Mepivacaine: a Closer Look at Its Properties and Current Utility William G

Anesthesia and Pain Control

Mepivacaine: a closer look at its properties and current utility William G. Brockmann, DDS, PhD

The use of mepivacaine in dentistry has remained strong since its use mepivacaine is based on its vasoconstrictor effect or lack thereof introduction in the 1960s. It has retained its place as a valuable local (depending on the formulation). However, the pharmacokinetics of anesthetic, either as a primary agent or as an alternative to lidocaine mepivacaine are not well understood or assumed to be similar to that or articaine. Mepivacaine is commonly used in medically compromised of other local anesthetics. It is important to understand the unique patients—for whom elevations in blood pressure or heart rate are not pharmacologic characteristics of mepivacaine in order to minimize the advisable—in a formulation with a vasoconstrictor, or in pediatric popu- potential for inadvertent toxicity. lations in a formulation without a vasoconstrictor. Pharmacologically, Received: October 16, 2013 these are the 2 groups most susceptible to side effects and toxicity, Accepted: November 24, 2013 thus mepivacaine is commonly indicated. Most often the decision to

urrently used local anesthetics and formulations exclusively with these charac- successful 2,6-xylidine-amide structure, their formulations each have indi- terizations in mind. Whereas the 2 different with emphasis on increasing the dura- Cvidual characteristics that allow them vasoconstrictors used in local anesthetics tion of action. In 1957, af Ekenstam et to claim clinically useful niches to validate bear many similarities to each other with al synthesized (along with many other their continued market presence. While similar clinical limitations, it is worthwhile structures with anesthetic properties) the introduction of articaine—in 1982 to look at mepivacaine by itself. mepivacaine and bupivacaine, both very in Canada and in 2000 in the US—has Rather than being a lidocaine substitute, similar in structure and with longer dura- gained much of the market share in North mepivacaine possesses distinct pharmaco- tions than lidocaine.5 Each preserved the America, lidocaine and mepivacaine have kinetic characteristics of its own that are 2,6-xylidine group on the aromatic ring, remained commonly used agents.1 In important for the clinician to understand. but each had a shortened intermediate Canada, where articaine is the most used This article reviews the unique pharmacol- chain, and replaced the terminal tertiary agent, a survey of general dentists showed ogy of mepivacaine and the potential clini- amine with a less basic methyl-piperidine that from 1993 to 2007, mepivacaine usage cal implications involved with its use. ring. Homologous local anesthetics that declined but remained the third most used share the mepivacaine structure, such agent.2 Mepivacaine’s niche has been con- History and chemistry: as bupivacaine and ropivacaine, are sidered by many dentists to be the “safer” pipecholyl xylidines referred to as pipecholyl xylidines due lidocaine alternative, to be used in elderly In the years immediately after the to the presence of this pipecholyl acid or cardiovascular disease patients, because it development of the xylidine derivative, moiety (Fig. 1). Bupivacaine differs from not only comes without a vasoconstrictor, lidocaine, there followed a series of mepivacaine only by substitution of the but it is available with levonordefrin, which chemical syntheses based upon the same methyl group on the piperidine ring by a is assumed to have less vasopressor potency and 25% of the direct beta effects on the heart.3 It is now known, however, that levonordefrin acts similarly to norepineph- rine, as it elevates not only systolic blood CH3 O O CH3 O pressure, but diastolic and mean arterial CH3 CH3 pressures as well. Used at 5 times the con- N CH3 centration of epinephrine, it possesses rela- NH N NH N NH tively the same or more potential for cardiac H C 3 Lidocaine CH3 stimulation, especially elevations in blood CH3 CH3 4 CH pressure. Mepivacaine is also commonly Mepivacaine Bupivacaine 3 used—in a formulation without levonorde- O CH3 frin—for children, as it is available without NH2 a vasoconstrictor for shorter postoperative HO N duration, whereas articaine and lidocaine H CH3 have longer durations and must have vaso- Pipecolic acid 2,6-Xylidine constrictors for their efficacy. Many general and pediatric practices use mepivacaine Fig. 1. Pipecholyl xylidines compared to lidocaine.

