Thioridazine toxicity

A 28-year-old woman with a long history of psychiatric problems was taking fluoxetine, diazepam, methylphe-nidate, and thioridazine 800 mg qds (17). Fluorescein angiography showed confluent areas of punctate hyperfluorescence, consistent with diffuse retinal pigment epithelial alteration secondary to acute thioridazine toxic effects. 

The higher serum concentrations in poor CYP2D6 meta-bolizers are associated with an increased risk of thioridazine toxicity (11). 

Several factors increase the risk of thioridazine toxicity pre-existing cardiac disease, hypokalemia, a glucose load, alcohol, exercise, and concomitant therapy with tricyclic antidepressants, erythromycin, co-trimoxazole, cisapride, risperidone, hydroxyzine, and drugs that inhibit CYP2D6 (some SSRIs, fluphenazine, and perphenazine) (11). 

Two patients stable taking thioridazine 600 or 800 mg daily had three and fivefold rises in plasma levels, respectively, when given propranolol, in increasing doses up to a total of 800 mg daily, over 26 to 40 days. No signs or symptoms of thioridazine toxicity were seen even though plasma levels had risen into the toxic range. Similarly, in another study thioridazine levels rose by about 55 to 370% in 5 patients taking propranolol 320 to 520 mg daily. ... 

The answer is b. (Katzung, p 4822) Haloperidol, a butyrophenone, is by far the most likely antipsychotic to produce extrapyramidal toxicides Other agents, such as piperazine (an aromatic phenothiazine), thiothixene (a thioxanthene), and pimozide (a diphenylbutyropiperidine) are comparitively less likely to produce extrapyramidal toxicity than haloperi-dol. The antagonism of dopamine in the nigrostriatal system might explain the Parkinson-like effects Both haloperidol and pimozide act mainly on D2 receptors, whereas thioridazine and piperazine act on ooadrenergie receptors, and have a less potent but definite effect on D2 receptors. 

Therapeutic serum level for thioridazine is 0.2 to 2.6 mcg/ml, and the toxic serum level is not established... 

The term behavioral toxicity has been used in the child psychiatry literature to describe the following adverse effects of antipsychotics, particularly low-potency phenothiazines (e.g., chlorpromazine, thioridazine) ... 

Chlorpromazine Blockade of D2 receptors >> 5 2 receptors .-Receptor blockade (fluphenazine least) muscarinic (M)-receptor blockade (especially chlorpromazine and thioridazine) Hx-receptor blockade (chlorpromazine, thiothixene) t central nervous system (CNS) depression (sedation) t decreased seizure threshold t QT prolongation (thioridazine) Psychiatric schizophrenia (alleviate positive symptoms), bipolar disorder (manic phase) nonpsychiatric antiemesis, preoperative sedation (promethazine) pruritus Oral and parenteral forms, long half-lives with metabolism-dependent elimination Toxicity Extensions of effects on a - and M- receptors blockade of dopamine receptors may result in akathisia, dystonia, parkinsonian symptoms, tardivedyskinesia, and hyperprolactinemia... 

A number of toxic effects on the blood have been documented, including agranulocytosis caused by chlorpromazine, hemolytic anemia caused by methyldopa, and megaloblastic anemia caused by methotrexate. Toxic effects on the eye have been noted and range from retinotoxicity caused by thioridazine to glaucoma caused by systemic corticosteroids. 

Neuroleptics increase the toxicity of the sunlight to human skin, causing discolorations and other adverse dermal reactions. Researchers noted this phenomenon, called phototoxicity, and set out to study its effects on cells loaded with the neuroleptics fluphenazine, perphenazine, or thioridazine (Bastianon et al., 2005). They found that exposure of these cells to light caused abnormalities in both the plasma membrane and mitochondria. 

Bastianon, C., Zanoni, R., Miolo, G., Caffieri, S., 6c Reddi, E. (2005). Mitochondria and plasma membrane as targets of UVA-induced toxicity of neuroleptic drugs fluphenazine, perphenazine and thioridazine. International Journal of Biochemistry Cell Biology 37, 901—908. 

The interaction of thioridazine with a tricyclic antidepressant is particularly dangerous, since both cause cardiac toxicity. One report concerned two young patients who developed ventricular dysrhythmias, from which they recovered (215). 

