It’s summer time! For many people that means sunbathing, going to the beach, eating ice cream and having the best time of the year. But with other people it means sneezing, congestion, and sore eyes. For people with hay fever, medications like antihistamines – such as fexofenadine – are vital. Fexofenadine is relatively new to the UK market – so let’s take a look at what it is!
Topical molecule for tropical weather
When the weather heats up plants decide it is time to get funky and so they make pollen. Bees might love pollen…
…but many people don’t! Unfortunately pollen can trigger an allergic response in some people, causing itchy eyes, runny or congested noses, sneezes, and just generally feeling like “outside is trying to kill me”. This allergic response is caused by the release of histamine in your body, so naturally the treatments to stop this response are called antihistamines!
Antihistamines have been used to treat the symptoms of hay fever – or seasonal allergies – since the 1960s. There is a large range of them available, many are known by their chemical name and others known by the brand names (have you heard of diphenyhydramine or benadryl? They’re the same thing!).
Fexofenadine is amongst the latest antihistamines used to treat hay fever. It has seen a massive increase in use in the UK this year because you can now buy it in a normal shop, where previously you needed a prescription from a doctor. If you get any of those tablets this year, here’s the molecule that is inside them:
Since it is relatively new to the mass market in the UK there’s a buzz about it and it’s flying off the shelves. Fexofenadine is currently in really high demand and in lots of local newspapers (Google News search for Fexofenadine in the UK).
So what’s so special about it? How is it different to hay fever medicines we’ve seen year after year?
Previously on Molecule of the Month…
The classic antihistamine is cetirizine. Way back in August 2019 we chose cetirizine to be our molecule of the month. Here’s what it looks like:
Other than laughing at how the old graphics used to look (it’s been a voyage of discovery and I’ve definitely found my style recently), it’s interesting to follow up on cetirizine now that there is another hay fever medication on the market in fexofenadine.
Fexofenadine works in a similar way to cetirizine for treating hay fever. They are both antagonists for H1 receptors.
An agonist is a molecule that gets stuck into a receptor and causes a response. Think of it like this – if you have a jigsaw puzzle and you’re down to the last piece there is only one shape that will fit in there. If you find a piece that fits and you slot it in and it completes the picture – WAHOO! You have a big reaction to finally completing your puzzle. Molecules that do this to their receptors are called agonists.
But what if you found a piece that fits… and you slot it in… but it’s from a different jigsaw? It makes a totally different picture. You’d be confused, right? That’s what can happen with medicines and their targets. One molecule would normally slot into the jigsaw-like receptor on a protein in your body and cause a response. The medicine molecule is designed to be close enough in shape to that jigsaw so that it will fit in but it doesn’t cause the same response! That’s where the name anti-agonist or antagonist comes from.
Spot the Difference
It’s no surprise then that two molecules with similar structures will usually have similar mechanisms. See if you can spot the difference between the structures of fexofenadine and cetirizine.
Cetirizine and Fexofenadine are the ‘new generation’ of antihistamines. Did you spot how similar the section on the left of the molecules are? There are the three hexagons (admittedly with some different bits hanging off them) in both molecules. This structure is what gives the molecule its shape and allows it to fit into the receptor.
Sometimes small changes in the structure of a molecule can make a big impact on the activity and behaviour of a drug molecule. The ‘jigsaw’ idea isn’t the whole story – we have to be able to get the puzzle pieces into the same ‘room’ as the jigsaw puzzle to begin with! In your body these rooms might be organs – your eyes, brain, liver, etc., or it could be your blood, or lymph, or skin. Each ‘room’ in your body requires slightly different approaches to get to. Changing the structure of your molecule might get them in to different rooms and maybe even rooms they aren’t meant to be in…
Old Generation Antihistamines
There’s a reason we needed a new generation of antihistamine drugs. Diphenyhydramine is an older antihistamine, here is what it looks like:
This particular molecule can get around a lot of the rooms in your body. It can cross the blood-brain-barrier – which normally protects your brain from molecules that might make you behave strangely – and therefore has side effects like drowsiness. This antihistamine might make you feel like you could go outside without sneezing constantly but you’ll be napping on the sofa instead!
