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J Am Dent Assoc, Vol 137, No 11, 1562-1571.
© 2006 American Dental Association
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RESEARCH

The pharmacokinetics and cardiovascular effects of high-dose articaine with 1:100,000 and 1:200,000 epinephrine



Elliot V. Hersh, DMD, MS, PhD, Helen Giannakopoulos, DMD, MD, Lawrence M. Levin, DMD, MD, Stacey Secreto, Paul A. Moore, DMD, PhD, MPH, Carrie Peterson, BS, Matthew Hutcheson, MS, Mohammed Bouhajib, MS, Ari Mosenkis, MD and Raymond R. Townsend, MD


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 DATA ANALYSIS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Objectives. The authors conducted a randomized, double-blind, two-way crossover clinical trial to compare the pharmacokinetics and cardiovascular effects of 11.9 milliliters of 4 percent articaine hydrochloride (HCl) plus 1:100,000 epinephrine (A100) with those of 11.9 mL of 4 percent articaine HCl plus 1:200,000 epinephrine (A200).

Methods. During two testing sessions, the authors administered injections of A100 and A200 over a seven-minute period (in one-cartridge doses unless otherwise noted): maxillary right first molar infiltration, maxillary left first molar infiltration, maxillary right first premolar infiltration, maxillary left first premolar infiltration, right inferior alveolar injection, left inferior alveolar injection, right long buccal infiltration (one-half cartridge) and left long buccal infiltration (one-half cartridge). They analyzed venous blood samples for articaine levels. They used noninvasive acoustic tonometry to measure a variety of cardiovascular parameters over a two-hour period.

Results. Plasma concentration curves of articaine over time were similar for both solutions, with peak concentrations and times to maximum concentration being 2,037 nanograms per milliliter and 22 minutes for A100 and 2,145 ng/mL and 22 minutes for A200. At the 10-minute point, the mean systolic blood pressure and heart rate were significantly elevated (P < .05) with A100 versus A200.

Conclusions. Maximum dose recommendations for the A100 solution also can be applied to the A200 solution. A200 produces less cardiovascular stimulation than does A100.

Clinical Implications. A200 is as safe as A100, and may be preferable to A100 in patients with cardiovascular disease and in those taking drugs that reportedly enhance the systemic effects of epinephrine.

Key Words: Dental local anesthetics; articaine; epinephrine; pharmacokinetics; blood pressure; cardiac output; arterial elasticity; arterial tonometer

Articaine hydrochloride formulated as a 4 percent solution containing 1:100,000 epinephrine (here called "A100") has been marketed in the United States since 2000.1 It possesses a unique structure, containing both an amide linkage in its intermediate chain and an ester side chain on a thiophene ring.2 The rapid conversion of this ester moiety to a carboxylic acid moiety in the bloodstream accounts for the relatively short half-life of the drug,3 and possibly an enhanced systemic safety profile compared with that of other dental local anesthetic solutions.4 The majority of clinical efficacy trials have reported no statistical advantage of 4 percent articaine with epinephrine over 2 percent lidocaine or 4 percent prilocaine with epinephrine with respect to enhanced anesthetic success rates or tissue penetration.2,5–10 However, one recent clinical trial and an open-label study using mandibular buccal infiltration anesthesia have reported that articaine is more effective than lidocaine.11,12 It has been suggested that a small but clinically discernable increase in anesthetic success rate for articaine over lidocaine might be noticed in a busy clinical practice, whereas some published clinical trials do not have sufficient statistical power to demonstrate a statistically significant difference.5

The addition of epinephrine to 4 percent articaine, as with its addition to 2 percent lidocaine,13–17 is required to produce an acceptable frequency of anesthetic success after mandibular block or maxillary infiltration injections.18,19 For example, after blinded maxillary premolar infiltration injections, the percentage of subjects judged to have profound pulpal anesthesia as measured by lack of response to electric pulp testing within 10 minutes of injection was 95.2 percent with A100, 93.5 percent with 4 percent articaine plus 1:200,000 epinephrine (here called "A200") and only 75.8 percent with 4 percent articaine without epinephrine.19 Researchers also saw a significantly lower success rate for articaine without epinephrine than for A100 or A200 after mandibular block injections.19 With respect to onset of action, anesthetic success rate and duration, there appears to be little or no difference between A100 and A200 when they are used for either maxillary infiltration or mandibular block anesthesia.19,20 However, a recent study involving patients who had undergone periodontal surgery revealed that while the profundity of anesthesia was similar, the administration of A100 resulted in significantly less intraoperative bleeding and a clearer surgical field than A200.21