70 November/December 2014 General Dentistry www.agd.org to 27.2 (at pH 6.5).22 In comparison, the Table. Physicochemical properties and relative in vitro conduction blocking relative anesthestic potency of prilocaine potency of the intermediate-acting amide local anesthetics.15 decreases by 66.5%, and mepivacaine decreases by 64.7%. Theoretically, Relative conduction mepivacaine would lose less potency Lipid solubility blocking potency when injected into areas of reduced pH MW base pKa Hydrophobicitya (distribution (in vitro, isolated b and this may be considered an advantage. Anesthetic (g/mol) (36°C) (mol/L) coefficient Q7.4 ) nerve fibers) However, realistically, this is a rare occur- Lidocaine 234 7.8 304 (366) 43 (110) 2.0 rence if a regional block is available. Prilocaine 220 8.0 129 25 1.8 Hypersensitivity and Mepivacaine 246 7.7 90 (130) 21 (42) 1.5 cross reactivity aOctanol/buffer partition coefficients for unprotonated species only: 25°C. Values in parentheses: 36°C. For patients who are known to be allergic b to sulphites, the availability of mepiva- Q7.4 = (total drug/ml octanol)/(total drug/ml buffer) at pH 7.4. Includes ionized and unionized partition coefficients. caine without vasoconstrictor and sodium Margins of error not shown. metabisulphite is a highly valuable clinical asset, since articaine and lidocaine must have vasoconstrictors added for their efficacy. Allergy to mepivacaine itself, as more lipid soluble butyl (C4H9) group. It These methods showed mepivacaine to well as any of the amide local anesthetics was not until the late 1970s, however, that have a correspondingly lower anesthetic is very rare, but does occur.23 Most case bupivacaine was approved for clinical use potency than lidocaine or prilocaine under reports of mepivacaine allergic reactions as a nerve blocker in dentistry.6-8 in vitro conditions.17 However, these mea- prior to the mid-1980s were related to Mepivacaine, being less toxic than surements were derived under controlled the methylparaben used as antimicrobials bupivacaine, was immediately evaluated conditions and do not directly reflect in in the cartridges; these were subsequently for clinical use in various types of regional vivo anesthetic potency. They also do not removed by FDA mandate.24 and dental anesthesia and was identi- correctly reflect the clinical end-points of A large 2009 study that analyzed the fied as having a faster onset and longer mepivacaine use, where success is measured French Pharmacovigilance database over duration than lidocaine without a vaso- by an adequate conduction block, and a 12-year period (1995-2006) found constrictor.9-12 Approved by the FDA in the physiologic variables that affect tissue 16 cases of allergic reactions to amide local 1960, it was subsequently studied in many concentration, diffusion, and ionization anesthetics, of which 11 were immediate dental trials, where it rapidly established are more complex. Animal studies with Type I reactions occurring within 1 hour its dual utility in dentistry when used live nerve blocks have shown the potency with severe symptoms.25 Of the Type 1 in a formulation without a vasoconstric- of mepivacaine to be equivalent or greater, reactions, 6 were due to lidocaine, 2 to tor or in a formulation with 1:20,000 with a faster onset time, and longer dura- mepivacaine, 2 to articaine, and 1 to bupi- levonordefrin (Neo-Cobefrin, Novocol tion of anesthesia than lidocaine and vacaine. Of the other 5 reactions, which Pharmaceutical of Canada, Inc.) which prilocaine.18 Mepivacaine, lidocaine, and were delayed-type skin reactions, 4 were markedly increased its duration.13,14 prilocaine have all been shown in numer- due to lidocaine and 1 to mepivicaine.25 ous clinical studies to have similar inter- Cross-reactivity among the amides, pre- Lipid solubility and potency mediate anesthetic efficacy, regardless of viously thought to be rare, was found in 6 Mepivacaine, lidocaine, and prilocaine differences in their lipid solubility.19-21 cases (38%) and all were between lidocaine are considered to be “intermediate” and mepivacaine. In patients with a true in terms of their lipid solubility and Effectiveness in infected tissues lidocaine or mepivacaine allergy, neither anesthetic potencies (Table).15 The cor- The ionization constant, or pKa, of lidocaine nor mepivacaine should be relation of lipid solubility, and the ability mepivacaine is also the lowest of the inter- used as a substitute due to very possible to penetrate membranes with increased mediate agents (articaine and lidocaine cross-allergenicity.25 affinity for hydrophobic binding sites have the same pKa). At 36°C, the pKa’s A 2006 report in Spain published a are the main determinants of anesthetic of the intermediate-acting agents are all similar case of a patient with confirmed potency.16 The lipid solubility and hydro- close enough to make onset times roughly lidocaine and mepivacaine allergies who phobicity (tendency to be readily soluble equivalent under normal physiologic con- was not allergic to bupivacaine, despite in nonpolar solvents but only sparingly in ditions.22 Estimates of the effects of acidic its structural similarity.26 No cross- water) is lowest in mepivacaine compared conditions such as those found in infected allergenicity to articaine was found in to the other local anesthetics. tissue—using quantitative structure- either study. The findings in these and Hydrophobicity correlates with in vitro activity relationship modeling (QSAR) other studies suggest that articaine may methods that measure conduction block- calculations—have shown the relative have rare cross-allergenicity with other ing (anesthetic) potency on isolated nerve anesthetic potency of lidocaine drops members of the amide class, including fibers, such as rabbit vagus and sciatic. 72.8% from a normalized 100 (at pH 7.4) delayed-type reactions.27,28

