Neuroleptics toxicity

Trihexyphenidyl (Artane) and benztropine (Cogentin) are prescription drugs used in the treatment both of Parkinson s disease and the extrapyramidal side effects produced by neuroleptic medication. They are occasionally abused for their mind-altering properties, which occur at toxic doses (Perry et al. 1978). Abusers often try to obtain these drugs by false representation of extrapyramidal symptoms, which are claimed to result from the use of phenothi-azines or other neuroleptics (Rubinstein 1978). 

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). 

Unfortunately, few of the studies that have attempted to relate the blood concentrations of neuroleptics to therapeutic response have fulfilled all these criteria. There is a suggestion that a "thera peutic window" exists for some phenothiazine neuroleptics. A therapeutic window is a range of concentrations of a drug measured in the blood that are associated with a good therapeutic response. Plasma concentrations outside this range are either too low to ensure a therapeutic response or so high that they induce toxic side effects. Despite the numerous studies of the relationship between the plasma concentration and the therapeutic response for a number of "standard" neuroleptics, it would appear that such correlations rarely account for more than 25% of the variance in clinical response to treatment. The existence of a therapeutic window for neuroleptics would therefore appear to be unproven. However, there could be ranges of plasma concentrations associated with optimal antipsychotic action, but these... 

The long-term toxic effects of lithium, such as nephrogenic diabetes insipidus, which has been calculated to occur in up to 5% of patients, and the rare possibility of lithium combined with neuroleptics being neurotoxic, has stimulated the research for other drug treatments. However, apart from the neuroleptics, these drugs have not been studied as extensively in the treatment of acute mania, but are worthy of consideration because of their reduced side effects. 

In CONCLUSION, lithium is universally accepted as a mood-stabilizing drug and an effective antimanic agent whose value is limited by its poor therapeutic index (i.e. its therapeutic to toxicity ratio). Neuroleptics are effective in attenuating the symptoms of acute mania but they too have serious adverse side effects. High potency typical neuroleptics appear to increase the likelihood of tardive dyskinesia. Of the less well-established treatments, carbamazepine would appear to have a role, particularly in the more advanced stages of the illness when lithium is less effective. 

Encephalopathic syndrome Encephalopathic syndrome has occurred in a few patients given lithium plus a neuroleptic. In some instances, irreversible brain damage occurred. Monitor closely for evidence of neurologic toxicity. 

Chronic stimulant abuse alters the personality of the abuser. These and related changes are the result of neurotoxicity and are not characterized as either acute drug effects or withdrawal signs. Individuals have delusions of being pursued or persecuted and therefore become suspicious and paranoid. They become self-occupied and hostile toward others. Long-term abuse can produce toxic psychosis that closely resembles schizophrenia and must be treated with neuroleptic drugs (haloperidol, chlorpromazine). This psychosis can develop even within 1 to 2 weeks if the person is on a run of very high doses of stimulants. 

Neuroleptics Competition for metabolism at CYP2D6 isoenzyme TCA toxicity due to possible 30% increase in TCA levels with coadministration Lower TCA dose or neuroleptic dose Geller, 1991... 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Despite this favorable result, lithium was hardly considered as a psychopharmaceutical for many years. There were a variety of reasons for this. Firstly, mania is not a very common psychosis and there is spontaneous remission in many cases. There were thus not so many occasions where lithium treatment was indicated. Secondly, lithium salts were considered to be toxic because for some time they had been given in excessive doses to patients with heart failure and in this way, had led to a number of fatalities (Cade, 1970). Thirdly, a few years after Cade s first publication psychiatrists attention had been claimed by chlorpromazine and the subsequent neuroleptics and antidepressants, thus explaining why lithium almost fell into oblivion. It was onl> in the 1960s that it once more attracted some interest, after the Danish psychiatrist Mogens Schou had shown that lithium salts were not only useful in the manic phase of manic depressive illness but also could prevent depressive episodes in patients suffering from bipolar psychoses. 

In general, lower doses (e.g., risperidone 2 to 6 mg/day olanzapine 5 to 20 mg/day) are preferable, usually sufficient, and help avoid toxicity. At these doses, results suggest that olanzapine has a substantially lower propensity than neuroleptics to evoke EPS, and perhaps TD. Indeed, early clinical trials were unable to distinguish olanzapine from placebo for EPS or akathisia. Further, there is some indication that doses of risperidone 10 mg may produce less improvement and more side effects than doses in the 4-8 mg dose range. 

Acute medical emergencies are a feature of this substance abuse with sometimes fatal results, and a wide variety of solvent-based products can be used. Management of these acute stages may include neuroleptics to control the agitation and toxic state which will settle over a few hours. No specific medical management is necessary after this, and a full network of support systems needs to be established. Education of the medical complications is crucial in any preventative programme and there needs to be community involvement in its management (Barnes 1979 Sourindhrin and Baird 1984). 

Amoxapine has neuroleptic properties that stem from its dopamine receptor-binding affinity. Similar to the neuroleptics, it may produce movement disorders. In toxic doses, amoxapine may provoke difficult-to-control convulsions. 

At high doses, both the major and minor tranquilizers are severely toxic and may cause coma, respiratory arrest, convulsions, acute renal failure, speech impairment, or death. However, at therapeutic doses, the neuroleptics have been associated with more severe, longterm side effects than the sedative-hypnotics. 

Mania can occur in any age group. Acute manic episodes in the elderly may best be managed with high potency neuroleptics. The use of lithium is not contraindicated in the elderly provided renal clearance is reasonably normal. The dose administered should be carefully monitored, as the half-life of the drug is increased in the elderly to 36-48 hours in comparison to about 24 hours in the young adult. The serum lithium concentration in the elderly should be maintained at about 0.5 mEq/litre. It is essential to ensure that the elderly patient is not on a salt-restricted diet before starting lithium therapy. The side effects and toxicity of lithium have been discussed in detail elsewhere (see p. 198 et seq.), and, apart from an increase in the frequency of confusional states in the elderly patient, the same adverse effects can be expected as in the younger patient. 

Trials of lithium in patients with acute psychosis (and not just mania) showed that lithium was inferior for the treatment of severely overactive patients, presumably because of its toxicity, but comparable to neuroleptics for the treatment of less overactive patients, regardless of diagnosis (Braden et al. 1982 Johnstone et al. 1988). A trial conducted in the 1960 comparing opium and chlorpromazine in acute schizophrenic patients showed equivalent improvement over three weeks with both drugs (Abse, Dahlstrom, Tolley 1960). 

As well as their effects on the brain, neuroleptics commonly produce other potentially lethal effects. They are all toxic to the heart, inducing conduction defects and arrhythmias. Olanzapine and clozapine also interfere with normal metabolism, causing what is known as metabolic syndrome. This syndrome has only recently been described and is defined as the occurrence of obesity, diabetes, hypertension and dyslipidaemia6 (Shirzadi Ghaemi 2006). The underlying cause of the syndrome is thought to be resistance to insulin. All these effects... 

Droperidol is an older neuroleptic, which was commonly used but is now withdrawn due to cardiac toxicity. 

The DNA-modified electrodes have been used for trace measurements of toxic amine compounds [141], and for trace measurements of phenothia-zine compounds with neuroleptic and antidepressive action [142], as well as detection of radiation-induced DNA damage [143]. 

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