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Haloperidol is a butyrophenone antipsychotic. It blocks dopaminergic D1 and D2 receptors in the brain. It is the best studied of all the typical antipsychotics, though the majority of studies have been conducted in psychiatric patients with unclear applicability to the undifferentiated acutely agitated ED patient.20 The peak serum concentration is achieved in approximately 20 minutes after IM administration (2 to 6 hours after PO administration), while adequate sedative effects can be expected within 30 to 60 minutes for both IM and IV administration. The duration of effect is approximately 24 hours.6,22,23
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Dose–response studies have demonstrated that a single dose of 7.5 to 10 mg of haloperidol may produce the best outcome with the fewest side effects. Higher doses yield lesser degrees of improvement while increasing the risk of adverse effects.4,5,31 While the utility of haloperidol as monotherapy is limited, the traditional combination therapy of haloperidol with a benzodiazepine is a first-line option for schizophrenia, mania, and psychosis.
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Droperidol is another butyrophenone neuroleptic that inhibits dopaminergic transmission. It is closely related to haloperidol but only available in a parenteral formulation. Compared to haloperidol, it has rapid absorption with a quicker onset of action (15 to 30 minutes) and a much shorter half-life (2.2 hours).22,23 The peak effect is achieved within 30 minutes of IM administration and the duration of effect is 6 to 8 hours. Consequently, compared to haloperidol, it has been shown to be more effective at acutely reducing agitation while requiring fewer repeat doses and causing fewer side effects.23 This medication has also been compared to benzodiazepines. Droperidol produces better sedation, requires fewer repeat doses, and results in a shorter ED length of stay compared to lorazepam alone.19,20,32–34 Despite these promising results, continued use of droperidol became controversial after the FDA issued a black box warning in 2001 secondary to the drug's potential for QTc prolongation.35
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Emergency Physicians should be aware of relevant side effects associated with typical antipsychotics. This includes EPS, cardiac arrhythmias, and neuroleptic malignant syndrome. Haloperidol has been associated with acute dystonias, parkinsonism, and akathisia. The frequency of EPS associated with haloperidol use varies significantly across studies, but has been cited to affect between 0% and 50% of patients.21,34 These side effects are of particular concern given that they may lead to increased patient agitation and medication refusal. Anticholinergic medications such as benztropine (0.5 to 2 mg IM or IV) or diphenhydramine (50 mg IM or IV) may be used to prevent or treat EPS. Droperidol has a lower incidence of EPS in the acute setting.33,34,36 Caution should be used when administering typical antipsychotics in patients with Parkinson disease, anticholinergic toxicity, PCP intoxication, or movement disorders. There was concern that antipsychotic agents lowered the seizure threshold in mice, but this has not been found in humans.11
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Typical antipsychotics cause QT interval prolongation, most likely due to their quinidine-like cardiac affects.6,19 While there have been reports of sudden death occurring with chemical restraint using typical antipsychotics, haloperidol is considered to have a low risk of causing QTc prolongation. Droperidol is recognized for its potential for causing dose-dependent prolongation of the QTc and subsequent dysrhythmias. However, multiple reviews of large series of patients receiving droperidol have concluded that while this medication can be associated with prolonged QT interval, there is not conclusive evidence that it can cause life-threatening cardiac events. ACEP guidelines recommend that if rapid sedation is needed, and after consideration of the possible adverse affects, droperidol may still be preferable to haloperidol.20 Despite this, droperidol use has dramatically decreased since the FDA black box warning. When using antipsychotic medications, it is important to understand the potential effects on the QTc interval. The likelihood of QTc interval change is increased when patients are already taking other medications that prolong the QTc, or when they have certain comorbidities. Caution should be used, especially in patients with cardiac disease or those taking antipsychotics chronically. If possible, obtain an ECG prior to the administration of a typical antipsychotic. Withhold typical antipsychotic medication if the QTc is above 500 ms or if the patient has risk factors associated with QT prolongation. If administered, do not give additional doses if the QTc increased by >25% after administration.19
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There has been additional concern that typical antipsychotics may be affiliated with neuroleptic malignant syndrome (NMS), which is characterized by mental status changes, muscular rigidity, fever, and autonomic instability. The risk of this complication may increase in patients receiving large amounts of typical antipsychotics over a short period of time, and may be further exacerbated in those who are poorly hydrated and restrained in a poorly ventilated holding room. It has been estimated that NMS is a rare complication seen in approximately 0.2% to 1% of patients using typical antipsychotics, thus these patients should be monitored for such physiologic changes.4,6,23