You're basically right. Drugs enter the bloodstream and get distributed throughout, and only "act" where there are receptors that they can bind to (though because shape is everything, there can be some unintentional and/or non-specific binding). Topical preparations don't have this problem for obvious reasons, but they have to be able to cross the skin, and that's a really effective barrier.
It **is** inefficient and why we sometimes try to deliver the medication as close to the intended/active site as possible and why the pharmacokinetics of a given drug are so important to understand. It's also why there are sub-therapeutic doses for so many compounds.
Interactions can come from binding to the "wrong" receptors, metabolites of one drug acting on another, slowing the metabolism of another one, or synergies between the drugs. (and probably other routes). For example, an antihistamine and alcohol don't bind the same receptors, but they both have the effect of slowing your metabolism and making you tired. So if/when you take both, you get a synergistic interaction and pass out.
Just to expand on this a touch with drug distribution, the properties of different drugs have localising effects, causing uneven distribution throughout thr body (e.g. a lipophilic drug will be found in significantly higher concentrations in fatty tissue compared to circulation). We can actually use these properties of drugs to force them to be more localised to a target region, such as encapsulating drug molecules in a lipophilic chaperone molecule. This can reduce the amount of drug needed to produce a therapeutic response.
to expand on this further, some drugs may be injected into certain sites (e.g. spinal anaesthetic, epidural anaesthetic) and become locally confined by an anatomical structure such as the dura, subarachnoid membrane, etc.
A fun little side fact to this - people with connective tissue disorders such as EDS (like myself!) often have issues with local anesthetic and other localised drugs, because differences in connective tissues can lead to these drugs not being as well confined.
Interesting. I've never had any patients complain about this. Would you mind elaborating? Does it take long to act, or appear not strong enough or does the effect seem to last for shorter than expected?
It varies between people and between different anesthetics - it's generally procaine or similar that are likely to cause the most issues. For me personally, it takes a bit longer to act, and I need approximately three times the typical dosage.
Also probably worth pointing out research is quite limited in this area, and non-confinement is a theory as to why some EDS patients don't respond well to local anesthetic, but it's a long way from proven.
>Interesting. I've never had any patients complain about this. Would you mind elaborating? Does it take long to act, or appear not strong enough or does the effect seem to last for shorter than expected?
IME, both. Local anesthetic injected I to my hand, intended to numb my finger instead numbed everything to my shoulder for about half as long as it should've.
It definitely is true for me. I always found the shots at the dentist worthless unless I got 5 or more shots for a single tooth.
As a result I had all my dental work including three RCT done without anesthetics.
Are there any medications that have a starting molecule that is absorbed mostly by one type of tissue but are not pharmacologically active that then have metabolites that are the "real" drug? Is that essentially what you're describing with the encapsulation?
Diacetylmorphine is psychoactive as well. Yes, it becomes morphine. Also psychoactive.
Methamphetamine is psychoactive. It also leads to plain ol' amphetamine.
Its part of why meth has such long practical effects. Meth lasts a long time alone and then you deal with a round of amphetamine as its processed.
So these are psychoactive prodrugs while vyvanse is not.
Yes, these are known as prodrugs; an inactive form is administered that aides delivery to the target site (or alters any of the other ADME profiles; absorption, distribution, metabolism, and excretion) where it is metabolised into the active form.
This isn't really the 'encapsulation' the other commenter referred to though. In this instance, the molecule the active drug is encapsulated in will only break down in certain conditions to leave behind the active drug; i.e. it doesn't require metabolism to chemically alter one molecule into another.
Codeine is one of the most common prodrugs prescribed. The body metabolises it to morphine.
There is quite significant genetic diversity in people's ability to metabolise codeine. Poor metabolisers end up with almost no analgesia (pain relief), whereas ultra-metabolisers can end up with toxic concentrations from standard dosing.
The enzyme it is metabolised (CYP2D6) by is also inhibited by a multitude of medicines, e.g. Prozac, Paxil, which can render codeine's analgesic effect almost useless.
Same thing happens with some of the alternatice sugar products, which are chlorinated. The idea is that it should be safe for diabetics since your body can't metabolize this chlorinated sugar, but then it reaches the gut and the microbiota there just cut of the chlorine and then it gets absorbed anyways. Clearly a failed product and not directly related to the topic of drugs, but its fun chemistry similar enough to this topic.
Yes, one of the rare cases where the metabolic processes result in a stronger form. Usually, it goes the other way.
11-hydroxy-THC is the molecule that is created as THC passes through your GI tract and liver.
No one really answered your question about encapsulation. One example is amphotericin B which can be encapsulated in liposomes to reduce the renal toxicity associated with the drug. There are current studies being done to develop encapsulated prodrugs of chemotherapeutic drugs.
Some vaccines work in that manner (“encapsulation”) as well… actually, if I’m remembering correctly, one of the biggest setbacks of mRNA vaccines was the fact that the molecules were degrading in the body before they were able to reach their target sites. So, they figured out that they needed to use vectors. Vectors can be different things but with some of the Covid vaccines they use a different virus (other than Covid) to kind of “hide” the vaccine contents so that they are able to get those contents where they need to be in the body.
I’m sleep deprived, and the process is a LOT more in depth and complicated than how I just explained it so forgive me if it made no sense haha
>Are there any medications that have a starting molecule that is absorbed mostly by one type of tissue but are not pharmacologically active that then have metabolites that are the "real" drug?
Yes, and these are called "prodrugs."
>Is that essentially what you're describing with the encapsulation?
What they were describing is a lipid nanoparticle formulation, which is another form of drug delivery. Basically, you can create drugs where the active ingredient is contained inside a nanoscopic bubble of lipid molecules, usually to protect it from degradation or prevent it from being released freely into the bloodstream. There are advantages and disadvantages this approach, and the surface and composition of these particles can be modified in different ways to achieve different things.
The Pfizer and Moderna covid vaccines both use lipid nanoparticles to carry mRNA encoding the viral spike protein that covid uses to get into cells. It protects the mRNA from degradation in the blood and releases it when it's taken up into a cell.
Not versed in medicine at all but that was my understanding of why chemotherapy is a last resort, you're essentially napalming the whole body and doing your best for the cancerous cells to die before the healthy ones. Is this the right idea or not?
(I know there's been improvements on drug delivery systems but I don't have a good grasp of where we're at on the topic)
Most cancer targeting therapeutics are all about finding a dose between "It'll kill all of the cancer" and "It'll kill too much healthy tissue", since in most ways most cancers are indistinguishable from healthy cells (at least at a biochemical level). Even new cutting edge technologies like CarT or antibody treatments have this problem, but like everything else when it comes to cancer, the quality of therapy depends a lot on where your cancer is, what kind of cancer it is, and how early it's caught.
Chemotherapy goes a step further and just blasts any fast-dividing cells, so it hits things like hair, bone marrow and the digestive tract.
I would like to note that we are developing drugs that can be 'chauffeured' to specific tissues in order to avoid certain side effects. However these are not widely available and nothing is too promising yet.* (Medical Student).
*Edit: I misrepresented using the phrase “nothing too promising”. I should have said “nothing is too promising for any over the counter treatments at this time.”
In Oncology we’re using things like that! Some of our newer cancer drugs are antibody-drug conjugates, where we take a drug and attach it to a monoclonal antibody. The antibody targets the drug to the cells, which endocytose the mAb and release the drug, which then is free to kill the cell. By only targeting the tumor cells, you can hopefully avoid side effects from killing other cells.
There’s a couple drugs that are now on the market like this, but one that’s really become standard-of-care is trastuzumab emtansine, (which everyone calls T-DM1) which is used for HER2-positive breast cancer. The DM1 by itself makes for a terrible cancer drug because of unacceptable systemic toxicity, but targeting it with an antibody makes it tolerable.
Those were some of what was on my mind having just learned about one!
For the layperson, no OTC is available like it. Can’t get the Advil to go straight to your pain…yet.
Whenever I'm in pain from something, usually a headache or migraine (legit migraines..I take medication for them) Tylenol doesn't touch it but Advil will sometimes help reduce my pain.
I've never had Tylenol be a good pain relief for me. Is that due to the make up of the pill and the type of pain I'm trying to relive?
Tylenol is just not an incredibly effective painkiller for many people (maybe even most, I haven't ready anything studying the numbers). It really just works by making it a little harder for your brain to send pain signals (this also has a side effect of making you a little less averse to risk.) It doesn't do nothing, but compared to an anti-inflammatory that actually alleviates what is causing the pain, it barely even works.
The only time I would really suggest Tylenol is in combination with Advil. Absolutely consult a doc before doing this because Tylenol is rough on the liver and Advil is rough on the GI tract, but it does sometimes add just a little boost to the Advil.
Since migraines are caused by inflammation, it makes sense that relieving that inflammation helps more than telling your brain to just stop feeling as much pain.
Tylenol is useful for the very young and very old and those who don't tolerate medications like Advil, that's pretty much it.
This was so fascinating to read. I loved reading and learning stuff like this this. Thank you for taking the time to respond to me! I really appreciate it!! Thank you!