To further investigate any safety differences between A100 and A200, we conducted a study using published maximum recommended doses of both solutions.22,23 At the time of our investigation, A200 was considered an investigational drug in the United States. On March 30, 2006, the U.S. Food and Drug Administration (FDA) approved A200 for marketing. Since A200 could be used as an alternative to A100 in patients for whom it may be desirable to limit the epinephrine burden, such as patients with cardiovascular disease, we addressed the following questions in our clinical trial:

– When administering near-maximum recommended doses of articaine (seven cartridges, or 476 milligrams) in healthy adults weighing 150 pounds or more, are blood levels of the local anesthetic significantly elevated with A200 (0.0595 mg epinephrine) compared with A100 (0.119 mg epinephrine)?
– At these same doses, is there less stimulation of the cardiovascular system with A200 than with A100?


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
DATA ANALYSIS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Fourteen healthy volunteers enrolled in this single-center, double blind, randomized, two-way crossover clinical trial. Before undergoing any study procedures, all subjects read and signed an informed consent and Health Insurance Portability and Accountability Act research authorization form that had been approved by the University of Pennsylvania Committee on Studies Involving Human Beings. To stay within published maximum recommended doses of 4 percent articaine (3.2 mg/lb),22,23 we required that all subjects weigh at least 150 lbs to qualify for the study. Subjects had to be between 21 and 65 years of age and have no contraindications to the administration of local anesthetics and their associated vasoconstrictors. Specific exclusions included known or suspected hypersensitivity reactions to amide local anesthetics or sulfites; significant history of cardiovascular disease, including unstable angina, cardiac arrhythmias or treated or untreated hypertension with systolic blood pressure greater than 140 millimeters or diastolic greater than 90 millimeters of mercury (mm Hg); significant history of neurological disorders; severe psychiatric conditions; severe or currently symptomatic bronchial asthma; and evidence of soft-tissue infection around any of the injection sites. We excluded from the study patients who had recently taken any of several classes of drugs because of possible adverse interactions with epinephrine or because their recent intake could confound some of the study results. The prohibited drugs were nonselective beta-blockers, monoamine oxidase inhibitors, tricyclic antidepressants, phenothiazines, butyrophenones, vasopressor drugs and ergot alkaloids. We also excluded subjects who were smokers or who had known or suspected alcohol or drug dependence.

The trial consisted of a one-hour screening visit and two treatment visits, each treatment visit followed by a phone call 24 hours later. The screening visit included a complete medical history, a brief head and neck examination, the recording of vital signs (blood pressure, pulse rate, respiratory rate) and the drawing of a venous blood sample for clinical hematology tests (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, platelet count and international normalized ratios). For the subject to continue his or her study participation, all hematology results had to be in the normal range or deemed clinically insignificant. In addition, all female participants had to undergo a urine pregnancy test at this visit and the subsequent two treatment visits, and the results had to be negative if they were to continue their study participation.

Within eight days of meeting all screening requirements, subjects were scheduled for their first treatment visit. We randomly assigned subjects to one of two treatment sequence groups (A100 followed at one to three weeks with A200 or A200 followed at one to three weeks with A100) so that approximately six subjects per treatment sequence would complete all study-related procedures. We required subjects to fast for six hours before their scheduled testing sessions, with intake of clear liquids allowed until one hour before the testing visit. On arrival for the study session, we fitted each subject with an acoustic tonometer (HDI/Pulse-Wave CR-2000 CardioVascular Profiling System, HDI, Eagan, Minn.) over the radial artery of one arm and with an automated blood pressure monitor on the opposite arm. The tonometer device we used generates a waveform that is calibrated by the oscillometric method with the blood pressure cuff on the opposite arm.24 Investigators have used this device extensively in clinical trials aimed at establishing early markers of cardiovascular disease.24,25 Cardiovascular measurements obtained through this noninvasive method correlate closely with invasive arterial measures (those obtained through arterial puncture) of heart rate, systolic blood pressure, diastolic blood pressure, stroke volume, cardiac output, small and large artery elasticity and systemic vascular resistance.24

