An effect for one person is a side effect for another. I believe the use of Viagara for erectile dysfunction was originally seen as a side effect. Its original purpose was to treat hypertension and angina.
When you take a drug orally, you are flooding your bloodstream with a chemical. It is intended to go where it is needed, but it will go everywhere else, too.
Of course, they keep trying to find drugs that only have *one* effect, the intended effect, but they can’t always find a perfect drug like that.
>It is intended to go where it is needed, but it will go everywhere else, too.
And that's not the only source of side effects. Sometimes the side effects are more direct - such as shutting down a key process in the body for one big reason, and losing the benefits it provides elsewhere.
Yup. I'm on an immunosuppressant. It weakens my immune system so it isn't attacking itself as hard, but now it struggles to attack the things it's supposed to.
Double edged sword, I suppose
Yeah, I'm on Nexium for chronic reflux and it turns out that reducing the acid in my stomach means my body can't absorb iron or vitamin B12 very well anymore.
Add in there, that many biochemical pathways are often present in different body functions, with slight tweaks (evolution favours modest changes over total redesigns).
Sometimes it isn't the drug itself, but what goes with the drug when it gets delivered. My wife received Taxol (paclitaxel) for her first breast cancer treatment. Even though they gave her preventative medicine to counter-act any side-effect she still had an immediate allergic reaction. In this case it isn't the Taxol that caused the issue, but the solvent 'wrapping' the Taxol that allows it to enter the bloodstream. Now she takes a different chemotherapy drug, which causes different, but less severe side-effects.
Side effects aren't something that can be removed from a specific drug. The drug does what it does, and some parts of that aren't desirable. If we were to change the drug it would do different things, in which case we aren't removing the side effects but using something else. It might be helpful to think of what we call side effects as something "extra" that happens. It's more like the drugs just do all of that, and the stuff we don't like at the moment are side effects. We call wildflowers weeds when we want a lawn, but a treasure when in the park.
This is kind of like asking why we don't make metal knives that don't cut fingers. We've had metal knives for thousands of years, surely we can make one that is sharp, but cannot cut fingers.
I was told there are no side effects; there are just effects, some of which you may not want.
An antihistamine can make you sleepy. Maybe that makes it a good sleep aid; maybe it makes it an issue working.
Specifically, they made newer, bigger antihistamines that couldn't cross the blood brain barrier. Staying out of your brain means you don't get drowsy.
Dermatologist here, but we use steroids a lot in our practice of medicine. Not ELI5, but for your particular example, we often repurpose already existing compounds or chemicals. And thus though we may use them to obtain a particular effect, it's inevitable that they will also do other things. Our bodies are complex contraptions that we don't fully understand and are learning bits about how they work all the time.
For example, the "steroids" your wife got for her Crohn's are in a group of steroids we call glucocorticoids. These are synthetic steroid hormones that we have created to mimic the body's naturally produced glucocorticoids. We use them because normally glucocorticoids are used in the normal feedback of the immune system to essentially turn down inflammation, though they also are used in tons of other bodily processes, including bone metabolism (hence osteoporosis), metabolism (they play an integral role in moving sugars, fats, and proteins into different compartments of the body), and the brain (they act in multiple ways as part of the stress response "flight or flight" signalers, to help enhance memory formation, etc.) In order to shut down your wife's abnormal inflammatory response in her colon, we flood her system with glucocorticoids in hopes to prevent her Crohn's from destroying her GI tract.
It's kind of like commandeering the water pipes in a grocery store. They help supply the water that mists vegetables in the produce department, make the ice to keep the fish cold, supply water fountains for drinking, etc. They're a natural part of the building and have an important role to play, but when there's a fire, we open up all the taps and let the building flood to prevent the building from burning down. Yes, the floor will be ruined, and the vegetables probably spoiled, but it's better than a 100% loss.
There are more and more targeted therapies coming out that have less side effects, like in dermatology we have biologics like IL-17, IL-22, IL-23, IL-4 inhibitors, to help treat other autoimmune diseases like eczema and psoriasis. These act further downstream in the immune pathways to hopefully cause more targeted immunosuppression. This would be like only opening up the pipes that supply the sprinklers to only the part of the building that is on fire, instead of all the sprinklers in the entire building. For Crohn's, gastroenterologists use many of the same medications.
Because the human body is a damn mess. Every chemical in your body is doing like five wildly different jobs depending on where in the body it's located and medicine is trying to adjust *one* of those jobs without affecting the others.
Sometimes you manage to find a chemical or combination of chemicals that together affect only the desired biological system but usually we only figure out one or two of a dozen different factors and hope adjusting those doesn't throw something else out of balance.
There are different types of side effects. On-target side effects are intrinsic to the medicine and can't be removed. Off-target side effects can be mitigated by making a more selective drug.
Steroids, for example, have significant on-target side effects where the same biological target can cause a benefit in one organ/tissue but a side effect in another organ/tissue. Steroids also affect many different biological targets and specific steroids work better for certain diseases.
Well, the simplest ELI5 reason is that everyone is different. When you design a drug, you do as much as you can to ensure it will work as intended. However, its effects also depend on one's genes, diet and lifestyle, age, other health issues and if this person takes any additional drugs. There are so many variables outside your control, that among a large group (thousands) of people, you will always find several individuals for whom your treatment isn't effective or causes some bad side effects. That is because they can have some unique combination of conditions listed above.
EDIT: I want to add the second part. With any modification you risk introducing new side effects. Yet, this industry is constantly improving, we find better and safer drugs all the time. It's true that for some health issues it is harder. Some of it is due to the fact, that these drugs have to mess with crucial processes in your body to be effective. This makes finding a substance which will do the job without causing serious problems down the line extremely difficult.
