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Local Anesthetics

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Local Anesthetics

Kevin Armstrong MD Department and Anesthesia and Perioperative Medicine  November 2007

 

Important points 

History  Some differences 

How they work Test dose  Onset   Adjunvants 

Lipid rescue Newer delivery systems  Tumescence  

 

History of Local Anesthetics 

Cocaine isolated 1856



1884 cocaine used in occular surgery



1880¶s Regional anesthesia plexus



1898 cocaine used in spinal anesthesia



1905 1st synthetic LA (procaine) introduced



1943 lidocaine synthesized



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

 

Differences

in structure of local

anesthetics Esters versus Amides

1) Af Affe fect ct met etab abol olis ism m 2) Affect tox oxiicity 3) Al Alle lerrgi gicc po pote tent ntia iall

 

Types of Local Anesthetics

 

Types of Local Anesthetics Esters

Procaine chloroprocaine tetracaine cocaine

 

Types of Local Anesthetics

AmidesLidocaine  prilocaine mepivacaine  bupivacaine ropivacaine

 

sitemaker.med.umich.edu

 

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 repolarization Voltage gated Na and Ca channels ch annels in DRG are similar 

 

Ty

 

Mechanism of Action for Local Anesthetics

Domain 4 S4 subunit

 

FIGURE

1. Model of the fourth ho mologous domain (D4) of the human skeletal muscle sodium  channel (hNaV1.4) with the S4 seg ment depicted as a rotating cylinder 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 odel.. A depolarizing rotation transfers R2 and R3 from an intracellularly to an extracellularly accessible accessibl e crevice, whereas Leu1452 and  Ala1453 are translocated in the o pposite direction. Coupled Movements in Voltage-gated Ion Channels Richard Horn Journal of General Physiology, Volume 120, Number 4, October 2002 449-453

 

Tetrododoxin 

Toxin from puffer fish



Blocks the Na channel  ± Used in research  ± Bl Bloc Blocks ocks ks fr fro o m the outer side of cell

 

Local Anesthetics 

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

 

Local Anesthetics  Diffusibility

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

 

Local Anesthetics 

Protein binding is related to the duration of  action. The site of action (the Na channel) is

p rimarilyaffinity proteinwill in a lipidaffect environ ment. of  Binding thus duration action.  Protein binding also plays a part in the availability of the drug as LA binds to lipoproteins in the blood stream.   And transfer to fetuses

 

Summary 

Clinical Pharmacology  The potency of Local Anesthetics, their onset and duration of action are primary deter mined by physicochemical properties of various agents and their inherent vasodilator activity of sa me local anesthetics. Li solubility thewater primary deter m inant of anesthetic potency and it is exppid ressed as liis pid: Partition Coefficient  Protein binding influences the duration of action  pKa of Local anesthetics deter mines the onset of action  The addition of vasoconstrictors, such as e pinephrine or phenylephrine can prolong duration of action of local anesthetics, decrease their  

absor ption (and the peak plasma level) and enhance the blockade.

 

From

NYSORA web site

Properties of Local Anesthetic Agents PROPERTIES

AMINOESTERS

AMINOAMIDES

rapid by plasma cholinesterase

slow, hepatic

Systemic toxicity

less likely

more likely

Allergic reaction

possible - PA P ABA derivatives form

very rare

breaks do down in in a am mpules (h (heat,sun)

very st stable c ch hemically

slow as a general rule

moderate to fast

higher th than PH PH = 7.4 ((8 8.5-8.9)

close to PH PH = 7 7..4 ((7 7.6-8.1)

Metabolism

Stability in solution

Onset of action

pKa's

 

pKa 

Understanding LA LA as they relate to pKa

 



The pH of the tissue and pKa of the agent  pKtissue The a are deter  the mm ost imp ortant pH The p H and of the ines the ratiofactors. of  ionized to nonnon-ionized -ionized drug. This ratio, in turn, depends on the pKa of the drug. Understanding

the ionization is necessary to understanding the drug's phar macological characteristics, such as onset, duration and phar macodynamics.

