Benzodiazepines


Article Author:
Connor Bounds


Article Editor:
Vivian Nelson


Editors In Chief:
Sherry Gossman


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
11/13/2018 6:37:02 PM

Indications

Benzodiazepines are especially important in the cessation of seizure activity, as 1% to 2% of emergency department visits annually in the United States are for seizures. Indications for benzodiazepine administration include, but are not limited to, anxiety disorders, insomnia, convulsive disorders, acute status epilepticus, induction of amnesia, spastic disorders, seizure disorders, and agitation. Benzodiazepines are especially important in the cessation of seizure activity, as 1% to 2% of emergency department visits annually in the United States are for seizures. Non-FDA approved administration of benzodiazepines is commonly found in the field of psychiatry. Indications here include Tourette's syndrome, delirium, delirium tremens, sleep disorders, and “abnormal movements associated with medications.”[1][2]

Mechanism of Action

Benzodiazepines are a class of drugs that act upon benzodiazepine receptors (BZ-R) in the central nervous system (CNS). The receptor is protein comprised of five transmembrane subunits that form a chloride channel in the center. The five subunits are comprised of two alpha, two beta, and one gamma subunit. The extracellular portions of the alpha and beta subunit proteins form a receptor site for gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. The extracellular portions of the alpha and gamma subunit proteins form a binding site for benzodiazepines. Activation of the BZ-R causes a conformational change to a central pore, which allows the entrance of chloride ions into the neuron. Addition of the chloride anion hyperpolarizes the neuron, resulting in the decreased firing of action potentials of that neuron.[3]

Administration

Benzodiazepines are commonly administered via the intravenous route. They may also be administered rectally, intranasally, and intramuscularly, as protocol/patient presentation dictates. For example, intranasal or intramuscular administration may be useful in actively seizing patients in which intravenous (IV) or oral administration cannot be safely performed. Rectal administration in pediatric patients may be used for seizure cessation.

Benzodiazepine administration can be performed by providing small doses of the medication until the desired effect (i.e., sedation, cessation of seizure activity, anxiolysis) has been achieved. It should be noted that with intravenous administration, it may take 3 to 5 minutes to achieve a CNS drug concentration adequate to produce the desired effect. Therefore, the adequate time between doses should be allowed to prevent oversedation of the patient.

Care should be taken in the neonatal and pre-term infant populations, as studies indicate these patients experience significant hypotension, particularly with co-administration of opioids, specifically fentanyl.

Additionally, resuscitation and airway management equipment must be readily available to providers during the administration of benzodiazepines. Airway management equipment may include nasopharyngeal or oropharyngeal airways, bag valve masks, blind insertion airway devices, laryngeal mask airways, or endotracheal intubation as training of emergency management service providers allows.

Adverse Effects

Common adverse effects of benzodiazepine administration include, but is not limited to:

  • Respiratory depression
  • Respiratory arrest
  • Drowsiness
  • Confusion
  • Headache
  • Syncope
  • Nausea/vomiting
  • Diarrhea
  • Tremor

In neonates, less than 1% of patients treated with benzodiazepines experience laryngospasm and/or bronchospasm. They may also experience ventricular arrhythmias including ventricular bigeminy or premature ventricular contractions, vasovagal syncope, bradycardia, or tachycardia. Gastrointestinal reactions may include retching, nausea/vomiting, and excess salivation. CNS and neuromuscular adverse effects may include euphoria, hallucination, ataxia, dizziness, seizure-like activity, and paresthesia. Visual disturbances may include diplopia (“double vision”), cyclic eyelid movement, loss of balance, and difficulty focusing the eyes on objects. 

Benzodiazepines may interact with ethanol, other benzodiazepines, and sedatives such as barbiturates, resulting in increased respiratory depression via a synergistic effect. Therefore, concomitant administration of benzodiazepines with patients under the influence of the preceding drugs should be carefully performed, with respiratory monitoring in place. 

Contraindications

Contraindications include known hypersensitivity to benzodiazepines and narrow-angle glaucoma. Glaucoma occurs when the intraocular pressure rises, thereby causing compression of the optic nerve near the posterior surface of the eye. Upon compression, the flow of cytoplasm from the cell body of the optic nerve starves the nerve fibers leading to the brain. This results in numerous issues, including ocular pain, nausea/vomiting, blurred vision, an intraocular pressure greater than 21 mmHg, edema of the corneal epithelium, and non-reactive pupils. 

As always, follow local protocols or contact Medical Control if any questions regarding administration, or withholding thereof, exist.

Monitoring

As noted above, these drugs may act as depressants to the CNS, specifically inhibiting respiratory drive. Therefore, careful monitoring of all vitals, especially blood pressure and respiratory rate, should be performed after administration of benzodiazepines. Waveform capnography, if available, should be seriously considered to monitor respiratory status.

Though the therapeutic index of benzodiazepines is high, monitoring of respiratory depression is critical. Respiratory arrest has been noted to occur with rapid injection of benzodiazepines via the intravenous route.

