Antipsychotic drugs toxicity

Antipsychotic, or neuroleptic drug Used in the treatment of schizophrenia. They are also used in the management of psychotic episodes associated with psychotropic drug toxicity and some neurodegenerative disorders. 

Clozapine and olanzapine are atypical antipsychotic drugs used in the treatment of schizophrenia. Their strnctnres are depicted in Scheme 2.36. The use of clozapine and olanzapine, which are more effective than standard neuroleptic drugs in the treatment of refractory schizophrenia, is, however, limited becanse of their adverse effects. These adverse effects are ascribed to the formation of the corresponding cation-radicals in living organisms under oxidation by bone marrow cells. These cation-radicals eliminate protons from the NH fragments and generate their nitrenium cations. The nitreninm cations are covalently bonnd to the life-important proteins. This results in the toxic effects of clozapine and olanzapine (Sikora et al. 2007). 

As noted above, OC failure may lead to accidental pregnancy and exposure of the developing fetus to potentially teratogenic properties of CBZ ( 383). Therefore, OC levels should be closely monitored and patients should notify their physician of spotting, an indicator of OC failure. Prothrombin time and the International Normalized Ratio (INR) should be monitored when patients are on warfarin and CBZ concomitantly. Patients stabilized on an antipsychotic may decompensate when CBZ is added. This may necessitate an increase in the antipsychotic dose and is one indication for TDM of antipsychotic drug levels ( 384). Conversely, when CBZ is discontinued, the dose of these other agents may need to be lowered to avoid toxicity. In summary ... 

Table 29-1 Antipsychotic Drugs Relation of Chemical Structure to Potency and Toxicities. ...

Two decades ago, there was a growing awareness of the inappropriateness and harmfulness of prescribing neuroleptics to elderly patients ( Antipsychotic Drug Therapy, 1988 Gomez et al., 1990 Sherman, 1987). The use of neuroleptics for the behavioral control of the elderly produces toxicity even more readily than in younger patients, and it cannot substitute for needed human services. Sherman (1987) called into question the pharmaceutical company practice of placing advertisements for neuroleptics like Haldol and Navane in journals with a geriatric-practice orientation. 

Risperdal, with its potent capacity to block dopamine D2 receptors, is the least atypical of all the so-called atypicals. Most of the cases of TD in children that I have evaluated have been caused by Risperdal. As you read in chapters 2-5 about the devastating toxicity of the antipsychotic drugs, keep in mind that America s drug watchdog agency has turned on its children by unleashing one of the worst iatrogenic disorders upon them. 

In three patients, plasma concentrations of maprotiline were increased by concomitant treatment with the atypical antipsychotic drug, risperidone (26). The data suggest that risperidone is a modest inhibitor of CYP2D6 and should therefore be used with caution in combination with drugs such as maprotiline, where increased plasma concentrations have the potential to cause serious toxicity. 

During 2004 a number of clinical trials were reported involving acute and maintenance studies of lithium, mostly either comparing new atypical antipsychotic drugs with lithium in bipolar disorder or in combined treatment studies. Of the relatively few studies of the adverse effects of lithium, most clustered in the areas of cardiovascular effects and issues regarding lithium toxicity. 

As the degree of presystemic elimination differs much between drugs and between individuals, the phenomenon of first-pass elimtnation adds to variation in systemic plasma concentrations, and thus particularly in initial response to the drugs that are subject to this process. When a drug is taken in overdose, presystemic elimination may be reduced, and bioavailability increased this may explain rapid onset of toxicity with antipsychotic drugs, many of which undergo first-pass elimination. 

These include amitraz (110), prepared from 54, a member of the form amidine class, active against mites and ticks, that have replaced organophosphorus compounds. Notably, amitraz is active against newer strains of pyrethroid-resistant ticks. The reaction of diphenylamine (8) with sulfur in the presence of iodine as catalyst yields the anthelmintic (worming agent) phenothiazone (phenothiazine) (111) (Scheme 24). It is too toxic for human use, though it is an intermediate in the production of antipsychotic drugs. 

The steady-state concentrations of antipsychotic drugs after multiple dosing have been measured to establish a relationship between plasma concentrations and clinical efficacy or to monitor adverse effects (360-363). The majority of drugs in the class seem to exhibit linear pharmacokinetics, despite the wide interindividual variations in pharmacokinetic properties observed for specific agents. Linear pharmacokinetics allows the dosage to be readily adjusted if the steady-state plasma concentration is in the sub-therapeutic or toxic range. 

Hazard Toxic by ingestion and inhalation, absorbed by skin. TLV 5 mg/m3. Toxic by skin absorption. Use Insecticide, manufacture of dyes, parent compound for chlorpromazine and related antipsychotic drugs, polymerization inhibitor, antioxidant. 

Van Putten T, Marder SR. Behavioral toxicity of antipsychotic drugs. J Clin Psychiatry 1987 48(Suppl 9) 13-19. 

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