Position statement: cathartics. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.

In preparing this Position Statement, all relevant scientific literature was identified and reviewed critically by acknowledged experts using agreed criteria. Well-conducted clinical and experimental studies were given precedence over anecdotal case reports and abstracts were not usually considered. A draft Position Statement was then produced and subjected to detailed peer review by an international group of clinical toxicologists chosen by the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists. The Position Statement went through multiple drafts before being approved by the Boards of the two societies and being endorsed by other societies. The Position Statement includes a summary statement for ease of use and is supported by detailed documentation which describes the scientific evidence on which the Statement is based. The administration of a cathartic alone has no role in the management of the poisoned patient and is not recommended as a method of gut decontamination. Experimental data are conflicting regarding the use of cathartics in combination with activated charcoal. No clinical studies have been published to investigate the ability of a cathartic, with or without activated charcoal, to reduce the bioavailability of drugs or to improve the outcome of poisoned patients. Based on available data, the routine use of a cathartic in combination with activated charcoal is not endorsed. If a cathartic is used, it should be limited to a single dose in order to minimize adverse effects.

Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans.

OBJECTIVE: To measure cardiac and other effects of thioridazine and relate these to the plasma concentration of the parent drug and its principal metabolites. METHODS: A double-blind, randomized-order crossover study involving nine healthy male subjects compared the effects of single doses of thioridazine (10 mg and 50 mg) with placebo. Plasma concentrations of thioridazine and its ring sulfoxide, side-chain sulfoxide, and side-chain sulfone metabolites were measured, together with effects on the ECG, blood pressure, salivary flow, and a batch of psychomotor tests for 72 hours after administration. RESULTS: Thioridazine, 50 mg, reduced standing systolic blood pressure (mean peak changes from baseline [95% CI] -32 mm Hg [-55, 10 mm Hg]; p < 0.01 versus placebo) and diastolic blood pressure (-14 mm Hg [-26, -2 mm Hg]; p < 0.05), increased standing heart rate (7 beats/min [-1, 16 beats/min]; p < 0.05), impaired psychomotor function, and prolonged the JT (20 ms1/2 [7, 34 ms1/2]; p < 0.05), QTa (22 ms1/2 [8, 36 ms1/2]; p < 0.05), and QTc (22 ms1/2 [11, 33 ms1/2]; p < 0.01) intervals, but had no effect on QT dispersion (-12 ms1/2 [-31, 6 ms1/2]). Thioridazine, 1.0 mg, also significantly increased QTc, but the effect was less marked (9 ms1/2 [-1, 19 ms1/2]; p < 0.05). Plasma thioridazine and metabolite concentrations did not correlate significantly with these effects. Maximum effects on QTc occurred after peak concentrations of thioridazine but before peak concentrations of the ring sulfoxide and side-chain sulfone metabolites. CONCLUSIONS: These data suggest that thioridazine has dose-related effects on ventricular repolarization and that the parent drug causes an important proportion of these effects, although its metabolites may also contribute.

Stereoselective cardiotoxic effects of terodiline.

OBJECTIVE: To study the cardiovascular and electrocardiographic (ECG) effects of the R(+)- and S(-)- enantiomers of terodiline. The racemic drug was previously used to treat detrusor instability but was withdrawn after it caused serious ventricular arrhythmias associated with prolongation of the QT interval. METHODS: A double-blind, placebo-controlled, randomized crossover study was performed that involved nine healthy volunteers who were given single oral doses of racemic terodiline hydrochloride (200 mg), R(+)-terodiline hydrochloride (100 mg), S(-)-terodiline tartrate (100 mg), or placebo. Plasma concentrations of each enantiomer and cardiovascular and ECG effects, including QT intervals and QT dispersion, were measured over 14 days after each treatment. RESULTS: Both racemic and R(+)-terodiline significantly increased QT interval, corrected QT interval (QTc), and QRS duration (all p < 0.05), without affecting QT dispersion. S(-)-Terodiline tartrate (100 mg) did not affect QTc. Peak effects occurred 8 hours after dosing when increases in QTc from baseline (95% confidence intervals) were -3 (-20, 13) for placebo, 23 (8, 37) for racemic terodiline, 19 (6, 33) for R(+)-terodiline, and 0 (-10, 9) ms1/2 for S(-)-terodiline. Although differences were observed between the pharmacokinetics of the two enantiomers, these were not sufficient to account for the differences in ECG effects, and elimination half-lives were similar. Elimination of terodiline enantiomers was not significantly delayed in two genotypic poor metabolizers of debrisoquin (CYP2D6). CONCLUSIONS: QT prolongation associated with racemic terodiline is caused exclusively by the R(+)-enantiomer, which therefore appears to be responsible for the ventricular arrhythmias caused by the drug.

