DESCRIPTION

Phenothiazines are neuroleptic medications used to treat a wide range of disorders; thioridazine (Mellaril) is covered in a separate chapter.

FORMS AND USES

• Substances include chlorpromazine (Thorazine), fluphenazine (Prolixin), mesoridazine (Serentil), perphenazine (Trilafon), prochlorperazine (Compazine), promethazine (Phenergan), and trifluoperazine (Stelazine).
• Phenothiazines are used as antiemetic agents, pain medications, antipsychotic agents, and anxiolytic agents; they are also used in the treatment of allergic reactions and hiccups.

TOXIC DOSE

Toxicity varies widely by agent, but ingestion of several grams has been associated with death.

PATHOPHYSIOLOGY

• Phenothiazines competitively inhibit several types of receptors, including alpha-₁- and alpha-₂-adrenergic, cholinergic, dopaminergic, histaminic and serotonergic receptors.
• In overdose, the primary effects involve CNS dysfunction and cardiac conduction abnormalities combined with anticholinergic effects and peripheral alpha-adrenoceptor blockade.

EPIDEMIOLOGY

• Poisoning is common.
• Toxic effects following exposure are typically mild to moderate.
• Death is rare, occurring in patients with delayed treatment or coingestion.

CAUSES

• Poisoning is usually attributable to a suicidal ingestion.
• Child abuse or neglect should be considered if the patient is less than 1 year of age; suicide attempt in patients over 6 years of age.

RISK FACTORS

• Children are more susceptible to the extrapyramidal side effects of prochlorperazine.
• In geriatric patients liver disease may result in drug accumulation from therapeutic doses.

PREGNANCY AND LACTATION

For all phenothiazines available in the United States: US FDA Pregnancy Category C. Studies show animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• RISK FACTORS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Toxic agents that produce CNS depression, especially those that also impair cardiac conduction, include type Ia antidysrhythmics, tricyclic antidepressant agents, chloroquine, antihistamines, and other agents.
• Other causes include primary CNS event (e.g., bleed, ischemia) or severe electrolyte abnormality (e.g., hypocalcemia).

SIGNS AND SYMPTOMS

• CNS depression is common.
• Seizures and cardiac dysrhythmias may develop in large overdose.

Vital Signs

• Tachycardia is common.
• In serious cases, hypertension may occur early, followed by hypotension.

HEENT

Mydriasis is common, but may be absent.

Cardiovascular

• Tachycardia, prolonged QTc, widened QRS, atrioventricular block, torsade de pointes, ventricular tachycardia or fibrillation, and sudden death may occur.
• Mesoridazine is more likely to produce cardiac effects.

Gastrointestinal

Constipation and ileus are common.

Hepatic

Cholestatic jaundice or mixed cholestatic and hepatocellular jaundice may occur after overdose or with therapeutic use.

Renal

• Urinary retention may occur.
• Priapism may occur rarely.

Hematologic

Agranulocytosis and anemia may occur with therapeutic use or after overdose.

Musculoskeletal

Rhabdomyolysis may occur in severe poisoning.

Neurologic

Agitation, CNS depression, coma, seizures, extrapyramidal symptoms, tardive dyskinesia (from acute overdose or chronic use), or neuroleptic malignant syndrome (NMS) may occur.

PROCEDURES AND LABORATORY TESTS

Essential Tests

ECG and cardiac monitoring:

• ECG effects are similar to type 1a antidysrhythmics such as quinidine (QRS or QT prolongation, ventricular dysrhythmia).
• Sinus tachycardia is common and indicates sufficient drug absorption to produce anticholinergic effects.

Recommended Tests

• Arterial blood gases should be ordered in patients with QRS widening, dysrhythmia, seizures, or mental status depression and those receiving bicarbonate therapy (pH should not exceed 7.55).
• Serum aspartate aminotransferase, alanine aminotransferase, and bilirubin are used to assess development of hepatitis or cholestatic jaundice.
• Serum creatine kinase is measured in patients with seizures or coma to assess rhabdomyolysis.
• Urinalysis may reveal pink, red, purple, orange, or rust-colored urine following overdose.
• Serum acetaminophen and aspirin levels are used in an overdose setting to detect occult overdose.
• Head CT, lumbar puncture, and bacterial cultures are ordered as needed to evaluate other causes of coma or seizures.
• Phenothiazine tablets may be radiopaque on abdominal radiography; however, the absence of visible pills does not rule out ingestion.

Not Recommended Tests

• Quantitative serum levels are not generally available or helpful.
• Phenothiazines may cross-react with tricyclic antidepressants in EMIT assay.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Cardiovascular
  • Gastrointestinal
  • Hepatic
  • Renal
  • Hematologic
  • Musculoskeletal
  • Neurologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Treatment should focus on appropriate airway management and treatment of seizure, hypotension, and cardiac dysrhythmia.
• The dose and time of exposure must be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Coma, cardiovascular toxicity, or other severe effects are present.
• Toxic effects are not consistent with phenothiazine toxicity.
• Coingestant, drug interaction, or underlying disease presents an unusual challenge.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Toxic effects are apparent.
• Coingestant, drug interaction, or underlying disease presents an unusual challenge.

