common mechanisms of action / pharmacodynamics & the root cause of psychiatric and neurological conditions
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On this page… (hide)
- 1. Just Do It
- 2. It’s All About Chemistry, Baby. Maybe.
- 3. Communications Breakdown
- 4. How’s the Reception?
- 5. Know Your Neurotransmitters
- 6. Anti-Shock Therapy
- 7. I Sing the Brain Electric
- 8. Bibliography
Pharmacodynamics is what a drug does. It is comprised of two parts, the mechanism of action, which is what it does to fix whatever the hell is wrong with you, and general pharmacodynamics, which is how it goes about doing that.
As I have written all over the place, when it comes to medications, the thing I hate most about support groups1, and how I try to make Crazymeds different from them, is their philosophy:
- all medications are unique
- every person is unique
- therefore finding the right medication is always a process of trial and error
- asking everyone how Fixitol (panacea HCl) or Fuckitol (placebo HBr) treated their Hypochondria is a ritual of support, and has no bearing on reality
If the real world operated like Support Group Land, the FDA would just approve any drug that didn’t kill people for everything. Got cancer? Let’s try Viagra, as the pharm rep just dropped off a truckload of samples!
Granted, the drug companies don’t help matters by describing most of their meds as “novel”2, i.e. unlike any other on the market. While technically correct for most drugs, both the drug companies and the support groups are basically wrong when it comes to medications dealing with the most complex system in the human body. People aren’t all that unique and the drugs aren’t all that different. While there are plenty of outliers when it comes to both people and meds, most of the drugs in the three major categories discussed in this article and on this site - antidepressants (ADs), antipsychotics (APs), and antiepileptic drugs (AEDs) - basically work the same way. That is, most ADs work in similar ways, and most APs work in similar ways. If you really oversimplify it, ADs and APs work in a ways that are completely opposite from each other.
If you look at the Clinical Pharmacology section of any crazy meds’ PI sheet you’ll see something along the lines of “The mechanism of action of Fixitol (panacea HCl) in humans is unknown, but is believed to be associated with its potentiation of neurotransmitter activity in the CNS.” In English: “We don’t know exactly how it works, but we think it has to do with making your brain juices work better.” And the reason why making your brain juices work better makes you feel better is because of the Monoamine Hypothesis of Depression, AKA the Chemical Imbalance Hypothesis of mental illness. Is the Chemical Imbalance Hypothesis even correct? I call it a hypothesis because there isn’t even enough evidence to make it a theory, in spite of its long history. While Monoamine Hypothesis is losing favor with most researchers, in a way I still like it. Why?
The traditional Chemical Imbalance Hypothesis is based on neurotransmitters, which I’ll explain a bit further down. With mood disorders and schizophrenia main neurotransmitters thought to be involved are serotonin and dopamine. If you broaden the hypothesis to include more brain juice, not just more monoamine neurotransmitters but all classes of neurotransmitters, along with hormones, enzymes, and whatever else is produced by genetic expression triggered or suppressed by the meds in your brain, liver, and just about anywhere else the receptors affected by the drugs exist, it simplifies things greatly. Simplifies? Yes, by lumping it all into something close to a “grand unified something-needs-to-be-tweaked theory” it covers most people. Some people probably do have something akin to a ‘chemical imbalance’ of neurotransmitters, hormones, etc. Others have too many or too few genes, or genes that are doing too much or too little. Still others may have a physical defect in neurotransmitter receptors that prevents them from getting the correct amount of a neurotransmitter. Or they have too many or too few receptors. With the wrong number of receptors, or receptors that don’t work to spec, the result is the same as if they had too much or too little of a particular flavor of brain juice.3 Now throw in the electrical system metaphor used to describe epilepsy, apply it to psychiatric disorders as well as neurological ones, and we pretty much cover everything. And none of these are mutually exclusive, so one person can have multiple instances of any number factors that cause brain cooties.
The Chemical Imbalance Hypothesis is easy to understand: you have too much or too little of something somewhere in your body. That is essentially no different than the basic principles of both Tradition Chinese Medicine and Hippocratic Medicine. The meds are a means of achieving harmony in your unbalanced chi/humors/temperaments/neurotransmitters/whatever the hell you want to call it. Granted, each med is likely to miss something for the way a particular condition is expressed in one person or everyone with it, and thus is only partially effective. And meds will affect things that have absolutely nothing to do with said condition, and that’s where side effects come from.
