aguirre5local_anesthetics.docx

8/11/2019 Aguirre5Local_anesthetics.docx

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Local anestheticsJames E. Hea vner

Introduction

Local anesthetics are widely used to prevent or treatacu te pain; to treat inflammatory, cancer related, andchroni c pain; and for diagnostic and prognostic

purposes. Dr ugs classified as local anesthetics reversibly bloc act ion potential propagation in a!ons by preventingthe sod ium entry that produces the potentials "#$. %ther actions of these drugs, however, such as anti&inflammatoryactions by interaction with '&protein receptors "($, arealso thought to be relevant to their use to prevent or treat pain. )ot h nociceptive and neuropathic pain aretargeted by thi s group of drugs. *ny part of thenervous system, from the periphery to the brain, may bewhere local ane sth et ics act to produce a desiredanesthetic or analgesic effect. * variety of formulationsof local anesthetics, routes of administration, andmethods of administration are used. +he drugs areformulated commercially or by med ical personnelaccording to intended route of adm inistr ati on or toaddress specific concerns or needs. In this article I

provide a concise review of the pharmacology of localanesthetics with an emphasis on current con cepts .

urr %pin *naesthesiol (- //0 1 /2(. (--3 Lippincott 4illiams 5 4il ins.

Department of *nesthesiology and 6hysiology, +e!as +echnology 7niversityHealth 8ciences enter, Lubboc , +e!as , 78*

orrespondence to JE Heavne r, D9:, 6hD, *nesthesiology, /0-# 2th 8treet,++7H8 , Lubboc , + 3-0 32/ (-0 32/ #?##; e&mail. @ames .heavnerAttuh sc.edu

,urrent %pinion in *naesthesiolog y (--3, (- / /0 1 /2(

(--3 Lippincott 4illiams 5 4il ins-


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Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


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//> Drugs in anaesthes ia

igure 2 esults of structure alterations amide lin ed igure 0 ,linical forms of ropivac aine

H /

H /

I %

H &

H /

H /

%

H & & H

/ H 3

:epivacaineIopivacaine )upivacaine 8&ropivacaine

O H / / H0 2 H < H / %

H & &H

/ H 3

+he aminoamide&lin ed local local anesthetics mepivacaine, ropivacaine,and bupivacaine vary only by substitution at on the basic molecule. *sthe number of carbon atoms increases at , potency, lipid solubility, and

protein binding increase. *dapted from "2$.

H /

I &rop iva caine

state is favored. %ver& ealous al alini ation can ca uselocal anesthetic molecules to precipitate from solution.

+he newest additions to clinically available local ane s&thetics, namely ropivacaine B ig. 0C and lev obu piv acain e,

igure ? esults of structure alterations ester lin ed

+he only difference between the 8 and &isomers of ropivacaine is their spatial orientation.

represent the following e!ploitation of technology tha t permits cost&favorable separation of racemic mi!tures of local anesthetics into pure enantiomers; and the searchfor local anesthetics with greater safety margins.8impli st ically stated, molecules with an asymmetriccarbon atom e!i st

in forms that are mirror images Bi.e. e!hibit Fhandnes sG,FchiralityGC, with images Benantiomers, ste re oisom ers C

#%

I

Q% Q H ( Q H ( Q

HI (

distinguished by how they rotate light according to theorientation of the structures in three dimensions. 9ariousterms are used to refer to the different enantiomers; I use8 and to designate two different enantiomers. *racem ic mi!ture contains eKual amounts of the and 8isome rs. ommercial formulations of ropivacaine andle vob upi va& caine contain the 8 enantiomer. ote thatlev obupi vacai ne is the 8 form of bupivacaine. +hemotive for ma r e ting pure enantiomers is evidence thatthe 8 form is less to !ic , more potent, and longer actingthan the form or the racemic mi!ture B+able #C.

6harmacodyna micseversible bloc of voltage&gated sodium channels in

a!ons is generally thought to be how local anesth etics

8tructural differences between procaine and tetracaine on the lipophilicB # C and hydrophilic end B ( C mar edly influence potency, to!icity,d uration of action and hydrolysis rate. LD?- , ?-R lethal dose.

+able # *nesthetic duration and to!icity of local anestheticisomers

Drug Duration +o!icity

Etidocaine 8 P 8 P :epivacaine 8 S 8 P

)upivacaine 8 S 8T opivacaine 8 S 8 T

EKui&effective # -./3 -.(?

