LA

Review of local anaesthetic agents

H. A. McLURE 1, A. P. RUBIN 2

1Department of AnaesthesiaSt. James’s University Hospital, Leeds, UK, LS9 7TF

2Department of AnaesthesiaRoyal National Orthopaedic Hospital

Stanmore, Middlesex, UK

The currently available local anaesthetic agentsare capable of providing high quality nerveblockade in a wide variety of clinical circum-stances. Our understanding of the mechanismsand consequences of toxicity is increasingrapidly. Knowledge of the chemistry of localanaesthetics has enabled clinicians to exploitthe increased safety of single isomer agents.However, the extent, if any, of this improve-ment in toxicity has yet to be proven.Established toxicity may be very difficult totreat and no specific reversing therapy is yetavailable. Until this occurs it is essential thatpractitioners of regional anaesthesia maintaintheir knowledge base and skill in techniques ofadministration of local anaesthetic, are able torecognise impending disaster, and constantlyupdate their skills in resuscitation.Key words: Anesthetics - Anesthesia - Anesthesia,local.

Local anaesthetic agents have a wide vari-ety of applications. They are used as the

backbone ingredients for local and regionalanaesthetic techniques, in the treatment ofacute pain during labour, and for analgesia inthe operative and postoperative period. Theyare also used in the management of chronicpain where local anaesthetic injections mayhave a prolonged effect, and are used to aiddiagnosis and management prior to neurolyticprocedures. In addition to these well recog-

nised analgesic nerve blocking functions,local anaesthetic agents also have a role in thediagnosis of suxamethonium apnoea (dibu-caine test), the treatment of cardiac arrythmias(lidocaine for ventricular arrythmias), asmucosal vasoconstrictors of the upper air-way (cocaine), to obtund the pressor res-ponse to tracheal intubation (intravenouslidocaine) and recreationally, as a drug ofabuse (cocaine).

The origins of local anaesthesia date backto 1884 when Carl Koller, a young Vienneseophthalmologist, discovered that cocaineinstilled into his own conjunctival fornix pro-duced localised insensitivity to touch andinjury.1 The subsequent evolution of use oflocal anaesthetics has seen a vast expansionin our knowledge of these drugs and in tech-niques of administration, although the agentsthemselves have changed comparatively less.Modern local anaesthetics are safer then theirpredecessors, but risks persist, and even theexperienced practitioner using the correctdose may provoke a fatal reaction. The cor-nerstone of safe practice is a thorough under-standing of the pharmacology and toxicity

Vol. 71, N. 3 MINERVA ANESTESIOLOGICA 59

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McLURE REVIEW OF LOCAL ANAESTHETIC AGENTS

of the agents used, in particular, dose andconcentration required, likely speed of onsetand duration of action. Clinicians adminis-tering local anaesthetic agents must be capa-ble of recognising impending toxicity, andhave access to the equipment, current knowl-edge and skills to manage these events.

The physiology of nerve conduction

Impulses are conducted along nerves bythe movement of sodium, potassium and cal-cium ions across the nerve membrane duringa rapid event called an action potential. Thealtered distribution of these ions brieflyreverses the electrical polarity of the mem-brane for 1-2 ms, generating small local elec-trical currents that are propagated along thenerve as a wave.

At rest, chemical and electrical gradientsacross the nerve membrane are established byion channels, which may be passive, active orvoltage-gated. Passive ion channels allowfree leakage of ions across the membrane,although the movement is disproportionatewith potassium moving more readily thansodium. Active Na/K ATPase channels pumpsodium out of the cell in exchange for potas-sium, in a ratio of 3 sodium to 2 potassiumions. Consequently, chemical gradients areestablished with high extracellular sodiumconcentrations and high intracellular potas-sium concentrations. The active pumping ofpositively charged sodium ions out of thecell by Na/K ATPase, coupled with the rapidpassive leak of positively charged potassiumions out of the cell along a concentrationgradient, generates a resting electrical poten-tial difference across the membrane, suchthat the inside of the cell is negatively charged(-70 to -90 mV) compared to the outside.

In addition to passive and active ion chan-nels the membrane contains voltage-gatedsodium channels, which open or closedepending on the membrane potential dif-ference. Each consists of a pore forming α-subunit and 1 or 2 β- subunits. The α-subunitis composed of 4 domains (D1-4) which con-tain 6 helical trans-membrane segments (S1-6). When the nerve is stimulated this structure

undergoes a series of conformational changescycling through four functional states: resting,activated, inactivated and deactivated.Although highly complex the channel canbe considered to have 2 functioning gates, anouter m gate and an inner h gate, whose statevaries with the membrane potential. In theresting state (-70 mV to -90 mV) the outer mgate is closed, but the inner h gate is open.On stimulation of the nerve (activation) theouter m gate opens. There is a rapid influx ofsodium ions along an electro-chemical gra-dient and the membrane potential rises. Ifsufficient sodium channels open and themembrane potential rises above a thresholdof around -60 mV, a widespread opening ofsodium channels is triggered, resulting in amuch more rapid influx of sodium ions suchthat the membrane potential may overshootneutral to around +20 mV. This causes theinner h gate to close, inactivating the sodiumchannel and preventing further sodium move-ment. The depolarisation of a section of mem-brane creates a potential difference relative toadjacent areas. This generates an electricalcurrent and raises the membrane potentialof these adjacent areas such that further depo-larisation occurs. Consequently, a wave ofdepolarisation flows along the nerve propa-gating the original stimulus.

In the inactivated phase there is no inwardmovement of sodium through the voltage-gated channels, but continued active pump-ing of sodium out of the cell by the Na/KATPase and leak of potassium through pas-sive ion channels restores the membranepotential towards the polarised state. Whenthe membrane potential reaches -60 mV theouter m gate closes and the channel is deac-tivated. During the inactivated and deacti-vated state the nerve is refractory to furtherstimulation. This prevents rapid redepolari-sation of that section of the axon and inhibitsretrograde conduction of the impulse.

