Benzodiazepines

Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. The drug class of benzodiazepines has anxiolytic, muscle-relaxant, hypnotic, sedative, and anticonvulsant properties. These agents are not generally recommended for long-term use, as patients can develop physiological and psychological dependence. Side effects may include cognitive impairment, somnolence, and respiratory depression.

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Chemistry and Pharmacodynamics

Chemical structure

  • Benzodiazepines have a typical heterocyclic ring system, which is a fusion between benzene and diazepine rings.
  • There are a variety of drugs in the benzodiazepine class, which vary based on the attached side group.
  • Different side groups affect the binding affinity and interaction with GABA receptors.
Structure of benzodiazepines

Structure of benzodiazepines:
The image on the left shows the classic 1,4-benzodiazepine ring. The image on the right shows the most common benzodiazepine ring system.

Image: “Core chemical structure of the benzodiazepine ring system” by Boghog2. License: Public Domain

Mechanism of action

  • Benzodiazepines bind to the gamma subunit of the GABAA receptor → enhance the binding activity of GABA to the pocket between the α and 𝛃 subunits of the GABAA receptor 
  • ↑ Frequency of chloride channel opening → ↑ chloride influx → inhibits action potential 
  • Flumazenil is a competitive antagonist of benzodiazepines at the GABAA receptor.

Physiologic effects

GABA:

  • GABA is the main inhibitory neurotransmitter in the CNS
  • Neurons that use GABA as a transmitter contain an enzyme called glutamic acid decarboxylase (GAD), which converts the amino acid glutamate into GABA.

GABA receptors:

  • GABAA and GABAC receptors are ionotropic receptors, and GABAB receptors are G-protein-coupled, or metabotropic, receptors. 
  • GABAA and GABAB receptors modulate the inhibitory activity of the CNS. GABAC receptors are found in the retinal cells of the eye; their exact function is unknown. 
  • GABAA receptors are pentameric structures and consist of 2 α (alpha) subunits, 2 𝛃 (beta) subunits, and 1 γ (gamma) subunit.  
  • GABAA receptor locations and effects:
    • Cerebral cortex → confusion, amnesia
    • Thalamus → disinhibition, sedation, motor inhibition
    • Limbic structures → anxiolysis, sedation 

Benzodiazepine therapeutic effects:

  • Anxiolytic
  • Skeletal muscle relaxant 
  • Sedative: mitigates excitement, lessens activity, and produces calmness
  • Anticonvulsant: a medication that controls seizures
  • Hypnotic: 
    • Induce drowsiness and promote the onset and maintenance of sleep
    • ↓ REM sleep (when dreaming occurs)
  • Anesthesia
Benzodiazepine Dose-Response Curve

Benzodiazepine dose-response curve:
The dose-response curve for benzodiazepines is shown above. Benzodiazepines exert anxiolytic properties at low doses and have a ceiling effect, in which increasing doses peak at anesthetic effects.

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Absorption

Lipophilic benzodiazepines have a more rapid absorption.

Distribution

  • Benzodiazepines and metabolites are highly protein bound.
  • Widely distributed:
    • Enter the CNS (lipid solubility also increases the rate)
    • Cross placenta

Metabolism

  • Hepatic
  • Cytochrome P450 isozymes involved:
    • CYP3A4
    • CYP2C19
  • Some metabolites may be active → increased duration of therapeutic effect
  • Metabolites are conjugated → glucuronides

Excretion

Elimination occurs through the kidney (glucuronides are excreted in the urine).

Pharmacokinetics comparison table

The table below highlights important benzodiazepine medications and addresses the properties of each. With respect to pharmacokinetics, it is important to pay attention to the onset of action, metabolism, and elimination.