We placed an 18-gauge venous indwelling catheter in the antecubital fossa of the arm fitted with the acoustic tonometer for the collection of articaine blood samples. We then took predose cardiovascular measures and two 7-milliliter predose blood samples. We applied topical 20 percent benzocaine before administering local anesthetic injections. At time = 0, we initiated the injections of seven cartridges (1.7 mL/cartridge) of A100 or A200 at the following sites and in the following order, using standard aspirating technique:

– one cartridge each for the right and left maxillary infiltration injections of the first molar;
– one cartridge each for the maxillary right and left infiltration injections of the first premolar;
– one cartridge each for the mandibular right and left inferior alveolar injections;
– one-half cartridge each for the mandibular right and left long buccal injections.

Each maxillary infiltration and mandibular block injection was given over one minute, while each long buccal injection was given over 30 seconds; the total time to perform each injection sequence was seven minutes. We then collected venous blood samples (7 mL) at eight, 10, 15, 20, 25, 30, 40, 50, 60, 90 and 120 minutes after the initiation of the first injection. We immediately placed blood samples on ice. We then added 350 microliters of 2 molar potassium fluoride solution and inverted the sample tubes 10 times to allow for adequate mixing to inactivate plasma esterases and prevent the conversion of articaine to its inactive metabolite articainic acid. We then centrifuged the samples, split them into two equal plasma aliquots and stored them at –20 C for future liquid chromatography tandem mass spectrometry analyses of plasma articaine concentrations. We gathered cardiovascular measures from the acoustic tonometer beginning at 10 minutes after the initiation of the first injection and then every 10 minutes through 120 minutes. At baseline and immediately after taking each blood sample, we elicited a subjective report of anesthetic characteristics from each subject using the following categories: normal sensation, slight feeling of numbness, moderate but not complete feeling of numbness and complete numbness of mouth. One to three weeks later, the subject returned to the clinic to receive the alternative articaine formulation.

We assessed adverse events during each session and in a telephone follow-up interview 24 hours later. During the study session, the protocol specified adverse events included unexpected pain on injection, positive aspiration during injection, discomfort at injection site, swelling at injection site, rash or other abnormal skin reaction, syncope and other nonspecified events observed by the investigators or eleicted by the subject. At the 24-hour telephone follow-ups, we asked subjects a yes/no question: "Have you noticed any changes in your health since yesterday’s testing session?" If the subject responded "Yes," we asked specific questions regarding location of the abnormality. We also elicited specific oral symptoms or complaints previously reported in the literature for local anesthetic injections (that is, swelling, headache, infection, pain, gingivitis, numbness or tingling).2 We included in the safety evaluations all subjects who received study medication. The investigators assigned all adverse events an intensity level of mild, moderate or severe before breaking the randomization code. Likewise, the investigators also assigned a relationship of the adverse event to the study drug: unlikely, possible, probable or unknown.


   DATA ANALYSIS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 DATA ANALYSIS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The primary hypothesis we tested in this study was whether there was no difference in peak plasma concentrations (Cmax) of articaine between A100 and A200. In addition to Cmax, we derived the following pharmacokinetic parameters for each solution: area under the plasma concentration curve (AUC), the time to maximum plasma concentrations (Tmax), the apparent first-order elimination rate constant (Kel) and T1/2 (the apparent elimination half-life). We performed all pharmacokinetic and statistical analyses using SAS, Version 8.2 (SAS Institute, Cary, N.C.). We performed analysis of variance on log-transformed AUC and Cmax and on untransformed Tmax, Kel, and T1/2 we declared a P value of less than or equal to .05 to be statistically significant. A total of 12 completed subjects would provide statistical power of 0.8 to detect a Cmax difference of 392.2 nanograms per mL between A100 and A200.

