Effect of Activated Charcoal on Acetaminophen Absorption

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Effect

of Activated

Charcoal

on Acetaminophen

Absorption

Gerhard Levy, Pharm.D., and J. Brian Houston, Ph.D.

From the Department of Pharmaceutic .s. School of Pharmacy, State t Tnitcrsity of Vew iork. Buffalo

ABSTRACT. Acetaminophen intoxication can cause hepatic, renal, and Inyocardial necrosis which is often fatal. These

lesions develop very rapidly, perhaps during the first pass of the drug through the liver. In case of acute ingestion of an overdose it is therefore essential to employ measures for reducing the absorption of acetaminophen. The effect of activated charcoal on acetaminophen absorption by normal volunteers was determined as a function of the dose of charcoal, the dosage form of acetaminophen, and the char-coal-to-acetaminophen dose ratio. The results indicate that activated charcoal can be an effective antidote for acute acetaminophen intoxication, if administered promptly and in sufficient quantity. Pediatrics, 58:432-435, 1976,

ACETAMINO-PHEN, ACTIVATED CHARCOAL, POISONING.

Acetaminophen, N-acetyl-p-aminophenol, is an

effective antipyretic and mild analgesic agent

which is widely used in pediatric and adult

medicine. Some 200 pharmaceutical products

marketed in the United States, including many

nonprescription products, contain this drug.’

While remarkably safe in ordinary doses,

acetam-mnophen can cause hepatic,2 renal,24 and/or

myocardial5 necrosis when taken in large

amounts. A significant number of these

intoxica-tions are fatal; 30 out of 890 cases admitted to

English hospitals in 1970 resulted in death.6 By

1971, the annual number of hospital admissions

for acetaminophen poisoning had increased to

1,500 in England.7 These reports and the

exten-sive availability of acetaniinophen in the United

States have led to expressions of concern in the

American pediatric literature.05 It is recognized

that the amount of acetaminophen contained in

the commercially available packages of tablets,

syrup, or elixir is sufficient to be potentially fatal

to small children.*

There is no established form of therapy which

has proved effective in preventing organ damage

caused by acetaminophen. . A recent report suggests that intravenously adm inistered

cys-teamine may be effective, but this substance is

not generally available and its use is still

experi-mental. It causes pronounced adverse effects on

the central nervous system which persist for 24 to

36 hours.t The hepatic damage caused by

acetam-inophen seems to develop very rapidly, perhaps

during the first pass of the drug through the liver.’

Pronipt action to reduce absorption is therefore

indicated in cases of acute overdosage or

acci-dental ingestion of large amounts of

acetamino-phen.

Because of its demonstrated effectiveness in

inhibiting the absorption of several other drugs in

man,’#{176}’ we have determined the effect of

acti-vated charcoal on the gastrointestinal absorption

of acetaminophen in relation to the dose of

charcoal, the dosage form of acetaniinophen, and

the charcoal-to-acetaminophen dose ratio.

METHODS

Five healthy male volunteers, 27 to 40 years

old, who by education and background (graduate

students in pharmaceutics) were capable of giving

their informed consent, participated in this study.

(

Received November 28; accepted for publication December 17, 1975.)

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PERCENTAGE OF DOSE RECOVERED IN URINE FROM Two

DIFFERENT FORMS OF ACETAMINOPHEN

TABLE III

EFFECT OF ACTIVATED CHARCOAL ON THE ABSORPTION OF

ACETAMINOPHEN GIVEN IN DIFFERENT FORMS

<.005 <.001 <.005

#{176}Tengrams of activated charcoal administered 30 minutes after ingestion of 1 gm of acetaminophen.

tSee Table I.

