eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Neuroleptic Agents

Kathryn Ruth Challoner, MD, FACEP, MPH, Associate Professor of Clinical Emergency Medicine, Department of Emergency Medicine, Keck School of Medicine, University of Southern California.
Edward J Newton, MD, FACEP, FRCPC, Professor of Clinical Emergency Medicine, Chairman, Department of Emergency Medicine, University of Southern California Keck School of Medicine

Updated: Sep 15, 2009

Introduction

Background

The neuroleptic agents are antipsychotic drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses. The first-generation 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)

Neuroleptics also are used as sedatives and tranquilizers, for their antiemetic properties, to control hiccups, and in the treatment of drug-induced psychosis. Any of the acute adverse effects of neuroleptics may occur in these settings.

Because of side effects, the newer (second-generation) antipsychotic agents were introduced beginning in the 1970s. 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 - A butyrophenone in clinical trial in the United States
• Zotepine¹

The toxicity of other neuroleptic agents are discussed in other eMedicine articles (see Toxicity, Selective Serotonin Reuptake Inhibitor and Toxicity, Lithium).

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 symptoms² : 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 syndrome² : 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, amisulpride, bifeprunox) 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 5-12%.

• 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

An increased incidence of toxicity is seen in elderly persons. This may be related to changes in metabolism or interaction with the use of multiple other drugs.

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. This is associated with an increased risk for cardiovascular disease.^3,4

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.

Differential Diagnoses

Other Problems to Be Considered

Malignant hyperthermia
Malignant catatonia
Serotonin syndrome
Thyrotoxicosis
Ecstasy toxicity

Workup

Laboratory Studies

• Perform laboratory tests depending on the nature of the presentation; patients with simple dystonia may require no tests, and patients with neuroleptic malignant syndrome may require multiple tests.
• Qualitative assays are available in most hospitals and are useful in identifying unknown ingestions. However, serum drug levels for major tranquilizers do not correlate well with the clinical severity of the overdose and are not useful.
• Because patients with major tranquilizer ingestion are often prescribed other medications, such as tricyclic antidepressants, benzodiazepines, or lithium, appropriate toxicology screening for these substances and for drugs of abuse is indicated. Serum toxicologic panels must always include a serum acetaminophen level.
• Routine electrolytes, blood urea nitrogen, creatinine, glucose, and bicarbonate are useful in determining hydration status, renal function, acid base status, and in excluding hypoglycemia as the cause for the alteration in sensorium.
• Pulse oximetry or arterial blood gas (ABG) sampling is indicated for patients in coma or with depressed gag reflex and diminished respiratory drive.
• Patients with neuroleptic malignant syndrome are critically ill and frequently sustain end-organ damage to the brain, liver, heart, lungs, and kidneys. Consequently, appropriate laboratory tests to monitor such damage are indicated.
• Creatinine kinase level
  • Continuous muscle contraction often produces muscle breakdown that is reflected by an increase in potassium, uric acid, and creatine kinase-MM.
  • Massive elevation of CK levels into the 100,000 range may occur and portends a significant risk of renal injury. Elevation of total CK higher than 3 times normal levels occurs in 50-100% of cases.
• Urinalysis
  • Muscle breakdown products (eg, myoglobin) precipitate in the kidney, and tubular dysfunction may occur. Dehydration promotes this precipitation.
  • The urinalysis may reveal a moderate-to-strong reaction on the dipstick for occult blood. Microscopic analysis typically reveals very few RBCs, which is indirect evidence for the presence of myoglobinuria. In advanced myoglobinuria, the urine is dark brown.
  • Urine specific gravity and hourly output can guide rehydration efforts. Myoglobin assays can be performed to confirm the diagnosis but are usually not required.
• Liver function tests: Severe sustained hyperthermia can result in hepatic necrosis, which is reflected in significant elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and glutamic-pyruvic transaminase (GPT) liver enzymes.
• Coagulation profile
  • Patients with NMS are prone to develop a coagulopathy or disseminated intravascular coagulation (DIC).
  • Establish baseline levels of prothrombin time (PT), activated partial thromboplastin time (aPTT), platelets, and fibrinogen.
• Various infections and septic shock may resemble NMS. Obtain a lactate level and blood, urine, and sputum cultures and perform a lumbar puncture to obtain cerebrospinal fluid (CSF) after a head CT for examination and culture.
• Consider thyroid function tests (TFTs) because thyrotoxicosis can present with many features similar to NMS.

