Phenothiazines, butyrophenones, and other related drugs are used widely to treat psychosis and agitated depression. In addition, some of these drugs (eg, prochlorperazine, promethazine, trimethobenzamide, 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. Table II-11 describes available antipsychotic agents.

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

1. Cardiovascular system. Antimuscarinic effects may produce tachycardia. Alpha₁-adrenergic blockade may cause hypotension, especially orthostatic hypotension. With very large overdoses of some agents, sodium channel blockade can cause widened QRS intervals. Many of these agents can cause QT prolongation.
2. Central nervous system. Centrally mediated sedation and antimuscarinic effects contribute to CNS depression. Alpha₁-adrenergic blockade causes small pupils despite antimuscarinic 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-63).

Extrapyramidal reactions, antimuscarinic side effects, and orthostatic hypotension are often seen with therapeutic doses. Tolerance to the sedating effects of the antipsychotics is well described, and patients on chronic therapy may tolerate much larger doses than do other persons.

1. Typical daily doses are given in Table II-11.
2. The toxic dose after acute ingestion is highly variable and depends on the medication involved.

Major toxicity is manifested in the cardiovascular system and CNS. Also, antimuscarinic intoxication may occur as a result of ingestion of benztropine (Cogentin) or other co-administered drugs.

1. Mild intoxication causes sedation, small pupils, and orthostatic hypotension. Antimuscarinic manifestations include dry mouth, absence of sweating, tachycardia, and urinary retention. Paradoxically, clozapine causes hypersalivation through an unknown mechanism.
2. Severe intoxication may cause coma, seizures, and respiratory arrest. The ECG usually shows QT-interval prolongation and rarely QRS prolongation. Hypothermia or hyperthermia may occur. Clozapine can cause a prolonged state of confusion and rarely cardiac toxicity. Risperidone, aripiprazole, and quetiapine can cause QT-interval prolongation, but delirium is less severe.
3. Extrapyramidal dystonic side effects of therapeutic doses include torticollis, jaw muscle spasm, oculogyric crisis, rigidity, bradykinesia, and pill-rolling tremor. These are more common with the butyrophenones.
4. Patients on chronic antipsychotic medication may develop the neuroleptic malignant syndrome, which is characterized by rigidity, hyperthermia, sweating, lactic acidosis, and rhabdomyolysis.
5. Clozapine use has been associated with agranulocytosis.
6. Promethazine can cause severe tissue damage after perivascular extravasation or unintentional intra-arterial, intraneural, or perineural injection. Avoid IV administration unless the line is freely flowing and the drug is given slowly.

Is based on a history of ingestion and findings of sedation, small pupils, hypotension, and QT-interval prolongation. Dystonias in children should always suggest the possibility of antipsychotic exposure. Phenothiazines are occasionally visible on plain abdominal radiographs.

1. Specific levels. Quantitative blood levels are not routinely available and do not help in diagnosis or treatment. Qualitative screening may easily detect phenothiazines in urine or gastric juice, but butyrophenones such as haloperidol are usually not included in toxicologic screens.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, creatine kinase (CK), arterial blood gases or oximetry, abdominal radiography (to look for radiopaque pills), and chest radiography.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
   2. Treat coma, seizures, hypotension, and hyperthermia if they occur.
   3. Monitor vital signs and ECG for at least 6 hours and admit the patient for at least 24 hours if there are signs of significant intoxication.
2. Specific drugs and antidotes. There is no specific antidote.
   1. Dystonic reactions. Give diphenhydramine, 0.5-1 mg/kg IM or IV, or benztropine.
   2. QRS-interval prolongation. Treat with sodium bicarbonate, 1-2 mEq/kg IV.
   3. Hypotension from these dugs probably involves vasodilation caused by alpha₁ receptor blockade. Treat with IV fluids and, if needed, a vasoconstrictor such as norepinephrine or phenylephrine. Theoretically, drugs with beta₂ agonist activity (eg, epinephrine, isoproterenol) may worsen hypotension.
   4. QT prolongation and torsade may respond to magnesium infusion or overdrive pacing.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary.
4. Enhanced elimination. Owing to extensive tissue distribution, most of these drugs are not effectively removed by dialysis or hemoperfusion. Repeat-dose activated charcoal has not been evaluated.