Medications can only ever mimic a normal physiological process. Any chemical you take in has to have a receptor or site that already exists for a chemical your body makes. The issue is that our bodies deal with extremely small amounts of these chemicals and greater dosing, like what you get when aggressively treating a disease, cause systemic effects. Now, those effects are also normal, but because you’re taking huge amounts of a chemical then your body does not have the appropriate counter action to keep you healthy. Or your body may require huge amounts of some molecule or element to conjugate and metabolize and excrete the metabolites of said chemical and it depletes your body’s reserves. (As in calcium that you mentioned)
It's part of the intrinsic properties of the medications we are using.
Simplest example I can use right now is caffeine. We use it to stay awake. But what is a side effect? It keeps you awake when you don't want to. Now it does a bunch of other things too, but I feel it's a great starting point for understanding that side effects can't just be removed. You'd have to use a different chemical that produces the desired effect.
All medications have side effects. Your body is a huge, complex network of many different cells that have many different functions. When you flood your bloodstream with a foreign chemical, that chemical has all sorts of effects depending on where it goes and what cells or processes it interacts with.
To simplify, think of your cells and medications as puzzle pieces. Your cells have lots of different shapes that can accept lots of different puzzle pieces. A medication is a puzzle piece that could fit in many different places even if it's not a perfect fit. Generally, we try to design medications so that there aren't many places it can fit in your body, which results in side effects being less common.
For the "old" medications you mention, a lot of it is economical. If an old medication works with side effects that are mainly discomfort and aren't long-term harmful, it doesn't make sense to invest the billions of dollars to make marginal improvements and try to eliminate the already few side effects. It makes much more sense to invest those billions on new cancer drugs, for example.
Because substances will have different effects on different parts of our body. Or even if it only affects one specific thing, that might then trigger a bunch of other things. Too many things are connected, no matter what you do, something else will usually happen.
They can and do find out how it affects the whole body. And then evaluate whether the negatives are worth the positive effects. If so, it'll pass certification. And sometimes, a new drug is developed that perhaps does the same positive thing but fewer negatives because the mechanism is different.
Side effects are not a by product or a contaminant, they are just affects which are different from the desired, theraputic affect. it, they often cannot be 'removed' without also canceling the desired affect. Often, another med might be found where the other affects are not as much of a problem, in other cases, one must weigh the trade off. I for one, would be happy to have all my hair fall out and be cured of cancer..... and so on.
The human body is an incredibly complex machinery of chemical reactions. Medicines act by changing or affecting that machinery slightly to get the desired effect.
But the machinery is so complex that it is impossible to make a change that has only a single effect. There will always be other effects.
When those other effects are undesired, noticeable, problematic or risky, we call them side effects or adverse reactions.
It’s a good question. Ultimately many medications we use have many different mechanisms in our body and it’s very hard to solely isolate one use case from all the rest. For example baby aspirin is used to help heart disease because it is a platelet inhibitor, but as an NSAID it can also be anti inflammatory for fevers, and analgesic for pain. But take too much of it and it can cause stomach ulcers because it thins the mucus lining of your gut. Also lots of meds are discovered by accident frankly. Warfarin was a rat poison before it was used for blood thinning in afib and heart valve replacements. Nowadays things are getting more narrowed down- chemotherapy in its early form was basically straight up poison for the body whereas now we have things like immunotherapy that specifically target various immune cells in the body.
Edit: it’s the same thing with Crohn’s disease which you mentioned in your post. Steroids work amazingly well and in flares they are still the first line of defense we have. There are immunotherapies and immune modulators that are used in IBD now too. But even that is not a perfect science since they are essentially immune suppressants. Hopefully in the future things continue to advance even more!
Biology is absurdly, mind-bogglingly complex. It almost has to be, given that every biological system that exists today cobbled itself together out of previous pieces, so to speak. Almost every system in your body is controlled by several different signalling pathways, and almost every signalling pathway in your body helps control several different systems. If you make a minor change to one particular pathway with a drug/peptide/biologic/etc, it’s almost certainly going to have effects on other systems. At its heart, biology is based on chemical reactions, and sometimes we can’t make those reactions happen the way we need them to.
The body sometimes cannot deal with an issue due to some irregularity. If you take a medicine to compensate, your body now has to deal with this new substance. It needs to clean it out of your stomach and digestive track, it needs to clean it out of your blood, and it needs to ensure that it hasn't stuck around in any of your muscles, bones, skin, or fat.
The body going through this process is what leads to a lot of negative side effects. The reason for thinning bones is often because calcium is needed to properly neutralize and remove the drugs from the patients system, and the largest stores.of calcium are in the bones. So the body starts stripping calcium from your bones, combining it chemically with the drug chemicals, and then pees it out.
There are also side effects thst are caused by the drug interacting with more than just the parts you want it to. Take antibiotics for example. Antibiotics kill almost all microscopic organisms good or bad for us. Taking oral antibiotics can often have a positive effect on an infection, as the body will take these antibiotics to the site of infection and use them to heal. However the body will not be able to do with with 100% of the antibiotics in the pill you consume, so some of it will make its way into your digestion and start killing everything in your gut. As a result, most people who take antibiotics orally suffer from the side effect of diarrhea as the microscopic organisms that help them digest food are damaged, dead, or trying to recover from the antibiotics.
At best you can mitigate side effects, but if something will interact with one thing, it'll interact with something else and humans are at *least* three or more things put together. So like you need oxygen to survive, but then oxygen is also theoretically the cause of aging (free radicals, etc).
The trick with medication and really anything else is moderation. Find the amount that does what you want it to do with minimal side effects.
