Therapeuic Drug Monitoring SESEEE Te Rh Raven res, Lt, New York Serum Lidocaine Concentrations Following Application to the Oropharynx: Effects of Cimetidine Roy C. Parish, *Vincent P, Gotz, *Larry M. Lopez, ‘Jawahar L. Mehta, and Stephen H. Curry Department of Pharmacy Practice, College of Pharmacy, University of Georgia, Athens, Georgia, and *Department of Pharmacy Practice and Division of Clinical Pharmacokinetics, College of Pharmac) ‘and *Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, U.S.A. Summary: Solutions of lidocaine hydrochloride are widely used for anesthesia, of the oropharynx and respiratory tract prior to endoscopic procedures. It is commonly believed that this route of administration is not associated with clinically significant systemic absorption of the drug, and large doses of topical lidocaine are routinely used in this setting. Serious adverse effects, including, seizures, occasionally occur. The extent of absorption of lidocaine from the oro- pharynx was studied in eight healthy volunteers. Wide variation in serum lido- caine concentrations was observed. A 14-fold range of peak lidocaine concen- trations occurred following idemtical, accurately metered doses of a lidocaine aerosol spray preparation. The effects of cimetidine on lidocaine pharmacoki- Neties were also studied. Therapeutic doses of oral cimetidine significantly increased the area under the lidocaine time~concentration curve (P = 0.019), but no effect on the terminal-phase elimination rate constant was observed. Serum concentrations of a)-acid glycoprotein, a major binding protein of lido- caine, were significantly elevated following cimetidine (p = 0.030). Maximum lidocaine concentration, time to reach maximum concentration, and mean residence time of lidocaine were unchanged following cimetidine. These ob- servations suggest an effect of cimetidine on the volume of distribution of lido- caine. Because of the wide variability in lidocaine pharmacokinetics and the potentially serious nature of adverse reactions, caution is advised in the use of topical lidocaine solutions in “standard” doses, Key Words: Lidocaine—Ci- metidine— Serum concentrations— Pharmacokinetics, Solutions of lidocaine hydrochloride are fre- quently used for anesthesia of oropharyngeal mucous membranes prior to endotracheal intuba- tion, bronchoscopy, and endoscopy. It is widely be- lieved that nonparenteral administration is asso- ciated with insignificant systemic absorption of li- docaine. This belief persists in spite of findings showing lidocaine absorption to be rapid and ex- ‘Address correspondence and reprint requests to Dr. Parish at Department of Pharmacy Practice, College of Pharmacy. Uni- versity of Georgia, Athens, GA 30602, U.S.A. 292 tensive from mucous membranes of the lungs, tra- chea, and pharynx (1-4). For example, Morrell and associates (1) found that application of lidocaine hydrochloride solutions to the pharynx resulted in peak serum lidocaine concentrations of ~1 ug/ml for each 1 mg/kg of lidocaine applied as a spray. Serum lidocaine concentrations of 1-5 g/ml are generally regarded as therapeutic for treatment of cardiac arrhythmias (5). Adriani and associates summarized several reports and concluded that ab- sorption of lidocaine from mucous membranes is nearly as rapid as delivery by intravenous infusion (6).CIMETIDINE AND TOPICAL LIDOCAINE 293 Large amounts of lidocaine are routinely admin- istered for oropharyngeal anesthesia prior to endos- copy. A common practice is for the patient to gargle with 15-30 ml of 24% lidocaine solution (300- 1,200 mg lidocaine) followed by additional drug delivered as a spray. Although most of the solutions in contact with mucous membranes offer the poten- tial for systemic absorption of large doses, either from rapid absorption or from accidental swal- lowing or aspiration. ‘Two of the authors (R.C.P. and V.P.G.) have re- cently participated in a report of generalized tonic clonic seizures in patients who gargled with 4% li- docaine solution prior to bronchoscopy or endos copy (7). One patient had congestive heart failure and the other was taking propranolol, both of which are known to decrease lidocaine metabolism, prob- ably because of reduced cardiac output and subse- quent decrease in