Essential o FLocal Anestezice(1)

98

Anesth Prog 53:98–109 2006 ISSN 0003-3006/06/$9.50� 2006 by the American Dental Society of Anesthesiology SSDI 0003-3006(06)

CONTINUING EDUCATION

Essentials of Local Anesthetic Pharmacology

Daniel E. Becker, DDS,* and Kenneth L. Reed, DMD†*Professor of Allied Health Sciences, Sinclair Community College, and Associate Director of Education, Miami Valley Hospital,Dayton, Ohio; †Private practice limited to anesthesia for dentistry, Arizona, and Clinical Associate Professor, The Oregon Health &Sciences University School of Dentistry, Portland, Oregon, and Clinical Associate Professor, Department of Maxillofacial Surgery,Section of Anesthesia and Medicine, School of Dentistry, The University of Southern California, Los Angeles, California

It is impossible to provide effective dental care without the use of local anesthetics.This drug class has an impressive history of safety and efficacy, but all local anes-thetics have the potential to produce significant toxicity if used carelessly. The pur-pose of this review is to update the practitioner on issues regarding the basic phar-macology and clinical use of local anesthetic formulations.

Key Words: Local anesthetic pharmacology

GENERAL PROPERTIES OF LOCALANESTHETICS

Local anesthetics interrupt neural conduction by inhib-iting the influx of sodium ions. In most cases, this followstheir diffusion through the neural membrane into theaxoplasm, where they enter sodium channels and pre-vent them from assuming an active or ‘‘open’’ state.The local anesthetic molecule consists of 3 components:(a) lipophilic aromatic ring, (b) intermediate ester or am-ide chain, and (c) terminal amine. Each of these con-tributes distinct properties to the molecule (Figure 1).

The aromatic ring improves the lipid solubility of thecompound, which can be enhanced further by aliphaticsubstitutions at locations designated (R). Greater lipidsolubility enhances diffusion through nerve sheaths, aswell as the neural membranes of individual axons com-prising a nerve trunk. This property correlates with po-tency because a greater portion of an administered dosecan enter neurons. Because bupivacaine is more lipidsoluble than lidocaine, it is more potent and is preparedas a 0.5% concentration (5 mg/mL) rather than a 2%concentration (20 mg/mL).

The terminal amine may exist in a tertiary form (3bonds) that is lipid soluble or as a quaternary form (4bonds) that is positively charged and renders the mole-cule water soluble. As explained above, the aromaticring determines the actual degree of lipid solubility, but

Received January 22, 2006; accepted for publication January 22,2006.

Address correspondence to Daniel E. Becker, DDS, 444 West 3rdStreet, Dayton, OH 45402.

the terminal amine acts as an ‘‘on-off switch’’ allowingthe local anesthetic to exist in either lipid-soluble or wa-ter-soluble conformations. The tertiary and quaternaryforms each play a pivotal role in the sequence of eventsleading to conduction block.

For the local anesthetic base to be stable in solution,it is formulated as a hydrochloride salt. As such, themolecules exist in a quaternary, water-soluble state atthe time of injection. However, this form will not pen-etrate the neuron. The time for onset of local anesthe-sia is therefore predicated on the proportion of mole-cules that convert to the tertiary, lipid-soluble structurewhen exposed to physiologic pH (7.4). The ionizationconstant (pKa) for the anesthetic predicts the proportionof molecules that exists in each of these states. By def-inition, the pKa of a molecule represents the pH atwhich 50% of the molecules exist in the lipid-solubletertiary form and 50% in the quaternary, water-solubleform. The pKa of all local anesthetics is �7.4 (physio-logic pH), and therefore a greater proportion the mol-ecules exists in the quaternary, water-soluble form wheninjected into tissue having normal pH of 7.4. Further-more, the acidic environment associated with inflamedtissues favors the quaternary, water-soluble configura-tion even further. Presumably, this accounts for difficultywhen attempting to anesthetize inflamed or infected tis-sues; fewer molecules exist as tertiary lipid-soluble formsthat can penetrate nerves. In these situations, bupiva-caine (pKa 8.1) would be least effective and mepiva-caine (pKa 7.6) would be most likely to provide effectiveanesthesia (Figure 2).

The intermediate chain or linkage provides a conve-

Anesth Prog 53:98–109 2006 Becker and Reed 99

Figure 1. Local anesthetic structure. All local anesthetics con-sist of 3 principal components, each contributing a distinctproperty.

Figure 2. Local anesthetic action. An injected local anestheticexists in equilibrium as a quaternary salt (BH�) and tertiarybase (B). The proportion of each is determined by the pKa ofthe anesthetic and the pH of the tissue. The lipid-soluble spe-cies (B) is essential for penetration of both the epineurium andneuronal membrane. Once the molecule reaches the axoplasmof the neuron, the amine gains a hydrogen ion, and this ion-ized, quaternary form (BH�) is responsible for the actual block-ade of the sodium channel. Presumably, it binds within thesodium channel near the inner surface of the neuronal mem-brane.

Table 1. Characteristics and Clinical Correlates

Characteristic Correlate Explanation

Lipid solubility Potency Greater lipid solubility enhances diffusion through neural coverings and cellmembrane, allowing a lower milligram dosage.

Dissociation constant Time of onset Determines the portion of an administered dose that exists in the lipid-solu-ble, tertiary molecular state at a given pH. Agents having a lower pKahave a greater proportion in the tertiary, diffusable state, and this hastensonset.