Effect of oxybutynin on the QTc interval in elderly patients with urinary incontinence.

1. Terodiline, an anticholinergic drug with calcium antagonist properties, is associated with QT prolongation and ventricular arrhythmias. It is not known if oxybutynin, a drug with a similar pharmacological profile, causes QT prolongation. ECGs were obtained before and at least 4 weeks after commencement of oxybutynin (mean daily dose 7.6, range 2.5-10 mg), in 21 elderly (mean age 75, range 58-88 years) patients treated for urinary incontinence. Heart rate, (mean +/- s.d.) 74 +/- 11 vs 69 +/- 11 beats min-1, -6 (-13,2), before vs during oxybutynin therapy, mean difference (95% confidence intervals); PR interval, 168 +/- 27 vs 156 +/- 27 ms, -11 (-26,3); QTc 454 +/- 27 vs 447 +/- 31 ms1/2, -9 (-23,5), and QTc dispersion, QTc max-QTc min, 68 +/- 24 vs 63 +/- 26 ms1/2, -1 (-15,14) were all unaltered by oxybutynin therapy. The lack of an effect on resting heart rate suggests that oxybutynin has little anticholinergic action at cardiac M2 receptors at usually administered doses. Oxybutynin therapy is not associated with QTc interval prolongation and is unlikely to produce ventricular arrhythmias.

Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence.

OBJECTIVE: Terodiline, an antimuscarinic and calcium antagonist drug, was used to treat detrusor instability but was withdrawn in 1991 after provoking serious ventricular arrhythmias associated with increases in the corrected QT interval (QTc). This research was performed to relate drug induced electrocardiographic changes in asymptomatic recipients to plasma concentrations of the R(+) and S(-) terodiline enantiomers. SETTING: Urological and geriatric clinics and wards. SUBJECTS: Asymptomatic patients taking terodiline in stable dose. METHODS: Electrocardiograms (50 mm/s) were collected from patients while they were taking terodiline and compared with ECGs obtained before or after terodiline. QT interval, heart rate corrected QT interval (QTc), and QT dispersion (QTd) were measured. Drug induced electrocardiographic changes were related to plasma concentrations of R(+) and S(-) terodiline. RESULTS: During terodiline treatment mean QTc and QTd were prolonged (491(43) and 84 (35) ms 1/2) compared with measurements made off therapy (443 (33) and 42 (17) ms 1/2, paired t tests, P < 0.002 and P < 0.01 respectively) in the 12 patients in sinus rhythm. The mean (95% confidence interval) drug induced increases were 48 (23 to 74) ms 1/2 for QTc and 42 (13 to 70) ms 1/2 for QTd. These increases correlated with total plasma terodiline (QTc: r = 0.77, P < 0.006, QTd: r = 0.68, P < 0.025) and with plasma concentrations of both terodiline enantiomers. CONCLUSIONS: Terodiline increases QTc and QTd in a concentration dependent manner. It is not clear whether this is a stereoselective effect and, if so, which enantiomer is responsible. The results suggest that drug induced torsade de pointes is a type A (concentration dependent) adverse drug reaction.

Redtide in the Philippines.

1. Redtide is a marine phenomenon that poses great risk to the health and economic livelihood of people in coastal areas. Paralytic shellfish poisoning develops when a person consumes molluscs containing toxic dinoflagellates and suffers neurological and/or gastrointestinal manifestations. 2. Four redtide incidents in the Philippines are presented. The manner in which the problems were managed are described. 3. The clinical features of redtide poisoning in the Philippines included gastro-intestinal and neurological features with deaths secondary to ventilatory failure. Mortality ranged from 0% to 12% in the different redtide episodes. 4. There are many lessons to be learned in handling this kind of natural disaster. For an effective toxicovigilance programme, there must be a central co-ordinating responsible organization, a clear definition of roles and functions and good inter-agency co-operation. Appropriate surveillance procedures, resources to intensify surveillance at times of risks, prompt warning system, and the ability to impose bans on consumption are also necessary. 5. Poisons centres can play an important role during times of redtide. This may include toxicovigilant activities, such as early warning and educational campaigns to consumers, and seminars in the recognition and management of paralytic shellfish poisoning. 6. The contribution of the epidemiologists in investigating and monitoring the extent of public health damage and patterns of poisoning in a coastal community is emphasized.