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Effect of oral activated charcoal on the absorption and elimination of drugs and toxins in humans
E F F E C T O F ORAL A C T I V A T E D C H A R C O A L ON THE ABSORPTION AND ELIMINATION )F DRUGS AND TOXINS IN HUMANS ~LKKOLA
Activated charcoal is an adsorbent which is able to adsorb a wide variety of substances onto its surface. Although the first systematic studies of charcoal as an antidote were performed in the 18th century, in many countries and in many hospitals its use as an antidote has not been accepted until recently. This has been probably due to lack of suitable formulations and direct experimental or clinical human studies. The effect of high single and repeated doses of charcoal on the absorption and elimination of various drugs has been studied intensively during the last 10 years [1]; [2]. As a result, particularly the initial management of intoxicated patients has changed.
included in some formulations, may have significant gastrointestinal and systemic side effects when charcoal is administered in high doses.
•
Charcoal dose
Factors affecting the antidotal efficacy of activated charcoal
Physiochemical properties and pharmaceutical formulation of charcoal The physicochemical properties of charcoal are of vital importance for its antidotal efficacy. The major determinants of these properties are the pore size and surface area of charcoal. Larger surface area provides better antidotal efficacy. Good quality charcoals have a surface area of 1000--3500 m2/g. The pharmaceutical formulation of charcoal has an influence on both the applicability and efficacy of oral activated charcoal. Water suspensions of charcoal are superior in antidotal use. The use of various flavoring and thickening agents cannot be recommended because their influence on the antidotal efficacy of charcoal is unpredictable. It should also be remembered that ethanol, sodium bicarbonate and sorbitol, which are Department of Anaesthesia, University of Helsinki, Haartmaninkatu 4, SF-00290 Helsinki, Finland.
Chemical nature and pharmaceutical formulation of agents ingested in intoxications Generally speaking most substances will be adsorbed effectively by activated charcoal. Known exceptions which have clinical significance are alcohols, iron, lithium, cyanide and strong acids and alkalis. The absorption of slowly absorbed formulations appears to be inhibited less than that of rapidly absorbing formulations. However, the reduction of efficacy can be counteracted by giving repeated doses of charcoal.
Completeness of adsorption depends greatly on the ratio of charcoal to poison, because according to the mass law there is an equilibrium between free and adsorbed poison. The higher the charcoal--poison ratio the more complete is the adsorption. Therefore, in the initial management of intoxicated patients, to be on the safe side, large doses (50--100 g) of charcoal should be used [2].
Gastrointestinal contents Although the presence of food in the stomach of patients with drug overdosages impairs the adsorption capacity of charcoal it also gives charcoal more time to effectively adsorb drugs in the gastrointestinal canal, possibly by slowing the gastric emptying rate [3]. Theoretically, ethanol in the gastrointestinal tract could affect the antidotal efficacy of charcoal. However, although ethanol impairs the adsorption capacity of charcoal in vitro, the concomitant ethanol ingestion does not affect the antidotal efficacy of charcoal significantly [4]. R#an. Urg., 1993, 2 (2 bis), 215-219
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216 -
X ° Conf4rence
de consensus
en r~animation
Stability of the charcoal--poison complex The binding of drugs and poisons to activated charcoal is a reversible process meaning that the compound once adsorbed can also desorb [2]. If adequately high doses of activated charcoal are used the desorption is seldom significant in clinical situations. The use of repeated doses of charcoal further reduces the risk of desorption.
Time--effect relationships Delay in the administration of charcoal after drug ingestion impairs the antidotal efficacy of oral charcoal. This means that charcoal should be given as soon as possible. However, because the absorption of drugs in serious overdosages may be considerably prolonged, there is no exact time limit to when charcoal should not be administered anymore.
Purgatives and whole bowel irrigation Theoretically, the quicker the charcoal--poison complex passes through the gastrointestinal tract, the less will be the desorption. Most studies in man have failed to demonstrate any substantial benefit from the combined use of purgatives and charcoal [5, 6]. The routine use of purgatives in combination with activated charcoal does not seem to be indicated. In some instances the use of laxatives may promote the evacuation of slowly absorbed formulations from the gastrointestinal tract and thus have a beneficial effect together with activated charcoal. The benefits of combining, for example, sorbitol to charcoal must be weighed against the potential risk for the individual patient. There have been cases of hypernatremia associated with the use of charcoal--sorbitol suspension. Whole bowel irrigation appears to be a promising method to reduce the absorption of drugs and toxic substances from the gastrointestinal tract. Theoretically, ingestion of charcoal prior to the whole bowel irrigation or whole bowel irrigation with some charcoal added to the irrigation solution could enhance the efficacy of both charcoal and whole bowel irrigation. However, recent studies have failed to show any benefit from the combined use of the activated charcoal with whole bowel irrigation [7].
