Antidepressant toxicity and the need for identification and concentration monitoring in overdose.

Antidepressant drugs are among the most commonly encountered causes of self-poisoning. These drugs include tricyclics, tetracyclics, bicyclics and monocyclics, as well as monoamine oxidase (MAO) inhibitors and selective serotonin reuptake inhibitors (SSRIs). Of these, the tricyclic antidepressants (TCAs) are generally more toxic in overdose, with major toxicity usually manifesting within the first 6 hours after overdose. Various studies indicate that patients at risk of toxicity from TCA overdose may be identified by neurological, cardiovascular and electrocardiography status, together with a quantitative estimate of the plasma drug concentration. While there are various methods available for such chemical estimations, the most satisfactory appears to be fluorescence polarisation immunoassay which gives rapid quantitative results for a variety of TCAs. The selective MAO-A inhibitor antidepressants and the SSRIs are relatively nontoxic when taken alone. However, overdoses of combinations of MAO inhibitors and either SSRIs or TCAs with serotonin reuptake blocking activity may result in a serotonin syndrome with a severe or fatal outcome. Features of this syndrome include hyperpyrexia, disseminated intravascular coagulation, convulsions, coma and muscle rigidity, which may not develop until 6 to 12 hours after overdose. While quantitative chemical identification of these drugs following overdose is helpful in confirming the diagnosis, it is not mandatory. The increasing use of MAO-A inhibitors and SSRIs in the treatment of depression suggests that careful clinical observation is required when combination overdoses are suspected.

Gas-liquid chromatographic determination of ibuprofen in human plasma.

A gas-liquid chromatographic method for the estimation of Ibuprofen in human plasma is described. The procedure is rapid with the free drug being analysed thus eliminating the need for any derivatisation steps. The method allows the drug concentrations to be analysed down to a level of 2 mg/l using 2 ml plasma.

Determination of paracetamol in human serum.

A procedure is described that gives quantitative extraction of paracetamol from serum. This, together with derivatisation and gas chromatography, provides a simple method that facilitates the rapid estimation of the drug in serum in the range 5--500 mg/litre.

Simultaneous determination of lidocaine, mexiletine, disopyramide, and quinidine in plasma by high performance liquid chromatography.

A high performance liquid chromatographic method is described for the simultaneous quantitation of four commonly prescribed antiarrhythmic drugs: lidocaine, mexiletine, disopyramide, and quinidine. An isocratic system using a reverse phase column was used to separate these compounds. Coefficients of variation were less than 4%.

The analysis of several nonopiate narcotic analgesics and cocaine in serum using high-performance liquid chromatography.

This paper describes a procedure for the quantitative determination of methadone, meperidine, normeperidine, pentazocine, propoxyphene, norpropoxyphene, and dextromoramide in serum down to levels of 10 micrograms/L and of cocaine down to 25 micrograms/L. The procedure involves a simple extraction technique and high-performance liquid chromatography and is suitable for use in overdose drug screening, forensic toxicology, therapeutic drug monitoring, and pharmacokinetic studies.

The use of buffered celite columns in drug extraction techniques and their proposed application in forensic toxicology.

The recoveries of acidic, basic, and neutral drugs through buffered celite columns are reported. The methods are rapid, simple, clean, and efficient, especially with compounds having a high volatility.

A comparison of the borate-celite column screening technique with other extraction methods in forensic toxicology.

The comparison of five different extraction techniques from postmortem tissues was reported. The borate/celite column chromatography technique generally gave the best yields and its use as a screening method in forensic toxicology was discussed.

Extraction procedures for some common drugs in clinical and forensic toxicology.

The results of four extraction systems for 86 drugs are reported. These systems were investigated with the view to obtaining a rapid, reliable, and efficient extraction technique in clinical and forensic toxicology.

The detection of some basic drugs and their major metabolites using gas-liquid chromatography.

A rapid method is described for the extraction and identification of a number of basis drugs and their metabolites in urine. Gas chromatography is used as the primary source of identification, and characteristic chromatograms and retention times for a number of drug metabolites are outlined.

Direct extraction procedure for the analysis of neutral drugs in tissue.

This paper describes an efficient extraction technique for the determination of neutral drugs in tissue. The extracts are clean and can be analyzed by gas liquid chromatography. The method gives good recoveries of most of the neutral drugs and the sensitivity is such that therapeutic levels can easily be detected.

Rapid identification of drugs in the overdosed patient.

A rapid analytical procedure is described for a variety of drugs that could be present in the overdosed patient. The technique used gives quantitative results for most of the drugs analyzed in serum using gas chromatography and incorporates thin-layer chromatography and spot tests for drug confirmation. The procedure is novel for it relies on the initial extraction of acidics, basics, and neutrals from serum acidified with hydroxhloric acid.

Simultaneous determination of clobazam, N-desmethyl clobazam and clonazepam in plasma by high performance liquid chromatography.

