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Introduction

  1. Pharmacology
    1. Haloperidol and droperidol are butyrophenone neuroleptic drugs, often referred to as “first-generation” or “typical” antipsychotics, that are useful for the management of acutely agitated psychotic patients and as antiemetics. They have strong central antidopaminergic activity and weak anticholinergic and anti-alpha-adrenergic effects.
    2. Olanzapine and ziprasidone are second-generation or “atypical” antipsychotic agents. They have weaker and more selective antidopaminergic activity and a higher ratio of serotonin-to-dopamine antagonism. This provides less risk for extrapyramidal side effects. However, olanzapine has greater anticholinergic effects, and both have greater antihistaminic and anti-alpha-adrenergic effects. Therefore, they have a greater propensity to cause sedation and orthostatic hypotension.
    3. Pharmacokinetics. Haloperidol is well absorbed from the GI tract and by the intramuscular route. Droperidol is available only for parenteral use and is well absorbed by the intramuscular route. Droperidol has a more predictable and rapid onset of 3-10 minutes, and both have peak pharmacologic effects that occur within 30-40 minutes of an intramuscular injection. Both drugs are metabolized principally by the liver. The serum half-life for haloperidol is 12-24 hours. Olanzapine and ziprasidone are well absorbed from the GI tract and by the intramuscular route. Olanzapine IM results in rapid absorption, with peak levels occurring within 15-45 minutes, whereas ziprasidone IM has peak levels occurring at approximately 30-60 minutes. Both drugs are metabolized principally by the liver. The serum half-life for olanzapine is 21-54 hours, and for ziprasidone, it is 2-5 hours.
  2. Indications
    1. Haloperidol is used for the management of acute agitated functional psychosis or extreme agitation induced by stimulants or hallucinogenic drugs, especially when drug-induced agitation has not responded to a benzodiazepine.
    2. Droperidol has a more rapid onset and greater efficacy for agitation and is also useful for drug- or toxin-induced nausea and vomiting. Its role in routine therapy is controversial because of a “black box” warning related to QT prolongation (see Item IV. D below). As a result, other antiemetics (eg, ondansetron and metoclopramide) are frequently used to control persistent nausea and vomiting.
    3. Olanzapine and ziprasidone by the intramuscular (IM) route are approved for the management of acute agitation associated with schizophrenia, in addition to bipolar mania for olanzapine. Both have been used for the management of acute undifferentiated agitation of either psychiatric or organic (eg, drug-induced) origin. They may have comparable efficacy to haloperidol when administered by the IM route to treat acute agitation.
    4. Note: Benzodiazepines are the usual first-line therapy for stimulant (eg, cocaine or amphetamine) intoxications and alcohol withdrawal syndromes. Combining an antipsychotic with a benzodiazepine may shorten the time to sedation for the treatment of acute agitation.
    5. Nonbenzodiazepine sedatives (either propofol or dexmedetomidine are often the preferred agents for sedation in mechanically ventilated adult ICU patients.
  3. Contraindications
    1. Severe CNS depression in the absence of airway and ventilatory control.
    2. Severe parkinsonism.
    3. Known hypersensitivity to the individual agent. Droperidol is structurally similar to haloperidol. Olanzapine is a thienobenzodiazepine and similar to clozapine. Ziprasidone has a unique chemical structure, a benzisothiazolyl piperazine.
    4. Prolonged QTc interval. Before droperidol administration, a 12-lead ECG is recommended.
  4. Adverse effects
    1. Haloperidol and droperidol produce less sedation and less hypotension than the atypical agents but are associated with a higher incidence of extrapyramidal side effects.
    2. Rigidity, diaphoresis, and hyperpyrexia may be a manifestation of neuroleptic malignant syndrome induced by haloperidol, droperidol, and other neuroleptic or antipsychotic agents.
    3. Antipsychotic agents may lower the seizure threshold and should be used with caution in patients with known seizure disorder or those who have ingested a convulsant drug.