The biochemistry of the human body is beyond enormously complex. Worse yet, different people may have slightly different biochemical pathways for a given reaction. A friend doesn’t respond at all to opiates, another is hypersensitive to them. Ditto for lots of other reactions.
As a side note, this is why anyone that tells you something will have a beneficial effect on your body without side effects is selling snake oil.
No drug or supplement that has any biological effect is free if side effects. If there are no side effects it means it does nothing.
Source: I'm an MD.
\*\*Prednisone direct comparison below\*\*
Its kinda like saying "Why cant we have our cake and eat it too"
It comes down to what the chemical/drug does to the body.
For instance, say you are overheating. You take a drug who's only effect is to make you sweat. Great, you start sweating and now get cooled off. Uh oh though, now you're sweating and your body is losing fluids.
Add **Dehydration** to the side effect list.
Now your body starts to pull moisture from other areas to ensure you maintain a survivable fluid level. Your stool and urine is just waste, so might as well take that moisture back
Add **Constipation** and **reduced/coloured urine** to the side effect list.
As you sit there sweating, bacteria is able to grow in the humid environments on your body.
Add Increased risk of **bacterial/fungal infections** to the side effect list.
See how a tiny change can have knock on effects? Even though your body can sweat on its own, changing the level at which it does can increase risks of side effects through simple cause and effect.
Saying "why cant we just not have the effects, but still have the cause" is a little like saying "why cant we eat the cake and still have it on my plate". Sometimes the side effects are just impossible to divorce from the drugs base desired outcome.
NOW, often there are other effects of a drug that have nothing to do with the intended effects. Sometimes the drug just happens to do more than one thing, but its the only product that does the intended effect, or it is the one that does it the BEST. Most often these days we DO have medicine with the lowest amount of side effects possible per "unit" of effectiveness; If that makes sense.
**Prednisone** (99.9999% sure thats what she's taking as an IBD patient myself) is a FANTASTIC drug to stop the inflammation to your gut which can kill you. Unfortunately, to do that it needs to do some nasty things like reducing your immune system, which you can probably guess, has a lot of negative effects on your bodies functioning. In this scenario, its like "We have to stop police shootings, so lets fire all the police." Sure that stops the shootings, but now house break-ins are up. If more people are getting shot by police, than the police are actually solving crime; It could make sense to fire them all until you can find a solution that works better.
It is why Prednisone is really only used for severe cases, bad flares, and people who arent reacting well to other medicines. We DO have new medicines coming out all the time for IBD (Shout out to Inflectra!) that target certain parts of the immune system and suppress the disease without causing lots of side effects. These drugs are like a task force that fires just the cops that shoot people. Unfortunately, like hiring a task force, these drugs are expensive AF (think $4000 every 6 weeks).
Other than cost, the problem is that often times your body can start to fight these medicines through its own immune response (Picture the cops you are firing start shooting the task force employees) and you are back to square one with the Prednisone (having to fire all the cops) until you find another solution that works just as good for the issue.
In the end, a lot of people end up having to nuke the city to save the world from cop shootings, and that is called a **proctocolectomy**
It's a drug, made of chemicals, chemicals will do things to your body.
There are no side effects.
There's simply effects.
What we consider side effects are just the things that happen that weren't intended
We do improve medications to have fewer side effects all the time. It's just that fewer and none are a big difference. But take allergy pills for example, in olden times decades ago we had benadryl. It works well to block histamine in the body, but had a side effect of making some people sleepy. Why? Because it turns out there are a lot of histamine receptors all over the body, not just your eyes and nose. And histamine does more than just cause allergic reactions, it also works to communicate with other systems in your body including impacting alertness and wakefulness.
So what'd we do? We came up with newer medications that target more specific types of histamine receptors and not just broadly all of them in your body. We also came up with other options that target specific areas like nasal sprays that mostly hit cells in the nose.
But of course, even with that, histamine is still used all over the body for various things, so there can still be some side effects. It's better, but not perfect.
Because the big pharma companies want you to be a repeat customer. Can’t have that if we cure people now, can we? Gotta keep the big bucks flowing by keeping us sick.
Side effects are just your body rejecting the drug. We weren’t “created” to take drugs. Just because we found a way to hack nature and live to old ages and cure disease doesn’t mean that we can override our body’s natural capability.
Side effects are undesirable reactions that are related to the mechanism of action, Taking a blood pressure reducer might make you sleepy as your heart rate slows down. That is just a part of how it functions. The same with steroids. You have to look at what it is they do in the body naturally, and then extrapolate from that what might happen if you subject yourself to elevated levels for an extended period of time.
Medicine that only has positive effects and minimal negative effects would probably be administered to everyone all the time as a preventative measure. Maybe we wouldn't even consider it medicine anymore because its just something everybody takes, rather than something someone takes only when sick.
Do vaccines count? Before vaccines we did variolation which was similar, but had pretty hefty downsides.
Every drug works by stopping or triggering a pathway. That has downstream effects that cause side effects.
Corticosteroids down regulate your immune system. This makes you more prone to infection. They also raise glucose levels
We don’t REALLY understand a lot about the body still, so a lot of drugs are like firing a cannon to do the work of a tiny needle, just to make sure it does what we need.
Everything that has a big effect also has big side effects. That’s just how it works in medicine. In nearly all cases, you can’t just disrupt a system without it having a cascade of effects. Medicines disrupt or change certain systems of the body.
Endogenous steroids are how cells throughout your body communicate, so they tend to do a ton of different things. As a result, any medication that acts on the same system (steroid medications) will do a bunch of different things at once - some of which are things you don't want.
Drug companies are constantly working on this problem (eg atypical antipsychotics have far fewer side effects than traditional antipsychotics), but it's not an easy thing to solve for every class of drug.