Admission Considerations

• Inpatient management in an intensive care setting is warranted for patients who develop seizure, CNS depression, or cardiac effects.
• Observation for 24 hours is probably warranted for patients who have ingested extended-release products.

DECONTAMINATION

Out of Hospital

Emesis should not be induced; coma or seizures may develop abruptly.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients presenting within 1 hour of a large ingestion or if serious effects are present.
• Lavage may be reasonable even though it is performed 4 to 6 hours after ingestion, due to the medication-induced slowing of the gastrointestinal tract.
• One dose of activated charcoal (1-2 g/kg) is administered without a cathartic if a substantial ingestion has occurred within the previous few hours.

ADJUNCTIVE TREATMENT

Seizure

A benzodiazepine is administered for initial control.

• Diazepam. Adult dose is 5 to 10 mg initially, repeated every 10 minutes or longer if needed; pediatric dose is 0.2 to 0.5 mg/kg, repeated every 10 minutes or longer if needed; the airway should be monitored closely.
• Lorazepam. Adult dosage is 2 to 4 mg intravenous push over 2 to 5 minutes, repeated every 10 minutes or longer if needed. Pediatric dosage is 0.1 mg/kg intravenous push over 2 to 5 minutes, not to exceed 4 mg/dose and repeated every 10 minutes or longer if needed; the airway should be monitored closely.
• If seizures persist or recur, another anticonvulsant such as phenobarbital or phenytoin is added.

Hypotension

• The patient should receive 10 to 20 ml/kg 0.9% saline intravenously and be placed in the Trendelenburg position.
• Further fluid therapy should be guided by central pressure monitoring to avoid volume overload.
• If the hypotension is unresponsive, a vasopressor is administered.
  • The dose of dopamine is 2 to 5 µg/kg/min intravenously, titrated to desired effect; rates above 20 µg/kg/min are unlikely to provide further benefit.
  • If hypotension is unresponsive, norepinephrine is added, 0.1 to 0.2 µg/kg/min, and titrated to desired effect.
  • A high rate of infusion may cause tissue ischemia.

Dysrhythmia or Conduction Abnormality

• Seizures must be controlled and acidemia corrected.
• If QRS widening is present, sodium bicarbonate (1-2 mEq/kg) is administered as an intravenous bolus and repeated as needed to narrow the QRS interval; arterial pH should not exceed 7.55.
• Lidocaine is used for ventricular tachycardia or multifocal premature ventricular complexes.
  • Adult dosage is 50 to 100 mg as an intravenous bolus, followed by an infusion of 2 to 4 mg/min, titrated to desired effect.
  • Pediatric dosage is 1 mg/kg bolus, followed by an infusion of 20 to 50 µg/kg/min, titrated to effect.
  • The bolus dose may be repeated in 10 to 15 minutes.
• Cardiac pacing may be required for atrioventricular block.
• Overdrive pacing may be required for torsade de pointes.

Dystonic Reaction

• Diphenhydramine is administered, 1 mg/kg/dose intravenously over 1 to 2 minutes.
• Maintenance for 1 to 2 days of diphenhydramine or benztropine for continuing symptoms is suggested.

Not Recommended Therapies

Forced diuresis, hemodialysis, and hemoperfusion are not recommended.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ADJUNCTIVE TREATMENT
  • Seizure
  • Hypotension
  • Dysrhythmia or Conduction Abnormality
  • Dystonic Reaction
  • Not Recommended Therapies

PATIENT MONITORING

• Continuous respiratory and cardiac monitoring and serial ECGs should be performed.
• Fluid and electrolytes, liver and renal function, and clinical indicators of toxicity should be followed.

EXPECTED COURSE AND PROGNOSIS

• Most patients who overdose on phenothiazines recover within 24 to 48 hours.
• Death may result in severe cases involving dysrhythmia, seizures, hypotension, or hyperthermia.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Patients may be discharged if they did not develop seizure or QRS widening, hypotension, or dysrhythmia (other than mild transient sinus tachycardia) during 6 hours of observation, and after they have received gastrointestinal decontamination and, if appropriate, a psychiatric evaluation.
• From the hospital. Patients may be discharged from the hospital after all clinical effects have resolved (hypotension, QRS widening, CNS depression, dysrhythmia) and after the ECG has been normal for 24 hours.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

DIAGNOSIS

Extended-release products may require admission and extended observation.

TREATMENT

Incomplete decontamination may result in prolonged symptoms or delayed deterioration.

FOLLOW-UP

Inadequate observation time may result in missing late complications of extrapyramidal symptoms or NMS.

Section Outline:

• DIAGNOSIS
• TREATMENT
• FOLLOW-UP

Poisoning by psychotropic agents: phenothiazine-based tranquilizers.

See Also: SECTION II, Hypotension, Seizures, Neuroleptic Malignant Syndrome and Serotonin Syndrome, and Ventricular Dysrhythmia chapters.

RECOMMENDED READING

Ellenhorn MJ. Neuroleptic drugs. In: Medical toxicology: diagnosis and treatment of human poisoning. Baltimore: Williams & Wilkins, 1997:662-669.

Malhotra AK, Litman RE, Pickar D. Adverse effects of antipsychotic drugs. Drug Safety 1993;9:429-436.

Author: Steven A. Seifert

Reviewer: Richard C. Dart