Table: Pharmacokinetics of benzodiazepines
DrugOnset of actionDurationMetabolismMajor active metabolites
AlprazolamIntermediateIntermediateCYP3A4No
ChlordiazepoxideIntermediateLongCYP3A4Yes
ClonazepamIntermediateIntermediateCYP3A4No
ClorazepateRapidLong
  • Prodrug
  • CYP3A4
Yes
DiazepamRapidLong
  • CYP2C19
  • 3A4
Yes
FlurazepamRapidLongCYP3A4Yes
LorazepamIntermediateIntermediateGlucuronidationNo
MidazolamRapidShortCYP3A4Yes
OxazepamSlowShortGlucuronidationNo
TemazepamSlowIntermediateGlucuronidationNo
TriazolamRapidShortCYP3A4No
Onset of action: rapid = 15–30 min; intermediate = 30–45 min; slow = 45–90+ min.
Duration: short = < 10 hours; intermediate = 10–36 hours; long = > 48 hours.

Indications

Benzodiazepines are CNS depressants. Therefore, they are clinically useful for situations when a sedating agent may be needed. The table below addresses individual agents and their indications. Here are general indications for benzodiazepines:

  • Seizure disorder: useful in the treatment of prolonged seizures in emergency settings
  • Alcohol withdrawal: ease withdrawal symptoms and prevent withdrawal seizures
  • Anxiety disorders:
    • Panic disorder
    • Generalized anxiety disorder
  • Insomnia: helpful in the short term but are not advised to be given for over a month for this indication
  • Anesthesia induction
Table: Benzodiazepines and their indications
MedicationFormulationIndications
AlprazolamOral
  • Anxiety disorders
  • Panic disorder
ChlordiazepoxideOral
  • Anxiety disorders
  • Alcohol withdrawal
  • Preoperative anxiety
ClonazepamOral
  • Panic disorder
  • Seizure disorders (mono- or adjunctive therapy: Lennox-Gastaut syndrome, akinetic, myoclonic, and absence seizures refractory to succinimides)
ClorazepateOral
  • Anxiety disorders
  • Alcohol withdrawal
  • Partial seizures: adjunct therapy
Diazepam
  • Oral
  • IV
  • IM
  • Rectal
  • Nasal
  • Anxiety disorders
  • Alcohol withdrawal
  • Muscle spasms
  • Seizures: adjunct therapy
  • Status epilepticus: adjunct therapy (injection only)
FlurazepamOralInsomnia
Lorazepam (Ativan®)
  • Oral
  • IV
  • IM
  • Anxiety disorders
  • Preanesthesia for anxiety or to produce amnesia/sedation
  • Status epilepticus
Midazolam (Versed®)
  • Oral
  • IV
  • IM
  • Nasal
  • Induction of anesthesia
  • Preoperative sedation/anxiolysis/amnesia
  • Sedation of intubated/mechanically ventilated patients
  • Acute intermittent seizures
OxazepamOral
  • Anxiety disorders
  • Alcohol withdrawal
Temazepam (Restoril®)OralInsomnia
Triazolam (Halcion®)OralInsomnia

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Adverse Effects and Contraindications

Overview

There are some high-yield points to pay attention to when considering benzodiazepines:

  • This class of medication should be used with caution in elderly patients and those with liver or kidney damage.
    • Major active metabolites, such as nordiazepam and N-Desalkylflurazepam, have long half-lives and accumulate over time. 
    • Thus, in elderly patients or patients with hepatic/renal impairment, the accumulation of active metabolites can lead to oversedation and anterograde amnesia. 
  • Hypnotic effects result in a rebound effect of increased REM sleep that occurs with discontinuation of benzodiazepines. This is especially the case with shorter-acting agents such as triazolam. 
  • All benzodiazepines should be used cautiously with opioids.

Adverse effects

  • Cardiovascular: hypotension 
  • Musculoskeletal: muscle weakness
  • Neurologic/psychiatric
    • Amnesia
    • Drowsiness
    • Dizziness
    • Sedation
    • Euphoria 
    • Ataxia
  • Respiratory: respiratory depression
  • Dermatologic: skin rash
  • Genitourinary: difficulty with micturition

Warnings

  • Beers criteria
  • Abuse potential: may cause euphoria with risk of dependence and drug withdrawal  
  • FDA C-IV controlled substances
  • Black-box warning: Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, or death.

