Chemistry and Pharmacodynamics
- 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.
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.
- 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.
- 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:
- Skeletal muscle relaxant
- Sedative: mitigates excitement, lessens activity, and produces calmness
- Anticonvulsant: a medication that controls seizures
- Induce drowsiness and promote the onset and maintenance of sleep
- ↓ REM sleep (when dreaming occurs)
Lipophilic benzodiazepines have a more rapid absorption.
- Benzodiazepines and metabolites are highly protein bound.
- Widely distributed:
- Enter the CNS (lipid solubility also increases the rate)
- Cross placenta
- Cytochrome P450 isozymes involved:
- Some metabolites may be active → increased duration of therapeutic effect
- Metabolites are conjugated → glucuronides
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.
|Drug||Onset of action||Duration||Metabolism||Major active metabolites|
Duration: short = < 10 hours; intermediate = 10–36 hours; long = > 48 hours.
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
Adverse Effects and Contraindications
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.
- Cardiovascular: hypotension
- Musculoskeletal: muscle weakness
- Respiratory: respiratory depression
- Dermatologic: skin rash
- Genitourinary: difficulty with micturition
- 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.
- Pediatrics < 6 months old: diazepam oral
- Premature Infants: lorazepam injection due to benzyl alcohol content
- Severe hepatic impairment (clonazepam and diazepam)
- Myasthenia gravis
- Sleep apnea
- Chronic obstructive pulmonary disease (COPD)
- Narrow-angle glaucoma
- Untreated open-angle glaucoma
- 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
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
- Respiratory depression
- Cardiorespiratory arrest
- 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).
- Reversal agent: flumazenil
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.
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- 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.
- 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/
- 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§ionid=41817537