PRESENTER: DR SABIN BHANDARIMODERATOR: DR JAGAT NARAYAN

PRASAD

Lignocaine vs Bupivacaine

Local Anesthetic

Local anesthetics are drugs that produce a reversible conduction blockade of impulses along central and peripheral nerve pathways after regional anesthesia.

Removal of the local anesthetic is followed by spontaneous and complete return of nerve conduction, with no evidence of structural damage to nerve fibers as a result of the drug's effects.

History

The first local anesthetic was Cocaine which was isolated from coca leaves by Albert Niemann in Germany in the 1860s.

The very first clinical use of Cocaine was in 1884 by Sigmund Freud who used it to wean a patient from morphine addiction.  

Kollar first introduced it to clinical ophthalmology as a topical ocular anesthetic. 

In 1884, Dr. William Stewart Halsted was the first to describe the injection of cocaine into a sensory nerve trunk to create surgical anesthesia.

Chronology of local anesthetics

CocaineBenzocaineProcaineTetracaineLidocaineCl2 procaineMepivacineBupivacaineRopivacaine

NiemannSalkowskiEinhornEislerLofgrenMarks, RubinEkenstamEkenstamSandberg

186018951904192819431949195619571989

EsterEsterEsterEsterAmideEsterAmideAmideAmide

Chemistry

All local anesthetics are weak bases, classified as tertiary amines. 

Lignocaine vs Bupivacaine

N

O

N

N

O

N

Structure Activity Relationship

“Lipophilicity” expresses the tendency of a compound to associate with membrane lipids

It is approximated by equilibrium partitioning into a hydrophobic solvent such as octanol.

The term “hydrophobicity,” expressed as octanol-buffer partitioning, is used to describe lipophilic property of local anesthetics.

Compounds with a more hydrophobic nature are obtained by increasing the size of the alkyl substituents on or near the tertiary amine and on the aromatic ring.

MODIFICATIONS

Lengthening carbon chains..Lipid solubility increasePotency increaseDuration of axn increase

Mepivacaine, bupivacaine, and ropivacaine are characterized as pipecoloxylidides and are chiral drugs, because their molecules possess an asymmetric carbon atom

These drugs may have a left- (S) or right- (R) handed configuration

S Bupivacaine R Bupivacaine

Mechanism of Action

Pain awareness, (nociception), is transmitted to the CNS by primary afferent fibers and relayed by secondary afferent fibers to the brain.

Transmission can be prevented by blocking the Na+ channels in the axons which reside: Outside the spinal cord (regional anesthesia) Inside the spinal cord (spinal anesthesia)

These drugs block conduction in all the cells that use Na+ channels for action potential.

Sodium channels exist in activated-open, inactivated-closed, and rested-closed states during various phases of the action potential.

Channels in the rested state, have a much lower affinity for LAs than activated and inactivated channels.

LA binds near the intracellular end of the sodium channel

Binding of local anesthetics is increased by membrane depolarization for 2 reasons:

1. More binding sites becomes accessible during activation: The guarded receptor model

2. Drug dissociation from the inactivated channels is slower than the resting channels: The modulated receptor model

So, the effect of a drug is more marked in rapidly firing axons than in resting fibers

Inhibition of adenyl cyclase

This property of bupivacaine explains the difficulty in resuscitating patients with epinephrine during bupivacaine induced cardiac arrest

Other targets of local anesthetics

Inhibition of cardiac calcium channels

Proposed as an additional reason for negative ionotropic effect of local anesthetics

Other targets of local anesthetics….

Other targets of local anesthetics….

Local anesthetics block voltage-dependent potassium ion channels

May also act on G-protein-coupled receptors.

Factors affecting..

• Protein binding

• linkage

• pKa• Lipid solubility

potency Time of onset

durationmetabolism

Hydrogen Ion Concentration

The speed and extent of permeation of the nerve's axon membranes and its residence depend on a particular drug's pKa and on the lipophilicity of its base and cation species.

drug Relative conduction blocking property

pka Hydrophobicity

Procaine 1 8.9 100

Lidocaine 2 7.8 366

Bupivacaine 8 8.1 3420

The pka effect…

Low pka

less ionized fraction of the drug

enhanced rate of diffusion across the nerve sheath and

nerve membrane

more rapid onset of anesthesia

The onset of action is also dependent on the dose or concentration of local anesthetic used.

For example, 0.25% bupivacaine possesses a rather slow onset of action, but increasing the concentration to 0.75% results in a significant acceleration of its anesthetic effect.