TABLE I TABLE II

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433

EFFECT OF ACTIVATED CHARCOAL ON THE ABSORPTION OF ACETAMINOPHEN GIVEN IN SOLUTION0

Charcoal Dose (% of Acetaminophen

Recovered in Urine)

Subject 0 gm S gm 10 gin

1 83.0 48.8 34.9

2 87.9 40.5 30.1

3 77.8 33.7 28.6

4 84.5 38.8 23.7

5 81.8 57.3 42.8

Mean 83.0 43.8 32.0

Relative 100.0 52.8 38.5

availability (%)t

P1: <.001 <.001

#{176}Onegram of acetaminophen as elixir alone or followed immediately by activated charcoal in 200 ml of water on an empty stomach.

tCalculated relative to the availability of acetaminophen from the elixir, without charcoal.

:$:Statistical significance of difference from control (acetami-nophen elixir, administered without charcoal) by paired

t-test.

Acetaminophen was administered in the morning

on an empty stomach as an elixir (Tylenol,

McNeil; lot No. SP3470), as a suspension

(Liqui-prin, Mitchum-Thayer, lot No. 54636), or as

tablets (Tylenol, McNeil, lot No. CH4715).

Acti-vated charcoal (Norit USP XVII) was

adminis-tered as a slurry in 200 ml of water. Except for

one experiment, the dose of acetaminophen was 1

gm. The different experiments were carried out in

random order, at least one week apart. Complete

urine collections were made every four hours for

the first 12 hours and then at the subject’s

convenience for an additional 36 hours. The urine

samples were assayed for total acetaminophen

(

i.e., acetaminophen and its conjugated

metabo-lites) by the method of Welch and Conney.’

Blank values of urine samples obtained from the

subjects ranged from 0.34 to 1.05 mg of

acetami-nophen equivalent per hour and were used to

correct the analytical results.

RESULTS

An average of 83% of the dose of

acetamino-phen was recovered as such and in the form of

conjugates in the urine after oral administration

of 1 gm in solution (Table I). The rest of the dose

is apparently converted to metabolites which are

not detected by the assay or which are eliminated

Acetaminophen

Subject

(% Recovered From 1-gm Dose)

Suspension Tablet

1 82.4 81.9

2 86.7 83.1

3 79.3 82.9

4 79.5 86.3

5 74.2 78.8

Mean 80.4 82.6

Relative availability (%)#{176} 96.9 99.5

P0 NS NS

#{176}SeeTable I.

Subject

Acetaminap #{176}

(

% Recovered in Urine)

Elixir Suspension Tablet

1 50.9 33.6 21.0

2 53.9 40.1 43.3

3 52.1 35.0 48.6

4 69.0 46.6 46.0

5 60.2 51.2 32.3

Mean 57.2 41.3 38.2

Relative availability 68.9 49.7 46.0

(%)t

P

by extrarenal routes. The extent of

acetamino-phen absorption in the experiments with

acti-vated charcoal is expressed in terms of relative

availability, which is the amount of drug and

metabolites recovered in the urine expressed as a

percentage of the amount recovered when

acetaminophen as the elixir is administered

without activated charcoal. The absorption of

acetaminophen, when administered as the elixir,

was

decreased substantially by either 5 or 10 gm

of activated charcoal given immediately after the

drug (Table I).

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TABLE IV

EFFECT OF ACTIVATED CHARCOAL ON ACETAMINOPHEN

ABSORPTION

Drug-Charcoal

Ratio (gin to gui)#{176}

Acetamin in

aphen Recovered Urine (%)

0.5 to 5 42.5

1.0 to 10 34.9

2.0 to 20 22.6

3.0 to 30 14.8

#{176}Acetaminophen given as elixir immediately followed by activated charcoal in 200 ml of water on an empty stomach

(subject 1).

The availability of acetaminophen from

pediat-nc suspension and from tablets was essentially

complete, relative to that of the elixir (Table II).

Ten grams of activated charcoal, given 30

minutes after 1 gm of acetaminophen as a

suspen-sion or as tablets, decreased significantly the

absorption of the drug (Table III). Activated

charcoal given 30 minutes after acetaminophen

elixir had a smaller but still significant effect on

the absorption of the drug (Table III). At a

constant activated charcoal-to-acetaminophen

dose ratio of 10:1, the effectiveness of the

adsorb-ent was substantially increased with an

increas-ing dose (Table IV).

