local tics

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Local Anesthetics

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Important points

y History

y Some differences

y How they work

y Test dosey Onset

yAdjunvants

y Lipid rescue

y Newer delivery systems

y Tumescence

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History of Local Anesthetics

y Cocaine isolated 1856

y 1884 cocaine used in occular surgery

y 1880s Regional anesthesia plexus

y 1898 cocaine used in spinal anesthesia

y 1905 1st synthetic LA (procaine) introduced

y 1943 lidocaine synthesized

y Mepivacaine (1957), Bupiv (63), Ropiv (96)

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Differences in structure of local anesthetics

Esters versus Amides

1) Affect metabolism

2) Affect toxicity3) Allergic potential

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Types of Local Anesthetics

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Esters

Procaine

chloroprocainetetracaine

cocaine

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Amides

Lidocaine

prilocaine

mepivacaine

bupivacaine

ropivacaine

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sitemaker.med.umich.edu

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Mechanism of Action for 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

Lido 4-10x less Bupiv 10-80x less

NB K channel involved in repolarizationVoltage gated Na and Ca channels in DRG are similar

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Ty

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Mechanism of Action for Local Anesthetics

Domain 4

S4 subunit

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FIGURE 1. Model of the fourth homologous domain (D4) of the human skeletal muscle sodium

channel (hNaV1.4) with the S4 segment depicted as a rotating cylinder. Four S4 residues are

shown: Arg1451 (R2), Leu1452, Ala1453, and Arg1454 (R3). The positions of the residues around

the S4 segment roughly correspond to those of an helical model. A depolarizing rotation transfers

R2 and R3 from an intracellularly to an extracellularly accessible crevice, whereas Leu1452 and

Ala1453 are translocated in the opposite direction.

Coupled Movements in Voltage-gated Ion ChannelsRichard Horn Journal of General Physiology, Volume 120, Number 4, October 2002 449-453

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Tetrododoxin

y Toxin frompuffer fish

y Blocks the Na channel Used in research

Blocks from the outer side of cell

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Local Anesthetics

yy Activity of local anesthetics is a function of their lipidActivity of local anesthetics is a function of their lipidsolubility, diffusibility, affinity for protein binding,solubility, diffusibility, affinity for protein binding,percent ionization at physiologic pH, andpercent ionization at physiologic pH, and

vasodilating properties.vasodilating properties.

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Local Anesthetics

y Lipid solubility is an important characteristic.Potency is related to lipid solubility, because 90% ofthe nerve cell membrane is composed of lipid. This

improve transit into the cell membrane

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Local Anesthetics

y Diffusibility (how well the LA diffuses diffusesthrough tissue to its site of action) will alsoinfluences the speed of action onset.

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Local Anesthetics

yy Protein binding is related to the duration of action.Protein binding is related to the duration of action.The site of action (the Na channel) is primarilyThe site of action (the Na channel) is primarilyprotein in a lipid environment. Binding affinity willprotein in a lipid environment. Binding affinity willthus affect duration of action.thus affect duration of action.

yy Protein binding also plays a part in the availability ofProtein binding also plays a part in the availability ofthe drug as LA binds to lipoproteins in the bloodthe drug as LA binds to lipoproteins in the bloodstream.stream.

yy And transfer to fetusesAnd transfer to fetuses

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Summary

y Clinical Pharmacologyy The potency of Local Anesthetics, their onset and duration of action areprimary determined byphysicochemical properties of various agentsand their inherent vasodilator activity of same local anesthetics.

y Lipid solubility is the primary determinant of anesthetic potency and it

is expressed as lipid: water Partition Coefficienty Protein binding influences the duration of actiony pKa of Local anesthetics determines the onset of actiony The addition of vasoconstrictors, such as epinephrine or phenylephrine

can prolong duration of action of local anesthetics, decrease theirabsorption (and the peakplasma level) and enhance the blockade.

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From NYSORA web site

Properties of Local Anesthetic Agents

PROPERTIES AMINOESTERS AMINOAMIDES

Metabolism rapid by plasma cholinesterase slow, hepatic

Systemic toxicity less likely more likely

Allergic reaction possible - PABA derivatives form very rare

Stability in solution breaks down in ampules (heat,sun) very stable chemically

Onset of action slow as a general rule moderate to fast

pKa's higher than PH = 7.4 (8.5-8.9) close to PH = 7.4 (7.6-8.1)

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pKa

y Understanding LA as they relate to pKa

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y The pH of the tissue and pKa of the agent

The pH and pKa are the most important factors.

The pH of the tissue determines the ratio ofionized to non-ionized drug. This ratio, in turn,depends on the pKa of the drug. Understanding theionization is necessary to understanding the drug's

pharmacological characteristics, such as onset,duration and pharmacodynamics.

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Henderson Hasselbalch equation

y The basis for understanding this equation is knowing thepKa of the agents, remembering that pKa equals the pH

where the ionized and non-ionized forms are atequilibrium. In other words, 50% of each form is present.

