I.

PREFACE
A. BACKGROUND
Physicians commonly use local anesthetics to perform minor
procedures and to improve analgesia for procedures performed under general
anesthesia. Local anesthetics improve postoperative pain control and reduce
the amount of postoperative narcotic required. This, inturn, can reduce
postoperative nausea, emesis and delayed return to bowel function. An ideal
local anesthetic provides complete sensory blockade on application and has
an adequate duration of effect to include the procedure and a generous
postoperative period.
Bupivacaine and lidocaine are two commonly used local analgesics.
The two amino amides are often used concurrently to combine the more rapid
onset of lidocaine and the longer duration of bupivacaine. Compared with
lidocaine, bupivacaine has a significantly longer duration of action and slower
time to onset. Bupivacaine has an onset of 5 min, a duration of 2 h to 4 h and
maximum dose of 2 mg/kg. The addition of epinephrine has an unknown
effect on onset while increasing duration and maximum dose to 3 h to 7 h and
3mg/kg, respectively. Lidocaine is known to have an onset <2 min, a duration
of 1 h to 2 h, and a maximum dose of 5 mg/kg, which improves to an onset
<2 min, a duration of 2 h to 6 h and toxicity of 7mg/kg with the addition of
epinephrine.
Each characteristic is dependent on multiple factors including volume
and concentration infused, location of administration and tissue pH. This
review discusses the different, characteristics, and compare lidokain and
buivacaine in used to local anesthesia.
B. OBJECTIVE
1. To Know How the Characteristics of Lidocaine as a Local Anesthetics
2. To Know How the Characteristics of Bupivacaine as a Local Anesthetics
3. To Compare Lidocaine snd Bupivacaine as a Local Anesthetics

II. LITERATURE REVIEW

A. NERVE CONDUCTION PHYSIOLOGY
The neural membrane contains a voltage difference of +60 mV (inner)
to -90 mV (outer). At rest the neural membrane is impermeable to Na+ ions,
and selectively permeable to K+ ions. The Na+/K+ pump maintains the ion
gradient. The K+ to Na+ gradient is constant at 30:1. Within the cell, the
concentration of K+ is kept at 30, and outside the cell it is maintained at 1.
Sodium, on the other hand, is at higher concentrations outside the cell.
At Rest
Outside Cell
-90 mV

K+ concentration low; Na+ concentration high

Neural Membrane
+ 60 mV

K+ concentration high; Na+ concentration low

Inside Cell

During an action potential, the nerve membrane switches its

permeability from K+ to Na+, changing the membrane potential from -90
to +60 mV (negative to positive) and back again.
Action Potential
Outside Cell
+60 mV

Na+

Neural Membrane
-90 mV

K+

Inside Cell
B. LOCAL ANESTHETICS
1. Historical Preseptive
Anesthesia by compression was common in the antiquity. Cold as
an anesthetic was widely used until the 1800s. The native Indians of Peru
chewed coca leaves and knew about their cerebral-stimulating effects and
possibly about their local anesthetic properties (there are some reports of
natives using an emulsion of chewed coca leaves and saliva on wounds).
The leaves of erythroxylon coca were taken to Europe where Niemann in
Germany isolated cocaine in 1860. Cocaine was introduced into Europe
in the 1800s following its isolation from coca beans. Sigmund Freud, the

noted Austrian psychoanalyst, used cocaine on his patients and became

addicted through self-experimentation (Keneeth, 2006).
In the latter half of the 1800s, interest in the drug became
widespread, and many of cocaine's pharmacologic actions and adverse
effects were elucidated during this time. In the 1880s, Koller introduced
cocaine to the field of ophthalmology, and Hall introduced it to dentistry.
Halsted was the first to report the use of cocaine for nerve blocks in the
United States in 1885 and also became addicted to the drug through selfexperimentation (Keneeth, 2006).
Cocaine is a good topical local anesthetic that also produces
vasoconstriction and for this reason it is still used, by some, as a topical
anesthetic in the nose and other mucous membranes. Cocaine blocks the
reuptake of cathecolamines from nerve endings. Total dose should not
exceed 100 mg (2.5 mL of a 4% solution), to avoid systemic effects like
hypertension, tachycardia and cardiac arrhythmias. Procaine, the first
synthetic derivative of cocaine, was developed in 1904. Lofgren later
developed lidocaine, the most widely used cocaine derivative, during
World War II in 1943 (Keneeth, 2006).
2. Chemical Structure of Local Anesthetic
Local anesthetics are weak bases with a pka above 7.4 and poorly
soluble in water. They are commercially available as acidic solutions (pH
4-7) of hydrochloride salts, which are hydrosoluble.Local anesthetics
produce a reversible loss of sensation in a portion of the body. Local
anesthetics may be used as the sole form of anesthesia, in combination
with general anesthesia, and/or to provide postoperative analgesia. A
typical local anesthetic molecule is composed of two parts, a benzene ring
(lipid soluble, hydrophobic) and an ionizable amine group (water soluble,
hydrophilic). These two parts are linked by a chemical chain, which can
be either an ester (-CO-) or an amide (-HNC-).The basic chemical
structure of a local anesthetic molecule consists of 3 parts:
a. Lipophilic group- an aromatic group, usually an unsaturated benzene
ring.
b. Intermediate bond- a hydrocarbon connecting chain, either an ester (CO-) or amide (-HNC-) linkage. The intermediate bond determines

the classification of local anesthetic.

c. Hydrophilic group- a tertiary amine and proton acceptor.