Chemical linkage Metabolism Esters are principally hydrolyzed in plasma by cholinesterases; amides areprimarily biotransformed within the liver.

Protein binding Duration Affinity for plasma proteins also corresponds to affinity for protein at the re-ceptor site within sodium channels, prolonging the presence of anestheticat the site of action.

nient basis for classification and also determines the pat-tern of biotransformation. Esters are hydrolyzed by plas-ma esterases, whereas amides are biotransformed in theliver. Esters are no longer packaged in dental cartridgesand are used infrequently with the exception of benzo-caine, which is found in several topical anesthetic prep-arations.

Like other drugs, local anesthetics vary in their ten-dency to bind with plasma proteins. When circulating inthe bloodstream, they bind to alpha-1-acid glycoprotein(acidic drugs more likely bind to albumin). This propertyof protein binding correlates with their affinity for pro-tein within sodium channels and predicts the durationthey will sustain neural blockade. Bupivacaine has thegreatest percent protein binding and is the longest act-ing of local anesthetics available in dental cartridges.The clinical performance of local anesthetics correlateswith 4 principal characteristics or properties that aresummarized in Table 1.

SYSTEMIC TOXICITY

Local anesthetics depress the central nervous system ina dose-dependent manner (see Figure 3). Low serumconcentrations are used clinically for suppressing cardi-

ac dysrhythmias and status seizures, but higher concen-trations induce seizure activity. Convulsive seizures arethe principal life-threatening consequence of local an-esthetic overdose. Presumably this is due to selective de-pression of central inhibitory tracts, which allows excit-atory tracts to run amuck. Evidence of lidocaine toxicitymay commence at concentrations �5 �g/mL, but con-vulsive seizures generally require concentrations �8 �g/mL.

In addition to neural blockade, peripheral actions ofmost local anesthetics include varying degrees of vaso-dilation, and this contributes to the hypotension ob-served after administration of large doses. It is essentialthat local anesthetics be respected as central nervoussystem depressants, and they potentiate any respiratorydepression associated with sedatives and opioids. Fur-thermore, serum concentrations required to produce

100 Essentials of Local Anesthetic Pharmacology Anesth Prog 53:98–109 2006

Figure 3. Systemic influences of lidocaine.

Figure 4. Serum concentrations following 3 routes of admin-istration.

seizures are lower if hypercarbia (elevated carbon diox-ide) is present. This is the case when respiratory de-pression is produced by concurrent administration ofsedatives and opioids. Goodson and Moore1 have doc-umented catastrophic consequences of this drug inter-action in pediatric patients receiving preoperative se-dation, along with excessive doses of local anesthetics.

Before we address the variables that influence system-ic serum concentrations, please consider the followingsuggestion for dose calculations. Percent solutions re-flect grams of solute (drug) dissolved in 100 mL of sol-vent. A 3% mepivacaine solution contains 3 g mepiva-caine dissolved in each 100 mL of solvent. Convertingthis to milligrams per milliliter, or milligrams per car-tridge, is bothersome. For convenience, use the follow-ing suggestions. First of all, consider anesthetic cartridg-es as containing 2 mL, not 1.8 mL. This error will over-estimate the dose and is therefore a safe practice. Fora given percent solution, move the decimal 1 place tothe right; the resulting number will reflect milligrams permilliliter. For example, 3.0% mepivacaine is 30 mg/mL.A dental cartridge contains 2 mL and therefore contains�60 mg of mepivacaine. Bupivacaine 0.5% contains 5mg/mL and therefore �10 mg per cartridge. After in-jection of 2½ cartridges of 2% lidocaine it is convenientto consider this as �5 mL at 20 mg/mL or 100 mgtotal.

In 1972, Scott et al2 published a study in a series ofclinical studies assessing variables that determine sub-sequent concentrations of local anesthetics in serum.The serum concentration was found to vary accordingto the route by which the anesthetic is injected. Usinglidocaine 400 mg, the highest serum levels illustrated inFigure 4 followed infiltration of vaginal mucosa and the

lowest followed subcutaneous abdominal infiltration. Ineach case, however, peak serum level occurred 20–30minutes after injection of lidocaine alone. Regardless ofthe route of administration, peak levels were reducedand the rate of absorption was delayed by adding va-sopressors such as epinephrine to the local anestheticsolution. It is reasonable to assume that systemic con-centrations after submucosal injection in the oral cavitywould approximate those after injection into vaginal mu-cosa because of similar vascularity.

Additional variables were also addressed during theselandmark studies. As expected, the dose and speed ofinjection are directly related to ultimate systemic serumconcentration. A solution’s concentration (eg, 2% vs3%) is not relevant; the systemic concentration dependson the total dose (eg, 20 mL of 3% or 30 mL of 2%each amount to 600 mg and produce the same serumconcentration). When using lidocaine or other anesthet-ics in concentrations �2%, one must consider the dose(milligrams) administered, not the volume (milliliters orcartridges).

Contrary to conventional thought, the age or weightof a patient does not predict systemic serum concentra-tion following doses calculated as mg/y age or mg/kg.When managing pediatric patients, maximum doses areconventionally expressed in mg/kg, and this should befollowed as a precaution. It is of little relevance foradults, however, and one should follow guidelines ex-pressed as maximum dose in milligrams, regardless ofweight or age. Obviously, this maximum amount shouldnot be exceeded when calculating doses for large chil-dren.