Lipid UH ( % -.> (.> (3.?

6rotein bound BRC 33.?


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Local anesthetics Heavner //$,

but thi sFsi e principleG was challenged " #.< -.2- -.> 3>R -. -.2- (.> (.3 -.?# (3.?


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/2- Drugs in anaesthes ia

infusion, intermittent infusionC ma e more thansu per ficial discussion of the distribution inetics of localanest heti cs from in@ection sites beyond the scope of thisre vie w.

*minoester&lin ed local anesthetics are hydroly ed byesterases in tissues and blood. *minoamide&lin ed localanesthetics are biotransformed primarily in the liver by

cytochrome 62?- en ymes. :etabolites may retain localanesthetic activity and to!icity potential, albeit usually atlower potency than the parent compo und.

9asoconstrictors "e.g. epinephrine # 2-- --- B(.? mgUmlC$are used to reduce absorption of local anesthetics intothe systemic circulation. +he value of doing so dependson vascularity of in@ection site and specific localan esth etic agent, which 1 among other considerations

1 vary in terms of intrinsic vasoactivity. +he valueof a dding sodium bicarbonate to solutions to enhancespeed of onset of local anesthetics also depends onin@ection site as well as physiochemical properties of thevarious local anesthetics. *ddition of sodium

bicarbonate increases the pH of solutions, whichincreases the ratio of uncharged to charged molecules.+his increases the number of local anesthetic moleculesin the form that most readily passes through biologicmembranes. Hyaluronidase Btissue&spreading factorC issometimes added to local anesthetic solutions tofacilitate s pread of solution at the in@ection site, therebyaffecting s peed of onset and e!tent of a bloc . +hisappears only to be useful when local anesthetic isin@ected behind the eyes in preparation for ophthalmologic surgery. H yalu roni& dase may be

in@ected with local anesthetic during epiduralneurolysis to treat pain with positive bene fit. * recentissue of +echniKues in egional *nesthesia and 6ain:edicine "(($ discussed in detail additives to localanes the t ics.

+o!icity+he to!ic effects of local anesthetics can be categori edas shown in +able /. +rue allergic reactions areassoci at ed with ami noe ste r&lin ed local anesthetics, notam ino am ide &lin ed ones. In a study of anaphylactic andana ph ylact oid reactions Bn P 3>/ patients patch tested four had

positive reactions to lidocaine, two of whom had historiesof sensitivity to local in@ections of

+able / ,ategories of local anesthetic to!ic reactions

+ype of reaction Details

Locali ed or systemic *llergic reactions8ystemic ardiacUvascular

entral nervous system:ethemoglob inemia

Locali ed +issue to!icity

lidocaine manifested by dermatitis. +hey concluded tha tcontact type I9 sensitivity to lidocaine may occur mor efreKuently than was previously though t.

It is common, but inappropriate, to refer to all advers eevents as Fallergic reactionsG. +issue to!icity, pri mar ymyoto!icity, and neuroto!icity can be produced by al llocal anesthetics if FhighG concentrations are used. 8i gns

and symptoms of varying degrees of neuropathy Be.g.transient neurologic symptoms, cauda eKuina syndro meChave been reported following spinal anesthesia with, for instance, (R and ?R lidocaine. In a recent sys tema ti creview, Waric et al. "(?$ compared the freKuency of tr an&sient neurologic symptoms and neurologic com pl ica tionsafter spinal anesthesia with lidocaine and with other localanesthetics. +hey found that the ris for dev elo pi ngtransient neurologic symptoms after spinal anesthesia wit hlidocaine was higher with lidocaine than with bu piv aca ine ,

prilocaine, procaine, and mepivacaine. 8ymptoms in al l patients disappeared spontaneously by the #-th

pos to per a& tive day. +he lithotomy position seems to bea pr edi spo s&ing factor. In #-, oster and arlson "(0$reported that, of the local anesthetics tested, procaine

produces the le ast and bupivacaine the most severemuscle in@ury. :or e recently, Win et al. "(3$ concludedthat the myoto !ic potential of ropivacaine is less thanthe potential of bupivacaine. )oth drugs, however,

produce morphol ogi&cally identical patterns of calcifiedmyonecrosis, form ati on of scar tissue, and a mar ed rateof muscle fiber reg ene r&ation in animals after continuous

peripheral nerve bloc s "(>$.

* variety of local anesthetics may produce methemog lo& binemia. 6rilocaine is the local anesthetic for which thereappears to be greatest ris for this to occur.