N
Lipophilic Group
Benzene Ring

Intermediate Bond

Hydrophilic Group

Ester or Amide Linkage

Tertiary Amine &

(-CO- ester or HNC- amide)

Proton Acceptor

This is the basis for the classification of local anesthetics as either

esters or amides. Injecting local anesthetics in the proximity of a nerve
triggers a sequential set of events, which eventually culminates with the
interaction of some of their molecules with receptors located in the Na+
channels of nerve membranes.
3. Structure Activity Relationships
The intrinsic potency, duration, and onset of action for a local
anesthetic are dependent upon:
a. Lipophilic-hydrophobic balance (lipid solubility)
The term lipophilic means fat loving, expressing the
tendency of the local anesthetic molecule to bind to membrane lipids.
The term hydrophobic means fear of water. The lipid membrane is a
hydrophobic environment. The term hydrophobicity is often used to
describe the physiochemical property of local anesthetics. Potency as
related to local anesthetics correlates with lipid solubility.
Determines both the potency and the duration of
action of local anesthetics, by facilitating their transfer
through membranes and by keeping the drug close to
the site of action and away from metabolism. In
addition, the local anesthetic receptor site in Na +
channels is thought to be hydrophobic, so its affinity for
hydrophobic

drugs

is

greater.

Hydrophobicity also

increases toxicity, so the therapeutic index of morelipid

soluble drugs is decreased (Longnecker et al., 2008).
In clinical practice, the potency of a local anesthetic is affected
by several factors including:
1) Hydrogen ion balance
2) Fiber size, type, and myelination
3) Vasodilator/vasoconstrictor properties (affects
rate of vascular uptake)
4) Frequency of nerve stimulation
5) pH (an acidic environment will antagonize the
block)
6) Electrolyte concentrations (hypokalemia and
hypercalcemia antagonizes blockade)
Duration of action is associated with lipid solubility. Highly
lipid soluble local anesthetics generally have a longer duration of
action due to decreased clearance by localized blood flow and
increased protein binding.
Local Anesthetic
AMIDES
Bupivacaine/LevoBupivacaine
Etidocaine
Ropivacaine
Mepivacaine
Lidocaine
Prilocaine
ESTERS
Tetracaine
Cocaine
Procaine
Chloroprocaine

Potency and Lipid Solubility/Duration of

Action
4/4
4/4
4/4
2/2
2/2
2/2
4/3
2/2
1/1
1/1
1= least; 4= greatest

b. Protein binding
Local anesthetics are bound in large part to plasma
and

tissue

proteins.

pharmacologically

The

active.

bound
The

portion

plasmatic

is

not

unbound

fraction is responsible for systemic toxicity. The most

important binding proteins in plasma are albumins and
alpha-1-acid glycoprotein (AAG). Although albumin has
a greater binding capacity than AAG, the latter has a
greater affinity for drugs with pka higher than 8, the
case for most local anesthetics. Newborn infants have
very low concentration of AAG, only reaching adult
values by 10 months of age. The elderly and debilitated
also frequently have decreased levels of albumin and
other plasma proteins. These patient populations could
be at increased risk for toxicity (Longnecker et al.,
2008).
On the other hand, AAG levels increase during stress
and for several days after the postoperative period.
Higher levels of AAG lead to decreased levels of
unbound fraction of local anesthetics and a decreased
potential for local anesthetic toxicity. However, changes
in protein binding are only clinically important for drugs
highly protein-bound, such as bupivacaine, which is
96% bound (Longnecker et al., 2008).
The fraction of drug bound to protein in plasma
correlates

with

the

duration

of

action

of

local

anesthetics: bupivacaine (95%) = ropivacaine (94%)> tetracaine

(85%) > mepivacaine (75%) > lidocaine 65%) > procaine (5%) and 2chloroprocaine (negligible).This suggests that the binding
site for the local anesthetic molecule in the sodium
channel receptor protein, may share a similar sequence
of amino acids with the plasma protein binding site.
Drugs

as

lidocaine,

tetracaine,

bupivacaine

and

morphine have been incorporated into liposomes to

prolong their duration of action. Liposomes are vesicles
with two layers of phospholipids, which slow down the
release of the drug (Longnecker et al., 2008).

c. Hydrogen Ion Concentration

Local anesthetics are weak bases, containing a positive charge
on the tertiary amine at a physiologic pH. Local anesthetics exist in
equilibrium between the basic uncharged (non-ionized) form, which is
lipid soluble, and the charged (ionized) cationic form, which is water
soluble. The measurement pKa expresses the relationship between the
non-ionized and ionized concentrations. Specifically, pKa is the pH at
which the ionized and non-ionized forms of the local anesthetic are
equal.
Non-Ionized Form

Ionized Form

pKa = pH at which ionized and non-ionized forms of local anesthetic are

equal.