Imaging Studies

• No specific radiographs are routinely required; however, if appropriate, the patient's individual condition may require the following radiographs:
  • Chest x-rays are important in patients requiring intubation and in those with any respiratory distress. Comatose patients are at risk for aspiration and chest x-rays are routinely obtained for this reason.
  • Kidney-ureter-bladder (KUB) x-rays may be helpful because phenothiazines are radio-opaque and are often observed on a plain film of the abdomen. This may be of some use if the ingestion is unknown and may help quantify the number of pills taken if the study is performed soon after ingestion. If obtained, KUB x-rays should be performed before administration of activated charcoal because it may hinder radiographic visualization.
  • CT scans of the head without contrast are indicated in some cases. Although not all patients with major tranquilizer ingestion require a CT scan of the head, it may be useful in comatose patients, those with seizures or status epilepticus, and in patients with focal neurologic deficits.

Other Tests

• A 12-lead electrocardiogram (ECG) and cardiac monitoring are indicated to look for potentially serious lengthening of the QT interval, AV block, or dysrhythmias. Symptoms generally present within 6 hours of ingestion; thus, monitoring patients for at least 6 hours is wise.
• Ferric chloride or Phenistix tests may be indicated as a qualitative screening tool to detect the presence of phenothiazines in either the serum or urine. Given the ready availability and reliability of qualitative colorimetric tests, bedside tests of limited accuracy are rarely indicated.

Procedures

• A lumbar puncture (LP) is indicated, usually following CT scan of the brain, because meningitis may present in a manner similar to NMS (high fever, altered mental status).

Treatment

Prehospital Care

Be aware that patients with major tranquilizer overdose are at risk of rapid deterioration with coma, seizures, hypotension, or dysrhythmias. They all require transport to a hospital facility because the severity of overdose cannot be ascertained immediately after ingestion.

• Prehospital treatment with activated charcoal, 1 g/kg, is indicated as soon as possible. This can be administered in the field if permitted by local protocol.
• Establish a large-bore IV line of isotonic sodium chloride solution in anticipation of possible hypotension or the need to administer medications.
• Seizure activity usually responds to diazepam in the usual anticonvulsant doses.
• Treat ventricular dysrhythmias with standard advanced cardiac life support (ACLS) pharmaceutical agents.

Emergency Department Care

ED care varies, depending on the patient's condition and on the care already provided in the field.

