Benzodiazepines (2024)

Continuing Education Activity

Benzodiazepines are a category of medications that exert their effects on benzodiazepine receptors in the central nervous system. Certain benzodiazepines, such as alprazolam, clobazam, chlordiazepoxide, and others, are approved by the United States Food and Drug Administration (FDA). These drugs are crucial for the cessation of seizure activity,as they account for 1% to 2% of United States emergency department visits annually.Benzodiazepines may be administered for various indications, including, but not limited to,insomnia, acute status epilepticus, induction of amnesia, agitation, and anxiety, spastic, and seizure disorders.

Proficiency in the complex pharmacology of benzodiazepinesallows for the development of personalized treatment plans tailored to meet the unique needs of each patient.This comprehensive understanding facilitates prudent decision-making in the prescription of benzodiazepines, optimizing dosage regimens while simultaneously minimizing the potential for adverse reactions.This activity provides an overview of the indications, mechanism of action, safe administration, adverse effects, contraindications, toxicology, and monitoring associated with the diverse physiological possibilitieswhen using benzodiazepines in the clinical setting. This activity also highlights the crucial role of the interprofessional healthcare team in gainingexpertise and delivering focused, secure, and personalized care.

Objectives:

Differentiate between various benzodiazepines, recognizing their unique pharmacological profiles, dosages, and potential adverse effects.
Implement personalized treatment plans, optimizing benzodiazepine dosages based on individual patient needs and responses.
Select monitoring strategies to ensure the safe and effective use of benzodiazepines, including regular assessment of therapeutic response and potential adverse effects.
Collaborate with an interprofessional healthcare team to share insights, discuss patient cases, and ensure a holistic approach to benzodiazepine management.

Access free multiple choice questions on this topic.

Indications

Benzodiazepines are a category of medications that exert their effects on benzodiazepine receptors in the central nervous system (CNS). These drugs are crucial for the cessation of seizure activity,as they account for 1% to 2% of United States emergency department visits annually.Benzodiazepines may be administered for various indications, including, but not limited to,insomnia, acute status epilepticus, induction of amnesia, agitation, andanxiety, spastic, and seizure disorders.The off-label use of benzodiazepines is prevalent in the field of psychiatry. Indications encompass conditions such as Tourette syndrome, delirium, delirium tremens, sleep disorders, and abnormal movements associated with medications, including tremors, tics, tardive dyskinesia, or chorea, among others.[1][2]

FDA-ApprovedIndications

The United States Food and Drug Administration (FDA) has approved a fewbenzodiazepines for the management of anxiety, seizures, and alcohol management, as mentioned below.

Alprazolam: Alprazolam is indicated for anxiety disorders and panic disorders, including agoraphobia.[3]

Chlordiazepoxide:Chlordiazepoxide is primarily indicated for themanagement of alcohol withdrawal syndrome.[4]

Clobazam: Clobazam is indicated for seizures associated with Lennox-Gastaut syndrome.[5]

Clonazepam:Clonazepam is indicated for treatingpanic disorder and agoraphobia.[3]It is also indicated for the treatment ofmyoclonic seizures and absence seizures.[6]

Clorazepate: Clorzapte is used for adjunct treatment of short-term management of anxiety disorders. It is also indicated for focal (partial) onset seizures.[7]

Diazepam: Diazepam is usedforalcohol withdrawal management.[7]Rectal diazepam is also indicated for treating febrile seizures.[8]

Estazolam: According to the American Academy of Sleep Medicine (AASM), estazolam is indicated for treating insomnia.[9]

Flurazepam: Flurazepam is indicated for the treatment of insomnia.[9]

Lorazepam: Lorazepam is used for anxiety disorders. According toAmerican Epilepsy Society guidelines, parenteral lorazepam is one of the first-line treatments for convulsive status epilepticus.[10]

Midazolam: Midazolam is indicated for convulsive status epilepticus and procedural sedation. Midazolam is used for sedation in mechanically ventilated patients in the MICU/SICU.[11]

Oxazepam: Oxazepam is indicated for anxiety disorders, and according to the ASAM (American Society of Addiction Medicine) guidelines, oxazepam is indicated for alcohol withdrawal syndrome.[12]

Quazepam:According to the American Collegeof Physicians, quazepam isindicatedmainly for treating chronic insomnia in adults.[13]

Temazepam: The AASM clinical practice guideline suggests temazepam forsleep onset and sleep maintenance insomnia.[9]

Triazolam: Triazolam is indicated primarily forsleep-onset insomnia.