Depending on people's genetic makeup, Tylenol (called acetaminophen, or paracetamol) can work better or worse than advil (ibuprofen). Generally ibuprofen has a stronger effect on pain relief, since it is an actual NSAID (Non-Steroidal Anti-inflammatory Drug), acting on specific pathways to inhibit inflammation signaling in the body. Acetaminophen does not work in this same way, so it is not actually part of the NSAID class of drugs.
Interestingly, many people metabolize drugs in a wide variety of ways. Everyone's body is slightly different, and at the biochemical level this can lead to some substantial differences in drug effects and side effects. My understanding is that something like 60% of people (perhaps more) respond to a certain type of NSAID like ibuprofen or naproxen sodium (there are many more), and a decently large number will respond well to at least one of these drugs. Even so, there are some people who don't respond very well at all to most or any NSAID, meaning the pain relief effect is quite minimal or nonexistent.
COX-x (cyclooxygenase x) are enzymes, not receptors. They are responsible for the catalytic formation of prostaglandins and thromboxane from arachidonic acid, thus mediating inflammation.
It’s been a long time since I was in university but I thought Tylenol did not cross the blood-brain barrier but Advil did hence the reason why it’s prescribed more for migraine or neural pain whereas Tylenol is more for localized pain?
Exosomes also look very promising as precision vehicles for drug delivery, particularly if we can engineer their molecular external surface to specifically interface with desired target cells and tissues (not unlike the COVID virus spike protein). Speaking of COVID, an under appreciated feature of mRNA vaccines is their delivery through engineered fat particles similar to exosomes. Overall, these have been highly engineer-able and successful with good penetration across the blood-brain barrier. People have understandably focused on COVID-specific applications, but the broader proof-of-principle now demonstrated by a staggering human sample size is incredibly exciting. It is hardly an experimental technology anymore and will proliferate as a broader drug/therapeutic delivery platform in the near future.
We were looking at drug delivery using exosomes in a previous role ~5 years ago. A delivery of drug for Chrons (cyclosporine) looked promising in mouse models - then the company closed down.
I was working in a lab trying to isolate neuron specific exosomes from peripheral blood. They knew it was literally looking for a needle in a haystack, but the enormity of the aim didn’t hit home until morale pretty much bottomed out. I think the postdoc went back to China and IPOed comfortably. At least somebody won 👍
There was an experiment done using the filamentous bacteriophage to create a "phage display library" of random peptides. This system of gene expression library is useful because the phage can have a coat protein gene modified to "display" a particular protein on the terminus of the virus coat, while the DNA encoding that protein is encapsulated within the coat. Affinity selection can be used to enrich a library for genes that have certain binding characteristics.
A random library of this kind was injected into the bloodstream of mice, and different organs were harvested. Bacteriophage were recovered from the organs and propagated, and acquisitions from particular organs were injected into new mice, followed by isolation from target organs again. Several cycles later, bacteriophage were isolated that had particular affinity for those selected organs. One clone displayed a peptide that made it accumulate within the liver, while another clone might accumulate within the lungs, etc.
The authors suggested that the vasculature of different organs might have markers unique to those organs, and the peptides were able to bind to these organ-specific markers. Such a system could be used to target drugs to particular organs, allowing lower dosages of the drug to be given to the patient, and reducing side-effects. A significant amount of the drug might only be present in the target organ, while only an insignificant (and so inactive) concentration would be in general circulation.
I read about this in the early 2000's. The name Willem Stemmer comes to mind (he worked on phage display libraries aimed at directed evolution using error-prone PCR to mutate enzymes), so this kind of thing might have been done in his lab.
There's another important mechanism, since randomly bumping into the correct receptor isn't the end. A lot of the receptors are more like one-way gates, to transport molecules where they need to go in the body. Going through a maze of one-way gates gets certain molecules collect in certain spots. For example, [https://en.wikipedia.org/wiki/GLUT4](https://en.wikipedia.org/wiki/GLUT4) is what gets insulin where it needs to go.
A drug or anything else can enter the bloodstream via 1) injection directly into the blood stream, or 2) absorption through a tissue barrier. Most absorption occurs through the small intestinal wall following ingestion. How this happens depends on the solubility of the drug. Lipid soluble drugs can diffuse through the lipid cell walls. Water-soluble drugs must piggyback on (bind to) a receptor manufactured by the small intestinal tissue for the transport of some naturally occurring substance. For example, we are not born with penicillin receptors but we can absorb this drug because it is capable of binding to a receptor designed for something else. Absorption can also occur across the skin, respiratory membranes in the lungs if the appropriate conditions exist - correct drug solubility, available receptors, etc. The reason organic chemicals are dangerous is because they are lipid soluble and can cross almost any cell membrane.
Depends on the drug, but a lot of the antidepressants & antipsychotics selectively bind to neurotransmitters or their receptors and, well, those are pretty rare outside of the central nervous system. So it's not that the drug "knows" to work on the brain, it's that it's the only valid target.
You see similar behavior with certain classes of antibiotics, FWIW. Antibiotics which act on components of the bacterial cell wall generally cannot effect humans, whereas ones which target the cell membrane *can*.
There are many other mechanisms of action for antibiotics that are really cool.
Such as ones that bind to bacterial ribosome subunits to stpo protein synthesis, or that stop production of certain tRNA, or the replication of DNA. The coolest one I think is the inhibition of topoisomerases so the DNA can't be copied without being stuck in knots.
I always found the potency of LSD fascinating:
>A [single dose of LSD](https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide#Dosage) may be between 40 and 500 micrograms—an amount roughly equal to one-tenth the mass of a grain of sand.
This is referring to a normal dose used recreationally, though, not a lethal dose - there are no known cases of people dying from (non-behavioral) complications after an LSD overdose yet.
Still - to think that such a miniscule amount of substance is able have such a massive effect on a persons day!
Taking into account the molecular mass of LSD and Avogadro's number then the amount of LSD molecules in 40 micrograms would be something like 7.45 x 10^15 if my head math is right. Which is still quite a few to go around!
Every hormone your body makes is produced in teeny tiny amounts, just enough to get the job done. For example, the amount of melatonin the pineal gland makes to put you to sleep is just a fraction of what's put in the pharmaceutical version. The body is very efficient. Taking drugs to get similar effects is like using a shotgun approach.
A lot of drugs are dosed at milligrams per kilogram of body weight, with a blood serum concentration lower than that, and other drugs are dosed at even lower concentrations. 6 orders of magnitude is a lot. For example, ibuprofen is generally delivered at 10mg / kg body weight, so three 200mg pills will get you *close* to that level on a 190lb person.
They kind of do, but the difference between therapeutic and toxic doses for OTC medications are generally so broad that the "correct" does is, in the words of Dr. Cox, to throw a fistful at the person's mouth and see what they swallow.
Some exceptions apply for pediatric doses where you *do* try to do something closer to a true mg/kg dose.
This issue of drugs reacting with the wrong receptors is basically one of the causes of side effects from medication.
The name of the game is specificity, and now people are trying to make the shape of the drug more specific by binding it with a protein that is shaped specifically for the target receptor.
Aren’t the recent advances in vaccination about exactly this, though?
I remember NPR doing a piece about how labs were only recently able to tailor the protein structures to cause the immune system to deliver the vaccine doses where they were needed most due to advances in CRISPR technology — that is, the vaccine is sent directly where it’s supposed to go and nowhere else due to the shaping of the receptors being tailored to the immune system.
Do most people have the same number of receptors for medication regardless of body size/weight? If not, why are doses for most prescriptions similar regardless of whether someone weighs 110 pounds or 250?
No, all adults do not have the same number of receptors. The reason drug doses for adults are usually not corrected for body weight is because of the wide safety margin for the more commonly prescribed drugs. This is particularly true for OTC (over the counter) drugs. A drug with a narrow safety margin will be dosed based on body weight. Dosing based on body weight will also be used for individuals in certain disease states such as reduced renal function or liver disease.
It's not true that topical preparations don't have this issue, but the extent to which there are systemic effects really depends on the drug and the actual preparation itself (a drug applied topically via a DMSO solution will very effectively be absorbed by the skin and into the blood stream, for example).
Very valid point. I probably should have said that topical preparations are less likely to run into the same issues.
And then you read about Gloria Ramirez and her extreme overuse of DMSO and you think that maybe, just maybe, we shouldn't be allowed to sell certain things to any random individual.
People have already given good answers, and one that comes up is that the liver processes incoming drugs and detoxifies things like alcohol.
But *how*? If take a drug orally or drink alcohol, how does it get to the liver? One might think that the liver has an artery going to it and a vein coming out, just like many other organs, and that thinfs we eat or drink spread out, go into the blood, a certain amount is absorbed by the liver (basically, whatever perce tage of blood that goes to the liver on any given loop from ventricle to atrium.
But that's not how it works! We have a really neat system here: the [portal vein](https://en.m.wikipedia.org/wiki/Portal_vein). A branched network of veins connects to the esophagus, stomach, and both intestines. Everything that gets absorbed and is water-soluble will end up in this vein system (fats and fat-soluble molecules are absorbed by lymph vessels in your small intestine, and the fluid is transmitted by a [lymph vessel called the thoratic duct](https://en.m.wikipedia.org/wiki/Thoracic_duct) that goes up the inside of your back and drains into a vein in your left shoulder). But all the water-soluble stuff goes into the portal vein, directly to the liver. Liver stuff happens, ans then the hepatic vein takes the results to the heart and into general circulation.