When considering the toxicity of any drug class, oneshould be mindful of metabolites, as well as the parentdrug. Local anesthetics are no exception. Lidocaine isbiotransformed in the liver to monoethylglycinexylidideand glycinexylidide. These metabolites have significantactivity and have been implicated in cases of lidocainetoxicity after repeated doses and continuous intravenousinfusions.

A metabolite of prilocaine, 0-toluidine, can oxidizethe iron in hemoglobin from ferrous (Fe2�) to ferric


Figure 5. Carrier � hapten � immunogen.

Figure 6. Sulfonamide as hapten.

(Fe3�). Hemes so altered do not bind oxygen, and nor-mal hemes on the same hemoglobin molecule do notreadily release their oxygen. This form of hemoglobinis called methemoglobin, and when �1% of total he-moglobin is so altered, the condition is called methe-moglobinemia. Patients appear cyanotic and becomesymptomatic when the proportion of methemoglobinexceeds 10 to 15%.3 The condition is rarely life threat-ening and responds to intravenous methylene blue,which reduces the hemes to their normal state. Methe-moglobinemia attributed to prilocaine is unlikely to fol-low the administration of recommended doses. Rarely,one may encounter a patient with hereditary methe-moglobinemia, which contraindicates the use of prilo-caine.

ALLERGY TO LOCAL ANESTHETICS

It is not unusual for patients to claim they are allergic tolocal anesthetics. Upon careful questioning, however,one generally finds that what they experienced was ei-ther a syncopal episode associated with the injection orcardiac palpitations attributed to epinephrine either con-tained in the solution or released endogenously. Al-though rare, reports of allergic reactions to local anes-thetics have appeared in scientific literature, but noneof these have confirmed an IgE-mediated hypersensitiv-ity reaction. Nevertheless, patients have occasionally ex-perienced symptoms consistent with an allergic reactionto amide local anesthetics.4,5 In some cases, these epi-sodes have been attributed to preservatives (methylpara-ben) or antioxidants (bisulfites) contained in the solu-tion.6 Methylparaben is included in multidose vials toprevent microbial growth. It is no longer found in single-dose vials or dental cartridges. Metabisulfites prevent theoxidation of vasopressors and are included only in den-tal cartridges containing epinephrine or levonordefrin.To clarify several misconceptions regarding allergic re-actions, a brief review of their pathogenesis is in orderas presented by Adkinson.7

For drugs to be immunogenic, they must be of largemolecular weight and possess multiple valences to berecognized by the immune cells. Large proteins such asinsulin fulfill these requirements and are well establishedas immunogenic. Most other molecules are too smalland must combine with other molecules that act as car-riers, in which case the drug is described as a hapten.This complex of a carrier and hapten can induce andelicit an allergic reaction (Figure 5). Frequently, a me-tabolite of the drug is the actual molecule that functionsas the hapten. This is true for beta lactam and sulfon-amide antibiotics. In the case of sulfonamides, the phe-nyl ring containing an amine substitution is the moietyparticipating in the formation of the immunogenic com-plex (Figure 6). This moiety is common to other deriv-atives of para-aminobenzoic acid (PABA) such as meth-ylparaben and some, but not all, ester local anesthetics.In these cases there may be the potential for cross al-lergenicity among similar compounds because of a com-mon moiety (eg, sulfa antibiotics, methylparaben, andesters of PABA).

It is careless to describe ‘‘esters’’ as more allergenicthan amide local anesthetics. An ester is merely a chem-ical linkage and imparts no immunogenicity to a com-pound. Rather, it is a molecular component joined bythis linkage that is the culprit. This misconception hascaused several agents to be inaccurately labeled as‘‘cross-allergenic’’ with sulfonamides. Articaine is clas-sified as an amide local anesthetic because of the linkagebetween its lipid-soluble ring and terminal amine. Itsthiophene ring contains a sulfur atom, which has noimmunogenic property, and an ester side chain that ren-ders the compound inactive after hydrolysis. However,articaine does not liberate a metabolite resemblingPABA and does not introduce concern regarding im-munogenicity. In contrast, procaine is representative ofesters derived from PABA and hydrolysis liberates amoiety that is potentially immunogenic (Figure 7).

A final misconception pertains to sulfites. These areincluded in local anesthetic solutions containing vaso-


Figure 7. Ester linkages of procaine and articaine.

Figure 8. Managing patients allergic to local anesthetics. Rule out common reactions misinterpreted as allergy (eg, syncope andtachycardia). Then establish that the nature of their reaction at least resembled a hypersensitivity reaction (eg, rash, pruritus,urticaria, dyspnea). If the drug is known, choose another amide, free of vasopressor so no bisulfites are present. Otherwise, referto an allergist, sharing this figure if necessary. Adapted from deShazo RD, Kemp SF. JAMA. 1997;278:1903.

pressors to prevent their oxidation. They are inorganiccompounds (�SO3) that have been implicated in allergicreactions, but they have no relation to immunogenicityattributed to PABA-related compounds. These agentsare also used as antioxidants in fresh fruits and vegeta-

bles to preserve their color and overall appearance. Pa-tients claiming allergy to such foods may experiencecross-reactions with local anesthetic solutions containingvasopressors.

Drug reactions with clinical manifestations suggestiveof immunological mechanisms, but known to lack animmune basis, are conventionally regarded as ‘‘pseu-doallergic’’ reactions. Such reactions are idiosyncratic inmechanism and should be distinguished from true aller-gy. When these reactions mimic the more severe IgE-independent syndromes, they are described as ‘‘ana-phylactoid’’ rather than anaphylactic. Anaphylactoid re-actions involve the same final common pathway as trueallergy, but the mechanism for the release of the vaso-active mediators is not immune mediated.