Remimazolam: Remimazolam was approved by the FDA in 2020 and is indicated for short (<30 mins) procedural sedation in adults.[14]

Mechanism of Action

Benzodiazepines are a class of drugs that act upon benzodiazepine receptors in the CNS. The receptor is a protein comprised of5 transmembrane subunits, which collectively shape a chloride channel in the center, namely the gamma-aminobutyric acid type A (GABA-A) receptor. These 5 subunits include 2 alpha subunits, 2 beta subunits, and 1 gamma subunit. The extracellular portions of the alpha and beta subunit proteins form a receptor site for GABA, which is an inhibitory neurotransmitter. The extracellular portions of the alpha and gamma subunit proteins form a binding site for benzodiazepines.

Activation of benzodiazepine receptors causes a conformational change to a central pore, allowing chloride ions to enter the neuron. The influx of the chloride anion results in hyperpolarization of the neuron, resulting in CNS depression.[15]Benzodiazepines increase the frequency of the GABA-A receptor Cl^– channel opening in the presence of GABA. In the absence of GABA, benzodiazepines have no effects on GABA-Areceptor function.[16]

Pharmaco*kinetics

Absorption: After oral administration, benzodiazepines are usually well absorbed from the gastrointestinal tract, exceptclorazepate, which undergoes decarboxylation in gastric juice before absorption. After intramuscular (IM) injection, the absorption of diazepam or chlordiazepoxide isslow, and the absorption oflorazepam or midazolamisusuallyquick. After intravenous (IV) administration, benzodiazepines are quickly distributed to the brain and the CNS. Midazolam is one of the most lipophilic benzodiazepines that crosses the blood-brain barrier and has a rapid onset of clinical effects.

Distribution:The benzodiazepines and their active metabolites avidly bind to plasma proteins. Plasma protein binding is approximately 70% for alprazolam, 85% for clonazepam, and 99% for diazepam. The concentration of benzodiazepines in the cerebrospinal fluid is approximately equal to that of free drugs in plasma. Diazepam is redistributedespecially rapidly.

Metabolism:The first phase of metabolism involves the formation ofN-desalkylatedmetabolitesthat are biologically active. Exceptions are triazolam, alprazolam and midazolam.The second phase of metabolism involves hydroxylation and usually yields an active derivative.The third phase of metabolism is the conjugationwith glucuronic acid.Most benzodiazepines are metabolized extensively by hepatic CYP3A4 and CYP2C19. Lorazepam undergoes direct glucuronidation without cytochrome p450 metabolism. Consequently, lorazepam can be used in patients with hepatic dysfunction.[17]Remimazolam is degraded tometabolite (CNS7054), which hasnegligible hypnotic activity.[18]

Elimination: Benzodiazepines and their metabolites are primarily excreted by the kidneys.Diazepam produces the active metabolites oxazepam, temazepam, and desmethyldiazepam, which further increase the drug action duration. The elimination half-life of benzodiazepines is increased in older patientsand patients with renal dysfunction.[19]

Administration

Available Dosage Forms and Strengths

Benzodiazepines are commonly administered via the oral andIV routes. As protocol dictates, they may also be administered rectally, intranasally, and IM. For instance, intranasal orIM administration may be useful in actively seizing patients where IV or oral administration cannot be safely performed. Rectal administration in pediatric patients may be used for seizure cessation when IV access has not been established.

Benzodiazepine administration involves delivering incremental doses of the medication until the desired effects, such as sedation, cessation of seizure activity, and anxiolysis, are achieved. However, achieving a CNS drug concentration sufficient for the desired effect through IV administration may take 3 to 5 minutes. Consequently, sufficient time should exist between doses to avoid over-sedation.

Furthermore, clinicians must ensure the availability of resuscitation and airway management equipment 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. The conversion factor can be estimated using the diazepam milligram equivalency.[20]

Adult Dosage

Alprazolam: For generalized anxiety disorder, initiate treatment with a dose of 0.25 to 0.5 mg, 3 times daily. The dose of alprazolam may be increased at intervals of 3 to 4 days to a daily dose of 4 mg. For panic disorders, a1 to 4 mg/d dose is used. Use the minimal effective clinical dose due to the potential for dependence.[3]

Chlordiazepoxide: For alcohol withdrawal syndrome, the suggested initial dose is 50 to 100 mg, followed by repeated doses of up to 300 mg/d as needed. Adjust the dose according to the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar) protocol.[21]

Clonazepam:The initial dose for adults with panic disorder is0.5 mg/d.Themaintenancedose for most patients is 1 mg/d. A dosage of 0.5 mg is given 3 times daily for seizure disorders, andthe maximumrecommended daily dose is 20 mg.