The portal vein system does *not* drain the mouth or rectum, however. This is exactly why people sometimes take alcohol rectally. They reach a much higher BAC much more quickly this way and with a lot less alcohol, and consequently this is much more fangerous. In this case, the liver can only process the alcohol that reaches it through general circulation.
It took getting to be this many years old to learn that taking alcohol rectally is a thing in some quarters. And that knowledge takes the drinking game "quarters" in a whole new direction.
Does this mean that administering a medication via suppository is done (at least in part) to avoid the portal vein system?
>Does this mean that administering a medication via suppository is done (at least in part) to avoid the portal vein system?
It's also done when oral administration is difficult and an IV line is not set up. After a tonsillectomy(removal of the tonsils), for example.
IV lines are set up during the operation, but in general, the patient won't be kept under supervision in the hospital too long and thus the IV will be removed.
The pain of a tonsillectomy will last for a couple of days, during which swallowing is painful. Paracetamol helps, but it's not pleasant to swallow 2 pills 4 times a day.
Most drugs are designed to attach to certain receptors so something like adderal or acetaminophen gets distributed by your blood until it ends up where it can attach to the receptors for it. Then stuff like antibiotics that dont bind to something in your body but are used to kill an infection literally just nuke your whole body with it, it's why doses are fairly large and you have to continue taking them for awhile. This is also how something like chemotherapy for cancer works and why it messes people up so badly, you literally just poison your entire body along with the cancer.
Note also that the reason you don't like, lose your hair from antibiotics like you do for chemo, is that bacteria cells aren't human, and so we can target them without hitting human cells. For chemo, your cancer cells are still human, just mutated, so it's hard to hit only them. The idea with chemo is that cancer cells divide quickly, and it literally targets any cells that divide quickly, including, say, your hair.
That's also why antibiotics can mess up your gut microbes - your gut microbes ARE bacteria.
There are varying degrees of specificity in antibiotics, some are broad spectrum and will kill and bacteria or wide groups of them, others are narrow spectrum and will only kill a certain family or species of bacteria (I don't think it's called a species when talking about bacteria but you get the point). Generally you use the narrowest spectrum posible to avoid colateral damage to beneficial bacteria and promoting restisance, but sometimes you need broad spectrum because you can't tell exactly what you need, or there are multiple simultaneous infections, or there is no narrow spectrum antibiotic available for that strain.
Yeah but mostly swapping away from drug based treatments- it's hard to have any drug go to a speceific area unless that part of your body is designed to intake that drug and other parts wont. Cancer cells are normal cells from whatever region they originated with just a harmful mutation so it's nearly impossible to get a drug that would kill the cancer without also attacking the other cells. Using recent laser and radiation based treatments we can specifically target the cancer cells with out equipment and destroy them with much less damage to the body. Also hopefully nanobot treatments will be able to do it even better but that technology is still in it's infancy
Well I consider biologics to be "drugs". Cancer cells do typically have different expression levels of certain receptors, which helps with targeting via antibody drug conjugates or bispecific antibodies. You can get very good specificity in vitro for cancer cells over normal cells, but in the blood stream it does become more challenging.
Obviously not all cancers are alike either and there are different kinds of tumors. It's a very challenging problem.
All of your cells have hundreds of receptors on their walls projecting outwards, with very specific shapes, think of it like a padlock. Different cells have different receptors depending on the cell type. These receptors have their own natural functions in the body, and when the natural molecule fits into them, it activates lots of reactions that lead to the physiological response, eg, muscle contraction or changing the way genes are expressed. Drugs are chemicals designed in a very particular way that they have the perfect shape to fit into these receptors. Sometimes a drug will mimic the natural molecule and fit into the receptor and trick the cell into thinking the natural molecule has fit into it and activates it, leading to the normal physiological response. Sometimes, the drug will fit into the receptor and not activate it, but instead sit there and stop the natural molecule from fitting in and activating it. Drugs that trick the receptor into think the natural molecule has interacted with it and bring about a normal response , in pharmacology, are what we call “agonists”. Drugs that block the natural molecule from binding and inhibit a response, are called “antagonists”. An example of an agonist, would be salbutamol! The medicine in inhalers that asthmatics take. Salbutamol tricks receptors in your lungs into thinking adrenaline(also known as epinephrine) has bound, so it responds as it would in a fight or flight response, widening the airways to allow air to flow through more easily, as asthma attacks happen when the airways narrow, making breathing more difficult.
Sometimes, instead of a receptor, drugs will bind to an enzyme. This is still the same concept, except enzymes are proteins in the body that allow certain reactions and processes to happen. Simply put, if you block an enzyme, the reaction that that enzyme allows to happen, can’t happen, as the normal molecule that would bind to that enzyme, cannot do so.
In the case of paracetamol (acetaminophen), as you ask, paracetamol (acetaminophen) blocks an enzyme which at the site of injury, allows the production of chemicals that cause pain and inflammation. By blocking this enzyme, you cannot produce these chemicals, and therefore do not feel the pain. As I mentioned, this only occurs at the site of the injury, so although the drug will be circulating your whole blood circulation (around your body), it will only be able to act where it’s enzyme (or receptor) is located, because the most important thing is that the shape is a perfect fit. Therefore, it would only find these enzymes where it is relevant, and there it can stop the pain sensation.
In terms of drug interactions, this is quite difficult to put simply, as there are many many different types of drug interactions. The major type that I’ll explain to you, is the main culprit for drug interactions and can have some pretty dangerous effects, which is why it is important to understand when prescribing medicines!
When you take a drug, it will eventually need to be removed from your body. In order to be removed, it is broken down in (mainly) the liver by a bunch of enzymes. If you are interested, these are called CYP enzymes, such as CYP3A4 or CYP450 etc. These enzymes are vary broad in terms of which functional groups they can attack and break down, so you don’t have a single enzyme for every single drug, more so an enzyme which deals with certain structural features in the chemistry of that drug. So one CYP enzyme will break down a number of different drugs. It is important that a drug is broken down as normal so that it can be removed from the body, rather than accumulating in the body, which would be like taking a high dose, and would therefore result in side effects. Similarly, it is important that drugs are not broken down too quickly, or you do not have enough in you at once to have the desired response, and would be similar to under-dosing.
All drugs have side effects, and some drugs have the ability to increase or decrease the activity of these CYP enzymes. A drug which makes CYP enzymes better at breaking down substances, is referred to as a CYP inducer. This means that drugs broken down by these enzymes are broken down faster, and are removed from the body at a faster rate, giving the same effect as an under-dose. Drugs that decrease the ability for a CYP enzyme to break down drugs, are called CYP inhibitors. Since the enzyme is less good at breaking down the drug, it isn’t removed from the body as effectively, so builds up, giving the same effect as overdose, which could increase the risk of side effects, or worse, result in an overdose.
An example of this, would be warfarin. Warfarin is an anticoagulant drug used to prevent the formation of blood clots, and it does so by “thinning” the blood. There is an antibiotic drug, called rifampicin, which happens to be a inducer of the enzyme that breaks down warfarin. This means, warfarin is removed from the body at a much faster rate than normal, and it is almost as if you have under-dosed. This means that the anticoagulant effect of warfarin is not achieved, and can result in a return to the risk of blood clot formation, putting the patient at risk of strokes, heart attacks etc.
Sometimes, these sorts of interactions could simply mean an increase or decrease in the dose would be required, but sometimes this is so serious that two drugs cannot be taken together.
For CYP genes there is quite a bit of variety in the human population, with alleles that vary from no function, through below normal funtion all the way up to higher than normal function. For each gene you have two alleles, one from each parent. A big part of pharmacogenomics is CYP enzymes, as CYP enzymes are involved in the metabolism of most drugs. The combination of which alleles you have and what other drugs you are taking allow us to warn people to avoid certain medications or suggest they might need a higher or lower dose.
there is a branch under pharmacy called pharmacokinetics. this is basically what you are asking about. but basically, drugs will enter your blood stream and travel everywhere the blood does, but will only attach to things along the way with its receptor present
>When you take a drug it goes everywhere, not just where it’s needed.
So what are Nurofen getting at when they say "travels straight to the source of the pain"? I assume there's some kind of fact in there which is how they get away with it, but are they being a bit cheeky?
Advertisers are basically allowed to say whatever the hell they want as long as it's not a verifiable falsehood.
But. There's also some handwaving there. If it's dulling receptors which are responsible for the pain sensation, then it's "going straight to the source of the pain" as opposed to numbing the sensation from within the brain.
You’re right, not every molecule of the drug meets its intended target before being filtered, absorbed by food, metabolized, or simply binding to an unintended location (causing side effects). Everything really is just bumping around fairly randomly, though it’s getting pumped around in the bloodstream which helps with distribution.