Toxicity

Some benzodiazepines are classified as pregnancy category D, indicating there is some fetal risk, but potential benefits may allow the use in pregnant women (in seizures, for example, where fetal mortality increases by 10% for every minute of maternal seizure activity). Several studies have indicated that specific benzodiazepines (diazepam and chlordiazepoxide) may increase the risk of congenital malformations in the fetus.

Others, such as flurazepam and temazepam are considered pregnancy class X drugs, as they have been shown to produce neonatal lethargy and problems in skeletal development in neonates, respectively.

Flumazenil is a GABA receptor agonist, acting to reverse the sedative effects of benzodiazepines. Flumazenil functions through competitive inhibition of the alpha-beta subunit GABA binding site. Administration of flumazenil should be carried out judiciously, as it may precipitate withdrawal seizures. Of note, one multi-center trial found that patients with excessive benzodiazepine ingestion could become “re-sedated” after flumazenil began to wear off. Naloxone may also be administered if patient history/presentation suggests that opiates were taken along with benzodiazepines and the patient is experiencing signs of respiratory distress/arrest. However, naloxone doses may be smaller than the standard 0.4 mg in suspected benzodiazepine and opioid co-ingestion. Doses of 0.05 mg may be recommended, as a withdrawal from opioids may precipitate vomiting. This becomes an issue in the sedated benzodiazepine overdosed patient, as they may be unable to protect their airway.

The FDA reminds providers that extreme care should be taken when administering benzodiazepines with other central nervous system depressants such as alcohol, barbiturates, and opioids.

The activated charcoal administration is contraindicated in benzodiazepine (BZ) toxicity/overdose. This is due primarily to altered mental status commonly associated with BZ overdose, which lends itself to aspiration of the activated charcoal.

Enhancing Healthcare Team Outcomes

A multidisciplinary approach to benzodiazepines

Benzodiazepines are one of the most widely prescribed drugs both in and out of the hospital. These agents are prescribed by many health care workers in different specialties, and while the drugs are effective for sedation, they also have the potential to cause harm. All healthcare workers including nurses who prescribe these agents must be fully aware of the side effects, misuse, and abuse of the drugs, and the potential to develop physical dependence. Further, the healthcare worker must know how to reverse a benzodiazepine in case of an overdose. Finally, liberal prescribing of these drugs is not recommended as their abuse potential is high. Additionally, the DEA has been clamping down on healthcare workers who prescribe these agents without a valid reason and/or no documentation.[4][5]


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Benzodiazepines - Questions

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Which of the following about benzodiazepines is false?



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Which sedative drug has spasmolytic activity?



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Which is true about benzodiazepines?



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Which of the following is not a property of benzodiazepines?



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Benzodiazepine pharmacology is related to what ion?



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A patient with low back pain has increased mobility and has begun to participate in activities of daily living. Which of the following medications would be most likely responsible for these behaviors?



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Which of the following best describes the actions of benzodiazepines?



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Which of the following is not caused by benzodiazepine use?



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Which of the following medications suppress respiration?



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Which of the following is NOT a long acting benzodiazepine?



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Which of the following is NOT a short-acting benzodiazepine?



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Which of the following is a medium acting benzodiazepine?



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The use of benzodiazepines is generally NOT associated with which of the following?



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Which of the following is important information a patient should be aware of when taking a benzodiazepine?



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Upon which neurotransmitter do benzodiazepines act?



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Which of the following medications increases the half-life of alprazolam?



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A 22-year-old girl and her friend go to a bar. After their first drink in the span of one hour, the girl suddenly falls down and is very lethargic. The friend brings her to the ER. The patient is unsteady on her feet and very sleepy but can answer some questions. She cannot recall any events that occurred at the bar. Her breathing is unlabored, but respirations are slow and shallow. Given this scenario, what is the most likely drug that was "slipped" into her drink?



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Which of the following is not a benzodiazepine?



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What is the mechanism of action of benzodiazepines?



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Benzodiazepines anxiolytic effects are attributed to their ability to do which one of the following?



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Temazepam is categorized in which of the following drug classes?



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A nurse is preparing to administer temazepam to a patient per a prescription during rounds. What is essential knowledge needed for the nurse to have regarding the safe administration of this medication? Select all that apply.



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Benzodiazepines - References

References

Maust DT,Solway E,Clark SJ,Kirch M,Singer DC,Malani P, Prescription and Nonprescription Sleep Product Use Among Older Adults in the United States. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2018 Sep 14     [PubMed]
Blanco C,Han B,Jones CM,Johnson K,Compton WM, Prevalence and Correlates of Benzodiazepine Use, Misuse, and Use Disorders Among Adults in the United States. The Journal of clinical psychiatry. 2018 Oct 16     [PubMed]
Poisbeau P,Gazzo G,Calvel L, Anxiolytics targeting GABA{sub}A{/sub} receptors: Insights on etifoxine. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. 2018     [PubMed]
Jørgensen MB,Osler M, Should benzodiazepines be avoided? Acta psychiatrica Scandinavica. 2018 Aug     [PubMed]
Revet A,Yrondi A,Montastruc F, [Good practices in prescribing benzodiazepines]. Presse medicale (Paris, France : 1983). 2018 Oct 29     [PubMed]

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