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Document Text Contents
Page 1

Anesthetic Pharmacology
Second Edition

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Page 590

Section 3
Chapter

36
Essential drugs in anesthetic practice
Local anesthetics

Francis V. Salinas and David B. Auyong

Introduction
Local anesthetics are administered to prevent or treat acute
perioperative pain. They are also utilized in the diagnosis and
treatment of cancer-related, chronic, and inflammatory pain
disorders. The traditional mechanism of action of local anes-
thetics is via blockade of axonal action potential generation or
propagation by prevention of voltage-gated sodium (Naþ) chan-
nel (VGSC) conductance that mediates these action potentials.
Additionally, local anesthetics also interact with calcium (Ca2þ)-
signaling G-protein-coupled receptors (GPCRs), and may medi-
ate their anti-inflammatory actions.

The clinical activity of local anesthetics is largely deter-
mined by their chemical structure and physicochemical prop-
erties. Aminoester local anesthetics are metabolized by plasma
cholinesterases, and aminoamides are metabolized in the liver.
The potency of local anesthetics correlates with increasing
molecular weight, which confers increased lipid solubility
and protein binding, both of which increase the duration of
action, but slow the onset of conduction block. Local anesthet-
ics exist in a dynamic equilibrium between the neutral lipid-
soluble form (which facilitates penetration of the axonal lipid
bilayer membrane to gain access to the intracellular receptor
within the VGSC) and the ionized hydrophilic form (which is
the active form once intracellular). The factors that govern the
rate and extent of local anesthetic systemic absorption are the
physicochemical properties of the local anesthetic, the total
mass of drug administered, and site of injection. Epinephrine
is the most widely used local anesthetic additive, and its vaso-
constrictive properties prolong the duration of action of local
anesthetics by decreasing vascular absorption.

Local anesthetics have the potential to cause direct toxicity
of nerves, but this is a rare occurrence in clinical application.
The potential systemic toxic effects of local anesthetics include
methemoglobinemia (primarily due to benzocaine and the
metabolite of prilocaine, o-toluidine), seizures, and malignant
ventricular dysrhythmias with cardiovascular collapse. True
allergic reactions to local anesthetics are rare, but may be
associated with the metabolites of the aminoester local anes-
thetics or preservatives in the local anesthetic solutions.

Mechanisms of actions of local
anesthetics
Functional anatomy of axons
Action potentials are the mechanism by which information
is transmitted between electrically excitable cells of the cen-
tral and peripheral nervous systems (see Chapter 17).
VGSCs are integral membrane proteins that are responsible
for initiation, propagation, and oscillation of electrical
impulses in electrically excitable tissues [1] (see Chapter 3).
Local anesthetics are most often administered in close prox-
imity to nerves within the peripheral and central nervous
systems. Peripheral nerves are mixed nerves containing both
afferent and efferent fibers that may be myelinated or
unmyelinated. Each peripheral nerve axon possesses its
own cell membrane, which contains the VGSC, responsible
for neural conduction. Nonmyelinated nerve fibers contain
multiple axons that are simultaneously encased by a single
Schwann-cell sheath. VGSCs are distributed all along the
axon of nonmyelinated nerve fibers. Propagation of action
potentials in nonmyelinated axons occurs when Naþ cur-
rents enter the axoplasm generating an action potential,
which then depolarizes the adjacent membrane. In contrast,
myelinated nerve fibers are segmentally encased by multiple
layers of myelin formed from the plasma membranes of
specialized Schwann cells that wrap around a single axon.
The myelin sheath may account for greater than 50% of the
thickness of myelinated nerve fibers. Periodic interruptions
in the myelin sheath (nodes of Ranvier) are where VGSCs
are concentrated along the axons of myelinated nerve fibers.
The presence of myelin significantly increases the speed of
axonal conduction by electrically insulating the cell mem-
brane from the surrounding conducting ionic medium. In
myelinated axons, Naþ currents are restricted to enter the
axoplasm through the nodes of Ranvier, allowing action-
potential propagation to jump from one Ranvier node to
the next (saltatory conduction). In general, increasing mye-
lination and nerve-fiber diameter are associated with

Anesthetic Pharmacology, 2nd edition, ed. Alex S. Evers, MervynMaze, Evan D. Kharasch. Published by Cambridge University Press. # Cambridge University Press 2011.