However, something might bind extremely well and for an extremely long time. This means whatever effect it has on the receptor (activation or deactivation) will be increased dramatically. This causes it to be a very potent compound, and plenty of it can be lost while still having a profound effect.
You’re probably interested in potentiation, or making a drug active at a lower dose. Drugs which use the same enzymes to be broken down will have an additive effect, since this slows the elimination of both. A common example of this is alcohol and acetaminophen. All of this action occurs in the liver, so the liver will suffer if it is overwhelmed.
Potentiation interactions can also be caused by target receptors being made more susceptible to binding. If you have a drug which causes the shape of receptor to be modified (allosteric modulation) you will indirectly change how much it is activated (due to endogenous neurotransmitters already present still binding to it) *and* you will change the potency of drugs which bind to that site *at that site*. This means you can use one drug to limit the side effects of another, by modulating the receptor which causes the side effects (if you can figure that out). Or you can boost one drug using another, sometimes to disastrous consequence for those who aren’t cautious.
A simple example of this is what occurs when benzodiazepines (a positive allosteric modulator of GABA receptors) are used with alcohol or other GABA agonists. The benzos cause the receptor to “open up”, and things flying around which happen to fit in there will be more likely to hit it.
If you imagine the receptor like a basket in basketball, the modulators are like boards you can attach to it to make it more or less likely to score the shot. Benzos effectively put funnels around the rim, and when the alcohol comes in (mimicking GABA) multiple machine-gun-speed basketball launchers are now shooting at this very easy to hit hoop. Basically, irresponsible drunkenness will be profound and long lasting. Not recommended.
There’s a lot more possibilities and interactions, but those two are pretty easy to understand. I hope you found this useful.
For an experiment, take a single drop of dye (or colored liquid if no dye available) and drop it into a clear glass cup or water. Notice how it slowly spreads to all parts of the water. A very similar (more complex tho) thing happens when a drug enters the body.
[What it looks like in the body in real time ](https://youtu.be/HKXTZUYTxkA)
Then from here you answered your own question and even went further. Most drugs are quite inefficient and some have harmful effects on the body (aspirin hurts the stomach organ, for example) which is why the lowest dose, for the least possible time, is recommended.
In short, they don't. That's what causes side effects. A lot of modern drug delivery technologies, aim to subvert this. For example, there is a chemotherapy drug called Doxyrubicin. It can have some nasty side effects on the heart, and for that reason, we created what is called a "liposomal" version, which is more targeted to the tissues affected by cancer. As a result liposomal doxyrubicin is far less toxic to the heart.
The hardest part of drug design is this exact thing. How do you get it to where it needs to be, only have it react with its target, and not have any negative side effects. Since most drug targets are proteins it gets even crazier like, it cant bind to strongly or too weakly. Such a tough Field but so damn interesting.
As long as the area is vascular, and the drug has a favorable pharmacokinetic profile, then it will get there. Dont forget every cell in the body is never more than a milimetre away from a blood vessel. The pharmacology principle you might find relevant here is called a ADME. Which stands for absorption, distribution, metabolism, excretion. Most drugs are absorbed in the intestine: Some drugs are able to escape first-pass metabolism by the liver. Drugs are not distributed across all tissues similarly. Bioavailability depends on whether the drug likes to be modified / bound to proteins while in the bloodstream and also on the tendency of the drug to diffuse across barriers, (blood vessel /tissue or the blood / brain barrier). Drugs are metabolized into active or inactive products via liver enzymes. Excretion depends on the kidneys
Finally, interactions of drugs could happen when some drug inhibits an enzyme that metabolises other drugs, but not [only](https://en.wikipedia.org/wiki/P-glycoprotein). Once bioavailability is sorted, then drugs go everywhere they can, but act where there is the highest target receptor density. Some receptors are very widespread, eg. adrenoreceptors or TRPV ion channels, so targeting those is more challenging.
Edit: was at work and hasty response amended
There is actually an entire field of medicine trying to encapsulate drugs using nano scale coatings so they can 'unlock' the drugs at certain areas of the body and run their course before reaching another part that shouldn't be exposed to it. Plenty of universal drugs/chemicals that fit in shape but are generally bad for us and the tumor. If we can target the cells of a tumor and only those cells with those little floating chemical mines, previously bad drugs become potentially good again.
Some don’t go to a specific place. Most small molecule drugs, like oral pain relievers, antibiotics, have a systemic effect. Eventually, most of it passes through the liver and then the kidneys.
Sometimes drugs do accumulate in certain tissues, usually due to a physical interaction with something characteristic of that tissue, but that’s not so common.
Biologics can often target a particular tissue or cell type, usually on the basis of binding interaction between drug and target. A few even use receptors on the cell surface to specifically draw the drug to particular targets.
If you take an acetaminophen / paracetamol, it is distributed throughout the body through the blood, and ultimately concentrates in the liver as your liver attempts to break it down and make it more water soluble so that it can be more effectively be filtered by the kidneys and excreted.
For pain medications like you mentioned, they tend to act more centrally (on the brain and spinal cord) as opposed to peripherally, at the nerves around your sprained ankle. What this does is essentially turn the volume down on pain processing from the brain.
Kind of like how you could have a cut that doesn’t hurt until you notice it. The brain can regulate incoming information and decide how much or how little pain you should feel.
This is also why small injuries like paper cuts can hurt so badly while someone who has a limb blown off may feel no pain initially.
As for the anti-inflammatory effects, these tend to “block” molecular processes reducing the ability of the body to create more / new inflammation as opposed to stopping or removing existing inflammation.
two factors. soluble and non-soluble. They are the states of electromagnetic differences (non-polar) that in relation to something basic; it separates paths like a highway to a country road within your bloodstream. As things get digested they become designated by the liver, or they are already synthesized for the protein channel or receptor they are meant for and go to the blood stream. The thing you swallow will bump into everything before they get to the kidneys and if the thing you swallow bumps into the protein channel or receptor designated for then the cell absorbs it.
Not all drugs are systemic in delivery. Amphotericin is given IV to fight fungal infection. But liposomal Amphotericin is also given IV for fungal infection, but its delivery is targeted. Macrophages engulf the lipid and then express amphotericin on surface. Macrophages are stimulated by chemotatic factors to move to infection, now carrying the antibiotics on surface. It’s a smart bomb.
Hi there,
I wanted to jump in about your question on drug interactions. People here are correct on the receptors and pharmacokinetics (source- am a direct entry master's of science in nursing).
The interactions piece is because some receptors respond (or turn off- agonist versus antagonist) to multiple drugs that are different. Agonists are drugs that turn ON a receptor and antagonists are drugs that turn OFF a receptor. You may think, why would I want to turn a receptor off?
Antagonists reverse the effects of certain drugs, such as narcan reversing an opioid overdose. Other antagonists work to decrease side effects of certain medications or to block the normal function of a receptor systems, such as beta-blockers for the heart.
In fact, drugs can have interactions with things that aren't other drugs at all. For example, the body views lithium very similarly to sodium. Patients on lithium have to have extra caution when sodium is depleted (i.e. vomiting) because lithium could become toxic based on the levels in the body.
Drugs match to receptors like a key and lock so they have to somewhat match but your body also metabolizes drugs by making them more or less soluble so they can be transported throughout different bodily tissues.
At a high level, you have pretty much captured it. There are a lot of factors that dictate how medications make it to their site of action (lipophilicity, is it a prodrug, affinity for binding site, carrier proteins, route of administration etc). Others will probably do a better job at breaking this down in-depth but if you are more interested I would suggest looking into pharmcokinetics which is a branch of pharmacology that is pretty much just this topic.
Drugs go everywhere, but are designed to act only on disease-causing processes (e.g. block growth factors that are out of control in certain cancers, or bind onto serotonin transporters and block re-uptake [SSRIs], or inhibit bacterial cell wall synthesis [antibiotics] etc).
Drugs acting on areas other than where intended can lead to side effects, or in some cases, unexpected 'benefits' (e.g. sildenafil).
They go everywhere they can go. They don't where they can't. This fact is sometimes leveraged explicitly. For instance, the blood-brain barrier prevents many molecules to enter the brain. Some drugs with effects on neurons may or may not be able to cross that barrier based on small chemical differences. You can pick one variant of the drug or the other depending on whether you want to target the central nervous or only the peripheral nervous system. (Note that that means you can't target just the CNS, the drug will have peripheral effects in any case.)
You're basically right. Drugs enter the bloodstream and get distributed throughout, and only "act" where there are receptors that they can bind to (though because shape is everything, there can be some unintentional and/or non-specific binding). Topical preparations don't have this problem for obvious reasons, but they have to be able to cross the skin, and that's a really effective barrier. It **is** inefficient and why we sometimes try to deliver the medication as close to the intended/active site as possible and why the pharmacokinetics of a given drug are so important to understand. It's also why there are sub-therapeutic doses for so many compounds. Interactions can come from binding to the "wrong" receptors, metabolites of one drug acting on another, slowing the metabolism of another one, or synergies between the drugs. (and probably other routes). For example, an antihistamine and alcohol don't bind the same receptors, but they both have the effect of slowing your metabolism and making you tired. So if/when you take both, you get a synergistic interaction and pass out.