If a patient describes a reaction that is clinically con-sistent with allergy, the dentist should avoid using theoffending agent until it is evaluated by an allergist. In theevent an anesthetic is required before medical clearancecan be obtained, the wisest choice would be either me-pivacaine or prilocaine without vasopressors. Conven-tional wisdom holds that, if local anesthetics do indeedproduce allergies, esters of PABA would be capable ofcross-reacting, but this would not be likely among amidelocal anesthetics. Furthermore, by avoiding those solu-tions containing vasopressors, one avoids bisulfites thatare included as antioxidants. Sensitivity to bisulfites ispossible, especially among asthmatic or atopic patients.These principles are the basis for the flowchart pre-sented in Figure 8. A patient should never be denied thebenefit of local anesthesia because of flawed assump-tions regarding allergy.


Table 2. Local Anesthetics Available in Cartridges11

Duration (min)

Anesthetic Preparation

Maximum SingleDose (mg)

mg/kg Total

MaximumInfiltration

PulpalSoft

Tissue

Inferior AlveolarBlock

PulpalSoft

Tissue

2% Lidocaine; 1 : 100,000 or 1 : 50,000 epinephrine3% Mepivacaine2% Mepivacaine; 1 : 20,000 levonordefrin4% Prilocaine4% Prilocaine; 1 : 200,000 epinephrine4% Articaine; 1 : 100,000 epinephrine0.5% Bupivacaine; 1 : 200,000 epinephrine

76.676*6*

7(5)†—

500400550400400—90

60255020406040

17090

130105140170340

854075556090

240

190165185190220220440

* Dose for prilocaine is conservative; some references allow 8 mg/kg and 600 mg total.† Dose for articaine is 7 mg/kg in the US package insert, but the Canadian package insert suggests 5 mg/kg for children.

LOCAL ANESTHETIC COMPARISONS

Cocaine was the first local anesthetic, discovered in1860. It is unique among the local anesthetics because,in addition to blocking impulse conduction along axons,it inhibits reuptake of neurotransmitters by adrenergicneuronal endings. Peripherally, this results in an accu-mulation of norepinephrine within sympathetic synap-ses leading to vasoconstriction and cardiac stimulation.Centrally, accumulation of norepinephrine results ingeneralized central nervous system stimulation. How-ever, additional adrenergic neurotransmitters are foundwithin the central nervous system, and their reuptake isinhibited as well. In particular, cocaine’s inhibition of do-pamine reuptake is pronounced and responsible for itseuphoric effect and potential for abuse. For all thesereasons, and because it has no greater anesthetic effi-cacy, cocaine receives little use medically except for top-ical application during certain ear-nose-throat and oph-thalmologic procedures. Because of the potential foradded sympathomimetic effects, epinephrine should beavoided when administering local anesthetics to patientssuspected of recent cocaine consumption.

Procaine (Novocain) was introduced in 1905 and be-came the first local anesthetic to gain wide acceptancein the United States. However, its popularity declinedafter the introduction of lidocaine in 1948. Today, li-docaine is the most widely used agent, but all local an-esthetics have comparable efficacy. They differ in po-tency and several pharmacokinetic parameters that ac-count for differences in the onset and duration of an-esthesia. Selection of a particular agent must take intoaccount the duration of the procedure planned and is-sues regarding vasopressor concentrations. For lengthyprocedures, bupivacaine is the logical choice, but it hasbeen implicated as one of the more painful agents dur-ing injection according to studies that have comparedvarious anesthetics.8–10 One strategy is to provide the

initial 60–90 minutes of anesthesia with a less irritatingagent (lidocaine or prilocaine) and then reinject theanesthetized tissue with bupivacaine to provide analge-sia well into the postoperative period. Such a strategyis most effective after nerve blocks; shorter durationshould be anticipated after soft tissue infiltration. SeeTable 2 for durations and maximum doses.

Despite anecdotal claims regarding the superiority ofarticaine (Septocaine, Ultracaine), double-blind studieshave confirmed that efficacy is comparable with lido-caine.12,13 Nevertheless, articaine has certain featuresthat make it an attractive choice for selected cases. Un-like other anesthetics having benzene as their aromaticring, articaine has a thiophene ring, which confersgreater lipid solubility than lidocaine. This propertyshould have allowed a lower concentration, but in factit was formulated as a 4% solution. Claims for successfulanesthesia after infiltration of the mandible are likely at-tributable to high lipid solubility and more molecules permilliliter injected when compared with lidocaine. Todate, there have been no published studies comparingarticaine with 4% lidocaine solutions for mandibular in-filtration. Furthermore, such concentrations of lidocainepresent an unacceptable risk for systemic toxicity, andthis concern introduces another attractive property ofarticaine, namely, pattern of clearance.

