Inhibition of theophylline absorption by activated charcoal

3 14

Brief clinical and laboratory observations

duction of beta-blocking agents, somewhat more success has been achieved. A disadvantage of this therapy is that the long-term side effects of high dosage beta-blockers have yet to be established. 7 The logical drug of choice would be one that would depress the spontaneous depolarization of the ectopic focus without having other deleterious side effects. Verapamil appears to fit this description. Verapamil blocks the slow inward calcium current in cardiac fibers, thereby slowing the ability of ectopic pacemakers to discharge prematurely?. ~' Verapamil has been used principally in intravenous form and has been most successful in the conversion of supraventricular tachycardia to sinus rhythm, but has also been effective in the stabilization of the rhythm in atrial flutter and fibrillation. 1~' Although this drug has been used outside of the United States for a considerable period of time with excellent results, experience with it in children throughout the world is still relatively limited.' We present our experience with this patient to guide other physicians in terms of dosages and routes of administration in children. REFERENCES

The Journal of Pediatrics February 1979

2. Gillette PC: The mechanisms of supraventricular tachycardin in children, Circulation 54:133, 1976. 3. Josephson ME, and Kastor JA: Supraventricular tachycardia: mechanisms and management, Ann Intern Med 87:346, 1977. 4. Gillette PC, and Garson A Jr: Electrophysiologic and pharmacologic characteristics of automatic ectopic atrial tachycardia, Circulation 56:571, 1977. 5. Jacobson JR, Andersen ED, Sande W, Viderbaek J. and Wennevold A: Chronic supraventricular tachycardia in infancy and childhood, Acta Paediatr Scand 64:597, 1975. 6. Keane JF, Plauth WH, and Nadas AS: Chronic ectopic tachycardia of infancy and childhood, Am Heart J 84:748, 1972. 7. Gillette PC, Garson A Jr, Eterovic E, Neches W, Muttins C, and McNamara DG: Oral propranolol treatment in infants and children, J PEDIATR92:141, 1978. 8. Rosen MR, Ilvento JR, Gelband H, and Merker C: Effects of verapamil on electrophysiologic properties of canine cardiac Purkinje fibers. J Pharmacol Exp Ther 189:414, 1974. 9. Wit AL, and Cranefield PF: Effect of verapamil on the sino atrial and atrioventricular nodes of the rabbit and the mechanism by which it arrests re-entrant atrioventricular nodal tachycardia, Circ Res 35:413, 1974. 10. Gotsman MS, Lewis BS, Bakst A, and Mitha AS: Verapamil in life-threatening tachyarrhythmias, S Afr Med J 46:2017, 1972.

1. Hugel FU, Meunicken U, and Wechselberg K: Supraventricular paroxysmal tachycardia during childhood and its treatment. Therapiewoche 26:5143, 1976.

Inhibition of theophylline absorption by activated charcoal Charles Sintek, M.S. (Pharm.), Leslie Hendeles, Pharm. D.,* and Miles Weinberger, M.D., Iowa City, Iowa

W I T H THE WIDESPREAD AVAILABILITY and increased use of theophylline, acute overdoses can be expected to occur, especially in the pediatric age group. Concern has recently been expressed about the danger of toxicity resulting from errors in administration or confusion about product concentration.'. Various in vitro and in vivo studies have documented From the Veterans Administration Hospital, the College of Pharmacy, the Department of Pediatrics, and the Clinical Research Center, the University of Iowa. Supported in part by Grant RR-59 from the General Clinical Research Centers Program, Division of Research Resources, National Institutes of Health, and by funds provided by the C~gllegeof Pharmacy, University of Iowa. *Reprint address: College of Pharmacy, Universityof 1own, Iowa City, 1,4 52242.

the efficacy of activated charcoal as an adsorbent for more than 30 different drugs and chemical c o m p o u n d s ? Since it adsorbs theophylline in vitro,' the present study was undertaken to evaluate the efficacy of activated charcoal in reducing the gastrointestinal absorption of theophyUine in healthy adult volunteers. Abbreviation used AUC: area under serum concentration-time curve METHODS

Four m e n and one woman, ,25 to 33 years of age, participated in the study after informed consent was obtained. None of the subjects was taking medications other than theophylline and all doses were withheld for 48 hours preceding each test day. Anhydrous theophylline, 7.7 +_ 0.4 m g / k g (mean _ S D ) , in the form of plain 0022-3476/79/200314+03500.30/0 9 1979 The C. V. Mosby Co.

