eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Sedative-Hypnotics

Author: Jeffrey S Cooper, MD, Clinical Assistant Professor, Department of Surgery, The University of Toledo College of Medicine; Consulting Staff, Department of Emergency Medicine, Mercy Children's Hospital
Contributor Information and Disclosures

Updated: Dec 15, 2009

Introduction

Background

Sedative-hypnotics are a group of drugs that cause CNS depression. Benzodiazepines and barbiturates are the most commonly used agents in this class. Other agents include the nonbarbiturate nonbenzodiazepine sedative-hypnotics, such as buspirone, zolpidem, ethchlorvynol, glutethimide, chloral hydrate, meprobamate, methaqualone, methyprylon, carisoprodol, and gamma-hydroxybutyrate (GHB) and its analog gamma-butyrolactone (GBL). Most severe sedative-hypnotic poisonings are deliberate (suicidal). These agents are also commonly abused as recreational drugs.

Barbiturates

  • Ultrashort acting - Methohexital (Brevital) and thiopental (Pentothal)
  • Short and intermediate acting - Amobarbital (Amytal), pentobarbital (Nembutal), secobarbital (Seconal), and butalbital (Fioricet, Fiorinal)
  • Long acting - Phenobarbital (Luminal)

Nonbarbiturates

  • Benzodiazepines
  • Carbamates - Meprobamate (Miltown)
  • Chloral derivatives - Chloral hydrate (Noctec)
  • Ethchlorvynol (Placidyl)
  • Piperidines - Glutethimide (Doriden) and methyprylon (Noludar)
  • Quinazolinone - Methaqualone (Quaalude)
  • Imidazopyridine - Zolpidem (Ambien), zaleplon (Sonata), eszopiclone (Lunesta) and alpidem
  • Antihistamines (over-the-counter sleep aids) - Diphenhydramine and doxylamine
  • GHB- Gamma-hydroxybutyrate

Pathophysiology

All the sedative-hypnotics are general CNS depressants. Most stimulate the activity of GABA, the principal inhibitory neurotransmitter in the CNS. GHB is a sedative-hypnotic recently banned for sale to the public because of frequent abuse and serious toxic adverse effects. GHB is a neuroinhibitory neurotransmitter or neuromodulator in the CNS. It also appears to increase GABA B receptor activity and dopamine levels in the CNS. Benzodiazepines are one of the most frequently prescribed medications in the world.

Frequency

United States

According to the 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System, 63,729 single exposures were documented for the sedative/hypnotics/antipsychotics drug category. Of these, 24 resulted in death.1

In 1998, a total of 70,982 sedative-hypnotic exposures were reported to US poison control centers, of which 2310 (3.2%) resulted in major toxicity and 89 (0.1%) resulted in death.

Mortality/Morbidity

  • Most of the serious ingestions are suicide-related. These drugs are also used with other drugs of abuse (eg, amphetamines, hallucinogens) to offset stimulatory effects.
  • Barbiturates have the highest morbidity and mortality of the sedative-hypnotics.
  • Pure benzodiazepine ingestion usually causes little more than sedation and ataxia; it very rarely results in death. Death from sedative-hypnotics is caused by respiratory arrest. Alprazolam (Xanax) is relatively more toxic than other benzodiazepines in overdose.

Clinical

History

The history should include the following information:

  • Agents ingested
  • Amount of ingestion
  • Time of ingestion
  • Cause and/or reason for ingestion (eg, accidental, intentional, suicide attempt, recreational)
  • Whether ingestion is acute or chronic
  • Past medical history and history of drug abuse
  • Circumstances surrounding the overdose

Physical

Focus the physical examination on vital signs and neurologic and cardiopulmonary status.

