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

B + H+BH+

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

Pore

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

H+

H+

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

AmideBupivacaine Analogues

AmideLidocaineAnalogues

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

COCAINE

BENZOCAINE

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

Lipid Solubility = Potency Lipid Solubility = Potency (and Duration)(and Duration)

Lipid Bi-layer

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

Protein Binding = DurationProtein Binding = Duration

Lipid Bi-layer

Protein Na+Channel

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

pKa = ONSET

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

LA~HC03

Adding NaHC03 does not “carbonate” a LA

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

Adding sodium bicarbonate raises the pH of the local anesthetic solution

“ion trapping”

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)

Fetal PharmacologyFetal Pharmacology

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

The Pharmacology of Local AnestheticsImportant stuff for everyday practice!

And for exams!!