What is the Difference Between Benzodiazepines and Nonbenzodiazepines

The key difference between benzodiazepines and nonbenzodiazepines is that benzodiazepines are hypnotics with a specific chemical structure characterized by a benzene ring fused with a diazepine ring, while nonbenzodiazepines are not structurally related to benzodiazepines but contain more favorable therapeutics and toxicological profiles.

Hypnotics such as benzodiazepines and nonbenzodiazepines are frequently prescribed for sleep disorders. This trend started in the 1960s and persisted up to date with fewer modifications. Benzodiazepines have obtained great success in the clinical setup; however, they are also associated with side effects such as alteration of the sleep architecture, agitation, cognitive impairment, confusion, depression, and dementia. Due to these limitations, alternative anxiolytic hypnotics such as nonbenzodiazepine have been developed with more favourable therapeutic and toxicological profiles. Both benzodiazepines and nonbenzodiazepines display the same mechanism of action; positive allosteric regulation of gamma amino-butyric acid (GABA) A receptor (GABA_A).

CONTENTS

1. Overview and Key Difference
2. What are Benzodiazepines 
3. What are Nonbenzodiazepines
4. Similarities – Benzodiazepines and Nonbenzodiazepines
5. Benzodiazepines vs Nonbenzodiazepines in Tabular Form
6. Summary – Benzodiazepines vs Nonbenzodiazepines

What are Benzodiazepines?

Benzodiazepine hypnotics are positive allosteric regulators of the GABA_A in the central nervous system. They are commonly prescribed for psychiatric disorders due to their sedative, hypnotic, anticonvulsant, and muscle-relaxant properties. Benzodiazepines are generally considered safe and effective for short-term use, while long-term use has been associated with lower drug efficacy and potential side effects. The common side effects of benzodiazepines include alteration of the sleep architecture, agitation, cognitive impairment, confusion, depression, and dementia.

Their action is primarily mediated through binding with the benzodiazepine binding site of the GABA_A, which ultimately promotes the binding of GABA into GABA_­A. The activation of GABA_A allows an influx of chloride ions resulting in hyperpolarization of the neuronal membrane to prevent the initiation of the new action potential. Benzodiazepines are rapidly absorbed in the gastrointestinal tract upon oral administration. The onset of action may vary from 30 minutes to 2 hours. They are extensively metabolized in the liver by glucuronide conjugation and microsomal oxidation.

What are Nonbenzodiazepines?

Nonbenzodiazepine hypnotics, or “Z” drugs, are commonly prescribed for psychiatric disorders and insomnia and are positive allosteric regulators of the central nervous system. These drugs were initially developed as immediate-release tablets; extended-release formulations such as Zolpidem have recently been introduced. Furthermore, the half-life of the nonbenzodiazepine and duration of action are varied from short-acting Zoleplon to moderately acting Zolpidem. These medications are structurally different from benzodiazepines and can selectively bind with the benzodiazepine binding site of the GABA_A receptor resulting in sedation. Nonbenzodiazepines are associated with narrower side effects with a lower risk of dependency and abusive potential.

Nonbenzodiazepines such as Zolpidem, Indiplon, and Ocinaplon are well absorbed after oral administration, with the peak plasma concentration achieved within 1-2 hours. After the absorption, they are well distributed to the tissues, including the central nervous system, by crossing the blood-brain barrier. Most nonbenzodiazepines are extensively metabolized in the liver by cytochrome p450 enzymes. The elimination half-life of nonbenzodiazepines depends on the drug. For instance, Zolpidem has a relatively low half-life of about 1-2 hours, while Eszopiclone has a longer half-life of about 6 hours. Moreover, the metabolized and unchanged drugs are primarily excreted with urine.

What are the Similarities Between Benzodiazepines and Nonbenzodiazepines?

• Benzodiazepines and nonbenzodiazepines are used mainly to treat insomnia.
• Both drug classes exhibit sedative effects by targeting the brain’s gamma-aminobutyric acid (GABA) neurotransmitter system.
• They act on the Benzodiazepine binding site of the GABA_A receptor complex, enhancing the effects of GABA.
• Both drug classes have a relatively fast onset of action, allowing quick sleep induction or reduced anxiety symptoms.
• Benzodiazepines and nonbenzodiazepines share potential side effects, including drowsiness, dizziness, impaired coordination, memory impairment, and potential for next-day residual effects.
• Similar precautions apply to both classes, such as caution in individuals with a history of substance abuse, respiratory conditions, liver or kidney dysfunction, or concurrent use of other central nervous system depressants.

What is the Difference Between Benzodiazepines and Nonbenzodiazepines?

Both benzodiazepines and nonbenzodiazepines are hypnotics, primarily prescribed to treat sleep disorders. Both drugs bind to the benzodiazepine binding site of the GABA_A receptor to enhance the effect of GABA in the central nervous system. However, there is a notable difference between benzodiazepines and nonbenzodiazepines. The structure of benzodiazepines is chemically characterized by the benzene ring fused with a diazepine ring, while the chemical structure of nonbenzodiazepines is different from benzodiazepines.

Nonbenzodiazepines are associated with narrower side effects and a lower risk of dependency and abusive potential compared to benzodiazepines. While benzodiazepines and nonbenzodiazepines are used to treat sleep disorders, benzodiazepines are also prescribed for other indications, such as anxiety disorders, panic disorders, and muscle spasms. In contrast, nonbenzodiazepines are primarily indicated for insomnia treatment.

Below is a summary of the difference between benzodiazepines and nonbenzodiazepines in tabular form for side-by-side comparison.

Summary – Benzodiazepines vs Nonbenzodiazepines

Anxiolytic hypnotics such as benzodiazepines and nonbenzodiazepines are primarily prescribed for sleep disorders. Both drugs bind with the benzodiazepine binding site of the GABA_A receptor, activating the GABA-mediated sedative effect. Due to their side effects, dependency, and abusive potential, benzodiazepines have been replaced with nonbenzodiazepines such as Zolpidem, Indiplon, and Ocinaplon. In addition to their safety and efficacy, nonbenzodiazepines are highly specific for the GABA_A receptors and have shorter half-lives resulting in rapid clearance. In addition to managing insomnia, benzodiazepines are also prescribed to treat anxiety disorders, panic disorders, and muscle spasms. In contrast, nonbenzodiazepines are highly specific for managing insomnia. So, this is the summary of the difference between benzodiazepines and nonbenzodiazepines.

Reference:

1. Mandrioli, Roberto, et al. “Metabolism of Benzodiazepine and Non-Benzodiazepine Anxiolytic-Hypnotic Drugs: An Analytical Point of View.” Current Drug Metabolism, vol. 11, no. 9, 2010, pp. 815–829.
2. Wagner, Judy, and Mary L. Wagner. “Nonbenzodiazepines for the Treatment of Insomnia.” Sleep Medicine Reviews, vol. 4, no. 6, 2000, pp. 551–581.

Image Courtesy:

1. “Benzodiazepine” By NEUROtiker – Own work (Public Domain) via Commons Wikimedia
2. “Zolpidem” By Harbinary – Own work using: PubChem (Public Domain) via Commons Wikimedia