Mark J. Goldberg

Enhancement of theophylline clearance by oral activated charcoal

A randomized crossover trial of the effect of oral activated charcoal on the kinetics of intravenous theophylline was carried out in six normal male subjects. After intravenous aminophylline (6 mg/kg), subjects received water or water with activated charcoal (140 gm) in divided doses over 12 hr. Serum theophylline concentrations were measured from 0 to 24 hr after the aminophylline infusion. Treatment with activated charcoal decreased the serum t½ from 6.4 ± 1.2 to 3.3 ± 0.4 (SEM) hr and the serum AUC from 78 ± 14 to 42 ± 4 mg · hr/l. Percent decrease in AUC after treatment with charcoal correlated positively with the endogenous theophylline serum t½ (r = 0.94). These results suggest that oral activated charcoal (1) enhanced the total body clearance of theophylline and (2) may be efficacious in the treatment of theophylline poisoning, especially in patients with prolonged serum t½s of theophylline.

Acceleration of the Body Clearance of Phenobarbital by Oral Activated Charcoal

We investigated the effect of multiple oral doses of activated charcoal on the pharmacokinetics of intravenously administered phenobarbital in a randomized crossover trial. Six healthy men volunteered to take 200 mg of phenobarbital sodium per 70 kg of body weight intravenously on two separate occasions. On one occasion, each subject received oral activated charcoal (180 g) in divided doses over three days after the infusion of phenobarbital. Serum levels of phenobarbital were measured in all subjects up to 96 hours after the infusion, and urinary excretion of phenobarbital was measured in two subjects 24 to 96 hours after the infusion. A pharmacokinetic analysis showed that the charcoal decreased the serum half-life of phenobarbital form 110 +/- 8 to 45 +/- 6 hours (S.E.M.) (P less than 0.01), increased the total body clearance of phenobarbital from 4.4 +/- 0.2 to 12.0 +/- 1.6 ml per kilogram per hour (P less than 0.01), and increased the nonrenal clearance from 52 to 80 per cent of the total body clearance. We conclude that oral administration of activated charcoal enhances the nonrenal clearance of phenobarbital.

Effects of size and frequency of oral doses of charcoal on theophylline clearance

The effect of size and frequency of oral doses of activated charcoal on theophylline kinetics was studied. Six fasting, healthy men received intravenous infusions of aminophylline (6 mg/kg) over 1 hr, followed by either no activated charcoal as a control, 5 gm activated charcoal every 2 hr for 6 doses, 10 gm every 2 hr for 6 doses, 10 gm every hr for 12 doses, 20 gm every 2 hr for 6 doses, or 40 gm every 4 hr for 3 doses. Five grams every 2 hr decreased serum theophylline t½ from the control of 9.1 ± 0.7 to 5.6 ± 0.4 (SE) hr and decreased the AUC from the control of 123 ± 11 to 79 ± 6 mg · hr/l. The regimen of 20 gm every 2 hr further decreased theophylline t½ to 4.3 ± 0.4 hr and decreased AUC to 62 ± 6 mg · hr/l. When a 120‐gm dose of activated charcoal was given as a regimen of 40 gm every 4 hr or as a regimen of 10 gm every hr, there were small differences in serum theophylline t½ (5.4 ± 0.3 and 4.3 ± 0.2 hr) and in AUC (73 ± 5 and 60 ±4 mg · hr/l). Repeated small doses of oral activated charcoal enhanced the total body clearance of theophylline, and larger doses induced a relatively small further increase. There was little difference between the effects of the same total dose every 4 hr vs every hour.

Diphenhydramine in Orientals and Caucasians

The kinetics and psychomotor effects of diphenhydramine were investigated in Orientals and Caucasians. Each of 5 Oriental and 5 Caucasian young adults received on 1 of 3 occasions diphenhydramine 50 mg/70 kg body weight either intravenously or orally, or placebo. Plasma levels of diphenhydramine were measured hourly for 8 hr at each session. Tests of subjective sedation and psychomotor performance were performed at hourly intervals. The results showed that after both intravenous and oral diphenhydramine, at all times Orientals had plasma levels approximately half those of Caucasians. With the assumption of linear kinetics and a l‐compartment open model, analysis of the data showed that the volume of distribution (VD) and plasma clearance (Cl) but not plasma half‐life (t½) were higher in Orientals than Caucasians: [VD = 480 ± 24 (SEM) and 292 ± 36 l/70 kg; Cl = 79 ± 7 and 51 ± 7 l/70 kg/hr; t ½ = 4.1 ± 0.4 and 4.3 ± 0.4 hr]. Unbound diphenhydramine in fresh plasma was higher in Orientals than Caucasians [24.0 ± 1.9% (SEM) and 14.8 ± 1.5%] and probably explains the increased VD in Orientals. Orientals had significantly less sedation and deterioration in psychomotor performance.