www.agd.org General Dentistry November/December 2014 71 Anesthesia and Pain Control Mepivacaine: a closer look at its properties and current utility

O Systemic absorption CH3 CYP1A2 (Major) CH3 O At therapeutic concentrations, mepiva- Glucuronide conjugate caine has an intrinsic vasodilating activ- NH N Hydroxylation NH N ity intermediate between lidocaine and H3C H C 29 3 prilocaine. In various arterial blood flow HO CH3 CYP3A4 CH3 studies, lidocaine markedly increased CYP1A2 3-OH-Mepivacaine Mepivacaine Urine blood flow whereas mepivacaine and prilocaine tended to either maintain or CYP3A4 N-demethylation 30-32 O decrease peripheral blood flow. This CH3 CH3 O would appear to be an additional safety Glucuronide conjugate factor, by keeping systemic levels low. NH N HO NH N However, in maxillary infiltration studies H H3C conducted by Goebel et al, serum levels CH CH3 of the mepivacaine formulation without 3 PPX (Minor) 4-OH-Mepivacaine vasoconstrictors were always higher and more persistent than lidocaine.33,34 Fig. 2. Mepivacaine metabolism. Complimentary studies by Goebel et al comparing lidocaine and mepivacaine with their respective vasoconstrictors, epi- CH CH3 CH nephrine and levonordefrin, also showed 3 3 CH3 O N-dealkylation O N-dealkylation O that mepivacaine produced significantly NH N NH 2 NH CH3 CH3 higher and more variable serum levels CYP3A4 NH NH than lidocaine at all time intervals.34,35 CH3 Lidocaine CH3 CH Medical studies comparing lidocaine and MEGX 3 GX CH mepivacaine in regional blocks also indi- 3 CYP1A2 cate that mepivacaine, even in the vaso- Minor NH constrictor formulation, produce higher 2 HO CH CH3 HO CH3 HO and more sustained systemic blood levels 3 CH3 CH O O 3 36,37 2,6-Xylidine on the order of 35% to 38%. N NH CH3 CH3 NH The studies by Goebel et al showed that NH NH2 mepivacaine displays mean peak levels CH 3-OH-Lidocaine CH 3-OH-MEGX 4-OH-Xylidine CH3 at about 30 minutes, with or without 3 3 a vasoconstrictor, while lidocaine with epinephrine produces peak levels earlier, Fig. 3. Lidocaine metabolism. at approximately 15 minutes.33-35 Since the duration of mepivacaine without a vasoconstrictor is about 30 minutes, reinjection at that time occurs at peak- ing serum levels. In addition, at all later systemic levels of local anesthetic, which also contributes to the formation of time intervals, differences in mepivacaine are 1.5 times higher than 2% mepivacaine 4-OH-mepivacaine.39 All these hydroxyl serum levels are not significantly different with levonordefrin, and thus has the most (OH) metabolites are excreted as glucuro- whether or not vasoconstrictor is used. potential for chronic accumulation.35 nide conjugates and comprise >50% of the Serum levels at time intervals beyond total mepivacaine dose. Urinary sampling 30 minutes in maxillary infiltration Metabolism and disposition shows the 3-OH-mepivacaine to be the studies are essentially the same regard- compared to other local major metabolite earlier in the process, less of whether or not the vasoconstrictor anesthetics with the 4-hydroxy compound produced formulation was used.38 The mean peak Mepivacaine, like the other amide later in smaller amounts, indicating the (Cmax) percentage difference between local anesthetics, undergoes extensive predominance of CYP1A metabolism.40 plain 2% mepivacaine and 2% mepi- hepatic biotransformation with <5% Demethylation by CYP3A produces pipe- vacaine with levonordefrin was only urinary excretion of the unchanged coloxylidide, a minor metabolite account- 8%, while the peak difference between drug. Metabolism is primarily through ing for about 1% of the urinary output. lidocaine with and without epinephrine hydroxylation of the parent compound Lidocaine metabolism involves similiar was 29%.32 Systemic levels of mepivacaine to inactive 3-OH-mepivacaine and enzymatic activities, but CYP3A4 plays decrease less when compared to lidocaine 4-OH-mepivacaine by CYP1A2 (Fig. 2). the larger role in dealkylation to the in the presence of a vasoconstrictor. A CYP1A2 is constitutive, and CYP1A1 major metabolite monoethylglycinex- formulation with 3% mepivacaine (no is the inducible isoform which also ylidide (MEGX), an active metabolite vasoconstrictor) produces the highest participates in metabolism. CYP3A that still retains central nervous system

72 November/December 2014 General Dentistry www.agd.org O CH3 O CH3 O CH3 H3C NH H3C NH H3C NH

NH C3H7 NH C3H7 NH C3H7 Carboxylesterases COOH S COOCH3 S S COOH Articaine Articainic Acid (>70%) Articainic Acid Glucuronide (<15%) Urine

Fig. 4. Articaine metabolism.