Local anesthetics are weak bases and contain a higher ratio of

ionized medication compared to non-ionized. Increasing the
concentration of non-ionized local anesthetic will speed onset. In
general, local anesthetics with a pKa that approximates physiologic
pH have a higher concentration of non-ionized base resulting in a
faster onset. On the other hand, a local anesthetic with a pKa that is
different from physiologic pH will have more ionized medication
which slows onset.
For example, the pKa for lidocaine is 7.8 and 8.1 for
bupivacaine. Lidocaine is closer to physiologic pH than bupivacaine.
Lidocaine has a greater concentration on non-ionized local anesthetic
than bupivacaine which results in a faster onset. Non-ionized and
ionized portions of local anesthetic solution exert distinct actions.
Lipid soluble, non-ionized form of the local anesthetic penetrates the
neural sheath and membrane. In the cell, the non-ionized and ionized
forms equilibrate. The ionized form of the local anesthetic binds with
the sodium channel. Once bound to the sodium channel, impulses

are not propagated along the nerve.

Determines the ratio between the ionized (cationic)
and the uncharged (base) forms of the drug. The pka of
local anesthetics ranges from 7.6 to 9.2. By definition
the pka is the pH at which 50% of the drug is ionized
and 50% is present as a base. The pka generally
correlates with the speed of onset of most local
anesthetics. The closer the pka is to physiologic pH, the
faster the onset. For example, lidocaine with a pka of
7.7 is 25% non-ionized at pH 7.4. Its onset is therefore
faster than bupivacaine, whose pka of 8.1 makes it only
15% non-ionized at that pH. One important exception is
2-chloroprocaine that, despite its pka of 9.1, has a very
rapid onset. This is usually attributed to the relatively
high concentrations (3%) used in clinical practice that
are possible thanks to its low toxicity. It has also been
claimed

that

2-chloroprocaine

has

better

tissue

penetrability (Longnecker et al., 2008).

Clinically, onset of action is not the same for all local anesthetics
with the same pKa. This is due to the intrinsic ability of the local
anesthetic to diffuse through connective tissue. Local anesthetics with
a pKa closest to the physiological pH generally have a higher
concentration of non-ionized molecules and a more rapid onset. Two
notable

exceptions

are

chloroprocaine

and

benzocaine.

Chloroprocaine has a high pKa and rapid onset. Benzocaine does not
exist in an ionized form and exerts its effects by alternate mechanisms.
4. Mechanism of Action
Local anesthetics produce a conduction block of neural impulses,
preventing the passage of Na+ through Na+ channels. Local anesthetics
do not alter the resting membrane potential. The Na+ channel acts as a
receptor

for

local

anesthetic

molecules.

Local

anesthetics

are

stereospecific. Local anesthetics ability to bind to sodium channels is

known as a state-dependent block. The open sodium channel is the

primary binding site of local anesthetics. This is followed by an
inactivated state.
Local anesthetics produce anesthesia by inhibiting excitation of
nerve endings or by blocking conduction in peripheral nerves. This is
achieved by anesthetics reversibly binding to and inactivating

+
Na

(sodium) channels. Sodium influx through these channels is necessary for

the depolarization of nerve cell membranes and subsequent propagation of
impulses along the course of the nerve. When a nerve loses depolarization
and capacity to propagate an impulse, the individual loses sensation in the
area supplied by the nerve (Morgan et al., 2006).
The resting potential of the cell membrane is negative (-70 mV)
and close to the potential determined by potassium alone. During
transmission of an action potential,

open

+
Na

+
Na

moves into the cell through

channels depolarizing the membrane and bringing its

potential to -20 mV or more. Local anesthetics are compounds that have

the ability to interrupt the transmission of the action potential in excitable
membranes by binding to specific receptors in the

+
Na

channels. This

action, at clinically recommended doses, is reversible. Conduction can

still continue, although at a slower pace, with up to 90% of receptors
blocked (Morgan et al., 2006).
The non-charged hydrophobic fraction (amide), which
exists in equilibrium with the hydrophilic charged portion
(amino), crosses the lipidic nerve membrane and initiates
the events that lead to Na+ channel blockade. Once inside
the cell, the pka of the drug and the intracellular pH
dictate a new equilibrium between the two fractions.

Because

of

the

relative

more

acidic

intracellular

environment, the relative proportion of charged fraction

(amino) increases. This hydrophilic, charged fraction is the
active form on the Na+ channel (Morgan et al., 2006).
The Na+ channel is a protein structure

that

communicates the extracellular of the nerve with its

axoplasm. It consists of four repeating alpha subunits and
two beta subunits, beta-1 and beta-2. The alpha subunits
are involved in ion movement and local anesthetic activity. It is
generally

accepted

that

the

main

action

of

local

anesthetics involves interaction with specific binding sites

within the Na+ channel. Local anesthetics may also block to
some degree calcium and potassium channels as well as Nmethyl-D-aspartate (NMDA) receptors. Local anesthetics do not
ordinarily affect the membrane resting potential. The Na +
channels seem to exist in three different states, closed
(resting),

open

and

inactivated.