Although articaine is classified as an amide becauseof linkage of its intermediate chain, the thiophene ringalso contains an ester side chain. This chain is hydro-lyzed by plasma esterases rendering the molecule inac-tive. The result is that articaine has a half-life of only 20minutes compared with �90 minutes for lidocaine andother amides that require hepatic clearance. For thisreason, articaine presents less risk for systemic toxicityat equipotent doses (eg, 1 cartridge 4% articaine vs 2cartridges 2% lidocaine). Presumably, this principlewould also confer greater safety during lengthy appoint-ments when additional doses of anesthetic must be ad-


Table 3. Incidence of Paresthesia in Canada During 199314

Anesthetic (No. ofCartridges Administered)

Cases ofParesthesia

Articaine (4,398,970)Prilocaine (2,353,615)Lidocaine (3,062,613)Mepivacaine (1,569,037)Bupivacaine (241,679)

104000

ministered. It should be clarified that articaine is classi-fied molecularly as an amide, not an ester of PABA, anddoes not present any concern for cross-allergy to PABAderivatives.

The advantages of articaine are tempered somewhatby reports of paresthesia after its use for inferior alveolarblocks. Haas and Lennon14 reported an increased inci-dence of paresthesias in Canada after the introductionof articaine in the mid 1980s. In 1993 alone, 14 casesof paresthesia were reported, and all were attributed toarticaine or prilocaine (see Table 3). Although the over-all incidence of paresthesia is low, one cannot discountthe increased risk that is apparently associated withhigher concentrations of local anesthetics when used fornerve blocks.

As part of the approval process for a new drug inthe United States, certain data must be submitted tothe US Food and Drug Administration. When articainewas being submitted for approval, the following datawere part of that application process and are consis-tent with those of Haas and Lennon.14 The entire textof the document may be found by searching the USFood and Drug Administration web site for the Statis-tical Review of Application Number 20-971. Lookingat study #96001.02US on page 12 of the document,it reads, ‘‘Once again, the articaine group appears tohave significantly higher risk of paresthesia (10 in 569,vs. 1 in 284 in the lidocaine group).’’ So, it appearsthere is a concern with respect to paresthesia when4% local anesthetic solutions are used. As with alldrugs, each practitioner needs to perform a ‘‘risk-ben-efit’’ analysis before using a medication. Only if thebenefit of using articaine outweighs the risk for thispractitioner in this patient should it be considered foruse. It might be wise to limit the use of these agentsfor infiltration and reserve their use in nerve blocks forfailed attempts with other agents.

MAXIMUM DOSES FOR LOCAL ANESTHETICS

The final issue to be considered is the maximum amountof anesthetic that can be used in a given patient. Ac-cording to the data originally presented by Scott et al,2

lidocaine 400 mg injected submucosally produces sys-temic serum concentrations well below toxic levels. Thisis approximately the amount found in 10 anesthetic car-tridges, and this number is conventionally cited as thelimit per dental appointment. Summaries of these stud-ies, and others regarding additional local anesthetics,are the basis for the maximum recommended doses list-ed in Table 2. But current information has not addressedissues regarding lengthy dental procedures that may welloutlast the duration of anesthesia provided by conven-tional agents. In such cases, decisions regarding addi-tional doses must be predicated on empiric judgment.

The serum half-life (T1/2) of the various local anes-thetics ranges from 90 minutes for conventional agentssuch as lidocaine to nearly 300 minutes for agents suchas bupivacaine. This decline commences after peak con-centration is achieved and declines after approximately20–30 minutes with anesthetics alone. (The time topeak concentration when combined with vasopressorsis not well documented, but adding an additional 10–15minutes would be a reasonable estimate.) Once the peakconcentration is achieved, additional doses will absorbas original doses are in decline. This is a perilous timebecause one cannot accurately predict the serum con-centration at any period. Additionally, individual patientvalues cannot be absolutely known because of the bell-shaped pattern of distribution for patient responses andrenders these theoretical calculations even more prob-lematic. However, given the fact that solutions contain-ing vasopressors are absorbed slowly and their peakconcentrations are reduced, it seems reasonable to as-sume that doses that do not exceed one fourth of themaximum permissible dose listed in Table 2 could beadministered during each subsequent hour of treatment.This suggestion presumes the patient has adequate he-patic perfusion and function and is not medicated withagents that delay hepatic clearance. During lengthy pro-cedures, however, one should anesthetize and completetreatment in one region before anesthetizing another.By following this principle, it is rarely necessary to ex-ceed maximum recommended limits. When using acombination of agents, guidelines for maximum dosesshould be regarded as additive. For example, if half themaximum dose for lidocaine has been administered, itwould be safe to administer up to half the maximumdose for mepivacaine.

VASOPRESSORS

Vasopressors are combined with local anesthetics toprovide local hemostasis in the operative field and todelay their absorption. Delayed absorption of local an-esthetics not only reduces the risk for systemic toxicity,


Figure 9. Cardiovascular influences of epinephrine. Patientsreceived submucosal infiltration of 3 cartridges (5.4 mL) of 2%lidocaine and 2% lidocaine with epinephrine 1 : 100,000.Changes in cardiovascular parameters were recorded as per-cent change. Heart rate (HR), stroke volume (SV), and cardiacoutput (CO) determine systolic blood pressure. Peripheral re-sistance (PR) determines diastolic blood pressure. Mean arte-rial pressure (MAP) is calculated as (SBP � 2 � DBP)/3.Adapted from Dionne et al.17

