local anesthetics

Local AnestheticsLocal Anesthetics

Dr V.RAMKUMARCONSULTANT DENTAL&FACIOMAXILLARY SURGEONREG NO: 4118 TAMILNADU-INDIA(ASIA)

Important pointsImportant points

HistoryHistory Some differencesSome differences How they workHow they work Test doseTest dose OnsetOnset AdjunvantsAdjunvants Lipid rescueLipid rescue Newer delivery systemsNewer delivery systems

History of Local AnestheticsHistory of Local Anesthetics

Cocaine isolated 1856Cocaine isolated 1856 1884 cocaine used in occular surgery1884 cocaine used in occular surgery 1880’s Regional anesthesia plexus1880’s Regional anesthesia plexus 1898 cocaine used in spinal anesthesia1898 cocaine used in spinal anesthesia 1905 11905 1stst synthetic LA (procaine) introduced synthetic LA (procaine) introduced 1943 lidocaine synthesized1943 lidocaine synthesized Mepivacaine (1957), Bupiv (’63), Ropiv (’96)Mepivacaine (1957), Bupiv (’63), Ropiv (’96)

Differences in structure of local Differences in structure of local anestheticsanesthetics

Esters versus Amides1) Affect metabolism2) Affect toxicity3) Allergic potential

Types of Local AnestheticsTypes of Local Anesthetics


EstersProcainechloroprocainetetracainecocaine


AmidesLidocaineprilocainemepivacainebupivacaineropivacaine

Mechanism of Action Mechanism of Action for Local Anestheticsfor Local Anesthetics

•Block propagation of action potential along neuron

prevent depolarization through blockade of Na Channel

voltage gated K channels also blocked by LA but the affinity of receptor much less

Local Anesthetics Local Anesthetics

Activity of local anesthetics is a function of Activity of local anesthetics is a function of their lipid solubility, diffusibility, affinity for their lipid solubility, diffusibility, affinity for protein binding, percent ionization at protein binding, percent ionization at physiologic pH, and vasodilating properties. physiologic pH, and vasodilating properties.


Lipid solubility is an important characteristic. Lipid solubility is an important characteristic. Potency is related to lipid solubility, because Potency is related to lipid solubility, because 90% of the nerve cell membrane is 90% of the nerve cell membrane is composed of lipid. This improve transit into composed of lipid. This improve transit into the cell membranethe cell membrane


Diffusibility (how well the LA diffuses Diffusibility (how well the LA diffuses diffuses through tissue to its site of action) diffuses through tissue to its site of action) will also influences the speed of action will also influences the speed of action onset. onset.


Protein binding is related to the duration of Protein binding is related to the duration of action. The site of action (the Na channel) is action. The site of action (the Na channel) is primarily protein in a lipid environment. primarily protein in a lipid environment. Binding affinity will thus affect duration of Binding affinity will thus affect duration of action.action.

Protein binding also plays a part in the Protein binding also plays a part in the availability of the drug as LA binds to availability of the drug as LA binds to lipoproteins in the blood stream.lipoproteins in the blood stream.

And transfer to fetusesAnd transfer to fetuses

SummarySummary Clinical PharmacologyClinical Pharmacology The potency of Local Anesthetics, their onset and duration of action The potency of Local Anesthetics, their onset and duration of action

are primary determined by physicochemical properties of various are primary determined by physicochemical properties of various agents and their inherent vasodilator activity of same local anesthetics.agents and their inherent vasodilator activity of same local anesthetics.