There is a much easier, and probably more accurate explanation for psychiatric and neurological problems.
The human brain is frequently described as the hub of the massive communication network that is your central nervous system (CNS). Everything from dreams and abstract thought to the pain of a stubbed toe and the instructions to your heart to keep it beating regularly originate from, or are sent to, your brain via electronic and/or chemical signals. Those signals originate from, or ultimately arrive at, highly specialized cells. These cells, called neurons, are the most complex we have, aren’t like anything else in our body, and vary wildly from each other depending on function and location. Neurons talk to each other, and other cells like glands and muscles, using electrical or chemical signals. The chemical signals are neurotransmitters, or as I like to call them, brain juice. Neurons also use electricity and brain juice within themselves to control what signals they’ll send to other cells.
Since this really fast system of chemical signalling works so well, why limit it to the brain? You have neurotransmitter receptors in your gut, liver, pancreas, and who knows where else. Paxil works so well for IBS because of all the serotonin receptors in your intestines. Paxil is literally a happy pill for your bowel to make it less irritable. On the down side you have dopamine receptors in your pancreas, which is why APs cause weight gain and diabetes. A lot of what the medications do is through genetic expression. You have CYP450 genes in your brain, your liver, and all over the place.
Brain cooties of all sorts, and some problems that aren’t considered neurological conditions but actually are, such as your heart not beating properly (arrhythmia)4, are caused by all the things I’ve listed above, and probably more, that prevent your personal communications network from functioning the way it should. As far as you and I are concerned it doesn’t make a difference if the cause is imbalanced chemicals, chi, or whatever. Let the people with all the impressive letters after their names fighting with each other over grant money figure out exactly how it works.
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The genius neuropsychopharmacologist I used to see when I lived in the Bay Area used a great metaphor5. Since your brain is one massive communication network, think of your thought process as listening to the radio. Also imagine yourself living in 2002, before podcasts and digital, satellite, and streaming radio took over the audio landscape6. When you brain is working as it should you can listen to the stations you want, or need to listen to at the appropriate volume. With different conditions you have little-to-no control over the station or volume. ADHD is being damned to nothing but overloud morning zoo programming. Bipolar is switching from loud techno to whatever makes you extremely sad at an even higher volume. Schizophrenia is difficult music (think Nurse with Wound, early SPK, etc) and apocalyptic Christianity, badly tuned so they randomly alternate, play on top of each other, or it’s just static, at varying levels of volume. You get the idea. The drugs allow you to control the station and volume.7
So let’s go with the Communications Interference Hypothesis of brain cooties
The meds help to correct whatever is causing the communications interference by adjusting the reception or transmission of the signal. Most Antidepressants (ADs) and antipsychotics (APs) do most of their work on the reception side of things, while most anti-epileptic drugs (AEDs) do most of their work on the transmission side. As mentioned above, to grossly oversimplify things, ADs primarily enhance/strengthen the reception, while APs primarily reduce it. As far as we know practically everything APs and ADs affect is chemical: neurotransmitters, hormones, and the enzymes produced by the genetic expression of CYP450 genes that are found mostly in your liver8. AEDs directly affect both chemical and electrical signals. The effect on electrical signals within a neuron potentially affects which chemicals neuron releases.
While the causes of various conditions treated with crazy meds aren’t necessarily due to a chemical imbalance, the best guess most of people who make the damn things have about how most of them work is either by adjusting how much you have in the way of particular brain juices, or fine tuning the amount of neurotransmitters neurons (or other cells) will receive. If the problem really is something like not having enough neurons or the neurons don’t have enough, say, serotonin receptors, well, SSRIs & TCAs might actually grow neurons. In humans, and not just mice.
To use yet another metaphor: it would be like using a pair of pliers to tighten a screw, but if you don’t have a screwdriver, or the screwdriver is broken, its handle is covered in something you’re allergic to (side effect) and you don’t have a way to cover your hand or the handle (nothing works to deal with the side effect), and you don’t have a dime or anything else that is a better replacement for a screwdriver, then a pair of pliers is better than either using a hammer or leaving the screw loose and risk the entire thing falling to pieces.