Local anaesthetics are weak bases. For bases, the pKa - pHrelationship is described by the Henderson Hasselbalchequation, as follows:

y pKa - pH= log_ionized

non-ionized

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Effect ofpH, and pKa

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

lidocaine exists in a ratio of 3:1 ionized to non-ionized:y 7.9 - 7.4=log [ionized/non-ionized]

y 0.5 =log [ionized/non-ionized]

y 3=ionized/non-ionized

y

3ionized~1non-ionized

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LowpH

y The pH of the tissue becomes relevant in conditions ofinfection or inflammation, in which the natural pH may bemore acidic. This acidity results in a greater proportion ofthe ionized (charged) form of the anaesthetic, therebydelaying or preventing the onset of action. For example, if

lidocaine (pKa 7.9) is administered into an area of infection(pH 4.9) emanating from a dental abscess, then:

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

The resulting ratio of 1,000:1 ionized to non-ionizedindicates a poorer penetration into the nerve tissue andtherefore a less effective nerve block

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Onset

y Is there a difference in the onset of different localanesthetics?

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Onset

AGENT Pot. Onset pKa %PB P. coef

Procaine 0.5-1% (Novocain) 1 Rap 8.9 5.8 0.02

Chloroprocaine 2-3% (Nesacain) 4 Rap 8.7 ? 0.14

Tetracaine 0.1-0.5% (Pontocain) 16 Slow 8.5 75.6 4.1

Lidocaine 1-5% (Xylocaine) 1 Rap 7.9 64.3 2.9

Mepivacaine 1.5% (Carbocaine) 1 Mod 7.6 77.5 0.8

Bupivacaine 0.25-0.75% (Marcainesensorcaine) 4 Slow 8.1 95.6 27.5

Etidocaine 0.5-1.5% (Duranest) 4 Rap 7.7 94 141

Prilocaine 1 7.9 55 0.9

Ropivacaine 0.75% (Naropin) 4 Mod 8.1 94 2.9

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Onset

y Does onset influence you practice?

y Where? OB

RA Chronic pain

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Onset of ActionOnset of Action

y Low pH as found in sites of infection will slow or prevent onset.

y The pKa values of most amides are similar; therefore, onsets aresimilar.

y Bupivacaine's higher pKa results in a slightly slower onset.

y The time for diffusion to the nerve is a factor --infiltrations are rapid;

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Onset

A comparison of warmed Bupivacaine and lidocaine forepidural top up for C/S

BJA 1994 72 221-3

Warming improved onset for lidocaine to pin prick

Test dose lidocaine and epinephrine time 0

Inadequate anesthesia bupiv x2, warmed B 1 and warmed L x 2

Bupiv0.5%

(n=27) 20oC

Lidocaine 2%n=28, 20oC

Bupiv 0.5%38oC n=29

Lido 38oCN=27

Onset to T6 29.9 (7.1) 27.0 (6.9) 29.8 (6.7) 24.4 (7.6)**

Pt ready for Sx

15 min

0 0 0 8

Volume 23.9 22.6 22.4 21.1

Use of

entonox/opioid

10 11 14 8

** p

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Onset

B BL L

(n 30) (n 30) (n 30)

y Duration of epidural; h 12.6 (6.2) 1.4 (5.6) 11.8 (5.3)

y No. of low-dose top-ups 7.4 (5) 7.2 (4.1) 7.9 (4.8)

dose of bupiv labour;mg 92.0 (57) 92.3 (49) 95.2 (48)y Time since l top-up; min 92.3 (45.1) 75.1 (33.2) 69.3 (40.9)

y Sensory level pre top-up T10 T10 T10

y Time to T4; min 14 12 10

y (1119.3 [625] (8.817 [638]) (918.5 [636])

y Maximum height of block T3 T3 T3

t

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at s va a efrom NYSORA web site

Ropivacaine is a long-acting, amide-type local anesthetic.

Its structure and pharmacokinetics are similar to those ofbupivacaine, however, ropivacaine exhibits significantlybetter cardiotoxicityprofile compared to bupivacaine.Duration of action for ropivacaine ranges 2.5-5.9 hours forepidural block to 8-13 hours for peripheral nerve block.Ropivacaine is also less lipid soluble and cleared via the

liver more rapidly than bupivacaine. Some studies haveshown less motor blocking effects of ropivacaine than that

of bupivacaine.Due to its better safetyprofileand significantly better sensory-motordifferentiation, Ropivacaine is currently the

long-acting anesthetic of choice in ourpractice.

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Mepivacaine is a local anesthetic of the amide type with an intermediate durationof action. Mepivacaine is used for infiltration and transtracheal anesthesia, andperipheral, sympathetic, regional (Bier block), and epidural nerve blocks.Compared with lidocaine, mepivacaine produces less vasodilatation and has a more

rapid onset and longer duration of action. In our practice, this is the #1intermediate-acting local anesthetic to use for peripheral nerve blocks.

