Anaesth Intens Care (1990),18,375-384
Review Role of Repeated Doses of Oral Activated Charcoal in the Treatment of Acute Intoxications A. McLuCKlE,· A. M. FORBESt AND K. F. ILETT* Department of Intensive Care, Sir Charles Gairdner Hospital, and Department of Pharmacology, University of Western Australia, Nedlands, Western Australia SUMMARY
While single dose activated charcoal is effective in preventing drug absorption, repeated doses not only prevent absorption but also can increase systemic drug clearance. The mechanism for the latter effect may involve interruption of enterohepatic recycling and/or promotion of drug exsorption from the systemic circulation into the gut lumen. A comprehensive review ofreported studies in volunteer subjects and overdose patients showed that repeated dose activated charcoal markedly decreased the half-life and/or increased the clearance of a wide range of drugs. Side-effects of the treatment were infrequent, but included aspiration pneumonia, diarrhoea and constipation. The addition oflaxatives to repeated dose charcoal treatment did not offer any significant increase in drug clearance and is not recommended. It is suggested that the optimal regimen for the use ofrepeat dose activated charcoal in acute drug intoxications is an initial dose of75-100 g, followed by 50 g every 4 hours until the risks of systemic drug toxicity are reduced to an acceptable level.
Key Words: PHARMACOKINETICS: activated charcoal, multiple doses; POISONING: multiple dose activated charcoal
In managing poisoned patients, active measures which can decrease the absorption of ingested drugs and poisons include emesis induced by syrup of ipecacuanha, gastric lavage and administration of activated charcoal. While syrup of ipecacuanha and gastric lavage give a similar recovery of many poisons from the stomach, I single dose (50-100 g) activated charcoal is consistently more effective in preventing drug absorption than either syrup of ipecacuanha or gastric lavage. 2-5 Recent studies have suggested that repeated doses of activated charcoal may, in addition to preventing absorption, increase the systemic clearance of a variety of drugs and poisons. 6-8 This review summarises the published data on the use of repeated doses of activated charcoal in the *F.F.A.R.A.C.S., Registrar, Department of Intensive Care. tF.R.C.P.E., F.F.A.R.A.C.S., F.F.A.R.C.S" Specialist, Department of Intensive Care. tPh.D., Senior Lecturer in Pharmacology. Address for Reprints: Dr. A. McLuckie, Department ofintensive Care, Sir Charles Gairdner Hospital, Nedlands, W.A. 6009, Australia. Accepted for publication March IS, 1990 Anaesthesia and Intensive Care. Vol. 18. No. 3. August. 1990
treatment of drug overdoses. In addition, we have formulated recommendations for a standard treatment regimen for repeat-dose activated charcoal in acute intoxications. Mechanism for enhancement ofdrug elimination by multiple doses of activated charcoal The various routes by which drugs and their metabolites may enter the lumen of the gastrointestinal tract are summarised in Figure 1. Single-dose activated charcoal is a well-established means of adsorbing many drugs and thus preventing their absorption into the blood stream. Multiple doses of charcoal can increase the amount of drug adsorbed where single dose drug binding is suboptimal because of poor binding characteristics of the drug, interference of food with binding or problems caused by the prolonged presence of sustained release drug products. The extent of biliary excretion of drugs and their conjugates is a reflection of the physicochemical characteristics of the drug. Enterohepatic recycling is interrupted by multiple doses of charcoal which trap drug and/or
