Benzodiazepines are a class of psychotropic medications with sedative-hypnotic, anxiolytic, anticonvulsant, and muscle relaxant effects. Benzodiazepines are among the most misused and misprescribed medications in the world.[1][2] Benzodiazepines carry a risk of increased sedation, cognitive impairment, and respiratory depression in those with liver impairments, and there is an increased risk of respiratory depression with opioid or alcohol use.
In 1955, chemist Leo Sternbach while working at Hoffmann-La Roche serendipitously identified the first benzodiazepine, chlordiazepoxide (Librium).[3] Initially thought to be less toxic and having little effect on respiratory depression, benzodiazepines became the most commonly prescribed medications in the mid-to-late 1970s. By the 1980s, concerns about addiction and abuse began to come up, particularly for older adults.
All benzodiazepines are metabolized by the liver. However, some benzodiazepines (i.e. - lorazepam, oxazepam, and tamazepam) do not go through cytochrome P450 metabolism (Phase I metabolism), and are only metabolized via glucuronidation (Phase II metabolism).
Benzodiazepines (and Z-drugs in general) are positive allosteric modulators (PAMs - this is not the same as agonists!) that act on γ-aminobutyric acid (GABA-A) receptor binding sites that potentiates GABA's inhibitory effect. The combination of GABA at the GABA-A receptor’s agonist site and a benzodiazepine-receptor agonist at the positive allosteric site increases the overall frequency of the chloride channel opening than GABA alone by itself. When a greater frequency of chloride ions to enter through the receptor, this increases polarization and increases GABA-mediated inhibitory action.
Benzodiazepines are highly protein bound, distribute widely in the body, and accumulate in lipid-rich areas such as the central nervous system and fatty tissue. The more lipophilic a benzodiazepine, the higher the rate of absorption and faster the onset of clinical action. For example, diazepam and midazolam have the highest lipid solubility and therefore also the quickest onset of action.
Most indications for benzodiazepines are based on short-term studies and used in acute medical conditions such as:
Note that most benzodiazepine equivalence estimates are based on expert clinical opinion, hypothesized equivalence tables (see above links). As a result, these values are meant as a guide and not a direct reflection of equivalence!
Benzodiazepines | Diazepam Equivalent (10 mg), PO | Duration of Action | Peak Onset (hours) | Half-life (hours) | Notes |
---|---|---|---|---|---|
Alprazolam | 0.5 mg | Short | 0.7-1.6 | 6-20 | High risk of misuse |
Clobazam | 20 mg | Long | 0.5-4 | 42-47 | Commonly used as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome |
Clonazepam | ~0.25 mg to 0.5 mg[5] | Long | 1-4 | 18-39 | Fast onset, long acting, high potency, partial serotonin agonist |
Diazepam | 10 mg | Long | 1 | 20-100 | Commonly used in management of alcohol withdrawal |
Estazolam | 1-2 mg | Intermediate | 1-6 | 10-24 | May be used in short-term management of insomnia |
Flurazepam | 15-30 mg | Short | 0.5-2 | 47-100* | May be used in short-term management of insomnia |
Lorazepam | 1 mg | Intermediate (PO) Short (SL/IV) | 1.-1.5 | 10-20 | Commonly used in pharmacological management of agitation, severe anxiety, alcohol withdrawal, seizure disorders, procedural sedation, insomnia |
Midazolam | 5 mg[6] | Short | 15 minutes (IM) | 3 | Seizures, procedural sedation, severe agitation |
Oxazepam | 20 mg | Short | 2-3 | 4-15 | Oxazepam is the active metabolite of diazepam and tamazepam (among others) |
Tamazepam | 10-20 mg | Short[7] | 0.75-1.5 | 8-22 | - |
Quazepam | 20 mg | Long | 2 | 25-100 | - |
Triazolam | 0.5 mg | Short | 0.75-2 | 2 | - |
Non-Benzodiazepines | |||||
Zaleplon | 20 mg | Short | 1 | 2 | Used in short-term treatment of insomnia |
Zolpidem | 20 mg | Short | 1 | 2 | Used in short-term treatment of insomnia |
Zopiclone | 15 mg | Short | 1-2 | 5-6 | Used in short-term treatment of insomnia |
Eszopiclone | 3 mg | Short | 1 | 6 | Used in short-term treatment of insomnia |
ATOM
benzodiazepines all have rapid onset and are short-acting, which increases risk for abuse, misuse, and addiction.A
- AlprazolamT
- TriazolamO
- OxazepamM
- MidazolamBenzodiazepines carry a higher adverse event rate compared to other psychotropics such as antidepressants.[8][9] Thus, it is particularly important to prescribers to have informed consent discussions with patients about the use of benzodiazepines and their short-term indicatons.
Drug | Interaction |
---|---|
Fluoxetine, fluvoxamine, sertraline | Decreases metabolism, and increases plasma levels of benzodiazepines metabolized by CYP3A4 (e.g. - alprazolam, diazepam) |
Carbamazepine | Increases metabolism and decreases plasma levels |
Isoniazid | Decreases metabolism, and increases plasma levels of benzodiazepines metabolized by CYP3A4 (e.g. - alprazolam, diazepam) |
Erythromycin | Decreases metabolism, and increases plasma levels of benzodiazepines metabolized by CYP3A4 (e.g. - alprazolam, diazepam) |