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increased conduction velocity. The presence of myelin
increases conduction velocity via saltatory conduction, and
the increased nerve diameter increases conduction velocity
via improved cable conduction properties.

The nerve fiber is the basic structural and functional unit
of peripheral nerves. A typical peripheral nerve is composed
of several axon bundles, or fascicles. A loose connective tissue
sheath called the endoneurium, composed of nonneural glial
cells, encases each axon. A second connective tissue sheath,
the perineurium, composed of several alternating layers of
flattened cells and collagen, encases individual fascicles.
Lastly, the entire peripheral nerve, consisting of multiple
fascicles, is encased in a moderately dense connective tissue
sheath known as the epineurium. The presence of these
multiple layers serves to protect the peripheral nerve, but also
presents a significant barrier to local anesthetics reaching
their intended site of action within the axonal cell mem-
branes. For example, a rat sciatic nerve model demonstrated
that only 1.6% of an administered dose of local anesthetic
penetrates into the nerve to achieve a functional block [2].
A classification of peripheral nerves based on size, presence of
myelin, speed of conduction, and physiological function is
presented in Table 36.1.

Molecular mechanisms of local
anesthetic action
Local anesthetics inhibit neuronal conduction by directly
binding to and inhibiting the ability of VGSCs to conduct
the inward Naþ current that mediates the rapid depolarizing
phase of the action potential [4]. The inhibition results from
local anesthetic binding at a receptor site in the channel’s
inner pore, accessible from the axoplasmic opening. Binding
of the local anesthetic is a dynamic process characterized by
differing affinities for the receptor site based on conforma-
tional changes of the VGSC, induced by temporal changes in
the membrane potential. At resting membrane potentials,

VGSCs predominantly exist in a resting (closed) conform-
ation. When a threshold depolarization is reached, VGSCs
are suddenly activated (opened), allowing the inward Naþ

current to further depolarize the membrane potential,
leading to further VGSC opening until the equilibrium
potential for Naþ is reached. Following activation of VGSC
and initiation of the action potential, the VGSCs rapidly
inactivate in order to terminate the action potential and
return the membrane to its resting potential. Within a few
milliseconds of activation, the VGSCs spontaneously
undergo a conformational change to an inactivated state,
whereupon the inward Naþ current ceases. Subsequent
depolarizations cannot open the VGSC from its inactivated
state. The VGSC must undergo a conformational change
back to the resting closed state before it is reprimed to open
again. Almost simultaneously, voltage-gated Kþ channels are
activated and open in response to depolarization, but with a
slight delay and at a slower rate than the VGSCs. The
inactivation of VGSCs in combination with outward Kþ

current via the activated Kþ channels results in membrane
repolarization to the negative resting membrane potential.
During the process of repolarization, the inactivated Naþ

channels and activated Kþ channels revert to their respective
resting (closed) conformations. Thus, a three-state kinetic
scheme conceptually describes the changes in VGSC con-
formation that accounts for the changes in Naþ (and Kþ)
conductance during depolarization and repolarization.

The commonly used local anesthetics are tertiary amines
that exist in a dynamic equilibrium between a neutral lipid-
soluble form and a hydrophilic, positively charged form,
depending on pKa and the pH of the aqueous milieu
where the local anesthetic is administered. Both ionized
and nonionized compounds with local anesthetic activity
can inhibit VGSCs. Permanently neutral local anesthetics
(e.g., the secondary amine benzocaine) freely permeate the
lipid bilayer membrane and inhibit inward Naþ conductance

Table 36.1. Classification of nerve fibers

Classification Diameter (μ) Myelin Conduction velocity
(m s–1)

Location Function

Aα 6–22 þ 30–120 Efferent to muscles Motor
Aβ 6–22 þ 30–120 Afferent from skin and

joints
Tactile and proprioception

Aγ 3–6 þ 15–35 Efferent to muscle spindle Muscle tone
Aδ 1–4 þ 5–25 Afferent sensory nerve Pain, cold temperature, and

touch

B < 3 þ 3–15 Preganglionic sympathetic Autonomic function
C 0.3–1.3 – 0.7–1.3 Postganglionic

sympathetic
Autonomic function, warm
temperature, Pain, and touch

Data from Stranding [3].