 

Henderson Hasselbalch equation 



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

 

Effect of pH, and pKa 

   

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 state (a charged base). For example, lidocaine has a pKa mines of The above for  deter  that at hysiologic pH,7.9. lidocaine exists inmaulat ratio of 3:1 ionized to pnonnon -ionized: -ionized: 7.9 - 7.4=log 7.4=log [ion [ionized [ionized/nonized/non /non-ionized] -ionized] 0.5 =log [ionized/non [ionized/non--ionized] -ionized] 100.5=ionized/non--ionized 100.5=ionized/non -ionized 3ionized~ 1non--ionized 1non -ionized

 

Low pH 

The pH of the tissue becomes relevant in conditions of  infection or inflammation, in which the natural pH may be more acidic. This acidity results in a greater  proportion of  the ionized (charged) for m of the anaesthetic, thereby delaying 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:  7.9 - 4.9 = lo log g [ioniz [io [ionized/nonnized ed/no /non n-ionized] -ionized]  103 = ionized/nonionized/non-ionized -ionized The resulting ratio of 1,000:1 ionized to nonnon -ionized -ionized indicates a poorer  penetration into the nerve tissue and therefore a less effective nerve block

 

Onset 

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

 

Onset from NYSORA web site AGENT

Pot.

Onset

pKa

%PB

P. coef

Procaine 0.5-1% (Novocain)

1

Rap

8.9

5.8

0.02

Chloroprocaine

4

Rap

8.7

?

0.14

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

8.1

94

2.9

2-3% (Nesacain)

Tetracaine 0.1-0.5% (Pontocai (Pontocain) n)

Mod

 

 

Onset  Does 

onset influence you practice?

Where?  ± OB  ± OB  ± RA  ± RA  ± Chronic Chro Ch ron nic pain

 

Onset

of Action

Onset

y y

y y

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;

 

Onset A comparison of warmed Bupivacaine and lidocaine forepidural top up for C/S BJA 1994 72 221-3 2 21-3 Warming improved onset for lidocaine lid ocaine to pin prick  Test dose dos e lidocaine and epinephrine epin ephrine time 0 Inadequate anesthesia bupiv x2, warmed B 1 and warmed L x 2 Bupiv0.5%

Lidocaine 2% n=28, 20oC

Bupiv

0.5% 38oC n=29

Lido 38oC  N=27

(n=27) 20oC

Onset to T6

29.9 (7.1)

27.0 (6.9)

29.8 (6.7)

24.4 (7.6)**

Pt ready for Sx

0

0

0

8

Volume

23.9

22.6

22.4

21.1

Use of  entonox/opioid

10

11

14

8

15 min

** p<0.05 to all other groups

 

Onset  

 

 

 

Studies looking at bupiv vs lidocaine ClarkV, McGradyE, SugdenC, DicksonJ, McLeodG. Speed of onset of sensory block for elective extradural Caesarean section: choice of agent and temperature of injectate. British Journal of Anasthesia Anas thesia 1994; 72: 221 3. 2 NortonAC, DavisAG, SpicerRj. Lignocaine 2% with adrenaline for epidural Caesarean section: a comparison with 0.5% bupivacaine. Anasthesia 1988; 43: 844 9. 3 ReidJA&ThorburnJ. Extradural bupivacaine or lignocaine for elective Caesarean section: the role of maternal posture. British Journal of Anasthesia 1988; 61: 149 53. 4 PaechMj. Epidural anasthesia for Caesarean section: a co mparison of 0.5% bupivacaine and 2% lignocaine both with adrenaline. Anasthesia and Intensive Care 1988; 16: 187 96

 

    

low-dose -dose Extending low-

epidural analgesia for emergency Caesarean section A section A comparison of three solutions 1173 ±1177 1177 D. N. Lucas, Anaesthesia, 1999, 54, pages 1173± Summary We conducted a prospective doubledouble-blind -blind randomised trial to compare bupivacaine 0.5%; a 50 : 50 mixture of bupivacaine 0.5%/lignocaine 2% with 1 : 200 000 adrenaline (final concentration); and lignocaine 2% with 1 : 200 000 adrenaline for converting a lowlow-dose -dose labour epidural into a block adequate for emergency Caesarean section. Ninety patients were studied, 30 in each group. There was no difference between the Onset groupstim in ethe timunaffected e taken forby bilateral loss cold sensation to reach T4. was the existing exis tingofsensory level prere-Caesarean -Caesarean section top-u -up;

 

Onset 

Duration



B



(n¼30)

of epidural; h

BL

(n¼30)

L (n¼30)

12.6 (6.2)

1.4 (5.6)

11.8 (5.3)