Mechanisms of enhanced drug and toxin elimination by multiple charcoal doses Many drugs and toxic agents are excreted into the gastrointestinal tract. The excretion may occur in gastric juice, bile, pancreatic secretions or other gastrointestinal fluids. Also the diffusion through the mucosal ("dialysis") membrane from capillaries into the gut is possible. Many of these compounds are R~an. Urg., 1993, 2 (2 bis), 215-219
then reabsorbed back into the blood. Activated charcoal adsorbs effectively and practically irreversibly many of those compounds in the gastrointestinal canal and prevents their reabsorption. The interruption of the enterohepatic and enteroenteric circulation by multiple oral doses of activated charcoal thus accelerates the rate of their elimination. The administration of multiple charcoal doses may be indicated also in some instances where charcoal does not actually increase the elimination. If the affinity of drug to charcoal is low or if the adsorption capacity of charcoal is saturated because of gastrointestinal contents or because of the drug itself, administration of multiple doses of charcoal increase its antidotal efficacy.
Effect of single and repeated doses of activated charcoal on the absorption and elimination of drugs and toxins in humans Antipyretic analgesics Generally speaking, antipyretic analgesics are adsorbed to charcoal moderately and some of them well. In humans the absorption of therapeutic aspirin doses (1--5 g) is reduced by 50 to 85 % with 20 to 50 g of activated charcoal. Repeated doses of charcoal enhance the elimination of salicylates. The efficacy of activated charcoal in reducing the absorption of paracetamol has been only moderate [2]. In severe paracetamol poisoning specific antidotes, Nacetylcysteine and methionine, must be used in order to prevent hepatic necrosis. In vitro these antidotes are adsorbed to charcoal to some extent, but this adsorption does not seem to be clinically significant and does not invalidate the concomitant oral administration of charcoal and N-acetylcysteine [8]. Charcoal reduces the absorption of indomethacin, phenylbutazone, piroxicam, mefenamic acid and tolfenamic acid [2]. Repeated doses of charcoal increase the elimination of phenylbutazone and piroxicam.
Other analgesics In healthy volunteers charcoal effectively reduces the absorption of dextropropoxyphene. Repeated doses of oral charcoal enhance the elimination of both dextropropoxyphene and norpropoxyphene [2]. Although there is no experimental data, there is no reason to believe that activated charcoal would not adsorb opiates and reduce their absorption. Charcoal is also likely to enhance, for example, the elimination of buprenorphine and methadone.
Hypnosedatives and anticonvulsants Activated charcoal binds most barbiturates effectively. Normally phenobarbitone has an elimination
X e Conf@rence d e c o n s e n s u s en r@animation - 21 7 -
half-life of about 100 h. Repeated doses of oral activated charcoal have shortened the half-life to about 20 h [9]. Charcoal also reduces the absorption and increases the elimination of carbamazepine, phenytoin, valproate, diazepam and meprobamate [2]. 40 g of oral activated charcoal administrated to a patient with diazepam intoxication shortened the elimination half-life of diazepam from 200 h to under 20 h [10].
Oral hypoglycemic agents I n vitro charcoal effectively adsorbs sulfonylureas. Especially the affinity of the second generation sulfonylureas to charcoal is good. In volunteers the immediate administration of 50 g of charcoal inhibited 80--90 % of the absorption of therapeutic chlorpropamide and tolbutamide doses. In humans it has been shown that multiple charcoal doses do not enhance the elimination of chlorpropamide [12], [13].
Antidepressants
Bronchodilatating drugs
Single dose charcoal effectively inhibits the gastrointestinal absorption of nortfiptyline, amitripyline, imipramine and doxepin. Repeated doses of charcoal increase the elimination of nortriptyline, amitriptyline and doxepin [2].
Activated charcoal reduces the gastrointestinal absorption of theophylline. Repeated doses of charcoal should be used in severe theophylline poisoning in order to prevent prolonged absorption if slowly absorbed theophylline preparations have been ingested. Repeated doses also increase the elimination [14].
Other psychopharmaca There is not much information on the efficacy of charcoal in poisonings caused by other psychopharmaca. I n vitro activated charcoal adsorbs well all the phenothiazines tested. Charcoal is certainly useful in reducing the absorption of phenothiazines. It probably also enhances their elimination. In humans charcoal has been shown to prevent the absorption of promazine very effectively [2].
Cardiac glycosides Activated charcoal adsorbs very effectively cardiac glycosides and increases their elimination, too. Charcoal may be the most effective treatment in inhibiting the gastrointestinal absorption of digoxin since the total amount of digoxin ingested is small (less than 100 mg) even in severe poisonings. The elimination half-life of digoxin has been shortened by about 50 % by repeat-dose charcoal [11].
Antiarrhythmic drugs Most antiarrhythmic drugs are highly toxic and can cause fatal intoxications. Activated charcoal inhibits the gastrointestinal absorption of, for instance, quinidine, disopyramide, mexiletine and flecainide very effectively [2]. 50 g of charcoal given 5 rain after quinidine (200 mg) reduced its absorption by 99 %. The elimination of quinidine and its isomer, quinine, is accelerated by charcoal [2].
lY-adrenoceptor antagonists In humans, 50 g of activated charcoal reduced the absorption of atenolol, pindolol and sotalol, given in therapeutic doses, by over 90 %. Repeated doses of charcoal have been shown to increase the elimination of sotalol and nadolol [2].