Chapter 36: Local anesthetics

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Page 1179

tyrosine hydroxylase 335

tyrosine kinase-associated
receptors 18, 47–48, 49,
50–51, 242

TZD (thiazolinediones) 879, 880,
993

UA see unstable angina

UGT (glucuronosyltransferase)
79–80

ulcers, gastric 486
non-steroidal anti-inflammatory
drugs 556–521, 847–848

proton pump inhibitors versus
histamine receptor
antagonists 848

ultra-rapid delayed rectifier
306–307

unconscious memory 212–213,
215–216; see also sleep/
consciousness

unfractioned heparin (UFH) 1095

unitary theory of anesthesia 359,
360, 361, 378

United States Renal Data System
(USRDS) 784

unstable angina (UA) 1091,
1092, 1101–1102;
see also myocardial ischemia

definition/diagnosis
1091–1092

management strategies 1094,
1095

pharmacologic/interventional
management 1092, 1093,
1094

upper motor neuron lesions
623–624

uptake measurement, inhaled
anesthetics 390

uptake rate, terminology 385

urethane 177

urine formation 786–790

urine output calculation 801

urine retention 535

use-dependent block 690

uterine contraction 955

valdecoxib 553–550;
see also cyclooxygenase-
2-specific inhibitors

validity, analytical 133–134

valproate 593, 594, 595, 596

vamicamide 673

Van der Waals interactions 2

vancomycin 970–971, 982

vanillylmandeic acid (VMA) 336

vaporizers 400

variable conductances , 251–253

variation between patients;
see also gender differences

biotransformation, drug 85
clearance 82, 83
disease states 84–85
drug biotransformation 82–85
drug interactions 82–83, 84

drug response analysis in
individuals 13–14, 14

drug response analysis in
populations 14–15, 14

neuromuscular blocking drugs
626

obstetrics 949
open-loop TCI 112, 113, 114
opioid effects 532–533
pain perception 140
pharmacogenetics 83–84
pharmacokinetics 68–69

vascular reactivity 277, 288
angiogenesis 280, 283
angiotensin II 284–285
arginine vasopressin 285
coagulation/inflammation
282–283

control of 285–286
drug action targets 286–287
endothelin 282
endothelium-dependent
relaxation 280–281

endothelium-derived
hyperpolarizing factor
281–282

endothelium-derived relaxing
factor 280, 281

extracellular matrix 277–278
nitric oxide 281
nonadrenergic noncholinergic
mechanisms 284

parasympathetic nervous
system 284

prostanoids 281
sympathetic nervous system
283–284

vascular endothelium 280,
727–728, 729

vascular smooth muscle (VSM)
278, 288, 726;
see also vasodilators

calcium voltage-gated ion
channels 278, 278, 279

contractile proteins 278
contraction mechanisms 278,
278

control of contractile site 726
endothelium role 727–728, 729

molecular mediators/
pharmomechanical coupling
725, 726–727, 728

myogenic contraction 279–280
neuronal regulation of vascular
tone and electromechanical
coupling 726, 727

physiology of muscle
contraction 724–726

vascular surgery, infusion
fluids 806

vascular system 317, 1079–1080;
see also cardiovascular
effects; heart function

vascular tone 1077–1078,
1088;
see also hemodynamics;
hypertension; hypotension

autonomic nervous system
1077–1078, 1079, 1080

coronary perfusion 1084
energetics 1080–1081,
1081–1082

heart rate 1084
hemodynamic problems and
impedence 1083–1084

hemodynamics 1078–1079,
1080

impedence/optimal
hemodynamics 1082–1083

inotropes 1086
inotropes-risks 1086–1087
nitric oxide 1087
oxygen consumption
1081–1082

pharmacology of available
drugs 1083, 1084–1085

pressure-volume analysis 1083

vasoactive agents 991;
see also vasodilators

ventricular function
1080–1081, 1081–1082

vasodilators 348, 724, 736–737,
1085–1086;
see also pulmonary
vasodilators

alpha-adrenergic agonists/
antagonists 730–731,
735–736

angiotensin converting
enzyme inhibitors 731,
735–736

angiotensin receptor blockers
732, 735–736

beta-adrenergic agonists 731,
735–736, 737

blood pressure control/
vascular tone 1085–1086

calcium channel blockers
733–734, 735–736, 737

calcium sensitizer 734,
735–736

catecholamine receptor
pharmacology 729–730, 737

clinical pharmacology 737
control of contractile site 726
dopamine agonists 731,
735–736