We used one-sided paired t tests to evaluate differences between A100 and A200 in heart rate, systolic blood pressure, diastolic blood pressure, stroke volume, cardiac output, large artery elasticity index, small artery elasticity index and systemic vascular resistance. If the assumption of normality was not met, we used the Wilcoxon signed rank test.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 DATA ANALYSIS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A total of 14 subjects enrolled in the study, with 13 completing both injection sessions. We recorded the following patient demographic and vital sign characteristics at the screening appointment (mean ± standard deviation [SD]); age (years), 28.5 ± 3.4 (range: 24 to 38); weight (lbs), 177.9 ± 16.4 (range: 160 to 220); pulse rate (beats/minute), 70.0 ± 4.4; diastolic blood pressure (mm Hg): 77.3 ± 6.3; systolic blood pressure (mm Hg), 128.9 ± 7.1; and respiratory rate (breaths/minute), 12.7 ± 0.5. We included only one woman in the study owing to the weight requirement necessary (150 lbs or greater) to not exceed doses of articaine higher than the maximum recommended level (3.2 mg/lb) while delivering seven cartridges of anesthetic solution. All subjects enrolled were young, healthy adults with normal or clinically nonsignificant screening laboratory values. We included all 14 subjects in the analysis of safety, 13 subjects in the analysis of cardiovascular parameters and only 12 subjects in the pharmacokinetic analyses. One subject withdrew consent between the first and second treatment sessions because he developed a sty on his eyelid. For the second subject, we lost the venous access for articaine sampling at eight, 10, 15 and 20 minutes after the injection during the first testing session, and we deemed these times critical for the pharmacokinetic comparisons.

Figure 1Go represents plasma articaine levels over time for both A100 and A200. The plasma concentration curves are nearly identical for both solutions with similar mean ± SD peak blood levels (1,870 ± 561 ng/mL for A100 and 1,970 ± 568 ng/mL for A200) at about 20 minutes and then declining for the remainder of the study period. Table 1Go further illustrates the similarity of the solutions in terms of the various calculated pharmacokinetic parameters. As illustrated by the ratio of the means, all values were within 5 percent of each other, with no significant differences between treatments. A relatively short half-life of approximately 44 minutes also is apparent for articaine.


Figure 1
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  		Figure 1. Plasma concentrations of articaine over time after the administration of seven cartridges of A100 or A200. A100: Articaine hydrochloride plus 1:100,000 epinephrine. A200: Articaine hydrochloride plus 1:200,000 epinephrine. ng/mL: Nanograms per milliliter.

 

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  		TABLE 1 Pharmacokinetic profiles of A100 and A200* solutions in 12 subjects.

 
Figures 2Go through 6GoGoGoGo (pages 1567–1570) present the cardiovascular data obtained during the 120-minute observation period. As shown in Figure 2Go, heart rate was elevated significantly (P = .047) at 10 minutes after the initiation of the injection procedures when subjects received A100 (a mean of 78.2 beats/minute ± 3.6 standard error of the mean) compared with A200 (69.6 ± 3.4 beats/minute). Systolic blood pressure (Figure 3Go) at 10 minutes also was significantly greater (P = .046) when subjects were treated with A100 (130.6 ± 2.4 mm Hg) than when they were treated with A200 (124.8 ± 2.3 mm Hg). Interestingly, diastolic blood pressure tended to decrease for both formulations for the first 30 minutes after the injections (Figure 3Go). A post hoc analysis revealed no significant difference in mean arterial pressure between the two anesthetic solutions at any time. While mean cardiac output values (which represent the product of heart rate and stroke volume) were similarly elevated for both solutions (6.32 ± 0.15 L/minute for A100 and 6.34 ± 0.21 L/minute for A200) at the 10-minute assessment (Figure 4Go), a significantly greater number of subjects (82 percent) displayed higher values during the A100 treatment than during the A200 (18 percent) treatment (P = .041, Wilcoxon signed rank test).


Figure 2
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  		Figure 2. Changes in heart rate over time after the administration of seven cartridges of A100 or A200. At 10 minutes after the initiation of the injections, subjects receiving A100 displayed significantly increased heart rates compared with those receiving A200. A100: Articaine hydrochloride plus 1:100,000 epinephrine. A200: Articaine hydrochloride plus 1:200,000 epinephrine.

 

Figure 3
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  		Figure 3. Changes in systolic blood pressure (BP) (top panel) and diastolic BP (bottom panel) over time after the administration of seven cartridges of A100 or A200. At 10 minutes after the initiation of the injections, subjects receiving A100 displayed significantly increased systolic BP compared with those receiving A200. A100: Articaine hydrochloride plus 1:100,000 epinephrine. A200: Articaine hydrochloride plus 1:200,000 epinephrine. mm Hg: Millimeters of mercury.

