Benzodiazepines and Other Sedatives, Hypnotics, and Anxiolytics

Abstract

The sedative, hypnotic, and anxiolytic class of medication includes benzodiazepines, barbiturates, and the nonbenzodiazepine “Z-drugs.” Tolerance, dependence, and withdrawal can occur with any of these medications when misused or used for treatment. Benzodiazepines are of concern with their use contributing to opioid overdoses. It is important to recognize and treat, as well as prevent, sedative, hypnotic, and anxiolytic use disorders. Cessation, especially abrupt withdrawal, of any of these medications can lead to a clinically significant withdrawal syndrome, which must be immediately recognized by providers and treated as a medical emergency. Benzodiazepines, barbiturates, and the nonbenzodiazepine “Z-drugs” have distinct, though variably overlapping, clinical manifestations of intoxication and withdrawal, which are described. Treatment of sedative-hypnotic use disorders, including pharmacological, therapeutic, and psychosocial, will be covered elsewhere in this book.

Appendices

Review Question #1

A 56-year-old female presents to her primary care doctor having good benefit for initiating sleep with diazepam, but finds that she feels groggy the next day. The duration of action of a benzodiazepine is based on which of the following:

• A. The drug itself

• B. The drug itself and its active metabolites

• C. The drug itself and inactive metabolites

• D. The drug itself and all metabolites, both active and inactive

• E. Only the drug’s active metabolites

Answer: B. The drug itself and its active metabolites.

Explanation: The duration of action of a benzodiazepine is based on the drug itself and its active metabolites. Inactive metabolites do not have clinical effect, and thus do not contribute to the duration of action of the benzodiazepine.

Reference: Sankar [22].

Review Question #2

An 8-year-old female with no medical history presents to the emergency room after finding her mother’s lorazepam and taking what was left in the bottle. She requires the administration of flumazenil due to excessive somnolence. Which of the following is true of flumazenil?

• A. It is metabolized by the kidney

• B. There are no scales that can be used to monitor the effect of flumazenil

• C. Once awoken with flumazenil, there is no need for readministration

• D. If there is a suspected co-ingestion with opioids, naloxone should be given prior to flumazenil

• E. Flumazenil can be given without consideration for a history of seizures

Answer: D.

Explanation: If there is a suspected co-ingestion with opioids, naloxone should be given prior to flumazenil as it is better tolerated and has a better safety profile. Flumazenil is metabolized by the liver. The Glasgow coma scale can be used to monitor the effects of flumazenil. Flumazenil has a short duration of action, and may need to be readministered. History of seizures should be considered before giving flumazenil in patients, particularly those with benzodiazepine dependence who are at risk for withdrawal seizures.

Reference: Weinbroum et al. [13]

Review Question #3

A 34-year-old man with insomnia asks a friend for medication to help sleep. He takes the medication, unaware of what he is taking, and experiences side effects. Which of the following is a possible adverse effect of barbiturate use?

• A. Cough suppression

• B. Stevens-Johnson syndrome

• C. Loss of appetite

• D. Constipation

• E. Increased immune response

Answer: B.

Explanation: Stevens-Johnson syndrome is an adverse effect of barbiturate use; others include development of acute intermittent porphyria attacks, neutropenia, and megaloblastic anemia. The other answers are not adverse effects of barbiturate use.

Reference: Sadock and Sadock [16].

Review Question #4

A 30-year-old medical student comes into the clinic requesting a short-term medication for anxiety for an upcoming flight overseas and is prescribed clonazepam. She asks her doctor about the mechanism of action of the medication she is given. The binding of benzodiazepines and barbiturates to the GABA-A receptor allow for the influx of which of the following:

• A. Sodium

• B. Chloride

• C. Bicarbonate

• D. Potassium

• E. Glutamate

Answer: B.

Explanation: The binding of benzodiazepines and barbiturates to the GABA-A receptor allows for the influx of negatively charged chloride ions. The other answers are simply distractors.

Reference: Twyman et al. [23].

Review Question #5

Which of the following is a correct statement regarding benzodiazepines and barbiturates and the receptors they act upon?

• A. Barbiturates have a more dangerous withdrawal syndrome because of their binding to the GABA-C receptor

• B. Barbiturates bind to the GABA-B receptor

• C. The alpha-1 subunit of the GABA-A receptor mediates sleep

• D. Benzodiazepines are less safe in overdose compared to barbiturates

• E. There is no cross-tolerance between barbiturates and benzodiazepines

Answer C.

Explanation: It is the alpha-1 subunit of the GABA-A receptor that is involved in mediating sleep (which is why the nonbenzodiazepine “Z-drugs” that act on the alpha-1 subunit are involved in promoting sleep). Barbiturates do have a dangerous withdrawal syndrome but they act on the GABA-A receptor, making answer choices a and b incorrect. Barbiturates are more dangerous in overdose compared to benzodiazepines and there is cross-tolerance between barbiturates and benzodiazepines.

Reference: Sadock and Sadock [16].

Review Question #6

A 72-year-old female who was overusing her daughter’s prescribed lorazepam recently stopped using it at the urging of her physician. According to the DSM-V, for how long should a person not meet any criteria for sedative, hypnotic, or anxiolytic use disorder (except for craving) in order to be considered in early remission?

• A. As soon as they stop using the substance

• B. 2 weeks

• C. 1 month

• D. 3 months

• E. 12 months

Answer D.

Explanation: This is a definition question from the DSM. Early remission is defined as at least 3 months.

Reference: American Psychiatric Association [10].