Antimicrobial agents Antimicrobial agents are seldom a problem in clinical toxicology. 0ral activated charcoal inhibits the gastrointestinal absorption of, for example, tetracycline, doxycycline, trimethoprim, isoniazid and chloroquine [2]. Dapsone is an antimicrobial agent which can cause severe poisoning. Activated charcoal reduces both its gastrointestinal absorption and increases its elimination. The efficacy of repeat-dose oral charcoal in dapsone intoxications is well comparable to the efficacy of hemodialysis [15].
Other drugs In volunteers activated charcoal has effectively reduced the gastrointestinal absorption of, for instance, phenylpropanolamine, diphenylhydramine, furosemide, cyclosporine and oestriol. Repeated doses of charcoal increase the elimination of methotrexate [2]. Charcoal also adsorbs the active ingredients of syrup of ipecac. However, in a clinical study, 50 g of charcoal did not prevent the emetic effect in any of the 10 intoxicated patients who were included in the study [16].
Metals, alcohols and other substances The efficacy of charcoal in metal poisoning has not been studied in man. Orally given, multiple-dose charcoal may increase the elimination of some metals from the body. However, generally speaking, metals, includind lithium and iron, are not adsorbed efficiently to activated charcoal. Charcoal does not affect the absorption of ethanol or methanol significantly [17]. In experimental animals activated charcoal seems to be able to reduce the mortality in ethylene glycol poisoning. I n vitro charcoal adsorbs ethylene glycol relatively inefficiently. This discrepancy may be caused by the toxic metabolites of ethylene glycol R~an. Urg., 1993, 2(2 bis), 215-219
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which in acute poisoning may be of major importance. High doses of oral activated charcoal reduce the gastrointestinal absorption of paraquat, kerosene, benzene and dichlorethane in experimental animals. Charcoal also adsorbs many other substances, including nicotine, strychnine and aflatoxins [2]. Cyanide is not adsorbed significantly to charcoal.
Relative efficacy of activated charcoal, emetics, and gastric lavage in the inhibition of drug absorption According to somewhat older studies, induced emesis seems to be more efficient than gastric lavage in emptying the stomach. Recently these older studies have been questioned because of the later technical development in orogastric tubes. It has been claimed that currently used, large orogastric tubes are able to remove larger volumes of gastric contents than the previously used tubes [18]. However, the question remains whether gastric emptying should be performed at all. Some years ago it was demonstrated that syrup of ipecac does not alter the clinical course of poisoned patients who are alert on presentation to the hospital [19]. Recent experimental studies have shown that oral activated charcoal is superior to emetics in reducing the absorption of that fraction of the drug which is still present in the stomach when charcoal or emetic is administered [20], [17]. In these studies therapeutic doses (from 10 mg to 2000 mg) of various drugs have been used. Despite this apparent handicap of experimental studies when compared to clinical intoxications, the experimental data are relevant to very many intoxications, because most drugs will cause fatal intoxications in the doses of a few grams, or even in much smaller doses! However, it is obvious that gastric emptying is likely to be more effective than activated charcoal alone in those poisonings where the amount of the drug ingested is large (e.g. aspirin and paracetamol poisonings) leading to the saturation of the adsorption capacity of charcoal or where the affinity of the particular agent to activated charcoal is poor (e.g. iron). The immediate administration of activated charcoal before other time-consuming procedures should be considered in most intoxications. It is important to remember that the administration of charcoal does not prevent gastric emptying to be performed later. Charcoal in the stomach can adsorb which otherwise could be absorbed to systemic circulation during the transport to the hospital and during the gastric emptying procedures. R6an. Urg., 1993, 2 ( 2 bis), 215-219
[] Toxicity and side effects of activated charcoal Activated charcoal itself has not been associated with specific toxicity. However, various additives used in combination with charcoal have caused side effects requiring medical intervention. In uremic patients continuous treatment with 20--50 g of charcoal per day given orally over periods of 4 to 20 months has not resulted in any significant side effects [2]. Rapid ingestion of large doses of charcoal may cause vomiting. Constipation, or sometimes diarrhea have occurred in some subjects receiving activated charcoal as watery suspensions orally. Major complications associated with the use of activated charcoal have been due to the aspiration of charcoal and gastric contents. Possible constipation caused by activated charcoal can be treated with sorbitol, paraffin oil or lactulose.
