Anticonvulsants and anxiolytics: Benzodiazepines

Benzodiazepines are a class of medications that act as a central nervous system depressant.  They have a wide variety of uses including anxiolytic effects, or to relieve anxiety; as anticonvulsants, or to manage seizure disorders; as a hypnotic for insomnia; as an anesthetic; and to treat withdrawal syndromes. They act by enhancing the main inhibitory neurotransmitter gamma-aminobutyric acid, or GABA, by binding to its receptor.  

It’s pretty well-established that your brain’s really important. It controls your feelings, your movements, your sleep, your memory… It controls everything, whether you’re aware of it or not. The cells that make up our brain are called neurons. Neurons communicate with each other through neurotransmitters. When one neuron is stimulated, it’ll release excitatory neurotransmitters like glutamate which bind to receptors on the next neuron. This causes the next neuron to depolarize and release its own excitatory neurotransmitters, propagating the signal throughout the brain.  

Now, we also have inhibitory neurons that will shut down this chain of events. These neurons release the main inhibitory neurotransmitter gamma-aminobutyric acid, or GABA, which binds to GABA receptors on other neurons. These receptors are large, multi unit complexes that form ligand-gated ion channels that open up to let Cl- ions into the cell. The influx of negatively charged ions causes hyperpolarization, where the cell’s membrane potential becomes more negative, which means it’s much more difficult for it to depolarize and fire off an action potential, meaning it’s less responsive to stimuli.  

Alright, now there are cases where neurons in the brain start sending out more excitatory signals than normal. This can occur due to either too much excitation by the excitatory neurotransmitters, or too little inhibition by the inhibitory neurotransmitters like GABA. Excessive excitatory signals can cause psychiatric disorders like anxiety, and neurological disorders like seizures and epilepsy.  

Okay, so one way we can decrease the excitatory signals is by enhancing the effect of inhibitory neurons through medication like benzodiazepines. They are composed of a benzene ring that consists of six carbon atoms fused to a diazepine ring that is made up of 5 carbon atoms and two nitrogen atoms.    
Now, based on the overall duration of action, these medications can be subdivided into short-acting benzodiazepines, like ALPRAZolam, Triazolam, Oxazepam, and Midazolam; intermediate-acting benzodiazepines, such as Temazepam, LORazepam, and ClonazePAM; and finally, long-acting benzodiazepines, like ChlordiazePOXIDE, DiazePAM, and Flurazepam. So, to remember short-acting benzodiazepines think of “ATOM”; for intermediate-acting, remember that these medications are tender, loving, and caring, or short TLC; and finally for long-acting benzodiazepines, think of alphabet and it’s order CDeF. These medications target the BZ site of GABAA receptors, which is located between ⍺1 and 2 subunits of the receptor. When both benzodiazepine and GABA bind to their separate sites on the receptor, benzodiazepines increase the frequency of Cl- channels opening, thereby increasing the influx of Cl- ions. As a result, high intracellular concentrations of Cl- ions cause membrane hyperpolarization, which means it’s much more difficult for neuron to depolarize and fire off an action potential. Now, a similar group of medications called barbiturates also function by binding to GABAA receptors. The important distinction is that barbiturates work by increasing the duration of Cl- channels opening and unlike benzodiazepines, they can cause the channels to open even in the absence of GABA.

Now, let’s draw a chart of the dose-dependent effects of benzodiazepines. On the left side of the chart, let’s place central nervous effects and on the bottom, let’s place dose. Low doses of benzodiazepines cause sedation, disinhibition, and anxiolysis; but as the dose increases, benzodiazepines cause hypnosis and anesthesia. Since they don’t have GABA mimetic effect, benzodiazepines reach the plateau; therefore they are not associated with medullary depression and coma.  

Alright, so benzodiazepines are indicated when the neurons get “super excited” and we want to calm them down like in anxiety disorders, or during a panic attack. It’s important to note that preferred medications for the long-term treatment of panic attacks are selective serotonin reuptake inhibitors, or short SSRIs, due to abuse potential, dependence, and tolerance of benzodiazepines. Benzodiazepines are also very effective anticonvulsants and are considered the treatment of choice for status epilepticus, which is when a person has over 5 minutes of ongoing seizures or multiple seizures without returning to normal in between. Certain benzodiazepines are also used for anesthesia since we basically want to depress the function of the patient’s nervous system. For the same reason, they are an effective treatment for insomnia, but they decrease REM sleep. Moreover, because they decrease REM sleep, they can also be used to treat night terrors, which is a sleep disorder similar to nightmares but far more dramatic as it’s associated with screaming and crying. Since alcohol and barbiturates also work by targeting GABAA receptors, benzodiazepines can be used to manage their withdrawal symptoms by decreasing their severity. DiazePAM can also be used as the second-line treatment for eclampsia, which is a life-threatening complication of pregnancy that is associated with seizures. But, it’s important to note that diazePAM should be used only if seizures recur after giving magnesium sulfate (MgSO4), which is the first-line treatment for eclampsia. Finally, they are sometimes used as muscle relaxants to treat spasms, like those caused by cerebral palsy.