Under

adequate

stimulation, the protein molecules of the channel undergo

conformational changes, from the resting state to the ionpermeable state or open state, allowing the inflow of
extracellular Na+, which depolarizes the membrane. After
a few milliseconds the channel goes then through a
transitional inactivated state, where the proteins leave the
channel closed and ion-impermeable. With repolarization
the proteins revert to their resting configuration (Morgan et
al., 2006).
Other

drugs,

(amitriptyline),

like

meperidine,

tricyclic
volatile

antidepressants
anesthetics

and

ketamine, also exhibit Na+ channel-blocking properties.

Tetrodotoxin and other biotoxins also interact with the Na +
channels, although their actions are exerted on the
extracellular side of the channel (Morgan et al., 2006).
5. Pharmacokinetic

In regional anesthesia local anesthetics are typically injected or

applied very close to their intended site of action; thus their
pharmacokinetic profiles are much more important determinants of
elimination and toxicity than of their desired clinical effect (Butterworth
et al., 2013).
a. Absorption
Most mucous membranes (eg, ocular conjunctiva, tracheal
mucosa) provide a minimal barrier to local action. Intact skin, on the
other hand, requires a high concentration of lipid-soluble local
anesthetic base to ensure permeation and analgesia. Systemic
absorption of injected local anesthetics depends on blood flow, which
is determined by the following factors (Butterworth et al., 2013):
1) Site of injection
The rate of systemic absorption is related to the vascularity of the
site of injection: intravenous (or intraarterial) > tracheal >
intercostal > paracervical > epidural > brachial plexus > sciatic >
subcutaneous.
2) Presence of vasoconstrictors
Addition of epinephrine, or less commonly phenylephrine, causes
vasoconstriction at the site of administration. Vasoconstrictors
have more pronounced eff ects on shorter-acting than longeracting agents.
3) Local anesthetic agent
More lipid-soluble local anesthetics that are highly tissue bound
are also more slowly absorbed. The agents also vary in their
intrinsic vasodilator properties.
b. Distribution
Distribution depends on organ uptake, which is determined by the
following factors(Butterworth et al., 2013):
1) Tissue perfusion
The highly perfused organs(brain, lung, liver, kidney, and heart)
are responsiblefor the initial rapid uptake ( phase), whichis
followed by a slower redistribution ( phase) tomoderately
perfused tissues (muscle and gut).
2) Tissue/blood partition coefficient

Increasinglipid solubility is associated with greater plasma

proteinbinding and also greater tissue uptake from anaqueous
compartment.
3) Tissue mass
Muscle provides the greatest reservoirfor distribution of local
anesthetic agents in thebloodstream because of its large mass.
c. Biotransformation and Excretion
The biotransformation and excretion of local anestheticsis defined by
their chemical structure(Butterworth et al., 2013):
1) Esters
Ester local anesthetics are predominantlymetabolized
pseudocholinesterase(plasma

cholinesterase

by
or

butyrylcholinesterase).Ester hydrolysis is very rapid, and the

water-solublemetabolites are excreted in the urine.
2) Amides
Amide local anesthetics are metabolized(N-dealkylation and
hydroxylation) by microsomalP-450 enzymes in the liver. The rate
of amidemetabolism depends on the specifi c agent (prilocaine>
lidocaine > mepivacaine > ropivacaine >bupivacaine) but overall
is consistently slower thanester hydrolysis of ester local
anesthetics. Decreasesin hepatic function (eg, cirrhosis of the
liver) or liver blood flow (eg, congestive heart failure, blockers,
orH 2 -receptor blockers) will reduce the metabolic rateand
potentially

predispose

patients

to

having

greaterblood

concentrations and a greater risk of systemictoxicity. Very little

unmetabolized local anestheticis excreted by the kidneys, although
water-solublemetabolites are dependent on renal clearance.
6. Clinical Pharmacology
General considerations related to local anesthetics include the following:
a. Anesthetic potency
The primary factor related to potency is the hydrophobicity (lipid
solubility) of the local anesthetic. Local anesthetics penetrate the
nerve membrane and bind to Na+ channels, which are hydrophobic.
Additional factors include:
1) Fiber size, type, and myelination Hydrogen ion balance
2) Vasodilator/vasoconstrictor properties (affects the rate of vascular

uptake) Frequency of nerve stimulation

3) pH (acidic environment will antagonize the block)
4) Electrolyte concentrations (hypokalemia and hypercalcemia
antagonizes blockade).
b. Onset of action
In the individual nerve, onset is related to the unique
physiochemical property of the local anesthetic. Clinically, the onset
of action is related to pKa, dose, and concentration.pKa when pKa
approximates the physiologic pH a higher concentration of nonionized base is available, increasing onset of action.Dose- the higher
the dose of local anesthetic administered, the faster the onset.
Concentration- higher concentrations of local anesthetic will result in
a more rapid onset.
c. Duration of action
Duration of action is dependent on individual local anesthetic
characteristics. Local anesthetics are classified as follows:
1) Short acting: procaine and chloroprocaine
2) Moderate acting: lidocaine, mepivacaine, prilocaine
3) Long acting: tetracaine, bupivacaine, etidocaine, ropivacaine,
levobupivacaine
One of the dominant factors related to the duration of action is protein
binding. Since local anesthetic molecules bind to a protein receptor,
the greater the affinity of the local anesthetic molecule to bind to a
protein and subsequently the longer it will remain bound extending the
duration of action.
Duration of action is influenced by peripheral vascular effects that
local anesthetics exhibit.Local anesthetics exhibit a biphasic effect on
vasculature

smooth

muscle.