•
Conclusions
Single doses of oral activated charcoal prevent effectively the gastrointestinal absorption of most drugs and toxins present in the stomach when charcoal is given. Known exceptions are strong acids and alkalis, alcohols, cyanide and metals like iron and lithium. In general, activated charcoal is more effective than gastric emptying. However, if the amount of drug or poison ingested is very large or if its affinity to charcoal is poor, the adsorption capacity of activated charcoal can be saturated. Repeated dosing with oral activated charcoal enhances the elimination of many toxicologically significant agents, e.g. aspirin, carbamazepine, dapsone, dextropropoxyphene, diazepam, cardiac glycosides, meprobamate, phenobarbitone, phenytoin, and theophylline. It also accelerates the elimination of many industrial and environmental intoxicants. In acute intoxications 50--100 g of oral activated charcoal should be administrated to acutely poisoned adult patients as soon as possible (children 1--2 g/kg). The only exceptions are probably patients poisoned with caustic alkalis or with mineral acids. Charcoal should be a part of first-aid kits both at home and at work. The "blind" administration of charcoal neither prevents later gastric emptying nor does it cause serious adverse effects on the condition that pulmonary aspiration in obtundent patients is prevented. However, it prevents or at least reduces further systemic absorption during transport to the hospital. High doses of sorbitol, other laxatives, sodium bicarbonate etc. included in some charcoal formulations have caused severe electrolyte disturbances and other side effects not associated with charcoal per se. In severe acute poisonings oral activated charcoal should be administered repeatedly (25--50 g at intervals of 4--6 hours) until recovery or until plasma concentrations have fallen to safe levels.
X ~ ConfGrence de consensus en rGanimation -
RGfGrences [11 ] [1] NEUVONEN P.J. - - Clinical pharmacokinetics of oral activated charcoal in acute intoxications. Clin. Pharmacokin., 1982, 7, 465-489. [2] NEUVONEN P.J., Olkkola K.T. - - Oral activated charcoal in the treatment of intoxications : Role of single and repeated doses. Med. Toxicol., 1988, 3, 33-58. [3] OLKKOLAK.T., NEUVONEN P.J. - - DO gastric contents modify antidotal efficacy of oral activated charcoal? Brit. J. Clin. PharmacoL, 1984, 18, 663-669. [4] NEUVONENP.J., OLKKOLAK.T., ALANEN T. - - Effect of ethanol and pH on the adsorption of drugs to activated charcoal: Studies in vitroand in man. Acta PharmacoL Toxicol., 1984, 54, 1-7. [5] GALINSKYR.E., LEvYG. - - Evaluation of activated charcoalsodium sulfate combination for inhibition of acetaminophen absorption and repletion of inorganic sulfate. Clin. Toxicol., 1984, 22, 21-30. [6] NEUVONENP.J., OLKKOLAK.T. - - Effect of purgatives on antidotal efficacy of oral activated charcoal. Hum. Toxicol., 1986, 5, 255-263. [7] ROSENBERGP.J., LIVINGSTONED.J., MCLELLAN B.A. - - Effect of whole-bowel irrigation on the antidotal efficacy or oral activated charcoal., 1988, 17, 681-683. [8] NORTH g.s., PETERSON R.G., KRENZELOK E.P. - - Effect of activated charcoal administration on acetylcysteine serum levels in humans. Am. J. Hosp. Pharrn., 1981, 39, 1022-1024. [9] NEUVONEN P.J., ELONEN E. - - Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. Europ. J. Clin. PharmacoL, 1980, 17, 51-57. [10] TRAEGER S.M., HAUG M.T. - - Reduction of diazepam serum half life and revesal of coma by activated charcoal
[12] [13]
[14]
[15] [16] [17]
[16] [19] [20]
219
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in a patient with severe liver disease. Clin. ToxicoL, 1966, 24, 329-337. BOLDYD.A.R., SMARTV., VALE J.A. - - Multiple doses of charcoal in digoxin poisoning. Lancet, 1985, 2, 1076-1077. NEUVONEN P.J., VARTIAINEN M., TOKOLA O. - - Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Europ. J. Clin. PharmacoL, 1983, 24, 557-562. NEUVONEN P.J., KARKKAINEN S. - - Effects of charcoal, sodium bicarbonate and ammonium chloride on chlorpropamide kinetics. Clin. PharmacoL Therap., 1983, 33, 396-393. PARK G.D., SPECTOR R., GOLDBERG M.J., JOHNSON G.F., FELDMAN R., QUEE O . K . - - Effect of the surface area of activated charcoal on theophylline clearance. J. Clin. PharmacoL, 1984, 24, 289-292. NEUVONEN P.J., ELONEN E., Mattila M.J. - - Oral activated charcoal and dapsone elimination. Clin. PharmacoL Therap., 1980, 6, 823-827. FREEDMAN G.E., PASTENAK S., KRENZELOK E.P. - - A clinical trial using syrup of ipecac and activated charcoal concurrently. Ann. Emerg. Med., 1987, 16, 164-166. NEUVONEN P.J., OLKKOLA K.T. - - Activated charcoal and syrup of ipecac in prevention of cimetidine and pindolol absorption in man after administration of metoclopramide as antiemetic agent. Clin. ToxicoL, 1984, 22, 103-114. WHEELER-USHER D.H., WANKE L.A., BAYER M.J. - - Gastric emptying. Risk versus benefit in the treatment of acute poisoning. Med. ToxicoL, 1986, 1, 142-153. KULIG K., BAR-OR D., CANTRILL S.V. et aL - - Management of acutely poisoned patients without gastric emptying. Ann. Emerg. Med., 1985, 14, 562-567. NEUVONEN P.J., KANNISTO H., HIRVlSALO E.L. - - Effect of activated charcoal on absorption of tolbutaminde and valproate in man. Europ. J. Clin. Pharmacol., 1963, 24, 243-246.
mnm
R#an. Urg., 1993, 2 ( 2 bis), 215-219
Activated charcoal is an adsorbent which is able to adsorb a wide variety of substances onto its surface. Although the first systematic studies of charcoal as an antidote were performed in the 18th century, in many countries and in many hospitals its use as an antidote has not been accepted until recently. This has been probably due to lack of suitable formulations and direct experimental or clinical human studies. The effect of high single and repeated doses of charcoal on the absorption and elimination of various drugs has been studied intensively during the last 10 years [1]; [2]. As a result, particularly the initial management of intoxicated patients has changed.
included in some formulations, may have significant gastrointestinal and systemic side effects when charcoal is administered in high doses.