Newer medications don’t do this, thanks to the modifications to their molecular structure. They don’t cross the blood-brain-barrier. Let’s compare structures…
Notice that those hexagons that were in cetirizine and fexofenadine are almost exactly the same here? We have the two phenyl rings still in diphenyhydramine but the third hexagonal ring structure is opened out. We’re just a few bonds short of keeping that third hexagon in place.
Changing the oxygen atom in diphenyhydramine for something else (nitrogen in cetirizine and carbon in fexofenadine) allows chemists to close up that hexagon and make a third ring. They also added loads of extra bits to the molecule on the right hand side and these additions and tweaks keep the molecule out of the brain while still treating the symptoms of hay fever.
Back to the Agonist Aunt
We mentioned above (and in August 2019) that antihistamines can work by just blocking the access to the H1 receptor. Those types of medicines are called agonists. But there are different ways that medicines can work.
They might bind to the H1 protein somewhere far away from the receptor and change its shape – preventing something getting into the receptor entirely. Instead of a bouncer blocking the door like our agonists, this is more like changing the door into a window and confusing anyone trying to get in.
Or, they might bind to the receptor itself but cause the opposite response to the intended molecule. Molecules that do this are called inverse agonists and a great example is the commonly used hay fever medication loratidine.
Loratidine might look completely different to the other molecules at first glance, but…
It’s all a matter of perspective and how we draw the molecules! If we position loratidine and fexofenadine over each other we can see that the three hexagonal rings are actually kept pretty well the same – but loratidine has an additional 7-membered ring.
Interestingly, loratidine is the least effective of the antihistamines in the form that you can get as a tablet, but once it gets into your body it gets converted into a much more active form – desloratidine. Many medicines undergo this transformation from one molecule to a more active form. They are metabolised so we call these versions active metabolites.
Now that small change in structure turns loratidine from the lowest impact of the antihistamines into desloratidine which has the highest impact!
How else can hay fever medicines help?
Other than blocking H1 receptors and being antihistamines, hay fever medications might target itchy eyes (also known as allergic conjunctivitis) or act on the immune system itself (steroids). Let’s have a look.
The most common medication for this is sodium cromoglicate eye drops. They act by stabilising mast cells.
Glucocorticoids like beclometasone reduce inflammatory responses. Beclametasone is available as a nasal spray which works well for some people. Unfortunately for me I always just sneeze the stuff straight back out.
It is also possible to go a bit more extreme on the steroids. Steroid treatments can also be given as an injection, but this can be a bit like using a hammer to crack a nut – it works but it’s overkill. It’s not recommended to take steroids over a prelonged period and shutting down entire chunks of your immune system to avoid sneezing a bit is risky if there is a global pandemic just around the corner!
You can be exposed to pollen repeatedly during the winter to build up immunity. Read about it at the bottom of this page from the NHS. It takes 3 years to really get working but in theory by the end of that you are actually ‘cured’ of hay fever. However – this is the one treatment that has to be done specifically in a medical facility because it also poses the most risk of giving you a dangerous allergic reaction!
So which one is best?
Some research suggests cetirizine is the best and has a longer-lasting effect, but also makes you the most drowsy. However – as I said above with the nasal spray treatment where it might work great if I could keep it in my nose but I sneeze it straight back out – each of these treatments will be slightly different for each person. Which one is best will depend on the person taking them. The important thing is try them out and get the advice of your GP on what might work best for you!
And remember – placebos can still be really powerful! If you’ve heard that eating local honey might help to reduce your hay fever, why not try it? The worst that can happen is that you get to eat loads of yummy honey.
Written and graphics by Phil Jemmett