Haloperidol toxicity

Mehta R, Reilly JJ. Manganese levels in a jaundiced longterm total parenteral nutrition patient potentiation of haloperidol toxicity Case report and literature review. J Parenter Enteral Nutr 1990 14(4) 428-30. 

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. 

Aggravation of the extrapyramidal effects of antipsychotic agents have been described and it has been reported that the use of lithium in combination with haloperidol may result in irreversible neurological toxicity. Lithium can increase the hypothyroid effects of antithyroid agents or iodides. 

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. 

C. Abuse of stimulants can produce toxic psychosis that closely resembles schizophrenia. An agent such as haloperidol or a phenothiazine will provide im-... 

The therapeutic serum level for haloperidol is 0.2 to 1 mcg/ml, and the toxic serum level is greater than 1 mcg/ml... 

Haloperidol Blocks central D2 Reduces vocal Tourette s syndrome Oral Toxicity Parkinsonism, other... 

Haloperidol Blockade of D2 receptors >> 5HT2A receptors Some a blockade, but minimal M receptor blockade and much less sedation than the phenothiazines Schizophrenia (alleviates positive symptoms), bipolar disorder (manic phase), Huntington s chorea, Tourette s syndrome Oral and parenteral forms with metabolism-dependent elimination Toxicity Extrapyramidal dysfunction is major adverse effect... 

Some toxicants that affect body temperature are shown in Figure 6.11. Among those that increase body temperature are benzadrine, cocaine, sodium fluoroacetate, tricyclic antidepressants, hexachlorobenzene, and salicylates (aspirin). In addition to phenobarbital and ethanol, toxicants that decrease body temperature include phenothiazine, clonidine, glutethimide, and haloperidol. 

Recent research has become more sophisticated in studying the toxic effect of neuroleptics on cells of neuronal processes. Ethier et al. (2004) found that haloperidol impairs striatal neuropeptide gene expression. They correlated this in rats with the production of catalepsy—a slowing down of bodily movements—thereby creating a study of the braindisabling effects of neuroleptics. These drugs damage cellular processes and simultaneously inhibit spontaneous movement. The overall reduction of spontaneity in patients is closely related to the so-called therapeutic effect. 

Risperidone was a fairly potent inhibitor of glucose transport but was not very toxic for cells [in their tests] and olanzapine, a modest inhibitor of glucose transport, actually stimulated proliferation of neuronal cells. Haloperidol was toxic for [experimental cells], however, it did not affect glucose transport. On the other hand, this drug inhibited mitochondrial function (energy metabolism), which may explain its toxicity. 

Metabolic polymorphisms affect the rate of clearance of certain drugs. A good example can be seen in the pharmacogenetics haloperidol in poor and extensive metabolizers of CYP2D6 (Figure 11.2). If a drug has a narrow therapeutic index (ratio of toxic dose/therapeutic dose), the polymorphism may produce toxic levels in the PM (Figure 11.3). 

Fluvoxamine has little inhibitory effect on CYP2D6 but is a potent inhibitor of CYP1A2 and CYP2C19. It also is a moderate inhibitor of CYP3A4, which is involved in the metabolism of haloperidol. When fluvoxamine (25, 75, and 150 mg/day, each for 2 weeks) was added to haloperidol in 12 patients with schizophrenia aged 22-59 years, plasma haloperidol concentrations rose dose-relatedly after fluvoxamine 25 mg/day haloperidol concentrations rose by about 20%, with additional 20% increases with each increment in fluvoxamine dose however, this was not associated with overt clinical toxicity (104). 

Hepatic enzyme inhibition by nefazodone can significantly raise concentrations and toxicity of haloperidol (29). 

Acute extrapyramidal reactions occur more often after ingestion of high-potency drugs, such as haloperidol and fluphenazine these respond to parenteral benzatropine, but anticholinergic drugs should be used judiciously, so as not to worsen peripheral or central autonomic toxicity. Other serious, but less frequent, complications include paralytic ileus and hypothermia. Acute renal insufficiency has been very rarely reported, but is apparently reversible and can occur secondary to severe hypotension or other causes after acute ingestion (615). 

A 55-year-old man who had been treated for a manic-depressive disorder for about 5 years developed toxic epidermal necrolysis after being given carbamazepine and haloperidol (35). 

PROPANOLOL, TIMOLOL CHLORPROMAZINE, HALOPERIDOL t plasma concentrations and efficacy of both chlorpromazine and propranolol during co-administration Propanolol and chlorpromazine mutually inhibit each other s hepatic metabolism. Haloperidol inhibits CYP2D6-mediated metabolism of propanolol and timolol Watch for toxic effects of chlorpromazine and propranolol 1 doses accordingly... 

CLOZAPINE, HALOPERIDOL, PERPHENAZINE, RISPERIDONE IMATINIB 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... 

CHLORPROMAZINE, CLOZAPINE, HALOPERIDOL, OLANZAPINE BUPROPION T plasma concentrations of these drugs with risk of toxic/adverse effects Smoking induces mainly CYP1A2 and CYP2E1. Thus de-induction takes place following cessation of smoking Be aware and watch for early features of toxicity. Consider reducing the dose... 

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