A method is described for the simultaneous determination of clobazam, its active metabolite N-desmethylclobazam, and clonazepam in plasma by high performance liquid chromatography. The drugs are extracted with diethyl ether from 1.0 ml plasma adjusted to pH 9.0 and separated on a C18 reverse phase column using a mobile phase of 40% acetonitrile in phosphate buffer pH 3.0. The ultraviolet absorbance is monitored at a wavelength of 313 nm. The method has a coefficient of variation of less than 5% and an overall recovery of greater than 85% and is sufficiently sensitive for the therapeutic monitoring of these drugs.

Rapid digestion and flameless atomic absorption spectroscopy of mercury in fish.

A rapid method is described for the determination of total mercury in fish samples. The sample is digested with nitric acid-sulfuric acid-potassium permanganate, and then reduced and aerated for measurement by flameless atomic absorption spectrophotometry. The average recoveries of organic and inorganic mercury added to fish were 93 and 95%, respectively. The uniformity of mercury levels in shark tissue has also been investigated.

A comparison of high-performance liquid chromatography and fluorescence polarization immunoassay for therapeutic drug monitoring of tricyclic antidepressants.

Although the manufacturer of the polyclonal fluorescence polarization immunoassay (FPIA) for tricyclic antidepressants (TCA) only recommends its use in the diagnosis of overdose, the assay is nevertheless widely used in therapeutic drug monitoring. Using plasma samples from 337 patients taking one of eight different tricyclic antidepressants, the authors investigated the performance of the TDx assay procedure for eight different TCAs by comparison to specific high-performance liquid chromatography (HPLC) assay methods. The regression correlation between the TDx assay value and that for active tricyclic measured by HPLC was poor (r2 < 0.9) for amitriptyline, clomipramine, dothiepin, and doxepin. The regression line for amitriptyline also had a significant positive y-axis intercept. Moreover, the TDx method overestimated the concentration of active drug to an extent that varied considerably between different TCAs and within the usual therapeutic range for a single TCA. The authors conclude that the TDx assay is probably satisfactory for routine TDM of desipramine, imipramine, nortriptyline, and trimipramine. However, it significantly overestimates therapeutic concentrations of amitriptyline, clomipramine, dothiepin, and doxepin. The use of TDx and HPLC assay methods by different laboratories for sequential therapeutic drug monitoring of TCAs in the same patient may confuse physicians and confound dose adjustment and patient management. Although their study shows that the TDx assay can give satisfactory therapeutic drug monitoring results for some drugs, the authors conclude that its use should be restricted to the evaluation of overdose as recommended by the manufacturer.

Gas-liquid chromatographic determination of theophylline in human plasma.

A gas-liquid chromatographic method for the estimation of theophylline in human plasma is described. The method is based on the methylation of theophylline on-column and allows the determination of concentration of the drug down to the level of 1.0 mu-g/ml in plasma.

Lack of dose dependent kinetics of theophylline.

Oral theophylline was given to 6 adults with airways obstruction. The initial dose was 125 mg daily and this was increased by 125 mg each week. The final total daily dose reached was determined by side effects and ranged from 500 mg to 1125 mg. At the end of each week and before the next dosage increment steady state, trough plasma theophylline concentrations were measured. For each individual and for the group as a whole there was a highly significant linear correlation between theophylline dose and trough plasma concentration. This indicates that for oral theophylline, in adults, dose-dependent kinetics do not play a significant role and dose may be adjusted without fear of a disproportionate rise in plasma concentration.

Disposition of dothiepin after overdose: effects of repeated-dose activated charcoal.

Although the tricyclic antidepressant dothiepin is often encountered in deliberate self-poisonings, there are no published studies of its disposition in overdose. In the present study, we have documented the plasma disposition of dothiepin and its major metabolites in eight overdose patients. All had high initial levels of dothiepin (819-3,851 micrograms/L), dothiepin-S-oxide (655-2,162 micrograms/L), nordothiepin (88-422 micrograms/L), and nordothiepin-S-oxide (176-530 micrograms/L) that were considerably above steady-state therapeutic concentrations. In three patients who received treatment with repeated-dose activated charcoal, dothiepin half-lives were 10.6, 12.5, and 13.1 h compared with the literature range of 18.5-24 h. All patients survived and none experienced any significant cardiovascular event despite exhibiting clinical signs of tricyclic antidepressant overdose. We suggest that repeated-dose activated charcoal treatment may decrease the dothiepin half-life after overdose.

Intravenous regional administration of methylprednisolone in rheumatoid arthritis.

Intravenous regional administration of corticosteroid (IVRAS) in the treatment of rheumatoid arthritis of the hand has not been reported previously. The method is based on a modification of Bier's block, with substitution of corticosteroid for local anaesthetic. Twenty-two patients were assessed in this double-blind, placebo-controlled study. The technique was safe and effective in improving grip strength, with a group mean improvement of more than 50%. Because suppression of endogenous cortisol production 24 h after treatment was commensurate with the dose of methylprednisolone used (40 mg), we could not exclude that the response may have been due to systemic steroid. Further studies are required to define the real value of IVRAS as it may offer alternative treatment of the joints and tendons within the hand and wrist in some patients rather than more prolonged oral therapy or individual, multiple joint or sheath injections.