 

Figure 4
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  		Figure 4. Changes in stroke volume (top panel) and cardiac output (bottom panel) over time after the administration of seven cartridges of A100 or A200. A100: Articaine hydrochloride plus 1:100,000 epinephrine. A200: Articaine hydrochloride plus 1:200,000 epinephrine. mL: Milliliters. L: Liters.

 

Figure 5
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  		Figure 5. Changes in large artery elasticity index (top panel) and small artery elasticity index (bottom panel) over time after the administration of seven cartridges of A100 or A200. At 70 minutes after the initiation of the injections, subjects receiving A100 displayed a significantly increased small artery elasticity compared with those receiving A200. A100: Articaine hydrochloride plus 1:100,000 epinephrine. A200: Articaine hydrochloride plus 1:200,000 epinephrine. mL: Milliliters. mm Hg: Millimeters of mercury.

 

Figure 6
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  		Figure 6. Changes in systemic vascular resistance over time after the administration of seven cartridges of A100 or A200. dynes-sec-cm5: Dynes per second per centimeter5. A100: Articaine hydrochloride plus 1:100,000 epinephrine. A200: Articaine hydrochloride plus 1:200,000 epinephrine.

 
Thirteen of the 14 subjects enrolled reported a subjective rating of 4 ("my mouth is completely numb") at some point during the 120-minute evaluation when they received either solution. One subject did not report a descriptive rating higher than 3 (moderate, but not complete, feeling of numbness) for either treatment session.

Considering the number of injections they received in a relatively short time, subjects generally tolerated both solutions well, with all adverse events being rated as of either mild or moderate intensity. As shown in Table 2Go (page 1570), a total of seven subjects reported 12 adverse events during exposure to A100 versus five subjects who reported six adverse events during exposure to A200. The most common adverse events were headache (one of 14, or 7.1 percent, for A100; three of 13, or 23.1 percent, for A200), drowsiness (one of 14, or 7.1 percent, for A100; two of 13, or 15.4 percent, for A200), positive aspiration (one of 14, or 7.1 percent, for A100; one of 13, or 7.7 percent, for A200), cardiac palpitation (two of 14, or 14.3 percent, for A100) and trismus (two of 14, or 14.3 percent, for A100). In the A100 group, we considered five adverse events (two episodes of palpitations, one episode of drowsiness, one episode of trismus and one headache) to be possibly or probably related to the study drug; in the A200 group, we considered two adverse events (two episodes of drowsiness) to be possibly or probably related to the study drug. We did not see statistically significant differences between treatment groups in the frequency of adverse events overall.


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  		TABLE 2 Adverse event profile of A100 and A200.*

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 DATA ANALYSIS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Our primary goal in this study was to determine if the lower epinephrine concentration of the investigational A200 formulation would result in Cmax of articaine than the A100 formulation that was marketed at the time of our study. The injection of seven cartridges (11.9 mL or 476 mg) of solution represented near-maximum recommended doses (3.2 mg/lb or 500 mg absolute maximum) of articaine in adults weighing 150 lbs or more. As shown in Table 1Go and Figure 1Go, the Tmax and a host of pharmacokinetic endpoints were similar for both solutions. Thus, it appears that the 1:200,000 epinephrine concentration is as adequate as the 1:100,000 concentration in delaying the systemic absorption of articaine and that the maximum recommended doses of articaine need not be altered in the A200 formulation from those recommended for the A100 formulation.

Typical amide local anesthetics such as lidocaine and mepivacaine, which depend on the liver for their metabolism, possess half-lives in the range of 90 to 100 minutes.5 In our study, we report a half-life of articaine as being slightly less than 45 minutes, whereas others have reported it to be as low as 20 to 25 minutes.3,26 The rapid conversion of the ester side chain on articaine’s thiophene ring to a carboxylic acid moiety by carboxyesterase enzymes in the plasma is a major determinant of articaine’s relatively short half-life.