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Duration of Local anesthetics

Dependent on

1)agent

2)site

3)adjuvant

4)route

5)vascularity

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Duration of Local anesthetics

Examples

Lidocaine bupivacaine

local infiltration 30-60 min 120-240

minor nerve block 60-120 180-360major nerve block 120-240 360-720

Epidural 30-90 180-300

addition of epi improved improved

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cal Anesthetic Time Line (minutes)

Infiltration plain sol'n With Epinephrine Spinal plain With Epinephrine Epidural plain sol'n With Epinephrin

hloroprocaine30-4545-60

idocaine 60-12090-180

Hyperbaric60

60-90

80-120120-180

epivacaine90-140140-200

etracaineHyperbaric120-180180-400

opivacaine140-200160-220

upivacaine180-360300-480

Hyperbaric120-360120-360

180-360120-240

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Intravenous Lidocaine in Chronic Pain

y Tetrodotoxin TTX

y Some Na channels resistant to TTX

y These may be important in Chronic pain

y With Chronic pain probably up/down regulationreceptor types

y IVlidocaine may work at these recptors

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Intravenous lidocaine in Chronic pain

Systemic administration of local anesthetic agents to relieveSystemic administration of local anesthetic agents to relieveneuropathic pain.neuropathic pain.

AUTHORS' CONCLUSIONS: Lidocaine and oral analogsAUTHORS' CONCLUSIONS: Lidocaine and oral analogs

were safe drugs in controlled clinical trials for neuropathicwere safe drugs in controlled clinical trials for neuropathicpain, were better than placebo, and were as effective aspain, were better than placebo, and were as effective asother analgesicsother analgesics. Future trials should enroll specific diseases and. Future trials should enroll specific diseases and

test novel lidocaine analogs with better toxicityprofiles. More emphasistest novel lidocaine analogs with better toxicityprofiles. More emphasisis necessary on outcomes measuring patient satisfaction to assess ifis necessary on outcomes measuring patient satisfaction to assess if

statistically significant pain relief is clinicallymeaningfulstatistically significant pain relief is clinicallymeaningful Cochrane Database Syst Rev. 2005 Oct 19;(4):Cochrane Database Syst Rev. 2005 Oct 19;(4):Challapalli VChallapalli V,,

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Intravenous Lidocaine

yy IntraIntra--Op Lidocaine and Ketamine Effect on PostoperativeOp Lidocaine and Ketamine Effect on PostoperativeBowel FunctionBowel Function

y This study is currently recruiting patients.Verified byUniversity of Saskatchewan September 2005Verified byUniversity of Saskatchewan September 2005

y Purposeyy Bowel function after bowel surgery is delayed (postoperative ileus)by bothBowel function after bowel surgery is delayed (postoperative ileus)by both

opiates and the surgery itself. We hypothesized that decreasing opiate use byopiates and the surgery itself. We hypothesized that decreasing opiate use byother analgesics will speed the return of bowel function after surgery. Lidocaineother analgesics will speed the return of bowel function after surgery. Lidocaineand Ketamine are drugs that appear to be synergistic and do not slowand Ketamine are drugs that appear to be synergistic and do not slow

peristalsisperistalsis.. This study is a Randomised Controlled Trial ofThis study is a Randomised Controlled Trial ofLidocaine Infusion Plus Ketamine Injection versus PlaceboLidocaine Infusion Plus Ketamine Injection versus Placebo

to to determine whether they will decrease opiate use andto to determine whether they will decrease opiate use andthen whether decreased opiate use will speed the return ofthen whether decreased opiate use will speed the return of

bowel function.bowel function.

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Intravenous Lidocaine

yy Fortypatients undergoing radical retropubic prostatectomy wereFortypatients undergoing radical retropubic prostatectomy were

studied with one half of the patients receivingstudied with one half of the patients receiving a lidocaine bolusa lidocaine bolus(1.5 mg/kg) and infusion (3 mg/min); the other half(1.5 mg/kg) and infusion (3 mg/min); the other halfreceived a saline infusionreceived a saline infusion. Lidocaine. Lidocaine--treated patients firsttreated patients firstexperienced flatulence in a significantly shorter time (P < 0.01)experienced flatulence in a significantly shorter time (P < 0.01)

than control patients. Lidocaine patients' hospital stay was alsothan control patients. Lidocaine patients' hospital stay was alsosignificantly shorter (P < 0.05);. IVlidocaine initiated beforesignificantly shorter (P < 0.05);. IVlidocaine initiated beforeanesthesia and continued 1 h postoperatively significantly sped upanesthesia and continued 1 h postoperatively significantly sped upthe return of bowel function. Lidocaine patients were also morethe return of bowel function. Lidocaine patients were also morecomfortable postoperativelycomfortable postoperatively

yy Lidocaine blood levels were variable (1.3Lidocaine blood levels were variable (1.3--3.7 micro g/mL), but3.7 micro g/mL), butnone approached a toxic level (>5 micro g/mL).none approached a toxic level (>5 micro g/mL).

yy LidocaineLidocaine--treated patients had shorter hospital stays,treated patients had shorter hospital stays,less pain, and faster return of bowel function. In thisless pain, and faster return of bowel function. In thispopulation, lidocaine infusion can be a useful adjunctpopulation, lidocaine infusion can be a useful adjunctin anesthetic managementin anesthetic management..

(Anesth Analg 1998;86:235(Anesth Analg 1998;86:235--9) Groudine, Scott B.9) Groudine, Scott B.