Lipid solubility is the primary determinant of anesthetic potency and it Lipid solubility is the primary determinant of anesthetic potency and it is expressed as lipid: water Partition Coefficient is expressed as lipid: water Partition Coefficient

Protein binding influences the duration of action Protein binding influences the duration of action pKa of Local anesthetics determines the onset of action pKa of Local anesthetics determines the onset of action The addition of vasoconstrictors, such as epinephrine or phenylephrine The addition of vasoconstrictors, such as epinephrine or phenylephrine

can prolong duration of action of local anesthetics, decrease their can prolong duration of action of local anesthetics, decrease their absorption (and the peak plasma level) and enhance the blockade. absorption (and the peak plasma level) and enhance the blockade.

pKapKa

Understanding LA as they relate to pKaUnderstanding LA as they relate to pKa

The pH of the tissue and pKa of the agentThe pH of the tissue and pKa of the agent

The pH and pKa are the most important factors. The pH and pKa are the most important factors. The pH of the tissue determines the ratio of The pH of the tissue determines the ratio of ionized to non-ionized drug. This ratio, in turn, ionized to non-ionized drug. This ratio, in turn, depends on the pKa of the drug. Understanding depends on the pKa of the drug. Understanding the ionization is necessary to understanding the the ionization is necessary to understanding the drug's pharmacological characteristics, such as drug's pharmacological characteristics, such as onset, duration and pharmacodynamics.onset, duration and pharmacodynamics.

Henderson Hasselbalch equationHenderson Hasselbalch equation

The basis for understanding this equation is knowing the The basis for understanding this equation is knowing the pKa of the agents, remembering that pKa equals the pH pKa of the agents, remembering that pKa equals the pH where the ionized and non-ionized forms are at equilibrium. where the ionized and non-ionized forms are at equilibrium. In other words, 50% of each form is present. Local In other words, 50% of each form is present. Local anaesthetics are weak bases. For bases, the pKa - pH anaesthetics are weak bases. For bases, the pKa - pH relationship is described by the Henderson Hasselbalch relationship is described by the Henderson Hasselbalch equation, as follows:equation, as follows:

pKa - pH= log_pKa - pH= log_ionizedionized non-ionizednon-ionized

Effect of pH, and pKaEffect of pH, and pKa

The pKa of amides ranges from 7.6 to 8.1. At physiologic The pKa of amides ranges from 7.6 to 8.1. At physiologic pH (7.4), most of the local anaesthetic is in the ionized pH (7.4), most of the local anaesthetic is in the ionized state (a charged base). For example, lidocaine has a pKa state (a charged base). For example, lidocaine has a pKa of 7.9. The above formulat determines that at physiologic of 7.9. The above formulat determines that at physiologic pH, lidocaine exists in a ratio of 3:1 ionized to non-ionized:pH, lidocaine exists in a ratio of 3:1 ionized to non-ionized:

7.9 - 7.4=log [ionized/non-ionized]7.9 - 7.4=log [ionized/non-ionized] 0.5 =log [ionized/non-ionized]0.5 =log [ionized/non-ionized] 100.5=ionized/non-ionized100.5=ionized/non-ionized 3ionized~3ionized~ 1non-ionized1non-ionized

Low pHLow pH

The pH of the tissue becomes relevant in conditions of The pH of the tissue becomes relevant in conditions of infection or inflammation, in which the natural pH may be infection or inflammation, in which the natural pH may be more acidic. This acidity results in a greater proportion of more acidic. This acidity results in a greater proportion of the ionized (charged) form of the anaesthetic, thereby the ionized (charged) form of the anaesthetic, thereby delaying or preventing the onset of action. For example, if delaying or preventing the onset of action. For example, if lidocaine (pKa 7.9) is administered into an area of infection lidocaine (pKa 7.9) is administered into an area of infection (pH 4.9) emanating from a dental abscess, then:(pH 4.9) emanating from a dental abscess, then:

7.9 - 4.9 = log [ionized/non-ionized]7.9 - 4.9 = log [ionized/non-ionized] 103 = ionized/non-ionized103 = ionized/non-ionized

The resulting ratio of 1,000:1 ionized to non-ionized The resulting ratio of 1,000:1 ionized to non-ionized indicates a poorer penetration into the nerve tissue and indicates a poorer penetration into the nerve tissue and therefore a less effective nerve blocktherefore a less effective nerve block

OnsetOnset

Is there a difference in the onset of different Is there a difference in the onset of different local anesthetics?local anesthetics?