*s the concentration of local anesthetic in the sys te miccirculation increases, various cardiovascular system andcentral nervous system signs and symptoms appear. +h erelative central nervous system and cardiovascular to !ic ityof local anesthetics has been of interest, especially af ter *lbright "(


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Local anesthetics Heavner /2#

with any of the sei ures, including #0 patients whoreceived bupivacaine bloc s.

:easures to prevent systemic to!ic reactions to localane s& thetics include following dose recommendations,in @ecting aliKuots over time, avoiding inadvertentin tra vas cul ar in@ections, and monitoring vital signs duringin @ection. )lan et recommended doses versus bloc &

specific recom &mended doses were recently discussed"/2,/?$. Dru g administration must be stopped shouldsigns or sym pto ms of to!icity develop. 8ei ures induced

by local anest het ics are usually self limiting, and reKuiremaintenance of respiratory gas e!change and control of muscle con tr act ions Be.g. intubation, o!ygenation, short&acting muscle par aly& sisC. Drugs such as propofol,thiopental, and dia epam ar e effective against thesesei ur es.

ardiovascular to!icity is treated according to *me ricanHeart *ssociation guidelines, depending on the nature of the to!icity. ecent evidence suggests that in som einstances lipid emulsion infusion may be beneficial "/0$.Data supporting the use of lipid emulsion relate to bup i&vacaine and may or may not apply to other localanest het ics "/3 1 2( $. onsideration must be given tothe car di ac effects of medications, such as propofol,when cho os ing a drug to treat local anesthetic&inducedconvul sions .

,onclusio nLocal anesthetics are widely used to manage acute ,chronic, and cancer pain and for diagnostic purposes .+hey have effects in addition to preventing sodium en tryinto a!ons that appear to contribute, at least in someinstances, to their pain&relieving action. ew formu&lations lead to prolonged action or to novel deliveryapproaches. Lipid emulsion reportedly is a new tool for treating bupivacaine cardiot o!icity.

eferences and recommended reading6apers of particular interest, published within the annual period of review, have

been highlighted as of special interest of outstanding interest*dditional references related to this topic can also be found in the urrent4orld Literature section in this issue Bp. /


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/2( Drugs in anaesthes ia

/? Iosenberg 6H, 9eering )+, 7rmey 4 . :a!imum recommended doses oflocal anesthetics a multifactorial concept. eg *nesth 6ain :ed (--2;(< ?02 1 ?3?.

/0 4einberg ', ipper , einstein DL, et al. Lipid emulsion infusion rescue sdogs from bupivacaine&induced cardiac to!icity. eg *nes 6ain :ed (--/;(> # 1 (-(.

/< de Jong H. Lipid infusion for cardioto!icity promiseZ Xes 1 panaceaZ ot "letter$. *nesthesiology (--3; #-0 0/? 1 0/0.+his paper discusses various clinical and e!perimental aspects related to the useof lipid emulsion to treat bupivacaine cardioto!icity.

2- :oore D . Lipid rescue from bupivacaine cardiac arrest a result of failure to ven tilate and mainta in cardiac perfusionZ *nesthesiology (- -3; #-0 0/0 1 0/ 3.+his paper discusses various clinical and e!perimental aspects related to the useof lipid emulsion to treat bupivacaine cardioto!icity.

/3 8hupa . Lipid emulsion for bupivacaine to!icity too soon to celebrateZ "letter$. *nesthesiology (--3; #-0 0/2 1 0/?.+his paper discusses various clinica l and e!perimental aspects related to the useof lipid emulsion to treat bupivacaine cardioto!icity.

2# 4einberg 'L. In reply "letter$. *nesthesiology (--3; #-0 0/3 . +his paper discusses various clinical and e!perimental aspects related to the useof lipid emulsion to treat bupivacaine cardioto!icity.

/> +ornero& ampello '. *dvanced cardiac life support for presumed bupiva& caine&related cardiac arrest "letter$. *nesthesiology (--3; #-0 0/?.+his paper discusses various clinica l and e!perimental aspects related to the useof lipid emulsion to treat bupivacaine cardioto!icity.

2( osenblatt :*, *bel :, ischer '4, Eisen raft J). In reply "letter$. *nesthe & siology (--3; #-0 0/3 1 0/>.+his paper discusses various clinical and e!perimental aspects related to the useof lipid emulsion to treat bupivacaine cardioto!icity.

aguirre5local_anesthetics.docx

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