Mechanism of local anaesthetic action

Local anaesthetics block nerve conductionby reversibly binding with the D4-S6 part ofthe α-subunit of the voltage-gated sodium

60 MINERVA ANESTESIOLOGICA Marzo 2005

REVIEW OF LOCAL ANAESTHETIC AGENTS McLURE

channels in the nerve membrane. This siteof action is intracellular, requiring local anaes-thetic to diffuse across the lipophilic lipopro-tein membrane. Local anaesthetic is admin-istered in an acidic solution that maintainsthe majority of the drug in the ionised solu-ble form. Once injected into the tissue it mustbe converted into the neutral unionised formin order to enter the nerve cell. The propor-tion of drug that is converted will dependupon the local anaesthetic pKa and the tissuepH. Once inside the cell the lower intracel-lular pH regenerates the ionised form, whichblocks the receptor within the sodium chan-nel. Sodium influx is reduced and the upsurgein the membrane potential slows. If a suffi-cient number of sodium channels are blockedthe threshold potential will not be reachedand impulse conduction stops. The restingmembrane and threshold potential remainthe same, but the action potential is tem-porarily halted.

In addition to the action of ionised localanaesthetic on the intracellular portion of thesodium channel the unionised local anaes-thetic also disrupts the intra-membrane por-tion of the channel. The local anaestheticaction is augmented by blockade of potassi-um channels, calcium channels and G-pro-tein-coupled receptors.2-4 The degree of neu-ronal block is affected by the diameter of thenerve. Larger diameter fibres (touch/pres-sure/motor) require higher concentrations oflocal anaesthetic to achieve a given degree ofblock, compared with small myelinated fibres(pain afferents). As the block proceeds dif-ferent sensory modalities are lost in the orderof pain, temperature, touch, deep pressurethen motor function.

The affinity of local anaesthetic for thesodium channel varies with the channel state,as conformational changes reveal or obscurethe local anaesthetic binding sites. In gener-al, affinity is highest when the sodium chan-nel is open (activated or inactive), and leastwhen the channel is closed (deactivated andresting). At very low frequencies of nervestimulation low concentrations of local anaes-thetic will produce a certain degree of block(termed tonic block). Increasing the fre-quency of stimulation allows greater amounts

of local anaesthetic to access the binding sitesso there is an increase in the degree of block(termed use-, phase- or frequency depen-dent-block).5 If the frequency of nerve stim-ulation is stopped the degree of blockrecedes. Currently, there is no evidence thatthis effect can be utilised to improve the qual-ity of the block.

In addition to state-dependent differencesin channel affinity there are differences inaffinity between local anaesthetics. Lidocainebinds and dissociates rapidly from the chan-nel, whereas bupivacaine binds rapidly, butdissociates more slowly. The stereo-isomersof bupivacaine have different dissociationrates with R-bupivacaine dissociating moreslowly than the S-isomer.6 Clinically, thesedifferences are relatively unimportant for neu-ronal block, but assume great significancefor cardio-toxicity.7 Specialised excitable tis-sue in the heart initiates and conducts theelectrical impulse that spreads through themyocardium and drives the cycle of con-traction and relaxation. This process is medi-ated by voltage-gated sodium channels,which are blocked by local anaesthetics.Lidocaine binds and dissociates quickly sothere is little chance of frequency-dependentblock developing. However, bupivacaine,particularly R-bupivacaine, dissociates muchmore slowly allowing a more pronouncedfrequency-dependent block to develop.Cardiac impulse conduction is slowed andlethal arrythmias, which are often refractoryto treatment, may occur.

Chemistry

Local anaesthetic agents conform to a sim-ilar molecular configuration consisting of alipophilic aromatic ring connected to ahydrophilic amine group (Figure 1). The link-ing chain may be used to classify the agentsas an ester, amide, ketone or ether. Othermolecules without this structure may alsohave local anaesthetic properties, but are notused clinically in this role (e.g. atropine, pro-pranolol, amitryptiline, meperidine).8, 9 Esterand amides have achieved popularity in clin-ical practice. Esters include cocaine, procaine,




BUPIVACAINE ETIDOCAINE

CH3

CH3

H O

N C

C4H9

N

CH3

CH3

H O

N C

C2H5

C N

C3H7

C2H5

LIGNOCAINE MEPIVACAINE

ROPIVACAINE 2-CHLOROPROCAINE

CH3

CH3

H O

N C

C3H7

N

PRILOCAINE PROCAINE

CH3H O

N C

H

C N

C3H7

CH3

ARTICAINE TETRACAINE

CH3

CH3

H O

N C

C2H5

N

C2H5

CH2

CH3

CH3

H O

N C

CH3

N

CL

CC2H5

N

C2H5

NH2

CH2CH2O

O

CC2H5

N

C2H5

NH2

CH2CH2O

O

CCH3

N

CH3

N

CH2CH2O

OH

C4H9

CH O

N C

H

C N

C3H7

CH3

CH3

S

O O

Figure 1. — Local anaesthetic agents conform to a similar molecular configuration consisting of a lipophilic aromaticring connected to a hydrophilic amine group.


2-chloroprocaine, tetracaine and benzocaine.Amides include lidocaine, bupivacaine, lev-obupivacaine, mepivacaine, etidocaine, prilo-caine, ropivacaine and articaine.

Stereochemistry

Organic molecules containing a carbonatom connected to 4 different groups mayexist in forms that are mirror images of eachother. These 2 forms are called stereo-iso-mers. They may be differentiated accordingto the direction they deflect polarised light,and are labelled as either S-(-)-laevorotatoryor R-(+)-dextrorotatory. Their physiochemi-cal properties are usually identical but theireffects on biological receptors can be dra-matically different. Stereo-isomerism is foundin bupivacaine, prilocaine, ropivacaine, eti-docaine and mepivacaine. Most are market-ed as racemic mixtures (equal proportionsof each stereo-isomer), with the exceptionof levobupivacaine (S-bupivacaine) and ropi-vacaine (S-ropivacaine). These single isomerlocal anaesthetics have fairly similar localanaesthetic efficacy to their racemic mixtures,but possess useful differences in terms oftheir toxicity profiles. Using an animal mod-el in 1972 Aberg showed that S-bupivacainehad reduced toxicity compared to R-bupiva-caine.10

Ionisation

Local anaesthetics are weak bases (pKa7.6-8.9) with esters tending to have higherpKa values (Table I). They are poorly solublein water and therefore constituted in acidicsolutions (pH 3-6), where they exist as a mix-ture of charged cationic molecule and neutralbase. The ratio of ionised to neutral basevaries, following the Henderson-Hasselbachequation with the dissociation constant (pKa)of that local anaesthetic and the solution pH;

pH=pKa+log [base]/[acid]

For a base pH=pKa+log [unionised]/ [ioni-sed].