Onset of Action

Onset of Action

Low pH as found in sites of infection will slow or prevent onset. The pKa values of most amides are similar; therefore, onsets are

similar. Bupivacaine's higher pKa results in a slightly slower onset. The time for diffusion to the nerve is a factor --infiltrations are rapid;

Duration of Local anestheticsDuration of Local anesthetics

Dependent on 1)agent 2)site 3)adjuvant 4)route 5)vascularity

Duration of Local anestheticsDuration of Local anesthetics

ExamplesLidocaine bupivacaine

local infiltration 30-60 min 120-240minor nerve block 60-120 180-360major nerve block 120-240 360-720Epidural 30-90 180-300addition of epi improved improved

Intravenous Lidocaine in Chronic Intravenous Lidocaine in Chronic PainPain

Tetrodotoxin TTXTetrodotoxin TTX Some Na channels resistant to TTXSome Na channels resistant to TTX These may be important in Chronic painThese may be important in Chronic pain With Chronic pain probably up/down With Chronic pain probably up/down

regulation receptor typesregulation receptor types IV lidocaine may work at these recptorsIV lidocaine may work at these recptors

CNS ToxicityCNS Toxicity

Tends to occur first (relative to CVS toxicity)See excitatory signs and symptoms firstFollowed by depressant signs

Circumoral and tongue numbnessLightheadedness and tinnitusVisual disturbanceMuscle twitchingConvulsions

COMARespiratory arrestCVS depression

CVS ToxicityCVS Toxicity

Alteration in the excitatory mechanismslower depolarization

decreased HRprolonged PR intervalwidened QRS

Arrythmiasbradycardiaectopic beatsventricular fibrillation

Decreased cardiac output on the basis ofHRcontractility

Treatment of ToxicityTreatment of Toxicity


Identify the problemsigns and symptomstemporal relationship

IV injection40-60 min post for peak plasma levels

CNStreatment with benzodiazepines


CVS signs and symptomsCNS effectsCVS effects

arrythmiaQRS changesigns of collapse fall in BP

With CVS toxicity The agent is an important consideration


When there is CVS collapseACLS

A B C’s

defibrillationEpinephrineVasopressinLidocaine?Bretylium?Amiodarone

Special preparationsSpecial preparations

EMLA lidocaine 2.5% prilocaine 2.5%requires 45-60 application on intact skin

TAC tetracaine 0.5% epi 1 in 2000 cocaine 10%application into woundmaximum dose for kids 0.05ml/Kgtoxicity due to cocaine

Tumescent Anesthesia lidocaine dilute epiliposuctiondose 35-55mg/KgPeak levels 8-12h later


www.aafp.org

TetrododoxinTetrododoxin

Toxin from puffer fishToxin from puffer fish Blocks the Na channelBlocks the Na channel

– Used in researchUsed in research– Blocks from the outer side of cellBlocks from the outer side of cell

Topical Local anestheticsTopical Local anesthetics

Tetracaine, Adrenaline (Epinephrine), and CocaineTetracaine, Adrenaline (Epinephrine), and Cocaine Tetracaine, adrenaline, and cocaine (TAC), a compound of 0.5 percent Tetracaine, adrenaline, and cocaine (TAC), a compound of 0.5 percent

tetracaine (Pontocaine), 0.05 percent epinephrine, and 11.8 percent tetracaine (Pontocaine), 0.05 percent epinephrine, and 11.8 percent cocaine, was the first topical anesthetic mixture found to be effective cocaine, was the first topical anesthetic mixture found to be effective for nonmucosal skin lacerations to the face and scalp.for nonmucosal skin lacerations to the face and scalp.22 From 2 to 5 mL From 2 to 5 mL of solution is applied directly to the wound using a cotton-tipped of solution is applied directly to the wound using a cotton-tipped applicator with firm pressure that is maintained for 20 to 40 minutes.applicator with firm pressure that is maintained for 20 to 40 minutes.2,2,33 However, the use of TAC is no longer supported by the However, the use of TAC is no longer supported by the literature because of general concern about toxicity and literature because of general concern about toxicity and expense, and federal regulatory issues involving expense, and federal regulatory issues involving medications containing cocainemedications containing cocaine. .