(CNS) toxicity. CYP1A contributes to Lidocaine clearance is reduced meta- duration of activity is determined by forming MEGX in addition to generat- bolically by inhibitors of CYP3A4, such vascular redistribution from the local site ing 3-OH-lidocaine which is converted as cimetidine, erythromycin, and azole and is only indirectly and weakly cor- to 3-OH-MEGX.41 These are all eventu- antifungals. Antidepressants and benzodi- related with final elimination of the drug ally eliminated as glucuronide conju- azepines that heavily utilize CYP3A4 have from the body. Total clearance (expressed gates. MEGX is metabolized to inactive also been associated with serious lidocaine in volume/time) is the removal of a drug glycinexylidide (GX) and excreted for toxicities, including sertraline (Zoloft), from a volume of plasma in a given unit the most part renally.42 The remaining escitalopram (Lexapro), desipramine of time as the sum of all clearances by all MEGX and GX is further broken down (Norpramin), and flurazepam (Dalmane).48 the various elimination mechanisms, such to 2,6-xylidine metabolites when the Because of the high hepatic extraction ratio as renal and hepatic. Of the currently used xylidine ring is removed by hydrolytic of lidocaine, drugs that reduce hepatic intermediate-acting agents, mepivacaine reactions involving hepatic carboxylester- blood flow also reduce its metabolism has the slowest total clearance. In compari- ases or amidases (Fig. 3).43 significantly. Beta-blockers that decrease son, the total body clearance of lidocaine Prilocaine metabolism occurs in the cardiac output, especially propranolol, is 3 times higher than that of mepivacaine liver and kidney by carboxylesterases decrease lidocaine elimination by decreas- (0.95-1.1 l/min vs 0.45 l/min).36 Medical and CYP3A4 that generate o-toluidine. ing hepatic blood flow.49 Propranolol also studies examining systemic levels of mepi- CYP2E1 produces hydroxylated toluidine prolongs mepivacaine blood levels, but vacaine after caudal or regional blocks have metabolites that represent more than 40% mepivacaine is not as dependent on hepatic clinically demonstrated the drug’s rela- of the urinary metabolites of prilocaine. blood flow since it has a lower hepatic tively long persistence.56,57 The typically O-toluidine and its hydroxylated variants clearance (extraction ratio) of 0.51 com- slower total clearance of mepivacaine is a can oxidize hemoglobin to methemoglo- pared to 0.72 for lidocaine.50-52 factor that can lead to potential accumula- bin, a critical dose-limiting restriction Pharmacokinetic drug interactions with tion in cases of repetitive dosing over time for prilocaine use.44 Drug interactions mepivacaine are more likely to involve or excessive doses, especially when children with prilocaine mainly involve inducers inhibitors of CYP1A2. Potent inhibition are involved.58-60 In neonates, the lidocaine of CYP3A4 (carbamazepine, phenytoin, of CYP1A2 occurs with selective serotonin total plasma clearance normalized to body rifampin), or other drugs that contribute receptor inhibitors fluvoxamine (Luvox) weight is not significantly different than to methemoglobinemia, such as benzo- and fluoxetine (Prozac) and moderate adults because more lidocaine is excreted caine, nitrates, or acetaminophen.45 inhibition with paroxetine (Paxil) and ser- renally and unchanged.61 The neonatal Articaine has the simplest and most traline (Zoloft).52 Other strong inhibitors of capacity for aromatic hydroxylation, rapid metabolism of the amides due to its CYP1A2 and drugs known to interfere with however, is very limited, thus the total carboxyl group ester linkage. Articaine mepivacaine metabolism include caffeine, plasma clearance of mepivacaine is <50% is metabolized rapidly into articainic grapefruit juice, fluoroquinolone antibiot- the adult clearance rate, coupled with a acid by plasma carboxylesterases with a ics, and verapamil (Calan), mexiletine hepatic