Documentation about thioridazine as the possible cause of sudden cardiac death is requested. The qu

Fråga: Documentation about thioridazine as the possible cause of sudden cardiac death is requested. The question is general, but also related to an 18-year-old patient treated with thioridazine and who has flat T-waves and increased Q-T interval.

Sammanfattning: The question of an association between thioridazine use and sudden death, and especially the issue of causality, is very difficult to address properly. At present, most of the evidence is circumstantial, but taken together with the well-established arrhythmogenic effects of phenothiazines we consider it prudent to call attention to the potentially fatal side effects of these drugs. Further prospective studies of the relationship between thioridazine use and sudden, unexpected death are needed.

Svar: Thioridazine is one of the phenothiazine derivatives which have been repeatedly found to be associated with cases of sudden death (1). The well-documented cardiovascular side effects of phenothiazines include arrhythmias, hypotension, negative inotropic effect and provide a plausible link between them and sudden death (2-4). According to Brown and Kocsis (5), other causes that have been suggested for the sudden death also include rapid vascular collapse, drug-induced seizures, mucus plugs in asthmatic patients, asphyxia caused by aspired food and pulmonary microembolism.

In humans, electrocardiographic changes occur most commonly after the therapeutic administration of thioridazine, are less common after therapeutic doses of chlorpromazine, and even less common after trifluoperazine (1). The degree of electrocardiographic repolarization abnormalities secondary to phenothiazine ingestion appears to be dose-related: 200 mg per day of thioridazine can sometimes be associated with detectable ECG changes, while these changes occur more consistently with doses exceeding 800 mg per day (2). Non-specific T-wave changes, ST segment depression and prolongation of the Q-T or PR interval have been noted in 50 per cent and 70 per cent of patients taking 100-300 mg and 150-900 mg of thioridazine daily, respectively (4). It is, however, important to recognize that the pharmacokinetics of thioridazine, as well as that of other neuroleptic drugs, varies widely between patients. Thus, concentration-effect rather than dose-effect relationship should be looked for.

Thioridazine is extensively biotransformed in vivo, by side-chain oxidation leading to mesoridazine and sulforidazine, by N-demethylation leading to northioridazine, and by ring sulfoxidation leading to thioridazine 5-sulfoxide. Thioridazine is believed to exert its antipsychotic effects mainly via its antidopaminergic functions in the CNS, and it has been shown that mesoridazine and sulforidazine contribute to these pharmacological effects (6). However, thioridazine ring-sulphoxide seems to have no antipsychotic effects, but it contributes to the cardiotoxicity of the drug (7,8), even more potently than does the parent compound (9,10). A recent paper about single-dose thioridazine metabolism in different debrisoquin hydroxylation phenotype (11) revealed that thioridazine is extensively oxidized by debrisoquin hydroxylase (cytochrome P450 IID6). The ring-sulphoxide reached a higher Cmax and had a much higher AUC in slow hydroxylators than in rapid hydroxylators. Although, we cannot, based on the single-dose study, conclusively predict the importance of debrisoquin hydroxylation phenotype for the kinetics and clinical outcome during continuous thioridazine therapy, slow hydroxylators of debrisoquin (7 per cent of the swedish population) might be more prone to get cardiovascular side effects because of accumulation of the ring sulphoxide metabolite.

The possible relationship between the thioridazine use and the occurrence of sudden, unexpected deaths has remained controversial (1,12,13). A retrospective investigation by Ungvari (12) suggested that the sudden death mortality rate of patients medicated with neuroleptic drugs was not higher than that of the general population of the same age distribution. These results were based on 11.935 patients treated with neuroleptics between January 1968 and December 1978, and of whom 8 died suddenly and unexpectedly. Haloperidol was the most commonly used neuroleptic in their clinical practice. In a survey of sudden death associated with the use of antipsychotic or antidepressant drugs from Finland (13), therapeutic use of phenothiazines was documented in all but 3 of 49 cases. Thioridazine was involved in over half of them, and thioridazine was the only antipsychotic drug associated with 15 cases. Only 5 cases were associated with any of the other antipsychotic or antidepressant drugs. The authors suggested that there were clear differences between the subgroups of psychotropic drugs after adjustment according to the use in the population, and although there are several uncontrolled confounding factors, that the overrepresentation of phenothiazines, especially thioridazine, among psychiatric patients who died suddenly was striking. However, the authors did not compare the sudden death mortality rate of patients treated with neuroleptic drugs with that of general population of the same age distribution.

Since thioridazine was approved for use in Sweden in 1960, only four cases of sudden death associated with thioridazine use have been reported to Swedish Adverse Drug Reactions Advisory Committee (SADRAC) between 1966 and 1995 (14). In these 4 cases, only one case had preexisting cardiac disease hypertrophic cardiomyopathy demonstrated by autopsy. In the other cases, no death cause could be found at autopsies, and the connection to the thioridazine use was judged as possible. It is to be emphasized that the number of reported cases may largely underestimate the true number of cases. In the present case, it is recommendable to determine the concentration of thioridazine in plasma in order to increase the safety of the treatment. 1 Lathers CM, Lipka LJ: Cardiac arrhythmia, sudden deat, and psychoactive agents. J Clin Pharmacol 1987; 27: 1-14 2 Elkayam U, Frishman W: Cardiovascular effects of phenothiazines. Am Heart J 1980; 100: 397-401 3 Kemper AJ, Dunlap R, Pietro DA: Thioridazine-induced torsade de pointes. Successful therapy with isoproterenol. JAMA 1983; 249: 2931-2934 4 Lipscomb PA: Cardiovascular side effects of phenothiazines and tricyclic antidepressants. A review with precautionary measures. Postgrad Med 1980; 67: 189-196 5 Brown RP, Kocsis JH: Sudden death and antipsychotic drugs. Hosp Community Psychiatry 1984; 35: 486-491 6 Dahl SG: Active metabolites of neuroleptic drugs: possible contribution to therapeutic and toxic effects. Ther Drug Monit 1982; 4: 33-40 7 Gottschalk LK, Dinovo E, Biener R, Nandi BR: Plasma concentration of thioridazine metabolites an ECG abnormalities. J Pharm Sci 1978; 67: 155-157 8 Axelsson R, Mårtensson E: Side effects of thioridazine and their relationship with the serum concentrations of the drug and its main metabolites. Curr Ther Res 1980; 28: 463-489 9 Hale PW Jr, Poklis A: Cardiotoxicity of thioridazine and two stereoisomeric forms of thioridazine 5-sulfoxide in the isolated perfused rat heart. Toxicol App Pharmacol 1986; 86: 44-55 10 Heath A, Svensson C, Mårtensson E: Thiordiazine toxicity - an experimental cardiovascular study of thioridazine and its major metabolites in overdose. Vet Hum Toxicol 1985; 27: 100-105 11 von Bahr C, Movin G, Nordin C, Liden A, Hammarlund-Udenaes M, Hedberg A, Ring H, Sjöqvist F: Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1991; 49: 234-240 12 Ungvari G: Neuroleptic-related sudden death (proven or a mere hypothesis?) Pharmakopsychiat 1980; 19: 29-33 13 Mehtonen O-P, Aranko K, Malkonen L, Vapaatalo H: A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland. Acta Psychiatr Scand 1991; 84: 58-64 14 SADRAC Report. Report nr.: 871668, 910902, 932310, 942438.