Heiman EM. Cardiac toxicity with thioridazine-tricyclic antidepressant combination. J Nerv Ment Dis 1977 165(2) 139-43. 

Chlorpromazine, and in some cases other phenothiazines, has been reported to increase plasma phenytoin concentrations (656-659), to reduce plasma phenytoin concentrations (657-661), or to have no effect (658). In one case co-administration of thioridazine caused phenytoin toxicity (662). 

Acute toxic effects of thioridazine on the eyes include nyctalopia, blurred vision, and dyschromatopsia, which typically become evident after 2-8 weeks of dosages over 800 mg/day. 

Davies SJ, Cooke LB, Moore AG, Potokar J. Discontinuation of thioridazine in patients with learning disabilities balancing cardiovascular toxicity with adverse consequences of changing drugs. BMJ 2002 324(7352) 1519-21. 

IMATINIB 1. ANTIARRHYTHMICS -flecainide, mexiletine, propafenone 2. ANTIDEPRESSANTS - fluoxetine, paroxetine, TCAs, trazodone, venlafaxine 3. ANTIPSYCHOTICS -clozapine, haloperidol, perphenazine, risperidone, thioridazine 4. BETA-BLOCKERS - metoprolol, propanolol, timolol 5. DONEPEZIL 6. METHAMPHETAMINE Imatinib may cause t plasma concentrations of these drugs, with a risk of toxic effects Inhibition of CYP2D6-mediated metabolism of these drugs Watch for early features of toxicity of these drugs... 

Toxic blood concentrations of some drugs (e.g. thioridazine) are not significantly higher than dierapeutic concentrations. This is not generally true of liver concentrations which, in postmortem specimens, may be over ten times higher than those obtained from patients on dierapeutic dose regimens. Liver analysis in these cases will provide a more certain indication of a fatal overdose. 

Chlorpromazine (Thorazine) and thioridazine (Mellaril), both phenothiazine derivatives, are used for their antipsychotic effects in the control of severely disturbed or agitated behavior and in schizophrenia. Thioridazine has a higher incidence of antimuscarinic effects but a lower incidence of extrapyramidal symptoms. Pigmentary changes of the retina have been reported occasionally in association with chlorpromazine therapy, although it is recognized that only thioridazine produces retinal toxicity. 

Thioridazine can cause significant retinal toxicity, leading to reduced visual acuity, changes in color vision, and disturbances of dark adaptation.These symptoms typically occur 30 to 90 days after initiation of treatment. The fundus often appears normal during the early stages of symptoms, but within several weeks or months a pigmentary... 

It is now recognized that the primary clinical fector associated with thioridazine retinopathy is the daily dose of drug. Before becoming aware of the dose-related retinal toxicity, dosages exceeding 1,600 mg daily were commonly prescribed. Few cases of pigmentary retinopathy have been reported, however, with daily dosages of less than 800 mg. 

Eye. Toxic cataract can be due to chloroquine and related drugs, adrenal steroids (topical and systemic), phenothiazines and alkylating agents. Comeal opacities occur with phenothiazines and chloroquine. Retinal injury occurs with thioridazine (particularly, of the antipsychotics), chloroquine and indomethacin. 

Sertindole is available only on a named patient basis, f Licenced indications for thioridazine were severely restricted in 2000 after evidence emerged of cardiovascular toxicity. 

For each antipsychotic agent there is a licensed maximum dose for example up to 1000 mg of chlorpromazine/day may be given under the United Kingdom licence. Prescribing beyond the licensed maximum dose requires specialist consent. When two antipsychotics are co-prescribed, the maximum antipsychotic dose should not exceed 1000 mg of chlorpromazine equivalents/day except under specialist supervision. For some antipsychotics the licenced maximum dose is considerably less than 1000 mg of chlorpromazine equivalents/day. For instance, the licenced maximum dose of thioridazine was reduced to 600 mg/day following concerns about its cardiovascular toxicity. Note... 

The postmortem blood concentration of carbamazepine has been reported in a case of suicide attributed to mixed drug toxicity with carbamazepine, lamotrigine, paroxetine, and thioridazine (86). It was 76 pmol/l. 

---