eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Neuroleptic Agents

Author: Kathryn Ruth Challoner, MD, FACEP, MPH, Associate Professor of Clinical Emergency Medicine, Department of Emergency Medicine, Keck School of Medicine, University of Southern California.
Coauthor(s): Edward J Newton, MD, FACEP, FRCPC, Professor of Clinical Emergency Medicine, Chairman, Department of Emergency Medicine, University of Southern California Keck School of Medicine
Contributor Information and Disclosures

Updated: Feb 29, 2008

Introduction

Background

The term neuroleptic refers to the effects on cognition and behavior of antipsychotic drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses. Also known as major tranquilizers and antipsychotic drugs, neuroleptic agents comprise a group of the following 7 classes of drugs:

• Phenothiazines, further divided into the aliphatics, piperidines, and piperazines
• Thioxanthenes (eg, thiothixene)
• Butyrophenones (eg, haloperidol)
• Dibenzoxazepines (eg, loxapine)
• Dihydroindolone (eg, molindone)
• Diphenylbutylpiperidine (eg, pimozide - used to treat Tourette syndrome)
• Benzisoxazole (eg, risperidone)

The adverse effects of neuroleptics are not confined to psychiatric patients. Neuroleptics also are used as sedatives, for their antiemetic properties, to control hiccups, to treat migraine headaches, as antidotes for drug-induced psychosis, and in conjunction with opioid analgesia. Any of the acute adverse effects of neuroleptics may occur in these settings.

The newer atypical antipsychotic agents include the following:

• Clozapine - High affinity for D4 receptor; use limited by its side effects
• Olanzapine (Zyprexa)  - A thienobenzodiazepine
• Quetiapine (Seroquel)
• Ziprasidone (Geodon)
• Aripiprazole (Abilify) - Partial agonism at the D-2 receptor
• Paliperidone - 9-hydroxyrisperidone
• Melperone - Approved in Europe and currently in clinical trial in the United States

Pathophysiology

The major tranquilizers have complex central nervous system (CNS) actions that are incompletely defined. Their therapeutic action is thought to be primarily owing to antagonism of central dopaminergic (D-2 receptor) neurotransmission, although they also have antagonist effects at muscarinic, serotonergic, alpha1-adrenergic, and H1-histaminergic receptors.

The newer atypical antipsychotics also have D-2 receptor antagonism, and most have 5-HT2 receptor antagonism. Aripiprazole does not have serotonin activity but has some partial dopamine agonism. These drugs have less chance of causing extrapyramidal side effects and a sustained elevated prolactin levels but have further serious metabolic side effects associated with their use.

Although all antipsychotic preparations share some toxic characteristics, the relative intensity of these effects varies greatly, depending on the individual drug. Generally, all neuroleptic medications are capable of causing the following symptoms:

• Hypotension: Phenothiazines are potent alpha-adrenergic blockers that result in significant orthostatic hypotension, even in therapeutic doses for some patients. In overdose, hypotension may be severe.
• Anticholinergic effects: Neuroleptic agent toxicity can result in tachycardia, hyperthermia, urinary retention, ileus, mydriasis, toxic psychosis, dry mucous membranes, and hot, dry flushed skin.
• Extrapyramidal symptoms: Alteration in the normal balance between central acetylcholine and dopamine transmission can produce dystonia, oculogyric crisis, torticollis, acute parkinsonism, akathisia, and other movement disorders. Chronic use of major tranquilizers is associated with buccolingual dysplasia (tardive dyskinesia [TD]), parkinsonism, and akathisia.
• Neuroleptic malignant syndrome: All of the major tranquilizers have been implicated in the development of neuroleptic malignant syndrome (NMS), a life-threatening derangement that affects multiple organ systems and results in significant mortality. Hypothalamic D-2 receptor blockade results in an elevated temperature set point; impairment of heat-dissipating mechanisms; and increased calcium release from the sarcoplasmic reticulum resulting in increased contractility, which results in hyperthermia and muscle rigidity.
• Seizures: Most major tranquilizers lower the seizure threshold and can result in seizures at high doses and in susceptible individuals. With loxapine, seizures may be recurrent.
• Hypothermia: Certain major tranquilizers prevent shivering, limiting the body's ability to generate heat.
• Cardiac effects: Prolongation of the QT interval and QRS can result in arrhythmias.
• Respiratory depression: Hypoxia and aspiration of gastric contents can occur in children and in mixed overdose.
• Sedation

Frequency

United States

Overdose of antipsychotic medication is more common among psychiatric patients than other individuals, although accidental ingestion by children is not uncommon. Antipsychotic medications are occasionally purchased illicitly on the street by drug users, who may then develop adverse effects (eg, dystonia). Increased overdose is now being seen in elderly persons, although some toxicity may be explained by age-related changes in metabolism.