• No specific antidote for any of the major tranquilizers exists.
• The standard approach to resuscitation (airway, breathing, circulation, drugs, and environment [ABCDE]) is employed as indicated by the patient's condition. Active airway management is indicated for patients who are in shock, status epilepticus, coma, or cardiac arrest.
• Placement of a Foley catheter may be necessary in comatose patients or those with shock or severe dehydration to monitor urine output and to obtain urine specimens in patients who may have urinary retention from the anticholinergic effects of the overdose.
• Activated charcoal
  • If used within 2 hours of ingestion, gastric lavage may be useful in decreasing the absorption of major tranquilizers. Protect the patient's airway before lavage if an altered level of consciousness is present. Many toxicologists now advise against lavage and recommend administering activated charcoal orally or by nasogastric tube.
  • Activated charcoal with a saline cathartic remains the GI decontamination method of choice. Major tranquilizers are generally well bound by activated charcoal and should be administered in standard doses as soon as possible postingestion.
  • Multiple dose activated charcoal is of limited benefit and cannot be used if an ileus is present.
• Ipecac syrup is never recommended.
• Hemoperfusion, hemodialysis, and forced diuresis are not effective.
• Seizures are treated in a step-wise fashion, beginning with benzodiazepines (eg, diazepam, lorazepam) and followed by barbiturates (eg, phenobarbital, pentobarbital).
• The combination of peripheral alpha-blockade and dehydration may result in severe hypotension during major tranquilizer overdose. Initial treatment involves administration of a volume challenge with isotonic sodium chloride solution. If the patient remains hypotensive after fluid challenge or manifests signs of cardiogenic shock, pressor agents may be required.
  • Norepinephrine is the preferred pressor agent in this circumstance because it has pure alpha-agonist effects.
  • Paradoxically, epinephrine or dopamine may lower the blood pressure because alpha-blockade from major tranquilizer causes unopposed beta-agonist peripheral vasodilation.
• For patients manifesting NMS with worsening hyperthermia, immediate cooling measures, such as fans, wet cloths, ice packs in groin and axilla, and rectal acetaminophen, are indicated.
• Dantrolene sodium (1-10 mg/kg) is recommended as adjunctive therapy for patients manifesting severe hyperthermia (rectal temperatures >105°F) and muscle rigidity.
  • Dantrolene is incompatible with acidic solutions and is mixed with sterile water for injection. It must be given directly by slow IV push or by intravenous piggyback into a large-bore IV near the needle with the IV fluid shut off. Great care must be taken to avoid extravasation into the tissues.
  • Dantrolene is given by 1-2 mg/kg doses until a maximum dose of 10 mg/kg or until the rectal temperature breaks.
  • Dantrolene may be effective in malignant hyperthermia by acting in dissociating the excitation-contraction coupling of skeletal muscles. While the precise mechanism of action and molecular targets are still incompletely known, dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. In the April 2004 issue of Anesthesia, Krause et al stated that recent studies have identified the ryanodine receptor (the major calcium release channel of the skeletal muscle sarcoplasmic reticulum) as a dantrolene-binding site.⁵ A direct or indirect inhibition of the ryanodine receptor is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene acts primarily peripherally and has no effect on the cardiovascular or respiratory systems in this acute setting.
  • Recent studies have questioned the efficacy of dantrolene⁶ , but anecdotal reports still advocate for its use. Dantrolene should not be used as monotherapy.
• Bromocriptine and amantadine are central dopaminergic agonists that may be effective in reversing the dopaminergic blockade caused by the neuroleptics. They have been reported as effective in treating NMS but work slowly (eg, over several days). They are given orally or by nasogastric tube.
• Oral levodopa, with or without carbidopa, and intravenous levodopa are therapies used more commonly in patients with Parkinson disease who develop NMS on sudden withdrawal of their dopaminergic therapy. Steroid pulse therapy is also useful in NMS for reducing the illness duration and improving symptoms in patients with Parkinson disease.

Consultations

• Notification of the regional poison control center is indicated.
• In complex or severe cases, consult with the regional poison control center or a medical toxicologist (certified through the American Board of Medical Toxicology or the American Board of Emergency Medicine) for additional information and patient care recommendations.
• A psychiatric assessment is indicated once the patient's medical condition has stabilized to determine any suicidal intent.

Medication

No specific antidotes exist for the adverse effects of neuroleptic medications. Because these effects are so diverse and do not occur in most cases, prophylactic treatment for seizures, dystonia, dysrhythmias, or NMS is not indicated.

GI decontaminants

Empirically used to minimize systemic absorption of the toxin. May only be of benefit if administered within 1-2 h of ingestion.

Activated charcoal (Liqui-Char)

Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.
For maximum effect, administer within 30 min of ingesting poison.
Generally mixed and administered with a saline cathartic (do not use sorbitol).

Dosing

Adult

1 g/kg (50-100 g) PO

Pediatric

1-2 g/kg (15-30 g) PO

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix with sherbet, milk, or ice cream (decreases adsorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdose of mineral acids and alkalies; unprotected airway with absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor for presence of bowel sounds to minimize risk of charcoal ileus; not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before giving activated charcoal; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black

Anticonvulsants

Indicated for seizures and status epilepticus associated with major tranquilizer overdose. Compared to lorazepam, advantages of diazepam are more rapid onset of action and decreased cost. The disadvantage is that diazepam has a brief duration of anticonvulsant activity (20 min) compared to lorazepam (several hours). Both drugs can aggravate hypotension, which may limit their usefulness in this setting.

Barbiturates are usually not necessary in neuroleptic overdose because most patients respond to benzodiazepines. Phenobarbital is the most commonly used anticonvulsant, but shorter-acting barbiturates are also effective.

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.
Seizures are relatively common in association with major tranquilizer overdose because most neuroleptics lower seizure threshold. In the ED, standard protocol is used for terminating seizures.

Dosing

Adult

5-10 mg IV

Pediatric

30 days to 5 years: 0.2-0.3 mg IV slowly; may repeat q5min X 2

Interactions

Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity); monitor for respiratory depression and hypotension with high or repeated doses

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life.
By increasing the action of GABA, a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Monitoring blood pressure after administering dose is important. Adjust prn.