clearance that is approximately plasma half-life of 20 minutes.46 Forty (Mexitil), and zileuton (Zyflo).53 Lastly, 25% that of adults.62 Concomittant drug percent to 70% is excreted as articainic significant hepatic CYP1A2 levels are not interaction from CYP1A inhibition would acid, and 4% to 15% as articainic acid present in infancy (<1 year), and may not also contribute to prolonged or toxic glucuoronide (Fig. 4). Almost all major be fully functional before the age of 3 years, blood levels. Prilocaine has a notably fast P450 cytochromes participate in the which prolongs metabolism of mepivacaine total clearance—almost 2.5 times that of remaining metabolism of articaine, but in infancy, whereas fetal CYP3A7 and lidocaine—which not only indicates high only 10% of the total dose is metabo- immature CYP3A are present at birth.54,55 hepatic extraction but also extrahepatic lized by cytochromes, making articaine The main difference in pharmacokinetic metabolism.63,64 This hydrolysis of the relatively resistant to pharmacokinetic safety levels between local anesthetics is the amide bond occurs very efficiently, con- 47 drug interactions. total clearance rate (Cltot). Local anesthetic sidering only 5% of prilocaine is excreted

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unchanged. Articaine has the fastest total in children should be used as a matter of 15. Stritchartz GR, Sanchez V, Arthur GR, Chafetz R, Martin body clearance of all amide local anesthet- course, and the maximum recommended D. Fundamental properties of local anesthetics. II. Measured octanol buffer partition coefficients and pKa ics, ranging from 3.9 l/min for intraoral dose should never be exceeded, especially values of clinically used drugs. Anesth Analg. 1990; 46 injections to 8.9 l/min for IV injections. when using 3% mepivacaine. It has been 71(2):158-170. In dentistry, local anesthetic toxicity recommended by many other authors that, 16. Ritchie JM, Greengard P. On the mode of action of lo- occurs more frequently in children, most since the 3% formulation is potentially cal anesthetics. Annu Rev Pharmacol. 1966;6:405- often with mepivacaine.65 Plain mepiva- 1.5 times more toxic than the 2% for- 430. 17. Wildsmith JAW, Gissen AJ, Gregus J, Covino BJ. Differ- caine is favored and useful in pediatric mulation, mepivacaine use in children be ential nerve blocking activity of amino-ester local an- dentistry for its shorter duration of activ- restricted to smaller volumes, and that its aesthetics. Br J Anaesth. 1985;57(6):612-620. ity, but plain mepivicaine leads to higher use be limited to supraperiosteal injections 18. Pateromichelakis S, Prokopiou AA. Local anaesthesia systemic levels which are subject to a slow whenever possible.60 efficacy: discrepancies between in vitro and in vivo studies. Acta Anaesthesiol Scand. 1988;32(8):672-675. total clearance rate. Even with levonorde- 19. Petersen JK, Luck H, Kristensen F, Mikkelsen L. A com- frin, serum levels are not decreased as they Author information parison of four commonly used local analgesics. Int J are with lidocaine and a vasoconstrictor. Dr. Brockmann is a clinical associate Oral Surg. 1977;6(1):51-59. Mepivacaine—especially 3% mepivacaine professor, Department of Oral Pathology, 20. Hinkley SA, Reader A, Beck M, Meyers WJ. An evalua- without a vasoconstrictor—has been Oral Medicine, Oral Radiology, University tion of 4% prilocaine with 1:200,000 epinephrine and 2% mepivacaine with 1:20,000 levonordefrin com- implicated in most reported fatalities of Missouri-Kansas City. pared with 2% lidocaine with:100,000 epinephrine due to excessive dosing.66,67 Factors that for inferior alveolar nerve block. Anesth Prog. 1991; contribute include practitioners not under- References 38(3):84-89. standing fully the implications of injecting 1. Pogrel MA. Permanent nerve damage from inferior al- 21. Cohen HP, Cha BY, Spangberg LS. Endodontic anesthe- veolar nerve blocks—an update to include articaine. sia in mandibular molars: a clinical study. J Endod. additional anesthetic in low body weight J Calif Dent Assoc. 