Volume 94 Number 2

Brief clinical and laboratory observations

3 15

Table. Activated charcoal effect on theophylline bioavailability

Peak serum concentration Ozg/ ml) Dose (rag)

Subject

1 500 2 500 3 600 4 600 5 500 Mean -+ 540 • 24.5 SEM Statistical significance

Theophylline I Theophylline alone + charcoal 17.9 14.4 16.7 16.3 12.3 15.5 -+ 1.0

3.3 9.1 11.9 13.2 12.2 9.9 _+ 1.8

Time to reach peak serum concentration (hr)

Area under concentration-time curve (ixg/hr/ml)

Theophvlline alone

Theophylline + charcoal

Theophylline alone

Theophylline + charcoal

Fraction of dose absorbed*

1.0 3.0 1.0 1.0 3.0 1.8 • 0.5

1.5 0.5 1.0 0.3 0.5 0.8 • 0.2

276.1 235.1 198.8 204.0 132.7 209.4 _+ 23.6

10.2 23.0 146.0 94.3 98.3 74.3 • 25.4

0.037 0.098 0.734 0.462 0.741 0.414--+0.151

P < 0.05

NS

P < 0.025

P < 0.025

NS = Differencenot statistically significant at P < 0.05 level. *Ratio of area under time-concentration curve of theophylline + charcoal to area under the time-concentration curve during theophylline alone. uncoated tablets (Slo-Phyllin 100 mg tablets, lot 6112876, Dooner Laboratories, Inc., Haverhill, M A 01830) was administered after a four-hour fast with 240 ml of water. Each subject received, in random assignment on different test days, either a slurry of 30 gm of activated charcoal (Activated Charcoal, USP, lot WEEB, Mallinckrodt, Inc., St. Louis, M O 63147) or 300 ml of water 30 minutes after

abruptly following administration of activated charcoal. The mean serum theophylline concentration went no higher than 9.9 +__ 1.8 ~ g / m l at 30 minutes, and the extent of absorption (fraction of dose absorbed) was significantly reduced to 0.41 _ 0.15 (P < 0.025).

theophylline. Five milliliter blood samples were obtained at 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 minutes, and then every two hours thereafter for 14 hours. Serum theophylline concentration was measured by reverse-phase, high-pressure liquid chromatography? The coefficient of variation of this method was 4% at 20/~g/ml. The extent of theophylline absorption when followed by charcoal was calculated by dividing the area under the serum concentration-time curve* of the theophyllineactivated charcoal trial by the A U C for the theophylline control. 6 The one-tailed t test for paired data was used to assess the statistical significance of the charcoal effect.

Theophylline is rapidly and completely absorbed from plain uncoated tablets when administered on an empty stomach, and the serum theophylline concentrations attained as a result of the administered dose in the current study are similar to those previously reported? In the presence of activated charcoal, only an average of 40% of the administered dose was absorbed. The individual fractions absorbed, however, ranged from 4 to 74%. This variability among subjects appeared to be related to the extent of theophylline absorption during the 30 minutes prior to administration of the charcoal. Although the average time between ingestion and arrival of the patient at the hospital is one hour, TM this preliminary investigation examines the effect of activated charcoal administered at 30 minutes in order to increase the likelihood of detecting a significant inhibition of theophylline absorption. The potential usefulness of activated charcoal in the treatment of acute overdoses depends upon the time interval between ingestion and the administration of charcoal, the dosage form of theophylline ingested, and the amount of activated charcoal that can be administered. Our results suggest that activated charcoal may be effective when given within 30 minutes of ingesting theophylline tablets. However, its efficacy may be reduced in patients who have already absorbed substantial quantities of the drug prior to administration of the charcoal. Activated charcoal may be less effective for preventing

RESULTS Theophylline, when administered alone in the fasting state, was rapidly absorbed, producing peak serum concentrations of 15.5 ___ 1.0 # g / m l (mean _+SEM) at 1.8 + 0.5 hours (Table). For the first 30 minutes, the rate of absorption during the charcoal trial was virtually identical (Figure). Absorption then appeared to stop *The AUC ( .f,'~C dr) was determined by the trapezoidal method7 and the AUC extrapolated to infinity ( So C dt) was determined by adding to that the area from the last data point (at 14 hours) to infinity. The area from the last point to infinity was calculated by dividing the serum concentration at that time (C,) by the elimination constant (K/.~Thus, AUC. . . .

fo C dt= j ~,'C dt + Cp/K.

