An Evaluation of the Effect of Repeated Doses of Oral Activated Charcoal on Salicylate Elimination

MISCELLANEOUS An Evaluation of the Effect of Repeated Doses of Oral Activated Charcoal on Salicylate Elimination Julie L. Ho, BSc Phm, Michael G. Tierney, MSc, and Garth E. Dickinson, MD, FRCPC The authors investigated the effect of repeated doses of oral activated charcoal on salicylate elimination in six healthy volunteers. On two occasions (phase I and phase II; separated by one week) each subject received 1300mg of aspirin as an aqueous solution. On the second occasion (phase II) each subject also received a total dose of 55 g of aqueous activated charcoal initiated 4 hours after salicyl ate administration (25 g initial Serum salicyl ate levels were dose, followed by three 10 g doses at two hour intervals). measured from one to twelve hours post aspirin ingestion. The pharmacokinetic analysis showed no significant change between phase I and phase II for either the saucy] ate under the concentration versus time curve from 4-12 elimination half-life or the area hours post aspirin ingestion. Reasons for the lack of effect of repeated doses of charcoal on salicylate elimination are discussed and, these results cannot necessarily be extra poIa ted to the overdose situation. Further investigation is warranted to assess the effect of patient. repeated doses of activated charcoal in the salicylate-overdosed T he efficacy of activated charcoal in adsorbing drugs in the gastrointestinal tract and preventing absorption of the drug is well known.1-2 It is widely documented that activated charcoal decreases drug absorption when it is given within a short period of time after ingestion of the drug.3 Unfortunately most adult drug overdoses do not present immediately after ingestion. Often times, absorption of the toxin is complete and the use of a single dose of charcoal is of questionable benefit. However, numerous studies have proven repeated doses of activated charcoal to be effective in increasing the clearance of certain drugs.4-9 Aspirin is a drug which is often implicated in drug overdose cases.10-11 The potential severity of aspirin overdoses and the importance of prompt and appropriate treatment for salicylate overdose has been recently reemphasized by a report which reviewed seven fatalities due to salicylate overdose.11 The toxicity associated with salicylate overdose involves acid-base disturbances, electrolyte and fluid imbal- From the Department of Pharmacy (Ho and Tierney), Department of Emergency Medicine (Dr. Dickinson), Ottawa General Hospital, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. Address for reprints: M.Tierney, Pharmacy Department, Ottawa General Hospital, 501 Smyth Rd. Ottawa, Ontario, Canada K1H 8L6. 366 #{149} J Clin Pharmacol 1989;29:366-369 ance, altered glucose metabolism, hyperthermia, renal failure, and bleeding disorders.12 Toxicity of salicylates is correlated with serum salicylate concentrations. In severely intoxicated patients hemodialysis is used as a means to enhance salicylate clearance from the body.1#{176}However, dialysis is an invasive and a relatively expensive procedure that is not available in all hospitals. In institutions where hemodialysis is unavailable it would be useful to have an alternate means of enhancing salicylate clearance. Repeated doses of charcoal may prove to be potentially useful in this situation. Case reports indicate that repeated doses of activated charcoal appear to enhance salicylate elimination in intoxicated patients.13’14 As these case reports are promising and studies have shown repeated doses of charcoal to be effective in increasing clearance of other drugs, it would be appropriate to test this hypothesis under more controlled conditions. The objective of this study was therefore, to assess the impact of repeated doses of activated charcoal on salicylate elimination. METHODS Study Six the Design healthy volunteers (3 women, 3 men) ages of 22 to 35 years of age participated between in the REPEATED DOSES OF TABLE ORAL ACTIVATED CHARCOAL Salicylate Pharmacokinetic Parameters With (Phase II) and Without (Phase I) Repeated Doses of Activated Charcoal Subject 1 Phase I 5.98 2 3.73 3 4 5.84 3.41 5 4.91 6 8.46 Mean SD 5.39 ±1.84 Not signif icantly study weights reviewed Phase II Phase I 937.2 361.5 709.3 273.2 5.36 2.46 4.84 ±1.30 (P> after giving ranged from 925.1 nitrile in approximately 349.0 642.2 ortho-anisic acid. duced salicylate 190.5 25, 12.5, Phase 575.7 6.07 4.811 different with AUC (jig. h/mi) From 4h-co Post IngestIon 5.74 4.39 II 1084.6 710.9 880.3 656.9 ±317.9 616.31 ±292.4 0.05). informed 51-109 a medical kg. history. consent. Health Subjects Subjects status was were not taking any prescribed medications; had no sensitivity to aspirin or charcoal; had no history of asthma or peptic ulcer disease; were not known to have a bleeding disorder; were not pregnant; and had not consumed salicylates within 24 hours of the study days. Phase I of the study was initiated with a single dose of 1300 mg of aspirin at 0830 hours after an overnight fast. The aspirin was administered as an oral solution of four, 325 mg aspirin tablets