The pKa is constant for any local anaes-thetic. It is the ambient pH that dictates theamount of each species present. Most cur-rent local anaesthetic agents have a pKagreater than physiological pH (7.4), so oninjection into tissue the new equilibriumfavours the ionised species. Consequently, areduced amount is available to block thenerve. Agents with a low pKa are less ionised,so there is an increased proportion of neutralbase available to penetrate the cell and speedthe onset of action. Inflamed tissue has alower pH so there is a greater ionisation anda reduction in efficacy.

Lipid solubility

Lipid solubility is important in determiningthe ability of a local anaesthetic to diffuseacross the lipid rich nerve membrane andaccess target receptors. It is quantified in thelaboratory by measurement of the relativedistribution of the local anaesthetic betweena reference aqueous phase (e.g. water orbuffer at physiological pH) and a non-aque-ous solvent phase (e.g. octanol, η-heptane,hexane). The distribution of the substancebetween these 2 phases enables calculationof a solvent partition coefficient. The higherthe partition coefficient, the higher the lipidsolubility, and the greater the local anaes-thetic potency. In clinical practice, localanaesthetics with high lipid solubilities requirethe use of lower concentration solutions toachieve the same neuronal block (e.g. bupi-vacaine 0.25-0.5% cf prilocaine 1-4%).

Protein binding

Local anaesthetics bind to plasma (albu-min, α1-acid glycoprotein) and tissue pro-teins. Albumin is considered to be a high vol-ume, low affinity site whereas α1-acid gly-coprotein is high affinity, but low volume.Protein binding has been shown to correlatewell with the duration of action of localanaesthetics, but other factors also have asignificant effect such as potency, doseadministered, addition of vasoconstrictors,



vascularity of the tissue and rate of metabo-lism. However, the latter effect is probablyless important than the rate at which theyare removed from their target receptors.Protein binding may vary, increasing in trau-ma, major surgery, chronic inflammation,cancer, and uraemia.11 Conversely, proteinbinding decreases during pregnancy, in thenewborn and with use of the contraceptivepill. As local anaesthetics are systemicallyabsorbed the plasma level rises slowly.However, once protein sites have becomesaturated, which may occur rapidly after acci-dental intravenous injection, there may be aprecipitous increase in plasma levels. Thiscan quickly lead to severe cardiovascular andcentral nervous system (CNS) toxicity withfew warning premonitory signs. A similar sit-uation occurs when plasma pH falls. Localanaesthetic dissociates from the protein mol-ecules causing a sudden rise in the free frac-tion.

Vaso-activity

Most local anaesthetics exhibit a biphasiceffect on blood vessels with vasoconstrictionat very low concentrations and vasodilata-tion at concentrations that are used clinical-

ly. However, there are significant differencesbetween agents. Cocaine has an intense vaso-constrictor effect, used therapeutically to pre-vent bleeding during instrumentation of theupper airway. In addition, ropivacaine has apronounced vasoconstrictor effect at low con-centrations which may reduce the require-ment for added vasoconstrictors.12-14 Isomer-specific differences have also been notedwith greater vasoconstriction with L-bupiva-caine compared to R-bupivacaine.15 In theo-ry, marked vasoconstriction may have dele-terious consequences following infiltrationaround end arteries, although this has neverbeen reported.

Absorption and distribution

Intravenously administered local anaes-thetic is initially distributed to highly per-fused organs such as brain, kidneys and heart,followed by less well perfused tissues such asskin, skeletal muscle and fat. Local absorptioninto those organs will be affected by lipidsolubility, pKa, protein binding as well asbinding to other blood born sites (e.g. ery-throcytes), tissue binding affinity and clear-ance, as well as patient factors such as cardiacoutput and metabolic status. The site of inject-


TABLE I.—Physiochemical properties.

Molecular pKa Speed Partition ProteinAgent weight (25 °C) on onset coefficient* Potency binding

(%)

Ester agentsCocaine 303 8.7 Slow — High 98Procaine 236 9 Slow 1.7 Low 62-Chloroprocaine 271 9.3 Rapid 9 Intermediate —Tetracaine 264 8.6 Slow 221 Intermediate 76Benzocaine 165 3.5 Slow — — —

Amine agentsLidocaine 234 7.7 Fast 43 Intermediate 64Mepivacaine 246 7.9 Slow 21 Intermediate 77Bupivacaine 288 8.1 Slow 346 High 95Levobupivacaine 288 8.1 Slow 346 High 96Ropivacaine 274 8.1 Slow 115 Intermediate 94Etidocaine 276 7.9 Fast 800 Intermediate 94Prilocaine 220 7.9 Fast 25 Intermediate 55Articaine 321 7.8 Fast — Intermediate 95

*Partition coefficients with h-octanol/buffer. Maximum doses vary depending on the individual patient, site and speed of injection.


ed local anaesthetic has a significant effect onplasma levels with the highest peak levelsfrom intercostal and caudal injections fol-lowed by lumbar epidural, brachial plexus,sciatic and femoral injections.16

Lung extraction

A large proportion of local anaesthetic isextracted temporarily during the first passthrough the lungs.17 This effect may be dueto the lower pH of lung tissue relative to plas-ma, resulting in a degree of ion trapping.Consequently, the lungs are able to attenuatethe toxic sequelae of accidental intravenousinjections of local anaesthetic.18 In patientswith right to left cardiac shunts this safetynet is absent and there is an increased risk oftoxicity. Following lung absorption the localanaesthetic is more slowly washed back intothe circulation.