We found more short-term cardiovascular effects with the A100 formulation than with the A200 formulation, as evidenced by the greater increase in heart rate and systolic blood pressure immediately after the completion of the injection (Figures 2Go and 3Go). While a previous study reported no difference between A100 and A200 in heart rate or blood pressure endpoints in patients undergoing the removal of a single lower impacted third molar, the injection volumes employed were only 4 mL, representing a 0.04-mg and a 0.02-mg epinephrine dose, respectively.27 The enhanced alpha-adrenergic and ß1–adrenergic effects exhibited by the larger volumes of local anesthetic (11.9 mL) administered in our study, especially with the A100 formulation (0.119 mg epinephrine), most likely contributed to this difference. These effects, however, dissipated rapidly, probably as a result of epinephrine’s short half-life.22 Interestingly, diastolic blood pressure fell initially with the injection of both solutions. This has been reported by others28 and represents the ß2 vasodilatory effects of epinephrine on certain systemic vascular beds, including skeletal muscle arterioles.15 This systemic vasodilatory property of epinephrine also is illustrated by the initial reduction in large- and small-artery elasticity (Figure 5Go) and in systemic vascular resistance (Figure 6Go) exhibited by both solutions. As illustrated in Figures 2Go and 4Go, the greater percentage of subjects exhibiting increases in cardiac output after receiving A100 at the 10-minute point was due almost exclusively to elevated heart rate, since stroke volume actually was numerically greater for A200 than A100 at all measurement points. Some investigators have reported increases in cardiac output and decreases in peripheral vascular resistance after the injection of 3.6 mL of 2 percent lidocaine with 1:80,000 epinephrine.29,30

Some investigators have recommended that 2 percent lidocaine be available with 1:200,000 epinephrine to reduce the possibility of cardiovascular stimulation that may be more likely to occur with lidocaine with 1:100,000 epinephrine in certain patient populations.31 However, unlike A200, which produces an anesthetic success rate and duration equivalent to those of A100 after electrical stimulation of the dental pulp,19 lidocaine with 1:200,000 epinephrine has been reported to be inferior to its 1:100,000 counterpart in a similar electric pulp stimulation paradigm.16 While patients who had undergone periodontal surgery exhibited equivalent anesthetic profundity with A200 and A100,21 the results of one study reporting enhanced endogenous norepinephrine release during tooth luxation with A200 versus A10027 deserve further investigation.

Small therapeutic volumes of dental local anesthetics with epinephrine seem to have relatively transient cardiovascular effects in healthy people. In healthy volunteers, a 1.8 mL injection of 2 percent lidocaine plus 1:100,000 epinephrine (0.018 mg epinephrine) was reported to increase heart rate by about two beats/minute for two minutes.32 In patients undergoing restorative dental procedures, a single cartridge of lidocaine plus 1:100,000 epinephrine (0.018 mg epinephrine) has been demonstrated to increase heart rate significantly, by about five beats per minute, but for only 10 minutes.33 Likewise, in healthy volunteers, 3.6 mL of 2 percent lidocaine plus 1:80,000 epinephrine (0.045 mg epinephrine) significantly increased heart rate for 10 minutes.34 In patients who had undergone oral surgery, 5.4 mL of 2 percent lidocaine plus 1:100,000 epinephrine (0.054 mg epinephrine) significantly increased cardiac output compared with lidocaine alone immediately after the completion of the dental injections.35

However, others have reported more sustained increases in cardiovascular endpoints with higher epinephrine doses. Two mL of lidocaine plus 1:25,000 epinephrine (0.08 mg epinephrine) significantly increased heart rate for at least 15 minutes when administered as a maxillary infiltration injection to normal volunteers.28 Troullos and colleagues36 demonstrated that eight cartridges of 2 percent lidocaine with 1:100,000 epinephrine (0.144 mg epinephrine) in patients undergoing the surgical removal of four impacted third molars significantly increased heart rate, systolic blood pressure and the pressure-rate product for at least 20 minutes. Additionally, they found an astonishing rise in plasma epinephrine levels of more than 27-fold. Unlike us, Troullos and colleagues enrolled subjects undergoing actual clinical procedures, and the cardiovascular changes in fact may be more sustained in this patient population, as opposed to healthy volunteers not undergoing dental procedures. Lipp and colleagues37 reported two distinct peaks in epinephrine blood levels after administration of 4 percent articaine with 1:100,000 epinephrine (2.0 mL) in subjects undergoing dental scaling procedures, one peak occurring seven to eight minutes after the injections and a second peak after the initiation of the dental procedure. The researchers hypothesized that epinephrine absorption might have been enhanced by the movement of the intraoral tissues during mouth opening and the manipulation of the tissues during the dental procedure.37 In our investigation, we administered repeated intraoral injections during the initial seven minutes of the study. In the administration of multiple injections, inadvertent intravenous injections may have occurred, causing large transient elevations in blood epinephrine levels, and thus possibly accounting for some of the reported side effects,37 such as palpitations.