Figure 10. Cardiovascular influences of norepinephrine (andlevonordefrin) versus epinephrine.18 A. Both drugs stimulateBeta1 receptors on cardiac muscle, which increase myocardialcontractility. This results in an increase in systolic pressure. B.Both drugs stimulate alpha receptors on vessels, which causesthem to constrict. Submucosal vessels contain only alpha re-ceptors, so both drugs produce local vasoconstriction wheninjected submucosally. But submucosal vessels are not illus-trated here; they do not influence diastolic pressure. Systemicarteries influence diastolic pressure and contain Beta2 recep-tors, which vasodilate and are far more numerous than alphareceptors. Norepinephrine has no affinity for Beta2 receptorsand constricts systemic arteries by activating the alpha recep-tors, even though they are less numerous. This increases dia-stolic pressure. Epinephrine, which has Beta2 as well as alphareceptor activity, produces vasodilation and a reduction in di-astolic pressure. C. Both drugs stimulate Beta1 receptors onthe Sino-atrial node, which increases heart rate. But this po-tential effect from norepinephrine is overridden by a reflexexplained as follows. Notice that epinephrine has no influenceon mean arterial pressure; systolic pressure increases but dia-stolic decreases and negates any effect on mean arterial pres-sure. Norepinephrine increases systolic, diastolic, and meanarterial pressures. The increase in mean arterial pressure stim-ulates baroreceptors in the carotid sinus, which trigger a vagalslowing of heart rate.

but also prolongs the duration of anesthesia. Epineph-rine is the most common agent used for this purpose,despite the fact that it exhibits considerable cardiac stim-ulation because of its beta-1 agonistic action in additionto its desired vasoconstrictive activity (alpha-1 agonisticaction).

Despite the popularity of epinephrine 1 : 100,000,concentrations �1 : 200,000 (5 �g/mL) offer no ad-vantage in terms of prolonging anesthesia or reducingserum concentrations of local anesthesia. Higher con-centrations do not provide better onset or duration forinferior alveolar nerve block15,16 or reduce local anes-thetic serum concentrations.2 However, greater concen-trations (eg, 1 : 100,000 [10 �g/mL] and 1 : 50,000[20 �g/mL]) may provide better hemostasis at the sur-gical site when this influence is desired.

To properly address safety issues regarding vasopres-sors, one must first appreciate principles of dose cal-culations. Solutions expressed as ratios represent gramsof solute (drug) dissolved in milliliters of solvent. A 1 :100,000 concentration of epinephrine contains 1 g epi-nephrine dissolved in 100,000 mL solvent. Convertingthis to milligrams or micrograms per milliliter is timeconsuming. This concentration is most common in localanesthetic solutions and is best memorized as 10 �g/mL. If one accepts the earlier suggestion that cartridgescontain 2 mL, it follows that a cartridge of local anes-thetic combined with epinephrine 1 : 100,000 contains�20 �g epinephrine. Simply double this amount whenusing solutions that contain epinephrine 1 : 50,000, andhalve those containing epinephrine in concentrations of1 : 200,000.

There is continued debate regarding deleterious influ-ences of vasopressors on patients with cardiovasculardisease. Clinical trials have confirmed unequivocally thateven small doses of epinephrine in local anesthetic so-

lutions have an influence on cardiovascular function (seeFigure 9). Dionne et al17 studied the influence of 3 car-tridges of 2% lidocaine with epinephrine 1 : 100,000(�60 �g or precisely 54 �g epinephrine). Submucosalinjection of this dose increased cardiac output, heartrate, and stroke volume. Peripheral resistance was re-duced, and mean arterial pressure remained essentiallyunchanged. This finding was consistent with that ac-cording to 10 �g/min epinephrine infusions presentedin standard texts.18 The issue we must address is wheth-er these influences pose a significant risk to patientswith cardiovascular diseases. Putative standards andguidelines continue to be presented but in fact are allanecdotal. Ultimately, the decision requires the dentistto exercise sound clinical judgment based on a thoroughanalysis of each patient under consideration. If consul-tation with the patient’s physician is indicated, discussthe anticipated dose range in terms of micrograms, notconcentrations or cartridges. For example, if 2–4 car-


Figure 11. Mechanism of epinephrine–beta-blocker interac-tion. The cardiovascular influences of epinephrine are medi-ated via alpha, Beta-1, and Beta-2 receptors and are alteredin patients medicated with nonselective beta blockers. Thesegraphs distinguish typical cardiovascular responses after a 10-to 20-�g test dose of epinephrine in a normal versus a beta-blocked patient (see Table 4 for additional explanation). Notethat the key underlying mechanism involves the influence ofepinephrine on systemic vascular resistance and subsequentdiastolic blood pressure (DBP).

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tridges of local anesthetic are planned, explain that youwill be using 40–80 �g of epinephrine infiltrated sub-mucosally, not 2–4 cartridges of epinephrine 1 :100,000. The physician is unfamiliar with a dose ex-pressed as cartridges or concentrations. As reference,consider the conventional epinephrine dose for allergicreactions is 0.3 mg or 300 �g.

Levonordefrin (NeoCobefrin) is the vasopressor com-bined with 2% mepivacaine solutions in the UnitedStates. It closely resembles norepinephrine rather thanepinephrine and lacks activity at Beta2 receptors. Epi-nephrine increases heart rate and systolic pressure butlowers diastolic pressure. In contrast, systemic admin-istration of norepinephrine increases systolic, diastolic,and mean arterial pressures, and this triggers a reflexslowing of heart rate.18 (This is illustrated and explainedin Figure 10.) Levonordefrin has been suggested as analternative to epinephrine-containing local anestheticswhen treating patients with cardiovascular heart diseasebecause it does not increase heart rate. However, ad-vocates fail to consider its undesirable influence onblood pressure. The 1 : 20,000 levonordefrin concen-tration found in mepivacaine is considered equipotentto standard 1 : 100,000 epinephrine concentrations interms of alpha receptor activity (vasoconstriction). Afterinfiltration, they have equivalent efficacy for constrictingsubmucosal vessels, and their influences on local hem-orrhage and anesthetic absorption are similar.