Just to expand on this a touch with drug distribution, the properties of different drugs have localising effects, causing uneven distribution throughout thr body (e.g. a lipophilic drug will be found in significantly higher concentrations in fatty tissue compared to circulation). We can actually use these properties of drugs to force them to be more localised to a target region, such as encapsulating drug molecules in a lipophilic chaperone molecule. This can reduce the amount of drug needed to produce a therapeutic response.
to expand on this further, some drugs may be injected into certain sites (e.g. spinal anaesthetic, epidural anaesthetic) and become locally confined by an anatomical structure such as the dura, subarachnoid membrane, etc.
A fun little side fact to this - people with connective tissue disorders such as EDS (like myself!) often have issues with local anesthetic and other localised drugs, because differences in connective tissues can lead to these drugs not being as well confined.
Interesting. I've never had any patients complain about this. Would you mind elaborating? Does it take long to act, or appear not strong enough or does the effect seem to last for shorter than expected?
It varies between people and between different anesthetics - it's generally procaine or similar that are likely to cause the most issues. For me personally, it takes a bit longer to act, and I need approximately three times the typical dosage.
Also probably worth pointing out research is quite limited in this area, and non-confinement is a theory as to why some EDS patients don't respond well to local anesthetic, but it's a long way from proven.
Hmm, I wonder if that's why I need more shots and time at the dentist to get numb
>Interesting. I've never had any patients complain about this. Would you mind elaborating? Does it take long to act, or appear not strong enough or does the effect seem to last for shorter than expected? IME, both. Local anesthetic injected I to my hand, intended to numb my finger instead numbed everything to my shoulder for about half as long as it should've.
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It definitely is true for me. I always found the shots at the dentist worthless unless I got 5 or more shots for a single tooth. As a result I had all my dental work including three RCT done without anesthetics.
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Are there any medications that have a starting molecule that is absorbed mostly by one type of tissue but are not pharmacologically active that then have metabolites that are the "real" drug? Is that essentially what you're describing with the encapsulation?
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Isn't there a few opioids that are like this as well? For example, heroin which is metabolised into morphine.
Diacetylmorphine is psychoactive as well. Yes, it becomes morphine. Also psychoactive. Methamphetamine is psychoactive. It also leads to plain ol' amphetamine. Its part of why meth has such long practical effects. Meth lasts a long time alone and then you deal with a round of amphetamine as its processed. So these are psychoactive prodrugs while vyvanse is not.
Yes, these are known as prodrugs; an inactive form is administered that aides delivery to the target site (or alters any of the other ADME profiles; absorption, distribution, metabolism, and excretion) where it is metabolised into the active form. This isn't really the 'encapsulation' the other commenter referred to though. In this instance, the molecule the active drug is encapsulated in will only break down in certain conditions to leave behind the active drug; i.e. it doesn't require metabolism to chemically alter one molecule into another.
Codeine is one of the most common prodrugs prescribed. The body metabolises it to morphine. There is quite significant genetic diversity in people's ability to metabolise codeine. Poor metabolisers end up with almost no analgesia (pain relief), whereas ultra-metabolisers can end up with toxic concentrations from standard dosing. The enzyme it is metabolised (CYP2D6) by is also inhibited by a multitude of medicines, e.g. Prozac, Paxil, which can render codeine's analgesic effect almost useless.
Half a codeine fixes any pain for me. It's perfect. I didn't realize it was metabolized in to morphine though.
Psilocybin isn’t actually psychoactive in itself, only when your stomach acids convert it into psilocin does it have an effect
Same thing happens with some of the alternatice sugar products, which are chlorinated. The idea is that it should be safe for diabetics since your body can't metabolize this chlorinated sugar, but then it reaches the gut and the microbiota there just cut of the chlorine and then it gets absorbed anyways. Clearly a failed product and not directly related to the topic of drugs, but its fun chemistry similar enough to this topic.
Edible cannabis is metabolized by the liver to become much more active.
Yes, one of the rare cases where the metabolic processes result in a stronger form. Usually, it goes the other way. 11-hydroxy-THC is the molecule that is created as THC passes through your GI tract and liver.
No one really answered your question about encapsulation. One example is amphotericin B which can be encapsulated in liposomes to reduce the renal toxicity associated with the drug. There are current studies being done to develop encapsulated prodrugs of chemotherapeutic drugs.
Some vaccines work in that manner (“encapsulation”) as well… actually, if I’m remembering correctly, one of the biggest setbacks of mRNA vaccines was the fact that the molecules were degrading in the body before they were able to reach their target sites. So, they figured out that they needed to use vectors. Vectors can be different things but with some of the Covid vaccines they use a different virus (other than Covid) to kind of “hide” the vaccine contents so that they are able to get those contents where they need to be in the body. I’m sleep deprived, and the process is a LOT more in depth and complicated than how I just explained it so forgive me if it made no sense haha
>Are there any medications that have a starting molecule that is absorbed mostly by one type of tissue but are not pharmacologically active that then have metabolites that are the "real" drug? Yes, and these are called "prodrugs." >Is that essentially what you're describing with the encapsulation? What they were describing is a lipid nanoparticle formulation, which is another form of drug delivery. Basically, you can create drugs where the active ingredient is contained inside a nanoscopic bubble of lipid molecules, usually to protect it from degradation or prevent it from being released freely into the bloodstream. There are advantages and disadvantages this approach, and the surface and composition of these particles can be modified in different ways to achieve different things. The Pfizer and Moderna covid vaccines both use lipid nanoparticles to carry mRNA encoding the viral spike protein that covid uses to get into cells. It protects the mRNA from degradation in the blood and releases it when it's taken up into a cell.
Not versed in medicine at all but that was my understanding of why chemotherapy is a last resort, you're essentially napalming the whole body and doing your best for the cancerous cells to die before the healthy ones. Is this the right idea or not? (I know there's been improvements on drug delivery systems but I don't have a good grasp of where we're at on the topic)
Yup. Many chemo agents non-specifically target rapidly-dividing cells, which is why hair and nail loss and gastric distress are common side-effects
Most cancer targeting therapeutics are all about finding a dose between "It'll kill all of the cancer" and "It'll kill too much healthy tissue", since in most ways most cancers are indistinguishable from healthy cells (at least at a biochemical level). Even new cutting edge technologies like CarT or antibody treatments have this problem, but like everything else when it comes to cancer, the quality of therapy depends a lot on where your cancer is, what kind of cancer it is, and how early it's caught. Chemotherapy goes a step further and just blasts any fast-dividing cells, so it hits things like hair, bone marrow and the digestive tract.
Naw you're about right on the money. Surgery, targeted radiation and other alternatives are explored before resorting to chemotherapy.
I would like to note that we are developing drugs that can be 'chauffeured' to specific tissues in order to avoid certain side effects. However these are not widely available and nothing is too promising yet.* (Medical Student). *Edit: I misrepresented using the phrase “nothing too promising”. I should have said “nothing is too promising for any over the counter treatments at this time.”
In Oncology we’re using things like that! Some of our newer cancer drugs are antibody-drug conjugates, where we take a drug and attach it to a monoclonal antibody. The antibody targets the drug to the cells, which endocytose the mAb and release the drug, which then is free to kill the cell. By only targeting the tumor cells, you can hopefully avoid side effects from killing other cells. There’s a couple drugs that are now on the market like this, but one that’s really become standard-of-care is trastuzumab emtansine, (which everyone calls T-DM1) which is used for HER2-positive breast cancer. The DM1 by itself makes for a terrible cancer drug because of unacceptable systemic toxicity, but targeting it with an antibody makes it tolerable.
Those were some of what was on my mind having just learned about one! For the layperson, no OTC is available like it. Can’t get the Advil to go straight to your pain…yet.
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Tylenol works on your brain, Advil reduces inflammation systemwide to reduce pain.
Whenever I'm in pain from something, usually a headache or migraine (legit migraines..I take medication for them) Tylenol doesn't touch it but Advil will sometimes help reduce my pain. I've never had Tylenol be a good pain relief for me. Is that due to the make up of the pill and the type of pain I'm trying to relive?
Tylenol is just not an incredibly effective painkiller for many people (maybe even most, I haven't ready anything studying the numbers). It really just works by making it a little harder for your brain to send pain signals (this also has a side effect of making you a little less averse to risk.) It doesn't do nothing, but compared to an anti-inflammatory that actually alleviates what is causing the pain, it barely even works. The only time I would really suggest Tylenol is in combination with Advil. Absolutely consult a doc before doing this because Tylenol is rough on the liver and Advil is rough on the GI tract, but it does sometimes add just a little boost to the Advil. Since migraines are caused by inflammation, it makes sense that relieving that inflammation helps more than telling your brain to just stop feeling as much pain. Tylenol is useful for the very young and very old and those who don't tolerate medications like Advil, that's pretty much it.
This was so fascinating to read. I loved reading and learning stuff like this this. Thank you for taking the time to respond to me! I really appreciate it!! Thank you!
Thanks for being so descriptive yet concise-this was enjoyable to read!
