DESCRIPTION

Sedative-hypnotic agents refers to nonbendiaze-pine drugs of various chemical structures whose predominant effect is CNS depression.

FORMS AND USES

These agents have sedative, hypnotic, anticonvulsant, and anxiolytic properties. Formulations include:

• Buspirone (Buspar) tablets
• Chloral hydrate (Aquachloral) suppositories, syrup, and tablets (triclofos sodium, Triclos, monosodium trichloroethyl phosphate)
• Chlormethiazole (Heminevrin, Distraneurine) caplets, syrup and tablets
• Glutethimide (Doriden) tablets
• Meprobamate (Miltown, Meprospan) tablets and elixir (Equanil, Equagesic, MB-TAB)
• Methaqualone (Quaalude) tablets and capsules
• Methyprylon (Noludar) tablets and capsules
• Ethchlorvynol
• Tramadol (Ultram)
• Zolpidem (Ambien)

Many of these drugs have been withdrawn from the U.S. market but are still available in other countries and from illicit sources. Some are used for treatment of and alcohol withdrawal syndromes.

Street Uses

• Glutethimide is used as a heroin potentiator or as an inexpensive heroin substitute; when combined with codeine, the mixes are called "loads."
• Methaqualone is used as an aphrodisiac and a "cocaine downer."

TOXIC DOSE

• Buspirone in doses of up to 300 mg causes minimal effects.
• Chloral hydrate causes toxicity in children at 1.5 g.
• One tablet of gluthethimide or meprobamate may produce sedation in a child.

PATHOPHYSIOLOGY

• All of these agents cause CNS and respiratory depression.
• The specific mechanism of action is often unclear (i.e., methaqualone, meprobamate); most are thought to enhance gamma-aminobutyric acid (GABA)-mediated activity in the CNS, thus increasing neuronal inhibition, similar to the effect of barbiturates.
• Chloral hydrate is metabolized to trichloro-ethanol, which produces its toxic effects.
• Buspirone may exert an effect on serotonin and dopamine-2 receptors in addition to enhancing norepinephrine metabolism in the locus ceruleus.
• The majority of these agents are hepatically metabolized; only meprobamate has significant renal elimination, and only glutethimide has enterohepatic circulation.

EPIDEMIOLOGY

• Poisoning is uncommon.
• Toxic effects are typically moderate.
• Death is rare and usually occurs in conjunction with other drug use (especially alcohol) and before reaching health care.

CAUSES

• Toxic ingestion is usually intentional.
• Child abuse or neglect must be considered if the patient is less than 1 year of age; suicide attempt if the patient is over 6 years of age.

RISK FACTORS

Liver disease may slow the metabolism of these compounds.

DRUG AND DISEASE INTERACTIONS

• Buspirone combined with a monoamine oxidase inhibitor may cause hypertension.
• Coingestion of any sedative-hypnotic agents with other CNS depressants increases toxicity.

PREGNANCY AND LACTATION

• Buspirone. US FDA Pregnancy Category B. Studies indicate no fetal risk, and there are no controlled human studies, or animal studies show an adverse fetal effect but well-controlled studies in pregnant women do not.
• Chloral hydrate, ethchlorvynol, and meprobamate. US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• Chloral hydrate, glutethimide, and meprobamate are excreted in breast milk and should not be taken during lactation.

Section Outline:

• DESCRIPTION
• FORMS AND USES
  • Street Uses
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• RISK FACTORS
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Toxic causes of generalized CNS depression are numerous: ethanol, antiseizure medications, and antidepressants, among others.
• Nontoxic causes include hypoxia, hypoglycemia, electrolyte abnormality, and intracranial infection or bleed, among others.

SIGNS AND SYMPTOMS

The predominant features are varying degrees of CNS depression, slurred speech, and impaired judgment and motor skills.

Vital Signs

Hypothermia, hypotension, and bradycardia may be present.

HEENT

• Occasional diplopia, blurred vision, nystagmus, or mydriasis may occur with any agent.
• Glutethimide may produce papilledema secondary to cerebral edema.
• Chlormethiazole may increase salivation.
• Ethchlorvynol has a pungent plastic or vinyl-like odor that may produce a mintlike aftertaste.
• Chloral hydrate has a pearlike odor.

Dermatologic

Chloral hydrate has irritant effects on skin and mucous membranes.

Cardiovascular

Chloral hydrate has negative inotropic effects, shortens the refractory period, increases automaticity, and may sensitize the myocardium to catecholamines, making the development of tachydysrhythmias more likely.

Pulmonary

• Respiratory depression is usually present.
• Pulmonary edema occurs in some cases (ethchlorvynol, methyprylon, meprobamate).
• Glutethimide produces thick, tenacious bronchial secretions.

Gastrointestinal

• Meprobamate, ethchlorvynol, and glutethimide may form concretions.
• Chloral hydrate has irritant effects in the gastrointestinal tract and can cause gastritis, esophagitis, and (rarely) gastrointestinal necrosis and esophageal stricture; it is also radiopaque.

Hepatic

Chloral hydrate can increase hepatic enzyme levels.

Renal

• Chloral hydrate can cause transient renal insufficiency.
• Myoglobinuria may develop with any sedative drug if prolonged coma occurs.