Misconceptions regarding adverse interactions be-tween vasopressors and antidepressants persist despiteliterature that dispels this concern. Most of these con-


cerns relate to pharmacokinetic interactions predicatedon clearance of catecholamines. Although neuronal up-take is the principal method for termination of endog-enous adrenergic neurotransmitters, hepatic biotrans-formation is the principal pathway for termination ofexogenously administered adrenergic drugs.18 Mostnoncatecholamines are metabolized in liver by mono-amine oxidase, but those having a catecholamine struc-ture are primarily inactivated by catechol-o-methyltrans-ferase. Epinephrine and levonordefrin are catechol-amines and are metabolized primarily by catechol-o-methyltransferase, not monoamine oxidase or neuronaluptake.18,19 Patients treated with monoamine oxidaseinhibitors are not hindered in clearing either of thesevasopressors.11 Newer antidepressants (eg, fluoxetine[Prozac]) selectively inhibit serotonin reuptake and like-wise are not a concern. Although they are not contra-indicated entirely, vasopressors should nevertheless beused with caution in patients receiving tricyclic antide-pressants. This particular class of antidepressants has anability to produce cardiac arrhythmias, which could bepotentiated by a similar tendency shared by all sympa-thomimetic agents. For these patients, vital signs shouldbe monitored continually if more than 1 or 2 cartridgescontaining any vasopressor are used.

Patients medicated with nonselective beta-blockingagents have heightened sensitivity to the systemic ef-fects of vasopressors.20 Beta blockers are used for theirability to block sympathetic influences on cardiac Beta1

receptors. Unfortunately, older agents are nonselectiveand also block Beta2 receptors on systemic arteries. Thisoffsets the tendency of epinephrine to dilate and insteadincreases systemic vascular resistance. Blood pressureincreases dramatically and is followed by a reflex slowingof heart rate. The mechanism of this interaction is de-tailed in Figure 11 and Table 4. Numerous reports ofstroke and cardiac arrest have been reported in medicalliterature warning of this potential interaction.21,22 Hy-pertensive responses have been reported after low dos-es of both epinephrine and levonordefrin.23 It is signifi-cant that this interaction will not occur in those patientsreceiving selective beta1 antagonists because, at conven-tional doses, these have little or no affinity for vascularbeta2 receptors. However, caution is still advised be-cause putative selectivity for beta1 receptors may not beabsolute, especially in patients medicated with high dos-es. The following are 2 guidelines to consider when us-ing vasopressors in patients medicated with beta block-ers:● Avoid the use of vasopressors, if reasonable.● If a vasopressor is to be used, record blood pressure

and heart rate, then proceed as follows: (a) after theinjection of each cartridge, pause 5 minutes and re-assess vital signs before administering any additional

local anesthetic; or (b) infiltrate the entire region tobe treated by using a cartridge to provide constric-tion of local vessels, then reinject the region with alocal anesthetic free of vasopressor.

Finally, some consideration should be given to maxi-mum permissible doses of vasopressors. To express lim-its in terms of appointments is impractical; time of treat-ment may be as brief as 30 minutes or as long as 3–4hours. The influence of a given dose of epinephrineamong patients is highly variable. Peak serum levels ofepinephrine after submucosal injection are generallyachieved within 5 minutes and decline rapidly due toinactivation by catechol-o-methyltransferase. Generally,the hemodynamic influences of epinephrine are wit-nessed within minutes of injection and have completelysubsided in 20 minutes. A dose of 40 �g (approximately2 cartridges containing epinephrine 1 : 100,000) is themost conservative and frequently cited dose limitationfor epinephrine in patients with significant cardiovas-cular disease. It should be clarified that this guidelinemore accurately reflects 30-minute time periods, not ap-pointments. A more reasonable suggestion should bebased on patient assessment, not maximal dose. If forany reason the medical status of a patient is in question,reassess vital signs within 5 minutes after the adminis-tration of each cartridge. If the patient is stable, addi-tional doses may be administered followed by a similarpattern of reassessment.

REFERENCES

1. Goodson JM, Moore PA. Life-threatening reactions af-ter pedodontic sedation: an assessment of narcotic, local an-esthetic and antiemetic drug interactions. J Am Dent Assoc.1983;107:239–245.

2. Scott DB, Jebson PJR, Braid DP, et al. Factors affectingplasma levels of lignocaine and prilocaine. Br J Anaesth.1972;44:1040–1049.

3. Prchal JT, Gregg X. Hemoglobinopathies: methemob-lobinemias, polycythemias and unstable hemoglobins. In:Goldman L, Ausiello D, eds. Cecil Textbook of Medicine.22nd ed. Philadelphia, Pa: WB Saunders Co; 2004.

4. Gall H, Kaufmann R, Kalveram CM. Adverse reactionsto local anesthetics: analysis of 197 cases. J Allergy Clin Im-munol. 1996;97:933–937.

5. Berkun Y, Ben-Zvi A, Levy Y, Galili D, Shalit M. Eval-uation of adverse reactions to local anesthetics: experiencewith 236 patients. Ann Allergy Asthma Immunol. 2003;91:342–345.