dosage/administration
735–736

eicosanoids 734, 735–736, 737
endothelin receptor agonists
732, 735–736, 737

endothelium role 727–728, 729
ganglionic blockers 733,
735–736, 737

hemodynamics 1078
magnesium 733, 737
mechanism of drug action
724, 725

molecular mediators/
pharmomechanical coupling
725, 726–727, 728

myogenic tone 726
neuronal regulation of vascular
tone/electromechanical
coupling 726, 727

new/emerging concepts
734–736

nitrovasodilators 728–729, 737
phosphodiesterase inhibitors
732, 735–736

physiology of muscle
contraction 724–726

potassium channel activators
732–733, 735–736, 737

renin inhibitors 732, 735–736
renin-angiotensin pathway
pharmacology 731–733, 737

vasopressin see arginine
vasopressin

Vaughan Williams drug
classification 691

vecuronium 612

ventilation mode 410–411

ventilatory depression
see respiratory depression

ventricular function
see cardiovascular effects;
coronary circulation; heart
function

ventrolateral preoptic nucleus
(VLPO) 376–377

verapamil 692, 693–694, 700, 702

vesicles, synaptic 192;
see also synaptic transmission

control of vesicle secretion
196–197

cycling 197–198, 206, 264, 265
drug action targets 206
fusion 263–264, 264–265, 266
heterogeneity 199

Index

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vesicles, synaptic (cont.)
neuromuscular function
263–264, 265

storage of neurotransmitters 196

vessel-poor group 388

vessel-rich group 388

vigabatrin 591–592

VIGOR (vaux gastrointestinal
outcomes research) 557

viral infection, and cancer 354;
see also antivirals

visceral nociception 231, 232

vitamins 904
alcohol users 1108
nutritional pharmacology
894–897, 901–902

VLPO (ventrolateral preoptic
nucleus) 376–377

VMA (vanillylmandeic acid) 336

volatile anesthetics see inhaled
anesthetics

voltage-gated ion channels 4, 41,
301; see also calcium ion
channels; potassium ion
channels; sodium ion
channels

effect on neuronal activity/
signalling 29

local anesthetics 239–241
pain transmission/
transduction 237

structure and function 29–31
types of 29

voltage-sensitive gating
299, 301

volume kinetics 802–803, 802

volume of distribution 57, 615

volume status, kidney function
791–793

vomiting; see also anti-emetics;
postoperative nausea and
vomiting

definition 855
physiology 855–856, 857

voriconazole 978, 979

VSM see vascular smooth muscle

wakefulness 177, 179, 180–182;
see also sleep/consciousness

wakening see emergence from
anesthesia

wake-up test 1036

warfarin 915, 924–926
adverse drug reactions
925–926

clinical pharmacology 925
dosage/administration 926
mechanism of drug action
924–925

new/emerging concepts 926
pediatric pharmacology 1134

water
body composition in elderly
patients 1139–1140

nutritional pharmacology
894–897

total body water 800

water tank analogy 388, 389

websites
delirium 1049
nutritional pharmacology 907

willingness to pay 172

withdrawal from drugs/alcohol
1106, 1108–1109

wobble, open-loop TCI 111

Wolff–Parkinson–White (WPW)
syndrome 703, 746

working memory 212, 226

xenobiotic transporters 92

xenobiotics 90, 97, 833

xenon 1156
anesthetic action mechanisms
374, 375

cerebral ischemia and anesthetic
neuroprotection 1154

diffusion into gas spaces 393
inhaled anesthetics
pharmacology 399

metabolism 392

zero-phase coherence 219

ziconotide 568
clinical pharmacology
568–569

dosage/administration 569
drug interactions 746–747
mechanisms of drug action
568–569

preclinical pharmacology 568

zinc fingers 53

zinc suspensions 878

ziprasidone 599, 600, 602

Zollinger–Ellison syndrome 847

zonisamide 591–592, 593, 594,
595, 597

Index

1194

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