DISCUSSION

As recently pointed out by Rumack and

Matthew,’7 there is apparently a general lack of

knowledge in the United States concerning the

toxicity of acetaminophen. With an awareness of

the problem and a high index of suspicion, these

investigators discovered 156 accidental ingestions

with four fatalities in Denver during one year

(1973 to 1974). It is important therefore to

develop methods for treating such accidental

ingestions and for preventing serious intoxications

with acetaminophen.

The average urinary recovery of

acetamino-phen and metabolites (acetaminophen

glucu-ronide and sulfate) from an orally administered

solution in this investigation (83% of the dose) is

similar to the recoveries obtained in other studies

with normal adults (reviewed by Levy et al.’5).

The commercial suspension and tablet products

of acetaminophen used in this investigation were

completely bioavailable (absorbed) relative to the

solution (elixir) of the drug (Table II). Activated

charcoal, given 30 minutes after either suspension

or tablets of acetammnophen, reduced absorption

of the drug by about 50% under the experimental

conditions. A more pronounced effect is likely

under clinical conditions (see below). The lesser

effect of activated charcoal on the absorption of

acetaminophen from the elixir is due to the rapid

absorption of the drug when administered in

solution. Activated charcoal would have to be

given very soon after ingestion of such a solution

to be effective. It is particularly important

there-fore to prevent access by infants and children to

the attractively colored and flavored

acetamino-phen solutions (elixir and syrup) and it is desirable

to limit the drug content of commercial packages

or prescriptions of these products.

Previous studies with aspirin have shown that

the effectiveness of activated charcoal, at a

constant activated charcoal-to-drug dose ratio,

increased with increasing dose.’ The same is true

for the effect of activated charcoal on

acetamino-phen absorption (Table IV). This probably

reflects the competitive effect of gastrointestinal

contents which becomes less pronounced as the

dose of activated charcoal is increased.’#{176} Another

factor which favors the effectiveness of activated

charcoal in cases of acute overdosage is the

inhibitory effect of acetaminophen (like aspirin)

on gastric emptying. “ This in turn slows the

absorption of the drug2#{176}(an effect which is also

documented for aspirin”’) and justifies the

admin-istration of activated charcoal even some hours

after the ingestion of massive doses of

acetamino-phen. It has been shown that activated charcoal

can “catch up” with a drug taken two or three

hours earlier.’ Activated charcoal is well

toler-ated in high doses (up to 100 gm for adults)21 and a

slurry in water is apparently well accepted by

most acutely intoxicated children.22 It should be

given “straight” and not with suspending agents

or other excipients unless these have been shown

not to interfere with its efficacy.2’ The most

useful place for activated charcoal is in the home,

where it can be administered promptly after

accidental drug ingestion. It is hoped that this and

previous reports demonstrating the efficacy of

activated charcoal10 ‘ will stimulate pediatricians

to encourage the inclusion of this valuable

anti-dote in the medicine cabinet of every home with

children.

Because of the variables of dose, dosage form,

and time, among others, dosage recommendations

for the use of activated charcoal in acute

acetam-inophen ingestions cannot be definitive and are

only offered as a guide. A dose of 50 to 100 gm of

activated charcoal as a well-dispersed slurry in

water is suggested for adults and a

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ARTICLES

435

emptying and therefore prolonged absorption in

cases of massive acetaminophen ingestion, it is

reasonable to administer activated charcoal up to

six hours (and perhaps even longer) after ingestion

of acetaminophen tablets or suspension.

How-ever, it is unlikely that activated charcoal would

be effective more than one half to one hour after

ingestion of acetaminophen in solution.