No. of lowlow-dose -dose top-u -ups dose of bupiv labour;mg

7.4 (5) 92.0 (57)

7.2 (4.1) 92.3 (49)

7.9 (4.8) 95.2 (48)



Time since l top-u -up; min

92.3 (45.1)

75.1 (33.2)

69.3 (40.9)



Sensory level pre top-u -up



Time to T4; min

 

T10 T 10 14 (11± (11  ±19.3 19.3 [6 [6±   25]

Maximum height of block

T3

T10 T 10

T10

12

10

±25] (8.8±  ±17 17 [6 [6±   38]) (8.8 ±38]) (9±  ±18.5 18.5(9[6 [6±  ±36]) 36])

T3

T3

 

What¶s Available from NYSORA web site

Ro ivacaineand is a plong-acting, amide-ty em local anesthetic. Its p structure har macokinetics arepsi ilar to those of  bupivacaine, however, ropivacaine exhibits significantly better cardiotoxicity profile compared to bupivacaine. Duration of action for ropivacaine ranges 2.5-5.9 hours for  epidural block to 8-13 hours for peripheral nerve block. Ro pivacaine also less id solubleSo and the liver  more rapisidly than bulippivacaine. mecleared studiesvia have shown less motor blocking effects of ropivacaine than that

to its better safety profile and significantly better sensory-motor  of bupivacaine. Due

differentiation, Ropivacaine is currently long-acting anesthetic of choice in our  the practice.

 

From

NYSORA web site

Mepivacaine is a local anesthetic anestheti c of the amide type with an inter mediate duration of  action. Mepivacaine is used for infiltration inf iltration and transtracheal anesthesia, and peripheral, sympathetic, regional (Bier block), and e pidural nerve blocks. Compared with lidocaine, mepivacaine produces less vasodilatation and has a action. In our practice, this is the #1 more rapid onset and longer duration of action. inter mediate-acting local anesthetic to use for peripheral nerve blocks.

 

Duration

of Local anesthetics

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

 

Duration

of Local anesthetics

Examples

local infiltration minor nerve block major nerve block E pidural addition of epi

Lidocaine 30-60 min 6 0- 12 0 1 20- 2 40 3 0- 90 improved

bupivacaine 120-240 1 80- 3 60 3 60- 7 20 1 80- 3 00 improved

 

From

NYSORA web site

cal Anesthetic Time Line (minutes)

Infiltra Infi ltration tion plain plain s sol'n ol'n With Epine Epinephrin phrine e

Spina Spinall plai plain nW With ith Epine Epinephrin phrine e

30-45 45-60

hloroprocaine

idocaine

60-120 90-180

Hyperbaric 60 60-90

80-120 120-180 90-140 140-200

epivacaine Hyperbaric 120-180 180-400

etracaine

140-200 160-220

opivacaine

upivacaine

Epidural Epidural plai plain ns sol'n ol'n With Epine Epinephrin phrin

180-360 300-480

Hyperbaric 120-360 120-360

180-360 120-240

 

Intravenous Lidocaine in Chronic

Pain 

Tetrodotoxin TTX



Some Na channels resistant to TTX



These may be important in Chronic pain



With Chronic pain probably up/down regulation receptor types



IV lidocaine may work at these recptors

 

Intravenous lidocaine in Chronic pain

Systemic administration of local anesthetic agents to relieve neuropathic pain.

 AUTHORS' CONCLUSIONS: Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if  statistically significant pain relief is clinically meaningful 

Cochrane Database Syst Rev. 2005 Oct 19;(4):Challapalli 19;(4):Challapalli V V,,

 

Intravenous Lidocaine 

Intra--Op Lidocaine and Ketamine Effect on Postoperative Bowel Intra Function  This study is currently recruiting patients. Verified by University of Saskatchewan September 2005  Purpose 

Bowel function after bowel surgery is delayed ( postoperative ileus)by both opiates and the surgery itself. We W e hypothesized that decreasing opiate use by other analgesics will speed the return of bowel function after surgery. Lidocaine and Ketamine are drugs that appear to be synergistic and do not slow peristalsis. This study is a Randomised Controlled Trial of  Infusion Plus Ketamine Injection versus Placebo Lidocaine to to deter mine whether they will decrease o piate use and then whether decreased opiate use will speed the return of  bowel function.