hepatic blood flow (8-10). Both patients had lidocaine concentrations >7 g/ml in serum collected shortly after the onset of seizure activity. Most patients, however, undergo the same procedure without adverse effect. It is possible that altered metabolism of lidocaine in these patients contributed to high serum lidocaine concentrations. Its also possible that interpatient variation in lido- caine pharmacokinetics gives rise to a wide range of serum lidocaine concentrations following stan- dardized doses. The present study was undertaken to examine the serum concentrations of lidocaine following its application to oropharyngeal mucous membranes. Since cimetidine is one of the most frequently pre- scribed drugs and is administered to many patients who undergo endoscopy, we studied its effect on serum lidocaine concentrations in healthy volun- teers. Serum concentrations of a,-acid glycoprotein (AAG), a major binding protein for lidocaine (11), were measured so that changes in protein binding could be considered as a possible explanation for any effects on serum lidocaine concentration that might be observed. MATERIALS AND METHODS Drug Administration Healthy, nonsmoking male subjects were re- cruited for this study. Institutional review board ap- proval was obtained, and subjects gave writen in- formed consent. The health status of each subject was assessed by means of a medical and drug history. physical ex- amination, and pertinent laboratory studies. No subject was included if he had laboratory findings consistent with hepatic or renal discase, significant physical findings or history of neurologic, hepat renal, or cardiac disease, or any condition requiring drug therapy. Each subject underwent two treatments sepa- rated by at least 48 h but not more than 21 days. In the first (contro!) treatment, 120 mg of lidocaine hy- drochloride was applied to the posterior pharynx by means of a metered dose aerosol preparation (Xylocaine 10% oral spray, Astra, lot 406063, expi- ration date 6/86). This concentrated solution was chosen to facilitate accurate dosing and minimize the volume of solution to reduce gagging or swal- lowing. The dose was administered as 12 0.1-ml sprays delivered within a 30-s period. Each subject ‘was instructed to avoid swallowing and to hold the solution in his mouth for 30 s following the spray. The subject was then instructed to expectorate sa- liva and drug solution, rinse the mouth with 30 ml of water, and expectorate the rinse solution. Blood was collected in glass test tubes through an indwelling venous catheter immediately before lidocaine administration and 5, 10, 15, 20, 30, 60, 120, 180, and 240 min after completion of spraying Blood was allowed to clot and was centrifuged for 15 min at 800 g. The serum was separated, frozen immediately, and stored at — 15°C. Analysis of all samples was completed within 30 days of collec- tion, The second (experimental) treatment was iden- tical to the control treatment except that each sub- ject took cimetidine 300 mg by mouth every 6 h for 2 days before the treatment and an additional dose fon the morning of the treatment (9 doses total) Only one subject missed a dose of cimetidine, this dose being omitted the morning of the day before the treatment Analysis of Lidocaine ‘Serum was analyzed for lidocaine content using. the enzyme multiplied immunoassay technique (EMIT, Syva). Details of this assay have been pub- lished elsewhere (12-14). This method is standard- ized using calibration solutions in the concentration range 1.0-12.0 g/ml with 1:36 dilution of the sample. Concentrations are reliably determined from 0.85 to 13.25 ug/ml (13,14). In our laboratory, Pherapeate Drag Monitoring, Vol 9, No.3. 