Adminis-tration of activated charcoal is recommended

only as an initial step in the treatment of

acci-dental acetaminophen ingestion. It should be

followed by appropriate medical assessment of

the patient, including the determination of

acetaminophen concentrations in plasma if the

patient’s history suggests that the amount

ingested may have been substantial, and

treat-ment in accordance with the clinical findings.

REFERENCES

1. Goulding R: Acetaminophen poisoning. Pediatrics

52:883, 1973.

2. Proudfoot AT, Wright N: Acute paracetamol poisoning. Br Med J 3:557, 1970.

3. Prescott LF, Wright N, Roscoe P, Brown 55:

Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1:519, 1971.

4. Boyer TD, Rouff SL: Acetaminophen-induced hepatic necrosis and renal failure. JAMA 218:440, 1971. 5. Will EJ, Tomkins AM: Acute myocardial necrosis in

paracetamol poisoning. Br Med J 2:430, 1971. 6. Sutton E, Soyka LF: How safe is acetaininophen? Clin

Pediatr 12:692, 1973.

7. The liver machine. Time, November 19, 1973, p 83. 8. Weiss CF: Acetaminophen: Potential pediatric hazard.

Pediatrics 52:883, 1973.

9. Prescott LF, Newton RW, Swainson CP, et a!:

Successful treatment of severe paracetamol over-dosage with cysteamine. Lancet 1:588, 1974. 10. Levy C, Tsuchiya T: Effect of activated charcoal on

aspirin absorption in man. Clin Pharmacol Ther 13:317, 1972.

11. Tsuchiya T, Levy G: Relationship between effect of activated charcoal on drug absorption in man and its adsorption characteristics in vitro. J Pharm Sci

61:586, 1972.

12. Sorby DL: Effect of adsorbents on dnig absorption: I. Modification of promazine absorption by activated

attapulgite and activated charcoal. J Pharm Sci 54:677, 1965.

13. Decker WJ, Shpall BA, Corby DG, et a!: Inhibition of

aspirin absorption by activated charcoal and apomorphine. Clin Pharmacol Ther 10:710, 1969. 14. Chaput de Saintonge DM, Herxheimer A: Activated

charcoal impairs propantheline absorption. Eur J

Gun Pharmacol 4:52, 1971.

15. Alvan C: Effect of activated charcoal on plasma levels of nortriptylene after single doses in man. Eur J Clin Pharmacol 5:236, 1973.

16. Welch RM, Conney AH: A simple method for the

quantitative determination of

N-acetyl-p-amino-phenol (APAP) in urine. Clin Chem 11:1064,

1965.

17. Rumack BH, Matthew H: Acetaminophen poisoning and toxicity. Pediatrics 55:871, 1975.

18. Levy G, Khanna NN, Soda D, et a!: Pharmacokinetics of acetaminophen in the human neonate: Formation

of acetaminophen glucuronide and sulfate in

rela-tion to plasma bilirubin concentration and

D-glucaric acid excretion. Pediatrics 55:818, 1975. 19. Weikel JH Jr, Lish PM: Gastrointestinal pharmacology

of antipyretic agents: II. Absorption and smooth muscle effects. Arch Int Pharmacodyn Ther

119:398, 1959.

20. Heading RC, Nimmo J, Prescott LF, Tothill P: The

dependence of paracetamol absorption on the rate

of gastric emptying. Br J Pharmacol 47:415, 1973. 21. Decker WJ, Corby DG: Activated charcoal as a

gastrointestinal decontaminant: Experiences with

experimental animals and human subjects. Clin

Toxicol 3:1, 1970.

22. Calvert WE, Corby DG, Herbertson LM, Decker WJ: Orally administered activated charcoal: Accept-ance by children. JAMA 215:641, 1971.

23. Levy G, Soda DM, Lampman TA: Inhibition by ice cream of the antidotal efficacy of activated

char-coal. Am J Hosp Pharm 32:289, 1975.

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1976;58;432

Pediatrics

Gerhard Levy and J. Brian Houston