Placental transfer

Local anaesthetics are able to diffuse acrossthe placenta, although ester local anaesthet-ics are hydrolysed rapidly in the blood, so donot cross the placenta in significant amounts.Amide local anaesthetics vary considerably intheir speed of placental transfer and degreeof foetal retention. Increased protein bind-

ing in the mother reduces the amount of localanaesthetic that is free and able to diffuseacross the placenta. Conversely, the foetushas low levels of α1-acid glycoprotein so hasa reduced concentration of local anaestheticbinding sites. In addition, foetal pH is lowerthan maternal, resulting in ion trapping ofagents with higher pKa values.19 The distrib-ution of local anaesthetics across the pla-centa has been demonstrated by measuringthe ratio of the concentration of local anaes-thetic in umbilical vein versus maternal arte-rial blood (bupivacaine 0.32, lidocaine 0.73,prilocaine 0.85). Less is known about trans-fer of local anaesthetic into breast milkalthough lidocaine has been detected in thebreast milk of a parturient.20

Clearance

Ester local anaesthetics undergo rapidhydrolysis in the plasma by non-specificesterases. The metabolites are inactive aslocal anaesthetics, but derivatives (p-aminobenzoic acid, PABA) can be allergenic.The speed of degradation lends a degree ofsafety as plasma levels fall quickly. Patientswith atypical plasma cholinesterases may beat higher risk of developing toxicity due toslower or absent plasma hydrolysis. Theexception to plasma hydrolysis is cocainewhich undergoes a slower process of metab-olism in the liver. Cocaine metabolites may bepresent in the urine for 24-36 h after admin-istration.

Amide local anaesthetics are much morestable in blood than esters (half-life of lido-caine=approximately 90 min, procaine=6min). They are cleared by hepatic metabolismwith a minimal fraction by renal mechanisms(less than 1-6%).11 Within the liver they under-go a complex process of biotransformation bymicrosomal enzymes (CYP450) followed byrenal excretion. Phase I involves hydroxyla-tion, N-dealkylation and methylation, fol-lowed by Phase II where the metabolites areconjugated with amino acids into less activeand inactive metabolites. The rate of metab-olism is highly dependent on liver bloodflow, and differs between agents with prilo-


TABLE I.—Physiochemical properties.

Maximum Maximum

Duration Toxicity dose-plain dose-with

(mg/kg) vasoconstric-tor (mg/kg)

Long Very high 1.5 —Short Low 8 10Short Low 10 15Intermediate Intermediate 1.5 2.5

— High — —

Intermediate Low 5 7Intermediate Low 5 7Long High 2 3Long Intermediate 2.5 3Long Intermediate 2.5 4Long Intermediate 5 6Intermediate Low 5 8Intermediate Low 7 —

Partition coefficients with h-octanol/buffer.


caine and etidocaine being the most rapid,lidocaine and mepivacaine intermediate, andropivacaine and bupivacaine the slowest.The clearance of prilocaine exceeds thatwhich would be possible by the liver aloneindicating other sites of metabolism, mostprobably the lung.

Ester local anaesthetics

Cocaine

Cocaine (2-β-carbomethyoxy-3-β-benzo-xytropane) is an ester of benzoic acid and isfound naturally in the leaves of Erythro-xyloncoca or of Erythroxylon truxillense, whichare indigenous to Bolivia and Peru. It is acolourless crystalline compound only slight-ly soluble in water, but soluble in most organ-ic solvents. It has been used medically andrecreationally for hundreds of years. In addi-tion to its local anaesthetic actions on nervemembranes it is also able to block the re-uptake of norepinephrine at sympathetic neu-rones, potentiating the effects of cate-cholamines and causing intense vasocon-striction. It is used as a topical anaesthetic, asit is well absorbed from all mucous mem-branes. Currently, concentrations of 1-10%are used for procedures involving the nasalmucosa. Traditionally, cocaine is combinedwith epinephrine and bicarbonate as Moffet’ssolution to provide a vasoconstrictor solu-tion. In overdose it produces hypertension,tachy-arrhythmias, tachypnoea, nausea and amyriad of central nervous system effects.Toxicity is enhanced by slower metabolismcompared to other ester local anaesthetics.

Procaine (Novocaine, Planocaine,Ethocaine, Neocaine)

The toxicity of cocaine led to the devel-opment of the first synthetic local anaesthet-ic, procaine (2-diethyl-4-aminoethyl-p-aminobenzoate) by Alfred Einhorn in 1905.This ester local anaesthetic is markedly lesstoxic than cocaine, but is a weak agent witha relatively slow onset and short duration of

action. Concentrations of 0.25% were usedfor infiltration, increasing to 5% for epiduralanaesthesia. Metabolism occurs by hydroly-sis to diethyl-aminoethanol and p-aminoben-zoic acid.

2-chloroprocaine (Nesacaine)

The low potency of procaine led to thedevelopment in 1952 of 2-chloroprocaine (2-diethylaminoethyl-4-amino-2-chloroben-zoate). This agent was more lipid soluble,more potent and so required lower concen-trations (2-3%). Clinically it has a rapid onsetand relatively short duration of action. Theoriginal formulation of 2-chloroprocaine washighly acidic (pH 3.3). Large doses acciden-tally injected into the cerebrospinal fluid pro-duced significant neurotoxicity. To reducethese injuries future formulations did not con-tain the preservative sodium metabisulfite.

Tetracaine (Amethocaine, Pontocaine)

Synthetized in 1928 by Eisleb, tetracainehas a moderate onset of action and a pro-longed duration. However, it was found to besignificantly more toxic than procaine and,although used for spinal anaesthesia in someareas, in modern practice it’s use is restrictedto topical anaesthesia for ophthalmic proce-dures, amethocaine lozenges for painfuloropharyngeal conditions and as ametop fortopical anaesthesia of the skin. Ametop (Smith& Nephew Healthcare Ltd) is an aqueouscream preparation containing 4% tetracaine.It penetrates skin rapidly, but can causesevere skin reddening.