At

low,

sub-clinical

doses,

vasoconstriction is noted. With larger, clinically relevant doses,

vasodilatation is seen. The degree of vasodilatation varies among
individual local anesthetics. For example, lidocaine> mepivacaine>
prilocaine. The effect of local anesthetics on vascular tone and
regional blood flow is complex and dependant on the following

concentration, time, and type of vascular bed.

C. LIDOCAINE
1. Introduction
Lidocaine has been used as an anesthetic and analgesic for more
than half a century. First synthesized in 1943, the injectable formulation
of lidocaine was approved for local and regional anesthesia. Since that
time, a variety of intravenous, intramuscular, and topical methods for
administering lidocaine have been developed. Although not well studied
in pediatric patients, this technique has the potential to reduce reliance on
opioids and may prove to be a valuable addition to pain management in
children.
2. Mechanism of Action
Lidocaine, is an amide local anesthetic agent. The amide
anesthetics block fast voltage-gated sodium channels in the cell
membrane of postsynaptic neurons, preventing depolarization and
inhibiting the generation and propagation of nerve impulses. At lower
blood concentrations, sensory neurons are primarily affected while at
higher concentrations the effects become generalized. Lidocaine also
possesses

anti-inflammatory

and

immunomodulating

properties.

Lidocaine has a rapid onset of action and an intermediate duration of

effect.
3. Pharmacokinetics and Pharmacodynamics
Lidocaine is widely distributed after IV administration, with a
volume of distribution in adults of 0.72.7 L/kg. It crosses both the
placental and blood-brain barriers. At therapeutic concentrations
lidocaine is 6080% protein bound, primarily to alpha-1-acid
glycoprotein. A dose or concentration-response relationship for the
analgesic effects of lidocaine has not been established, but several
investigators have reported efficacy with plasma concentrations less than
those needed to control arrhythmias (1.55 mcg/mL) and well below the
level typically associated with toxicity (6 mcg/mL). The concentration of
lidocaine achieved in the blood after application of transdermal lidocaine
patches depends on both surface area covered and duration of
application.
Lidocaine is rapidly metabolized in the liver, both lidocaine and its
metabolites are excreted by the kidneys; less than 10% of a dose is

excreted in the urine as unchanged drug. The mean systemic clearance in

a study of 15 adults was 0.64 0.18 L/min. The average half-life of
lidocaine in adults is 1.52 hours; however it may be prolonged in
patients receiving lidocaine infusions for periods longer than 24 hours.
Lidocaine is not removed by dialysis.
4. Contraindication
Lidocaine is contraindicated

in

patients

with

known

hypersensitivity. Allergic reactions to lidocaine appear to be rare, but

cases of angioedema, laryngospasm, bronchospasm, pruritus, urticaria,
anaphylactoid reactions, and shock have been reported. There appears to
be minimal cross sensitivity to lidocaine in patients allergic to paraaminobenzoic acid derivatives such as procaine, tetracaine, or
benzocaine. Lidocaine should not be used as an analgesic in patients with
second or third-degree heart block, or severe sinoatrial block without a
pacemaker. Lidocaine analgesia should be considered only in patients
with stable cardiovascular and hemodynamic parameters.
Early symptoms of lidocaine toxicity include central nervous
system (CNS) excitation, with nervousness, lightheadedness or dizziness,
anxiety, confusion, tinnitus, blurred or double vision, a sensation of heat,
cold, or numbness, twitching, tremor, and vomiting. The period of CNS
excitation may be brief in some patients, while others may not exhibit
this phase and will present with symptoms of CNS depression. Patients
may also exhibit tachypnea, tachycardia, fever, and metabolic acidosis.
At higher concentrations (> 5 mcg/mL), symptoms may progress to
tonic-clonic seizures, blood pressure and heart rate lability, respiratory
depression, and cardiovascular collapse.
Intravenous lipid emulsion has been shown to be an effective tool
for reducing lidocaine concentrations. The American Society of Regional
Anesthesia and Pain Medicine (ASRA) recommends that lipid emulsion
be considered in patients with systemic local anesthetic toxicity
following airway management, administration of benzodiazepines for
seizures, and control of cardiac arrhythmias. The ASRA guidelines
recommend a bolus of 1.5 mL/kg 20% lipid emulsion followed by a 0.25
mL/kg/min infusion with adjustment based on patient response. The

