Clozapine nervous system

A large number of compounds in which thiophene was fused to other heterocyclic rings have been investigated, notably in the central nervous system agents. For example, the benzodiazepine derivative (365) is reported to be more active than Clozapine in conditioned avoidance response tests in the rat (80JMC878). The activity of such fused-ring thiophenes has been reviewed (81JHC1277). 

The presentation of neuroleptic malignant syndrome with clozapine can be different from that associated with traditional neuroleptic drugs (SEDA-28, 66), and the authors of a recent report have pointed out the differential diagnosis with heat stroke, a medical emergency with the two cardinal features of raised core body temperature (40° C) and central nervous system dysfunction, which is fatal in up to 50% of cases (205). 

CIMETIDINE ANTIPSYCHOTICS -CHLORPROMAZINE, CLOZAPINE, HALOPERIDOL, OLANZAPINE, PERPHENAZINE, RISPERIDONE, SERTINDOLE, THIORIDAZINE, ZUCLOPENTHIXOL T plasma concentrations of these antipsychotics, with risk of associated adverse effects - Drugs Acting on the Nervous System, Antipsychotics Cimetidine is an inhibitor of CYP3A4 (sertindole, haloperidol, risperidone) CYP2D6 (chlorpromazine, risperidone, zudopenthixol, thioridazine, perphenazine) and CYP1A2 (clozapine, olanzapine, sertindole, haloperidol) Avoid concomitant use. Choose alternative acid suppression... 

Of 524 inquiries received by the National Poisons Information Service concerning new neuroleptic drugs over 9 months, only 45 cases involved overdose with a single agent (olanzapine, n — 10 clozapine, n — 8 risperidone, n — 10 sulpiride, n = 16) (503). There were no deaths or cases of convulsions. Cardiac dysrhythmias occurred only with sulpiride. Symptoms were most marked with clozapine most patients had agitation, dystonia, central nervous system depression, and tachycardia. Most of the patients who had taken risperidone were asymptomatic. 

Drag overdose Fatal and non-fatal cases of clozapine overdose have been reported [SED-15, 833 SEDA-32, 98]. The minimal dose for severe poisoning and the factors that influence acute human clozapine intoxication have been studied in 73 cases of acute clozapine monointoxication reported to the Swiss Toxicological Information Center [94 ]. The most common symptoms were central nervous system depression (63%), tachycardia (40%), restlessness/agitation (16%), confusion/disorientation (15%), dysarthria (15%), arterial hypertension (11%), bradykinesia (9.6%), respiratory depression... 

Casamenti et al. [1399] developed a method for screening 11 central nervous system drugs (phenobarbital, olanzapine, clozapine, risperidone, loxapine, haloperidol, imipramine, amitriptyline, fluoxetine, chlorpromazine, paroxetine) on a Cjg column (A = 230 nm) using a 20/11.7 water (0.4g tetramethylammonium perchlorate with 0.2 mL of 7% (m/m) HCIO4 to pH 2.8 with ammonia)/acetonitrile mobile phase. Keep in mind that perchlorates, when concentrated with some metals, are hazardous. Elution was complete in 35 min with good resolution for most compounds. Plots of the effects of mobile phase modifier level and percent acetonitrile on overall retention are presented. Linear ranges of 25-5000 ng/mL with detection limits of 10-250 ng/mL (analyte dependent) are reported. 

Nervous System A preliminary study reported that clozapine responders may have fewer extrapyramidal symptoms than nonresponders [110 ]. 

Nervous System Parkinsonism was present in 46% of 150 elderly patients being treated with haloperidol and xmrelated to plasma concentrations or duration of use [151 ]. Two cases of neuroleptic-induced catatonia following the administration of intravenous haloperidol are described both patients recovered following discontinuation of haloperidol [152 ]. A case of neuroleptic malignant syndrome in a 48-year-old male is reported with index exposure to intravenous haloperidol that resolved on discontinuation [153 ]. Obsessive-compulsive symptoms are associated with a number of SGAs particularly clozapine however a case report describes the development of obsessive-compulsive symptoms in a learning disability patient treated with haloperidol [154 ]. 

Nervous system TD is less commonly associated with SGAs but certain factors may increase risk. A case of an adolescent female with mental retardation and schizophrenia use developing TD with chronic use of olanzapine is reported [168 ]. This patient was subsequently successfully treated with clozapine. Similarly, the presence of Dandy-Walker variant likely predisposed a 20-year-old male to TD which had first developed on FGAs and exacerbated with olanzapine before improving on low-dose aripiprazole [169 ]. A case of a 24-year-old male who developed TD after reinstatement of olanzapine and a course of ECT is reported [170 ]. 

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