DISCUSSION

3 16

Brief cfinical and laboratory observations

The Journal of Pediatrics Februa O' 1979

by administration of activated charcoal, however, may be more appropriate for patients ingesting unusually large doses. If both ipecac and charcoal are used, it is imperative that the emetic be given first, since ipecac is adsorbed by activated charcoal and thus rendered ineffective. Some sustained release theophylline preparations require 8 hours or longer to be completely absorbed," suggesting that the addition o f a nonadsorbed saline cathartic such as sodium sulfate be considered to decrease gut transit time.

16

E

14

-~,

r x.._

\\\\\

12

"~

o

10

_~

6

~

4

~

2

X2

F~

",j

The authors wish to thank the nurses of the Clinical Research Center for their contribution to the study; Leon Burmeister, Ph.D., Department of Preventive Medicine and Environmental Health, University of Iowa, who reviewed the statistical analysis; and Barry H. Rumack, M.D., Director, Rocky Mountain Poison Center, Denver, Colorado, for his suggestions. REFERENCES

co 0

I

i

i

I

I

I

4

6

8

10

12

14

Time (hours)

Figure. Mean _+SEM concentration-time curves for serum theophylline alone (.--.) and theophylline followed by activated charcoal (.__.) in five healthy adult volunteers. toxicity following ingestion of theophylline solutions, which are absorbed to a greater extent during the first 30 minutes than of the plain uncoated tablets used in the present study) In contrast, the absorption of delayed or sustained release products may be more completely inhibited. In addition, charcoal may be effective after a longer time interval with these slowly absorbed products. Although 30 gm of activated charcoal effectively inhibited the absorption of 500 to 600 mg of theophylline in this study, it is not possible to predict whether this amount would be adequate for larger doses. Initial treatment of acute theophylline ingestion should include prompt measures to reduce gastrointestinal absorption. The results of the present study suggest that the use of activated charcoal, if administered within the first half-hour after ingestion, may be an adequate therapeutic measure. Induction of emesis with ipecac followed

1. Chipps BE, Talamo RC, and Teets KC: Theophylline and the danger of differing absorption capabilities, J PEDIATR 91:346, 1977. 2. Vaucher Y, Lightner ES, and Walson PD: Theophylline poisoning, J PEDIATR90:827, 1977. 3. Corby DG, and Decker WJ: Management of acute poisoning with activated charcoal, Pediatrics 54:324, 1974. 4. Sintek C, Hendeles L, and Weinberger M: Activated charcoal adsorption of theophylline in vitro, Drug Intell Clin Pharm 12:158, 1978. 5. Orcutt J J, Kozak PP, Gillman SA, et al: Micro-scale method for theophylline in body fluids by reversed-phase, highpressure liquid chromatography, Clin Chem 23:599, 1977. 6. Gibaldi M, and Perrier D: Pharmacokinetics, New York, 1975, Marcel Dekker, Inc., p 149. 7. Gibaldi M, and Perrier D: Pharmacokinetics, New York, 1975, Marcel Dekker, Inc., pp 293-296. 8. Gibaldi M, and Perrier D: Pharmacokinetics, New York, 1975, Marcel Dekker, Inc., pp 150-151. 9. Hendeles U Weinberger M, and Bighley L: Absolute bioavailability of oral theophylline, Am J Hosp Pharm 34:525, 1977. 10. Dabbous IA, Bergman AB, and Robertson WO: The ineffectiveness of mechanically induced vomiting, J PEDIATR66:952, 1965. 11. Hendeles L, Weinberger M, and Bighley L: Absorption characteristics of various oral theophylline dosage forms, presented at the American Congress of Allergy and Immunology, New York City, March 30, 1977.

Cerebrovascular complications in phencyclidine intoxication Carl J. Crosley, M.D.,* and Eugene F. Binet, M.D., Syracuse, N.Y.

From the Departments of Neurology, Pediatrics and Radiology, SUNY, Upstate Medical Center. *Reprint address: Department of Neurology, SUNY Upstate Medical Center, 750 E. Adams St., Syracuse, NY 13210.

Phencyclidine is a commercially available anesthetic agent used in veterinary medicine. It is a popular street drug and is sold as angel dust, "PeaCe Pill," and other pseudonyms. Intoxication in adults occurs, and the 0022-3476/79/200316+03500.30/0 9 1979 The C. V. Mosby Co.