Contraindications

  • Age: 
    • Pediatrics < 6 months old: diazepam oral
    • Premature Infants: lorazepam injection due to benzyl alcohol content 
  • Severe hepatic impairment (clonazepam and diazepam)
  • Myasthenia gravis
  • Respiratory:
    • Sleep apnea 
    • Chronic obstructive pulmonary disease (COPD)
    • Bronchitis
  • Ophthalmic:
    • Narrow-angle glaucoma
    • Untreated open-angle glaucoma

Drug interactions

  • Avoid other CNS depressants and sedatives (e.g., opioids, barbiturates, ethanol) 
  • Strong CYP3A4 or CYP2C19 inhibitors are contraindicated (e.g. itraconazole, ketoconazole) → ↑ benzodiazepine levels
  • Strong CYP3A4 or CYP2C19 inducers →  ↓ benzodiazepine levels

Overdose

These drugs rarely lead to overdose in isolation. When combined with other classes of drugs, such as alcohol and opiates, there is a much higher risk for toxicity. 

  • Symptoms of overdose:
    • Slurred speech and drowsiness
    • Hypotension
    • Respiratory depression
    • Coma
    • Cardiorespiratory arrest
  • Management:
    • Reversal agent: flumazenil 
      • Benzodiazepine antagonist
      • Beware of the potential for seizures in patients on long-term therapy.
    • Supportive care 
      • Maintain airway and intubate, if required.
      • IV fluids for hypotension; vasopressors if the patient is not fluid responsive
      • Bradycardia should be managed with pharmacologic therapy (e.g., atropine).

Clinical Relevance

The following are therapeutic uses of benzodiazepines:

  • Anxiety disorders: mental disorders that (combined) are the most prevalent type of psychiatric disorder in the United States. Anxiety disorders are characterized by excessive worry and fear. Examples include separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, and anxiety disorder due to another medical condition.  
  • Panic disorder: involves recurrent, unexpected (without a cue or trigger) panic attacks. Panic attacks are sudden bursts of intense fear or discomfort that culminate within minutes and may be associated with symptoms of sweating, palpitations, fear, nausea, and shortness of breath. 
  • Alcohol withdrawal: a group of symptoms that manifest upon abrupt cessation of the consumption of ethanol when it has been ingested regularly for a prolonged period of time. Symptoms of alcohol withdrawal consist of autonomic hyperactivity, hallucinations, anxiety, agitation, and tremors. Fatal complications can also potentially arise, such as seizures, delirium, and Wernicke-Korsakoff syndrome.

References

  1. O’Donnell, JM, Bies, RR, Shelton, RC. (2018). Drug therapy of depression and anxiety disorders. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. New York, NY: McGraw-Hill. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2189&sectionid=169518711
  2. IBM Micromedex® DRUGDEX®. (2021). IBM Watson Health, Greenwood Village, Colorado, USA. Retrieved June 11, 2021, from https://www.micromedexsolutions.com/
  3. Precision Dose Inc. Midazolam hydrochloride syrup. (2015). In: DailyMed. Bethesda (MD): U.S. National Library of Medicine. Retrieved June 11, 2021, from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9a443652-6aff-4e27-83fe-90c65fa0f3c1
  4. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. (2013). Arlington, VA, American Psychiatric Association.
  5. Khanna, AK, et al. (2018). Respiratory depression in low acuity hospital settings-Seeking answers from the PRODIGY trial. J Crit Care. https://doi.org/10.1016/j.jcrc.2018.06.014.  
  6. Griffin, CE, et al. (2013). Benzodiazepine pharmacology and central nervous system-mediated effects. The Ochsner Journal, 13(2): 214–223. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/
  7.  Trevor, AJ, and Way, WL. (2012). Sedative-hypnotic drugs. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 373–382). McGraw-Hill Companies, Inc. https://accesspharmacy.mhmedical.com/content.aspx?bookid=514&sectionid=41817537

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