Principles of Office Anesthesia: Part II. Topical AnesthesiaPrinciples of Office Anesthesia: Part II. Topical Anesthesia

SURITI KUNDU, M.D.,SURITI KUNDU, M.D.,

EMLAEMLA Eutectic Mixture of Local Anesthetics Eutectic Mixture of Local Anesthetics Most pure anesthetic agents exist as solids. Most pure anesthetic agents exist as solids.

Eutectic mixtures are liquids and melt at lower Eutectic mixtures are liquids and melt at lower temperatures than any of their components, temperatures than any of their components, permitting higher concentrations of permitting higher concentrations of anesthetics.anesthetics. Eutectic mixture of local anesthetics Eutectic mixture of local anesthetics (EMLA) represents the first major breakthrough for (EMLA) represents the first major breakthrough for

dermal anesthesia ondermal anesthesia on intact skin.intact skin. It consists of 25 mg It consists of 25 mg per mL of lidocaine, 25 mg per mL of prilocaine, a thickener, an per mL of lidocaine, 25 mg per mL of prilocaine, a thickener, an emulsifier, and distilled water adjusted to a pH level of 9.4.emulsifier, and distilled water adjusted to a pH level of 9.4.3 3

Etymology: Greek Etymology: Greek eutEktos eutEktos easily melted, from easily melted, from eu- + tEktos eu- + tEktos melted, from melted, from tEkein tEkein to melt -- more at to melt -- more at THAW11 of an alloy or solutionof an alloy or solution :: having the lowest melting point having the lowest melting point possiblepossible22 :: of or relating to a eutectic alloy or solution or its melting or of or relating to a eutectic alloy or solution or its melting or freezing pointfreezing point

– Principles of Office Anesthesia: Part II. Topical AnesthesiaPrinciples of Office Anesthesia: Part II. Topical AnesthesiaSURITI KUNDU, M.D.,SURITI KUNDU, M.D.,

http://www.m-w.com/dictionary/thaw

IontophoresisIontophoresis Iontophoresis is a method of delivering a topical Iontophoresis is a method of delivering a topical

anesthetic with a mild electric current. Lidocaine-soaked anesthetic with a mild electric current. Lidocaine-soaked sponges are applied to intact skin, and electrodes are sponges are applied to intact skin, and electrodes are placed on top of the anesthetic. A DC current is then placed on top of the anesthetic. A DC current is then applied to the skin applied to the skin (Figure 2). (Figure 2). The anesthetic effect The anesthetic effect occurs within 10 minutes and lasts approximately 15 occurs within 10 minutes and lasts approximately 15 minutes. The depth of anesthesia can reach up to 1 to 2 minutes. The depth of anesthesia can reach up to 1 to 2 cm.cm.12 12

Although the effectiveness of iontophoresis has been Although the effectiveness of iontophoresis has been compared favorably to that of EMLA, it remains compared favorably to that of EMLA, it remains underused. Some patients find the mild electrical underused. Some patients find the mild electrical sensation uncomfortable. The apparatus is expensive sensation uncomfortable. The apparatus is expensive and bulky, and cannot be used over large surface areas and bulky, and cannot be used over large surface areas of the body.of the body.88 Other applications using iontophoresis are Other applications using iontophoresis are still being developed.still being developed.

– Principles of Office Anesthesia: Part II. Topical AnesthesiaPrinciples of Office Anesthesia: Part II. Topical AnesthesiaSURITI KUNDU, M.D.,SURITI KUNDU, M.D.,

IontophoresisIontophoresis

IontophoresisIontophoresis

Comparison of EMLA and lidocaine iontophoresis for cannulation Comparison of EMLA and lidocaine iontophoresis for cannulation analgesia.analgesia.