2007;35(4):271-273. 1993;19(7):370-373. children, basing the dosage on the number 2. Gaffen AS, Haas DA. Survey of local anesthetic use by 22. Canos-Rius N, Martin-Biosca Y, Sagrado S, Villanueva- of carpules rather than the patient’s weight, Ontario dentists. J Can Dent Assoc. 2009;75(9):649. Camanas RM, Medina-Hernandez MJ. Estimation of and in many instances not understanding 3. James P. Cassidy, James C. Phero, William H. Grau. Epi- the effect of the acidosis and alkalosis on the anes- the synergistic effects of concommitant nephrine: systemic effects and varying concentrations thetic potency of local anesthetics by biopartitioning in local anesthesia. Anesth Prog. 1986;33(6):289-297. micellar chromatography and micellar electrokinetic opioids or CNS depressants in pediatric 4. Robertson VJ, Taylor SE, Gage TW. Quantitative and chromatography. Eur J Med Chem. 2005;40(2):215- sedation protocols. For example, opioids qualitative analysis of the pressor effects of levonorde- 223. such as meperidine can decrease convul- frin. J Cardiovasc Pharmacol. 1984;6(5):929-935. 23. Speca SJ, Boynes SG, Cuddy MA. Allergic reactions to sant thresholds by producing respiratory 5. af Ekenstam, Egner B, Pettersson G. N-alkyl pyrrolidine local anesthetic formulations. Dent Clin North Am. and N-alkylpiperidine carboxylic acid amides. Acta 2010;54(4):655-664. acidosis and elevating arterial carbon Chem Scand. 1957;11:1183-1190. 24. Luebke NH, Walker JA. Discussion of sensitivity to dioxide, which increase the CNS toxicity 6. Henn F, Brattsand R. Some pharmacological and preservatives in anesthetics. J Am Dent Assoc. 1978; of local anesthetics.68 All these factors can toxicological properties of a new long-acting local 97(4):656-657. contribute to toxicity due to mepivacaine’s analgesic, Lac-43 (marcaine), in comparison with 25. Fuzier R, Lapeyre-Mestre M, Mertes PM, et al. Immedi- inherent characteristic of maintaining mepivacaine and tetracaine. Acta Anaesthiol Scand ate-and delayed-type allergic reactions to amide local Suppl. 1966;21:9-30. anesthetics: clinical features and skin testing. Pharma- prolonged and relatively high serum levels 7. Lund P, Cwik J, Vallesteros F. Bupivacaine—a new coepidemiol Drug Saf. 2009;18(7):595-601. even when used with a vasoconstrictor. long-acting local anesthetic agent. A preliminary clini- 26. Gonzalez-Delgado P, Anton R, Soriano V, Zapater P, cal and laboratory report. Anesth Analg. 1970;49(1): Niveiro E. Cross-reactivity among amide-type local an- Conclusion 103-114. esthetics in a case of allergy to mepivacaine. J Investig 8. Laskin JL, Wallace WR, DeLeo B. Use of bupivacaine Allergol Clin Immunol. 2006;16(5):311-313. Mepivacaine is an efficacious and useful hydrochloride in oral surgery - a clinical study. J Oral 27. Bircher AJ, Messmer SL, Surber C, Rufli T. Delayed-type intermediate-acting local anesthetic for Surg. 1977;35(1):25-29. hypersensitivity to subcutaneous lidocaine with toler- use in dentistry as it can be used when 9. Dhuner KG, Egner B, Ekenstam BA, Oljelundo O, Ulfen- ance to articaine: confirmation by in vivo and in vitro required and without a vasoconstrictor. dahl LR. Trials with carbocaine; a new local anaesthet- tests. Contact Dermatitis. 1996;34(6):387-389. The presence of a vasoconstrictor increases ic drug. Brit J Anaesth. 1956;28(11):503-506. 28. Duque S, Fernandez L. Delayed-type hypersensitivity 10. Dhuner K, Oljelund O, Aagesen G. Carbocain-d, 1-N- to amide local anesthetics. Allergol Immunopathol the duration of action but has little effect methyl-pipecolic acid 2, 6-dimethylanilide; a new local (Madr). 2004;32(4):233-234. on systemic blood levels. The slower total anesthetic agent. Acta Chir Scand. 1957;112(5):350- 29. Blair MR. Cardiovascular pharmacology of local anaes- clearance of mepivacaine makes it more 358. thetics. Brit J Anaesth. 