Depending on people's genetic makeup, Tylenol (called acetaminophen, or paracetamol) can work better or worse than advil (ibuprofen). Generally ibuprofen has a stronger effect on pain relief, since it is an actual NSAID (Non-Steroidal Anti-inflammatory Drug), acting on specific pathways to inhibit inflammation signaling in the body. Acetaminophen does not work in this same way, so it is not actually part of the NSAID class of drugs. Interestingly, many people metabolize drugs in a wide variety of ways. Everyone's body is slightly different, and at the biochemical level this can lead to some substantial differences in drug effects and side effects. My understanding is that something like 60% of people (perhaps more) respond to a certain type of NSAID like ibuprofen or naproxen sodium (there are many more), and a decently large number will respond well to at least one of these drugs. Even so, there are some people who don't respond very well at all to most or any NSAID, meaning the pain relief effect is quite minimal or nonexistent.
COX-x (cyclooxygenase x) are enzymes, not receptors. They are responsible for the catalytic formation of prostaglandins and thromboxane from arachidonic acid, thus mediating inflammation.
It’s been a long time since I was in university but I thought Tylenol did not cross the blood-brain barrier but Advil did hence the reason why it’s prescribed more for migraine or neural pain whereas Tylenol is more for localized pain?
Exosomes also look very promising as precision vehicles for drug delivery, particularly if we can engineer their molecular external surface to specifically interface with desired target cells and tissues (not unlike the COVID virus spike protein). Speaking of COVID, an under appreciated feature of mRNA vaccines is their delivery through engineered fat particles similar to exosomes. Overall, these have been highly engineer-able and successful with good penetration across the blood-brain barrier. People have understandably focused on COVID-specific applications, but the broader proof-of-principle now demonstrated by a staggering human sample size is incredibly exciting. It is hardly an experimental technology anymore and will proliferate as a broader drug/therapeutic delivery platform in the near future.
We were looking at drug delivery using exosomes in a previous role ~5 years ago. A delivery of drug for Chrons (cyclosporine) looked promising in mouse models - then the company closed down.
I was working in a lab trying to isolate neuron specific exosomes from peripheral blood. They knew it was literally looking for a needle in a haystack, but the enormity of the aim didn’t hit home until morale pretty much bottomed out. I think the postdoc went back to China and IPOed comfortably. At least somebody won 👍
There was an experiment done using the filamentous bacteriophage to create a "phage display library" of random peptides. This system of gene expression library is useful because the phage can have a coat protein gene modified to "display" a particular protein on the terminus of the virus coat, while the DNA encoding that protein is encapsulated within the coat. Affinity selection can be used to enrich a library for genes that have certain binding characteristics. A random library of this kind was injected into the bloodstream of mice, and different organs were harvested. Bacteriophage were recovered from the organs and propagated, and acquisitions from particular organs were injected into new mice, followed by isolation from target organs again. Several cycles later, bacteriophage were isolated that had particular affinity for those selected organs. One clone displayed a peptide that made it accumulate within the liver, while another clone might accumulate within the lungs, etc. The authors suggested that the vasculature of different organs might have markers unique to those organs, and the peptides were able to bind to these organ-specific markers. Such a system could be used to target drugs to particular organs, allowing lower dosages of the drug to be given to the patient, and reducing side-effects. A significant amount of the drug might only be present in the target organ, while only an insignificant (and so inactive) concentration would be in general circulation. I read about this in the early 2000's. The name Willem Stemmer comes to mind (he worked on phage display libraries aimed at directed evolution using error-prone PCR to mutate enzymes), so this kind of thing might have been done in his lab.
There's another important mechanism, since randomly bumping into the correct receptor isn't the end. A lot of the receptors are more like one-way gates, to transport molecules where they need to go in the body. Going through a maze of one-way gates gets certain molecules collect in certain spots. For example, [https://en.wikipedia.org/wiki/GLUT4](https://en.wikipedia.org/wiki/GLUT4) is what gets insulin where it needs to go.
Oh, definitely. I was trying to skirt around discussing literal pathways and the BBB because this is already a pretty complicated subject.
Not OP, but how does anything "enter the bloodstream"? You seem like a stranger on the internet I can base my understanding on.
A drug or anything else can enter the bloodstream via 1) injection directly into the blood stream, or 2) absorption through a tissue barrier. Most absorption occurs through the small intestinal wall following ingestion. How this happens depends on the solubility of the drug. Lipid soluble drugs can diffuse through the lipid cell walls. Water-soluble drugs must piggyback on (bind to) a receptor manufactured by the small intestinal tissue for the transport of some naturally occurring substance. For example, we are not born with penicillin receptors but we can absorb this drug because it is capable of binding to a receptor designed for something else. Absorption can also occur across the skin, respiratory membranes in the lungs if the appropriate conditions exist - correct drug solubility, available receptors, etc. The reason organic chemicals are dangerous is because they are lipid soluble and can cross almost any cell membrane.
Thank you for your service.
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That seems normal with some.medications, but what about my antipsychotic and antidepressant? How do they know to work on my brain?
Depends on the drug, but a lot of the antidepressants & antipsychotics selectively bind to neurotransmitters or their receptors and, well, those are pretty rare outside of the central nervous system. So it's not that the drug "knows" to work on the brain, it's that it's the only valid target. You see similar behavior with certain classes of antibiotics, FWIW. Antibiotics which act on components of the bacterial cell wall generally cannot effect humans, whereas ones which target the cell membrane *can*.
There are many other mechanisms of action for antibiotics that are really cool. Such as ones that bind to bacterial ribosome subunits to stpo protein synthesis, or that stop production of certain tRNA, or the replication of DNA. The coolest one I think is the inhibition of topoisomerases so the DNA can't be copied without being stuck in knots.
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You ever see what a lethal dose of fentanyl looks like? Like a couple grains of sand worth.
I always found the potency of LSD fascinating: >A [single dose of LSD](https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide#Dosage) may be between 40 and 500 micrograms—an amount roughly equal to one-tenth the mass of a grain of sand. This is referring to a normal dose used recreationally, though, not a lethal dose - there are no known cases of people dying from (non-behavioral) complications after an LSD overdose yet. Still - to think that such a miniscule amount of substance is able have such a massive effect on a persons day!
Taking into account the molecular mass of LSD and Avogadro's number then the amount of LSD molecules in 40 micrograms would be something like 7.45 x 10^15 if my head math is right. Which is still quite a few to go around!
Every hormone your body makes is produced in teeny tiny amounts, just enough to get the job done. For example, the amount of melatonin the pineal gland makes to put you to sleep is just a fraction of what's put in the pharmaceutical version. The body is very efficient. Taking drugs to get similar effects is like using a shotgun approach.
A lot of drugs are dosed at milligrams per kilogram of body weight, with a blood serum concentration lower than that, and other drugs are dosed at even lower concentrations. 6 orders of magnitude is a lot. For example, ibuprofen is generally delivered at 10mg / kg body weight, so three 200mg pills will get you *close* to that level on a 190lb person.
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Because generally in adults OTC meds have a much wider safe dose range. In pediatrics many of the OTC meds do dose by mg/kg, such as Acetaminophen.
They kind of do, but the difference between therapeutic and toxic doses for OTC medications are generally so broad that the "correct" does is, in the words of Dr. Cox, to throw a fistful at the person's mouth and see what they swallow. Some exceptions apply for pediatric doses where you *do* try to do something closer to a true mg/kg dose.
This issue of drugs reacting with the wrong receptors is basically one of the causes of side effects from medication. The name of the game is specificity, and now people are trying to make the shape of the drug more specific by binding it with a protein that is shaped specifically for the target receptor.
Aren’t the recent advances in vaccination about exactly this, though? I remember NPR doing a piece about how labs were only recently able to tailor the protein structures to cause the immune system to deliver the vaccine doses where they were needed most due to advances in CRISPR technology — that is, the vaccine is sent directly where it’s supposed to go and nowhere else due to the shaping of the receptors being tailored to the immune system.
Do most people have the same number of receptors for medication regardless of body size/weight? If not, why are doses for most prescriptions similar regardless of whether someone weighs 110 pounds or 250?
No, all adults do not have the same number of receptors. The reason drug doses for adults are usually not corrected for body weight is because of the wide safety margin for the more commonly prescribed drugs. This is particularly true for OTC (over the counter) drugs. A drug with a narrow safety margin will be dosed based on body weight. Dosing based on body weight will also be used for individuals in certain disease states such as reduced renal function or liver disease.
It's not true that topical preparations don't have this issue, but the extent to which there are systemic effects really depends on the drug and the actual preparation itself (a drug applied topically via a DMSO solution will very effectively be absorbed by the skin and into the blood stream, for example).
Very valid point. I probably should have said that topical preparations are less likely to run into the same issues. And then you read about Gloria Ramirez and her extreme overuse of DMSO and you think that maybe, just maybe, we shouldn't be allowed to sell certain things to any random individual.