1987294 R. C. PARISH ET AL. this assay had within-day and between-day coeffi cients of variation (CV) of 3.43 and 4.42%, respec- tively, at 4.0 g/ml. Samples having concentrations <0.85 ug/ml were assayed with 1:6 dilutions of the sample and division of the automated analyzer reading by a factor of 6. This modification extended the lower limit of the assay to 0.14 yg/ml. The within-day CV of this procedure was 2.62% and the between-day CV was 8.58%, both at 0.4 ug/ml. Some samples containing lidocaine concentration <0.14 g/ml required a further modification of the assay procedure. These samples were assayed using a technique developed by us and reported previously (15). This method adapted the assay to the range 0.03-0.15 g/ml through alterations of sample dilution and buffer concentration, Within- day and between-day CVs for this technique were 3.05 and 4.92%, respectively, at 0.08 g/ml. Pharmacokinetic Analysis Lidocaine concentration-time data were plotted on semilogarithmic graph paper for each subject The terminal-phase elimination rate constant (B) was calculated by means of least-squares regres- sion using the data points lying on the terminal straight-line portion of the graph. Area under the curve was calculated from time zero to the last sample time (f,) using the trapezoidal rule. The area under the curve after the final sample time was cal- culated by dividing the concentration in the last sample (C,) by B. This area was added to the area derived by the trapezoidal rule and the sum taken as the area under the curve from time zero to in- finity (AUC +) ‘Area under the first moment curve (AUMC) was determined by means of the trapezoidal rule from time zero to ty. The area under the curve after the final sample was calculated as 1,C,/B + Cy/B*. This area was added to the area from time zero to f, and the total was taken as AUMC. Mean residence time (MRT) was calculated as AUMC/AUC. Maximum serum lidocaine concentration (Cys) was the highest observed concentration, and time to peak (tax) Was the time of earliest appearance of Coax ‘No attempt was made to determine the amount of, lidocaine lost in rinsing the mouth following appli- cation of the spray. The actual dose available for absorption is therefore unknown, and apparent oral Therapeutic Drug Monitoring, Vo. 9, No. 3.1987 clearance was not calculated. For the same reason, distribution volumes were also not calculated. ‘Acid Glycoprotein Determination Concentrations of AAG were determined for each subject under each treatment using a radial immu- nodiffusion assay (M-Partigen, Calbiochem- Behring). All determinations of AAG were per- formed using the time zero sample of serum from each treatment period. Statistical Analysis Independence of means of observed data be- tween control and cimetidine treatments was tested using the paired-difference 1 test for data collected as continuous data (AAG concentration, MRT, AUCo+e Crary ad B). Trax data were treated as ordinal data. Tests of significance of observed dif- ferences of this variable were done using the Wil- coxon matched-pairs signed-rank test. Statistical significance was defined as a probability value (p) of <0.08 for individual tests. RESULTS, Three subjects withdrew before receiving any treatment because venous access could not be easily achieved. Nine subjects remained, whose ages ranged from 22 to 35 years. Data from one subject were not included in the statistical analysis because the characteristics of the time—concentra- tion curve indicated that the terminal portion lay below the range of any of the assay techniques and the observations were representative of the distri- bution phase. It was not possible, therefore, to cal- culate B for this subject. Data for the remaining eight subjects were included in the final analyses (able 1). TABLE 1. Subject characteristics Age Weight Lidocaine delivered Subject ka) (mgs) 1 2 or 178 2 2 90 2.03 3 2 ns Es 4 3 MS 20 5 51 ws ust é 2% 7s rst 7 2 709. 16 8 2 m0 150 Mean 70.4 13 SD. 9.68 026CIMETIDINE AND Tay Was generally later (5 of 8 subjects) fol- lowing cimetidine, but the mean difference was not statistically significant (Table 2). Two subjects had no change, and one subject reached Cray earlier after the cimetidine treatment. There was wide variation in Cpa, during the con- trol phase (Table 2). Cig, ranged from 0.10 to 1.40 pg/ml. Similar variability was observed in the treat- ment phase. Differences in Cpa, between control and cimetidine treatments ranged from ~29.4 to + 139.0% with a mean change + 32.2%. These di ferences, however, were not significant (p = 0.07). Neither MRT nor was significantly affected by cimetidine (Table 2). Changes in 8 for individual subjects ranged from —51.3 to + 126.7%; the mean Percentage change following cimetidine was +0.29%. The mean change in MRT following ci- metidine