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IVLocal Anesthetics

y

Effect of ciprofloxin on thepharmacokinetics of intravenouslidocaine.

y BACKGROUND AND OBJECTIVE: Recent studies havesuggested that cytochrome P-450 isoenzyme 1A2 has animportant role in lidocaine biotransformation. We havestudied the effect of a cytochrome P-450 1A2 inhibitor,ciprofloxacin, on the pharmacokinetics of lidocaine

y ). CONCLUSION: The plasma decay of intravenouslyadministered lidocaine is modestly delayed by

concomitantly administered ciprofloxacin. Ciprofloxacinmay increase the systemic toxicity of lidocaine Eur J Anaesthesiol. 2005 Oct;22(10):795Eur J Anaesthesiol. 2005 Oct;22(10):795--9.9. Isohanni

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SafetyIssues Related to Local Anesthetics

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SafetyIssues Related to Local Anesthetics

Related to

1) Drug

2) Dose3) Site of administration

4) Condition of the patient

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CNS Toxicity

Tends to occur first (relative to CVS toxicity)

See excitatory signs and symptoms first

Followed by depressant signs

Circumoral and tongue numbness

Lightheadedness and tinnitus

Visual disturbance

Muscle twitchingConvulsions

COMA

Respiratory arrest

CVS depression

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CVS Toxicity

Alteration in the excitatory mechanism

slower depolarization

decreased HR

prolonged PR intervalwidened QRS

Arrythmias

bradycardia

ectopic beats

ventricular fibrillation

Decreased cardiac output on the basis of

HR

contractility

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Treatment of Toxicity

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Identify the problem

signs and symptoms

temporal relationship

IV injection40-60 min post for peak plasma levels

CNS

treatment with benzodiazepines

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CVS signs and symptoms

CNS effects

CVS effectsarrythmia

QRS change

signs of collapse fall in BP

With CVS toxicity

The agent is an important consideration

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When there is CVS collapse

ACLS

AB Cs

defibrillation

Epinephrine

Vasopressin

Lidocaine?

Bretylium?

Amiodarone

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Lipid Rescue

y Relatively new concept

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NanoparticlesScavenging Nanoparticles: An Emerging Treatment for Local

Anesthetic Toxicityy The authors of the lipid-based studies speculated that four mechanisms

mayplay a role in the success of resuscitation. In their primaryhypothesis, the lipid infusion may create plasma lipiddroplets capable of segregating uncharged bupivacainemolecules from plasma, which makes them unavailablefor interaction at their target sites. The authors supported thistheory by showing that bupivacaine molecules preferentially segregatedfromplasma to their lipid infusion in a 1:12 ratio. 29 In two of the otherproposed mechanisms, the lipid acts within tissue. Here, lipid or itscomponent fatty acids either interact in a clinically significant way withtissue bupivacaine molecules or directly overcome bupivacainesinhibitory effect on cellular metabolism by supplying substrate forcellular energyproduction.30,31 [ 30, 31] Finally, the lipid infusion may

act on nitric oxide pathways and reverse bupivacaines inhibitory effects.29 Building on this work and assuming that sequestration of bupivacaineis an important aspect of resuscitation in the aforementioned lipid-based studies, some investigators have hypothesized even greatersegregation of bupivacaine into lipid may occur with large reductions inparticle size to the dimension of the nanometer. Regional Anesthesia andPMRegional Anesthesia andPMJulyJuly -- May, 2005 pp: 380May, 2005 pp: 380--384384 Renehan,Renehan,

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Regional Anesthesia andPMRegional Anesthesia andPMJulyJuly -- May, 2005 pp: 380May, 2005 pp: 380--384384 RenehanRenehan,,

Regional Anesthesia andPMJuly May 2005 pp: 380 384Renehan

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Regional Anesthesia andPMJuly - May, 2005 pp: 380-384Renehan,

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Toxicty

Email

Reported adverse event cases ofmethemoglobinemia associated withbenzocaine products

.

The researchers identified 198 cases that described unique adverseevents linked to the use of benzocaine. Of these, 132 cases (66.7%) wereeither definitely or probably episodes of MHb. Sprayproductscontaining benzocaine accounted for 123 (93.2%) of the adverse events.In every one of these cases in which a tissue type was specified,

benzocaine was applied to mucosal tissue. Of the 132 episodes ofMHb, there were 107 episodes that were considered seriousand two deaths. In neither case that resulted in death was

benzocaine considered the principle suspect cause.

MDNews 6/18/2004. Arch Intern Med. 2004;164:1192-6 Moore

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Special 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 wound

maximum dose for kids 0.05ml/Kg

toxicity due to cocaine

Tumescent Anesthesialidocaine dilute epi

liposuction

dose 35-55mg/Kg

Peak levels 8-12h later

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Special preparations

www.aaf .or

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Topical Local anesthetics

y Tetracaine, Adrenaline (Epinephrine), and Cocaine

y Tetracaine, adrenaline, and cocaine (TAC), a compound of 0.5 percenttetracaine (Pontocaine), 0.05 percent epinephrine, and 11.8 percentcocaine, was the first topical anesthetic mixture found to be effective fornonmucosal skin lacerations to the face and scalp.2 From 2 to 5 mL of

solution is applied directly to the wound using a cotton-tippedapplicator with firmpressure that is maintained for 20 to 40

minutes.2,3 However, the use of TAC is no longer supportedby the literature because of general concern about toxicityand expense, and federal regulatory issues involvingmedications containing cocaine.