May be due to mass diffusion because of the large number of molecules placed in the vicinity of peripheral nerves.

Duration of action

Local anesthetics which are alkaline binds avidly to alpha 1 glycoprotein.

Acidic drugs binds to albumin.The protein binding indirectly denotes the

avidity with which the receptor protein is bound by the local anesthetics.

More the local anesthetic is protein bound, longer is its duration of action. E.g. bupivacaine > lignocaine

Duration of action…

The duration of anesthesia is also markedly influenced by the peripheral vascular effects of the local anesthetic drugs.

Most local anesthetics have biphasic effect on vascular smooth muscle

At low concentrations these agents tend to cause vasoconstriction, whereas at higher, clinically administered concentrations, they cause vasodilation

E.g. lignocaine causes more vasodilation than bupivacaine which results in the greater systemic absorption and shorter duration of action of lignocaine.

Addition of Vasoconstrictors

The duration of action of a local anesthetic is proportional to the time the drug is in contact with nerve fibers.

Thus epinephrine (1:200,000 or 5 μg/mL), norepinephrine and phenylephrine may be added to local anesthetic solutions.

Epinephrine significantly extends the duration of both infiltration anesthesia and peripheral nerve blockade with lidocaine

But produces only mild intensification of blockade and modest prolongation of epidural or peripheral blocks with bupivacaine.

DIFFERENTIAL BLOCKADE

There is selective blockade of preganglionic sympathetic nervous system B fibers in response to low concentrations of local anesthetics.

Slightly higher concentrations of local anesthetics interrupt conduction in small fibers C and small and medium sized A fibers, with loss of sensation for pain and temperature .

However touch, proprioception, and motor function are still present, so that the patient will sense pressure but not pain with surgical stimulation.

DIFFERENTIAL BLOCKADE…….

Typically shown by bupivacaineContinuous epidural infusions of bupivacaine in a

concentration of 0.0625% to 0.1% are useful for labor epidural analgesia, especially when administered in combination with opioids and other additives.

Bupivacaine 0.25% may be used for more intense analgesia (particularly during combined epidural–light general anesthesia cases) with moderate degrees of motor block.

Bupivacaine at concentrations of 0.5% to 0.75% is associated with a more profound degree of motor block.

Relative size and susceptibility of different types of nerve fibers to LAs.

  Fiber Type Function

Diameter

μm

Myelination

Conduction Velocity

(m/s)

Sensitivity

to Block

Type A          

  Alpha Motor 6-22 Heavy 30-120 ++

  Beta Touch, propioception 6-22 Heavy 30-120 ++

  Gamma Muscle spindles 3-6 Heavy 15-35 ++++

  Delta Pain, cold temperature 1-4 Heavy 5-35 +++

Type B Preganglionic autonomic < 3 Light 3-15 ++

Type C          

  Dorsal root Pain 0.3-1.3 None 0.7-1.3 +

  Sympathetic Postganglionic 0.4-1.2 None 0.1-2.0 ++

Mixtures of Local Anesthetics

Used to compensate for the short duration of action of certain rapidly acting agents such as chloroprocaine and lidocaine and the long latency of longer-acting agents such as tetracaine and bupivacaine.

Clinical results in studies of combinations have been mixed.

Not to use maximum doses of two local anesthetics as their toxicities are not independent.

Changes during pregnancy

Doses of local anesthetics must be decreased because of:

1. mechanical factors associated with pregnancy i.e., dilated epidural veins decrease the volume of the epidural and subarachnoid spaces.

2. direct effects of hormones, especially progesterone, which causes increased sensitivity (more rapid onset of conduction blockade).

Pharmacokinetics

Absorption and Distribution:Influenced by the Site of injection DosageUse of vasoconstrictors and Pharmacologic profile of the drug

Blood levels after local anesthetic injection

INTERCOSTAL CAUDAL ED LUMBAR ED

BRACHIAL PLEXUSS/C

Blood levels…

A 5-µg/mL concentration of epinephrine (1 : 200,000) significantly reduces the peak blood levels of lidocaine irrespective of the site of administration, thus lowers its potential systemic toxicity.

Peak blood levels of bupivacaine is minimally influenced by the addition of a vasoconstrictor after injection into the lumbar epidural space, but will decrease its rate of absorption when used for peripheral nerve blocks.

