset, Duration, and Quality of AnesthesiaAnesthesia
• 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 thefaster it comes on, the betterthe block, the longer itlasts, and the greater the toxicity
Pharmacology of Local AnestheticsPharmacology of Local Anesthetics 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
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 AnestheticsPharmacology of Local Anesthetics 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 AnestheticsPharmacology of Local Anesthetics 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 AnestheticsPharmacology of Local Anesthetics 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
Comparison of pH-Adjusted Comparison of pH-Adjusted Solutions for Epidural AnesthesiaSolutions for Epidural Anesthesia
While the difference in onset times (3-4 min.) owing to pH adjustment are statistically significant, they are not clinically important
0
1
2
3
4
5
6
7
On
se
t (m
inu
tes
)1.37%Lido
1.37 %Lido
1.5 %Lido
1.5 %Lido
1.5 %Lido
Analgesia
pH 4.6 7.5 4.55 7.2 6.35Epi Yes Yes Yes Yes No
Comparison of pH-Adjusted Comparison of pH-Adjusted Solutions for Epidural AnesthesiaSolutions for Epidural Anesthesia
The plain (no Epi) solution produces nearly the same effect as does the pH adjustment of the Epi containing solution
0
1
2
3
4
5
On
se
t (m
inu
tes
)1.5 % Lido 1.5 % Lido 1.5 % Lido
Analgesia
pH 4.55 7.2 6.35
Epi Yes Yes No
0
1
2
3
4
0 10 20 30 40 50 60 70 80 90
Minutes
Res
pon
se t
o D
eep
Pin
chControl NaHCO3 pH 7.75 Plain pH 6.6 NaOH pH 7.85
1% Lido Rat Sciatic Nerve Block1% Lido Rat Sciatic Nerve Block
Sinnott, et al. Anesthesiology 2000;93:1045-52Sinnott, et al. Anesthesiology 2000;93:1045-52
Plain
NaOH
NaHCO3
Pharmacology of Local AnestheticsPharmacology of Local Anesthetics 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
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 2.5% lidocaine and 2.5% prilocaine in an oil and water emulsion
Pharmacology of Local AnestheticsPharmacology of Local Anesthetics 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
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 WomenMedian Nerve Block in Pregnant and Non-Pregnat Women
0
10
20
30
40
50
60
70
80
90
100R
ed
uct
ion
in A
ctio
n P
ote
nti
al
Am
plit
ud
e (
% o
f co
ntr
ol)
0 5 10 15 20
Minutes after injection
Preg
Non-Preg
J Butterworth, et al. Anesthesiology 1990;72:962-5
Pharmacology of Local AnestheticsPharmacology of Local Anesthetics 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
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: 564-75
Intercostal > caudal > epidural > brachial plexus > subcutaneous
MetabolismMetabolismPlease refer to your syllabusSome key words
Volume of distributionClearance-1-acid-glycoproteinCytochrome P450T1/2 (half life)
Intervillousspace Cm
Uterine artery
Umbilical vein
Umbilical artery
Uterine vein
MaternalShunt
FetalShunt
Maternal Cm =UtA conc free drug
Fetal Cf =UmA conc free drug
Intervillousspace Cf
PlacentaFick’s Law
passive diffusion
Determinants of UtA Cm:Total DoseRoute of administrationEpinephrine in solutionMaternal metabolism and excretionMaternal protein bindingMaternal pH and pKa of drug
Determinants of UmA Cf:Umbilical vein concentration (input)Fetal pHFetal protein bindingFetal tissue uptakeNonplacental elimination
Fetal hepatic metabolismFetal renal excretion
Factors influencing fetal uptake of drugsFactors influencing fetal uptake of drugs
Maternal plasma Fetal plasma
Placenta
80% binding 67% binding
boundboundboundbound
boundbound
Free(20%)
Free(33%)
(4) + (1) 5 molecules
(1) + (2) 3 molecules
Effect of differential protein bindingEffect of differential protein binding by maternal and fetal blood by maternal and fetal blood
Effect of pH on Fetal Lidocaine ConcentrationEffect of pH on Fetal Lidocaine Concentration
Continuous maternal lidocaine infusion
1.2
1.0
0.8
0.6
Normalfetus pH7.30-7.35
Fetal acidemiapH6.90-7.18
Fetal NaHCO3CorrectionpH7.22-7.40
FA toMALidoConc