mechanism for the beneficial effect of lipid emulsion is not clearly

understood. It has been suggested that fat emulsion serves as a "lipid
sink" in the systemic circulation, facilitating dissolution of lidocaine into
the lipid micelles of the emulsion which are then cleared by the liver.
Administration of lipid emulsion also provides free fatty acids to meet
the increased metabolic demands occurring as the result of a lidocaine
overdose.
5. Adverse Effect
Transdermal lidocaine patches and low-dose lidocaine infusions are
generally well-tolerated. Patients should be monitored for signs of CNS
excitation (lightheadedness, dizziness, vision changes, headache,
numbness or tingling of the mouth, tremors, or vomiting). After
transdermal application, the most commonly reported adverse reactions
include dermatitis, erythema, a burning sensation, bruising, petechia,
pruritus, vesicle formation, and blistering or exfoliation of the skin.
These reactions are typically mild and resolve within hours after patch
removal.
6. Drug interactions
Transdermal lidocaine patches and low-dose lidocaine infusions
are generally well-tolerated. Patients should be monitored for signs of
CNS excitation (lightheadedness, dizziness, vision changes, headache,
numbness or tingling of the mouth, tremors, or vomiting). After
transdermal application, the most commonly reported adverse reactions
include dermatitis, erythema, a burning sensation, bruising, petechia,
pruritus, vesicle formation, and blistering or exfoliation of the skin.
These reactions are typically mild and resolve within hours after patch
removal.
7. Availability
Lidocaine injection is available from multiple manufacturers in
5 mg/mL (0.5%), 10 mg/mL (1%), 15 mg/mL (1.5%), and 20 mg/mL
(2%) concentrations. Both single dose and multiple-dose products are
available. Multiple-dose vials may contain a preservative. The 10 mg/mL
and 20 mg/mL single-dose vials are typically used to prepare lidocaine
infusions. Transdermal 5% lidocaine patches are available as the original

product and as a generic product in boxes of 30 patches. Each 10 cm x 14

cm patch contains 700 mg lidocaine in an aqueous base
8. Dosing Recommendations
At this time, there are no definitive guidelines for the use of
transdermal lidocaine 5% patches in children. Case reports describe using
to two patches for 12 hours per 24-hour period in children 6 years of
age and older. Patches should only be applied to intact skin and use of
external heat sources such as heating pads which may increase absorption
is not recommended. Once a patch is removed, it should be folded and
discarded in a container inaccessible to children or pets. After use, the
patch will still contain more than 600 mg of drug, enough to produce
severe toxicity if swallowed or chewed.
As with the lidocaine patch, there is limited information
available on the use of lidocaine infusions for analgesia in children. In
the papers published to date, low-dose infusions have been initiated with
a lidocaine bolus of 1 mg/kg followed by an infusion of 0.51.5 mg/kg/hr
in children as young as 1 year of age. Higher infusion rates have been
used in patients with refractory chronic pain.
D. BUPIVACAINE
Bupivacaine, is a widely used amide local anesthetic; its structure is
similar to that of lidocaine except that the amine-containing group is a butyl
piperidine. Bupivacaine is a potent agent capable of producing prolonged
anesthesia. Its long duration of action plus its tendency to provide more
sensory than motor block has made it a popular drug for providing prolonged
analgesia during labor or the postoperative period. By taking advantage of
indwelling catheters and continuous infusions, bupivacaine can be used to
provide several days of effective analgesia (Caterall & Mackie, 2007).
1. Mechanism of Action
Bupivakain as local anesthetics prevent generation/conduction of
nerve impulses by reducing sodium permeability & increasing action
potential threshold(Caterall & Mackie, 2007).
2. Pharmacokinetics

Bupivacaine

is

rapidly

absorbed

from

the

injection

site,

gastrointestinal, and respiratory tract. 95% bound to plasma proteins and

is metabolized in the liver. Metabolites in the form of ester and amidetype local anesthetics, mostly excreted with urine. Onset of action of
bupivacaine between 1 to 17 minutes depending on the mode of
administration and the dose given(Caterall & Mackie, 2007).
3. Toxicity
Bupivacaine is more cardiotoxic than other local anesthetics. This
reflects the fact that bupivacaine block of sodium channels is potentiated
by the long action potential duration of cardiac cells (as compared to
nerve

fibers).

Studies

have

shown

that

the

most

common

electrocardiographic finding in patients with bupivacaine intoxication is

slow idioventricular rhythm with broad QRS complexes and eventually,
electromechanical dissociation. Clinically, this is manifested by severe
ventricular arrhythmias and myocardial depression after inadvertent
intravascular administration of large doses of bupivacaine (Caterall &
Mackie, 2007).
Although lidocaine and bupivacaine both rapidly block cardiac Na+
channels during systole, bupivacaine dissociates much more slowly than
does lidocaine during diastole, so a significant fraction of Na+ channels at
physiological heart rates remains blocked with bupivacaine at the end of
diastole. Thus, the block by bupivacaine is cumulative and substantially
more than would be predicted by its local anesthetic potency. At least a
portion of the cardiac toxicity of bupivacaine may be mediated centrally,
as direct injection of small quantities of bupivacaine into the medulla can
produce malignant ventricular arrhythmias. Bupivacaine-induced cardiac
toxicity can be very difficult to treat, and its severity is enhanced by
coexisting acidosis, hypercarbia, and hypoxemia.Local anesthetics,
especially bupivacaine, also inhibit basal and epinephrine-stimulated
cAMP production. This finding places greater emphasis on aggressive
epinephrine therapy during bupivacaine-induced cardiotoxicity. The (S)isomer, levobupivacaine, appears to have a lower propensity for