Lung Extraction:Lungs extract local anesthetics such as

lidocaine and bupivacaine. Placental Transfer: Plasma protein binding influences the rate and

degree of diffusion of local anesthetics across the placenta

Bupivacaine, which is highly protein bound (approximately 95%), has an umbilical vein-maternal arterial concentration ratio of about 0.32.

During prolonged labour, acidosis in the fetus can result in accumulation of local anesthetic molecules in the fetus (ion trapping).

Biotransformation and Excretion

The aminoamide drugs undergo enzymatic degradation primarily in the liver.

Lidocaine is metabolized more rapidly than bupivacaine.

The principal metabolic pathway of lidocaine is oxidative dealkylation in the liver to monoethylglycinexylidide (MEGX) followed by hydrolysis of this metabolite to xylidide.

MEGX has approximately 80% of the activity of lidocaine for protecting against cardiac dysrhythmias and prolonged elimination half-time.

Biotransformation and Excretion……

The possible pathways for bupivacaine metabolism include aromatic hydroxylation, N-dealkylation, amide hydrolysis, and conjugation.

Excretion of the metabolites of amide-type local anesthetics occurs via the kidney.

Less than 5% of the unchanged drug is excreted via the kidney into urine.

The ester, or procaine-like, drugs undergo hydrolysis in plasma by the pseudocholinesterase enzymes.

Pharmacokinetic alterations

Old age:The half-life of lidocaine after intravenous

administration averaged 80 minutes in human volunteers varying in age from 22 to 26 years, as compared to an average 138 minutes in those 61-71 years.

Newborn infants:Have immature hepatic enzyme systems thus

prolonged elimination of lidocaine and bupivacaine. Prolonged infusion rates of bupivacaine for

neonates and young infants should not exceed 0.2 mg/kg/hr

Pharmacokinetic alterations…..

Prolonged lidocaine infusions in neonates should not exceed 0.8 mg/kg/hr.

The potential for toxicity with lidocaine infusions in neonates is increased by the accumulation of its principal metabolite, monoethylglycinexylidide (MEGX), which can cause seizures.

Hepatic diseases:Decreased hepatic blood flow or impaired hepatic

enzyme function produce a substantial elevation of blood levels of the aminoamide local anesthetics.

Toxicity – Systemic toxicity

The CNS is more susceptible to the actions of systemic local anesthetics than the cardiovascular system

The dose or blood level of local anesthetic required to produce CNS toxicity is usually lower than that resulting in circulatory collapse.

Central Nervous System toxicity

Generalized CNS toxicity may occur from systemic absorption or direct vascular injection.

Readily cross the blood brain barrierProduce dose-dependent CNS toxicity.Low doses produce CNS depression, and higher

doses result in CNS excitation and seizures.The rate of intravenous administration also

affects signs of CNS toxicityHigher rates of infusion of the same dose will

lessen the appearance of CNS depression while leaving excitation intact.

Dose-Dependent Systemic Effects of Lidocaine

PLASMA CONCENTRATION(µg/mL)

EFFECT

1-5 Analgesia

5-10 LightheadednessTinnitusNumbness of tongue

10-15 SeizuresUnconsciousness

15-20 ComaRespiratory arrest

>25 Cardiovascular depression

CNS toxicity…..

Local anesthetic potency for generalized CNS toxicity approximately parallels action potential blocking potency.

External factors which can increase potency for CNS are acidosis and increased PCO2

Increased PCO2 increase in the proportion of free drug available for diffusion into the brain

Acidosis decrease the plasma protein binding of local anesthetic agents and increase the proportion of free drug available for diffusion into the brain

CNS toxicity….

Two reasons for CNS toxicity by La1. The inhibitory pathways are blocked earlier

so the facilitatory neurons functions in unopposed manner.

2. It can also be caused by net stimulation of release of glutamate in the CNS.

CNS toxicity- Lgnocaine vs Bupivacaine

A meta-analysis concluded that the pooled relative risk for transient neurologic symptoms after spinal anesthesia with lidocaine was 6.7-fold higher than with bupivacaine and 5.5-fold higher than with prilocaine.

“Transient neurologic symptoms (back pain, paresthesias, radicular pain, or hypoesthesia) does not display a dose-dependent response, as 0.5% lidocaine results in similar incidences of TNS as 5% spinal lidocaine.”

CNS toxicity…..

5% lidocaine in viscous, dense solutions through narrow intrathecal catheters has been associated with a high frequency of transient or longer-term radicular symptoms or even cauda equina syndrome as compared to bupivacaine.