1975;47(Suppl):247-252. susceptible to the various mechanisms 11. Luduena FP, Hoppe JO, Coulston F, Drobeck HP. The 30. Lindorf HH. Investigation of the vascular effect of new- pharmacology and toxicology of mepivacaine, a new er local anesthetics and vasoconstrictors. Oral Surg that can lead to chronic toxicity, such as local anesthetic. Toxicol Appl Pharmacol. 1960;2:295- Oral Med Oral Pathol. 1979;48(4):292-297. the lack of fully functional enzymes in 315. 31. Willatts DG, Reynolds F. Comparison of the vasoactivi- infants, inadvertant excessive dosing of 12. Goulding CE Jr, Ozdil T, Powell WF. Carbocaine: clinical ty of amide and ester local anaesthetics. An intrader- 3% mepivacaine, or repeated dosing in appraisal of 132 cases. Anesth Analg. 1961;40:523- mal study. Br J Anaesth. 1985;57(10):1006-1011. conjunction with long appointments, 527. 32. Lofstrom JB. 1991 Labat Lecture. The effect of local 13. Ross N, Dobbs EC. A preliminary study on carbocaine. anesthetics on the peripheral vasculature. Reg Anesth. renal failure, or drug inhibition of CYP1A J Am Dent Soc Anesthesiol. 1960;7(9):4-5. 1992;17(1):1-11. (in elderly patients). Children <5 years 14. Lock F, Vernino D, Sadove M. Mepivacaine HCI (carbo- 33. Goebel WM, Allen G, Randall F. The effect of commer- of age are most susceptable to overdose caine): a preliminary clinical study. J Oral Surg Anesth cial vasoconstrictor preparations on the circulating and are also often given sedation that can Hosp Dent Serv. 1961;19:16-20. venous serum level of mepivacaine and lidocaine. increase toxicity. Weight-based dosing J Oral Med. 1980;35(4):91-96.

74 November/December 2014 General Dentistry www.agd.org Published with permission of the Academy of General Dentistry. © Copyright 2014 by the Academy of General Dentistry. All rights reserved. For printed and electronic reprints of this article for distribution, please contact [email protected].

34. Goebel W, Allen G, Randall F. Circulating serum levels 45. Centers for Diease Control and Prevention. Prilocaine- in commonly used regional block procedures. Anesthe- of mepivacaine after dental injection. Anesth Prog. induced methemoglobinemia—Wisconsin, 1993. siology. 1972;37(3):277-287. 1978;25(2):52-56. MMWR Morb Mortal Wkly Rep. 1994;43(35):655-657. 58. Moore DC, Bridenbaugh LD, Bagdi PA, Bridenbaugh 35. Goebel WM, Allen G, Randall F. Comparative circulat- 46. Oertel R, Rahn R, Kirch W. Clinical pharmacokinetics of PO. Accumulation of mepivacaine hydrochloride during ing serum levels of mepivacaine with levo-nordefrin articaine. Clin Pharmacokinet. 1997;33(6):417-425. caudal block. Anesthesiology. 1968;29(3):585-588. and lidocaine with epinephrien [sic]. Anesth Prog. 47. US Food and Drug Administration Center for Drug 59. Morishima HO, Daniel SS, Finster M, Poppers PJ, James 1979;26(4):93-97. Evaluation and Research. Approval Package for LS. Transmission of mepivacaine hydrochloride (carbo- 36. Simon MAM, Vree TB, Gielen MJM, Booij LHJ, Lagerw- Application Number 20-971. Available at: http:// caine) across the human placenta. Anesthesiology. erf AJ. Similar motor block effects and disposition ki- www.accessdata.fda.gov/drugsatfda_docs/ 1966;27(2):147-154. netics between lidocaine and (±)mepivacaine in nda/2000/020971_septocaine_biopharmr.pdf. 60. Chin KL, Yagiela JA, Quinn CL, Henderson KR, Duperon patients undergoing axillary brachial plexus block dur- Accessed August 13, 2014. DF. Serum mepivacaine concentrations after intraoral ing day case surgery. The Scientific World. 2002;2: 48. Klein JA, Kassarjdian N. Lidocaine toxicity with tumes- injection in young children. J Calif Dent Assoc. 2003; 1306-1319. cent liposuction. A case report of probable drug inter- 31(10):757-764. 37. Takasaki M. Blood concentrations of lidocaine, mepiva- actions. Dermatol Surg. 1997;23(12):1169-1174. 