•
Charcoal dose
Factors affecting the antidotal efficacy of activated charcoal
Physiochemical properties and pharmaceutical formulation of charcoal The physicochemical properties of charcoal are of vital importance for its antidotal efficacy. The major determinants of these properties are the pore size and surface area of charcoal. Larger surface area provides better antidotal efficacy. Good quality charcoals have a surface area of 1000--3500 m2/g. The pharmaceutical formulation of charcoal has an influence on both the applicability and efficacy of oral activated charcoal. Water suspensions of charcoal are superior in antidotal use. The use of various flavoring and thickening agents cannot be recommended because their influence on the antidotal efficacy of charcoal is unpredictable. It should also be remembered that ethanol, sodium bicarbonate and sorbitol, which are Department of Anaesthesia, University of Helsinki, Haartmaninkatu 4, SF-00290 Helsinki, Finland.
Chemical nature and pharmaceutical formulation of agents ingested in intoxications Generally speaking most substances will be adsorbed effectively by activated charcoal. Known exceptions which have clinical significance are alcohols, iron, lithium, cyanide and strong acids and alkalis. The absorption of slowly absorbed formulations appears to be inhibited less than that of rapidly absorbing formulations. However, the reduction of efficacy can be counteracted by giving repeated doses of charcoal.
Completeness of adsorption depends greatly on the ratio of charcoal to poison, because according to the mass law there is an equilibrium between free and adsorbed poison. The higher the charcoal--poison ratio the more complete is the adsorption. Therefore, in the initial management of intoxicated patients, to be on the safe side, large doses (50--100 g) of charcoal should be used [2].
Gastrointestinal contents Although the presence of food in the stomach of patients with drug overdosages impairs the adsorption capacity of charcoal it also gives charcoal more time to effectively adsorb drugs in the gastrointestinal canal, possibly by slowing the gastric emptying rate [3]. Theoretically, ethanol in the gastrointestinal tract could affect the antidotal efficacy of charcoal. However, although ethanol impairs the adsorption capacity of charcoal in vitro, the concomitant ethanol ingestion does not affect the antidotal efficacy of charcoal significantly [4]. R#an. Urg., 1993, 2 (2 bis), 215-219
-
216 -
X ° Conf4rence
de consensus
en r~animation
Stability of the charcoal--poison complex The binding of drugs and poisons to activated charcoal is a reversible process meaning that the compound once adsorbed can also desorb [2]. If adequately high doses of activated charcoal are used the desorption is seldom significant in clinical situations. The use of repeated doses of charcoal further reduces the risk of desorption.
Time--effect relationships Delay in the administration of charcoal after drug ingestion impairs the antidotal efficacy of oral charcoal. This means that charcoal should be given as soon as possible. However, because the absorption of drugs in serious overdosages may be considerably prolonged, there is no exact time limit to when charcoal should not be administered anymore.
Purgatives and whole bowel irrigation Theoretically, the quicker the charcoal--poison complex passes through the gastrointestinal tract, the less will be the desorption. Most studies in man have failed to demonstrate any substantial benefit from the combined use of purgatives and charcoal [5, 6]. The routine use of purgatives in combination with activated charcoal does not seem to be indicated. In some instances the use of laxatives may promote the evacuation of slowly absorbed formulations from the gastrointestinal tract and thus have a beneficial effect together with activated charcoal. The benefits of combining, for example, sorbitol to charcoal must be weighed against the potential risk for the individual patient. There have been cases of hypernatremia associated with the use of charcoal--sorbitol suspension. Whole bowel irrigation appears to be a promising method to reduce the absorption of drugs and toxic substances from the gastrointestinal tract. Theoretically, ingestion of charcoal prior to the whole bowel irrigation or whole bowel irrigation with some charcoal added to the irrigation solution could enhance the efficacy of both charcoal and whole bowel irrigation. However, recent studies have failed to show any benefit from the combined use of the activated charcoal with whole bowel irrigation [7].