Clobazam: For Lennox-Gastaut syndrome,an adjunct to antiepileptic drugs, the initial dose is 10 mg for patients with a body weight of more than 30 kg. The dose is increased to20 mg after1 week. The usual maintenance dose after2 weeks is40 mg.In patients with a body weight of <30 kg, the dose should be reduced to half the recommended dose. Study findings indicate that patients with seizure improvement on starting dosages of 10 to 20 mg/day of clobazammay have better seizure control ifthe dosage is increased beyond the maximumrecommended dosage of 40 mg/day.[5]

Clorazepate: The initial dose in patients with focal (partial) onset seizures in patients over 12 years is 7.5 mg, 3 times daily. Themaximum recommended dose is90 mg/d.[7]

Diazepam: ASAM 2020 guidelines recommend front-loading for patients experiencing severe alcohol withdrawal (eg, CIWA-Ar ≥19). A withdrawal symptom severity scale guides a front-loading regimen(eg, 10 mg diazepam orally every hour if CIWA-Ar score ≥10) or according to a fixed schedule (eg, 20 mg diazepam orally every 2 hours for3 doses).[12]The recommended dose of diazepam (rectal) for febrile seizures is 0.5 mg/kg.[8][22]

Estazolam: According to AASM, the dose of estazolam for sleep onset and sleep maintenance insomnia is 1 to 2 mg at bedtime.[9]

Flurazepam: Flurazepam is indicated for the treatment of insomnia.The recommended dose of flurazepam is 15 mg for women and 30 mg for men.

Lorazepam: According to AES guidelines, IV lorazepam (0.1 mg/kg) is administered as an initial dose for convulsive status epilepticus; the maximum recommended dose is 4 mg. The dose may be repeated at 3 to 5 minutes.[10]

Midazolam: Midazolam isadministered 10 mgIM for convulsive status epilepticus as a single dose. Midazolam is preferred for patients without IV access.Intranasal midazolam (0.2 mg/kg, maximum dose, 10 mg) can be used in prehospital settings. For procedural sedation in patients <60, 0.5 to 2.5 mg IV should beadministered slowly over at least 2 minutes.Clinicians should fully evaluate the sedative effect before administering another dose. In MICU/SICU, midazolam is used as an alternative agent for sedation in mechanically ventilated patients. An intermittent dosing strategy is preferred to avoid drug accumulation. The Richmond Agitation Sedation Scale (RASS) goalis 0 to −2.[11][23][24]

Oxazepam: For alcohol withdrawal syndrome, oxazepam is administered with a symptom-triggered dosing approach. ForCIWA-Ar scores between 8 and 15, 15 mg oxazepam is administered and 30 mg oxazepam is givenfor CIWA-Ar >15.[12]

Quazepam:Quazepam is suggested as an alternative drug for sleep onset and sleep maintenance insomnia. The recommended dose is 7.5 mg/d at bedtime. The dose of quazepam can be increased to 15 mg, butthe drug has a long half-life; hence, concern exists regarding accumulation and daytime impairment.[13]

Temazepam:The AASM Clinical Practice Guideline recommends temazepam forsleep onset and sleep maintenance insomnia. The recommended dose is7.5 to 15 mg daily at bedtime. Temazepam improvestotal sleep time, decreases sleep latency, and improves sleep quality. According to the American College of Physicians (ACP) guidelines, all patients with chronic insomnia should receive cognitive behavioral therapy as the initial treatment intervention.[9][13]

Triazolam: Triazolam is indicated primarily forsleep-onset insomnia. The recommended dose is0.125 to 0.25 mg daily at bedtime. Limit the use to 4 to 8 weeks.[12]

