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Phenothiazines, butyrophenones, and other related drugs are used widely to treat psychosis and agitated depression. In addition, some of these drugs (eg, prochlorperazine, promethazine, and droperidol) are used as antiemetic agents. Suicidal overdoses are common, but because of the high toxic-therapeutic ratio, acute overdose seldom results in death. A large number of newer agents that often are referred to as “atypical antipsychotics” have been developed. Atypical antipsychotics differ from other neuroleptics in their binding to dopamine receptors and their effects on dopamine-mediated behaviors. Overdose experience with these agents is limited. Table II–11 describes available antipsychotic agents.

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Table II-11 Antipsychotic Drugs

  1. Mechanism of toxicity. A variety of pharmacologic effects are responsible for toxicity, involving primarily the cardiovascular system and CNS.

    1. Cardiovascular system. Anticholinergic effects may produce tachycardia. Alpha-adrenergic blockade may cause hypotension, especially orthostatic hypotension. With very large overdoses of some agents, quinidine-like membrane-depressant effects on the heart may occur. Many of these agents can cause QT prolongation (See Circulation).

    2. Central nervous system. Centrally mediated sedation and anticholinergic effects contribute to CNS depression. Alpha-adrenergic blockade causes small pupils despite anticholinergic effects on other systems. Extrapyramidal dystonic reactions are relatively common with therapeutic doses and probably are caused by central dopamine receptor blockade. The seizure threshold may be lowered by unknown mechanisms. Temperature regulation is also disturbed, resulting in poikilothermia.

    3. Pharmacokinetics. These drugs have large volumes of distribution (Vd = 10–30 L/kg), and most have long elimination half-lives (eg, chlorpromazine half-life = 18–30 hours). Elimination is largely by hepatic metabolism (see Table II–61).

  2. Toxic dose. Extrapyramidal reactions, anticholinergic side effects, and orthostatic hypotension ...

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