Mechanisms of enhanced drug and toxin elimination by multiple charcoal doses Many drugs and toxic agents are excreted into the gastrointestinal tract. The excretion may occur in gastric juice, bile, pancreatic secretions or other gastrointestinal fluids. Also the diffusion through the mucosal ("dialysis") membrane from capillaries into the gut is possible. Many of these compounds are R~an. Urg., 1993, 2 (2 bis), 215-219
then reabsorbed back into the blood. Activated charcoal adsorbs effectively and practically irreversibly many of those compounds in the gastrointestinal canal and prevents their reabsorption. The interruption of the enterohepatic and enteroenteric circulation by multiple oral doses of activated charcoal thus accelerates the rate of their elimination. The administration of multiple charcoal doses may be indicated also in some instances where charcoal does not actually increase the elimination. If the affinity of drug to charcoal is low or if the adsorption capacity of charcoal is saturated because of gastrointestinal contents or because of the drug itself, administration of multiple doses of charcoal increase its antidotal efficacy.
Effect of single and repeated doses of activated charcoal on the absorption and elimination of drugs and toxins in humans Antipyretic analgesics Generally speaking, antipyretic analgesics are adsorbed to charcoal moderately and some of them well. In humans the absorption of therapeutic aspirin doses (1--5 g) is reduced by 50 to 85 % with 20 to 50 g of activated charcoal. Repeated doses of charcoal enhance the elimination of salicylates. The efficacy of activated charcoal in reducing the absorption of paracetamol has been only moderate [2]. In severe paracetamol poisoning specific antidotes, Nacetylcysteine and methionine, must be used in order to prevent hepatic necrosis. In vitro these antidotes are adsorbed to charcoal to some extent, but this adsorption does not seem to be clinically significant and does not invalidate the concomitant oral administration of charcoal and N-acetylcysteine [8]. Charcoal reduces the absorption of indomethacin, phenylbutazone, piroxicam, mefenamic acid and tolfenamic acid [2]. Repeated doses of charcoal increase the elimination of phenylbutazone and piroxicam.
Other analgesics In healthy volunteers charcoal effectively reduces the absorption of dextropropoxyphene. Repeated doses of oral charcoal enhance the elimination of both dextropropoxyphene and norpropoxyphene [2]. Although there is no experimental data, there is no reason to believe that activated charcoal would not adsorb opiates and reduce their absorption. Charcoal is also likely to enhance, for example, the elimination of buprenorphine and methadone.
Hypnosedatives and anticonvulsants Activated charcoal binds most barbiturates effectively. Normally phenobarbitone has an elimination
X e Conf@rence d e c o n s e n s u s en r@animation - 21 7 -
half-life of about 100 h. Repeated doses of oral activated charcoal have shortened the half-life to about 20 h [9]. Charcoal also reduces the absorption and increases the elimination of carbamazepine, phenytoin, valproate, diazepam and meprobamate [2]. 40 g of oral activated charcoal administrated to a patient with diazepam intoxication shortened the elimination half-life of diazepam from 200 h to under 20 h [10].
Oral hypoglycemic agents I n vitro charcoal effectively adsorbs sulfonylureas. Especially the affinity of the second generation sulfonylureas to charcoal is good. In volunteers the immediate administration of 50 g of charcoal inhibited 80--90 % of the absorption of therapeutic chlorpropamide and tolbutamide doses. In humans it has been shown that multiple charcoal doses do not enhance the elimination of chlorpropamide [12], [13].
Antidepressants
Bronchodilatating drugs
Single dose charcoal effectively inhibits the gastrointestinal absorption of nortfiptyline, amitripyline, imipramine and doxepin. Repeated doses of charcoal increase the elimination of nortriptyline, amitriptyline and doxepin [2].
Activated charcoal reduces the gastrointestinal absorption of theophylline. Repeated doses of charcoal should be used in severe theophylline poisoning in order to prevent prolonged absorption if slowly absorbed theophylline preparations have been ingested. Repeated doses also increase the elimination [14].
Other psychopharmaca There is not much information on the efficacy of charcoal in poisonings caused by other psychopharmaca. I n vitro activated charcoal adsorbs well all the phenothiazines tested. Charcoal is certainly useful in reducing the absorption of phenothiazines. It probably also enhances their elimination. In humans charcoal has been shown to prevent the absorption of promazine very effectively [2].
Cardiac glycosides Activated charcoal adsorbs very effectively cardiac glycosides and increases their elimination, too. Charcoal may be the most effective treatment in inhibiting the gastrointestinal absorption of digoxin since the total amount of digoxin ingested is small (less than 100 mg) even in severe poisonings. The elimination half-life of digoxin has been shortened by about 50 % by repeat-dose charcoal [11].
Antiarrhythmic drugs Most antiarrhythmic drugs are highly toxic and can cause fatal intoxications. Activated charcoal inhibits the gastrointestinal absorption of, for instance, quinidine, disopyramide, mexiletine and flecainide very effectively [2]. 50 g of charcoal given 5 rain after quinidine (200 mg) reduced its absorption by 99 %. The elimination of quinidine and its isomer, quinine, is accelerated by charcoal [2].
lY-adrenoceptor antagonists In humans, 50 g of activated charcoal reduced the absorption of atenolol, pindolol and sotalol, given in therapeutic doses, by over 90 %. Repeated doses of charcoal have been shown to increase the elimination of sotalol and nadolol [2].