yy Principles ofOffice Anesthesia: Part II. Topical AnesthesiaPrinciples ofOffice Anesthesia: Part II. Topical Anesthesia

y SURITIKUNDU, M.D.,

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EMLAy Eutectic Mixture ofLocal Anestheticsy Most pure anesthetic agents exist as solids.Eutectic mixtures are liquids and melt atlower temperatures than any of theircomponents, permitting higher concentrationsof anesthetics. Eutectic mixture of local anesthetics(EMLA) represents the first major breakthrough fordermal anesthesia on intact skin. It consists of 25 mgper mL of lidocaine, 25 mg per mL ofprilocaine, a thickener, anemulsifier, and distilled water adjusted to a pH level of 9.4.3

y Etymology: GreekeutEktos easilymelted, fromeu- + tEktosmelted, fromtEkein tomelt -- more at THAW1 of an alloy orsolution : having the lowest melting pointpossible2 : of or relating to a eutectic alloy or solution or its melting orfreezingpoint Principles ofOffice Anesthesia: Part II. Topical AnesthesiaPrinciples ofOffice Anesthesia: Part II. Topical AnesthesiaSURITIKUNDU, M.D.,

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Iontophoresisy Iontophoresis is a method of delivering a topical

anesthetic with a mild electric current. Lidocaine-soaked sponges are applied to intact skin, andelectrodes are placed on top of the anesthetic. ADCcurrent is then applied to the skin (Figure 2). Theanesthetic effect occurs within 10 minutes and lastsapproximately 15 minutes. The depth of anesthesia

can reach up to 1 to 2 cm.12y Although the effectiveness of iontophoresis has been

compared favorably to that ofEMLA, it remainsunderused. Some patients find the mild electricalsensation uncomfortable. The apparatus is expensive

and bulky, and cannot be used over large surface areasof the body.8 Other applications using iontophoresisare still being developed. Principles ofOffice Anesthesia: Part II. Topical AnesthesiaPrinciples ofOffice Anesthesia: Part II. Topical AnesthesiaSURITIKUNDU, M.D.,

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Iontophoresis

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Iontophoresis

y Comparison of EMLA and lidocaine iontophoresis forcannulation analgesia.

CONCLUSIONS: Although lidocaine iontophoresis iseffective

more quickly than the eutectic

mixture of local

anaesthetic cream, the superior quality of analgesiaproduced by the eutectic mixture in this study should be

borne in mind if these treatments are used electively

y Eur J Anaesthesiol. 2004 Mar;21(3):210-3. Moppett

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LiposomesLiposomes are comprised of lipid layers

surrounded by aqueous layers. They are ableto penetrate the stratum corneum becausethey resemble the lipid bilayers of the cellmembrane.A liposomal delivery system recently becameavailable as an over-the-counter product called ELA-Max. It

contains 4 percent lidocaine cream in a liposomal matrix and isFDA-approved for the temporary relief ofpain resulting fromminor cuts and abrasions. ELA-Max is applied to intact skin for15 to 40 minutes without occlusion.15-17 In limited studies,ELA-Max has also proved effective in providing dermal analgesiabefore chemical peeling.18 The safety of its application to mucousmembranes has not been evaluated.5Despite a paucity of data

and lack of an FDA indication, clinicians are be

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

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Liposome

www.bioteach.ubc.ca

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Liposomal Bupivacaine

A Novel Liposomal Bupivacaine Formulationto Produce Ultralong-Acting Analgesia

y Conclusions: This novel liposomal formulation hada favorable drug-to-phospholipid ratio andprolonged the duration of bupivacaine analgesia ina dose-dependent manner. If these results inhealthy volunteers can be duplicated in the clinical

setting, this formulation has the potential tosignificantly impact the management ofpain.

Anesthesiology:Volume 101(1) July 2004 pp 133Anesthesiology:Volume 101(1) July 2004 pp 133--137137 Grant,

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Liposomal Bupivacainey Themedian duration of analgesia with 0.5% standard

bupivacaine was 1 h. The median durations of analgesiaafter 0.5, 1.0, and 2.0% liposomal bupivacaine were19, 38, and 48 h, respectively.

y Although the data presented with this novel LMVVformulation are veryencouraging because we found that LMVVbupivacaine was well tolerated andthat it significantlyprolonged the duration of analgesia compared to standard

bupivacaine, there are a number of issues that must be resolved before theformulation can be introduced for clinical use. Stability of theformulation during prolonged storage, batch-to-batch

variability in physicochemical characteristics, andadaptability of the method for upscaling for large

batch sizes remain to be determined. The primary objective ofthe current study was to establish proof of concept regarding the efficacy ofLMVVbupivacaine in humans. The dose of LMVVbupivacaineadministered in this study was lowonly 17.5 mg. Before the efficacy ofLMVVbupivacaine in various painful conditions can be evaluated, a study todetermine its maximum tolerated dose in humans is necessary.

Li

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Liposomes

y Liposomal Drug Delivery for Postoperative Pain

Management Translational vignetteyy Although the plasma concentration versus time curve is flatter for theAlthough the plasma concentration versus time curve is flatter for the

extendedextended--release formulation, overall bioavailability is similar.release formulation, overall bioavailability is similar.