CONCLUSIONS: Although lidocaine iontophoresis is CONCLUSIONS: Although lidocaine iontophoresis is effective more quickly than the eutectic mixture of local effective more quickly than the eutectic mixture of local anaesthetic cream, the superior quality of analgesia anaesthetic cream, the superior quality of analgesia produced by the eutectic mixture in this study should be produced by the eutectic mixture in this study should be borne in mind if these treatments are used electivelyborne in mind if these treatments are used electively

LiposomesLiposomesLiposomes are comprised of lipid layers Liposomes are comprised of lipid layers

surrounded by aqueous layers. They are able surrounded by aqueous layers. They are able to penetrate the stratum corneum because they to penetrate the stratum corneum because they resemble the lipid bilayers of the cell resemble the lipid bilayers of the cell membrane. membrane. A liposomal delivery system recently became A liposomal delivery system recently became available as an over-the-counter product called ELA-Max. It available as an over-the-counter product called ELA-Max. It contains 4 percent lidocaine cream in a liposomal matrix and is contains 4 percent lidocaine cream in a liposomal matrix and is FDA-approved for the temporary relief of pain resulting from minor FDA-approved for the temporary relief of pain resulting from minor cuts and abrasions. ELA-Max is applied to intact skin for 15 to 40 cuts and abrasions. ELA-Max is applied to intact skin for 15 to 40 minutes without occlusion.minutes without occlusion. In limited studies, ELA-Max has also In limited studies, ELA-Max has also proved effective in providing dermal analgesia before chemical proved effective in providing dermal analgesia before chemical peeling.peeling. The safety of its application to mucous membranes has The safety of its application to mucous membranes has not been evaluated.not been evaluated. Despite a paucity of data and lack of an FDA Despite a paucity of data and lack of an FDA indication, clinicians are beindication, clinicians are be

ginning to use ELA-Max for topical anesthesia before other dermatologic ginning to use ELA-Max for topical anesthesia before other dermatologic procedures. procedures.

LiposomeLiposome

www.bioteach.ubc.ca

Uses of Local AnestheticsUses of Local Anesthetics

TopicalLocal infiltrationMinor peripheral nerve blockadeMajor peripheral nerve blockadeNeuraxial blockadeTumescent anesthesiaChronic pain


EMLA lidocaine 2.5% prilocaine 2.5%requires 45-60 application on intact skin

TAC tetracaine 0.5% epi 1 in 2000 cocaine 10%application into woundmaximum dose for kids 0.05ml/Kgtoxicity due to cocaine

Tumescent Anesthesia lidocaine dilute epiliposuctiondose 35-55mg/KgPeak levels 8-12h later

CVS ToxicityCVS Toxicity

Cardiovascular collapse on the basis of malignant rhythmdecreased contractilityvascular dilation

Newer Local anestheticsNewer Local anestheticsDirect cardiac effects of intracoronary bupivacaine, Direct cardiac effects of intracoronary bupivacaine,

levobupivacaine and ropivacaine in the sheep.levobupivacaine and ropivacaine in the sheep.In previous preclinical studies we found that central nervous system In previous preclinical studies we found that central nervous system (CNS) excito-toxicity reversed the cardiac depressant effects (CNS) excito-toxicity reversed the cardiac depressant effects

All three drugs produced tachycardia, decreased All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: Thirteen of 19 animals died of ventricular fibrillation: No significant differences in survival or in fatal doses between these No significant differences in survival or in fatal doses between these

drugs were found.drugs were found.

The findings suggest that ropivacaine, levobupivacaine The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity direct fatal cardiac toxicity when administered by left when administered by left intracoronary arterial infusion in conscious sheep and do not explain intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosagethe differences between the drugs found with intravenous dosage

Br J Pharmacol. 2001 Feb;132(3):649-58. Br J Pharmacol. 2001 Feb;132(3):649-58. Chang DHChang DH, ,

Limitations of Local AnestheticsLimitations of Local Anesthetics

Amount and complexity of the work to be donePatientArea to be anesthetizedDuration of procedureImmobility

New and not-so new New and not-so new Developments in Local Developments in Local