crushed and mixed with 250 mL of water. Phase II was performed after a one week washout period under the same conditions as those mentioned above for phase I. Phase II differed from phase I in that volunteers received aqueous activated charcoal according to the following protocol: activated charcoal 25 g/100 mL at approximately 4 hours post aspirin ingestion; activated charcoal 10 g/40 mL at 6, 8, and 10 hours post aspirin ingestion, for a total of 55 g of charcoal. The volunteers continued fasting for the first hour post aspirin ingestion and limited food intake around the time of charcoal ingestion in phase II. No other attempt was made to control or restrict diet during the study period. The protocol for the study was reviewed and approved by the Human Experimental Procedures Committee at our institution. Assay Blood samples heparinized MISCELLANEOUS were catheter collected just through an indwelling before and at approxi- ELIMINATION mately 1, 2, 3, 4, 6, 8, 10 and 12 hours post aspirin ingestion. The samples were allowed to clot, were centrifuged and the serum kept frozen at -17 C until time of assay. Salicylate concentrations were determined using a high pressure liquid chromatography method. The assay conditions were as follows: the column used was a Lichrosorb RP-2 10 im (Altex Scientific) column; the mobile phase was 40% aceto- I HaIf.IIfe (hours) From 4-.12h Post Ingestion SALICYLATE AN 0.085% 2.2. using 6.25 and Pharmacokinetic phosphoric The internal The acid to adjust pH to standard used was calibration curves concentrations 3.125 pro50, Calculations was produced. The elimination was determined using regression in each subject using (k) for salicylate linear 100, g/mL. To analyze the data, we assumed elimination followed linear kinetics tration range encountered. For each rithmic serum salicylate concentration curve were of 200, that salicylate in the concensubject a logaversus time rate constant least-squares the last five points in the terminal phase of the curve (ie, 4-12 hours). Salicylate half-life was calculated by 0.693/ k. Area under the curve (AUC) from 4 h-post apsirin ingestion was determined for each subject using the trapezoidal rule. Statistical Analysis The differences between sample means lyzed using the students t test for paired statistical significance defined as P <0.05. were data anawith RESULTS For the 12 treatment periods in the study, peak serum salicylate concentrations ranged from 55.2-136.4 zg mL. In all cases peak concentrations were measured by three hours post ingestions. Correlation coefficients for the elimination decay curve from 4-12 hours post ingestion ranged from 0.9471.000. Measurable salicylate concentrations were detected in all serum samples. The salicylate elimination half-lives and the area under the concentration versus time curves for the six subjects for both phase I and phase II are given in Table I. Treatment with activated charcoal did not significantly change the salicylate elimination halflife nor the area under the concentration versus time curve, as compared with the control treatment without charcoal. 367 HO DISCUSSION Hillman and Prescott have reported five cases in which repeated doses of charcoal (75 g initially then 50 g q4 h until symptoms were relieved) appeared to enhance salicylate elimination when compared with six controls.13 Two further salicylate overdose cases have been reported in which repeated doses of charcoal (55 g q4 h-total dose 150 g, and 50 g q2.5 h-total dose 250 g) produced a relatively rapid decline in serum salicylate concentrations.14 A number of studies have demonstrated that repeated doses of activated charcoal increase the clearance of theophylline,4 phenobarbital,57 carbamazepine,5 phenylbutazone,5 digoxin,8 and dapsone.9 This effect is independent of the effect on absorption. There are two main proposed mechanisms by which activated charcoal increases the clearance of drugs from the body. The first mechanism is that activated charcoal interrupts the enterohepatic circulation of compounds.2 The second mechanism, often termed “gastrointestinal dialysis,” is that activated charcoal establishes a concentration gradient between the blood and the gastrointestinal fluids.2-3 Activated charcoal adsorbs the toxin from the gastrointestinal fluids, thus decreasing the amount of diffusable drug from these fluids and at the same time optimizing the concentration gradient which allows more drug to diffuse into the gut.3 Our study was designed to eliminate any effect that charcoal may have on salicylate absorption. The aspirin was given as an aqueous solution in a fasting state to maximize absorption and the charcoal was not initiated until four hours after aspirin administration. It was postulated that repeated doses of activated charcoal would enhance salicylate clearance. Results from our study, however, do not support this. Our study showed no significant change in the salicylate elimination half-life nor in the area under the concentration versus time curve between phase I (control) and phase II (charcoal treatment). Limitations of our study may explain the unexpected findings. First, it might be argued that sample