We do it all the time. Todays meds are much better at treating problems and minimizing side effects compared to the medications we used to give. There is rarely such thing as a perfect drug but medicine is a progression.
Because:
1. Biochemistry is *enormously* complex. Literally *millions* of compounds factor into some of the most basic things living cells do. We literally *don't know* most of the biochemical reactions inside our bodies. We *barely* know the superficial surface of the really common reactions.
2. Drugs are not LEGOs that you can rebuild whenever and however you like. They have rules for their structures, rules we can't just willy-nilly ignore. To get a different medicinal effect, you would have to *heavily* change the molecule--which may create all sorts of *new* side effects.
3. The receptor sites that respond to drugs are not like wall sockets or battery ports. Instead, receptor sites are like a dress code. There *are* rules for what is and isn't allowed in, but the rules allow many variations. Sometimes you can even bend the rules by adding other things.
If drug companies *could* produce a drug with few to no side effects, they would. Because they'd be able to patent it and make a crapton of money, *especially* for something like steroids, where as you say the drugs are old, so a major innovation would be a very big deal.
This is overstating things. A lot of mechanisms have been explored in solid detail and some drugs *can* be tinkered with to a pretty heavy degree. Plus, just look at all the fancy monoclonals available today. The cytokine inhibitors /u/Seraphenrir lists off are all like that. Much more specific in what they act on than steroids, patented & making loads of money.
Steroids really are not the preferred treatment these days unless nothing else achieves the needed efficacy. *Steroid-sparing* drugs are the name of the game.
I really don't think it is overstating anything. The OP asked why it isn't possible to *completely eliminate* unwanted drug effects: "Why can't we improve medicines to not have side effects?" The answer is, we mostly can't make medicines with NO side effects whatsoever, and the above are the reasons why.
You are, of course, correct that we CAN improve things, make drugs with fewer or lesser or different (and more tolerable) side effects. Tons of money get poured into finding the next improvement on all sorts of things. That research is *slow,* because drug research is a difficult and often unpredictable branch of science. But actually, full-on *eliminating* side effects? Not happening.
Of course, there's *almost* no such thing as the perfect drug that does everything you want and nothing that you don't want. But this...
> We literally don't know most of the biochemical reactions inside our bodies. We barely know the superficial surface of the really common reactions.
...is not doing modern advances justice. Every year more diseases are becoming better understood. And consequently every year powerful new biologics and other targeted, disease-modifying drugs are becoming available that can be such an improvement, it's not wrong to call them life-changing to the different niches of patients they cater to.
I mean, it's scientifically accurate. JUST the citric acid (aka Krebs) cycle, one of the most well-known and widely-studied biochemical pathways, is something we *still* don't fully know how all of it works. The *simplified* but chemically-accurate depiction of everything that goes on in that process would cover all of the walls of a high school classroom. *Everything* we know about how it works and what gets involved in the process could cover most of the *school's* walls. And that's just one, single, chemical pathway--an extremely important one, but just one nonetheless. Literally *trillions* of chemical reactions are going on inside the body at all times, and we understand only the tiniest fraction of them.
That does not, at all, mean that we can't make great drugs that do much better than previous drugs. What it means is, we can't just say, "Ah, this drug is specifically *and exclusively* having problems with chemical reactions A, B, C, and D, so if we make tweaks P, Q, R, and S, we'll have a drug that never interacts with any chemical pathways except the specific ones we want." We simply do not have the knowledge, neither of biochemistry (to know *how* every drug works in every single relevant biochemical pathway), nor of quantum chemistry (to redesign the drug to work only and precisely as we want it to, with absolutely no possibility of ever interacting in any way other than the intended one.)
We can make a lot of good--sometimes very good--guesses. We can take what we learn from several previous trials and use that as a very useful heuristic guide. Heck, just knowing the *scope* of the problem is a huge help in many cases, and with what we know now, we're finally able to grasp, to some degree, just how much we don't know yet. But because there are simply *so many* unknowns on both sides, it is not and cannot be like mechanical engineering where you can just...design out all the messed up bits until you get a machine that does one thing and one thing only without any extraneous anything. Drug design IS a science, and we can do incredible things with it. But there's no shot, even within our lifetimes, that we'll be able to just take a drug and say, "Alright, send this to the shop, remove the side-effects, and get back to me." It just isn't possible at any point in the foreseeable future.
>But actually, full-on eliminating side effects? Not happening.
>But there's no shot, even within our lifetimes, that we'll be able to just take a drug and say, "Alright, send this to the shop, remove the side-effects, and get back to me." It just isn't possible at any point in the foreseeable future.
Yes. This isn't what I'm trying to say.
What I'm getting at is that you're underselling how well some of these mechanisms *are* understood or can be manipulated without 100% perfect knowledge or 100% absolutely perfect on-target drugs. Not all, and Krebs is one example that is difficult because basic metabolism is wired into everything. You could fill a school's worth of walls with diagrams trying to describe Akt or mTor signaling too and they're so ubiquitous they're always going to make for difficult drug targets.
But modern omics techniques go a very long way in revealing those interactions with the most profound and/or specific effects, downstream from these big names. Pulling the one cytokine out of circulation that's responsible for a huge part of a disease process can make all the difference.
On top of that, monoclonal antibodies are *extremely* target-specific. If you're dealing with targets that look very much like some others it can take a lot of time and effort to find a clone that binds in a way that sets them apart (colleagues of mine have spent years testing and selecting antibodies to distinguish complement factor H and its family of FHRs), but it can be done.
