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Toxicity, Sedative-Hypnotics
Updated: Dec 10, 2007
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
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.
- Mild intoxication
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| Follow-up: Toxicity, Sedative-Hypnotics |
| References |
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Further Reading
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