AlthoughAlthough the exact mechanism ofthe exact mechanism ofin vivoin vivo drug releasedrug releasefrom MVL particles is not known, it is believed to befrom MVL particles is not known, it is believed to bethe result of a gradual erosion or reorganization of thethe result of a gradual erosion or reorganization of the

lipid membraneslipid membranesy Summary and Conclusions

y Liposomes are effective drug delivery systems to improve thetherapeutic efficacy of drugs by increasing drug circulationtimes, facilitating targeting of drugs, and enhancing stability

without compromising safety or tolerability. Extended-releaseMVL preparation has proved to be an effective drug deliveryvehicle for morphine sulfate; extended-release MVL morphine

sulfate exhibits an extended duration ofpain relief for up to 48hours postoperatively without compromising safety ortolerability, according to initial clinical studies.

Regional Anesthesia and PRegional Anesthesia and PMM SeptSept -- May, 2005 pp: 491May, 2005 pp: 491--496496 EugeneEugene

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Encapsulation of mepivacaineEncapsulation of mepivacaineyy Encapsulation of mepivacaine prolongs the analgesiaEncapsulation of mepivacaine prolongs the analgesia

provided by sciatic nerve blockade in mice.provided by sciatic nerve blockade in mice.

PURPOSE: Liposomal formulations of local anesthetics (LA) arePURPOSE: Liposomal formulations of local anesthetics (LA) areable to control drugable to control drug--delivery in biological systems, prolongingdelivery in biological systems, prolongingtheir anesthetic effect. This study aimed to prepare, characterizetheir anesthetic effect. This study aimed to prepare, characterizeand evaluate in vivo drugand evaluate in vivo drug--delivery systems, composed of largedelivery systems, composed of largeunilamellar liposomes (LUV), for bupivacaine (BVC) andunilamellar liposomes (LUV), for bupivacaine (BVC) andmepivacaine (MVC).mepivacaine (MVC).

yy CONCLUSION: MVC(LUV) provided a LA effectCONCLUSION: MVC(LUV) provided a LA effectcomparable to that of BVC. We propose MVC(LUV)comparable to that of BVC. We propose MVC(LUV)drug delivery as a potentially new therapeutic optiondrug delivery as a potentially new therapeutic optionfor the treatment of acute pain since the formulationfor the treatment of acute pain since the formulation

enhances the duration of sensory blockade at lowerenhances the duration of sensory blockade at lowerconcentrations than those ofplain MVC.concentrations than those ofplain MVC. Can J Anaesth. 2004 JunCan J Anaesth. 2004 Jun--Jul;51(6):566Jul;51(6):566--72.72. de Araujode Araujo

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Uses of Local Anesthetics

Topical

Local infiltration

Minor peripheral nerve blockadeMajor peripheral nerve blockade

Neuraxial blockade

Tumescent anesthesia

Chronic pain

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IV Local anesthetics

Perioperative Intravenous Lidocaine Has PreventivePerioperative Intravenous Lidocaine Has PreventiveEffects on Postoperative Pain and MorphineEffects on Postoperative Pain and MorphineConsumption After Major Abdominal SurgeryConsumption After Major Abdominal Surgery IMPLICATIONS: The perioperative administration ofIMPLICATIONS: The perioperative administration of

systemic smallsystemic small--dosedose lidocaine reduces pain during surgerylidocaine reduces pain during surgery

associated with the developmentassociated with the developmentof pronounced centralof pronounced centralhyperalgesia, presumably by affectinghyperalgesia, presumably by affecting mechanoinsensitivemechanoinsensitivenociceptors, because these have been linkednociceptors, because these have been linkedto theto theinduction of central sensitization and were shown toinduction of central sensitization and were shown tobebeparticularly sensitive to smallparticularly sensitive to small--dose lidocainedose lidocaine lidocaine 2%lidocaine 2% (bolus injection of1.5 mg/kg in 10 min followed by(bolus injection of1.5 mg/kg in 10 min followed by

an IV infusionan IV infusion of1.5 mg kgof1.5 mg kg--11 h h--11),),

yAnesth Analg 2004;98:1050-1055 Koppert

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Tumescent Anesthesiayy Plasma lidocaine levels and risks after liposuction withPlasma lidocaine levels and risks after liposuction with

tumescent anaesthesia.tumescent anaesthesia.

Background: It is common today to use tumescent anaesthesiaBackground: It is common today to use tumescent anaesthesiawith large doses of lidocaine for liposuction.with large doses of lidocaine for liposuction. The purpose of the preseThe purpose of the presestudy was to evaluate lidocaine plasma levels and objective and subjectivestudy was to evaluate lidocaine plasma levels and objective and subjectivesymptoms during 20 h after tumescent anaesthesia with approximately 35 mgsymptoms during 20 h after tumescent anaesthesia with approximately 35 mgper kg bodyweight of lidocaine for abdominal liposuction. Methods: Three litrper kg bodyweight of lidocaine for abdominal liposuction. Methods: Three litr