61. Mihaly G, Moore RG, Thomas J, Triggs EJ, Thomas D, caine and bupivacaine during caudal analgesia in chil- 49. Stenson RE, Constantino RT, Harrison DC. Interrela- Shanks C. The pharmacokinetics and metabolism of dren. Acta Anaesthesiol Scand. 1984;28(2):211-214. tionships of hepatic blood flow, cardiac output, and the anilide local anaesthetics in neonates. I. Ligno- 38. Goebel WM, Allen G, Randall F. The effect of commer- blood levels of lidocaine in man. Circulation. 1971; caine. Eur J Clin Pharmacol. 1978;13(2):143-152. cial vasoconstrictor preparations on the circulating ve- 43(2):205-211. 62. Moore RG, Thomas J, Triggs EJ, Thomas DB, Burnard nous serum level of mepivacaine and lidocaine. J Oral 50. Popescu SM, Nechifor M, Baniceru M, Croitoru O, ED, Shanks CA. The pharmacokinetics and metabolism Med. 1980;35(4):91-96. Popescu F. Effect of propranolol on mepivacaine serum of the anilide local anaesthetics in neonates. III. Mepi- 39. Oda Y, Furuichi K, Tanaka K, et al. Metabolism of a new concentrations in dental practice. Oral Surg Oral Med vacaine. Eur J Clin Pharmacol. 1978;14(3):203-212. local anesthetic, ropivacaine, by human hepatic cyto- Oral Pathol Oral Radiol Endod. 2008;105(4):e19-e23. 63. Yagiela JA. Local anesthetics. Anesth Prog. 1991; chrome P450. Anesthesiology. 1995;82(1):214-220. 51. Dillane D, Finucane BT. Local anesthetic systemic toxic- 38(4-5):128-141. 40. Meffin PJ, Thomas J. The relative rates of formation ity. Can J Anaesth. 2010;57(4):368-380. 64. Arthur GR, Scott DH, Boyes RN, Scott DB. Pharmacoki- of the phenolic metabolites of mepivacaine in man. 52. von Moltke LL, Greenblatt DJ, Duan SX, et al. Phenace- netic and clinical pharmacological studies with mepiva- Xenobiotica. 1973;3(10):625-632. tin O-deethylation by human liver microsomes in vitro: caine and prilocaine. Br J Anaesth. 1979;51(6): 41. Orlando R, Piccoli P, De Martin S, Padrini R, Floreani inhibition by chemical probes, SSRI antidepressants, 481-485. M, Palatini P. Cytochrome P450 1A2 is a major deter- nefazodone and venlafaxine. Psychopharmacology 65. Moore PA, Hersh EV. Local anesthetics: pharmacology minant of lidocaine metabolism in vivo: effects of liver (Berl). 1996;128(4):398-407. and toxicity. Dent Clin North Am. 2010;54(4):587-599. function. Clin Pharmacol Ther. 2004;75(1):80-88. 53. Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 ac- 66. Hersh EV, Helpin ML, Evans OB. Local anesthetic mor- 42. Imaoka S, Enomoto K, Oda Y, et al. Lidocaine metabo- tivity in clinical practice: why, how, and when? Basic tality: report of case. ASDC J Dent Child. 1991;58(6): lism by human cytochrome P-450s purified from he- Clin Pharmacol Toxicol. 2005;97(3):125-134. 489-491. patic microsomes: comparison of those with rat 54. Tateishi T, Nakura H, Asoh M, et al. A comparison of 67. Moore PA. Preventing local anesthesia toxicity. J Am hepatic cytochrome P-450s. J Pharmacol Exper Ther. hepatic cytochrome p450 protein expression between Dent Assoc. 1992;123(9):60-64. 1990;255(3):1385-1391. infancy and postinfancy. Life Sci. 1997;61(26):2567- 68. Moore PA, Goodson JM. Risk appraisal of narcotic se- 43. Alexson SEH, Diczfalusy M, Halldin M, Swedmark S. 2574. dation for children. Anesth Prog. 1985;32(4):129-139. Involvement of liver carboxylesterases in the in vitro 55. Tanaka E. In vivo age-related changes in hepatic drug- metabolism of lidocaine. Drug Metab Dispos. 2002; oxidizing capacity in humans. J Clin Pharm Ther. 1998; 30(6):643-647. 23(4):247-255. Manufacturer 44. Higuchi R, Fukami T, Nakajima M, Yokoi T. Prilocaine- 56. Moore DC, Bridenbaugh LD, Bagdi PA, Bridenbaugh Novocol Pharmaceutical of Canada, Inc., and lidocaine-induced methemoglobinemia is caused PO. Accumulation of mepivacaine hydrochloride during Cambridge, Ontario by human carboxylesterase-, CYP2E1-, and CYP3A4- caudal block. Anesthesiology. 1968;29(3):585-588. 519.623.4800, www.novocol.com mediated metabolic activation. Drug Metab Dispos. 57. Tucker GT, Moore DC, Bridenbaugh PO, Bridenbaugh 2013;41(6):1220-1230. LD, Thompson GE. Systemic absorption of mepivacaine