Lidocaine is especially neurotoxic in a concentration-dependent fashion.

They achieve sufficiently high intraneural concentrations.

Cardio Vascular Toxicity

The cardiotoxicity of bupivacaine appears to differ from that of lidocaine in the following manner:

1. The CC/CNS ratio of bupivacaine is much lower than that of lidocaine.

2. Ventricular arrhythmias are more common with bupivacaine than lidocaine.

3. The 0.75% bupivacaine is no longer recommended for obstetrics patients in US.

4. Cardiac resuscitation is more difficult after bupivacaine induced cardiac arrest when compared to lidocaine.

CVS Toxicity

Two features of bupivacaine's sodium channel blocking abilities may enhance its cardiotoxicity:

1. Bupivacaine exhibits a much stronger binding affinity to resting and inactivated sodium channels than lidocaine.

2. Bupivacaine dissociates from sodium channels during cardiac diastole much more slowly than lidocaine.

CVS Toxicity…..

CVS Toxicity…..

Bupivacaine possesses a high affinity for sodium channels in the cardiac myocyte.

Bupivacaine also inhibits myocyte release and utilization of calcium and reduces mitochondrial energy metabolism, especially during hypoxia.

“Central and peripheral nervous systems may be involved in the increased cardiotoxicity with bupivacaine.”

CVS Toxicity…..

Central effect:Neural activity in the nucleus tractus

solitarii of rats is markedly diminished by intravenous doses of bupivacaine immediately prior to development of hypotension.

Direct intracerebral injection of bupivacaine can elicit sudden dysrhythmias and cardiovascular collapse.

CVS toxicity…..

Peripheral effect:Bupivacaine possesses a potent peripheral

inhibitory effect on sympathetic reflexes

that has been observed even at blood concentrations similar to those measured after uncomplicated regional anesthesia.

Bupivacaine also has potent direct vasodilating properties, which may exacerbate cardiovascular collapse.

Myotoxicity of Local Anesthetics

The more potent, longer-acting agents bupivacaine and etidocaine cause more localized skeletal muscle damage than the less potent, shorter-acting agents lidocaine and prilocaine.

May involve actions on mitochondria.

Effect is reversible, and muscle regeneration occurs rapidly and is complete within 2 weeks after the injection of local anesthetic agents.

Other toxicities

Allergic Reactions to Local Anesthetics:Rare and usually involve type I (immunoglobulin

E) or type IV (cellular immunity) reactions. Type I reactions as anaphylaxis may occur, and

are more common with ester than amide local anesthetics.

True type I allergy to aminoamide agents is extremely rare.

Hepatic dysfunction following the administration of bupivacaine seems most likely to represent an allergic reaction.

Other toxicities…..

Methemoglobinemia :RareMay follow the administration of certain drugs

or chemicals that cause the oxidation of hemoglobin to methemoglobin more rapidly than methemoglobin is reduced to hemoglobin.

Includes topical local anesthetics - prilocaine, benzocaine, Cetacaine® and lidocaine.

EMLA-a mixture of lidocaine and prilocaine may cause methemoglobinemia in infants and children.

Uses of Lignocaine vs Bupivacaine

Topical anesthesia:

Bupivacaine is generally not used as a topical agent.

Various formulations and concentrations of lignocaine are used for topical application.

Preparations of lignocaine for topical anesthesia

preparations

concentration

use

2%-4% Solution Oropharynx, tracheobronchial tree, nose

2% Jelly Urethra

2.5%-5% Ointment Skin, mucous membrane, rectum

2% Viscous Oropharynx

10% Suppositories Rectum

10% Aerosol Gingival mucosa

Preparations of lignocaine for topical anesthesia

EMLA: Is a eutectic mixture of 2.5% lidocaine base

and 2.5% prilocaine baseUsed for venipuncture, intravenous

cannulation, skin grafting, and a range of other uses, including circumcision.

LET:Lidocaine 4%,Epinephrine1 : 20,000 and

Tetracaine0.5% , solution is used as a topical anesthesia through cut skin in pediatric emergency departments for liquid application into lacerations that require suturing.

Tumescent Anesthesia

Commonly used by plastic surgeons during liposuction procedures

Involves the subcutaneous injection of large volumes of dilute local anesthetic in combination with epinephrine and other agents.

Total doses of lidocaine ranging from 35 to 55 mg/kg have been reported to produce safe plasma concentrations, which may peak more than 8 to 12 hours after infusion.