Antimicrobial agents Antimicrobial agents are seldom a problem in clinical toxicology. 0ral activated charcoal inhibits the gastrointestinal absorption of, for example, tetracycline, doxycycline, trimethoprim, isoniazid and chloroquine [2]. Dapsone is an antimicrobial agent which can cause severe poisoning. Activated charcoal reduces both its gastrointestinal absorption and increases its elimination. The efficacy of repeat-dose oral charcoal in dapsone intoxications is well comparable to the efficacy of hemodialysis [15].
Other drugs In volunteers activated charcoal has effectively reduced the gastrointestinal absorption of, for instance, phenylpropanolamine, diphenylhydramine, furosemide, cyclosporine and oestriol. Repeated doses of charcoal increase the elimination of methotrexate [2]. Charcoal also adsorbs the active ingredients of syrup of ipecac. However, in a clinical study, 50 g of charcoal did not prevent the emetic effect in any of the 10 intoxicated patients who were included in the study [16].
Metals, alcohols and other substances The efficacy of charcoal in metal poisoning has not been studied in man. Orally given, multiple-dose charcoal may increase the elimination of some metals from the body. However, generally speaking, metals, includind lithium and iron, are not adsorbed efficiently to activated charcoal. Charcoal does not affect the absorption of ethanol or methanol significantly [17]. In experimental animals activated charcoal seems to be able to reduce the mortality in ethylene glycol poisoning. I n vitro charcoal adsorbs ethylene glycol relatively inefficiently. This discrepancy may be caused by the toxic metabolites of ethylene glycol R~an. Urg., 1993, 2(2 bis), 215-219
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218 -
X ° Conf6rence
de consensus
en r6animation
which in acute poisoning may be of major importance. High doses of oral activated charcoal reduce the gastrointestinal absorption of paraquat, kerosene, benzene and dichlorethane in experimental animals. Charcoal also adsorbs many other substances, including nicotine, strychnine and aflatoxins [2]. Cyanide is not adsorbed significantly to charcoal.
Relative efficacy of activated charcoal, emetics, and gastric lavage in the inhibition of drug absorption According to somewhat older studies, induced emesis seems to be more efficient than gastric lavage in emptying the stomach. Recently these older studies have been questioned because of the later technical development in orogastric tubes. It has been claimed that currently used, large orogastric tubes are able to remove larger volumes of gastric contents than the previously used tubes [18]. However, the question remains whether gastric emptying should be performed at all. Some years ago it was demonstrated that syrup of ipecac does not alter the clinical course of poisoned patients who are alert on presentation to the hospital [19]. Recent experimental studies have shown that oral activated charcoal is superior to emetics in reducing the absorption of that fraction of the drug which is still present in the stomach when charcoal or emetic is administered [20], [17]. In these studies therapeutic doses (from 10 mg to 2000 mg) of various drugs have been used. Despite this apparent handicap of experimental studies when compared to clinical intoxications, the experimental data are relevant to very many intoxications, because most drugs will cause fatal intoxications in the doses of a few grams, or even in much smaller doses! However, it is obvious that gastric emptying is likely to be more effective than activated charcoal alone in those poisonings where the amount of the drug ingested is large (e.g. aspirin and paracetamol poisonings) leading to the saturation of the adsorption capacity of charcoal or where the affinity of the particular agent to activated charcoal is poor (e.g. iron). The immediate administration of activated charcoal before other time-consuming procedures should be considered in most intoxications. It is important to remember that the administration of charcoal does not prevent gastric emptying to be performed later. Charcoal in the stomach can adsorb which otherwise could be absorbed to systemic circulation during the transport to the hospital and during the gastric emptying procedures. R6an. Urg., 1993, 2 ( 2 bis), 215-219
[] Toxicity and side effects of activated charcoal Activated charcoal itself has not been associated with specific toxicity. However, various additives used in combination with charcoal have caused side effects requiring medical intervention. In uremic patients continuous treatment with 20--50 g of charcoal per day given orally over periods of 4 to 20 months has not resulted in any significant side effects [2]. Rapid ingestion of large doses of charcoal may cause vomiting. Constipation, or sometimes diarrhea have occurred in some subjects receiving activated charcoal as watery suspensions orally. Major complications associated with the use of activated charcoal have been due to the aspiration of charcoal and gastric contents. Possible constipation caused by activated charcoal can be treated with sorbitol, paraffin oil or lactulose.
•
Conclusions
Single doses of oral activated charcoal prevent effectively the gastrointestinal absorption of most drugs and toxins present in the stomach when charcoal is given. Known exceptions are strong acids and alkalis, alcohols, cyanide and metals like iron and lithium. In general, activated charcoal is more effective than gastric emptying. However, if the amount of drug or poison ingested is very large or if its affinity to charcoal is poor, the adsorption capacity of activated charcoal can be saturated. Repeated dosing with oral activated charcoal enhances the elimination of many toxicologically significant agents, e.g. aspirin, carbamazepine, dapsone, dextropropoxyphene, diazepam, cardiac glycosides, meprobamate, phenobarbitone, phenytoin, and theophylline. It also accelerates the elimination of many industrial and environmental intoxicants. In acute intoxications 50--100 g of oral activated charcoal should be administrated to acutely poisoned adult patients as soon as possible (children 1--2 g/kg). The only exceptions are probably patients poisoned with caustic alkalis or with mineral acids. Charcoal should be a part of first-aid kits both at home and at work. The "blind" administration of charcoal neither prevents later gastric emptying nor does it cause serious adverse effects on the condition that pulmonary aspiration in obtundent patients is prevented. However, it prevents or at least reduces further systemic absorption during transport to the hospital. High doses of sorbitol, other laxatives, sodium bicarbonate etc. included in some charcoal formulations have caused severe electrolyte disturbances and other side effects not associated with charcoal per se. In severe acute poisonings oral activated charcoal should be administered repeatedly (25--50 g at intervals of 4--6 hours) until recovery or until plasma concentrations have fallen to safe levels.