Benzocaine (Americaine)

Benzocaine (ethyl p-aminobenzoate) is aprocaine derivative with no amino terminus.It is very poorly soluble in water so is usedtopically where it is very slowly absorbed. Itis formulated in a gel or lozenges and is usedin dentistry or for mucosal irritation.



Topical agents

Topical agents may be used to provide sur-face anaesthesia of mucous membranes, thecornea or the skin. Unlike injection tech-niques where local anaesthetic is placeddirectly into the tissue around the nerve, top-ical anaesthetics must cross tissue barriers tohave their effect. This may be achieved byeither using a drug with a low pKa value,ensuring generous proportions of theunionised base form are present, or usingmuch greater concentrations of local anaes-thetic than would be injected. In the UKagents that are used exclusively for topicalanaesthesia are all esters and include tetra-caine (Amethocaine), oxybuprocaine (Beno-xinate), proxymetacaine (Proparacaine) andbenzocaine (Dequacaine). All except ben-zocaine are used in ophthalmology wherethey produce excellent topical anaesthesia.Clinical differences are stinging whendropped onto the eye (proxymetacaine least,tetracaine worst, oxybuprocaine in between),and corneal toxicity, which is worst withtetracaine. Benzocaine has a very low pKavalue so even in acidic conditions it existsalmost entirely in the unionised form and isable to penetrate mucous membranes. It ishighly toxic and consequently is used only fortopical anaesthesia in patients with painfulsuperficial oropharyngeal conditions.

Amide local anaesthetics

Lidocaine (lignocaine, xylocaine, dalcaine,octocaine)

Synthesized by Lofgren and Lundqvist inSweden in 1943, then introduced clinicallyin 1947, lidocaine (diethylamoinoacetyl-2-6-xylidine) is a tertiary amide derivative ofdiethylamino-acetic acid. It has become oneof the most widely used local anaestheticsacross the world. In concentrations of 0.5-2% it produces a rapid onset of intense motorand sensory nerve blockade. Higher con-centrations (5%) were used for spinal anaes-thesia until reports of transient radicular irri-tation suggested these concentrations may

be neurotoxic.21 However, there is laborato-ry data suggesting that even lower concen-trations may result in neurotoxicity, althoughthere are no data to support this in humans.22

Protein binding is relatively low so the dura-tion of action is intermediate, and repeatedinjection may reveal tachyphylaxis. It is alsoused intravenously as a class 1b anti-arrhyth-mic agent. As a marker of its impressive safe-ty intravenous lidocaine is often used in vol-unteer studies to familiarise the subjects withthe symptoms of local anaesthetic toxicity,although even in the controlled environmentof clinical research this safe local anaesthet-ic has resulted in a fatality.23, 24

Mepivacaine (carbocaine, polocaine, scandi-caine, meaverin)

Mepivacaine [1-methyl-2-(2,6-xylylcarba-moyl)-piperidine] is the methyl derivative ofN-alkyl pipecoloxylidine, and is structurallyrelated to bupivacaine and ropivacaine. Itwas synthesized in 1956 by Ekenstam andEgner and was the second amide local anaes-thetic to be introduced. Clinically, it has afast onset, similar to that of lidocaine, but alonger duration due to a lack of vasodilatoractivity. Systemic toxicity is very low, butslow neonatal clearance rates have limitedits use in obstetrics. The reliable safety recordhas ensured that mepivacaine in concentra-tions of 0.5-2% is a popular choice for a widerange of regional anaesthetic proceduresincluding intravenous regional anaesthesia(IVRA).

Bupivacaine (marcaine, sensorcaine, carbos-terin)

Bupivacaine [1-butyl-2-(2,6-xylylcarba-moyl)-piperidine] was introduced in 1963. Itis the butyl derivative of N-alkyl pipe-coloxylidine and is structurally related tomepivacaine and ropivacaine. It is a potentagent (commercial preparation concentra-tions 0.1-0.75%) with a slow onset, butdespite this, is a popular choice due to itsprolonged duration of action. Concerns abouttoxicity and difficulties in resuscitation withthe higher concentrations of bupivacaine



have led to the removal of 0.75% bupiva-caine from obstetric anaesthesia.25 Similarly,the use of bupivacaine for IVRA is inadvis-able.

Levobupivacaine (chirocaine)

Standard bupivacaine is a racemic mixtureof two isomers. Both isomers have similarlocal anaesthetic efficacy, but the S-isomerhas a safer side effect profile.26, 27 There areanimal and human volunteer data to show areduction in central nervous system and car-diovascular toxicity with levobupivacaine,although in some studies the difference isrelatively modest and much less than the dif-ference between racemic bupivacaine andlidocaine. Despite the improved toxicity pro-file there have been reports of severe adversereactions, and it is yet to be establishedwhether these differences will be significantin clinical practice where toxicity often occursthough intravascular injection and massiveoverdose.28 Of note, European legislationstates that the percentual w/v should beexpressed in terms of the free base alonerather than the hydrochloride salt, which isthe case with Marcaine. This difference inexpressed formulation means that similarconcentrations of levobupivacaine contain11% more molecules than are found in theracemate. This may offset some of the mea-sured advantages in terms of toxicity.

Ropivacaine (Naropin)

Synthesized in the 1950s, but not intro-duced clinically until 1996, ropivacaine (N-n-propyl-2,6-pipecoloxylidide) is the propylderivative of N-alkyl pipecoloxylidine, the3rd in the mepivacaine, bupivacaine series.29

It has a similar onset and duration of actionas bupivacaine, but is less potent requiringconcentrations of up to 1%. In low con-centrations ropivacaine appears to have adifferential sensory/motor block with adegree of motor sparing, although this dis-appears with the higher concentrations thatare capable of providing a dense motorblock. The preservation of motor functionis appealing in areas where ambulation isdesirable, such as on the labour ward or

following surgery. The duel effect may bedue to reduced lipid solubility, preventingropivacaine from penetrating the larger Aβfibres. However, the full explanation is like-ly to be more complex as the motor sparingdifferential block is not seen with other lesslipid soluble agents.