was + 17.59%, and the range was —40.7 to + 72.0%, AUC... was significantly increased (p = 0.019) following cimetidine (Table 2). The mean increase in AUC, was +52.0%, and individual changes ranged from —6,7 to +175.9%. AAG concentrations were significantly higher after the cimetidine treatment than during the con- trol treatment (p = 0.030). Only one subject's AAG concentration was lower following cimetidine, and this subject's Crux Was also lower following cimet dine. One subject's serum AAG concentration was unchanged between the two treatments, and this subject had identical Cpa, in both phases of the study. Of the remaining Six subjects whose serum AAG concentration was higher following cimeti- dine, five had higher Cy, following cimetidine. These results are summarized in Tables 2 and 3 ‘One subject (subject 2) reported slight dysphoria TOPICAL LIDOCAINE 295 during the control treatment, ~20 min after r ceiving lidocaine. This subject also reported light headedness during the cimetidine treatment, also ~20 min after receiving lidocaine. No other ad- verse effects of drug administration or blood with- drawal were observed. DISCUSSION ‘These data show that absorption of lidocaine from the oropharynx is highly variable, a finding consistent with those of other studies of lidocaine pharmacokinetics. Without the effect of cimetidine, our subjects had a 14-fold range of peak serum lido- caine concentrations resulting from identical, accu- rately metered doses of 120 mg. Peak concentra- tions in subject 2 were approximately four times the mean of all subjects. Even with this subject omitted, Cay varied over a greater than three-fold range. These findings suggest that there may be ex- treme variability in serum lidocaine concentrations in patients undergoing standardized pharyngeal and tracheal anesthetic procedures, with the result that ‘occasional patients may absorb sufficient amounts of the drug to experience serious adverse reactions, Variation in the amount of lidocaine lost in rinsing may have contributed to this variability, but the magnitude of this loss reflects 10 some extent the uptake by mucous membranes and so may be a function of variability in absorption phenomena. We reported seizures in two patients in conjunction with a standardized high-dose topical application of lidocaine (7), and high-dose regimens may be ‘common (16). Abundant evidence indicates that ab- sorption of lidocaine from the oropharynx and tra- cheobronchial tree is rapid and extensive (1-4,6), TABLE 2. Effects of cimetidine on pharmacokinetics of lidocaine a) Caton MRT win) Benin AUC tus inn Subject Control Cimetisine Comrol Cimsisne change Control Cimetidine change Contol Cimetsine change Control Cimetiine change 1% m0 08280 wm” M67 V0 oO amo sa we De aed 2 Fob tteor Takeo 265 Gomes OomeT ana asa SS 3s ee oe Sina iss war st9 comet amas nt oe ‘ak Te 4 @ Oo oa2 am taste "409 omnoy Donn si3eF 2S ha a Te ee $ 1 sa as) “SRO er oas “69 oom” oolom «92 ao ahed 7 3 082“ ahah sano 1? omnee amas ind SST a 1s a) ata 00 Hk at 'SG Damm dome? ses Tha Ine Mean os oa e320 M0 +178 Come OOOTIE 603 I SRS sem ols oie als 337 127 ooo? ome iss tak a paos p=am 026 prow pono ‘MRT, mean residence time: SEM, sand ior of mean Therapentie Brug Monitoring, Vl, 9, No.3, 1987296 R. C. PARISH ET AL. TABLE 3. Changes in serum ay-acid glycoprotein ‘Serum ayacid glycoprotein (mpi) Subject Control Cimetidine Percent change 1 392 153 +17 2 183 ia “103 3 ae 585 nt 4 3 ra +45 5 155 fo sw 6 93 789 two 7 382 103.0 710 8 22 "22 00 Mean 687 B86 SD 130 200 p= 0.030 Although serious adverse reactions such as sei- zures are rarely reported, their potentially serious nature should discourage the concept of an “ac ceptable rate” of occurrence. Milder reactions such as mental status changes may be unnoticed in el- derly or seriously ill patients if the physician per- forming the endoscopic procedure is not alert for these subtle effects. Such reactions may thus be under-reported. Given the extreme variability in li- docaine absorption reported in the literature and supported by this study, it seems prudent to ascribe infrequent serious adverse reactions to interpatient pharmacokinetic variability rather than idiosyn- crasy. Within this more cautious view, indiscrimi- nate use of large