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Issue 22 Science Shoutout Understanding Science

Danger in disguise

🕒 7 min

The most prescribed drug in the world is atorvastatin (the inhibitor of cholesterol production in the liver, used to lower blood cholesterol levels). However, the most prescribed group of drugs are benzodiazepines. Behind the elegant and “clean” chemical structure of three rings – benzene, diazepine and phenyl ring lays a group of drugs so powerful and potentially harmful, and yet… so safe. Their list of indications is amongst the longest of all drugs, but they are also known as most commonly used drugs without doctors’ prescription. Not only are they being sold in the streets and on the black market, but they are also shared with friends and family as a “help” to get through a stressed or hard period in one’s life. What’s worse, because of their clinical efficiency when used properly, even doctors often prescribe them for minor problems and in the wrong dosages, or for too long of a time period. Although there are many positive sides of benzodiazepines and they can be extremely useful for many patients, which we will talk about in a minute, there is also a great risk attached to them, which not so many people are aware of. But let’s start from the beginning – how do they work?

The many faces of GABA receptor

Every neuron in our body has GABA receptor somewhere in their membrane. The GABA stands for gamma-aminobutyric acid – the main inhibitory neurotransmitter in mammals’ central nervous system. There are 2 types of GABA receptor: GABAa (an ionotropic channel which regulates the intake of chloride ions) and GABAb (metabotropic channel which is directly connected to the intracellular protein machinery). For today’s topic, GABAa is the only one that concerns us. However, you should be aware that both GABAa and GABAb are further divided into subgroups depending on the structure of their subunits (all GABA receptors are built of 5 subunits, or polypeptide chains which slightly differ in different GABAa and GABAb subgroups). So, to make it simple, imagine GABAa receptors as a hand – just as a hand has 5 fingers, GABAa receptor has 5 subunits and each of them is susceptible to interactions with different ligands and molecules. Whenever one of the subunits of the receptor reacts with some ligand, it changes its 3D structure a bit, which either results in opening the chloride channel and letting the ions flow into the cell, or closing it temporarily.

The binding sites of benzodiazepines are located between the two adjacent subunits α1 and β2. What’s interesting, when benzodiazepine binds to the receptor, it doesn’t directly change the structure of the GABA receptor causing it to open the channel for chloride ions, but rather enhances the effects of already bound gamma-aminobutyric acid (GABA) neurotransmitter. To be more precisely, benzodiazepines cause the chloride ion channels to open more frequently. That kind of indirect pharmacological activation  is called allosteric activation. While most of the people know that benzodiazepines are used for problems with sleep and anxiety, the fact that they also have an effect on respiration is not exactly a common knowledge. Dosages a bit higher than the therapeutic ones already can cause troubled and slowed down breathing and, what’s worse, it’s due to the inhibitory effects of benzodiazepines in the brain region responsible for autonomous breathing. In higher dosages, benzodiazepines and other GABA receptor agonist can stop the excitatory signals that your brain sends to your lungs, causing you to stop breathing.

The dos and dont’s of benzodiazepines

While we’re at it, let’s talk a little about their various indications apart from hypnosis or “sleeping pill”. Benzodiazepines are among the oldest drugs used for sedation. Their calming effects with concomitant reduction of anxiety are experienced already at low doses but are usually accompanied by depressant effects on psychomotor and cognitive functions, so some may appear “slow” when they move around, but also when you talk to them. Interestingly, although it’s not uncommon for students to take a benzodiazepine pill when studying for a test to “calm themselves”, benzodiazepines can cause a dose-dependent anterograde amnesia, meaning that once their pharmacological effects wear off, the individual who took the pill won’t remember anything that happened to him while he was under the influence of the drug. Also, studies have shown that, due to a decreased cognitive function caused by benzodiazepines, new information is harder to process and remember while the drug is still in the system. Because of the anterograde amnesia, this group of drugs is often used in surgical procedures, but has also been criminalized and used as a “rape pill”.

Moving on, their rapid penetration of brain tissue and fast tissue redistribution when given intravenously  make them perfect anesthetic agents. Since they enhance the inhibitory action of GABA, they can inhibit polysynaptic reflexes and even depress neural transmission to muscle tissues, therefore causing the skeletal muscles to relax when trapped in a muscle spasm. Furthermore, due to their ability to stop the development and spread of epileptic convulsions, they are commonly used as anticonvulsants. Last but not least is the effect of benzodiazepines on the cardiovascular system – at doses up to those causing hypnosis, only a slight blood pressure lowering effect has been observed. However, in patients with heart failure or significant blood loss, benzodiazepines can cause both significant drop in blood pressure and decreased myocardial activity (causing the heart to beat slower and weaker).

To sum up, despite their colorful palette of effects, the most common indication they are used for is treating different kinds of anxiety and sleep disorder. Even though this group of drugs has many positive sides (very well known mechanism of action, fast onset of pharmacological action, wide therapeutic window, numerous indications and good tolerance in patients), the fact that they also cause addiction and pharmacological tolerance after only a few weeks of their consistent intake, which is by the way a new diagnosis by itself, makes you wonder are they really even worth the risk.  

Promiscuous receptor

Now, one of the important properties of GABA receptors is their promiscuity which can be a problem and a blessing at the same time – a danger in disguise. Barbiturates, the “sleeping pills” that, among others, killed Merlyn Monroe, also have their designated binding site on GABA receptors, but while benzodiazepines cause the ion channel to open more frequently, barbiturates cause them to stay open longer than usual. Ultimately, the effect is more or less the same.

Figure 2. The binding sites of benzodiazepines and alcohol on GABA receptor (By BruceBlaus – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=44968541)

However, what I would like to talk a little more about here is another GABA receptor ligand – ethanol. Ethanol, or commonly referred to as just alcohol, also has it’s own binding site on the GABA receptor (as shown on the Figure 2). When bound to the GABA receptor, ethanol also increases the effects of already bound GABA on GABA receptor, similar to benzodiazepines. Even more so, just like benzodiazepines, through it’s allosteric activation of GABA receptor ethanol also causes respiratory depression, and in very high doses can even cause coma. At the same time, lower doses of alcohol have also been shown to have an antianxiety effect, causing the consumer to feel better. Why is this important? If you think about it, benzodiazepines are a standard “go-to” therapy in patients who suffer from anxiety and depression. Alcohol, on the other hand is often a “homemade remedy” for those struggling with depression as they are more prone to reach for an alcoholic beverage to “release their pain and worries”. When combined in a little higher dosage, the combination of benzodiazepines and alcohol can be fatal, which happens more than one would expect. The cause of death is either complete respiratory depression resulting in respiratory arrest (or simply put – you just stop breathing), or you end up falling in a very deep sleep and choking on your own vomit because your stomach wants to get rid of the alcohol, but the brain is so much inhibited from benzodiazepines and alcohol that you just can’t wake up.

Wake up

A very bad day for someone with severe depression who decides to drink the pain away and take a few pills more than prescribed can end up being their last day. The reason I decided to write about this so directly is because we don’t talk about this enough in our society. It’s time to start talking about the negative sides of benzodiazepines, their weaknesses and the risks that go along. As with every drug – they can be very useful, even life saving for so many people, but we have to take better control over their overconsumption – both legal and illegal.

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