Select Page

Benzodiazepine Mechanism of Action

Benzodiazepines, like alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin) and clonazepam) act on the central nervous system (CNS) and brain. They are known pharmacologically as GABAergic agents, sedative-hypnotics, or minor tranquilizers.

Benzodiazepines work by enhancing a very important neurotransmitter called GABA (gamma-aminobutyric acid) at the GABA A receptor. This results in the sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties for which the drugs are prescribed.

 

By BruceBlaus – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=44968541

GABA is the chief inhibitory neurotransmitter in the mammalian central nervous system. Its role is in reducing neuronal excitability and, in humans, it is also responsible for the regulation of muscle tone. If your nervous system was a car, GABA functions much like the “brakes”. When the “car” takes off speeding down the road (excitability of the nervous system), GABA functions as the “brakes” to calm and slow it down.

Simply put, GABA sends its inhibitory message by binding at special sites called GABA-A receptors on the outside of the receiving neuron. Once GABA is bound to the GABA-A receptor, the neuron opens a channel which allows chloride ions to pass inside of the neuron. These negative chloride ions make the neuron less responsive to other neurotransmitters (norepinephrine [noradrenaline], serotonin, acetylcholine and dopamine) which would normally excite it. Benzodiazepines also bind to their own receptors (benzodiazepine receptors) that are situated on the GABA-A receptor. Combination of a benzodiazepine at this site acts as a booster to the actions of GABA, allowing more chloride ions to enter the neuron, making it even more resistant to excitation.

This short video explains this concept visually:

A simplified visual of how benzodiazepines (and barbiturates) work is illustrated in this simple animation video:

How Do Benzodiazepines Impact the Brain?

Long-term benzo usage can cause what is known as ‘uncoupling’ of the GABA-A receptor. Uncoupling results in a decrease in the ability of BZs to potentiate the action of GABA on GABA-A receptors and in a decrease in the ability of GABA to potentiate BZ binding. This may be due to changes in GABA-A receptor gene expression where the neurons swap out GABA-A receptors that contain subunits benzos bind to with ones that don’t, to combat the action of the drug. FDA information for Ativan states withdrawal symptoms can be experienced by some after as little as one week of use, suggesting uncoupling occurs even with shorter-term use. In depth information on how the GABA-A receptors work with benzodiazepines can be found here.

When the brain’s output of excitatory neurons is reduced, a consequence of the enhancement of GABA’s inhibitory activity caused by benzodiazepines, there may be impairment of certain functions, as the excitatory neurotransmitters are necessary for normal alertness, memory, muscle tone and coordination, emotional responses, endocrine gland secretions, heart rate and blood pressure control and a host of other functions. Other benzodiazepine receptors not linked to GABA are present in the kidney, colon, blood cells and adrenal cortex and these may also be affected by some benzodiazepines. These direct and indirect actions are responsible for the well-known adverse effects of dosage with benzodiazepines.

There are also various subtypes of benzodiazepine receptors, all of which have slightly different actions. The alpha 1 subtype is responsible for sedative effects, the alpha 2 for anti-anxiety effects, and both alpha 1 and alpha 2 (as well as alpha 5) for anticonvulsant effects. All benzodiazepines combine, to a greater or lesser extent, with all these subtypes and all enhance GABA activity in the brain.

What are Z Drugs and How Are They Similar to Benzodiazepines?

Non-benzodiazepines, sometimes referred to as ‘Z-drugs’ or hypnotics, are also a class of psychoactive drugs that are very similar to the benzodiazepines. 

Most Z-drugs, like Zolpidem (Ambien), zaleplon (Sonata) and eszopiclone (Lunesta), are approved and prescribed for insomnia or sleep disorders. For this reason, they have very short half-lives ranging from 2-6 hours (in the non-elderly).

The pharmacodynamics (biochemical and physiological effects) of Z-drugs are almost identical to the benzodiazepine drugs. For this reason, the Z-drugs have similar effects and also risks to the benzodiazepines. Z-drugs differ from benzodiazepines in their chemical structure, which makes them unrelated molecularly to benzodiazepines.

The nonbenzodiazepines are activators of the GABA-A receptor. Like the benzodiazepines, they exert their effects by binding to and activating the benzodiazepine site of the receptor complex. Many of the Z-drugs are subtype selective (see subtypes discussed above) and are therefore novel in that they can provide specific effects (e.g., hypnotics with no anxiolytic effects). 

A review of the literature regarding hypnotics, including the nonbenzodiazepine Z-drugs, concluded that these drugs cause an unjustifiable risk to the individual and to public health and lack evidence of long-term effectiveness due to tolerance. The risks include dependence, accidents, and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep. If difficult interdose withdrawal symptoms arise between doses of these short-acting Z-drugs, sometimes a diazepam substitution taper may be necessary. It is preferred that the Z-drugs should be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible in the elderly.

Both benzodiazepines and Z-drugs are recommended for short-term use only and both classes of drugs can cause tolerance, interdose withdrawal, physical dependence, and withdrawal syndromes upon discontinuation. They both require slow and gradual tapers to discontinue them safely.