Several case series of cardiac arrest and death during plastic surgical procedures.

Local Infiltration Anesthesia

Involves the extravascular placement of local anesthetic in the area to be anesthetized (placement of an intravascular cannula).

Lidocaine is the local anesthetic most often selected. Plain solution Epinephrine

containing sol

Drug Conc(%)

Max Dose (mg)

Duration (min)

Max Dose (mg)

Duration (min)

Lidnocaine 0.5-1 300 30-60 500 120

Bupivacaine

0.25-0.5

175 120-240 200 180-240

Peripheral Nerve Block Anesthesia

Achieved through the injection of local anesthetic solutions into tissues surrounding individual peripheral nerves or nerve plexuses.

Minor nerve blocks:Procedures involving single nerve entities such as the ulnar or radial nerve.Major nerve blocks: Blockade of two or more distinct nerves or a nerve plexus or the blockade of very large nerves at more proximal sites (i.e., the femoral and sciatic nerves).

Minor Nerve Blocks:Plain solution Epineph

containing sol

Drug Conc(%) Usual Vol (mL)

Dosage (mg)

Aver durat (min)

Average Duration (min)

Lidocaine 1 5-20 50-200 60-120 120-180

Bupivacaine 0.25-0.5 5-20 12.5-100 180-360 180-240

Major Nerve Blocks:Drug with epi 1:200000

Usual Conc(%)

Usual Vol (mL)

Max Dosage (mg)

Usual onset (min)

Usual Duration (min)

Lidocaine 1-2 30-50 500 10-20 120-140

Bupivacaine 0.25-0.5 30-50 225 20-30 360-720

Intravenous Regional Anesthesia (Bier Block)

Involves the intravenous administration of a local anesthetic into a tourniquet-occluded limb.

The local anesthetic diffuses from the peripheral vascular bed to nonvascular tissue such as axons and nerve endings.

Lidocaine has been the drug used most frequently for intravenous regional anesthesia.

Approximately 3 mg/kg (40 mL of a 0.5% solution) of preservative-free lidocaine without epinephrine is used for upper extremity procedures and 50 to 100 mL of a 0.25% lidocaine solution has been used for lower limb surgeries.

Bupivacaine is not recommended for intravenous regional anesthesia, considering its greater likelihood than other local anesthetics for producing cardiotoxicity when the tourniquet is deflated at the conclusion of the anesthetic agent.

Central Neural Blockade

Epidural anesthesia:Local anesthetics produce epidural anesthesia

by diffusion across the dura to act on nerve roots and passage into the paravertebral area through the intervertebral foramina, thus producing multiple paravertebral nerve blocks.

Lidocaine is used epidurally in 1.5% to 2% concentrations.

Bupivacaine remains the most widely used long-acting local anesthetic and is used in concentrations from 0.125% to 0.75%.

Comparative Onset Times and Analgesic Durations of Local Anesthetics Administered Epidurally in 20- to

30-mL Volume

Duration (min)

Drug Conc (%) Onset (min)

Plain 1 : 200,000 Epinephrine

Lidocaine 2 15 80-120 120-180

Bupivacaine

0.5-0.75 20 165-225

180-240

Spinal Anesthesia

Drug Usual Conc (%)

Usual Vol (mL)

Total Dose (mg)

Baricity Glusose conc (%)

Usual Duration (min)

Lidocaine

1.5,5.0

1-2 100- 200

Hyperbaric

7.5 30-90

Bupivacaine

0.5 3-4 15-20

Isobaric 90-200

0.75 2-3 15-20

Hyperbaric

8.25 90-200

Lidocaine use is associated with more neurotoxicity than bupivacaine.

Other uses

Suppression of Ventricular Cardiac Dysrhythmias:In addition to suppressing ventricular cardiac

dysrhythmias, the intravenous administration of lidocaine may increase the defibrillation threshold.

Suppression of Generalized Tonic-Clonic Seizures: Suppressed by the intravenous administration of low doses

of lidocaine or mepivacaine. Anti-inflammatory Effects:Useful in mitigating perioperative inflammatory injuryMay modulate inflammatory responses by inhibiting

inflammat ory mediator signalling . Also inhibit neutrophil accumulation at sites of

inflammation and impair free radical and mediator release.

Bronchodilation Inhaled lidocaine and ropivacaine

attenuate hista mine - induced bronchospasm and induce airway anesthesia ( which reflects topical airway anesthesia ).