6. Schatz M. Adverse reactions to local anesthetics. Im-munol Allergy Clin North Am. 1992;12:585–609.

7. Adkinson NF Jr. Drug allergy. In: Adkinson NF Jr, Yun-ginger JW, Busse WW, et al, eds. Middleton’s Allergy: Prin-ciples and Practice. 6th ed. Philadelphia, Pa: Mosby Inc;2003.


8. Morris R, McKay W, Mushlin P. Comparison of painassociated with intradermal and subcutaneous infiltration withvarious local anesthetic solutions. Anesth Analg. 1987;66:1180–1182.

9. Wahl MJ, Overton D, Howell J, Siegel E, Schmitt MM,Muldoon M. Pain on injection of prilocaine plain vs. lidocainewith epinephrine. A prospective double-blind study. J AmDent Assoc. 2001;132:1396–1401.

10. Wahl MJ, Schmitt MM, Overton DA, Gordon MK. In-jection pain of bupivacaine with epinephrine vs. prilocaineplain. J Am Dent Assoc. 2002;133:1652–1656.

11. Yagiela JA. Local anesthetics. In: Dionne RA, PheroJP, Becker DE, eds. Management of Pain & Anxiety in theDental Office. St Louis, Mo: WB Saunders/Elsevier Science;2002.

12. Malamed SF, Gagnon S, Leblanc D. Efficacy of arti-caine: a new amide local anesthetic. J Am Dent Assoc. 2000;131:635–642.

13. Mikesell P, Nusstein J, Reader A, Beck M, Weaver J.A comparison of articaine and lidocaine for inferior alveolarnerve blocks. J Endod. 2005;31:265–270.

14. Haas DA, Lennon D. A 21 year retrospective study ofreports of paresthesia following local anesthetic administra-tion. J Can Dent Assoc. 1995;61:319–330.

15. Dagher FB, Yared GM, Machtou P. An evaluation of2% lidocaine with different concentrations of epinephrine forinferior alveolar nerve block. J Endod. 1997;23:178–180.

16. Tofoli GR, Ramacciato JC, de Oliveira PC, et al. Com-parison of effectiveness of 4% articaine associated with 1:100,000 or 1:200,000 epinephrine in inferior alveolar nerveblock. Anesth Prog. 2003;50:164–168.

17. Dionne RA, Goldstein DS, Wirdzek PR. Effects of di-azepam premedication and epinephrine-containing local an-esthetic on cardiovascular and catecholamine responses to oralsurgery. Anesth Analg. 1984;63:640–646.

18. Hoffman BB. Catecholamines, sympathomimeticdrugs, and adrenergic receptor antagonists. In: Hardman JG,Limbird LE, Gilman AG, eds. Goodman and Gilman’s ThePharmacological Basis of Therapeutics. 10th ed. New York,NY: McGraw-Hill; 2001.

19. Lawson NW, Meyer DJ. Autonomic nervous systemphysiology and pharmacology. In: Barash PG, Cullen BF,Stoelting RK, eds. Clinical Anesthesia. 3rd ed. Philadelphia,Pa: JB Lippincott Co; 1997.

20. Becker DE. Clinical implications of autonomic phar-macology. J Oral Maxillofac Surg. 1992;50:734–740.

21. Foster CA, Aston SJ. Propranolol-epinephrine inter-action: a potential disaster. Plast Reconstr Surg. 1983;72:74–78.

22. Gandy W. Severe epinephrine-propranolol interaction.Ann Emerg Med. 1989;18:98–99.

23. Mito RS, Yagiela JA. Hypertensive response to levon-ordefrin in a patient receiving propranolol: report of a case. JAm Dent Assoc. 1988;116:55–57.


CONTINUING EDUCATION QUESTIONS

1. Beckercaine is a newly released local anesthetic classifiedas an ester and is compounded with epinephrine 1 :200,000. It has twice the lipid solubility of lidocaine, andother data are as follows, with corresponding data for li-docaine in parentheses: pKa � 7.5 (7.9) Protein binding92% (65%). All of the following are correct regarding thisnew wonder-drug EXCEPT:A. It is likely formulated as a 1% solution.B. It has a faster onset than lidocaine.C. It is metabolized in plasma.D. It has a shorter duration than lidocaine.

2. Which of the following reflect accurate doses contained in5 mL (�2.5 cartridges) prilocaine 4% with 1 : 200,000epinephrine?A. Prilocaine 20 mg; epinephrine 50 �g.B. Prilocaine 200 mg; epinephrine 25 �g.C. Prilocaine 20 mg; epinephrine 25 �g.D. Prilocaine 200 mg; epinephrine 10 �g.

3. Hypertensive events attributed to drug interaction have oc-curred after the administration of local anesthetics contain-ing epinephrine in patients medicated with which of thefollowing?A. Nonselective beta blockers.B. MAOI antidepressants.C. SSRI antidepressants.D. a and b are correct.E. a, b, and c are correct.

4. The maximum recommended dose is 500 mg for lidocainewith epinephrine and 400 mg for mepivacaine. Anesthesiais difficult to obtain, and you have administered 6 cartridgesof 2% lidocaine with epinephrine to remove 4 third molars.Two sites remain sensitive, and you elect to reinject with3% mepivacaine to avoid more epinephrine. Which of thefollowing number of cartridges would be the maximumnumber you can safely administer? (Assume 2 mL per car-tridge.)A. 1B. 3C. 5D. 7

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Essential o FLocal Anestezice(1)