Basics
Description
- Neuroleptics (antipsychotics) used for management of:
- Psychotic disorders
- Agitation
- Dementia in the elderly
- Autism and behavioral problems in children
- Eating disorders
- Antiemetic
- Migraine headaches
- Acute overdose:
- Symptoms usually mild to moderate
- CNS and cardiovascular symptoms predominate
- CNS depression, seizure, and coma possible
- Dystonic reactions (dystonia):
- Most common adverse effect
- Can occur at any time, often within 48 hr of starting medication
- Akathisia:
- Patient has motor restlessness and feels a need to pace or move constantly
- Occurs within hours to weeks of starting medication
- Neuroleptic malignant syndrome (NMS):
- Idiosyncratic, life-threatening event
- Can occur at any time but most commonly in overdose, dose increase, and during the 1st wk of usage
- Tardive dyskinesia:
- Movement disorder usually affecting patients after years of taking neuroleptics
- Treated by decreasing, discontinuing, or changing the drug
Etiology
- Typical neuroleptics (phenothiazines, butyrophenones) strongly antagonize dopaminergic receptors, these include:
- Haloperidol (Haldol)
- Chlorpromazine (Thorazine)
- Prochlorperazine (Compazine)
- Thioridazine (Mellaril)
- Fluphenazine (Prolixin)
- Promethazine (Phenergan)
- Droperidol (Inapsine)
- Hydroxyzine (Atarax)
- Typical neuroleptics also have varying degrees of antagonism for histamine, muscarinic, andα-adrenergic receptors.
- Atypical neuroleptics have weaker dopaminergic antagonism and moderate serotonergic antagonism, these include:
- Asenapine (Saphris)
- Aripiprazole (Abilify)
- Clozapine (Clozaril)
- Paliperidone (Invega)
- Risperidone (Risperdal)
- Olanzapine (Zyprexa)
- Quetiapine (Seroquel)
- Ziprasidone (Geodon)
Diagnosis
Signs and Symptoms
- Acute overdose:
- Symptom onset within 6 hr, 9 hr with aripiprazole, up to 24 hr with extended-release formulations (paliperidone)
- Can be delayed if anticholinergic symptoms predominate
- CNS:
- Ranges from mild sedation to coma
- Anticholinergic delirium possible
- Extrapyramidal symptoms (dystonia, akathisia)
- Seizures
- Cardiovascular:
- Tachycardia (anticholinergic)
- Hypotension (antiadrenergic)
- QT prolongation
- Torsade de pointes (rare)
- Respiratory:
- Respiratory depression
- Loss of airway reflexes
- GI:
- Genitourinary:
- Dystonic reactions:
- Involuntary muscle spasms of face, neck, back, and limbs
- Dramatic appearance is frightening to patient and family
- Laryngeal dystonia is a rare form that may cause stridor and dyspnea.
- NMS:
- Occurs in <1% of patients, 30% mortality
- Severe hyperthermia
- Skeletal muscle rigidity
- Altered mental status
- Autonomic dysfunction
- Electrolyte disturbance
- Rhabdomyolysis
- Agranulocytosis:
- Seen with clozapine and olanzapine
- Occurs with chronic treatment
- Diabetes:
- Hyperglycemia, new-onset diabetes, and DKA have all been reported with initiation of neuroleptics.
Essential Workup
- Monitor vital signs with significant ingestions.
- Cardiac monitor
- Pulse oximetry
- Core body temperature for hyperthermia
Diagnosis Tests & Interpretation
Lab
- Electrolytes, BUN, creatinine, glucose, LFTs
- CBC for clozapine overdose, WBC can be elevated in NMS
- Creatine phosphokinase (CPK) levels if NMS suspected, agitation, or prolonged immobilization
- Serum drug screen with drug levels for possible coingestions based on history:
- Aspirin
- Acetaminophen
- Lithium
- Valproate
- Phenytoin
- Phenobarbital
- Urine toxicologic screens are rarely helpful
- False-negatives and false-positives can be misleading
- Quantitative levels are rarely available and not helpful in acute management
Imaging
- ECG:
- QT prolongation
- QRS prolongation (rare)
- Head CT:
- Indicated for significant mental status change
Differential Diagnosis
- Serotonin syndrome
- Malignant hyperthermia (if recent anesthesia)
- Antidepressant overdose
- Anticholinergic crisis
- Sympathomimetic overdose
- Opioid overdose
- Occult head injury
- Endocrine disorder
- Sepsis
- Heat stroke
Treatment
Pre-Hospital
Bring medication bottles when transporting patient to hospital.
Initial Stabilization/Therapy
Airway, breathing, and circulation management (ABCs):
- Administer supplemental oxygen.
- Consider naloxone, thiamine, D50 (or check blood glucose) for altered mental status
- Intubate if respiratory depression
Ed Treatment/Procedures
- Supportive care is the mainstay of treatment
- Decontamination:
- Administer single dose of activated charcoal if ingestion within 1 hr
- Do not give charcoal to patient with unprotected airway
- Use NG tube for charcoal only if pt is intubated
- Consider whole bowel irrigation if large amounts of extended-release formulation ingested (paliperidone)
- Hemodialysis unlikely to be helpful due to high degree of protein binding
- Consider lipid emulsion therapy for cardiovascular collapse
- Hypotension:
- 0.9% normal saline (NS) IV fluid bolus
- Treat resistant hypotension with norepinephrine or phenylephrine
- Dopamine may be ineffective
- Ventricular dysrhythmias:
- Class IA, IB, and III antidysrhythmics can potentiate cardiotoxicity. Lidocaine can be used in refractory cases
- Magnesium for prolonged QT
- Cardioversion if hemodynamically unstable
- Consider intralipid (20% lipid emulsion) for cardiovascular collapse
- For asymptomatic QTc prolongation, replete potassium, calcium, and magnesium to normal levels
- QRS prolongation (>120 msec) should be treated with sodium bicarbonate therapy
- Dystonic reactions:
- Administer diphenhydramine or benztropine mesylate.
