Oh, I hate insomnia. I have absolutely no patience with my body’s inability to sleep, so I am a very stroppy insomniac; I huff and puff and get angry with my body. I drink warm milk, and take baths and inhale lavender and do meditative deep breathing and I still can’t sleep and then I get really annoyed and moody and huff and puff some more. As a result of this low tolerance for sleeplessness, I have, in the past, resorted to buying over-the-counter sleeping tablets to knock me out, before my insane grumpiness causes someone else to knock me out instead in a far more painful manner.
I think it’s fascinating that you can take a tablet and it will make you sleepy, and in typical pharmacology-nerd fashion, because I know how to have a good time, the first time I bought some, I went home and looked up how they worked. And it turns out I was right, it’s totally fascinating, which in a way is a shame because if it had been really very dull, it might have sent me to sleep and stopped me needing the tablets in the first place, but anyway.
I think one of the most intriguing things about drugs is that they’re not always used for the thing they were designed for, that is often a drug will have a side effect that turns out to be at least as useful, if not more so, than its original action. Over-the-counter sleeping tablets are a brilliant example of this; originally the key active ingredient in most non-prescription sleeping tablets, diphenhydramine, was an anti-histamine prescribed to decrease allergic symptoms. However, it turned out that whilst it does do that very well, it also makes people terribly drowsy. In some cases, that’s an incredibly annoying side effect. For example, a hay-fever drug that simply makes you sleep through the entire summer might be effective, but it’s kind of unhelpful. On the other hand, if you actually just WANT to go to sleep, it’s a highly useful thing.
So, diphenhydramine binds to receptors known as histamine H1 receptors. Receptors are molecules that just need a hug, they want another molecule, a ligand, to come along and bind them tightly, so they feel all loved and snuggly and secure. Once the H1 receptor has hugged a histamine molecule, it feels inspired and happy, ready to go out and do its job in the cell. All full of the joys of life, it chats happily to a nearby G-protein, and this interaction triggers a cascade of signalling molecules, all passing messages along a chain to cause a downstream effect. In brain cells, this effect is ultimately to cause ions to enter the cell, changing the negative charge, so that the neuron is awake and alert, primed and ready to send excited messages around the body about stuff, and things, and more stuff! In this situation, histamine effectively keeps your nerve cells bouncy and on their toes.
Histamine hugs excite the H1 receptor, stimulating downstream signalling…
If, however, diphenhydramine or a similar antihistamine is in the vicinity, everything plays out slightly differently. Diphenhydramine competes with histamine to give the H1 receptor a hug, and when it wins the battle for a cuddle, it has a very different effect. Histamine is an H1 receptor agonist, meaning that hugs from histamine increase the activity of the receptor. Diphenhydramine, on the other hand, is an inverse agonist, when it gives the H1 receptor a cuddle, the effect is relaxing rather than inspiring, the receptor gets less excited and doesn’t start a conversation with the nearby G-protein. Instead, it settles down into a relaxed state. And the G-protein, with no message from the H1 receptor, doesn’t do anything either and there is no signalling cascade triggered in the cell.
Diphenhydramine hugs relax the H1 receptor, making it sleepy and preventing signalling.
Without the signalling cascade, the negative charge of your brain cells doesn’t change, your neurons are not primed for action, instead they’re sitting around having a cup of warm milk and dozing off. Their reactions are slower, and when your brain cells react slower, that manifests as drowsiness, making it easier for you to drift off happily into sleep, without anyone hitting you with a baseball bat or anything. Lovely.
The Molecular Circus 
This is brilliant. First of all had my science teacher said things like “Receptors are molecules that just need a hug,” I would have got more than a C in my GCSE exam. I like feeling that molecules are hugging to knock me out. Genuine question – do prescribed sleepers work in the same way but are just stronger versions of over the counter sleepers or do they work differently which is why they have to be prescribed?
Thanks Elsie!
Prescribed sleeping tablets work differently to OTC ones, they’re not antihistamines, instead they target a different receptor, the GABA-A receptor. One of the main reasons they have to be prescribed though, is that they can be very addictive. Your brain gets used to functioning with them, so when you stop taking them your brain doesn’t immediately switch back to normal, giving withdrawal symptoms. I’ll do a proper detailed list on them one day!
K x
Being addicted to prescribed sleeping tablets would be like being addicted to hugs! Imagine going to the doctors “I can’t sleep, can I have some more of those tablets that hug you to sleep”
I love it! Thanks 🙂
I have one question though… How would the image be if there was an antagonist in instead of an agonist or an inverse agonist?
Hi MLJ, I’m so glad you enjoyed! So, the quickest summary is that agonists cause the receptor to do something, inverse agonists cause them to do the opposite thing, and antagonists simply block the effects of agonists (both normal and inverse). So, if there were an antagonist in the picture, no agonist or inverse agonist would be able to bind the receptor, and nothing would happen. The end result would perhaps be the same as with an inverse agonist, it just goes about things differently. I hope that makes sense?
K x