376
A. McLuCKIE ET AL.
metabolites many hours after ingestion. Excretion in gastric juice or exsorption into the intestine is generally thought to be of minor importance. However, reabsorption in more distal parts of the gut may be responsible for this impression. While such excretion is small for some drugs (e.g. frusemide 9) it can be significant for others (e.g. theophyllinelO,ll). Passive diffusion of unbound (free) drug from the systemic circulation down a concentration or pH gradient into the gastrointestinallumen is the presumed mechanism for such transfer. Multiple doses of charcoal will provide maximum adsorption of suitable drug molecules, thus maintaining the concentration gradient and increasing systemic clearance. The effect should be greatest for drugs with medium to long half-lives. Effects of multiple doses of activated charcoal on . drug elimination Data showing the effect of multiple doses of activated charcoal on drug elimination have been summarised for both volunteer (Table 1) and patient (Table 2) studies. The volunteer studies have used crossover designs where subjects were studied on two
occasions (with and without charcoal). These studies have shown substa~ial increases in clearance (1.4 to 5.3 fold) and concomitant decreases in half-life for a wide variety of drugs (Table 1). However, activated charcoal failed to increase elimination of chlorpropamide and imipramine. It should be noted that the results of these volunteer studies may overestimate the ability of activated charcoal to increase drug elimination since ethical considerations limit the drug dosage to therapeutic amounts, while usual doses of charcoal are still maintained. Studies of the efficacy of multiple-dose activated charcoal in patients have now been reported for several drugs (Table 2). For the most part, these were overdose situations and decreases in drug half-life ranged from 37 to 92%. In some cases, the investigators were able to obtain an estimate of drug half-life before starting therapy with charcoal and have compared this to the post-treatment halflife. In other studies, only post-treatment half-lives were obtained and these data can only be compared with other literature reports of drug half-life in overdose patients. The effects of multiple-dose activated charcoal on the elimination of individual drugs are discussed in the following sections. ANALGESICS AND ANTI-INFLAMMATORY DRUGS
Aspirin In a study of five overdose patients, multiple doses of activated charcoal reduced salicylate halflife from a mean of 27 to 3.2 hours.29 Recently, a study in thirteen volunteer subjects 13 has shown that three doses of activated charcoal were superior to either one or two doses in preventing aspirin absorption and/or increasing its non-renal clearance (Figure 2). :l 100
..,0 'S
~
~ ~ i 0:
Colon
I.-Schematic representation of the gastrointestinal tract and liver showing points at which drug molecules (0) may enter or leave the gut and/or interact with activated charcoal ( . . ) . 1, oral absorption; 2, gastric secretion; 3, intestinal secretion! passive diffusion; 4, biliary excretion; 5, passive absorption of nonabsorbed drug; 6, passive reabsorption of hydrolysed drug conjugates. FIGURE
:;)
~ ~
80 60
40
20 0 0
2
3
NUMBER OF DOSES OF CHARCOAl
FIGURE 2.-Urinary recovery (48 hr) of total salicylate after oral aspirin (1.94 g) administration to volunteer subjects with or without activated charcoal (50 g/dose). Drawn from data of Barone et al. (1988). Anaesthesia and Intensive Care, Vol. 18, No. 3, August, 1990
377
ACTIVATED CHARCOAL IN ACUTE INTOXICATIONS TABLE 1 Effects of repeated doses of activated charcoal on drug elimination in volunteers
Drug Amitriptyline Aspirin
Plasma clearance (Ilhr) Without With charcoal charcoal
Drug dose
Dose of activated charcoal
6
0.075 g orally
50 g after 6 hr, then 12.5 g every 6 hrX 8
13
1.94 g orally
50 g after I and 5 hr or 50 g after I, 5 and 9 hr
0.4 g orally
50 g after 10 hr, then 17 g at 14, 24, 36 and 48 hr
1.32
0.104
n
Carbamazepine
Half-life (hr)t With Without charcoal charcoal 27.4