of buffered solution of 0.08% lidocaine with epinephrineof buffered solution of 0.08% lidocaine with epinephrine.. Results: LidocaineResults: Lidocaine33.2 +/33.2 +/-- 1.8 mg/kg was given at a rate of 116 +/1.8 mg/kg was given at a rate of 116 +/-- 11 ml/min. Peakplasma level11 ml/min. Peakplasma level(2.3 +/(2.3 +/-- 0.63 microg/ml) of lidocaine occurred after 50.63 microg/ml) of lidocaine occurred after 5--17 h17 h

yy Conclusion:Doses of lidocaine up to 35 mg/kg were sufficient forConclusion:Doses of lidocaine up to 35 mg/kg were sufficient for

abdominal liposuction using the tumescent technique and gave nabdominal liposuction using the tumescent technique and gave nfluid overload or toxic symptoms in eight patients,fluid overload or toxic symptoms in eight patients,but with this dosbut with this dosthere is still a risk of subjective symptoms in association with the peak level ofthere is still a risk of subjective symptoms in association with the peak level oflidocaine that may appear after discharge.lidocaine that may appear after discharge.

Acta Anaesthesiol Scand. 2005 Nov;49(10):1487Acta Anaesthesiol Scand. 2005 Nov;49(10):1487--90.90.NordstromNordstrom

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Tumescent Anesthesia

yy Deaths Related to LiposuctionDeaths Related to Liposuction

yy ConclusionsConclusions Tumescent liposuction can be fatal,Tumescent liposuction can be fatal,perhapsperhaps in partin part because of lidocaine toxicity orbecause of lidocaine toxicity orlidocainelidocaine--related drug interactions.related drug interactions.

y In tumescent liposuction, reported doses of lidocaine range from10 to 88 mg per kilogram,8 several times higher than themaximal recommended dose of 4.5 mg per kilogram (or up to 7mg per kilogram with epinephrine) typically used forsubcutaneous infiltration.21,22 The 1991 guidelines of the

American AcademyofD

ermatologists for tumescent liposuctionsuggested a maximal dose of 35 mg of lidocaine per kilogram,23

which was increased to at least 55 mg per kilogram in 1997

NEJM V340:1471NEJM V340:1471--14751475 RamaRama

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Myotoxicity

The long term myotoxic effects of bupivacaine and ropivacaine aftercontinuous peripheral nerve blocks.

IMPLICATIONS: In a period of 4 wk after peripheral nerve block, both long-acting

local anesthetics, bupivacaine and ropivacaine, produced calcific myonecrosis

suggestive of irreversible skeletal muscle damage. In comparison with ropivacaine,

however, the extent of bupivacaine-induced muscle lesions was significantly larger.

Anesth Analg. 2005 Aug;101(2):548-54, Zink W,

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CVS Toxicity

Cardiovascular collapse on the basis of

malignant rhythm

decreased contractilityvascular dilation

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Newer Local anesthetics

Direct cardiac effects of intracoronarybupivacaine, levobupivacaine and ropivacainein the sheep.In previous preclinical studies we found that central nervous system(CNS) excito-toxicity reversed the cardiac depressant effects

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

drugs were found.

The findings suggest that ropivacaine, levobupivacaineand bupivacaine have similar intrinsic ability to causedirect fatal cardiac toxicitywhen administered by leftintracoronary arterial infusion in conscious sheep and do not explainthe differences between the drugs found with intravenous dosage

Br J Pharmacol. 2001 Feb;132(3):649Br J Pharmacol. 2001 Feb;132(3):649--58.58. Chang DH,

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Limitations of Local Anesthetics

Amount and complexity of the work to be done

Patient

Area to be anesthetized

Duration of procedureImmobility

New and not-so newDevelopments in Local

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pAnesthetics

Toxicity

Duration

Ropivacaine

Levobupivacaine

liposomal encapsulated local anesthetics

surface, charge, size & lamella structure

depts.washington.edu/anesth/ regional/ropivacainetext.html

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p g / / g / p

y Pharmacokinetic parametersRopivacaine is 2-3 times less lipid soluble and has asmaller volume of distribution, greater clearance,and shorter elimination half-life than bupivacaine inhumans.3 The two drugs have a similar pKa andplasma protein binding


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y Ropivacaine is slightly less potent thanbupivacaine.When used for spinal anesthesia, 0.75%ropivacaine produces less intense sensory and

motor block than 0.5% bupivacaine.5 However,multiple clinical trials comparing the two localanesthetics in epidural and axillary blockdemonstrate similar potency of bupivacaine and

ropivacaine with respect to the intensity of sensoryanesthesia.


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yy Epinephrine does not prolong the durationEpinephrine does not prolong the durationof ropivacaine block.of ropivacaine block.The addition of epinephrine does not prolong theThe addition of epinephrine does not prolong the

duration of ropivacaine in subclavian brachialduration of ropivacaine in subclavian brachialplexusplexus1717,,1818 or epiduralor epidural1919block. Low concentrationsblock. Low concentrationsof ropivaciane mayproduce clinically significantof ropivaciane mayproduce clinically significant

vasoconstriction, which is not increased further byvasoconstriction, which is not increased further by

the addition of epinephrine.the addition of epinephrine.