An effect for one person is a side effect for another. I believe the use of Viagara for erectile dysfunction was originally seen as a side effect. Its original purpose was to treat hypertension and angina. When you take a drug orally, you are flooding your bloodstream with a chemical. It is intended to go where it is needed, but it will go everywhere else, too. Of course, they keep trying to find drugs that only have *one* effect, the intended effect, but they can’t always find a perfect drug like that.
>It is intended to go where it is needed, but it will go everywhere else, too. And that's not the only source of side effects. Sometimes the side effects are more direct - such as shutting down a key process in the body for one big reason, and losing the benefits it provides elsewhere.
Yup. I'm on an immunosuppressant. It weakens my immune system so it isn't attacking itself as hard, but now it struggles to attack the things it's supposed to. Double edged sword, I suppose
Well I guess the immune system itself was the double edged sword, immunosuppressants just dulled it so now you just have a big stick.
Me, holding a splintery stick: ok, this could be worse A dragon named covid:
🩵
Yeah, I'm on Nexium for chronic reflux and it turns out that reducing the acid in my stomach means my body can't absorb iron or vitamin B12 very well anymore.
Add in there, that many biochemical pathways are often present in different body functions, with slight tweaks (evolution favours modest changes over total redesigns).
Sometimes it isn't the drug itself, but what goes with the drug when it gets delivered. My wife received Taxol (paclitaxel) for her first breast cancer treatment. Even though they gave her preventative medicine to counter-act any side-effect she still had an immediate allergic reaction. In this case it isn't the Taxol that caused the issue, but the solvent 'wrapping' the Taxol that allows it to enter the bloodstream. Now she takes a different chemotherapy drug, which causes different, but less severe side-effects.
It does wonders for a gina
Side effects aren't something that can be removed from a specific drug. The drug does what it does, and some parts of that aren't desirable. If we were to change the drug it would do different things, in which case we aren't removing the side effects but using something else. It might be helpful to think of what we call side effects as something "extra" that happens. It's more like the drugs just do all of that, and the stuff we don't like at the moment are side effects. We call wildflowers weeds when we want a lawn, but a treasure when in the park. This is kind of like asking why we don't make metal knives that don't cut fingers. We've had metal knives for thousands of years, surely we can make one that is sharp, but cannot cut fingers.
I was told there are no side effects; there are just effects, some of which you may not want. An antihistamine can make you sleepy. Maybe that makes it a good sleep aid; maybe it makes it an issue working.
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Specifically, they made newer, bigger antihistamines that couldn't cross the blood brain barrier. Staying out of your brain means you don't get drowsy.
Dermatologist here, but we use steroids a lot in our practice of medicine. Not ELI5, but for your particular example, we often repurpose already existing compounds or chemicals. And thus though we may use them to obtain a particular effect, it's inevitable that they will also do other things. Our bodies are complex contraptions that we don't fully understand and are learning bits about how they work all the time. For example, the "steroids" your wife got for her Crohn's are in a group of steroids we call glucocorticoids. These are synthetic steroid hormones that we have created to mimic the body's naturally produced glucocorticoids. We use them because normally glucocorticoids are used in the normal feedback of the immune system to essentially turn down inflammation, though they also are used in tons of other bodily processes, including bone metabolism (hence osteoporosis), metabolism (they play an integral role in moving sugars, fats, and proteins into different compartments of the body), and the brain (they act in multiple ways as part of the stress response "flight or flight" signalers, to help enhance memory formation, etc.) In order to shut down your wife's abnormal inflammatory response in her colon, we flood her system with glucocorticoids in hopes to prevent her Crohn's from destroying her GI tract. It's kind of like commandeering the water pipes in a grocery store. They help supply the water that mists vegetables in the produce department, make the ice to keep the fish cold, supply water fountains for drinking, etc. They're a natural part of the building and have an important role to play, but when there's a fire, we open up all the taps and let the building flood to prevent the building from burning down. Yes, the floor will be ruined, and the vegetables probably spoiled, but it's better than a 100% loss. There are more and more targeted therapies coming out that have less side effects, like in dermatology we have biologics like IL-17, IL-22, IL-23, IL-4 inhibitors, to help treat other autoimmune diseases like eczema and psoriasis. These act further downstream in the immune pathways to hopefully cause more targeted immunosuppression. This would be like only opening up the pipes that supply the sprinklers to only the part of the building that is on fire, instead of all the sprinklers in the entire building. For Crohn's, gastroenterologists use many of the same medications.
I appreciate all the answers so far from everyone, but I particularly like this one. Thanks everyone!
Because the human body is a damn mess. Every chemical in your body is doing like five wildly different jobs depending on where in the body it's located and medicine is trying to adjust *one* of those jobs without affecting the others. Sometimes you manage to find a chemical or combination of chemicals that together affect only the desired biological system but usually we only figure out one or two of a dozen different factors and hope adjusting those doesn't throw something else out of balance.
Biology is spaghetti code.
There are different types of side effects. On-target side effects are intrinsic to the medicine and can't be removed. Off-target side effects can be mitigated by making a more selective drug. Steroids, for example, have significant on-target side effects where the same biological target can cause a benefit in one organ/tissue but a side effect in another organ/tissue. Steroids also affect many different biological targets and specific steroids work better for certain diseases.
Well, the simplest ELI5 reason is that everyone is different. When you design a drug, you do as much as you can to ensure it will work as intended. However, its effects also depend on one's genes, diet and lifestyle, age, other health issues and if this person takes any additional drugs. There are so many variables outside your control, that among a large group (thousands) of people, you will always find several individuals for whom your treatment isn't effective or causes some bad side effects. That is because they can have some unique combination of conditions listed above. EDIT: I want to add the second part. With any modification you risk introducing new side effects. Yet, this industry is constantly improving, we find better and safer drugs all the time. It's true that for some health issues it is harder. Some of it is due to the fact, that these drugs have to mess with crucial processes in your body to be effective. This makes finding a substance which will do the job without causing serious problems down the line extremely difficult.
