Updated Review, StatPearls, Nov/20: Benzodiazepines

Benzodiazepines

https://www.ncbi.nlm.nih.gov/books/NBK470159/#article-18220.s1

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, acute status epilepticus, induction of amnesia, spastic disorders, seizure disorders, and agitation. 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 a protein comprised of five transmembrane subunits that form a chloride channel in the center, i.e., GABA-A receptor. 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. The influx 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 oral and intravenous routes. 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, 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 angle-closure glaucoma. Glaucoma occurs when the intraocular pressure rises, thereby causing compression of the optic nerve near the posterior surface of the eye. This compression of the lamina cribrosa can lead to axonal damage with subsequent disruption of anterograde and retrograde axonal transport.  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 the 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-A receptor antagonist, acting to reverse the sedative effects of benzodiazepines. Flumazenil functions through competitive inhibition of the alpha-gamma subunit of the GABA-A receptor. 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 opioids 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 strongly 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) ingestion 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

An interprofessional 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 professionals in different specialties, and while the drugs are effective for sedation, they also have the potential to cause harm. All healthcare professionals including physicians 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. Benzodiazepines, e.g., midazolam are DEA scheduled IV drugs.  Further, healthcare professionals,e.g., physicians, nurses, pharmacists, etc. 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 professionals who prescribe these agents without a valid reason and/or no documentation.[4][5]