Anticonvulsants and anxiolytics: Barbiturates

Barbiturates are a class of medications that are used as anticonvulsants to manage seizure disorders; to induce anesthesia in surgical procedures; as anxiolytics to relieve anxiety; and to manage insomnia. Barbiturates enhance the effect of gamma-aminobutyric acid, or GABA, which is the major inhibitory neurotransmitter in the brain, 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 in the nervous system, 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, which 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, and that means it’s less responsive to stimuli.

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 barbiturates. Common medications in this class include amobarbital, butabarbital, methohexital, PENTobarbital, PHENobarbital, and primidone, which is a prodrug of PHENobarbital. Another medication from this group is thiopental, but it’s not available in the U.S. and Canada anymore. These medications target the GABAA receptors but they bind at a different site than GABA or benzodiazepines. At lower doses, barbiturates enhance the effect of GABA by increasing the duration 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 the neuron to depolarize and fire off an action potential. This differentiates them from benzodiazepines which also work by binding to GABAA receptors, but in contrast to barbiturates, they work by increasing the frequency of Cl- channels opening. So remember, barbiDurates increase duration! At higher doses, these medications can mimic GABA effect by triggering the opening of these channels even without GABA. In addition, barbiturates block excitatory glutamate receptors called AMPA receptors and decrease neuronal excitability; but they also inhibit voltage-gated calcium channels and decrease the release of glutamate.

Now, let’s draw a chart of the dose-dependent effects of barbiturates. On the left side of the chart, let’s place central nervous effects; and on the bottom let’s place dose. Low doses of barbiturates cause sedation, disinhibition, and anxiolysis; but as the dose increases, barbiturates cause hypnosis, anesthesia, medullary depression, and eventually coma. 

Now at a higher dose, barbiturates also inhibit the electron transport chain, which is a process that occurs within the inner mitochondrial membrane and results in the synthesis of adenosine triphosphate, or ATP. ATP is the main form of energy that keeps all of our body cells going. So when the electron transport chain gets interrupted, the ATP synthesis doesn’t happen and that can eventually lead to the death of the cell. Barbiturates also induce a class of enzymes called cytochrome P450. These enzymes are involved in the metabolism of various medications like benzodiazepines, phenytoin, quinidine, warfarin, and others. Increased cytochrome P450 activity can cause these medications to break down more rapidly, so larger doses may be needed to achieve a therapeutic effect.  

Alright, now barbiturates are indicated when the neurons get “super excited” and we want to calm them down, like during an epileptic seizure where clusters of neurons in the brain become temporarily impaired and start firing off a ton of excitatory signals. Moreover, PHENobarbital is the first-line treatment for neonatal convulsions. Also, this feature makes them useful for treating acute anxiety states like a panic attack. In addition, barbiturates can be used for preoperative sedation and to induce anesthesia; but they can also be given as a hypnotic to induce sleep since we basically want to depress the function of the person’s nervous system. Finally, in life-threatening conditions, such as increased intracranial pressure, these medications can be used to decrease cerebral blood flow and induce coma, which is also known as the barbiturate-induced coma.