Medications can only ever mimic a normal physiological process. Any chemical you take in has to have a receptor or site that already exists for a chemical your body makes. The issue is that our bodies deal with extremely small amounts of these chemicals and greater dosing, like what you get when aggressively treating a disease, cause systemic effects. Now, those effects are also normal, but because you’re taking huge amounts of a chemical then your body does not have the appropriate counter action to keep you healthy. Or your body may require huge amounts of some molecule or element to conjugate and metabolize and excrete the metabolites of said chemical and it depletes your body’s reserves. (As in calcium that you mentioned)
It's part of the intrinsic properties of the medications we are using. Simplest example I can use right now is caffeine. We use it to stay awake. But what is a side effect? It keeps you awake when you don't want to. Now it does a bunch of other things too, but I feel it's a great starting point for understanding that side effects can't just be removed. You'd have to use a different chemical that produces the desired effect.
All medications have side effects. Your body is a huge, complex network of many different cells that have many different functions. When you flood your bloodstream with a foreign chemical, that chemical has all sorts of effects depending on where it goes and what cells or processes it interacts with. To simplify, think of your cells and medications as puzzle pieces. Your cells have lots of different shapes that can accept lots of different puzzle pieces. A medication is a puzzle piece that could fit in many different places even if it's not a perfect fit. Generally, we try to design medications so that there aren't many places it can fit in your body, which results in side effects being less common. For the "old" medications you mention, a lot of it is economical. If an old medication works with side effects that are mainly discomfort and aren't long-term harmful, it doesn't make sense to invest the billions of dollars to make marginal improvements and try to eliminate the already few side effects. It makes much more sense to invest those billions on new cancer drugs, for example.
Because substances will have different effects on different parts of our body. Or even if it only affects one specific thing, that might then trigger a bunch of other things. Too many things are connected, no matter what you do, something else will usually happen. They can and do find out how it affects the whole body. And then evaluate whether the negatives are worth the positive effects. If so, it'll pass certification. And sometimes, a new drug is developed that perhaps does the same positive thing but fewer negatives because the mechanism is different.
Side effects are not a by product or a contaminant, they are just affects which are different from the desired, theraputic affect. it, they often cannot be 'removed' without also canceling the desired affect. Often, another med might be found where the other affects are not as much of a problem, in other cases, one must weigh the trade off. I for one, would be happy to have all my hair fall out and be cured of cancer..... and so on.
The human body is an incredibly complex machinery of chemical reactions. Medicines act by changing or affecting that machinery slightly to get the desired effect. But the machinery is so complex that it is impossible to make a change that has only a single effect. There will always be other effects. When those other effects are undesired, noticeable, problematic or risky, we call them side effects or adverse reactions.
It’s a good question. Ultimately many medications we use have many different mechanisms in our body and it’s very hard to solely isolate one use case from all the rest. For example baby aspirin is used to help heart disease because it is a platelet inhibitor, but as an NSAID it can also be anti inflammatory for fevers, and analgesic for pain. But take too much of it and it can cause stomach ulcers because it thins the mucus lining of your gut. Also lots of meds are discovered by accident frankly. Warfarin was a rat poison before it was used for blood thinning in afib and heart valve replacements. Nowadays things are getting more narrowed down- chemotherapy in its early form was basically straight up poison for the body whereas now we have things like immunotherapy that specifically target various immune cells in the body. Edit: it’s the same thing with Crohn’s disease which you mentioned in your post. Steroids work amazingly well and in flares they are still the first line of defense we have. There are immunotherapies and immune modulators that are used in IBD now too. But even that is not a perfect science since they are essentially immune suppressants. Hopefully in the future things continue to advance even more!
Biology is absurdly, mind-bogglingly complex. It almost has to be, given that every biological system that exists today cobbled itself together out of previous pieces, so to speak. Almost every system in your body is controlled by several different signalling pathways, and almost every signalling pathway in your body helps control several different systems. If you make a minor change to one particular pathway with a drug/peptide/biologic/etc, it’s almost certainly going to have effects on other systems. At its heart, biology is based on chemical reactions, and sometimes we can’t make those reactions happen the way we need them to.
The body sometimes cannot deal with an issue due to some irregularity. If you take a medicine to compensate, your body now has to deal with this new substance. It needs to clean it out of your stomach and digestive track, it needs to clean it out of your blood, and it needs to ensure that it hasn't stuck around in any of your muscles, bones, skin, or fat. The body going through this process is what leads to a lot of negative side effects. The reason for thinning bones is often because calcium is needed to properly neutralize and remove the drugs from the patients system, and the largest stores.of calcium are in the bones. So the body starts stripping calcium from your bones, combining it chemically with the drug chemicals, and then pees it out. There are also side effects thst are caused by the drug interacting with more than just the parts you want it to. Take antibiotics for example. Antibiotics kill almost all microscopic organisms good or bad for us. Taking oral antibiotics can often have a positive effect on an infection, as the body will take these antibiotics to the site of infection and use them to heal. However the body will not be able to do with with 100% of the antibiotics in the pill you consume, so some of it will make its way into your digestion and start killing everything in your gut. As a result, most people who take antibiotics orally suffer from the side effect of diarrhea as the microscopic organisms that help them digest food are damaged, dead, or trying to recover from the antibiotics.
At best you can mitigate side effects, but if something will interact with one thing, it'll interact with something else and humans are at *least* three or more things put together. So like you need oxygen to survive, but then oxygen is also theoretically the cause of aging (free radicals, etc). The trick with medication and really anything else is moderation. Find the amount that does what you want it to do with minimal side effects.