Dosing

Adult

0.5-2 mg IV slowly; titrate to effect

Pediatric

Infants and children: 0.1 mg/kg IV slowly; may repeat q5min X 2

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

Documented hypersensitivity; preexisting CNS depression, hypotension, and narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease; monitor for respiratory depression with high or repeated doses; contains benzyl alcohol, which may be toxic to infants in high doses

Phenobarbital (Barbita, Luminal)

Interferes with transmission of impulses from thalamus to cortex of brain. Effective in terminating convulsions, but use is often limited by hypotension associated with neuroleptic overdose.

Dosing

Adult

15-20 mg/kg IV slowly; not to exceed 1 g

Pediatric

15-20 mg/kg IV slowly

Interactions

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and fatality; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy); menstrual irregularities also may occur

Contraindications

Documented hypersensitivity; severe respiratory disease, marked impairment of liver function, and nephritic patients

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema

Midazolam (Versed)

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access

Dosing

Adult

0.01-0.05 mg/kg IV (usually 0.5-4 mg)

Pediatric

<32 weeks: 0.5 mcg/kg/min IV infusion
>32 weeks: 1 mcg/kg/min IV infusion
Children: 0.05-0.2 mg/kg IV over 2-3 min, followed by 1-2 mcg/kg/min continuous infusion
Status epilepticus (refractory to standard therapy), >2 months and children: 0.15 mg/kg followed by continuous infusion of 1 mcg/kg/min, titrating dose upward q5min until seizures controlled

Interactions

Sedative effects may be antagonized by theophyllines; narcotics, cimetidine, ethanol, and erythromycin may accentuate sedative effects because of decreased clearance; reduce dose of thiopental by 15% when using together

Contraindications

Documented hypersensitivity; preexisting hypotension, narrow-angle glaucoma, and sensitivity to propylene glycol (diluent)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, pulmonary disease, renal impairment, hepatic failure, neuromuscular disease, hypotension, and patients >60 y; monitor for respiratory depression with high or repeated doses; consider lower dosages in organic brain syndrome and patients who may have inhibition of benzodiazepine metabolism and clearance (eg, using nicotine, taking cimetidine)

Cardiovascular agents

Use of direct-acting alpha-agonists is preferred when hypotension persists after adequate volume challenge with isotonic sodium chloride solution IV. Pressors with actions at beta- and alpha-receptors (eg, dopamine, epinephrine) may exert only a beta (vasodilatory) effect in the face of neuroleptic-induced alpha blockade; consequently, a paradoxical drop in blood pressure may occur if the pressors are used.

Dysrhythmias are relatively common in neuroleptic overdose. Prolongation of the QT interval may result in torsade de pointes. The quinidinelike effect on the slope of phase 0 of the ECG may result in widening of the QRS. Magnesium may be an effective treatment.

Norepinephrine (Levophed)

Stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases.

Dosing

Adult

0.5-1.0 mcg/min (usually 2-12 mcg/min) IV; titrate to effect

Pediatric

0.1 mcg/kg/min IV; carefully titrate to effect

Interactions

Atropine enhances the pressor response by blocking the reflex bradycardia caused by norepinephrine

Contraindications

Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and area of infarct extended

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Correct blood-volume depletion, if possible, before giving norepinephrine therapy; extravasation may cause severe tissue necrosis and, thus, should be administered into a large vein; caution in occlusive vascular disease; monitor for cardiac ischemia and dysrhythmias

Magnesium sulfate

Currently DOC for treatment of torsade de pointes and may be an effective antiarrhythmic for ventricular and supraventricular tachycardia.

Dosing

Adult

Step 1: 2 g IV bolus over 3-5 min
Step 2: Repeat 2 g IV bolus if partial response in 15 min but monitor for hypotension
Step 3: Pacing or isoproterenol if torsade de pointes continue

Pediatric

0.2-0.4 mEq/kg (25-50 mg/kg) IV slowly

Interactions

Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade observed with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants, betamethasone, and cardiotoxicity of ritodrine

Contraindications

Documented hypersensitivity; heart block, Addison disease, myocardial damage, hypermagnesemia, renal failure, or severe hepatitis

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

May alter cardiac conduction leading to heart block in digitalized patients; monitor respiratory rate, deep tendon reflex, and renal function when electrolyte is administered parenterally; caution when administering because may produce significant hypertension or asystole; in overdose, calcium gluconate (10-20 mL IV of 10% solution) can be administered as antidote for clinically significant hypermagnesemia

Skeletal Muscle Relaxant

Dantrolene is currently recommended as treatment for hyperthermia associated with neuroleptic malignant syndrome. Acts to restore calcium entry into muscle sarcoplasmic reticulum, causing muscle relaxation and decreasing heat production from muscle.

