Benzodiazepine [BSA]

Benzodiazepines (BZDs) are commonly known as "sleeping pills" in our lives. However, the functions of benzodiazepines are more than just sedation and hypnosis. First of all, benzodiazepines are representatives of anti-anxiety drugs. They take effect quickly and are especially suitable for panic attacks. In other anxiety disorders, they are often used for acute treatment before SSRI or SNRI drugs take effect. Secondly, it has an anticonvulsant effect and is commonly used in patients with epilepsy and alcohol withdrawal. Thirdly, it has a skeletal muscle relaxant effect and can relieve the patient's tonic spasm state.

Figure 1. Representation of the benzodiazepines (BDZ) action mechanism and their role in the nervous impulse inhibition. (Sources: Sanabria E, et al. 2021)

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human body. GABA receptors can be divided into three subtypes: GABAA receptors, GABAB receptors, and GABAC receptors. After the activation of A receptors and C receptors, chloride ions flow in; after the activation of B receptors, potassium ions flow out, both of which play a role in hyperpolarizing the cell. After the neuron is hyperpolarized, the discharge is inhibited, the excitability of the neuron is reduced, and the transmission of excitatory neurotransmitters such as 5-HE and NE is also inhibited, thereby playing a central nervous system inhibitory effect. Among the three receptor subtypes, GABAA receptors regulate anxiety and sleep. After benzodiazepines bind to BZD receptors on the GABAA receptor complex, on the one hand, they open chloride ion channels, and on the other hand, they promote the binding of GABA to GABAA receptors, which increases the frequency of chloride ion channel opening, promotes chloride ion influx from a dual pathway, and enhances central inhibition. In other words, benzodiazepines stimulate GABA receptors in the ascending reticular activating system, enhance the inhibition and blocking of cortical and limbic arousal responses after the brainstem reticular formation is stimulated, thereby playing an anti-anxiety, sedative and hypnotic role. All benzodiazepines have similar pharmacological actions. When using them specifically, their respective pharmacokinetic characteristics are usually referred to in order to find the most suitable one. These characteristics include the speed of onset (distribution half-life), the retention time in the body (elimination half-life), the main metabolic decomposition pathway, etc. After oral administration, most BZDs are rapidly absorbed in the intestine, are highly lipophilic and protein-bound, and are metabolized in the liver. In the liver, most are metabolized by CYP3A4 and CYP2C19. Therefore, other drugs that affect CYP enzyme metabolism can interact with BZDs, such as prolonging the half-life of the drug, thereby prolonging the clinical effect. Oxazepam and lorazepam directly bind to glucuronic acid in the liver, without being metabolized by CYP450 enzymes, and are not easy to interact with other drugs. Among them, the clearance rate of oxazepam is almost unaffected by age and liver disease, and it is relatively safe among all BZDs. Other BZDs should be used with caution in patients with liver damage.

BZDs are usually divided into three categories based on their elimination half-life: short-acting (<10 hours), intermediate-acting (10-24 hours) and long-acting (>24 hours). Representatives of short-acting drugs are triazolam and midazolam, which have a rapid onset and a short duration of action; representatives of intermediate-acting drugs are alprazolam, estazolam, oxazepam, and lorazepam; representatives of long-acting drugs are clonazepam (Clonazepam) and diazepam (Valium), which are slowly metabolized and usually produce pharmacologically active metabolites. Repeated administration can accumulate in the body and has a long duration of action. For insomnia patients, medium-acting drugs are suitable for those who have difficulty falling asleep and maintaining sleep; long-acting drugs are suitable for those who wake up early, but they have a long half-life and often have a "hangover" feeling, which affects the next day's activities. Especially in the elderly, they are prone to fall risks and are rarely used to help sleep. Although short-acting drugs are very effective for difficulty falling asleep, they are addictive and more likely to cause forgetfulness. Of course, benzodiazepines are not recommended as the first choice for both anxiety and insomnia patients, which is at least partly due to the dependence and withdrawal risks of BZDs. When a drug is used for a long time and then stopped, the time when withdrawal symptoms appear is related to the retention time of the drug (or its active metabolite) in the body. Therefore, short- and medium-acting BZDs are more likely to have acute withdrawal reactions (common insomnia, tremor, anxiety, muscle tension, etc., less common perceptual disorders, psychotic symptoms, epileptic seizures, etc.), and the withdrawal symptoms caused by long-acting BZDs usually appear later and are milder. Withdrawal symptoms also occur more often in cases of high-dose use. Therefore, the principle of using BZDs is short-term, low-dose, and intermittent treatment. If possible, try to reduce the dosage slowly, and it is recommended to reduce the dosage by 10% every 1-2 weeks. Another reason for the reduction in the use of benzodiazepines is the concern about the risk of forgetfulness and cognitive impairment. GABAA receptors are distributed in the hippocampus, so the use of BZDs will interfere with the establishment of memory pathways and affect recent memory. But this is generally considered to be short-term and reversible, and can recover on its own after stopping the drug. However, some studies in recent years have suggested that long-term use of BZDs may increase the risk of Alzheimer's disease. Although this is very controversial, some studies have suggested that there is no connection between the two, but the use of BZDs in the elderly population requires weighing the risks and benefits.

Benzodiazepine derivatives
BZDs
Benzos