What is the toxic concentration of zuclopenthixol (Cisordinol)?/nIs there a risk of interaction wit

Fråga: What is the toxic concentration of zuclopenthixol (Cisordinol)? Is there a risk of interaction with alimemazine and levomepromazine? A middle-aged woman with an acute relapse of psychosis was admitted to hospital and zuclopenthixol (Cisordinol) 20 mg orally was started once daily. Because of lack of response eight days later she was given intramuscular injections of zuclopenthixol hydrochloride (Cisordinol, 10 mg/mL, 1.5 mL) and acetate (Cisordinol-Acutard, 50 mg/mL, 1.0 mL). She had slight extrapyramidal symptoms and was given a few doses of anticholinergics (orphenadrine and biperiden). She was on propiomazine (Propavan) and 100 mg of levomepromazine (Nozinan) at bedtime. Three to four days later she was wound up and anxious and was therefore given diazepam and later alimemazine (Theralen). Later that night she was found dead in bed. Forensic toxicologic analysis revealed the following amounts of drugs expressed per gram of femoral blood: zuclopenthixol 0.19 micrograms (ug), levomepromazine 0.2 ug, desmethyl-levomepromazine 0.2 ug, orphenadrine 0.9 ug, diazepam 0.5 ug, nordiazepam 0.4 ug, alimemazine 0.1 ug, dihydropropiomazine 0.07 ug.

Sammanfattning: The concentration of zuclopenthixol measured in this patient is in the order previously reported to be lethal (0.2 ug/mL or almost 500 nmol/L). Whether this is due to an interaction or deliberate intoxication cannot be clearly answered based on the available data.

Svar: The ordinary daily dosage of zuclopenthixol is 10 to 40 mg, but doses up to 150 mg can be used. Onehundred and fifty mg to a 19-year-old and 375-700 mg to an adult has been reported to give moderate intoxication (1).

With a molecular weight of 400.97 g/mol (2), the measured concentration of zuclopenthixol (0.19 ug/g) in post-mortal blood translates into 474 nmol/kg. With a density of 1.054 kg/L for live blood (3) this gives a concentration of 499 nmol/L. Since postmortal changes can alter the distribution of drugs, this must be assessed with some caution. There are, however, published case reports of fatal intoxications; one case in which the concentration of zuclopenthixol was in this range (441 nmol/L) but in a few others the concentrations were much higher (1500 and 975 nmol/L, respectively) (4,5,6). The concentrations in heart blood were higher still (5).

According to the manufacturer, lethal concentrations of zuclopenthixol are 0.20 ug/mL, which equals 0.19 ug/g or 499 nmol/L (7). An epidemiological study has suggested tricyclic neuroleptics (such as zuclopenthixol) to be more toxic than other neuroleptics (8).

There are three possible explanations for the fatal outcome in this case: poor metabolic capacity, metabolic interaction, or deliberate intoxication.

This very patient had been on zuclopenthixol before and five years ago was stated to have insufficient efficacy when having a trough concentration of 74 nmol/L (therapeutic window 7-30 nmol/L) upon taking 80 mg/day (9). We do not know anything of concomitant medication then, but both the dosing and the concentration are fairly high, suggesting that the metabolic capacity isn´t very poor. There is a possibility to genotype this patient for CYP2D6. The Forensic Toxicology Department has limited material, though, and wants to save this for further analyses.

There is little information available on the metabolism of alimemazine in humans, but it is probably mainly metabolised by CYP2D6 as is other phenothiazines. There is no information that it inhibits CYP2D6, but has a limited inhibitory effect on the metabolism of citalopram (which is mainly metabolised by CYP2C19) (1, 10).

Since both levomepromazine and zuclopenthixol are metabolised by CYP2D6 (1), there will be competition of the available enzyme and the half-lives of both drugs might be prolonged. It has been shown that the metabolic ratio of debrisoquine (a phenotypic marker of CYP2D6, which enzyme is also known as debrisoquine hydroxylase) increases by a factor of four (i.e. the enzyme is inhibited) by levomepromazine at a daily dose of 10 mg for a week (11). Thus it may well be that saturation kinetics may have been reached while giving 100 mg levomepromazine daily for a fortnight. The concentration of levomepromazine (0.2 ug/g) was not extremely high, but the therapeutic window is said to be 0.02-0.14 ug/mL) and fatalities have been described of a combination of amobarbital (9.02 ug/mL) and levomepromazine (0.231 ug/mL) (12), even though far higher concentrations (4.1 ug/mL) were measured in a fatal case of intoxication of levomepromazine alone (13).

There is, of course, always a possibility that a patient collects pills and takes them in order to commit suicide. I do not see that we can exclude that possibility based on the presented data, but it is also very possible that this patient has been a victim of a serious metabolic interaction, that is not mentioned in Fass (1).

We recommend this case be reported to the Regional adverse drug reactions monitoring centre.