doses of lidocaine in endoscopic procedures should be discouraged; the smallest dose that produces an acceptable level of comfort for the patient should be used. It may be advisable to limit the initial dose to the range approved for intravenous administration. ‘AUCo..» Was significantly increased following ci- metidine in this study. This observation is consi tent with a reduction in clearance, a reduction in volume of distribution, or systematic differences in dose between control and cimetidine treatments. Differences in dose would be expected to result in a change in Cy, between the study phases, and this was not observed. Although an estimate of the power of the statistical tests (17) indicates insuffi cient power to rule out an unobserved increase in Cran itis not apparent how a systematic difference in retained dose might arise. The p value of 0.019 associated with observed differences in AUC sug- gests that random variation is not the source of this ‘observation. We believe that the observation repre- sents a real effect of cimetidine on either clearance or volume of distribution. Therapeutic Drug Monitoring, Vol, 9, No.3, 1987 Reduction of lidocaine clearance by cimetidine is generally accepted. Some investigators have sug- ested that reduced hepatic blood flow is the mech- anism by which this effect is produced (18-21), Others either have found reduced hepatic extrac- tion sufficient to explain reduced clearance (22) or have observed that cimetidine does not reduce he- patic blood flow in normal subjects (23,24) or in pa- tients with cirrhosis (25). The design of our study did not allow differentiation between these mecha- nisms relative to the effects of cimetidine. Our observations of a significant increase in AUC)... without a significant change in B are in agreement with those of Jackson et al. (26) and Wing et al. (22), who observed significant reduc- tions in the volume of distribution of lidocaine. Our findings of significantly increased serum AAG con- centrations following cimetidine suggest that i creased protein binding is the mechanism by which volume of distribution may be reduced. Since vari ation in plasma AAG concentration accounts for ~75%6 of the variation in lidocaine plasma protein binding (11,27), and AAG concentrations were si nificantly higher following cimetidine in our study, there is a strong possibility that our results do in fact reflect a change in volume of distribution. Al- though Jackson and associates (26) did not detect a change in serum AAG concentrations, they re- ported that the lidocaine volume of distribution cor- relates negatively with AAG concentration, Further study of these factors will be necessary for a full characterization of the cimetidine-lidocaine inter- action. ‘The cimetidine-lidocaine interaction has been shown to be independent of gender, cigarette smoking (22), or age (28). This suggests that our findings of widely variable serum lidocaine concen- trations following topical application to the oro- Pharynx in young, healthy subjects may also be ap- plicable to elderly patients. Acknowledgment: Reagent kits for the EMIT lidocai assay were kindly supplied by the Syva Company, Palo Alto, California. Astra Pharmaceutical Products, Inc., Westborough, Massachusetts, furnished Xylocaine® Oral Spray. The authors are grateful to these firms for their support. The authors also gratefully acknowledge the contribution of Dr. John A Pieper, College of Pharmacy, University of Tennessee at Memphis, who provided pure samples of lidocaine metabolites which were used in evaluating the specificity of the modified lidocaine assay. ‘The assistance of Dr. Robert G. Macdonald in placing venous catheters is gratefully acknowledged.CIMETIDINE AND TOPICAL LIDOCAINE REFERENCES Morrell DF, Chappell WA. White IWC. Topical enalgeia of the upper airway with lignocaine. 5 Afr Med J 1982:61 SSi-3, MoBurney A, Jones DA. Stanley PJ, Ward JW. Absorption of lignocaine and bupivacaine from the respiratory tract during fibreoptic bronchoscopy. Br J Clin Pharmacol 1984: 17616, Chinn WM, Zavala DC, Ambre J. Plasma levels of lidocaine following nebulized aerosol administration. Chee! 19771 as Karvonen S, Jokinen K, Karvonen P, Hollmén A. 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