Structurally, ropivacaine has an asymmet-ric carbon so forms racemic mixtures,although the commercial preparation is thepurified S-isomer.30 This single isomer prepa-ration has reduced cardiovascular and centralnervous system toxicity compared to racemicbupivacaine, and adverse events followingaccidental intravascular injection may be eas-ier to treat.31 Relative to other agents the tox-icity of ropivacaine is intermediate betweenbupivacaine and lidocaine, although the tox-icity advantage over bupivacaine is offset byreduced potency. Despite encouraging lab-oratory reports of improved safety, systemictoxicity has occurred.32, 33

Etidocaine (Duranest)

Etidocaine [2-(N-ethylpropylamino)-butyro-2,6-xylidine], was first described by Adams in1972. It has a similar structure to lidocaine.Clinically, it has an equally rapid onset ofaction, but a much more prolonged dura-tion. It produces a very intense motor block,thought to be due to high lipid solubility.Predictably, this confers high potency andconcentrations of 0.25-1.5% are used. Theprofound motor block has prevented etido-caine from gaining popularity in obstetricanalgesia where maintained ambulation iscurrently desirable.

Prilocaine (Citanest, Xylonest, Distanest)

Originally described by Lofgren and Tegnerin 1960 prilocaine [N-(2-propylaminopropi-onyl)-O-toluidine] is a secondary amide ana-logue of lidocaine, with a similarly rapidonset, but longer duration.34 The O-toluidinestructure lacks an aromatic methyl group,which are present on most other amides.Tissue uptake and metabolism are rapid soplasma levels fall quickly. This feature increas-es the safety profile of prilocaine, making ita popular choice for IVRA. Toxicity may be



manifest by the usual signs and symptomsof local anaesthetic overdose. In addition,ortho-toluidine, one of the breakdown prod-ucts of prilocaine metabolism, is able to con-vert ferrous iron to ferric iron in haemoglo-bin, causing methaemoglobinaemia. Treat-ment is with high concentrations of oxygenand intravenous methylene blue (1 mg/kg).Neonates are particularly at risk because theirred cells are deficient in methaemoglobinreductase. Interestingly, high doses of meth-ylene blue (>7 mg/kg) may also causemethaemoglobinaemia.

Prilocaine is also found in EMLA (EutecticMixture of Local Anaesthetics), an oil/wateremulsion containing 2.5% prilocaine and 2.5%lidocaine. Both constituents have a meltingpoint considerably higher than body tem-perature, yet combined as a eutectic mixturethey have a lower melting point (18 °C) thaneither substance separately. Room tempera-ture is cool enough for EMLA to exist as acream, which then liquefies slightly in contactwith the skin. EMLA is able to penetrate theskin easily so is used extensively in paedi-atrics to reduce the pain of venepuncture.Caution must be exercised when using largeamounts as methaemoglobinaemia has beendescribed.35, 36 Broken or inflamed skinshould be avoided as absorption may great-ly exceed that intended.

Articaine (Carticaine, Ultracaine, Septanest,Astracaine)

Articaine {4-methyl-3-[2-(propylamino)pro-pionamido]-2-thiophenecarboxylate}, wassynthesized in 1969 by Rusching, but notused clinically until the mid-1970s in Ger-many.37 Unlike other amide local anaesthet-ics articaine has a thiophene ring. Thisincreases its lipid solubility to a value close tothat of prilocaine and not surprisingly it isused in similar concentrations (2-4%). It hasa low pKa and clinical studies have confirmeda rapid onset of action. Protein binding ishigh and a prolonged duration might beexpected. However, unlike other amide localanaesthetics articaine contains an additionalester group, so that metabolism occurs in theplasma by non-specific cholinesterases as

well as in the liver. The rapid offset of arti-caine has been demonstrated by Allman inophthalmic blocks, where it may prove use-ful as ocular movement returns rapidly afterthe completion of surgery. In addition, therapid fall in plasma levels will also reducethe risks of toxicity. However, in patientswith known deficiency of plasma cholineste-rases an alternative choice would be appro-priate.

Toxicity

Local anaesthetics are safe drugs, but theyhave the potential to cause serious harm ifused without caution. In 1979 Albright’s edi-torial drew the attention of the anaestheticcommunity to the risks of intravascular injec-tion of etidocaine and bupivacaine.25 He high-lighted the unreliability of the aspiration test,the fact that cardiovascular collapse couldoccur without preceding hypoxia and thatresuscitation may be difficult. Such severereactions are rare, but can follow absorptionof an inappropriately high dose, or acciden-tal intravascular injection of an appropriatedose. The magnitude of the effect will dependon the toxicity of the drug, the dose admin-istered, the speed and site of administration,as well as the physical status of the patient interms of age, medical conditions and preg-nancy. Methods to reduce the incidence ofthese events include careful techniques ofneedle placement, aspiration prior to everyslow injection, the use of a test dose, frac-tionated doses, adequate time between dos-es, the use of a less toxic local anaesthetic,awareness of maximum doses in differentsettings, and the addition of other agents(opioids, clonidine, hyaluronidase, bicar-bonate, epinephrine) to reduce the amount oflocal anaesthetic required.

When toxicity occurs the sequence of sys-tem involvement depends upon the routeof administration and the speed at whichtoxic plasma levels occur. If plasma levelsrise slowly the central nervous system (CNS)is affected first. Symptoms are generally exci-tatory, possibly due to inhibition of inhibito-ry neurons via GABA receptors. Patients may



report perioral and tongue paraesthesia, ametallic taste, and dizziness, then developslurred speech, diplopia, tinnitus, confusion,restlessness, muscle twitching and convul-sions. At higher plasma levels there is wide-spread sodium channel blockade with moregeneralised neuronal depression leading tocoma. Treatment should be relatively straight-forward and is aimed at maintaining oxy-genation, fluids, vasopressors, inotropes withthe use of anticonvulsants where appropri-ate.

