Correlation of initial amitriptyline concentration reduction with activated charcoal therapy in overdose patients.

Plasma amitriptyline concentrations were measured serially in nine overdose patients and correlated with the timing and amount of each patient's initial activated charcoal therapy. A direct correlation was found between the time to initial charcoal therapy (Tc) and the plasma concentration half-life of amitriptyline (T 1/2) calculated for the first seven to 18 hours of hospitalization; T 1/2 = 2.68 + 0.047 Tc (r = 0.78, P less than 0.05). An inverse trend of T 1/2 with the initial amount of charcoal administered was also noted. Nortriptyline, the major metabolite of amitriptyline, decreased in two of three patients who received greater than or equal to 50 gm of activated charcoal within 60 minutes of presentation. These findings support previous in vitro and human volunteer studies advocating the rapid administration of activated charcoal in acute tricyclic antidepressant overdoses.

Evaluation of Syva EMIT Toxicological Serum Tricyclic Antidepressant Assay.

Tricyclic antidepressant (TCA) overdose is a common, potentially life-threatening finding in patients seen in emergency departments. There is a need to rapidly differentiate the TCA overdose from others in the emergency unit population. The Syva EMIT Toxicological Serum Tricyclic Antidepressant Assay for serum tricyclic antidepressant levels on 87 patients being evaluated for possible TCA overdose in the emergency department of the University of Cincinnati Hospital was examined. Serum tricyclic antidepressant concentrations were also determined by high performance liquid chromatography (HPLC), and comprehensive urine drug screening was performed by several methods. The EMIT assay correctly identified all 53 negative patients whose TCA levels were less than 300 ng/mL. The remaining 34 patients had positive TCA levels greater than 300 ng/mL by EMIT; however, 22 were confirmed by HPLC. Phenothiazines and phenothiazine metabolites were present in the remaining 12 unconfirmed patients, indicating a cross reaction with this class of drugs. It was concluded that the assay is useful to exclude the presence of serious TCA ingestion when a result of less than 300 ng/mL is obtained. However, a result of greater than 300 ng/mL is not specific for TCAs only, as evidenced by the cross reactions obtained with phenothiazines.

Bicarbonate therapy for the cardiovascular toxicity of amitriptyline in an animal model.

The beneficial hemodynamic effects of sodium bicarbonate as treatment for tricyclic antidepressant poisoning were investigated in an animal model. Seven adult dogs (17.5 to 20 kg) were poisoned by an intravenous infusion of amitriptyline. Toxicity was defined as a doubling of the initial QRS width. A continuous infusion was used to maintain toxicity for 30 minutes after which 44.5 mEq of sodium bicarbonate was administered intravenously. Five of the animals survived to completion of the experiment. Three of the surviving animals developed dysrhythmias. All dysrhythmias ceased within one minute of administration of sodium bicarbonate. An increase in mean blood pressure (P less than .05) and serum pH (P less than .05) and a decrease in mean QRS width (P less than .05) occurred following administration of sodium bicarbonate. The maintenance of toxicity for 30 minutes suggests that this model can be used for future studies of tricyclic antidepressant poisoning.

Evaluation of amitriptyline pharmacokinetics during peritoneal dialysis.

The pharmacokinetics of a single oral dose of amitriptyline were examined in five functionally anephric patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The concentration of the parent drug and its major metabolite nortriptyline in plasma were measured by high performance liquid chromatography. Patients on CAPD did not have a significantly extended elimination half-life (t 1/2) as compared to literature controls. However, the variation in t 1/2 was extremely large in both the CAPD and normal renal function groups (range 15-34 h and 24-70 h, respectively). No statistically significant change was observed (p less than 0.05). Although a major route of elimination was removed and there was no change in t 1/2, the drug levels in these patients should be closely monitored because of the large variability in patient metabolism.

Amoxapine in human overdose.

Amoxapine, a tricyclic antidepressant, is metabolized to 8-hydroxyamoxapine and 7-hydroxyamoxapine. There are few reports on the metabolism of this drug and correlation of clinical symptoms in overdose patients. Five such patients admitted to the Emergency Unit of the University of Cincinnati Hospital were studied. Clinically, all had seizures and evidence of altered cardiac function. The amounts of the parent drug and the 7- and 8-hydroxy metabolites were measured and, in all cases, the parent and 8-hydroxy metabolite were present in both urine and serum. In contrast, the 7-hydroxyamoxapine was found in trace amounts in the serum of only two patients, but in the urine of all the patients observed. These observations were confirmed by gas chromatographic/mass spectroscopic analysis. The pattern of metabolism was analogous to that found in patients on maintenance doses of the drug. In two overdose patients, it was possible to monitor the levels as a function of time. The elimination curve of parent and metabolite was first order with a half-life of 8.5 to 15.0 and 48 hr, respectively.

Liquid-chromatographic determination of amoxapine and 8-hydroxyamoxapine in human serum.

We describe a liquid-chromatographic procedure for amoxapine and 8-hydroxyamoxapine, its active metabolite, in serum. We used a mu-Bondapak C18 reversed-phase column and a mobile phase of acetonitrile/water (74/26 by vol) plus 26 microL of n-butylamine per liter. The compounds were measured at 254 nm, with 8-methoxyloxapine as internal standard. Necessary pre-analysis purification consisted of adsorbing the drug from serum onto extraction columns, eluting with 1-butanol/hexane (1/5 by vol), re-extracting into aqueous acid, and from that re-extracting again into the elution-solvent mixture. We prefer this procedure for monitoring both therapeutic and toxic concentrations of amoxapine, because parent drug and metabolite are measured separately.