 

Intravenous Lidocaine 

patients undergoing radical retropubic prostatectomy were studied with one half of the patients receiving a lidocaine

Forty

bolus (1.5 mg/kg) and infusion (3 mg/min); the other  half received a saline infusion. LidocaineLidocaine-treated -treated patients first experienced flatulence in a significantly shorter time (P <  0.01) than control patients. Lidocaine patients' hospital stay was also significantly shorter (P < 0.05);. IV lidocaine initiated before anesthesia and continued 1 h postoperatively significantly sped up the return of bowel function. Lidocaine patients were also more comfortable postoperatively  Lidocaine blood levels were variable (1.3(1.3-3.7 -3.7 micro g/mL), but none approached a toxic level (>5 micro g/mL). 

Lidocaine---treated Lidocaine treated patients had shorter hospital stays, less pain, and faster return of bowel function. In this population, lidocaine infusion can be a useful adjunct in anesthetic management.

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

IV Local Anesthetics  Effect

of ciprofloxin on the pharmacokinetics of intravenous lidocaine. 

BACKGROUND AND OBJECTIVE: Recent studies have suggested that cytochrome PP-450 -450 isoenzyme 1A2 has an important role in lidocaine biotransfor mation. We W e have studied studied the effect of a cytochrome PP-450 -450 1A2 inhibitor, ciprofloxacin, on the phar macokinetics of lidocaine  ). CONCLUSION: The plasma decay of intravenously ministered ad is modestly delayed by mitantlylidocaine conco administered ciprofloxacin.

Ci rofloxacin ma increase the s stemic to toxicit of   

Safety Issues Related to Local  Anesthetics

 

Safety Issues Related to Local  Anesthetics Related to 1) D r u g 2) Dose 3) Si Site te of ad admi mini nist stra rati tion on 4) Co Cond ndit itio ion n of th thee pat patie ient nt

 

CNS Toxicity Tends to occur occ ur 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 twitching Convulsions COMA Respiratory arrest CVS depression

 

CVS Toxicity Alteration in the excitatory mechanism slower depolarization decreased HR   prolonged PR interval widened QRS Arrythmias  bradycardia ectopic beats ventricular fibrillation Decreased cardiac output on the basis of  HR  contractility

 

Treatment of Toxicity

 

Treatment of Toxicity Identify the problem signs and symptoms temporal IVrelationship injection 40-60 min post for peak plasma levels CNS treatment with benzodiazepines

 

Treatment of Toxicity CVS signs and symptoms CNS effects CVS effects arrythmia QRS change signs of collapse fall in BP With CVS toxicity The agent is an important consideration

 

Treatment of Toxicity When there is CVS collapse A B C¶ C¶ssACLS defibrillation E pinephrine Vasopressin Lidocaine? Bretylium? Amiodarone

 

Lipid Rescue 

Relatively new concept

 

Nanoparticles Scavenging Nanoparticles: An Emerging Treatment for Local Anesthetic Toxicity id-based -based studies speculated that four mechanisms  The authors of the lipidmay play a role in the success of resuscitation. In their primary

hypothesis, the lipid infusion may create plasma lipid droplets capable of segregating uncharged bupivacaine molecules from plasma, which makes them unavailable un available for  interaction at their target sites. The authors supported this theory by showing that bupivacaine molecules preferentially segregated from  plasma to their lipid infusion in a 1:12 ratio. 29 In two of the other  proposed mechanisms, the lipid acts within tissue. Here, li pid or its component fatty acids either interact in a clinically significant signific ant way with tissue bupivacaine molecules or directly overcome bupivacaine¶s inhibitory effect on cellular metabolism by supplying substrate for  cellular energy production.30,31 [ 30 30,, 31 31]] Finally, the lipid infusion may act on nitric oxide pathways and reverse bupivacaine¶s inhibitory effects. 29 Building on this work and assuming that sequestration of  bupivacaine is an important aspect of resuscitation in the aforementioned lipidid-based -based studies, some investigators have hypothesized even greater segregation of bupivacaine into lipid may occur with large reductions in particle size to the dimension of the

nanometer.  