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y Ropivacaine is indistinguishable frombupivacaine when used in obstetric anesthesia.When continuous infusions of 0.25% ropivacaine werecompared with 0.25% bupivacaine in lumbar epidural

labor analgesia in two randomized double-blindclinical trials, no difference was detected in betweenthe two drugs in intensity, duration or incidence ofmotor block, onset and quality of sensory analgesia,number of instrumented deliveries, number of C-

sections, or neonatal neurobehavioral scores at 24hours.11,12 Neonates in the ropivacaine group hadhigher neurobehavioral scores before 24 hours

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y ConclusionsRopivacaine is slightly less potent than

bupivacaine, but multiple studies show that it canprovide adequate surgical anesthesia when used in

similar concentrations. Ropivacaine is half aspotent as bupivacaine in its direct negativeinotropic effect and slowing of ventricularconduction. Apotential for sudden ventriculararrhythmias still exists with systemic ropivacaine

toxicity. Any slight advantage ropivacaine has overbupivacaine may be eliminated if higherconcentrations of ropivacaine are used.

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Ropivacaine

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RopivacaineRelated Articles, Links

Arterial and Venous Pharmacokinetics ofRopivacaine with and without Epinephrine after Thoracic

Paravertebral Block.

BACKGROUND:: Animal and volunteer studies indicate that ropivacaine is associated with less neurologic and cardiac toxicity thanbupivacaine. Ropivacainemay offer advantages when used for thoracic paravertebral block. This study was designed to describe thepharmacokinetics of ropivacaine after thoracic paravertebral block. METHODS:: Twenty female patients undergoing electiveunilateral breast surgery were randomly assigned to receive a single bolus thoracic paravertebral injection of 2 mg/kg ropivacaine,

with or without 5 mug/ml epinephrine. Simultaneous arterial and venous blood samples were obtained for plasma ropivacaine assay.Data were analyzed with NONMEM, using two possible absorptionmodels: conventional first-order absorption and absorption

following the inverse gaussian density function. RESULTS::Epinephrine reduced the peakplasma concentrations and delayed thetime ofpeak concentration of ropivacaine in both the arterial and venous blood. The time course of drug input into the systemiccirculation was best described by two inverse gaussian density functions. The median bioavailability of the rapid component wasapproximately 20% higher when epinephrine was not used. Themean absorption times were 7.8 min for the rapid absorptionphaseand 697 min for the slow absorption phase, with wide dispersion of the absorption function for the acute phase. The half-time of

arterial-venous equilibration was 1.5 min. CONCLUSION:: The absorption of ropivacaine after thoracicparavertebral block is described by rapid and slow absorption phases. The rapid phaseapproximates the speed of intravenous administration and accounts for nearly half of ropivacaine

absorption. The addition of 5 mug/ml epinephrine to ropivacaine significantly delays its systemicabsorption and reduces the peakplasma concentration.

Anesthesiology. 2005 Oct;103(4):704-711. Karmakar *.

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Ropivacainey

Bupivacaine, levobupivacaine andropivacaine: are they clinically different?Evaluating randomised, controlled trials that have compared thesethree local anaesthetics, this chapter supports the evidence thatboth levobupivacaine and ropivacaine have a clinical profile similarto that of racemic bupivacaine, and that the minimal differences

observed between the three agents are mainly related to theslightly different anaesthetic potency, with racemic

bupivacaine>levobupivacaine>ropivacaine. However, thereduced toxic potential of the two pure left-isomerssupports their use in those clinical situations in whichthe risk of systemic toxicity related to either overdosing

or unwanted intravascular injection is high, such asduring epidural or peripheral nerve blocks

Best Pract Res Clin Anaesthesiol. 2005 Jun;19(2):247Best Pract Res Clin Anaesthesiol. 2005 Jun;19(2):247--68.68.Casati.

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Levobupivacaine

The central nervous system and cardiovascular effects ofThe central nervous system and cardiovascular effects oflevobupivacaine and ropivacaine in healthy volunteers.levobupivacaine and ropivacaine in healthy volunteers.

We compared the central nervous system (CNS) and cardiovascular effects ofWe compared the central nervous system (CNS) and cardiovascular effects oflevobupivacaine and ropivacaine when given IVto healthymale volunteers (n =levobupivacaine and ropivacaine when given IVto healthymale volunteers (n =14) in a double14) in a double--blinded, randomized, crossover trial. Subjects receivedblinded, randomized, crossover trial. Subjects received

levobupivacaine 0.5% or ropivacaine 0.5% after a test infusion with lidocaine tolevobupivacaine 0.5% or ropivacaine 0.5% after a test infusion with lidocaine tobecome familiar with the early signs of CNS effects.become familiar with the early signs of CNS effects. IMPLICATIONS:IMPLICATIONS:This study compared directly, for the first time, the toxicityThis study compared directly, for the first time, the toxicityof levobupivacaine and ropivacaine in healthy volunteers.of levobupivacaine and ropivacaine in healthy volunteers.Levobupivacaine and ropivacaine produced similar centralLevobupivacaine and ropivacaine produced similar central

nervous system and cardiovascular effects when infused IVnervous system and cardiovascular effects when infused IVat equal concentrations, milligram doses, and infusionat equal concentrations, milligram doses, and infusionrates.rates.

Anesth Analg. 2003 Aug;97(2):412Anesth Analg. 2003 Aug;97(2):412--6,6,StewartStewart

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Chirality

local tics

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