size was too small. There was considerable interindividual variation in salicylate half-life and area under the curve eg. salicylate half-life range of 3.41-8.46 h. However the power of the statistical test used is influenced by the variability in the change in salicylate pharmacokinetics between phase I and phase II as opposed to the interindividual variation. Given the variability in the change in the salicylate elimination rate constant observed, we determined in the ability to the power of the study to be 84% detect a one-hour difference in salicylate elimina- 368 #{149} J Clin Pharmacol 1989;29:366-369 ET AL tion half-life between control phase and treatment phase. This is within acceptable limits but does not preclude the possibility of missing a real difference. The observation that both salicylate half-life and area under the curve showed a trend towards reduction raises the possibility that a significant difference would be found with a larger sample size. Another possible limitation of our study was the dose of aspirin used. A relatively small dose (1300 mg) was used, yielding correspondingly low serum salicylate concentrations. Due to the limits of assay sensitivity, the time to which we could draw blood samples was restricted. This limited our period of (4 to 12 hours post dose). comparison to 8 hours Consequently sampling occurred over only one to two salicylate half-lives and this may have been too short to detect a significant difference. Also, with the relatively short half-lives observed in our study, it becomes difficult to further reduce the half-life to a significant extent with repeated doses of charcoal. In a salicylate intoxication the half-life is prolonged and serum salicylate concentrations can be followed for longer periods of time; therefore, the effect of repeated charcoal doses may become more apparent. Presumably it is only the free (or unbound) drug that can leave the circulatory system. In the concentration range observed in our study salicylate protein binding is approximately 9#{216}%,15 and this may limit the efficacy of “gastrointestinal dialysis.” At salicylate concentrations encountered in an intoxication, protein binding is reduced to about 76% 15 and this should facilitate enhanced salicylate clearance with repeated doses of activated charcoal. A third potential limitation of our study was the amount of charcoal administered. Approximately 99% of aspirin from aqueous solutions will be adsorbed by charcoal when a charcoal-aspirin ratio of 10:1 is used.16 Levy and Tsuchiya showed that there was a dose-dependent increase in the efficacy of activated charcoal when the 10:1 ratio of charcoal to aspirin was held constant (charcoal doses 10-50 g/aspirin doses 1-5 g).17 In the two previously mentioned cases, in which a total of 150 g (case 1) and 250 g (case 2) of charcoal were given, the charcoal:aspirin ratio was less than 10:1 (150 g:20 g-case 1/250 g:100 g-case 2) yet there was a relatively rapid decline in the serum salicylate concentrations.14 In our study we used a charcoal:aspirin ratio much larger than 10:1 (55 g charcoal:1.3 g aspirin), thus it appears unlikely that our results could be due to insufficient charcoal. However, desorption of aspirin from charcoal in the gastrointestinal tract has been reported.1718 If this desorption process took place during our study it could help to explain our DOSES REPEATED OF ORAL ACTIVATED CHARCOAL results. Our study design might also be criticized for having little control on diet during the study. However, concomitant food intake does not influence the ability of repeated doses of charcoal to enhance theophylline elimination19 and therefore we do not believe that the lack of dietary restrictions influenced our results. We believe our findings to be important because they highlight the problems one faces in attempting to design a study whose results may be extrapolated to the overdosed patient. Other studies investigating the impact of repeat doses of charcoal on drug elimination should take these into consideration. The resuits of our study cannot be extrapolated to the overdose situation. It has recently been reported that repeated doses of charcoal reduce salicylate absorption to a greater extent than a single dose of charcoal in an aspirin overdose model.2#{176}As salicylate absorption is often delayed in an aspirin overdose it is also likely that benefit from repeated doses of charcoal will be conferred in many cases of aspirin overdose. For the reasons mentioned above when discussing the limitations to our study it is possible that in overdosed patients repeated doses of activated charcoal will significantly increase the elimination of the salicylate. It is necessary to gather and analyze more case studies and/or carry out animal studies in order to appropriately assess the effect of repeated doses of activated charcoal on salicylate elimination in the overdose situation. 3. Levy charcoal. SALICYLATE C: Gastrointestinal N EngI J Med 5. Neuvonen sorption and body Engi 7. Pond SM, Olson treatment activated charcoal. 9. Neuvonen and dapsone PJ, Elonen elimination. 10. 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