  • General
    • Mild toxicity resembles ethanol intoxication. Severe respiratory depression is more likely to occur when the sedative-hypnotic is ingested with other CNS depressants.
    • Flexor or extensor posturing can be present in coma resulting from sedative drug ingestion. It does not imply structural damage in this setting.
  • Barbiturates
    • Mild intoxication is characterized by ataxia, incoordination, nystagmus, slurred speech, and altered level of consciousness.
    • Moderate poisoning leads to respiratory depression and hyporeflexia.
    • Severe poisoning leads to flaccid areflexic coma, apnea, and hypotension.
    • Generally, 10 times the hypnotic dose produces severe toxicity.
    • Occasionally, hyperreflexia, rigidity, clonus, and Babinski signs are present.
    • Miosis is common, but mydriasis may be present with certain agents.
    • The nonbarbiturates, such as methyprylon and glutethimide, more commonly present with mydriasis.
    • Hypotension is usually secondary to vasodilation and negative cardiac inotropic effects.
    • Complications
      • Noncardiogenic pulmonary edema
      • Hypothermia
      • Delayed gastric emptying (therefore, late lavage and multiple charcoal is effective)
      • Skin lesions (clear vesicles and bullae on an erythematous base at contact surfaces) occur in 6% of ingestions and in approximately 50% of lethal ingestions.
  • Methaqualone (Quaalude)
    • Resembles barbiturate poisoning
    • Has more pronounced motor problems (eg, ataxia) and is known as wallbanger because of this phenomenon
    • Can lead to severe muscular hypertonicity and seizures
  • Glutethimide (Doriden)
    • Loss of brainstem reflexes
    • Flaccidity
    • Anticholinergic effects
    • Delayed gastric emptying
    • May cause hyperthermia or heatstroke
  • Ethchlorvynol (Placidyl)
    • Pungent odor of breath and gastric contents
    • Prolonged coma (up to 2 wk)
    • Acute respiratory distress syndrome (ARDS) predominates in IV use
  • Chloral hydrate
    • Synergistic with alcohol (knockout drops, Mickey Finn)
    • Cerebellar incoordination
    • Severe gastritis and GI bleed
    • Multiple dermatologic effects, including purpura, bullae, urticaria, and erythema multiforme (EM)
    • CNS depression with cardiopulmonary collapse
    • Associated with hepatitis, gastritis, proteinuria, and dysrhythmias
    • Odor of pears
    • Radiopaque
  • Imidazopyridine
    • Sleepwalking or other complex bizarre behaviors
    • Chromaturia (blue-green urine discoloration) has been reported with zaleplon (Sonata) overdose.
    • Prolonged coma and respiratory failure
  • Meprobamate
    • CNS and respiratory depression
    • Hypotension (common)
  • GHB and GBL
    • Mild intoxication
      • Slurred speech
      • Disinhibition
      • Euphoria
      • Mild lethargy
      • Moderate intoxication
      • CNS and mild respiratory depression
      • Agitation when stimulated
      • Myoclonus
    • Severe intoxication
      • Unresponsive coma
      • Miosis
      • Bradycardia
      • Mild hypotension
      • Seizures
      • Respiratory depression and apnea
    • After ingestion, the onset of effects occurs within 15 minutes and peaks in 1.5-2 hours. Elimination of GHB is rapid (elimination half-life 1-2 h). The duration of clinical effects is 2-8 hours.

More on Toxicity, Sedative-Hypnotics

Overview: Toxicity, Sedative-Hypnotics
Differential Diagnoses & Workup: Toxicity, Sedative-Hypnotics
Treatment & Medication: Toxicity, Sedative-Hypnotics
Follow-up: Toxicity, Sedative-Hypnotics
References
[ CLOSE WINDOW ]

References

  1. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057. [Medline]. [Full Text].

  2. Barnett R, Grace M, Boothe P, et al. Flumazenil in drug overdose: randomized, placebo-controlled study to assess cost effectiveness. Crit Care Med. Jan 1999;27(1):78-81. [Medline].

  3. Bledsoe BE. No more coma cocktails. Using science to dispel myths & improve patient care. JEMS. Nov 2002;27(11):54-60. [Medline].

  4. Clark RF, Sage TA, Tunget C, Manoguerra AS. Delayed onset lorazepam poisoning successfully reversed by flumazenil in a child. Case report and review of the literature. Pediatr Emerg Care. Feb 1995;11(1):32-4. [Medline].