The one cardiovascular difference that appeared late in the observation period, a significant difference in small-artery elasticity at 70 minutes, probably does not represent an effect of the vasoconstrictor, since, as was found in one study, epinephrine blood levels return to baseline within approximately 30 minutes after dental injections.37 Changes in cardiovascular function seen after 30 minutes likely represent multiple factors, including homeostatic cardiovascular reflex responses and a reduction in patient anxiety owing to the completion of the injection procedures.

While changes in heart rate and systolic blood pressure with the A100 solution were not clinically significant in our investigation, it must be stressed that the subject population consisted of young healthy adults who did not have significant cardiovascular disease and were not taking drugs such as nonselective ß-blockers or tricyclic antidepressants, which are reported to enhance the pressor and/or cardiac stimulatory effects of epinephrine.15,22,23,38–40 While some studies have shown that relatively low doses of epinephrine (≤ 0.054 mg) often are well-tolerated by many of these patients,40–42 the doses of epinephrine employed in our study would be considered excessive in these patient populations15,22,23,38–40,42,43 and could result in far more pronounced cardiovascular changes than we saw in the healthy volunteers in our study.


   CONCLUSIONS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 DATA ANALYSIS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
After the injection of seven cartridges of local anesthetic, we found that the pharmacokinetic profiles of A100 and A200 were similar. Therefore, we believe that the current maximum dosage recommendations of 3.2 mg/lb for the A100 solution also can be applied to the A200 solution. However, compared with A200, A100 induced significant increases in heart rate and systolic blood pressure shortly after the completion of the injections. A200 may be a preferable alternative to A100 when it would be desirable to limit cardiovascular stimulation in certain patient populations.


   FOOTNOTES
 

DISCLOSURE: Novocol Pharmaceuticals, Cambridge, Ontario, Canada, provided the funding for the study described in this article. Dr. Moore has served as a clinical research consultant to Novocol Pharmaceuticals during the development of its 4 percent articaine 1:200,000 epinephrine product. Ms. Peterson is an employee of Novocol Pharmaceuticals.


Dr. Hersh is a professor of pharmacology, Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, 240 South 40th St., Philadelphia, Pa. 19104-6003, e-mail "evhersh{at}pobox.upenn.edu". Address reprint requests to Dr. Hersh.


Dr. Giannakopoulos is an assistant professor of oral andmaxillofacial surgery, Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia.


Dr. Levin is an associate professor of oral and maxillofacial surgery, Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia.


Ms. Secreto is research coordinator, Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia.


Dr. Moore is a professor of pharmacology and the chair, Department of Anesthesiology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pa.


Ms. Peterson is a senior quality assurance associate, Scientific and Regulatory Affairs, Novocol Pharmaceuticals of Canada, Cambridge, Ontario, Canada.


Mr. Hutcheson is a partner, Biostatistics, Tegra Analytics, Doylestown, Pa.


Mr. Bouhajib is a vice president, Laboratory Operations, Laboratory Operations, Pharma Medica Research, Mississauga, Ontario, Canada.


Dr. Mosenkis is a fellow, Renal Hypertension, School of Medicine, University of Pennsylvania, Philadelphia. He is currently a nephrologist in private practice, Cleveland Clinic Health System, Euclid, Ohio.


Dr. Townsend is a professor of medicine, Renal Hypertension, School of Medicine, University of Pennsylvania, Philadelphia.


When the studies described in this article were performed in 2005, the 4 percent articaine 1:200,000 epinephrine formulation was considered an investigational formulation by the U.S. Food and Drug Administration.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 DATA ANALYSIS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. FDA drug approvals list. Available at: "www.fda.gov/cder/da/da.htm". Accessed Sept. 13, 2006.

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  3. Oertel R, Rahn R, Kirch W. Clinical pharmacokinetics of articaine. Clin Pharmacokinet 1997;33(6):417–25.[Medline]

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A. Szabo, N. Szentandrassy, P. Birinyi, B. Horvath, G. Szabo, T. Banyasz, I. Marton, P. P. Nanasi, and J. Magyar
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