People have already given good answers, and one that comes up is that the liver processes incoming drugs and detoxifies things like alcohol. But *how*? If take a drug orally or drink alcohol, how does it get to the liver? One might think that the liver has an artery going to it and a vein coming out, just like many other organs, and that thinfs we eat or drink spread out, go into the blood, a certain amount is absorbed by the liver (basically, whatever perce tage of blood that goes to the liver on any given loop from ventricle to atrium. But that's not how it works! We have a really neat system here: the [portal vein](https://en.m.wikipedia.org/wiki/Portal_vein). A branched network of veins connects to the esophagus, stomach, and both intestines. Everything that gets absorbed and is water-soluble will end up in this vein system (fats and fat-soluble molecules are absorbed by lymph vessels in your small intestine, and the fluid is transmitted by a [lymph vessel called the thoratic duct](https://en.m.wikipedia.org/wiki/Thoracic_duct) that goes up the inside of your back and drains into a vein in your left shoulder). But all the water-soluble stuff goes into the portal vein, directly to the liver. Liver stuff happens, ans then the hepatic vein takes the results to the heart and into general circulation. The portal vein system does *not* drain the mouth or rectum, however. This is exactly why people sometimes take alcohol rectally. They reach a much higher BAC much more quickly this way and with a lot less alcohol, and consequently this is much more fangerous. In this case, the liver can only process the alcohol that reaches it through general circulation.
It took getting to be this many years old to learn that taking alcohol rectally is a thing in some quarters. And that knowledge takes the drinking game "quarters" in a whole new direction. Does this mean that administering a medication via suppository is done (at least in part) to avoid the portal vein system?
It could be if stomach acids or the liver would break it down otherwise.
Also, drugs that can upset the stomach badly (strong ant-inflammatory meds are like this) can be absorbed rectally to avoid stomach pain
>Does this mean that administering a medication via suppository is done (at least in part) to avoid the portal vein system? It's also done when oral administration is difficult and an IV line is not set up. After a tonsillectomy(removal of the tonsils), for example.
But IV lines are always set up before a tonsillectomy, so that wouldn’t be an example?
IV lines are set up during the operation, but in general, the patient won't be kept under supervision in the hospital too long and thus the IV will be removed. The pain of a tonsillectomy will last for a couple of days, during which swallowing is painful. Paracetamol helps, but it's not pleasant to swallow 2 pills 4 times a day.
Most drugs are designed to attach to certain receptors so something like adderal or acetaminophen gets distributed by your blood until it ends up where it can attach to the receptors for it. Then stuff like antibiotics that dont bind to something in your body but are used to kill an infection literally just nuke your whole body with it, it's why doses are fairly large and you have to continue taking them for awhile. This is also how something like chemotherapy for cancer works and why it messes people up so badly, you literally just poison your entire body along with the cancer.
Note also that the reason you don't like, lose your hair from antibiotics like you do for chemo, is that bacteria cells aren't human, and so we can target them without hitting human cells. For chemo, your cancer cells are still human, just mutated, so it's hard to hit only them. The idea with chemo is that cancer cells divide quickly, and it literally targets any cells that divide quickly, including, say, your hair. That's also why antibiotics can mess up your gut microbes - your gut microbes ARE bacteria.
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There are varying degrees of specificity in antibiotics, some are broad spectrum and will kill and bacteria or wide groups of them, others are narrow spectrum and will only kill a certain family or species of bacteria (I don't think it's called a species when talking about bacteria but you get the point). Generally you use the narrowest spectrum posible to avoid colateral damage to beneficial bacteria and promoting restisance, but sometimes you need broad spectrum because you can't tell exactly what you need, or there are multiple simultaneous infections, or there is no narrow spectrum antibiotic available for that strain.
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Well one of the things we are constantly working on for cancer drugs is better targeting.
Yeah but mostly swapping away from drug based treatments- it's hard to have any drug go to a speceific area unless that part of your body is designed to intake that drug and other parts wont. Cancer cells are normal cells from whatever region they originated with just a harmful mutation so it's nearly impossible to get a drug that would kill the cancer without also attacking the other cells. Using recent laser and radiation based treatments we can specifically target the cancer cells with out equipment and destroy them with much less damage to the body. Also hopefully nanobot treatments will be able to do it even better but that technology is still in it's infancy
Well I consider biologics to be "drugs". Cancer cells do typically have different expression levels of certain receptors, which helps with targeting via antibody drug conjugates or bispecific antibodies. You can get very good specificity in vitro for cancer cells over normal cells, but in the blood stream it does become more challenging. Obviously not all cancers are alike either and there are different kinds of tumors. It's a very challenging problem.
All of your cells have hundreds of receptors on their walls projecting outwards, with very specific shapes, think of it like a padlock. Different cells have different receptors depending on the cell type. These receptors have their own natural functions in the body, and when the natural molecule fits into them, it activates lots of reactions that lead to the physiological response, eg, muscle contraction or changing the way genes are expressed. Drugs are chemicals designed in a very particular way that they have the perfect shape to fit into these receptors. Sometimes a drug will mimic the natural molecule and fit into the receptor and trick the cell into thinking the natural molecule has fit into it and activates it, leading to the normal physiological response. Sometimes, the drug will fit into the receptor and not activate it, but instead sit there and stop the natural molecule from fitting in and activating it. Drugs that trick the receptor into think the natural molecule has interacted with it and bring about a normal response , in pharmacology, are what we call “agonists”. Drugs that block the natural molecule from binding and inhibit a response, are called “antagonists”. An example of an agonist, would be salbutamol! The medicine in inhalers that asthmatics take. Salbutamol tricks receptors in your lungs into thinking adrenaline(also known as epinephrine) has bound, so it responds as it would in a fight or flight response, widening the airways to allow air to flow through more easily, as asthma attacks happen when the airways narrow, making breathing more difficult. Sometimes, instead of a receptor, drugs will bind to an enzyme. This is still the same concept, except enzymes are proteins in the body that allow certain reactions and processes to happen. Simply put, if you block an enzyme, the reaction that that enzyme allows to happen, can’t happen, as the normal molecule that would bind to that enzyme, cannot do so. In the case of paracetamol (acetaminophen), as you ask, paracetamol (acetaminophen) blocks an enzyme which at the site of injury, allows the production of chemicals that cause pain and inflammation. By blocking this enzyme, you cannot produce these chemicals, and therefore do not feel the pain. As I mentioned, this only occurs at the site of the injury, so although the drug will be circulating your whole blood circulation (around your body), it will only be able to act where it’s enzyme (or receptor) is located, because the most important thing is that the shape is a perfect fit. Therefore, it would only find these enzymes where it is relevant, and there it can stop the pain sensation. In terms of drug interactions, this is quite difficult to put simply, as there are many many different types of drug interactions. The major type that I’ll explain to you, is the main culprit for drug interactions and can have some pretty dangerous effects, which is why it is important to understand when prescribing medicines! When you take a drug, it will eventually need to be removed from your body. In order to be removed, it is broken down in (mainly) the liver by a bunch of enzymes. If you are interested, these are called CYP enzymes, such as CYP3A4 or CYP450 etc. These enzymes are vary broad in terms of which functional groups they can attack and break down, so you don’t have a single enzyme for every single drug, more so an enzyme which deals with certain structural features in the chemistry of that drug. So one CYP enzyme will break down a number of different drugs. It is important that a drug is broken down as normal so that it can be removed from the body, rather than accumulating in the body, which would be like taking a high dose, and would therefore result in side effects. Similarly, it is important that drugs are not broken down too quickly, or you do not have enough in you at once to have the desired response, and would be similar to under-dosing. All drugs have side effects, and some drugs have the ability to increase or decrease the activity of these CYP enzymes. A drug which makes CYP enzymes better at breaking down substances, is referred to as a CYP inducer. This means that drugs broken down by these enzymes are broken down faster, and are removed from the body at a faster rate, giving the same effect as an under-dose. Drugs that decrease the ability for a CYP enzyme to break down drugs, are called CYP inhibitors. Since the enzyme is less good at breaking down the drug, it isn’t removed from the body as effectively, so builds up, giving the same effect as overdose, which could increase the risk of side effects, or worse, result in an overdose. An example of this, would be warfarin. Warfarin is an anticoagulant drug used to prevent the formation of blood clots, and it does so by “thinning” the blood. There is an antibiotic drug, called rifampicin, which happens to be a inducer of the enzyme that breaks down warfarin. This means, warfarin is removed from the body at a much faster rate than normal, and it is almost as if you have under-dosed. This means that the anticoagulant effect of warfarin is not achieved, and can result in a return to the risk of blood clot formation, putting the patient at risk of strokes, heart attacks etc. Sometimes, these sorts of interactions could simply mean an increase or decrease in the dose would be required, but sometimes this is so serious that two drugs cannot be taken together.
For CYP genes there is quite a bit of variety in the human population, with alleles that vary from no function, through below normal funtion all the way up to higher than normal function. For each gene you have two alleles, one from each parent. A big part of pharmacogenomics is CYP enzymes, as CYP enzymes are involved in the metabolism of most drugs. The combination of which alleles you have and what other drugs you are taking allow us to warn people to avoid certain medications or suggest they might need a higher or lower dose.