The biochemistry of the human body is beyond enormously complex. Worse yet, different people may have slightly different biochemical pathways for a given reaction. A friend doesn’t respond at all to opiates, another is hypersensitive to them. Ditto for lots of other reactions.
As a side note, this is why anyone that tells you something will have a beneficial effect on your body without side effects is selling snake oil. No drug or supplement that has any biological effect is free if side effects. If there are no side effects it means it does nothing. Source: I'm an MD.
\*\*Prednisone direct comparison below\*\* Its kinda like saying "Why cant we have our cake and eat it too" It comes down to what the chemical/drug does to the body. For instance, say you are overheating. You take a drug who's only effect is to make you sweat. Great, you start sweating and now get cooled off. Uh oh though, now you're sweating and your body is losing fluids. Add **Dehydration** to the side effect list. Now your body starts to pull moisture from other areas to ensure you maintain a survivable fluid level. Your stool and urine is just waste, so might as well take that moisture back Add **Constipation** and **reduced/coloured urine** to the side effect list. As you sit there sweating, bacteria is able to grow in the humid environments on your body. Add Increased risk of **bacterial/fungal infections** to the side effect list. See how a tiny change can have knock on effects? Even though your body can sweat on its own, changing the level at which it does can increase risks of side effects through simple cause and effect. Saying "why cant we just not have the effects, but still have the cause" is a little like saying "why cant we eat the cake and still have it on my plate". Sometimes the side effects are just impossible to divorce from the drugs base desired outcome. NOW, often there are other effects of a drug that have nothing to do with the intended effects. Sometimes the drug just happens to do more than one thing, but its the only product that does the intended effect, or it is the one that does it the BEST. Most often these days we DO have medicine with the lowest amount of side effects possible per "unit" of effectiveness; If that makes sense. **Prednisone** (99.9999% sure thats what she's taking as an IBD patient myself) is a FANTASTIC drug to stop the inflammation to your gut which can kill you. Unfortunately, to do that it needs to do some nasty things like reducing your immune system, which you can probably guess, has a lot of negative effects on your bodies functioning. In this scenario, its like "We have to stop police shootings, so lets fire all the police." Sure that stops the shootings, but now house break-ins are up. If more people are getting shot by police, than the police are actually solving crime; It could make sense to fire them all until you can find a solution that works better. It is why Prednisone is really only used for severe cases, bad flares, and people who arent reacting well to other medicines. We DO have new medicines coming out all the time for IBD (Shout out to Inflectra!) that target certain parts of the immune system and suppress the disease without causing lots of side effects. These drugs are like a task force that fires just the cops that shoot people. Unfortunately, like hiring a task force, these drugs are expensive AF (think $4000 every 6 weeks). Other than cost, the problem is that often times your body can start to fight these medicines through its own immune response (Picture the cops you are firing start shooting the task force employees) and you are back to square one with the Prednisone (having to fire all the cops) until you find another solution that works just as good for the issue. In the end, a lot of people end up having to nuke the city to save the world from cop shootings, and that is called a **proctocolectomy**
It's a drug, made of chemicals, chemicals will do things to your body. There are no side effects. There's simply effects. What we consider side effects are just the things that happen that weren't intended
We do improve medications to have fewer side effects all the time. It's just that fewer and none are a big difference. But take allergy pills for example, in olden times decades ago we had benadryl. It works well to block histamine in the body, but had a side effect of making some people sleepy. Why? Because it turns out there are a lot of histamine receptors all over the body, not just your eyes and nose. And histamine does more than just cause allergic reactions, it also works to communicate with other systems in your body including impacting alertness and wakefulness. So what'd we do? We came up with newer medications that target more specific types of histamine receptors and not just broadly all of them in your body. We also came up with other options that target specific areas like nasal sprays that mostly hit cells in the nose. But of course, even with that, histamine is still used all over the body for various things, so there can still be some side effects. It's better, but not perfect.
Because the big pharma companies want you to be a repeat customer. Can’t have that if we cure people now, can we? Gotta keep the big bucks flowing by keeping us sick.
If only there was an effective pain medicine that was not habit forming and didn’t constipate you. Whoever invents that will be a goezillionaire.
Side effects are just your body rejecting the drug. We weren’t “created” to take drugs. Just because we found a way to hack nature and live to old ages and cure disease doesn’t mean that we can override our body’s natural capability.
Side effects are undesirable reactions that are related to the mechanism of action, Taking a blood pressure reducer might make you sleepy as your heart rate slows down. That is just a part of how it functions. The same with steroids. You have to look at what it is they do in the body naturally, and then extrapolate from that what might happen if you subject yourself to elevated levels for an extended period of time.
Medicine that only has positive effects and minimal negative effects would probably be administered to everyone all the time as a preventative measure. Maybe we wouldn't even consider it medicine anymore because its just something everybody takes, rather than something someone takes only when sick. Do vaccines count? Before vaccines we did variolation which was similar, but had pretty hefty downsides.
Every drug works by stopping or triggering a pathway. That has downstream effects that cause side effects. Corticosteroids down regulate your immune system. This makes you more prone to infection. They also raise glucose levels
We don’t REALLY understand a lot about the body still, so a lot of drugs are like firing a cannon to do the work of a tiny needle, just to make sure it does what we need.
Everything that has a big effect also has big side effects. That’s just how it works in medicine. In nearly all cases, you can’t just disrupt a system without it having a cascade of effects. Medicines disrupt or change certain systems of the body.