International

Many formulations of major tranquilizers are used in Europe and are not available in the United States. Several of the atypical antipsychotics (ie, sertindole, zotepine, amisulpride, bifeprunox, melperone) are not approved by the FDA for use in the United States.

Mortality/Morbidity

Mortality is relatively rare with overdose of antipsychotic medication. However, if neuroleptic malignant syndrome occurs, the mortality rate ranges from 20-30%.

• It is not uncommon for patients to be taking multiple psychiatric medications (eg, lithium, cyclic or other antidepressants, benzodiazepines), and the combination of these medications in overdose often results in higher mortality rates.
• Although antipsychotic medications may have minimal morbidity and mortality in adults, ingestion of a single dose by a toddler may be lethal.
• Toxicity of antipsychotic medications may be increased by co-ingestion of other agents, particularly drugs with similar metabolic pathways.

Race

No scientific data have noted a difference in outcome of neuroleptic overdose that is attributable to race.

Sex

Certain adverse effects of neuroleptic overdose are most common in males, while others are most common in females. For example, TD is most common in older women, whereas neuroleptic malignant syndrome is most common in males.

Age

Acute dystonic reactions are most common in young people, whereas TD is most common in older people.

Clinical

History

The history is often unreliable or unavailable in intentional overdose. If patients are able to provide a history, they often can identify the type and dose of medication ingested; however, independently verify this information and consider other possible ingestions.

Patients with an acute overdose of major tranquilizers have a broad range of responses, depending on their degree of psychiatric derangement, age, habitual use of medications, and individual susceptibility to specific effects.

• Patients are usually somnolent, sedated, and hypoactive; however, actively psychotic patients may require massive doses of antipsychotics to control behavior without becoming sedated.
• In massive overdose, the patient may be comatose and require intubation and respiratory support.
• Patients ingesting antipsychotic medications, either short-term or long-term, often present to the ED with complaints of involuntary movement disorders.
  • Dystonia, primarily manifesting as involuntary movement of the tongue, face, neck, or mouth
  • Torticollis
  • Oculogyric crisis
  • Opisthotonus
• Neuroleptic malignant syndrome
  • Diffuse muscle rigidity
  • Autonomic instability, including elevated core temperature
  • Base the diagnosis on clinical findings, medications found on the patient or at the home, family interviews, or old medical records. The exact definition depends on the reference cited, although it is essentially cited as core temperature higher than 39°C, lead-pipe rigidity, altered mental status, and autonomic instability in the presence of neuroleptic drug use. Laboratory findings include an elevated creatine kinase (CK) level, leucocytosis, and electrolyte abnormalities.
• Hypotension and dysrhythmias may produce syncope, near syncope, orthostatic dizziness, and generalized weakness.
• Occasionally, patients present with a new onset seizure or are discovered in a postictal state.
• Dysrhythmia
  • Phenothiazines are notorious for causing prolongation of the QT interval on the ECG and are associated with torsade de pointes. Other ECG findings include prolongation of the PR and QRS intervals and blocks.
  • Similar to the anticholinergic effects of these medications, alpha blockade and postural hypotension may result in reflex tachycardia.
• Phenothiazines are associated with priapism caused by alpha blockade.
• Phenothiazines may cause photosensitivity, resulting in a blotchy red or purple discoloration of skin when it is exposed to sunlight.

Physical

Numerous physical findings are potentially associated with overdose of major tranquilizers, although some patients may remain relatively asymptomatic.