Dantrolene (Dantrium)

Stimulates muscle relaxation by modulating skeletal muscle contractions at site beyond myoneural junction and acting directly on muscle itself. Doses may be repeated, not to exceed 10 mg/kg.

Dosing

Adult

1 mg/kg through large-bore IV carefully with IV fluids shut off; avoid extravasation; see dosing and technique above

Pediatric

Administer as in adults

Interactions

Toxicity may increase with the coadministration of clofibrate and warfarin; coadministration with estrogen may increase hepatotoxicity in women >35 y; concurrent use with verapamil can lead to hyperkalemia and myocardial depression

Contraindications

Documented hypersensitivity; active hepatic disease (hepatitis, cirrhosis)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause hepatotoxicity (use only for recommended indications); caution in impaired pulmonary function and severe cardiac insufficiency; may cause photosensitivity with exposure to sunlight

Antihistamines

Agents with anticholinergic properties are effective in terminating acute dystonias associated with neuroleptic use.

Diphenhydramine (Benadryl)

Anticholinergic medications help restore balance between dopaminergic and cholinergic neurotransmission. Dopaminergic transmission is decreased by neuroleptic drugs.

Dosing

Adult

1 mg/kg IV; up to 50 mg

Pediatric

Administer as in adults

Interactions

Potentiates effect of CNS depressants; because of alcohol content, do not give syrup dosage form to patients taking medications that can cause disulfiramlike reactions

Contraindications

Documented hypersensitivity; MAOIs; hyperthermia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, and urinary tract obstruction

Dopamine agonist

Can reverse the dopamine blockade caused by neuroleptics and has been reported to be useful in reversing NMS symptoms.

Bromocriptine (Parlodel)

Semisynthetic ergot alkaloid derivative. Strong D2-receptor agonist, partial D1-receptor agonist. Stimulates dopamine receptors in corpus striatum.
Approximately 28% absorbed from the GI tract and metabolized in the liver. Approximate elimination half-life is 50 h with 85% excreted in feces and 3-6% eliminated in urine.

Dosing

Adult

2.5-5 mg PO or NG tube bid

Pediatric

Not established

Interactions

Toxicity may increase with ergot alkaloids and isometheptene; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease bromocriptine effects

Contraindications

Documented hypersensitivity; ischemic heart disease, peripheral vascular disorders

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic disease; suppresses lactation and should not be given to breastfeeding women

Amantadine (Symmetrel)

Inhibits N-methyl-D-aspartic acid (NMDA) receptor-mediated stimulation of acetylcholine release in rat striatum. May enhance dopamine release, inhibit dopamine reuptake, stimulate postsynaptic dopamine receptors, or enhance dopamine receptor sensitivity.

Dosing

Adult

100 mg PO or NG tube bid

Pediatric

Not established

Interactions

Drugs with anticholinergic or CNS stimulant activity increase amantadine toxicity; the concurrent administration of hydrochlorothiazide plus triamterene with amantadine may increase plasma concentrations of amantadine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in liver disease, uncontrolled psychosis, eczematoid dermatitis, seizures, and in those receiving CNS stimulant drugs; reduce dose in renal disease when treating Parkinson disease; do not discontinue this medication abruptly

Follow-up

Further Inpatient Care

• Patients who develop signs of potentially serious toxicity require admission.
• Patients who remain asymptomatic after a period of observation (6 h recommended) can be discharged home or given psychiatric evaluation.
• Potentially serious signs of toxicity include persistent hypotension, dysrhythmias or abnormal ECG, seizures, or movement disorders that fail to respond to anticholinergic treatment.
• Patients with dysrhythmias, status epilepticus, coma, or those who require pressor agents to maintain blood pressure should be treated in an ICU setting.
• Repeated doses of activated charcoal every 6 hours without cathartics may increase clearance of some neuroleptics that undergo enterohepatic circulation. There must be no ileus of the gut for this method of enhanced elimination. Perform standard measures for treating comatose patients (eg, eye care, position changes).
• Once the patient is stable and awake, psychiatric evaluation can take place before discharge from hospital.