,

Regional Anesthesia andPMJuly andPMJuly - Ma May, y, 2005 200 2005 5 pp: 380 380---384 384 Renehan

 

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

 

Toxicty Reported adverse event cases of methemoglobinemia associated with benzocaine products . Em ail The researchers identified 198 cases that described unique adverse events linked to the use of benzocaine. Of these, 132 cases (66.7%) were either definitely or probably episodes of MHb. Spray products containing 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 of MHb, there were 107 episodes that were considered serious and two deaths. In neither case that resulted in death was benzocaine considered the principle suspect cause.

 

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 Anesthesial aliidocaine dilute liposuction dose 35-55mg/Kg Peak levels 8-12h later 

ep i

 

Special preparations

www.aaf .or   

Topical Local anesthetics 

Tetracaine, Adrenaline (Epinephrine), and Cocaine  Tetracaine, adrenaline, and cocaine (TAC), a compound of 0.5 percent tetracaine (Pontocaine), 0.05 percent epinephrine, and 11.8 percent cocaine, was the first topical anesthetic mixture found to be effective for nonmucosal skin lacerations to the face and scalp.2 From 2 to 5 mL of solution is applied directly to the wound using a cottoncotton-ti -tipped 2,3 3 applicator with fir m pressure that is maintained for 20 to 40 minutes.2,

However, the use of TAC is no longer supported by the literature because of general concern about toxicity and expense, and federal regulatory issues involving medications containing cocaine. 

Principles of Office Anesthesia: Part II. Topical Anesthesia



SURITI KUNDU, M.D.,

 

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

Eutectic mixtures are liquids and melt at lower  temperatures than any of their components, per mitting higher concentrations of  anesthetics. Eutectic mixture of local anesthetics (EMLA) represents the first major breakthrough for  der mal anesthesia on intact skin. It consists of 25 mg per mL of lidocaine, 25 mg per mL of prilocaine, a thickener, an emulsifier, and distilled water adjusted to a pH level of 9.4.3 eu-- + tEktos tEkto tEk tos s  Etymology: Greek eutEktos easily melted, from eu melted, from tEkein to melt -- more at THAW 1 of an alloy or  solution : having the lowest melting point possible 2

: of or relating freezing point to a eutectic alloy or solution or its melting or 

 ±

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

 

Iontophoresis 

Iontophoresis is a method of delivering a topical anesthetic with a mild electric current. LidocaineLidocainesoaked sponges are applied to intact skin, and electrodes are placed on top of the anesthetic. A DC current is then applied to the skin (F igu igur e 2). The

anesthetic effect occurs within 10 minutes and lasts approximately 15 minutes. The depth of anesthesia can reach up to 1 to 2 c m.12   Although the effectiveness of ionto phoresis has been compared favorably to that of EMLA, it remains underused. Some patients find the mild electrical sensation uncomfortable. The apparatus is expensive and bulky, and cannot be used over large surface areas of the body.8 Other applications using iontophoresis are still being developed.  ±

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

 

Iontophoresis

 

Iontophoresis 

Comparison of EMLA and lidocaine iontophoresis for cannulation analgesia.

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

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

 

Liposomes Liposomes are comprised of lipid layers surrounded by aqueous layers. They are able to penetrate the stratum corneum because they resemble the lipid bilayers of the cell  A liposomal delivery system recently became m embrane. available as an overover -the -thethe-counter  -counter product called ELAELA-Max. -Max. It contains 4 percent lidocaine cream in a liposomal matrix and is FD A A-a -approved for the temporary relief of pain resulting from  minor cuts and abrasions. ELAELA-Max -Max is applied to intact skin for  15--17 -17 In limited studies, ELA15 to 40 minutes without occlusion.15 ELAMax has also proved effective in providing der mal analgesia before chemical peeling.18 The safety of its application to mucous membranes has not been evaluated.5 Despite a paucity of data and lack of an FD A indication, clinicians are be ginning to use ELAELA-Max -Max for topical anesthesia before other  der matologic procedures.

 

Liposome

www.bioteach.ubc.ca

 

Liposomal Bupivacaine A Novel Liposomal Bupivacaine Formulation to Produce UltralongUltralong-Acting -Acting Analgesia  Conclusions: This novel liposomal for mulation had a favorable drugdrug-to -to to--phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dosedose-de -dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this for mulation has the potential to significantly impact the management of pain.   Anesthesiology: Volu me

101(1) July 2004 pp 133133-137 -137 Grant,

 

Liposomal Bupivacaine 

The median duration of analgesia with 0.5% standard bupivacaine was 1 h. The median durations of analgesia

after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, res pectively. 