• Anticholinergic syndrome: Toxic psychosis, agitation, confusion, mydriasis, urinary retention, ileus, hot flushed dry skin, and tachycardia may occur.
• Movement disorders
  • Increased muscle tone, extrapyramidal symptoms, akathisia, restless legs, parkinsonism, or dystonia may occur.
  • After chronic use of these medications (>24 mo), certain patients develop irreversible TD that consists of characteristic involuntary movements of the face, lips, and tongue.
  • A disorder associated with intravenous use of prochlorperazine (Compazine) has been noted. Patients with this disorder become intensely anxious and restless and occasionally elope from the ED. These patients describe this acute dysphoric reaction as being very uncomfortable and creating the urge to crawl out of their skin. Whether this is an intense form of akathisia or a new movement disorder is unclear.
• Neuroleptic malignant syndrome
  • Patients with NMS have impressive physical findings that may evolve over several days.
  • Initial findings usually involve increased muscle tone, worsening extrapyramidal symptoms, and altered mental status.
  • Diffuse lead-pipe muscle rigidity is invariably present at some point during the condition. Chronic muscle contraction leads to rhabdomyolysis and, consequently, myoglobinuric renal failure. CK levels often are dramatically elevated (50-100% of cases). Muscle rigidity may be observed without NMS.
  • Hyperthermia manifesting as core temperature elevation from 101-108°F or higher is common. At the high range of temperature, acidosis results and essential enzymatic functions cease, resulting in multiple organ failure and possibly death. Hyperthermia may be observed in many patients who take neuroleptic medications without full-blown NMS.
  • Patients with NMS are generally confused and disoriented and may become catatonic or comatose.
• Miscellaneous abnormalities include metabolic acidosis, pulmonary edema, acute respiratory distress syndrome (ARDS), renal failure, rhabdomyolysis, and disseminated intravascular coagulation (DIC).
• Virtually all neuroleptics produce some degree of extrapyramidal (EP) dysfunction because of inhibition of dopaminergic transmission in the basal ganglia. Several forms of extrapyramidal symptoms (EPS) are associated with neuroleptic toxicity.
  • Acute dystonia
    • Ingestion of a single therapeutic dose of a neuroleptic can result in involuntary muscle contraction of the face, neck, tongue, extraocular muscles, and, less commonly, of the limbs, larynx, or pharynx. The onset of symptoms is usually delayed several hours.
    • Certain neuroleptics (eg, haloperidol, fluphenazine) are more potent inhibitors of dopamine in the basal ganglia and, consequently, cause more prominent EP symptoms.
    • Patients present with torticollis, tongue protrusion or deviation, oculogyric crisis, opisthotonus, trismus, and gait disorders. The condition is more common in children (often after administration of neuroleptic antiemetics) and is self-limited. Response to anticholinergic medications is usually dramatic, although the condition may recur over the next several days.
  • Parkinsonism
    • Resulting from prolonged inhibition of basal ganglia D-2 transmission, certain patients who take neuroleptics develop typical features of parkinsonism, including tremor, shuffling gait, and muscle rigidity.
    • The condition is more common in elderly patients, in those with preexisting parkinsonism, and in females. It responds to anticholinergic medication.
  • Akathisia: Motor restlessness and the urge to move are dose-related and occur in up to 20% of cases.
  • Tardive dyskinesia
    • TD is a manifestation of chronic neuroleptic toxicity that is often permanent. It is characterized by involuntary repetitive movement of the lips and tongue (buccolingual dysplasia), limbs (choreoathetosis), and eyes (rapid blinking movements).
    • Older women are most susceptible to TD; however, it may occur at any age after 24 months of therapy.
• All neuroleptics lower the seizure threshold to some degree, although certain ones (eg, chlorpromazine, clozapine, loxapine) have greater convulsant effects than others (eg, haloperidol, fluphenazine). The epileptogenic effect is dose-dependent, and the most common type of convulsion observed is a generalized tonic-clonic seizure.
• Adverse effects associated with long-term neuroleptic use include galactorrhea (hyperprolactinemia), priapism, elevated liver function test results and cholestatic jaundice, skin photosensitivity, and agranulocytosis (associated with use of clozapine). Use of the atypical antipsychotics is associated with a metabolic syndrome characterized by type 2 diabetes (increased insulin resistance), dyslipidemia, and hypertension with associated obesity.

Causes

Administration of neuroleptic medications can result in any of the consequences listed above; however, certain combinations of medications (eg, lithium + haloperidol, anticholinergics + haloperidol), depot preparations (eg, fluphenazine), and stronger neuroleptics (eg, haloperidol) are more likely to produce adverse effects, including NMS.

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