LOCAL ANESTHETICS:

INTRODUCTION
 Local anesthetics reversibly block impulse conduction
along nerve axons and other excitable membranes that
utilize sodium channels as the primary means of action
potential generation.
 Clinically, local anesthetics are used to block pain
sensation from—or sympathetic vasoconstrictor impulses
to—specific areas of the body.
Basic pharmacology of local anesthetics
Chemistry
 Most local anesthetic agents consist of a lipophilic group
(eg, an aromatic ring) connected by an intermediate chain
via an ester or amide to an ionizable group (eg, a tertiary
amine).
 In addition to the general physical properties of the
molecules, specific stereochemical configurations are
associated with differences in the potency of stereoisomers
(eg, bupivacaine, ropivacaine). Because ester links are
more prone to hydrolysis than amide links, esters usually
have a shorter duration of action.
Ester Potency Duration of Action
Procaine = 1
Cocaine 2 Medium
Procaine (Novocain) 1 Short

Tetracaine (Pontocaine) 16 Long

Benzocaine Surface use
only

Amides
Lidocaine (Xylocaine) 4 Medium
Mepivacaine 2 Medium
(Carbocaine, Isocaine)
Bupivicaine (Marcaine), 16 Long
Ievobupivacaine (Chirocaine)

Prilocaine (Citanest) 3 Medium

Ropivacaine (Naropin) 16 Long

 Pharmacokinetics
 The pharmacokinetics of the ester-based local anesthetics
have not been extensively studied owing to their rapid
breakdown in plasma (elimination half-life < 1 minute).
 Local anesthetics are usually administered by injection
into dermis and soft tissues located in the area of nerves.
 Absorption and distribution are not as important in
controlling the onset of effect as in determining the rate of
offset of local analgesia, and the likelihood of CNS and
cardiac toxicity.
 Topical application of local anesthetics (eg, transmucosal
or transdermal) requires drug diffusion for both onset and
offset of anesthetic effect.
Pharmacokinetic Properties of Several Amide Local
Anaesthetics.
Agent Half-Time of t1/2 (Elimination (h) Vdss (L) CL (L/min)
Distribution
(min)

Bupivacaine 28 3.5 72 0.47

Lidocaine 10 1.6 91 0.95

Mepivacaine 7 1.9 84 0.78

Prilocaine 5 1.5 261 2.84

Ropivacaine 23 4.2 47 0.44

Absorption
 Systemic absorption of injected local anesthetic from the
site of administration is determined by several factors,
including dosage, site of injection, drug-tissue binding,
local blood flow, use of vasoconstrictors (eg, epinephrine),
and the physicochemical properties of the drug itself.
 Application of a local anesthetic to a highly vascular area
such as the tracheal mucosa or the tissue surrounding
intercostal nerves results in more rapid absorption and thus
higher blood levels than if the local anesthetic had been
injected into a poorly perfused tissue such as tendon,
dermis, or subcutaneous fat.
 For regional anesthesia involving block of large nerves,
maximum blood levels of local anesthetic decrease
according to the site of administration in the following
order:
 intercostal (highest) > caudal > epidural > brachial
plexus > sciatic nerve (lowest).
 Vasoconstrictor substances such as epinephrine
reduce systemic absorption of local anesthetics from
the injection site by decreasing blood flow in these
areas. This is important for drugs with intermediate or
short durations of action such as procaine, lidocaine,
and mepivacaine (but not prilocaine).
 Since blood levels are lowered up to 30% when
vasoconstrictors are added to local anesthetics,
localized neuronal uptake is enhanced because of
higher local tissue concentrations in the region of drug
administration, and the systemic toxic effects are
reduced. Furthermore, when used in spinal anesthesia,
epinephrine acts directly
on the cord to both enhance and prolong local anesthetic-
induced spinal anesthesia by acting on 2 adrenoceptors,
which inhibit release of substance P (neurokinin-1) and
reduce sensory neuron firing.
Distribution
The amide local anesthetics are widely distributed after
intravenous bolus administration.
There is also evidence that sequestration can occur in
lipophilic storage sites (eg, fat).
 After an initial rapid distribution phase, which consists of
uptake into highly perfused organs such as the brain, liver,
kidney, and heart, a slower distribution phase occurs with
uptake into moderately well-perfused tissues, such as
muscle and the gastrointestinal tract.
 As a result of the extremely short plasma half-lives of the
ester type agents, their tissue distribution has not been
extensively studied.
Metabolism and excretion
 The local anesthetics are converted in the liver (amide
type) or in plasma (ester type) to more water-soluble
metabolites and then excreted in the urine.
 Since local anesthetics in the uncharged form diffuse
readily through lipid membranes, little or no urinary
excretion of the neutral form occurs.
 Acidification of urine promotes ionization of the tertiary
amine base to the more water-soluble charged form, which
is more readily excreted.
 Ester-type local anesthetics are hydrolyzed very rapidly in
the blood by circulating butyrylcholinesterase
(pseudocholinesterase) to inactive metabolites. Therefore,
procaine and chloroprocaine have very short plasma half-
lives (< 1 minute).
 The amide linkage of amide local anesthetics is
hydrolyzed by liver microsomal cytochrome P450
isozymes.
 As a result, toxicity from amide-type local anesthetics is
more likely to occur in patients with hepatic disease.