 Although the data presented with this novel LMVV for mulation are very encouraging because we found that LMVV bu pivacaine was well tolerated and that it significantly prolonged the duration of analgesia compared to standard bupivacaine, there are a nu mber of issues that must be resolved before the

Stability of the for mulation during prolonged storage, batch batch--to -toto-batch -batch variability in physicochemical characteristics, and for mulation can be introduced for clinical use .

adaptability of the method for upscaling for large batch sizes remain to be deter mined. The primary objective of  the current study was to establish proof of concept regarding the efficacy of  LMVV bupivacaine in humans. The dose of LMVV bupivacaine administered in this study was low² low²only ²only 17.5 mg. Before the efficacy of  LMVV bupivacaine in various painful conditions can be evaluated, a study to deter mine its maximum tolerated dose in humans is necessary.

 

Liposomes  

Liposomal Drug Delivery for Postoperative Pain Management Translational vignette  Although the plasma concentration versus time curve is flatter for the extended--release extended -release for mulation, overall bioavailability is si milar.

 Although the exact mechanism of  of in in vivo drug release

from MVL particles is not known, it is believed to be the result of a gradual erosion or reorganization of  the lipid membranes 

Summary and Conclusions



Liposomes are effective drug delivery syste ms to improve the therapeutic efficacy of drugs by increasing drug circulation times, facilitating targeting of drugs, and enhancing stability without compromising safety or tolerability. ExtendedExtended-release -release MVL preparation has proved to be an effective drug delivery vehicle for mor phine sulfate; extendedextended-release -release MVL mor phine sulfate exhibits an extended duration of pain relief for up to 48 posto perativelytowithout compro mising safety or  hours tolerability, according initial clinical studies.



Regional Anesthesia and PM PM Sept - Ma May May, y, 20 2005 05 pp: 491491--496 496 Eugene

 

Encapsulation 

of mepivacaine

Encapsulation

of mepivacaine prolongs the analgesia provided by sciatic nerve blockade in mice.

PURPOSE: Liposomal for mulations of local anesthetics (LA) are able to control drugdrug-delivery -delivery in biological systems, prolonging their anesthetic effect. This study ai med to prepare, characterize and evaluate in vivo drugdrug-delivery -delivery systems, composed of large unilamellar liposomes (LUV), for bupivacaine (BVC) and mepivacaine (MVC). 

CONCLUSION: MVC(LUV) provided a LA effect prothera posepeutic compdelivery arable toasthat BVC. We MVC(L V) drug a pof otentially new opUtion for the treatment of acute pain since the for mulation enhances the duration of sensory blockade at lower  concentrations concentratio ns than those of plain MVC.  ± Ca Can n J Ana A Anaesth. naes esth th.. 200 2 2004 004 4 Ju Jun Junn -Jul;51(6):566 -Jul;51(6):566Jul;51(6):566--72. 72. de Araujo

 

U ses of Local Anesthetics Topical 

Local Minorinfiltration peripheral

nerve blockade Major peripheral nerve blockade  Neuraxial blockade Tumescent anesthesia a nesthesia Chronic pain

 





IV Lo al anestheti  s Perioperative Intravenous Lidocaine Has Preventive Effects on Postoperative Pain and Morphine Consumption After Major Abdominal Surgery  ± IMPLICATIONS: The perioperative administration of systemic small--dose small -dose lidocaine lidocaine reduces pain during surgery su rgery associated associated with the development development of pronounced pronoun ced central central hyperalgesia, hyperalgesia, presumably by affecting affecting mechanoinsensitive nociceptors, because these these have been linked to the induction induction of central central sensitization sensit ization and were shown to be particularly particularly particularly sensitive sensitive to small--dose small -dose lidocaine 

lidocaine 2% (bolus injection of 1.5 mg/kg in 10 min followed followe d by -1), an IV infusion infusion of 1.5 mg · kg--11 · h-1

  Anesth

Analg 2004;98:10502004;98:1050-1055 -1055 Koppert

 