Remimazolam: Remimazolam was approved by the FDA in 2020 and is indicated for short (<30 mins) procedural sedation in adults.For procedural sedation in adult patients, administer 5 mg IV remimazolam over 1 minute. To maintain procedural sedation, administer 2.5 mg IV (as needed) over 15 seconds. For induction, inASA (American Society of Anesthesiologists) class III and IV patients, 2.5 to 5 mgIVover 1 minute is administered based on the clinical condition. To maintain procedural sedation in ASA class III and IV patients, administer 1.25 to 2.5 mgIV as needed over 15 seconds. Wait for at least 2 minutes before administration of an additional dose.[14]

Specific Patient Populations

Hepatic impairment:Lorazepam and oxazepam metabolism is minimally affected by liver disease. As discussed above, lorazepamis the safest empiric choice among benzodiazepines for treatingalcohol withdrawal syndrome and inpatients with hepatic impairment. Administerremimazolam with caution in severe hepatic impairment.[25]

Renal impairment: In renal impairment, decreasedclearance and plasma protein-binding results in increased unbound (active) benzodiazepine concentration. According to a study,lorazepam may be safe in patients with ESRD.A risk of accumulation exists with diazepam. Lower starting doses should be used, and the dose should be cautiously titrated to clinical response.[19][26]

Pregnancy consideration:Mostbenzodiazepines are classified as former FDA pregnancy category D medication, indicating some fetal risk, but potential benefits may allow the use in pregnant women (when 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, including cleft palate 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 (exencephaly and fusion or asymmetry of ribs) in neonates, respectively.

All benzodiazepines should be particularly avoided during the first trimester of pregnancy.[27]According to the National Institute for Health and Care Excellence (NICE) guidelines, clinicians should not suggest benzodiazepines topregnant women. However, benzodiazepines can be used to managesevere anxiety, agitation, and seizures. The use of benzodiazepines during pregnancy isassociated with neonatal hypotonia and withdrawal. Counseling is important to taper down benzodiazepines in women who are planning for pregnancy.[28][29]

Breastfeeding considerations: Care should be taken in the neonatal and pre-term infant populations, as studies indicate these patients experience significant hypotension, particularly with coadministration of opioids, specifically fentanyl. A safety scoring system suggests that midazolam, lorazepam, and oxazepam can be used cautiously. The use of benzodiazepines during lactation should be avoided unless a compelling indication is present.[30][31][32]

Older patients:The American Geriatric Society Beers Criteria identifies benzodiazepines as potentially inappropriate for older adults due to heightened sensitivity and reduced clearance. This elevated risk inolder patients can lead to cognitive impairment, falls, and fractures. However, reasonable use of benzodiazepines may be warranted, such as in the management of seizure disorders, alcohol withdrawal, periprocedural sedation, and severe generalized anxiety disorder.[33]

Pediatric patients: Per the American Epilepsy Society guidelines, theIV administration of lorazepam and diazepam effectively stops seizures lasting at least 5 minutes. Additionally, rectal diazepam, IM midazolam, intranasal midazolam, and buccal midazolam are probably effective.[10]

Adverse Effects

Benzodiazepine administration may lead to common adverse effects, including, but not limited to, respiratory depression, respiratory arrest, drowsiness, confusion, headache, syncope, nausea and vomiting, diarrhea, and tremors.

In neonates, less than 1% of patients treated with benzodiazepines experience laryngospasm and 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 and 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.Long-term use of benzodiazepinescan lead to cognitive impairment.[34]Rare cases of cholestatic liver injury have been reported with benzodiazepines like alprazolam, clonazepam, diazepam, andflurazepam.[35]Hypertension, as well as hypotension, is observed with remimazolam. Monitor the blood pressure during the procedure.[36]

Drug-Drug Interactions

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.[37]

Lorazepam and oxazepam are metabolizedby uridinediphosphate glucuronosyltransferases (UGTs). Inducers of UGT, such as carbamazepine, phenobarbital, phenytoin, and rifampin, may induce the metabolism and decrease the efficacy.[7]

Excessive sedation can result from concurrent administration of benzodiazepine-like midazolam, triazolam, alprazolam, or diazepam administered with strong CYP3A4 inhibitors such as itraconazole, ketoconazole,grapefruit juice, clarithromycin, nefazodone, ritonavir. Avoid concurrent administration.[38][39]