21.1
Reference 12 \3.
2.4
32
17.6
14
49.7
46.9
15
Chlorpropamide
6
0.25 g orally
50 g after 6 hr, then 12.5 g every 6 hr X 8
Dapsone
5
0.5 g orally
50 g after 10 hr, then 17gevery 12hrX4
20.5
10.8
16
Dextropropoxyphene
6
130 mg
50 gat 6 hr, then 12.5 g every 6hrX 8
31.1
21.1
17
11
1011g/kg IV
25 g initial, then 25 g every 4 hr X 4, then 25 g every 6 hr X 4
12.2
18.0
36.5
21.5
18
6
11 l1g/kg IV
20 g initial, then 20 g every 4 hr X 8, then 20 g after a further 12 hr
16.8
22.7
23.1
17.0
19
Digitoxin
6
1411g/kg IV
20g every 4 hrX 9, then 20 g every 12hrX5
110.6
51.1
19
Doxepin
8
50 mg
15 g after 3 hr then 10 g after 6,9, 12 and 24hr
Imipramine
4
18011g/kg 20 g every 2 hr X 4, IV then every 3 hr X 2, then every 4 hr X 3
Nadolol
8
0.08g orally
0.5 g after 3 and 4 hr, then 0.25 g every hr X 8
Phenobarbitone
6
0.2g
40 g initial, then 20 g every 6 hr X 5, then 20 g after a further 12 and 36 hr
0.31
Digoxin
IV
0.24
0.47
63.7
84.3
17.9
16.2
20
59.5
55.8
9.0
10.9
21
17.3
11.8
22
0.84
110
45
23
5
0.2g orally
50 g after 10 hr, then 17 gat 14, 24, 36 and 48 hr
0.28
1.38
110
19.8
14
Phenylbutazone
5
0.2g orally
50 g after 10 hr then 17 gat 14, 24, 26 and 48 hr
0.09
0.13
51.5
36.7
14
Quinine
7
0.6g orally
50 g every 4 hr X 4
8.2
4.6
24
Sotalol
7
160 mg
50 gat 6 hr, then 12.5 g every 6 hrX 8
9.4
7.6
25
Theophylline
6
6 mglkg IV
40 g initial, then 20 g every 2 hr X 3, then 20 g every 3 hr X 2
6.4
3.3
26
7
8 mg/kg IV
30 g every 2 hr X 4
10.2
4.6
27
6
6 mg/kg IV
40 g initial then 20 g at 2, 4, 6, 9 and 12 hr
12.7
4.0
28*
t data as means • significant decrease in absorption using urinary data * volunteer subjects with hepatic cirrhosis Anaesthesia and Intensive Care, Vol. 18, No. 3, August, 1990
11.8
2.49
18.4
5.08
378
A. McLuCKlE ET AL. TABLE 2 Effects of repeated doses of activated charcoal on drug elimination in patients
Drug Aspirin
Maximum plasma concentration (mgll)
Dose of activated charcoal
425-655
5
75 g initial, then 50 g every 4hr
99,83
2
60g every 4hrX6
Cyclosporin
6.7
Dapsone
23
Digoxin
n
Half-life (hr)t Without With charcoal charcoal
60 g initial then 30 g every 4hrX2 3
8.3 X 10-3
27
Reference
3.2
29
7.7, 12.7 9
2.7
30* 31
20 g every 6 hr X 8
77
12.7
32
20 g every 6 hr X 8
88
13.5
16
20 g every 6 hr X 4
33
11.4
16
14
33
100 g initial, then 50 g every 4hrX 7 20 g every 4 hr X 8, then 20 g after a further 12 hr
93.3
29.3
19*
Digoxin
9 X 10-3
50 g initial, then 25 g every 6hrX 8
175
33.6
34
Digitoxin
0.27 X 10-3
50 g initial, then 60 g every 8hrX8
162
18
35
Meprobamate
Phenobarbitone
Phenytoin
3.2
50 g every 4 hrX 5
4.4
36
2.4
75 g initial, then 50 g every 6hrX 5
4.5
36
36
37
132
10
50 g initial, then 17 g every 4 hr until extubated
93
141
40g every 4hrX6
Review Role of Repeated Doses of Oral Activated Charcoal in the Treatment of Acute Intoxications A. McLuCKlE,· A. M. FORBESt AND K. F. ILETT* Department of Intensive Care, Sir Charles Gairdner Hospital, and Department of Pharmacology, University of Western Australia, Nedlands, Western Australia SUMMARY
While single dose activated charcoal is effective in preventing drug absorption, repeated doses not only prevent absorption but also can increase systemic drug clearance. The mechanism for the latter effect may involve interruption of enterohepatic recycling and/or promotion of drug exsorption from the systemic circulation into the gut lumen. A comprehensive review ofreported studies in volunteer subjects and overdose patients showed that repeated dose activated charcoal markedly decreased the half-life and/or increased the clearance of a wide range of drugs. Side-effects of the treatment were infrequent, but included aspiration pneumonia, diarrhoea and constipation. The addition oflaxatives to repeated dose charcoal treatment did not offer any significant increase in drug clearance and is not recommended. It is suggested that the optimal regimen for the use ofrepeat dose activated charcoal in acute drug intoxications is an initial dose of75-100 g, followed by 50 g every 4 hours until the risks of systemic drug toxicity are reduced to an acceptable level.