Tumescent Anesthesia 

Plasma lidocaine levels levels and risks after liposuction with tumescent anaesthesia. Background: It is common today to use tumescent anaesthesia with large doses of lidocaine for li posuction. The pur pose of the present study was to evaluate lidocaine plasma levels and objective and subjective symptoms during 20 h after tumescent anaesthesia with approximately 35 mg per kg bodyweight of lidocaine for abdominal liposuction Methods: Three litres of buffered buff ered solution of 0.08% lidocaine with epinephrine   Results: Lidocaine 33.2 +/+/- 1.8 1.8 mg/kg was given at a rate of 116 +/+/ - 11 ml/min Peak plasma levels (2.3 +/ +/-- 0.63 0.63 microg/ml) of lidocaine occurred after 5 5--17 -17 h



Conclusion: Doses of lidocaine up to 35 mg/kg were sufficient fo abdominal liposuction using the tumescent technique and gave fluid overload or toxic symptoms in eight patients, but with this dose there is still a risk of subjective symptoms in association with the peak level of  lidocaine that may appear after discharge. 

 Acta Anaesthesiol Scand. 2005 Nov;49(10):1487Nov;49(10):1487-90. -90.

Nordstrom

 

Tumescent Anesthesia  Deaths

Related to Liposuction  C on onc lusions lusions Tumescent liposuction can be fatal, perhaps in part because of lidocaine toxicity or  lidocainelidocaine --related related drug interactions. 

In tumescent liposuction, reported doses of lidocaine range from 10 to 88 mg per kilogram,8 several times higher than the maximal recommended dose of 4.5 mg per kilogram (or  up to 7 mg per kilogram with epinephrine) typically used for  21,,22 The 1991 guidelines of the subcutane subcu subcutaneous taneous ous infi infiltra infiltration. ltration tion..21  American Academy of Der matologists for tumescent liposuction suggested a maximal dose dose of of 35 35 mg of  lidocaine per kilogram,23 whi which ch was increased increased increase d to ³at least least 55 mg per kilogram´ in 1997



NEJM V340:1471V340:1471--1475 1475 R ama ama

 

Myotoxicity The long term myotoxic effects of bupivacaine and ropivacaine after  continuous 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, W,

 

CVS Toxicity Cardiovascular collapse on the basis of  malignant rhythm decreased contractility vascular dilation

 

Newer Local anesthetics Direct

cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep. In previous preclinical studies we found that central nervous syste m  (CNS) excitoexcito-toxicity -toxicity reversed the cardiac depressant effects

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

The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain

the differences between the drugs found with intravenous dosage dos age Br J Phar macol. 2001 Feb 132 3 :649--58. 58. Chan

DH

 

 

Limitations of Local Anesthetics Amount and complexity of the work to be done Patient Area to be anesthetized Duration of procedure Immobility

 

New and not not--so -so new D

evelo pments in Local  Anesthetics Toxicity Duration Ropivacaine Levobupivacaine

liposomal encapsulated local anesthetics surface, charge, size & lamella structure

 

Ropivacaine depts.washington.edu/anesth/ regional/ropivacaine regional/ropivacaine ropivacainetext.ht text.html



Pharmacokinetic parameter p arameters s Ropivacaine is 22-3 -3 times less lipid soluble and has a smaller volume of distribution, greater clearance, and shorter elimination half--life half  -life than bupivacaine in humans.3 The two drugs have a similar pKa and plasma protein binding

 

Ropivacaine depts.washington.edu/anesth/ regional/ropivacaine regional/ropivacaine ropivacainetext.ht text.html



Ropivacaine is slightly less potent than bupivacaine. When used for spinal anesthesia, produces ropivacaine less intense0.75% sensory and motor block than 0.5% bupivacaine.5 However, multiple clinical trials comparing the two local anesthetics anesthet ics in epidural and axillary block demonstrate similar potency of bupivacaine and ropivacaine with respect to the intensity of sensory anesthesia.

 

Ropivacaine depts.washington.edu/anesth/ regional/ropivacaine regional/ropivacaine ropivacainetext.ht text.html

 Epinephrine

does not prolong the duration of  ropivacaine block.

The addition of epinephrine does not prolong the duration of ropivacaine in subclavian brachial 17,,18 or epidural19 block. Low concentrations plexus17 of ropivaciane may produce clinically significant vasoconstriction, which is not increased further by vasoconstriction, the addition of epinephrine.