cardiovascular toxicity than the racemic mixture or the (R)-isomer and

has recently been approved for clinical use(Caterall & Mackie, 2007).
4. Dosage
Bupivacaine 0.25% is used for local anesthesia with maximum dosage
175 mg. If it used without epinephrine, maximum dosage for infiltration
anesthesa is 2 mg/kgBW (Caterall & Mackie, 2007).
E. COMPARISON OF BUPIVACAINE AND LIDOCAINE
Lidocaine and bupivacaine are two commonly used medications to
numb the skin for minor procedures. Lidocaine has a faster onset.
Bupivacaine has a longer duration. They are often combined with epinephrine
to increase the length of action. These medications are used to control pain at
the time of the operation and to decrease discomfort immediately afterward
(Collins, 2011).
A systematic review has found that lidocaine demonstrated the shortest
mean onset of anesthesia (3.1 min) and bupivacaine the longest (7.6 min).
Lidocaine also demonstrated the shortest mean duration of anesthesia (1.8 h)
and ropivacaine the longest mean duration (21.5 h). Lidocaine with
epinephrine demonstrated the least mean pain on injection (26 mm on a visual
analog scale) and bupivacaine with epinephrine the most mean pain (53 mm).
Lidocaine with epinephrine provides a good short-term anesthesia and may
reduce the risk of injury or complication while the finger in still anesthetized.
Bupivacaine with lidocaine provides good long-term anesthesia and may
reduce the need for postprocedural anesthesia. Ropivacaine likely provides
the longest duration of anesthesia but the absence of epinephrine means a
tourniquet must be used to create a bloodless field and thus is contraindicated
in some procedures such as flexor tendon repairs where active testing may be
required (Vinycomb et al., 2014).
Spivey et al (1987) comparing clinical using of lidocaine and
bupivacain. Spivey et al conducted a study to determine the degree of
anesthesia obtained during and after repair of lacerations using lidocaine 1%
versus bupivacaine 0.25%, a long-acting local anesthetic. Lidocaine and
bupivacaine were administered in a double-blind, randomized fashion to 104

patients. Each patient was asked to rate his pain on a 0 to 10 scale (0, no pain;
10, severe pain) prior to administration of the anesthetic. They then rated pain
on an identical scale at 30 minutes, and one, two, three, four, five, six, 12, 18,
and 24 hours after completion of suturing.
The mean baseline pain was 2.96 for the lidocaine group and 3.07 for
the bupivacaine group. This decreased to less than 1.0 in both groups 30
minutes after infiltration. It remained low for the bupivacaine group for the
next five hours, but increased almost to preanesthesia levels by two hours in
the lidocaine group. A three-way analysis of variance revealed a significant
difference (P less than .001) between the pain response of the two groups.
There was no statistical difference (P greater than .05) between the age of the
patients, size of laceration, and amount of drug used. The study shows that
patients do experience pain after a wound is sutured and the anesthetic has
worn off. It also demonstrates that bupivacaine significantly reduces the pain
a patient may experience after repair of a wound (Spivey et al, 1987)
Valvano et al., (1996) compared the efficacy, degree of discomfort, and
time elapsed before anesthesia of digital block with a combination of 1%
lidocaine/.25% bupivacaine and with .25% bupivacaine alone. The results is
bupivacaine 25% digital block induces anesthesia in the same period of time
and with equivalent pain of injection as a 1:1 lidocaine 1%/bupivacaine 25%
combination. It is not necessary to use lidocaine/bupivacaine in an attempt to
achieve faster onset of local anesthesia (Valvano et al., 1996).
Thomson et al., (2006) used three local anesthetics for digital nerve
block: 2% lidocaine with 1:100,000 epinephrine, 2% lidocaine, and 0.5%
bupivacaine. The local anesthetic agent to be used in each finger was
randomized. A double-blind design was used. Volunteers reported the time
that each of their fingers returned to normal sensation at the tip. At an average
of 24.9 hours, bupivacaine (0.5%) provides a significantly longer digital
anesthesia time than the average 10.4 hours achieved by 2% lidocaine with
epinephrine (1:100,000), which in turn provides twice as long an anesthesia
time as 2% lidocaine (average, 4.9 hours) (Thomson et al., 2006).
Alhelail et al., (2009) compared the efficacy in terms of pain of
injection, time of onset and duration of action of digital blocks of bupivacaine
0.5% alone and lidocaine 1% with epinephrine (1:100,000). Pain of injection

was measured as the primary outcome using a 0-100 mm visual analogue

scale. The time before anaesthesia to pinpricks was recorded and the duration
of anaesthesia was reported by all volunteers. Statistical analysis was
conducted using the non-parametric Wilcoxon signed rank test. The results of
this study is lidocaine (1%) with epinephrine (1:100 000) was significantly
less painful and had a shorter duration of action than bupivacaine (0.5%),
which had a similar onset of action for digital nerve block (Alhelail et al.,
2009)

III. CONCLUSION
1. Local anesthetics produce anesthesia by inhibiting excitation of nerve endings
or by blocking conduction in peripheral nerves. This is achieved by
anesthetics reversibly binding to and inactivating

+
Na (sodium) channels.