Pharmacodynamics
Mechanism of action
 The primary mechanism of action of local anesthetics is
blockade of voltage-gated sodium channels.
 The excitable membrane of nerve axons, like the
membrane of cardiac muscle and neuronal cell bodies
maintains a resting transmembrane potential of –90 to –60
mV.
 During excitation, the sodium channels open, and
a fast inward sodium current quickly depolarizes
the membrane toward the sodium equilibrium
potential (+40 mV). As a result of depolarization,
the sodium channels close (inactivate) and
potassium channels open.
 The outward flow of potassium repolarizes the
membrane toward the potassium equilibrium
potential (about –95 mV); repolarization returns the
sodium channels to the rested state.
 The transmembrane ionic gradients are
maintained by the sodium pump. These ionic fluxes
are similar to those in heart muscle, and local
anesthetics have similar effects in both tissues.
Clinical pharmacology of local anesthetics
 Local anesthetics can provide highly effective analgesia in
well-defined regions of the body.
 The usual routes of administration include topical
application (eg, nasal mucosa, wound margins), injection in
the vicinity of peripheral nerve endings (infiltration) and
major nerve trunks (blocks), and injection into the epidural
or subarachnoid spaces surrounding the spinal cord.
 Intravenous regional anesthesia (so-called Bier block) is
used for short surgical procedures (< 60 minutes) involving
the upper and lower extremities. This is accomplished by
intravenous injection of the anesthetic agent into a distal
vein while the circulation of the limb is isolated with a
proximally placed tourniquet.
 The choice of local anesthetic for infiltration, peripheral
nerve blocks, and central neuraxis blockade is usually
based on the duration of action required.
 Procaine and chloroprocaine are short-acting; lidocaine,
mepivacaine, and prilocaine have an intermediate duration
of action; and tetracaine, bupivacaine, levobupivacaine,
and ropivacaine are long-acting local anesthetics.
 The anesthetic effect of the agents with short and
intermediate durations of action can be prolonged by
increasing the dose or adding a vasoconstrictor agent (eg,
epinephrine or phenylephrine).
 The vasoconstrictor slows the removal of the local
anesthetic from the injection site. In addition, it decreases
the blood level and the probability of CNS toxicity.
 The onset of local anesthesia can be accelerated by the
addition of sodium bicarbonate (1–2 mL) to the local
anesthetic solution. This maximizes the amount of drug in
the more lipid-soluble form.

Toxicity
 The two major forms of local anesthetic toxicity are:
1) Systemic effects following absorption of the local
anesthetic from their site of administration
2) Direct neurotoxicity from the local effects of these drugs
when administered in close proximity to the spinal cord
and other major nerve trunks. When blood levels of
local anesthetics rise rapidly, adverse effects on
several major organ systems may be observed.
Central nervous system Toxicity
 All Local Anesthetics at low concentrations and all local
anesthetics have the ability to produce sleepiness, light-
headedness, visual and auditory disturbances, and
restlessness.
 An early symptom of local anesthetic toxicity is circumoral
and tongue numbness and a metallic taste.
 At higher concentrations, nystagmus and muscular
twitching occur, followed by overt tonic-clonic convulsions.
 Seizures induced by local anesthetics can also be treated
with intravenous anesthetic drugs (eg, thiopental 1–2
mg/kg, propofol 0.5–1 mg/kg, midazolam 0.03–0.06 mg/kg,
or diazepam 0.1–0.2 mg/kg).
Cardiovascular system Toxicity
 The cardiovascular effects of local anesthetics result partly
from direct effects on the cardiac and smooth muscle
membranes and partly from indirect effects on the
autonomic nervous system.
 Local anesthetic agents block cardiac sodium channels
and thus depress abnormal cardiac pacemaker activity,
excitability, and conduction.