Model for theophylline overdose treatment with oral activated charcoal

The effect of repeated oral doses of activated charcoal on theophylline kinetics was studied in six subjects with hepatic cirrhosis and five patients with moderate theophylline poisoning to determine whether an activated charcoal regimen would be a useful strategy in patients with theophylline poisoning who did not require hemoperfusion. Six subjects with cirrhosis were injected IV with 6 mg/kg aminophylline followed by either water or water with activated charcoal (140 gm) in divided doses over 12 hr. In these subjects, treatment with activated charcoal decreased the mean (±SE) serum theophylline t½ from 12.7 ±4.0 hr to 4.0 ±0.7 hr. Subjects with the longest control t½s demonstrated the greatest charcoal effect. We developed a mathematical model that predicts that treatment with repeated oral doses of activated charcoal would result in an average serum theophylline t½ of 7.1 hr or less even if the subjects endogenous theophylline t½ is very long. In a pilot study of five patients with moderate theophylline poisoning, treatment with repeated oral doses of activated charcoal was well tolerated and led to a mean (±SE) t½ that was shorter than expected (4.9 ± 0.8 hr, range 3.1 to 7.1 hr). We conclude that repeated oral doses of activated charcoal are relatively more effective in decreasing the serum theophylline t½ in persons with long endogenous t½s and that this may be useful for certain patients with mild or moderate theophylline poisoning.

Effect of the Surface Area of Activated Charcoal on Theophylline Clearance

Abstract: The effect of the surface area of activated charcoal on theophylline clearance was studied. Eight fasting, healthy men received intravenous infusions of either aminophylline (6 mg/kg, N = 3) or theophylline (5 mg/kg, N = 5) over 1 hour followed by either 5 Gm standard activated charcoal every 2 hours, 20 Gm every 2 hours, or 5 Gm PX‐21 activated charcoal (with 3.6 times the surface area) every 2 hours. Theophylline t1/2 and AUC with each regimen were respectively 6.3 ± 0.5 (S.E.) hours and 88.9 ± 8.4 mg/liter · hr with 5 Gm standard activated charcoal, 5.3 ± 0.3 hours and 75.4 ± 4.9 mg/liter · hr with 5 Gm PX‐21, and 4.9 ± 0.2 hours and 67.7 ± 3.6 mg/liter · hr with 20 Gm standard activated charcoal. There was a relationship between the activated charcoal surface area and the reduction in theophylline t1/2 and AUC. We conclude that the clearance of theophylline is related to the surface area of activated charcoal administered and that PX‐21 may be a more potent activated charcoal product for enhancing theophylline removal.

The effect of sorbitol and activated charcoal on serum theophylline concentrations after slow‐release theophylline

The effect of the addition of sorbitol to an oral regimen of multiple doses of activated charcoal on serum theophylline concentrations was studied after the ingestion of slow‐release theophylline in nine healthy male volunteers. At 6, 7, 8, 10, and 12 hours after Theo‐24 (1200 mg/70 kg) ingestion, each subject received, in a randomized crossover design, either 300 ml water, 20 gm activated charcoal in water, or 20 gm activated charcoal in water plus 75 ml 70% sorbitol at 6 and 8 hours only. The serum AUCs from 6 to 30 hours after Theo‐24 ingestion during the water, charcoal, and charcoal plus sorbitol phases were 305 ± 16, 113 ± 6, and 85 ± 10 mg‐hr/L (mean ± SE), respectively. We conclude that the addition of sorbitol to an oral regimen of multiple doses of activated charcoal decreased the serum theophylline concentrations after therapeutic doses of slow‐release theophylline to a significantly greater extent than did the activated charcoal regimen alone.

Diphenhydramine : kinetics and psychomotor effects in elderly women

Kinetics and sedative and psychomotor effects of diphenhydramine were investigated in elderly Caucasian women (>64 yr old). In a double‐blind trial, each of 12 healthy subjects received on one of three occasions 50 mg/70 kg IV or oral diphenhydramine HCl or oral placebo. Plasma levels of diphenhydramine were measured in six subjects and tests of sedation and psychomotor performance were performed hourly for 8 hr in all subjects. Kinetic analysis showed that the volume of distribution (295 ± 50[SEM] 1/70 kg), clearance (42 ±5 l/70 kg/hr), and plasma t½ (4.9 ±0.7 hr) were of the same order as in young adults. As in young adults, there was minimal psychomotor impairment after oral and after intravenous diphenhydramine. In contrast to young adults, however, elderly women did not report significant sedation after diphenhydramine. These results suggest that diphenhydramine may not be an effective sedative/hypnotic in elderly women.

Lack of effect of oral activated charcoal on imipramine clearance

The effect of oral activated charcoal on the pharmacokinetics of intravenous imipramine was studied in a randomized, crossover trial. Four normal men received intravenous imipramine (12.5 mg/70 kg) on two separate occasions, followed by either water or water plus high‐surface‐area activated charcoal (180 gm) in divided doses over 24 hours. Serum imipramine concentrations were measured from 0 to 24 hours after the imipramine infusion. There was no difference in the mean (± SE) t½ (9.0 ± 0.8 vs. 10.9 ± 1.6 hours), apparent volume of distribution (11.2 ± 2.1 vs. 12.4 ± 2.1 L/kg), or systemic clearance (992.2 ± 138.3 vs. 930.3 ± 101.9 ml/min/70 kg) of imipramine after dosing without and with oral activated charcoal, respectively (P > 0.05; paired t test). These results suggest that multiple oral doses of activated charcoal do not increase the clearance of imipramine in man.

Amoxapine Overdose: Report of Two Patients with Severe Neurologic Damage

Excerpt Amoxapine (Asendin, Lederle Laboratories, Pearl River, New York), a tricyclic dibenzoxazepine antidepressant, has been recently marketed in the United States. Development of new tricyclic a...