    4. Large doses of haloperidol can prolong the QT interval and cause torsade de pointes. The FDA issued a black box warning for droperidol advising that QT prolongation and torsade de pointes have occurred at or below recommended doses. Ziprasidone may have a greater propensity for QT interval prolongation compared with olanzapine. Risk factors for torsade de pointes arrhythmias may include bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, congenital long-QT syndrome, and concomitant use of other drugs that cause QT prolongation.
    5. All antipsychotic drugs may cause orthostatic hypotension and tachycardia. The atypicals have a greater propensity than do haloperidol and droperidol.
    6. Some oral haloperidol tablets contain tartrazine dye, which may precipitate allergic reactions in susceptible patients.
    7. The FDA has issued a black box warning for olanzapine and ziprasidone concerning increased mortality in geriatric patients with dementia-related psychosis.
    8. The FDA has issued a black box warning for olanzapine concerning postinjection delirium/sedation syndrome. This has been associated with the use of the extended-release preparation for IM administration. Use of this product is restricted through the Zyprexa Relprevv Patient Care Program.
    9. Atypical antipsychotics have been associated with hyperglycemia, ketoacidosis, hyperosmolar coma, and death.
    10. Ziprasidone should be used with caution in patients with renal impairment because the excipient (cyclodextrin) in the IM preparation is cleared renally.
    11. Olanzapine has anticholinergic effects and can cause tachycardia, dry mouth, and constipation.
    12. Use in pregnancy. FDA Category C (indeterminate). These drugs are teratogenic and fetotoxic in animals and cross the placenta. Their safety in human pregnancy has not been established (Introduction).
  5. Drug or laboratory interactions
    1. Antipsychotics can potentiate CNS-depressant effects of opioids, antidepressants, phenothiazines, ethanol, barbiturates, and other sedatives.
    2. Combined therapy with lithium may increase the risk for neuroleptic malignant syndrome.
    3. Combined therapy with agents that cause prolongation of the QT interval may increase the risk for a torsade de pointes arrhythmia.
  6. Dosage and method of administration
    1. Oral. Give 2-5 mg of haloperidol PO; repeat once if necessary; usual daily dose is 3-5 mg 2-3 times per day (children older than 3 years: 0.05-0.15 mg/kg/d or 0.5 mg in two to three divided doses). Olanzapine is available as a rapidly disintegrating oral tablet; 10 mg has been used in adults to control agitation in patients with acute psychiatric disorders.
    2. Parenteral. Caution: Monitor the QT interval continuously and treat torsade de pointes if it occurs (Table I-7).
      1. Haloperidol. Give 2.5-10 mg of haloperidol lactate IM; may repeat once after 20-30 minutes and hourly if necessary (children older than 3 years: same dosing as orally). Haloperidol lactate is not approved for IV use in the United States, but has been used widely and is apparently safe (the decanoate salt formulation is a monthly depo product and is only given by deep IM injection).
      2. Droperidol. Usual adult dose for delirium is 5 mg IM, and sedative dose is 2.5-5 mg IM (administer additional doses titrated to desired effect). For antiemetic effects, usually given for 30-60 minutes as a premedication, 0.625-1.25 mg (children 2-12 years old: 0.01-0.125 mg/kg/dose; maximum 1.25 mg/dose) by slow IV. Note: not the preferred antiemetic agent for children. See warnings described above.
      3. Olanzapine. Usual adult dose for acute agitation is 5-10 mg IM (with additional 10-mg doses titrated at least 2 hours from the first dose and 4 hours from the second dose to the desired effect, up to a maximum daily dose of 30 mg). These higher doses are associated with a higher risk for orthostatic hypotension. Use lower dose (2.5-5 mg) in patients at risk for hypotensive reactions. Safety and efficacy of parenteral use in children are unknown.
      4. Ziprasidone. Usual adult dose for acute agitation is 10-20 mg IM (with additional 10-mg doses titrated every 2 hours or 20-mg doses every 4 hours, up to a maximum daily dose of 40 mg). Safety and efficacy of parenteral use in children are unknown.