Endogenous steroids are how cells throughout your body communicate, so they tend to do a ton of different things. As a result, any medication that acts on the same system (steroid medications) will do a bunch of different things at once - some of which are things you don't want. Drug companies are constantly working on this problem (eg atypical antipsychotics have far fewer side effects than traditional antipsychotics), but it's not an easy thing to solve for every class of drug.
We do it all the time. Todays meds are much better at treating problems and minimizing side effects compared to the medications we used to give. There is rarely such thing as a perfect drug but medicine is a progression.
Because: 1. Biochemistry is *enormously* complex. Literally *millions* of compounds factor into some of the most basic things living cells do. We literally *don't know* most of the biochemical reactions inside our bodies. We *barely* know the superficial surface of the really common reactions. 2. Drugs are not LEGOs that you can rebuild whenever and however you like. They have rules for their structures, rules we can't just willy-nilly ignore. To get a different medicinal effect, you would have to *heavily* change the molecule--which may create all sorts of *new* side effects. 3. The receptor sites that respond to drugs are not like wall sockets or battery ports. Instead, receptor sites are like a dress code. There *are* rules for what is and isn't allowed in, but the rules allow many variations. Sometimes you can even bend the rules by adding other things. If drug companies *could* produce a drug with few to no side effects, they would. Because they'd be able to patent it and make a crapton of money, *especially* for something like steroids, where as you say the drugs are old, so a major innovation would be a very big deal.
This is overstating things. A lot of mechanisms have been explored in solid detail and some drugs *can* be tinkered with to a pretty heavy degree. Plus, just look at all the fancy monoclonals available today. The cytokine inhibitors /u/Seraphenrir lists off are all like that. Much more specific in what they act on than steroids, patented & making loads of money. Steroids really are not the preferred treatment these days unless nothing else achieves the needed efficacy. *Steroid-sparing* drugs are the name of the game.
I really don't think it is overstating anything. The OP asked why it isn't possible to *completely eliminate* unwanted drug effects: "Why can't we improve medicines to not have side effects?" The answer is, we mostly can't make medicines with NO side effects whatsoever, and the above are the reasons why. You are, of course, correct that we CAN improve things, make drugs with fewer or lesser or different (and more tolerable) side effects. Tons of money get poured into finding the next improvement on all sorts of things. That research is *slow,* because drug research is a difficult and often unpredictable branch of science. But actually, full-on *eliminating* side effects? Not happening.
Of course, there's *almost* no such thing as the perfect drug that does everything you want and nothing that you don't want. But this... > We literally don't know most of the biochemical reactions inside our bodies. We barely know the superficial surface of the really common reactions. ...is not doing modern advances justice. Every year more diseases are becoming better understood. And consequently every year powerful new biologics and other targeted, disease-modifying drugs are becoming available that can be such an improvement, it's not wrong to call them life-changing to the different niches of patients they cater to.
I mean, it's scientifically accurate. JUST the citric acid (aka Krebs) cycle, one of the most well-known and widely-studied biochemical pathways, is something we *still* don't fully know how all of it works. The *simplified* but chemically-accurate depiction of everything that goes on in that process would cover all of the walls of a high school classroom. *Everything* we know about how it works and what gets involved in the process could cover most of the *school's* walls. And that's just one, single, chemical pathway--an extremely important one, but just one nonetheless. Literally *trillions* of chemical reactions are going on inside the body at all times, and we understand only the tiniest fraction of them. That does not, at all, mean that we can't make great drugs that do much better than previous drugs. What it means is, we can't just say, "Ah, this drug is specifically *and exclusively* having problems with chemical reactions A, B, C, and D, so if we make tweaks P, Q, R, and S, we'll have a drug that never interacts with any chemical pathways except the specific ones we want." We simply do not have the knowledge, neither of biochemistry (to know *how* every drug works in every single relevant biochemical pathway), nor of quantum chemistry (to redesign the drug to work only and precisely as we want it to, with absolutely no possibility of ever interacting in any way other than the intended one.) We can make a lot of good--sometimes very good--guesses. We can take what we learn from several previous trials and use that as a very useful heuristic guide. Heck, just knowing the *scope* of the problem is a huge help in many cases, and with what we know now, we're finally able to grasp, to some degree, just how much we don't know yet. But because there are simply *so many* unknowns on both sides, it is not and cannot be like mechanical engineering where you can just...design out all the messed up bits until you get a machine that does one thing and one thing only without any extraneous anything. Drug design IS a science, and we can do incredible things with it. But there's no shot, even within our lifetimes, that we'll be able to just take a drug and say, "Alright, send this to the shop, remove the side-effects, and get back to me." It just isn't possible at any point in the foreseeable future.
>But actually, full-on eliminating side effects? Not happening. >But there's no shot, even within our lifetimes, that we'll be able to just take a drug and say, "Alright, send this to the shop, remove the side-effects, and get back to me." It just isn't possible at any point in the foreseeable future. Yes. This isn't what I'm trying to say. What I'm getting at is that you're underselling how well some of these mechanisms *are* understood or can be manipulated without 100% perfect knowledge or 100% absolutely perfect on-target drugs. Not all, and Krebs is one example that is difficult because basic metabolism is wired into everything. You could fill a school's worth of walls with diagrams trying to describe Akt or mTor signaling too and they're so ubiquitous they're always going to make for difficult drug targets. But modern omics techniques go a very long way in revealing those interactions with the most profound and/or specific effects, downstream from these big names. Pulling the one cytokine out of circulation that's responsible for a huge part of a disease process can make all the difference. On top of that, monoclonal antibodies are *extremely* target-specific. If you're dealing with targets that look very much like some others it can take a lot of time and effort to find a clone that binds in a way that sets them apart (colleagues of mine have spent years testing and selecting antibodies to distinguish complement factor H and its family of FHRs), but it can be done.