Key Words: PHARMACOKINETICS: activated charcoal, multiple doses; POISONING: multiple dose activated charcoal
In managing poisoned patients, active measures which can decrease the absorption of ingested drugs and poisons include emesis induced by syrup of ipecacuanha, gastric lavage and administration of activated charcoal. While syrup of ipecacuanha and gastric lavage give a similar recovery of many poisons from the stomach, I single dose (50-100 g) activated charcoal is consistently more effective in preventing drug absorption than either syrup of ipecacuanha or gastric lavage. 2-5 Recent studies have suggested that repeated doses of activated charcoal may, in addition to preventing absorption, increase the systemic clearance of a variety of drugs and poisons. 6-8 This review summarises the published data on the use of repeated doses of activated charcoal in the *F.F.A.R.A.C.S., Registrar, Department of Intensive Care. tF.R.C.P.E., F.F.A.R.A.C.S., F.F.A.R.C.S" Specialist, Department of Intensive Care. tPh.D., Senior Lecturer in Pharmacology. Address for Reprints: Dr. A. McLuckie, Department ofintensive Care, Sir Charles Gairdner Hospital, Nedlands, W.A. 6009, Australia. Accepted for publication March IS, 1990 Anaesthesia and Intensive Care. Vol. 18. No. 3. August. 1990
treatment of drug overdoses. In addition, we have formulated recommendations for a standard treatment regimen for repeat-dose activated charcoal in acute intoxications. Mechanism for enhancement ofdrug elimination by multiple doses of activated charcoal The various routes by which drugs and their metabolites may enter the lumen of the gastrointestinal tract are summarised in Figure 1. Single-dose activated charcoal is a well-established means of adsorbing many drugs and thus preventing their absorption into the blood stream. Multiple doses of charcoal can increase the amount of drug adsorbed where single dose drug binding is suboptimal because of poor binding characteristics of the drug, interference of food with binding or problems caused by the prolonged presence of sustained release drug products. The extent of biliary excretion of drugs and their conjugates is a reflection of the physicochemical characteristics of the drug. Enterohepatic recycling is interrupted by multiple doses of charcoal which trap drug and/or
376
A. McLuCKIE ET AL.
metabolites many hours after ingestion. Excretion in gastric juice or exsorption into the intestine is generally thought to be of minor importance. However, reabsorption in more distal parts of the gut may be responsible for this impression. While such excretion is small for some drugs (e.g. frusemide 9) it can be significant for others (e.g. theophyllinelO,ll). Passive diffusion of unbound (free) drug from the systemic circulation down a concentration or pH gradient into the gastrointestinallumen is the presumed mechanism for such transfer. Multiple doses of charcoal will provide maximum adsorption of suitable drug molecules, thus maintaining the concentration gradient and increasing systemic clearance. The effect should be greatest for drugs with medium to long half-lives. Effects of multiple doses of activated charcoal on . drug elimination Data showing the effect of multiple doses of activated charcoal on drug elimination have been summarised for both volunteer (Table 1) and patient (Table 2) studies. The volunteer studies have used crossover designs where subjects were studied on two
occasions (with and without charcoal). These studies have shown substa~ial increases in clearance (1.4 to 5.3 fold) and concomitant decreases in half-life for a wide variety of drugs (Table 1). However, activated charcoal failed to increase elimination of chlorpropamide and imipramine. It should be noted that the results of these volunteer studies may overestimate the ability of activated charcoal to increase drug elimination since ethical considerations limit the drug dosage to therapeutic amounts, while usual doses of charcoal are still maintained. Studies of the efficacy of multiple-dose activated charcoal in patients have now been reported for several drugs (Table 2). For the most part, these were overdose situations and decreases in drug half-life ranged from 37 to 92%. In some cases, the investigators were able to obtain an estimate of drug half-life before starting therapy with charcoal and have compared this to the post-treatment halflife. In other studies, only post-treatment half-lives were obtained and these data can only be compared with other literature reports of drug half-life in overdose patients. The effects of multiple-dose activated charcoal on the elimination of individual drugs are discussed in the following sections. ANALGESICS AND ANTI-INFLAMMATORY DRUGS
Aspirin In a study of five overdose patients, multiple doses of activated charcoal reduced salicylate halflife from a mean of 27 to 3.2 hours.29 Recently, a study in thirteen volunteer subjects 13 has shown that three doses of activated charcoal were superior to either one or two doses in preventing aspirin absorption and/or increasing its non-renal clearance (Figure 2). :l 100
..,0 'S
~
~ ~ i 0:
Colon
I.-Schematic representation of the gastrointestinal tract and liver showing points at which drug molecules (0) may enter or leave the gut and/or interact with activated charcoal ( . . ) . 1, oral absorption; 2, gastric secretion; 3, intestinal secretion! passive diffusion; 4, biliary excretion; 5, passive absorption of nonabsorbed drug; 6, passive reabsorption of hydrolysed drug conjugates. FIGURE
:;)
~ ~
80 60
40
20 0 0
2
3
NUMBER OF DOSES OF CHARCOAl
FIGURE 2.-Urinary recovery (48 hr) of total salicylate after oral aspirin (1.94 g) administration to volunteer subjects with or without activated charcoal (50 g/dose). Drawn from data of Barone et al. (1988). Anaesthesia and Intensive Care, Vol. 18, No. 3, August, 1990
377
ACTIVATED CHARCOAL IN ACUTE INTOXICATIONS TABLE 1 Effects of repeated doses of activated charcoal on drug elimination in volunteers
Drug Amitriptyline Aspirin
Plasma clearance (Ilhr) Without With charcoal charcoal
Drug dose
Dose of activated charcoal
6
0.075 g orally
50 g after 6 hr, then 12.5 g every 6 hrX 8
13
1.94 g orally
50 g after I and 5 hr or 50 g after I, 5 and 9 hr
0.4 g orally
50 g after 10 hr, then 17 g at 14, 24, 36 and 48 hr
1.32
0.104
n
Carbamazepine
Half-life (hr)t With Without charcoal charcoal 27.4
21.1
Reference 12 \3.