Hematologic

Glutethimide causes (rarely) leukopenia, thrombocytopenia, and aplastic anemia.

Fluids and Electrolytes

Lactic acidosis can occur in severe toxicity complicated by hypoxia and prolonged hypotension.

Neurologic

• Depression, lethargy, dysarthria, dystonia, headache, ataxia, prolonged or cyclic coma, amnesia, incoordination, hypertonicity, seizures, incontinence, myoclonus, tremor, hyperreflexia, vertigo, rare hyperexcited states, anxiety, and hallucinations, but rarely death, can occur due to CNS depression.
• Dysphoria may develop with buspirone.
• Muscular hypertonicity may occur with methaqualone.
• Glutethimide can produce an anticholinergic syndrome, along with loss of brainstem reflexes, hyporeflexia, and flaccid muscle tone; it also may cause cerebral edema.

Genitourinary

Buspirone can cause dysuria, enuresis, nocturia, and priapism with therapeutic use.

PROCEDURES AND LABORATORY TESTS

Essential Tests

No tests may be needed for minimally symptomatic patients.

Recommended Tests

• Serum electrolytes, glucose BUN, and creatinine are measured to assess the cause of CNS depression and seizures.
• ECG and pulse oximetry are used to assess cardiovascular effects.
• Serum acetaminophen, aspirin, and ethanol levels in an overdose setting are measured to detect occult ingestion.
• Urinalysis and serum creatine kinase are used to evaluate for rhabdomyolysis in comatose patients.
• Head CT, lumbar puncture, cultures, and other tests as needed are used to assess CNS depression.

Not Recommended Tests

Drug levels of any of these agents are not clinically useful.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Hepatic
  • Renal
  • Hematologic
  • Fluids and Electrolytes
  • Neurologic
  • Genitourinary
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

Treatment should focus on

• Supportive care with appropriate airway management.
• Dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care professional should call the poison control center when:

• CNS, respiratory, or myocardial depression or other serious effects are present.
• Toxic effects are not consistent with sedative-hypnotic poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Any significant symptoms or history of coingestion with other CNS depressants are present.
• Drug interaction or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management is warranted if the patient is persistently symptomatic or hemodynamically unstable, or has experienced a potentially large ingestion.

DECONTAMINATION

Out of Hospital

Ipecac is not recommended due to possibility of rapid patient deterioration.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients presenting within 1 hour of a large ingestion or if serious effects are present.
• One dose of activated charcoal (1-2 g/kg) can be administered if a substantial ingestion has occurred within the previous few hours.
• Whole-bowel irrigation may be useful for treatment of meprobamate ingestion, but also may be helpful with other ingestions, due to slowed gastrointestinal motility.

ANTIDOTES

• There is no specific antidote for most sedative-hypnotic poisonings.
• In the case of chloral hydrate ingestion, there has been one anecdotal report of positive response to flumazenil (Romazicon) administration.

ADJUNCTIVE THERAPIES

• Hypotension
  • Atropine should be used to correct hypotension related to bradycardia.
  • Patient should also receive 10 to 20 ml/kg 0.9% saline intravenously and be placed in the Trendelenburg position.
  • Further fluid therapy should be guided by central pressure monitoring to avoid volume overload.
  • Vasopressor can be added if needed.
• Seizures
  • Patent airway must be maintained.
  • Benzodiazepine can be administered for initial control.
  • If seizures persist or recur, another anticonvulsant such as phenobarbital may be added.
• Hemodialysis has been recommended in the treatment of chloral hydrate, meprobamate, and ethchlorvynol poisoning in the presence of hemodynamic instability that persists despite supportive care.
• beta-blockers are considered the first line of drugs for the treatment of chloral hydrate-related cardiotoxicity.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE THERAPIES

PATIENT MONITORING

Respiratory and hemodynamic parameters should be monitored continuously.

EXPECTED COURSE AND PROGNOSIS

• Toxic effects may be delayed and prolonged due to decreased gastrointestinal motility and the long half-life of some agents; toxicity may persist for days after overdose.
• Recovery is usually complete unless complications of hypoxia, repeated seizures, or coma develop.
• Possible complications:
  • Aspiration pneumonia and complications of prolonged coma may occur.
  • Chloral hydrate may rarely cause renal failure, gastrointestinal bleed, esophageal stricture, and hepatitis.
  • Ethchlorvynol may cause pulmonary edema due to direct capilloalveolar damage.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department
  • Asymptomatic patients may be discharged following 6 hours of observation and psychiatric evaluation, if needed.
  • Prolonged observation may be needed for meprobamate poisoning due to its ability to form concretions and prolong drug absorption.
• From the hospital. Patient may be discharged following resolution or stabilization of toxic effects and after psychiatric evaluation, if needed.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

Other sources of altered mental status such as intracranial injury or infection should be assessed.

Poisoning by sedatives and hypnotics.

See Also: SECTION II, Hypotension and Seizures chapters; SECTION III, Flumazenil chapter; and SECTION IV, Ethchlorvynol chapter.

RECOMMENDED READING

Ellenhorn MJ. Sedative-hypnotics. In: Medical toxicology: diagnosis and treatment of human poisoning, 2nd ed. Baltimore: Williams & Wilkins, 1996:684-703.

Author: Christopher Layton

Reviewer: Richard C. Dart