  5. Tintinalli JE, et al, eds. Emergency Medicine: A Comprehensive Study Guide. 4th ed. New York: McGraw-Hill; 1995.

  6. Rosen P, Barkin R, et al, eds. Emergency Medicine: Concepts and Clinical Practice. 3rd ed. St Louis: Mosby-Year Book; 1996.

  7. Giri AK, Banerjee S. Genetic toxicology of four commonly used benzodiazepines: a review. Mutat Res. Jun 1996;340(2-3):93-108. [Medline].

  8. Greenberg DA, Simon RP. Flexor and extensor postures in sedative drug-induced coma. Neurology. Apr 1982;32(4):448-51. [Medline].

  9. Hamad A, Sharma N. Acute zolpidem overdose leading to coma and respiratory failure. Intensive Care Med. Jul 2001;27(7):1239. [Medline].

  10. Hojer J, Salmonson H, Sundin P. Zaleplon-induced coma and bluish-green urine: possible antidotal effect by flumazenil. J Toxicol Clin Toxicol. 2002;40(5):571-2. [Medline].

  11. Isbister GK, O'Regan L, Sibbritt D, Whyte IM. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol. Jul 2004;58(1):88-95. [Medline].

  12. Liskow B, Pikalov A. Zaleplon overdose associated with sleepwalking and complex behavior. J Am Acad Child Adolesc Psychiatry. Aug 2004;43(8):927-8. [Medline].

  13. Lovett B, Watts D, Grossman M. Prolonged coma after eszopiclone overdose. Am J Emerg Med. Jul 2007;25(6):735.e5-6. [Medline].

  14. Meyer S, Kleinschmidt S, Gottschling S, Gortner L, Strittmatter M. [Gamma-hydroxy butyric acid: neurotransmitter, sedative and party drug]. Wien Med Wochenschr. Jul 2005;155(13-14):315-22. [Medline].

  15. Riegel W. Use of continuous renal replacement therapy for detoxification?. Int J Artif Organs. Feb 1996;19(2):111-2. [Medline].

  16. Rossman PG, Knesper DJ. The early phase of hospital treatment for disruptive adolescents! The integration of behavioral and dynamic techniques. J Am Acad Child Psychiatry. 1976;15(4):693-708. [Medline].

  17. Worthley LI. Clinical toxicology: part I. Diagnosis and management of common drug overdosage. Crit Care Resusc. Sep 2002;4(3):192-215. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

sedative-hypnotic exposure, sedative-hypnotic toxicity, sedative-hypnotic poisoning, sedative-hypnotic overdose, CNS depression, benzodiazepines, barbiturates, nonbarbiturate nonbenzodiazepine sedative hypnotics, buspirone, zolpidem, ethchlorvynol, glutethimide, chloral hydrate, meprobamate, methaqualone, methyprylon, carisoprodol, gamma-hydroxybutyrate, GHB, gamma-butyrolactone, GBL, GABA, flumazenil, Quaalude, methohexital, Brevital, thiopental, Pentothal, amobarbital, Amytal, pentobarbital, Nembutal, secobarbital, Seconal, butalbital, Fioricet, Fiorinal, carbamates, meprobamate, Miltown, chloral derivatives, Noctec, ethchlorvynol, Placidyl, piperidines, glutethimide, Doriden, methyprylon, Noludar, quinazolinone, methaqualone, imidazopyridine, zolpidem, Ambien, alpidem, diphenhydramine, doxylamine

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Jeffrey S Cooper, MD, Clinical Assistant Professor, Department of Surgery, The University of Toledo College of Medicine; Consulting Staff, Department of Emergency Medicine, Mercy Children's Hospital
Jeffrey S Cooper, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Medical Editor

Lance W Kreplick, MD, MMM, FAAEM, FACEP, Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC
Lance W Kreplick, MD, MMM, FAAEM, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives
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

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency 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, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.