Further Outpatient Care

• Follow-up with a psychiatrist is recommended for patients with intentional overdose and for those who require medication changes because of adverse effects from neuroleptics.

Inpatient & Outpatient Medications

• Most patients with neuroleptic overdose recover without sequelae and do not require ongoing medical treatment.
  • Patients who have developed NMS pose a difficult problem if they require ongoing antipsychotic  medication monitoring and adjustment.
  • Neuroleptics have been successfully reintroduced following episodes of NMS, but this must be done carefully and under the supervision of a psychiatrist.
  • Alternative medications with a lower potency that are less likely to produce NMS may be used.

Transfer

• Patients with an acute overdose of neuroleptic medication can be transferred if they are stable for a period of 6 hours. Transferring a patient before 6 hours of observation is imprudent because risk of developing seizures, hypotension, and dysrhythmias is present.
• Patients with NMS are critically ill and generally are not candidates for transfer, unless the initial treating facility is unable to provide adequate medical care. Once the patient appears to be improving and is clinically stable with decreasing CK levels and normal mentation, transfer may be undertaken safely.

Complications

• The vast majority of patients with acute neuroleptic overdose recover completely. However, prolonged periods of hypoxia, hyperthermia, status epilepticus, or hypotension may result in permanent neurologic or cardiac disability.
• TD is the most frequently noted permanent disability related to prolonged use of neuroleptics.

Prognosis

• The outcome from an acute overdose of neuroleptic medication is usually favorable.
• Permanent deficits occur in very few cases.
• Poor outcomes are most often associated with small children, patients who develop NMS, and those who sustain dysrhythmias or prolonged hypotension.
• TD is usually permanent.
• Parkinsonism, akathisia, and dystonias remit on discontinuation of the drug.

Patient Education

• In cases of accidental toddler ingestions, educate parents on how to childproof their homes from a toxicologic perspective.
• For excellent patient education resources, visit eMedicine's Drug Overdose Center, Poisoning - First Aid and Emergency Center, and Mental Health and Behavior Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Medicolegal Pitfalls

• Patients with chronic psychiatric disease or altered consciousness from an acute overdose may be unable to provide an adequate history. Consequently, essential elements of clinical evaluation may be lacking (eg, exact nature of drugs ingested, history of recent trauma, myocardial infarction). As a result, these patients and, indeed, all patients who are unable to provide adequate history, represent a higher medicolegal risk.
  • Failure to aggressively treat the hyperthermia associated with neuroleptic overdose or NMS results in increased morbidity and increased legal risk.
  • Failure to diagnose NMS in its early stages with mild signs and symptoms and failure to discharge the patient without stopping the neuroleptic agent increase medicolegal risk.

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Keywords

neuroleptic agent toxicity, neuroleptic poisoning, major tranquilizers, antipsychotic drugs, phenothiazines, aliphatics, piperidines, piperazines, thioxanthenes, butyrophenones, dibenzoxazepines, dihydroindolone, diphenylbutylpiperidine, benzisoxazole, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, NMS, seizures, hypothermia, arrhythmias, respiratory depression, involuntary movement disorders, dystonia, torticollis, oculogyric crisis, opisthotonus, dysrhythmia, acute dystonia, parkinsonism, akathisia, tardive dyskinesia, dantrolene, tardive dyskinesia

Contributor Information and Disclosures

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.
Kathryn Ruth Challoner, MD, FACEP, MPH is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.

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
Edward J Newton, MD, FACEP, FRCPC is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Royal College of Physicians and Surgeons of Canada, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Peter MC DeBlieux, MD, Professor of Clinical Medicine and Pediatrics, Section of Pulmonary and Critical Care Medicine, Program Director, Department of Emergency Medicine, Louisiana State University Health Sciences Center
Peter MC DeBlieux, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Radiological Society of North America, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Chair, Department of Emergency Medicine, Director of Medical Toxicology - Allegheny General Hospital, Associate Professor, Department of Emergency Medicine, Drexel University College of Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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