AnestheticsAnesthetics

ToxicityDuration

RopivacaineLevobupivacaine

liposomal encapsulated local anestheticssurface, charge, size & lamella structure

RopivacaineRopivacaine

Pharmacokinetic parametersPharmacokinetic parametersRopivacaine is 2-3 times less lipid soluble Ropivacaine is 2-3 times less lipid soluble and has a smaller volume of distribution, and has a smaller volume of distribution, greater clearance, and shorter elimination greater clearance, and shorter elimination half-life than bupivacaine in humans.half-life than bupivacaine in humans.33 The The two drugs have a similar pKa and plasma two drugs have a similar pKa and plasma protein binding protein binding


Ropivacaine is slightly less potent than Ropivacaine is slightly less potent than bupivacaine.bupivacaine.When used for spinal anesthesia, 0.75% When used for spinal anesthesia, 0.75% ropivacaine produces less intense sensory and ropivacaine produces less intense sensory and motor block than 0.5% bupivacaine.motor block than 0.5% bupivacaine.55 However, However, multiple clinical trials comparing the two local multiple clinical trials comparing the two local anesthetics in epidural and axillary block anesthetics in epidural and axillary block demonstrate similar potency of bupivacaine and demonstrate similar potency of bupivacaine and ropivacaine with respect to the intensity of sensory ropivacaine with respect to the intensity of sensory anesthesia.anesthesia.


Epinephrine does not prolong the duration of Epinephrine does not prolong the duration of ropivacaine block.ropivacaine block.The addition of epinephrine does not prolong the The addition of epinephrine does not prolong the duration of ropivacaine in subclavian brachial duration of ropivacaine in subclavian brachial plexusplexus1717,,1818 or epidural or epidural1919 block. Low concentrations block. Low concentrations of ropivaciane may produce clinically significant of ropivaciane may produce clinically significant vasoconstriction, which is not increased further by vasoconstriction, which is not increased further by the addition of epinephrine.the addition of epinephrine.


Ropivacaine is indistinguishable from Ropivacaine is indistinguishable from bupivacaine when used in obstetric anesthesia.bupivacaine when used in obstetric anesthesia.When continuous infusions of 0.25% ropivacaine were When continuous infusions of 0.25% ropivacaine were compared with 0.25% bupivacaine in lumbar epidural compared with 0.25% bupivacaine in lumbar epidural labor analgesia in two randomized double-blind labor analgesia in two randomized double-blind clinical trials, no difference was detected in between clinical trials, no difference was detected in between the two drugs in intensity, duration or incidence of the two drugs in intensity, duration or incidence of motor block, onset and quality of sensory analgesia, motor block, onset and quality of sensory analgesia, number of instrumented deliveries, number of C-number of instrumented deliveries, number of C-sections, or neonatal neurobehavioral scores at 24 sections, or neonatal neurobehavioral scores at 24 hours.hours.1111,,1212 Neonates in the ropivacaine group had Neonates in the ropivacaine group had higher neurobehavioral scores before 24 hourshigher neurobehavioral scores before 24 hours

TUMECCENT ANESTHESIATUMECCENT ANESTHESIA

Tumescent anesthesiaTumescent anesthesia is technique for delivery is technique for delivery of local anesthesia that maximizes safety by using of local anesthesia that maximizes safety by using pharmacokinetic principles to achieve extensive pharmacokinetic principles to achieve extensive regional anesthesia of skin and subcutaneous regional anesthesia of skin and subcutaneous tissue. The subcutaneous infiltration of a large tissue. The subcutaneous infiltration of a large volume of very dilute lidocaine and epinephrine volume of very dilute lidocaine and epinephrine causes the targeted tissue to become swollen and causes the targeted tissue to become swollen and firm, or tumescent, and permits procedures to be firm, or tumescent, and permits procedures to be performed on patients without subjecting them to performed on patients without subjecting them to the inherent risks of local anesthesia and blood the inherent risks of local anesthesia and blood lossloss

local anesthetics

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