Contraindications

Warnings and Precautions

Contraindications of benzodiazepines includea known case of angle-closure glaucoma.Benzodiazepineshave muscle relaxant effects that can affect the function of the sphincter pupillae muscle of the iris.[40]Benzodiazepines are also contraindicated in patients with priorhypersensitivity reactions.Anaphylaxis and angioedema have been reported.[41]Remimazolam is contraindicated in patients with a history of hypersensitivity reaction to dextran 40.[42]

Box Warning

Concomitant use of benzodiazepines with opioids can lead tosedation, severe respiratory depression, coma, and death. Avoid combination.[43]

Monitoring

Benzodiazepines are CNS depressants specifically inhibiting respiratory drive. Therefore, careful monitoring of all vitals, especially blood pressure and respiratory rate, should be performed after the administration of benzodiazepines. In addition, waveform capnography should be considered to monitor respiratory status.Though the therapeutic index of benzodiazepines is high, monitoring respiratory depression is critical. Respiratory arrest has been noted to occur with rapid injection of benzodiazepines via theIV route.[44]

Toxicity

Signs and Symptoms of Overdose

Patients may exhibit extreme sedation, cognitive impairment, and ataxia, often accompanied by slurred speech. Respiratory depression represents a critical concern, necessitating prompt medical intervention. Cardiovascular effects, such as hypotension and bradycardia, further underscore the systemic consequences of benzodiazepine toxicity.

Management of Overdose

Benzodiazepineoverdose requiresmanagingthe airway, breathing, and circulation according to the American Heart Association (AHA) guidelines.[47]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. Flumazenil administration should be prudent, as it may precipitate withdrawal seizures. Of note, one multicenter 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 sedated benzodiazepine-overdosedpatients, as they may be unable to protect their airways.[48][49]The activated charcoal administration is contraindicated in benzodiazepine overdose. This is due primarily to altered mental status commonly associated withbenzodiazepine overdose, whichincreases the risk of aspiration of activated charcoal.[50]

Recommendations

TheAHA 2023 guidelines provide recommendations for cardiac arrest or toxicity due to benzodiazepine poisoning.Isolated benzodiazepine poisoning rarely causes life-threatening hemodynamic instability or respiratory depression.Flumazenil removes benzodiazepine-mediated suppression of the sympathetic system. It can lead to adverse cardiac events, including supraventricular tachycardia, ventricular dysrhythmias, and asystole, especially when coupled with other arrhythmogenic drugs or hypoxia. Flumazenil may not fully reverse respiratory depression in mixed overdoses, and the decision to administer flumazenil should consider potential concomitant opioid or CNS depressant poisoning, with naloxone often preferred.[51]

Enhancing Healthcare Team Outcomes

Benzodiazepines arecommonlyprescribed drugs inoutpatient andhospitalizedpatients. Benzodiazepines are effective for sedation and anxiolysis; they also have the potential to cause harm. All healthcare professionals, includingclinicians who prescribe these agents, must be fully aware of the drug'sadverse effects, misuse, abuse, and potential to develop physical dependence. Benzodiazepines are DEA-Scheduled IV drugs. Pharmacists should perform medication reconciliation and report to clinicians in case of significant drug-drug interaction. Anesthesiologists and certified registered nurse anesthetists are crucial in procedural sedation.

Nurses have an important role in monitoring patients in mechanically ventilated patients. Neurologists should be consulted for the appropriate use of benzodiazepines like clobazam for Lennox-Gastaut syndrome. Intensivists have an importantrole when benzodiazepines are used for sedation in mechanically ventilated patients. Emergency medicine physicians and nurses should rapidly stabilize the patient in overdose.When the patient is stable, the psychiatrist should be consulted. Psychiatrists play a crucial role in patients suffering from benzodiazepine use disorder. Finally, liberal prescribing of these drugs is not recommended as their abuse potential is high. Furthermore, the DEA has been cracking down on healthcare professionals who prescribe these agents without a valid reason and proper documentation.[52][53]

Benzodiazepine therapy requires the collaborative approach of an interprofessional healthcare team of clinicians,specialists, pharmacists, andspecialty-trained nurses working together to accomplish optimal patient outcomes. A study concluded that interprofessionalteam-based models that include clinical pharmacists and primary care physicians for anxiety and insomnia couldassist in optimizing therapy and minimizing the risk associated with benzodiazepine use.[54]

Review Questions

References

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: Disclosure: Connor Bounds declares no relevant financial relationships with ineligible companies.
: Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.
: Disclosure: Vivian Nelson declares no relevant financial relationships with ineligible companies.