 

Ropivacaine depts.washington.edu/anesth/ regional/ropivacaine regional/ropivacaine ropivacainetext.ht text.html



Ropivacaine is indistinguishable from bupivacaine when used in obstetric .

anesthesia When continuous infusions of 0.25% ropivacaine were compared with 0.25% bupivacaine in lumbar  epidural labor analgesia in two randomized double--blind double -blind clinical trials, no difference was detected in between the two drugs in intensity, duration or incidence of motor block, onset and quality of sensory analgesia, number of  instrumented deliveries, number of C C--sections, -sections, or  11,,12 11

neonatal neurobehavioral scores at 24 hours. Neonates in the ropivacaine group had higher   



Conclusions Ropivacaine is slightly less potent than pivacaine, bu but msurgical ultiple studies showwhen that itused can provide adequate anesthesia in similar concentrations. concentrations. Ro R opivacaine is half as potent as bupivacaine in its direct negative inotropic effect and slowing of ventricular  conduction. A potential for sudden ventricular  arrhythmias still exists with systemic ropivacaine toxicity. Any slight advantage ropivacaine has over  bupivacaine may be eliminated if higher 

concentrations concentratio ns of ropivacaine are used.  

Ropivacaine

 

Ropivacaine Arterial and Venous Arterial Venous Pharmacokinetics of Ropivacaine with and without Block.

Epinephrine after Thoracic

Related Articles, Links

Paraverte Paravertebral bral

BACKGROUND:: Animal and volunteer studies indicate that ro pivacaine is associated with less neurologic and cardiac toxicity than bupivacaine. Ropivacaine may offer advantages when used for thoracic paravertebral block. This study was was designed to describe the phar macokinetics of ropivacaine after thoracic paravertebral block. METHODS:: Twenty Twenty ffe emale patients undergoing elective unilateral 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 absor ption models: conventional first-order absor ption and absor ption following the inverse gaussian density function. RESULTS:: Epinephrine reduced the peak plasma concentrations and delayed the time of peak concentration of ropivacaine in both the arterial and venous blood. The time course of drug input into the systemic circulation was best described by two inverse gaussian density functions. The median bioavailability of the rapid component was approximately 20% higher when epinephrine was not used. The mean absor ption times were 7.8 min for the rapid absor ption phase and 697 min for the slow absor ption phase, with wide dispersion of the absor ption function for the acute phase. The half-time of  arterial-venous equilibration was 1.5 min. CONCLUSION::

The absor ption of ropivacaine after thoracic

paravertebral block is described by ra pid and slow absor ption phases. The rapid phase approximates the speed of intravenous administration and accounts for nearly half of ro pivacaine absor ption. The addition of 5 mug/ml epinephrine to ropivacaine significantly signifi cantly delays its systemic absor ption and reduces the peak plasma concentration.  Anesthesiology.. 2005 Oct;103(4):704-71  Anesthesiology Oct;103(4): 704-711. 1. Karmakar *.

 

Ropivacaine 

Bupivacaine,

levobupivacaine and ropivacaine: are they clinically different? Evaluating randomised, controlled trials that have compared these three local anaesthetics, this chapter supports the evidence that both levobupivacaine and ropivacaine have a clinical profile similar to that of racemic bupivacaine, and that the minimal differences observed between the three agents are mainly related to the slightly different diff erent anaesthetic potency, with racemic bupivacaine>levobupivacaine>ropivacaine. However, the

reduced toxic potential of the two pure leftleft-iso -isomers supports their use in those clinical c linical situations in which the risk of systemic toxicity related to either overdosing or unwanted unwanted intravascular injection is high, such as during epidural or peripheral nerve blocks

Best Pract Res Clin Anaesthesiol. 2005 Jun;19(2):247 68. Casati Casati..  

Levobupivacaine The central nervous system and cardiovascular effects of  levobupivacaine and ropivacaine in healthy volunteers. We compared the central nervous system (CNS) and cardiovascular effects eff ects of  levobupivacaine and ropivacaine when given IV to healthy male volunteers (n = 14) in a doubledouble--blinded, blinded, randomized, crossover trial. Subjects received levobupivacaine 0.5% or ropivacaine 0.5% after a test infusion inf usion with lidocaine to become familiar with the early signs of CNS effects. IMPLICATIONS:

This study compared directly, for the first time, the toxicity pivacaine pivacaineproduced of levobu and in healthy volunteers. pivacaine pivacaine Levobu and roro sim ilar central nervous system and cardiovascular effects when infused IV at equal concentration concentrations, s, milligram doses, and infusion rates. 

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

 

Chirality

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