Cardiovascular toxicity can be difficult totreat and usually follows CNS symptoms,unless the overdose has occurred by intravas-cular injection, when cardiovascular collapsemay occur almost immediately. Imminenttoxicity may be heralded by development ofbradycardia, with a long PR interval andwidened QRS complex. Increasing blood lev-els lead to varying degrees of block, theappearance of multi-focal ectopic beats, re-entrant arrhythmias, tachycardia and ven-tricular fibrillation. Similarly to CNS toxicity,treatment is supportive, relying on the useof oxygen, fluids, vasopressors, inotropesand anti-arrhythmics where needed. Amioda-rone and bretylium may be useful, and thereis evidence suggesting lipid emulsion infu-sions and clonidine may have a role.38, 39

Circulatory arrest due to bupivacaine and eti-docaine may be refractory to treatment, andas depression of neurological functioninduced by the local anaesthetic may have aneuro-protective role, resuscitation shouldbe prolonged.

There is an increasing amount of laboratorydata confirming the improved safety of thenew single isomer local anaesthetics. Caremust be taken in interpretation of some ofthese comparative studies as equal doses ofdrugs with differing potencies are adminis-tered. Nancarrow et al. administered toxicintravenous doses of bupivacaine, ropiva-caine and lidocaine to sheep, and found aratio of lethal doses of 1:2:9.40 Lidocaine treat-ed sheep died with respiratory depression,bradycardia and hypotension, but withoutarrhythmias, whereas 3 of 4 bupivacaine treat-ed sheep died after sudden onset of ventric-ular arrhythmias in the absence of hypoxia or

acidosis. The ropivacaine treated sheep diedin a similar way to the lidocaine treatedsheep, but with the addition of ventriculararrhythmias, or as a result of the sudden onsetof ventricular arrhythmias alone. The arrhyth-mias precipitated by local anaesthetics are aresult of depression of the rapid depolarisa-tion phase (Vmax) of the cardiac action poten-tial. This leads to slowed conduction withprolongation of the PR and QRS interval,allowing re-entrant rhythms and predisposingto ventricular tachycardia. Arlock quantifiedthis effect by measuring Vmax in a guinea pigmodels, showing that bupivacaine depressedVmax more than lidocaine, with ropivacaineintermediate.41

The effects of arrhythmias on cardiac out-put are augmented by myocardial depres-sion. The precise effects of different localanaesthetics on myocardial function may beconfounded in whole animal models as localanaesthetic-induced convulsions are associ-ated with cardiovascular stimulation.42 In anattempt to isolate the cardiovascular effectsChang et al. infused bupivacaine, levobupi-vacaine and ropivacaine directly into thecoronary arteries of conscious sheep.43 Nosignificant differences were found in survivalor fatal doses, indicating that, unlike withintravenous infusions, when these agents areinfused directly into coronary arteries theymay have equal cardiac toxicity.44 Grobanused an anaesthetised dog model to com-pare the arrhyhthmogenicity of bupivacaine,levobupivacaine, lidocaine and ropivacaine.No difference was found between bupiva-caine or either of the single isomeric forms.45

In a similar experiment Morrison comparedintracoronary injections of bupivacaine, lev-obupivacaine and ropivacaine in anaes-thetised swine.46 Unlike Chang they foundlittle difference in fatal dose between lev-obupivacaine and ropivacaine, but greatercardiotoxicity with racemic bupivacaine.Feldman et al. showed that similar doses ofropivacaine and bupivacaine caused con-vulsions in dogs, but that the mortality ratewas lower in the ropivacaine treated ani-mals.31 Isolated organ experiments havelinked local anaesthetic toxicity in the brainwith disturbances in the heart.47 The variation



in results noted in these studies may be aresult of species-specific differences inresponse or may be a reflection of the com-plex interplay between the CNS, themyocardium, and general anaesthesia dur-ing local anaesthetic toxicity.

The results from animal studies sometimesconflict, and translating these results tohuman subjects may not be appropriate.Consequently, healthy volunteer studies havecompared the cardiovascular and CNS effectsof intravenously infused local anaesthetics.Scott administered a maximum of 150 mg ofropivacaine and racemic bupivacaine to vol-unteers.48 Of the 12 subjects, seven toleratedthe maximum dose of ropivacaine, whereasonly 1 subject was able to tolerate 150 mg ofbupivacaine. Plasma levels showed that CNSand cardiovascular symptoms occurred atlower plasma levels with bupivacaine thanropivacaine. In addition, myocardial depres-sion and prolongation of the QRS intervalwere reduced with ropivacaine. Bardsley etal. used intravenous infusions of lidocaineto familiarise 12 healthy volunteers with theCNS effects of local anaesthetic toxicity.23 Afew days later the volunteers received intra-venous infusions of levobupivacaine or bupi-vacaine at a rate of 10 mg/min until they hadreceived 150 mg, or had begun to experi-ence CNS toxic effects. Cardiovascular mon-itoring demonstrated that, despite higher plas-ma levels, levobupivacaine depressedmyocardial function significantly less thanbupivacaine (mean [SD] stroke index –5.2[7.4] ml · m-2 vs -11.9 [8.4] ml · m-2, p=0.001).Equal doses of intravenous levobupivacainewere compared with ropivacaine by Stewartet al.49 No differences were found in terms ofCNS symptoms or cardiovascular effects.Animal and human volunteer studies haveshown improved safety with levobupivacaineand ropivacaine in terms of convulsive thresh-old, arrhythmogenicity, myocardial depres-sion and ease of resuscitation in comparisonwith racemic bupivacaine. Despite theseadvantages they may still provoke severe tox-ic reactions. In addition, the improved safe-ty margin may be offset by reduced localanaesthetic potency, particularly with ropi-vacaine.