2. The intrinsic potency, duration, and onset of action for a local anesthetic are
dependent

upon

lipophilic-hydrophobic

balancen,

protein

binding,

andhydrogen ion concentration.

3. Lidocaine, is an amide local anesthetic agent. The amide anesthetics block
fast voltage-gated sodium channels in the cell membrane of postsynaptic
neurons, preventing depolarization and inhibiting the generation and
propagation of nerve impulses
4. Bupivacaine, is a widely used amide local anesthetic; its structure is similar to
that of lidocaine except that the amine-containing group is a butyl piperidine.
5. Lidocaine has a rapid onset of action and an intermediate duration of effect
and Bupivacain has a slower onset than Lidocaine but has longer duration of
effect.
6. Study observed that lidocaine (1%) with epinephrine (1:100 000) was
significantly less painful and had a shorter duration of action than
bupivacaine (0.5%), but the other study said it is not necessary to use
lidocaine/bupivacaine in an attempt to achieve faster onset of local anesthesia.

REFERENCES
Alhelail, M., Al-Salamah, M., Al-Mulhim, M., Al-Hamid, S. 2009. Comparison of
bupivacaine and lidocaine with epinephrine for digital nerve blocks.
Emergency Medicine Journal 26(5): 347-350.
Butterworth, J.F., D.C. Mackey, J.D. Wasnick. 2013. Local Anesthetics in Morgan
and Mikhails: Clinical Anesthesiology, 5th ed. New York: Lange
Medical Books
Clinical Anesthesiology, 4th edition. New York: Lange Medical Books.
Collins, J., Raman, C. M. 2011. Effectiveness Study of Differents Local Anesthetic
Mixtures.
Available
at
https://clinicaltrials.gov/ct2/show/study/NCT01243112.
Heavner, J.E. (2008). Pharmacology of local anesthetics. In D.E. Longnecker et
al (eds) Anesthesiology. New York: McGraw-Hill Medical.
Joyce, J.A. (2002). A pathway toward safer anesthesia: stereochemical advances.
AANAJournal, 70, 63-67.
Katzung, B.G. (1992). Section 1: basic principles. In B.G. Katzung Basic &
clinicalpharmacology, 5thedition. Norwalk, Connecticut: Appleton and
Lange.
Keneeth, L. R., Becker, D. E. 2006. Essentials of Local Anesthetic Pharmacology.
Anesth Prog 53:98109.
Longnecker, D. E., Brown, D. L., Newman, M. F., Zappol, W. M. 2008.
Pharmacologic of Local Anesthesi at Anesthesiology. New York:
McGraw-Hill Companies (E-Book).
Morgan, G.E., Mikhail, M.S., Murray, M.J. (2006). Local Anesthetics. In G.E.
Morgan et al
Morgan, G.E., Mikhail, M.S., Murray, M.J. 2006. Local Anesthetics. In G.E.
Morgan et al Clinical Anesthesiology, 4th edition. New York: Lange
Medical Books (E-Book).
Spivey, W.H, McNamar, R.M, MacKenzie, R.S., Bhat, S., and Burdick, W.P.,
1987. A Clinical Comparison of Lidocain and Bupivacaine, Annual
Emergency Medicine Jul; 16(7): 752-7
Stoelting, R.K. & Hillier, S.C. (2006). Pharmacology and pharmacodynamics of
injected and inhaled drugs. In R.K. Stoelting & S.C. Hillier (eds)
Pharmacology & Physiology in AnestheticPractice, 4thedition.
Philadelphia: Lippincott Williams & Wilkins.

Strichartz, G.R. & Berde, C.B. (2005). Local Anesthetics. In R.D. Miller
Millers Anesthesia,6th edition. Philadelphia: Elsevier Churchill
Livingstone.
Thomson, C. J., Lalonde, D. 2006. Randomized Double-Blind Comparison of
Duration of Anesthesia among Three Commonly Used Agents in Digital
Nerve Block. Plastic and Reconstructive Surgery 118(2): 429-432.
Valvano, M. N., Stephen, L. 1996. Comparison of Bupivacaine and
Lidocaine/Bupivacaine for Local Anesthesia/Digital Nerve Block.
Annals of Emergency Medicine 27(4): 490-492.
Vinycomb, T. I., Sahhar, L. J. 2014. Comparison of Local Anesthetics for Digital
Nerve Blocks: A Systematic Review. Journal of Hands Surgery. 39(4):
744-751.