Benzodiazepines and Barbiturates

Benzodiazepines

In class today, we studied pharmacology of GABA-A receptors, specifically Benzodiazepine's. Of personal interest as I've been on lorazepam (fast acting for agitation, mood swings) and clonazepam (longer lasting). Unfortunately the body develops a tolerance and these don't work anymore.

Benzodiazepines work by enhancing the activity of GABA in the brain, leading to decreased neuronal excitability. However, their unique pharmacokinetic profile and molecular binding mechanisms can result in in how quickly it takes effect, how long it stays in the body, and how it is metabolized. Some benzos are short-acting and have a rapid onset of action, while others are long-acting and have a slower onset of action but a longer duration of effect.

Common ones are

Alprazolam (Xanax): used for anxiety disorders and panic attacks.

• binds to the benzodiazepine site on the GABA-A receptor, located at the interface between the alpha and gamma subunits. This binding increases the affinity of the receptor for GABA, leading to enhanced GABAergic inhibition and decreased neuronal excitability.

Diazepam (Valium): used to treat anxiety disorders, muscle spasms, and as a pre-operative sedative.

• binds to same site but has a higher affinity for this site than alprazolam. 
• binding increases the opening of the Cl- ion channel, leading to increased ion influx and hyperpolarization of the neuron.

Lorazepam (Ativan): used to treat anxiety disorders, insomnia, and as a pre-operative sedative.

• binds to the same site, but with a higher affinity. 
• enhances GABAergic inhibition by increasing the duration of the chloride channel opening, leading to longer-lasting hyperpolarization and greater suppression of neuronal activity

Clonazepam (Klonopin): used to treat anxiety disorders and seizure disorders.

• binds to a different site on the GABA-A receptor, called the benzodiazepine recognition site (BZR). 
• binding enhances the affinity of the receptor for GABA, leading to increased GABAergic inhibition and decreased neuronal excitability.

Temazepam (Restoril): used to treat insomnia.

• binds to the benzodiazepine site on the GABA-A receptor but a shorter duration of action than diazepam or lorazepam. Temazepam enhances GABAergic inhibition and produces sedative and anxiolytic effects.

Midazolam (Versed): used as a sedative for medical procedures or surgeries.

• binds to the same site on the GABA-A receptor as diazepam and lorazepam, but with a higher affinity for the receptor. 
• binding enhances GABAergic inhibition and produces sedative and anxiolytic effects, as well as anterograde amnesia.

Oxazepam (Serax): used to treat anxiety disorders and alcohol withdrawal symptoms.

• binds to the same site on the GABA-A receptor as diazepam and lorazepam, but shorter duration of action. 
• binding enhances GABAergic inhibition and produces sedative and anxiolytic effects

Barbiturates

Prior to the development of Benzos were the Barbiturates (sedative and hypnotic drugs) that act on the central nervous system. They were commonly used in the past to treat anxiety, insomnia, seizure disorders, and in autism (hyperactivity and aggression) but have largely been replaced by benzodiazepines due to their higher risk of side effects and potential for abuse. Celebrity barbiturate OD deaths include - Elvis, Janis Joplin, Marilyn Monroe and Jimi Hendrix.

• Phenobarbital: used primarily as an anticonvulsant to treat seizure disorders and as a sedative for anesthesia.
• Pentobarbital: used as a sedative for anesthesia, as well as for the treatment of insomnia and anxiety disorders.
• Amobarbital: used for the treatment of insomnia, as well as for sedation before medical procedures.
• Secobarbital: used for the treatment of insomnia, as well as for sedation before medical procedures.
• Butalbital: used in combination with other drugs, such as acetaminophen and caffeine, to treat tension headaches.

Barbiturates can have potentially serious side effects, including drowsiness, dizziness, impaired coordination, respiratory depression, and addiction. They can also interact with other drugs and increase the risk of overdose. Due to the potential risks associated with barbiturates, they are typically only used in certain medical situations and under close medical supervision. 

Molecular Mechanisms.

Barbiturates work by enhancing the activity of the inhibitory neurotransmitter GABA in the brain. Like benzodiazepines, barbiturates bind to specific sites on the GABA-A receptor in the brain, but they have a distinct mechanism of action.

Barbiturates bind to a specific site on the GABA-A receptor that is distinct from the benzodiazepine site. This site is located within the transmembrane region of the receptor and is known as the barbiturate binding site or the "modulatory site". When barbiturates bind to this site, they increase the duration of GABA-mediated chloride ion channel opening, leading to an increase in chloride ion influx and hyperpolarization of the neuron. This hyperpolarization makes it more difficult for the neuron to reach its threshold for firing an action potential, resulting in decreased neuronal excitability.

In addition to their effects on GABA-A receptors, barbiturates also bind to other ion channels in the brain, such as voltage-gated sodium channels and calcium channels, and modulate their activity. This can contribute to their sedative and anesthetic effects.

The effects of barbiturates are dose-dependent, with low doses producing sedative effects and higher doses producing anesthesia. At very high doses, barbiturates can cause respiratory depression and death.