Allergy

Monk reported the first case of allergy tolocal anaesthetics in 1920.50 He describedthe development of contact dermatitis in thehands of a dentist who was repeatedlyexposed to apothesin, an ester local anaes-thetic. Further reports of mild hypersensi-tivity reactions followed, but very fewpatients developed anaphylaxis.51 The aller-genic trigger was found to be para-aminobenzoic acid (PABA), which is gener-ated as an intermediate metabolite on esterhydrolysis. Sensitivity to PABA may occurthrough exposure to ester local anaesthet-ics, or to cosmetics and foodstuffs that con-tain preservatives that are antigenically sim-ilar. In addition, sulphonamide substancesstructurally resemble PABA so cross reactiv-ity may occur when sulphonamide sensitivepatients are then exposed to ester local anes-thetics.

The development of amide local anaes-thetics in the 1940s reduced reporting of aller-gic reactions. Allergy to amides is now recog-nised as being extremely rare, with somespecialists estimating that less than 1% ofreported allergic reactions to amide localanaesthetics represent true immune systemmediated responses.51 Local anaesthetics aretoo small (<300 daltons) to be antigenic, butmay bind to plasma or tissue proteins as ahapten that possesses antigenic properties.

Reports of allergic reactions are common-ly reported to have occurred in the dentalchair following a local anaesthetic injection.In reality this is likely to have been a vaso-vagal response in a highly anxious patientin an upright dental chair. Alternatively, theymay have received an intra-vascular injec-tion of local anaesthetic containing epi-nephrine with surprising and unpleasant car-diovascular effects. However, although aller-gy to amide local anaesthetics is rare thesereports must be taken seriously and appro-priate investigations or referral organised.Allergists may perform skin prick testing forthose with a history of mild allergy, or uselaboratory in vitro tests (lymphocyte prolif-eration test) in patients with a history of ana-phylaxis.



Local toxicity

Localised toxicity occurs following injectionof local anaesthetic directly into a structure orwhen a structure is exposed to a high con-centration for a prolonged period. Directinjection into a muscle provokes an intenseinflammatory reaction resulting in areas ofmuscle necrosis, which is worsened by addedvasoconstrictors.52 Healing may be accom-panied by fibrosis and localised contracture,which is rarely significant, except in oph-thalmic local anaesthesia where damage todelicate extra-ocular muscles may producerestrictive muscle defects resulting in symp-tomatic diplopia and the need for correctivestrabismus surgery.

Reports of transient radicular irritation andconus medullaris syndrome following spinalanaesthesia with the use of 5% lidocaine,or where microcatheters were used for con-tinuous spinal analgesia, have alerted anaes-thetists to the potential problems of localanaesthetic-induced neurotoxicity.53, 54

Although attributed to the use of highly con-centrated local anaesthetic there is laboratoryevidence that even clinically useful con-centrations of lidocaine (2%) are able tocause neurotoxicity.22 Despite this unset-tling evidence, neurotoxicity is rarely a clin-ical problem.

Future developments

Liposomes

None of the available local anaesthetics, intheir current formulation, have a durationbeyond a few hours. A slightly more pro-longed action may be achieved by adding avasoconstrictor, which reduces washout ofthe local anaesthetic. Where local anaes-thetic action is required for days or weeks,an infusion device using a catheter andmechanical pump are required. However,the local anaesthetic reservoir and pumpare often bulky devices, prone to technicalproblems, and the catheter and connectionsmay be a significant source of infection. Apossible solution is the development of lipo-

somal preparations. Liposomes are small(0.03-10 µm) hollow spheres with a phos-pholipid bilayer wall. High concentrations oflocal anaesthetic solution in an aqueousmedium can be encapsulated within theliposome. They are biocompatible, non-immunogenic and degrade slowly allowinggradual release of their contents. In addi-tion, their relatively large size prevents dis-persal away from the site of injection. Theslow release of local anaesthetic preventshigh peak plasma levels reducing thechances of systemic toxicity. Clinical studieswith a variety of agents have shown promis-ing prolongation of the duration of localanaesthetic action.55-57 The technology ofliposomal local anaesthetics is exciting, withthe prospect of a preparation comprised ofa solution of fast acting local anaestheticcontaining liposomes filled with long act-ing local anaesthetic agent ie fast onset andvery prolonged duration. However, at pre-sent there are significant problems to beovercome to achieve a stable formulation,without batch to batch variations in phys-iochemical properties, and there is still rel-atively little data on the safety of these com-pounds in humans.58

Butyl amino-benzoate

A new agent for nerve blockade is butylamino-benzoate (BAB). Originally discov-ered in 1923 BAB has interesting properties.Unlike most current local anaesthetics it hasa very low pKa and is poorly soluble in bothaqueous and lipid mediums. Myelin and dur-al permeability is very limited. It appears to beselective for Aδ- and C- fibres so that it pro-duces minimal motor block. It undergoes rapidhydrolysis, although the duration of blockmay be exceedingly prolonged (weeks). Thisis probably related to the formulation whichhas a slow release effect. It is suspended inpolyethylene glycol and polysorbate-80(Butamben) and has been demonstrated toproduce a prolonged effect when adminis-tered via the epidural route in oncologypatients.59 Consequently, it may provide auseful alternative to phenol or alcohol neu-rolysis.



Riassunto

Gli anestetici ad azione locale. Una review

Gli anestetici ad azione locale attualmente disponi-bili sono in grado di garantire un blocco nervoso dialta qualità in un’ampia gamma di circostanze cliniche.La nostra comprensione dei meccanismi e delle con-seguenze della tossicità sta aumentando rapidamente.La comprensione della struttura chimica degli anesteti-ci ad azione locale ha reso i clinici in grado di sfruttarel’aumentata sicurezza di singoli isomeri. Tuttavia,l’ampiezza, se esiste, di questo miglioramento dellatossicità deve ancora essere provata. La tossicità notapuò essere molto difficile da trattare e non è ancoradisponibile alcuna terapia specifica invertente. Sino ache questo non accadrà è essenziale che i sommin-istratori di anestesia regionale siano preparati ed abilicirca le tecniche di somministrazione di anestetici adazione locale, che siano in grado di riconoscere i dis-astri imminenti e che aggiornino costantemente laloro abilità nella rianimazione.

Parole chiave: Agenti anestetici - Anestetici locali -Anestesia.

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LA

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