- Treatment should be continued for 3 days to prevent recurrence.
- NMS:
- Recognition and cessation of neuroleptics is critical.
- Active cooling for hyperthermia
- Aggressive benzodiazepines for agitation
- Severe cases may require bromocriptine (dopamine agonist) or dantrolene (a direct-acting muscle relaxant)
- Consider intubation and neuromuscular blockade
- Seizures:
- Treat initially with diazepam or lorazepam.
- Phenobarbital for persistent seizures
- There is no role for phenytoin in toxin-induced seizures
- Anticholinergic delirium:
- Benzodiazepines are 1st-line agents
- Physostigmine can be used with caution
- Physostigmine is contraindicated in a patient with dysrhythmias, heart block, or interval prolongation on EKG
Medication
- Activated charcoal: 1 " 2 g/kg PO
- Benztropine mesylate: 1 " 2 mg IV or PO
- Bromocriptine: 2.5 " 10 mg q8h PO
- Dantrolene: 2 " 3 mg/kg/d as continuous infusion (10 mg/kg max.)
- Diazepam: 5 " 10 mg IV q10 " 15min
- Diphenhydramine: 25 " 50 mg IV (1 mg/kg)
- Lidocaine 1 " 2 mg/kg followed by infusion
- Lipid emulsion (20%) 1.5 mL/kg bolus followed by 0.25 mL/kg/min infusion for 30 " 60 min, may repeat bolus for persistent hemodynamic compromise
- Lorazepam: 2 " 4 mg (peds: 0.03 " 0.05 mg/kg) IV q10 " 15min
- Magnesium sulfate: 1 " 2 g IV over 5 " 15 min
- Norepinephrine: 1 " 2 Όg/kg/min IV titrate to BP
- Phenobarbital: 10 " 20 mg/kg IV (loading dose); monitor for respiratory depression
- Physostigmine 0.5 mg IV q3 " 5min
Follow-Up
Disposition
Admission Criteria
- Overdose with CNS sedation, agitation, dysrhythmias, or vital sign abnormalities to monitored bed or ICU
- NMS require ICU care
- New-onset diabetes (secondary to neuroleptic use) with severe hyperglycemia and/or ketoacidosis.
Discharge Criteria
- Asymptomatic after 6 hr of observation
- Longer observation required for aripiprazole and paliperidone ingestion as well as ingestion of extended release formulations
Issues for Referral
- Patients with unintentional (accidental) poisoning require poison prevention counseling.
- Patients with intentional (e.g., suicide) poisoning require psychiatric evaluation.
- New-onset diabetes requires primary care/endocrine follow-up.
Follow-Up Recommendations
- Psychiatric referral for intentional overdoses
- Primary care follow-up for accidental ingestions or medication side effect follow-up
Pearls and Pitfalls
- Neuroleptics represent a group of drugs with diverse indications and a wide range of toxicity.
- Most overdoses are mild, and CNS depression predominates.
- Dystonic reactions are the most common side effect of neuroleptics. These reactions are dramatic in appearance but easily treatable.
- NMS is a potentially fatal reaction that can be seen in acute or chronic usage of neuroleptics.
- Newer antipsychotics can have delayed onset up to 24 hr.
- Contact the poison control center for further guidance
Additional Reading
- Levine M, Ruha AM. Overdose of atypical antipsychotics: Clinical presentation, mechanisms of toxicity and management. CNS Drugs. 2012;26:601 " 611.
- Lipscombe LL, Levesque L, Gruneir A, et al. Antipsychotic drugs and hyperglycemia in older patients with diabetes. Arch Intern Med. 2009;169:1282 " 1289.
- Minns AB, Clark RF. Toxicology and overdose of atypical antipsychotics. J Emerg Med. 2012;43:906 " 913.
- Ngo A, Ciranni M, Olson KR. Acute quetiapine overdose in adults: A 5-year retrospective case series. Ann Emerg Med. 2008;52:541 " 547.
- Reulbach U, D Όtsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007;11:R4.
- Wittler MA. Antipsychotics. In: Marx, ed. Rosens Emergency Medicine. 7th ed. St. Louis, MO: Mosby; 2009.
- www.lipidrescue.org.
Codes
ICD9
- 969.1 Poisoning by phenothiazine-based tranquilizers
- 969.2 Poisoning by butyrophenone-based tranquilizers
- 969.3 Poisoning by other antipsychotics, neuroleptics, and major tranquilizers
- 333.92 Neuroleptic malignant syndrome
ICD10
- T43.501A Poisoning by unsp antipsychot/neurolept, accidental, init
- T43.3X1A Poisoning by phenothiaz antipsychot/neurolept, acc, init
- T43.4X1A Poisoning by butyrophen/thiothixen neuroleptc, acc, init
- G21.0 Malignant neuroleptic syndrome
SNOMED
- 291121009 Poisoning by anti-psychotic agent
- 48534006 Poisoning by phenothiazine-based tranquilizer (disorder)
- 16248006 Poisoning by butyrophenone-based tranquilizer (disorder)
- 15244003 Neuroleptic malignant syndrome (disorder)