2.4
32
17.6
14
49.7
46.9
15
Chlorpropamide
6
0.25 g orally
50 g after 6 hr, then 12.5 g every 6 hr X 8
Dapsone
5
0.5 g orally
50 g after 10 hr, then 17gevery 12hrX4
20.5
10.8
16
Dextropropoxyphene
6
130 mg
50 gat 6 hr, then 12.5 g every 6hrX 8
31.1
21.1
17
11
1011g/kg IV
25 g initial, then 25 g every 4 hr X 4, then 25 g every 6 hr X 4
12.2
18.0
36.5
21.5
18
6
11 l1g/kg IV
20 g initial, then 20 g every 4 hr X 8, then 20 g after a further 12 hr
16.8
22.7
23.1
17.0
19
Digitoxin
6
1411g/kg IV
20g every 4 hrX 9, then 20 g every 12hrX5
110.6
51.1
19
Doxepin
8
50 mg
15 g after 3 hr then 10 g after 6,9, 12 and 24hr
Imipramine
4
18011g/kg 20 g every 2 hr X 4, IV then every 3 hr X 2, then every 4 hr X 3
Nadolol
8
0.08g orally
0.5 g after 3 and 4 hr, then 0.25 g every hr X 8
Phenobarbitone
6
0.2g
40 g initial, then 20 g every 6 hr X 5, then 20 g after a further 12 and 36 hr
0.31
Digoxin
IV
0.24
0.47
63.7
84.3
17.9
16.2
20
59.5
55.8
9.0
10.9
21
17.3
11.8
22
0.84
110
45
23
5
0.2g orally
50 g after 10 hr, then 17 gat 14, 24, 36 and 48 hr
0.28
1.38
110
19.8
14
Phenylbutazone
5
0.2g orally
50 g after 10 hr then 17 gat 14, 24, 26 and 48 hr
0.09
0.13
51.5
36.7
14
Quinine
7
0.6g orally
50 g every 4 hr X 4
8.2
4.6
24
Sotalol
7
160 mg
50 gat 6 hr, then 12.5 g every 6 hrX 8
9.4
7.6
25
Theophylline
6
6 mglkg IV
40 g initial, then 20 g every 2 hr X 3, then 20 g every 3 hr X 2
6.4
3.3
26
7
8 mg/kg IV
30 g every 2 hr X 4
10.2
4.6
27
6
6 mg/kg IV
40 g initial then 20 g at 2, 4, 6, 9 and 12 hr
12.7
4.0
28*
t data as means • significant decrease in absorption using urinary data * volunteer subjects with hepatic cirrhosis Anaesthesia and Intensive Care, Vol. 18, No. 3, August, 1990
11.8
2.49
18.4
5.08
378
A. McLuCKlE ET AL. TABLE 2 Effects of repeated doses of activated charcoal on drug elimination in patients
Drug Aspirin
Maximum plasma concentration (mgll)
Dose of activated charcoal
425-655
5
75 g initial, then 50 g every 4hr
99,83
2
60g every 4hrX6
Cyclosporin
6.7
Dapsone
23
Digoxin
n
Half-life (hr)t Without With charcoal charcoal
60 g initial then 30 g every 4hrX2 3
8.3 X 10-3
27
Reference
3.2
29
7.7, 12.7 9
2.7
30* 31
20 g every 6 hr X 8
77
12.7
32
20 g every 6 hr X 8
88
13.5
16
20 g every 6 hr X 4
33
11.4
16
14
33
100 g initial, then 50 g every 4hrX 7 20 g every 4 hr X 8, then 20 g after a further 12 hr
93.3
29.3
19*
Digoxin
9 X 10-3
50 g initial, then 25 g every 6hrX 8
175
33.6
34
Digitoxin
0.27 X 10-3
50 g initial, then 60 g every 8hrX8
162
18
35
Meprobamate
Phenobarbitone
Phenytoin
3.2
50 g every 4 hrX 5
4.4
36
2.4
75 g initial, then 50 g every 6hrX 5
4.5
36
36
37
132
10
50 g initial, then 17 g every 4 hr until extubated
93
141
40g every 4hrX6