X ~ ConfGrence de consensus en rGanimation -
RGfGrences [11 ] [1] NEUVONEN P.J. - - Clinical pharmacokinetics of oral activated charcoal in acute intoxications. Clin. Pharmacokin., 1982, 7, 465-489. [2] NEUVONEN P.J., Olkkola K.T. - - Oral activated charcoal in the treatment of intoxications : Role of single and repeated doses. Med. Toxicol., 1988, 3, 33-58. [3] OLKKOLAK.T., NEUVONEN P.J. - - DO gastric contents modify antidotal efficacy of oral activated charcoal? Brit. J. Clin. PharmacoL, 1984, 18, 663-669. [4] NEUVONENP.J., OLKKOLAK.T., ALANEN T. - - Effect of ethanol and pH on the adsorption of drugs to activated charcoal: Studies in vitroand in man. Acta PharmacoL Toxicol., 1984, 54, 1-7. [5] GALINSKYR.E., LEvYG. - - Evaluation of activated charcoalsodium sulfate combination for inhibition of acetaminophen absorption and repletion of inorganic sulfate. Clin. Toxicol., 1984, 22, 21-30. [6] NEUVONENP.J., OLKKOLAK.T. - - Effect of purgatives on antidotal efficacy of oral activated charcoal. Hum. Toxicol., 1986, 5, 255-263. [7] ROSENBERGP.J., LIVINGSTONED.J., MCLELLAN B.A. - - Effect of whole-bowel irrigation on the antidotal efficacy or oral activated charcoal., 1988, 17, 681-683. [8] NORTH g.s., PETERSON R.G., KRENZELOK E.P. - - Effect of activated charcoal administration on acetylcysteine serum levels in humans. Am. J. Hosp. Pharrn., 1981, 39, 1022-1024. [9] NEUVONEN P.J., ELONEN E. - - Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. Europ. J. Clin. PharmacoL, 1980, 17, 51-57. [10] TRAEGER S.M., HAUG M.T. - - Reduction of diazepam serum half life and revesal of coma by activated charcoal
[12] [13]
[14]
[15] [16] [17]
[16] [19] [20]
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in a patient with severe liver disease. Clin. ToxicoL, 1966, 24, 329-337. BOLDYD.A.R., SMARTV., VALE J.A. - - Multiple doses of charcoal in digoxin poisoning. Lancet, 1985, 2, 1076-1077. NEUVONEN P.J., VARTIAINEN M., TOKOLA O. - - Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Europ. J. Clin. PharmacoL, 1983, 24, 557-562. NEUVONEN P.J., KARKKAINEN S. - - Effects of charcoal, sodium bicarbonate and ammonium chloride on chlorpropamide kinetics. Clin. PharmacoL Therap., 1983, 33, 396-393. PARK G.D., SPECTOR R., GOLDBERG M.J., JOHNSON G.F., FELDMAN R., QUEE O . K . - - Effect of the surface area of activated charcoal on theophylline clearance. J. Clin. PharmacoL, 1984, 24, 289-292. NEUVONEN P.J., ELONEN E., Mattila M.J. - - Oral activated charcoal and dapsone elimination. Clin. PharmacoL Therap., 1980, 6, 823-827. FREEDMAN G.E., PASTENAK S., KRENZELOK E.P. - - A clinical trial using syrup of ipecac and activated charcoal concurrently. Ann. Emerg. Med., 1987, 16, 164-166. NEUVONEN P.J., OLKKOLA K.T. - - Activated charcoal and syrup of ipecac in prevention of cimetidine and pindolol absorption in man after administration of metoclopramide as antiemetic agent. Clin. ToxicoL, 1984, 22, 103-114. WHEELER-USHER D.H., WANKE L.A., BAYER M.J. - - Gastric emptying. Risk versus benefit in the treatment of acute poisoning. Med. ToxicoL, 1986, 1, 142-153. KULIG K., BAR-OR D., CANTRILL S.V. et aL - - Management of acutely poisoned patients without gastric emptying. Ann. Emerg. Med., 1985, 14, 562-567. NEUVONEN P.J., KANNISTO H., HIRVlSALO E.L. - - Effect of activated charcoal on absorption of tolbutaminde and valproate in man. Europ. J. Clin. Pharmacol., 1963, 24, 243-246.
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R#an. Urg., 1993, 2 ( 2 bis), 215-219