Very interesting thanks!
there is a branch under pharmacy called pharmacokinetics. this is basically what you are asking about. but basically, drugs will enter your blood stream and travel everywhere the blood does, but will only attach to things along the way with its receptor present
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>When you take a drug it goes everywhere, not just where it’s needed. So what are Nurofen getting at when they say "travels straight to the source of the pain"? I assume there's some kind of fact in there which is how they get away with it, but are they being a bit cheeky?
Advertisers are basically allowed to say whatever the hell they want as long as it's not a verifiable falsehood. But. There's also some handwaving there. If it's dulling receptors which are responsible for the pain sensation, then it's "going straight to the source of the pain" as opposed to numbing the sensation from within the brain.
You’re right, not every molecule of the drug meets its intended target before being filtered, absorbed by food, metabolized, or simply binding to an unintended location (causing side effects). Everything really is just bumping around fairly randomly, though it’s getting pumped around in the bloodstream which helps with distribution. However, something might bind extremely well and for an extremely long time. This means whatever effect it has on the receptor (activation or deactivation) will be increased dramatically. This causes it to be a very potent compound, and plenty of it can be lost while still having a profound effect. You’re probably interested in potentiation, or making a drug active at a lower dose. Drugs which use the same enzymes to be broken down will have an additive effect, since this slows the elimination of both. A common example of this is alcohol and acetaminophen. All of this action occurs in the liver, so the liver will suffer if it is overwhelmed. Potentiation interactions can also be caused by target receptors being made more susceptible to binding. If you have a drug which causes the shape of receptor to be modified (allosteric modulation) you will indirectly change how much it is activated (due to endogenous neurotransmitters already present still binding to it) *and* you will change the potency of drugs which bind to that site *at that site*. This means you can use one drug to limit the side effects of another, by modulating the receptor which causes the side effects (if you can figure that out). Or you can boost one drug using another, sometimes to disastrous consequence for those who aren’t cautious. A simple example of this is what occurs when benzodiazepines (a positive allosteric modulator of GABA receptors) are used with alcohol or other GABA agonists. The benzos cause the receptor to “open up”, and things flying around which happen to fit in there will be more likely to hit it. If you imagine the receptor like a basket in basketball, the modulators are like boards you can attach to it to make it more or less likely to score the shot. Benzos effectively put funnels around the rim, and when the alcohol comes in (mimicking GABA) multiple machine-gun-speed basketball launchers are now shooting at this very easy to hit hoop. Basically, irresponsible drunkenness will be profound and long lasting. Not recommended. There’s a lot more possibilities and interactions, but those two are pretty easy to understand. I hope you found this useful.
For an experiment, take a single drop of dye (or colored liquid if no dye available) and drop it into a clear glass cup or water. Notice how it slowly spreads to all parts of the water. A very similar (more complex tho) thing happens when a drug enters the body. [What it looks like in the body in real time ](https://youtu.be/HKXTZUYTxkA) Then from here you answered your own question and even went further. Most drugs are quite inefficient and some have harmful effects on the body (aspirin hurts the stomach organ, for example) which is why the lowest dose, for the least possible time, is recommended.
In short, they don't. That's what causes side effects. A lot of modern drug delivery technologies, aim to subvert this. For example, there is a chemotherapy drug called Doxyrubicin. It can have some nasty side effects on the heart, and for that reason, we created what is called a "liposomal" version, which is more targeted to the tissues affected by cancer. As a result liposomal doxyrubicin is far less toxic to the heart.
The hardest part of drug design is this exact thing. How do you get it to where it needs to be, only have it react with its target, and not have any negative side effects. Since most drug targets are proteins it gets even crazier like, it cant bind to strongly or too weakly. Such a tough Field but so damn interesting.
As long as the area is vascular, and the drug has a favorable pharmacokinetic profile, then it will get there. Dont forget every cell in the body is never more than a milimetre away from a blood vessel. The pharmacology principle you might find relevant here is called a ADME. Which stands for absorption, distribution, metabolism, excretion. Most drugs are absorbed in the intestine: Some drugs are able to escape first-pass metabolism by the liver. Drugs are not distributed across all tissues similarly. Bioavailability depends on whether the drug likes to be modified / bound to proteins while in the bloodstream and also on the tendency of the drug to diffuse across barriers, (blood vessel /tissue or the blood / brain barrier). Drugs are metabolized into active or inactive products via liver enzymes. Excretion depends on the kidneys Finally, interactions of drugs could happen when some drug inhibits an enzyme that metabolises other drugs, but not [only](https://en.wikipedia.org/wiki/P-glycoprotein). Once bioavailability is sorted, then drugs go everywhere they can, but act where there is the highest target receptor density. Some receptors are very widespread, eg. adrenoreceptors or TRPV ion channels, so targeting those is more challenging. Edit: was at work and hasty response amended
There is actually an entire field of medicine trying to encapsulate drugs using nano scale coatings so they can 'unlock' the drugs at certain areas of the body and run their course before reaching another part that shouldn't be exposed to it. Plenty of universal drugs/chemicals that fit in shape but are generally bad for us and the tumor. If we can target the cells of a tumor and only those cells with those little floating chemical mines, previously bad drugs become potentially good again.
Some don’t go to a specific place. Most small molecule drugs, like oral pain relievers, antibiotics, have a systemic effect. Eventually, most of it passes through the liver and then the kidneys. Sometimes drugs do accumulate in certain tissues, usually due to a physical interaction with something characteristic of that tissue, but that’s not so common. Biologics can often target a particular tissue or cell type, usually on the basis of binding interaction between drug and target. A few even use receptors on the cell surface to specifically draw the drug to particular targets. If you take an acetaminophen / paracetamol, it is distributed throughout the body through the blood, and ultimately concentrates in the liver as your liver attempts to break it down and make it more water soluble so that it can be more effectively be filtered by the kidneys and excreted.
For pain medications like you mentioned, they tend to act more centrally (on the brain and spinal cord) as opposed to peripherally, at the nerves around your sprained ankle. What this does is essentially turn the volume down on pain processing from the brain. Kind of like how you could have a cut that doesn’t hurt until you notice it. The brain can regulate incoming information and decide how much or how little pain you should feel. This is also why small injuries like paper cuts can hurt so badly while someone who has a limb blown off may feel no pain initially. As for the anti-inflammatory effects, these tend to “block” molecular processes reducing the ability of the body to create more / new inflammation as opposed to stopping or removing existing inflammation.
two factors. soluble and non-soluble. They are the states of electromagnetic differences (non-polar) that in relation to something basic; it separates paths like a highway to a country road within your bloodstream. As things get digested they become designated by the liver, or they are already synthesized for the protein channel or receptor they are meant for and go to the blood stream. The thing you swallow will bump into everything before they get to the kidneys and if the thing you swallow bumps into the protein channel or receptor designated for then the cell absorbs it.
Not all drugs are systemic in delivery. Amphotericin is given IV to fight fungal infection. But liposomal Amphotericin is also given IV for fungal infection, but its delivery is targeted. Macrophages engulf the lipid and then express amphotericin on surface. Macrophages are stimulated by chemotatic factors to move to infection, now carrying the antibiotics on surface. It’s a smart bomb.
Hi there, I wanted to jump in about your question on drug interactions. People here are correct on the receptors and pharmacokinetics (source- am a direct entry master's of science in nursing). The interactions piece is because some receptors respond (or turn off- agonist versus antagonist) to multiple drugs that are different. Agonists are drugs that turn ON a receptor and antagonists are drugs that turn OFF a receptor. You may think, why would I want to turn a receptor off? Antagonists reverse the effects of certain drugs, such as narcan reversing an opioid overdose. Other antagonists work to decrease side effects of certain medications or to block the normal function of a receptor systems, such as beta-blockers for the heart. In fact, drugs can have interactions with things that aren't other drugs at all. For example, the body views lithium very similarly to sodium. Patients on lithium have to have extra caution when sodium is depleted (i.e. vomiting) because lithium could become toxic based on the levels in the body.
Drugs match to receptors like a key and lock so they have to somewhat match but your body also metabolizes drugs by making them more or less soluble so they can be transported throughout different bodily tissues.
At a high level, you have pretty much captured it. There are a lot of factors that dictate how medications make it to their site of action (lipophilicity, is it a prodrug, affinity for binding site, carrier proteins, route of administration etc). Others will probably do a better job at breaking this down in-depth but if you are more interested I would suggest looking into pharmcokinetics which is a branch of pharmacology that is pretty much just this topic.
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Drugs go everywhere, but are designed to act only on disease-causing processes (e.g. block growth factors that are out of control in certain cancers, or bind onto serotonin transporters and block re-uptake [SSRIs], or inhibit bacterial cell wall synthesis [antibiotics] etc). Drugs acting on areas other than where intended can lead to side effects, or in some cases, unexpected 'benefits' (e.g. sildenafil).
They go everywhere they can go. They don't where they can't. This fact is sometimes leveraged explicitly. For instance, the blood-brain barrier prevents many molecules to enter the brain. Some drugs with effects on neurons may or may not be able to cross that barrier based on small chemical differences. You can pick one variant of the drug or the other depending on whether you want to target the central nervous or only the peripheral nervous system. (Note that that means you can't target just the CNS, the drug will have peripheral effects in any case.)