When dealing with the reception of chemical signals, a drug is thought to act in one or more of the following ways:
- As a reuptake inhibitor. Using our radio metaphor, reuptake inhibitors would increase the volume.
- As an antagonist. Antagonists would decrease the volume.
- As an agonist. Agonist is complicated, but tuning the station to eliminate static is close enough.
Neurons can send or receive signals using multiple neurotransmitters and ion channels. To keep it simple I’ll write things from the perspective of one type of signalling method or brain juice per neuron.
Reuptake inhibitors prevent a neurotransmitter from being absorbed further into the neuron, broken down and recycled. This allows your synapses to marinade in whatever the target brain juice is for a longer period of time, as well as increases the amount since the method of transporting the neurotransmitter is being slowed down. This enhances the transmission of the signal through the CNS’ communications network.
Monoamineoxidase inhibitors (MAOIs) create an effect similar to reuptake inhibitors, in that they slow down not the transportation mechanism, but the chemical that breaks down the neurotransmitter. This causes a build-up in all monoamine neurotransmitters, not just the ones listed below (except GABA, glutamate, and CRF, which aren’t monoamine neurotransmitters) to varying degrees, both within and on the surface of a neuron. In an oversimplified way (this is an overview after all), MAOIs have end results that are similar to reuptake inhibitors, with the most popular ones on the market acting like high-potency SNRIs.
An antagonist attaches itself (binds) to the receiving neuron’s receptors that soaks up the brain juice involved and reduces transmission of the neurotransmitter and decreases the strength, or volume, of the signal. How well it does so is called its affinity.
What an agonist does is on spectrum of functions9. As far as most crazy meds are concerned it’s just like the name implies, the opposite of an antagonist. It binds to a neuron’s receptor and enhances, or otherwise fine-tunes reception of the signal.
There are dozens of known neurotransmitters, perhaps hundred yet to be discovered, categorized in more way than AEDs are. But the brain juices most crazy meds are thought to do the most work on are:
- Dopamine (DA)
- Serotonin (5HT)
- Norepinephrine/Noradrenaline (NE)
- Histamine (H)
- Gamma-aminobutyric acid (GABA)
- Acetylcholine (ACh)
- Corticotropin-releasing factor/hormone (CRF)
- Melatonin (MT)
Dopamine, sweet, sweet, dopamine. While it is best known as the reward & pleasure neurotransmitter, the pleasure title really belongs to others, like the endorphins and oxytocin. In addition to making us feel good about ourselves, dopamine also makes us feel energetic and helps us to think imaginatively. Anyone who has experienced, or has been around someone experiencing bipolar mania or the positive symptoms of schizophrenia can recognize how too much dopamine can explain things like over-inflated self-worth, not needing to sleep, and delusional behavior to the point of hallucinating.
Serotonin, or 5-hydroxytryptamine (5HT)10, carries the signals for so many things in your brain, your gut, your cardiovascular system and elsewhere that it actually makes sense why drugs that affect it have contradictory side effects like constipation and diarrhea, insomnia and excessive drowsiness, or that serotonergic drugs like SSRIs can make depression worse. There are at least 20 5HT receptors in the human brain dealing with practically everything: anxiety, addictive behavior, appetite, cognition, hallucinations, impulsiveness, memory & learning, mood, nausea & vomiting, sleep, sociability, sexuality, and thermoregulation. To further complicate matters, serotonin regulates dopamine, which is one reason why too much serotonin can make you depressed.
There isn’t much out there regarding norepinephrine/noradrenaline (NE/NA) and depression, and even less for bipolar disorder and schizophrenia. There is some research on the contradictory roles of NE and anxiety. Contradictory in that some people with anxiety spectrum disorders are helped by serotonin and norepinephrine reuptake inhibitors (SNRIs), while other people are ready to hit the ceiling if you say, “Hello” have sky-high plasma NE levels. Most of the research I can find has to do with ADD/ADHD, and how some of the classic symptoms of ADD/ADHD (poor impulse control, inability to pay atten…SQUIRREL!!) are expressed in mood and anxiety disorders, schizophrenia, and so forth.
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While 5HT regulates sleep, the two neurotransmitters that have the most affect on sleep are histamines and melatonin. Antihistamines like diphenhydramine are sold as non-prescription, or over-the-counter (OTC) insomnia medications. Many APs are described as Benadryl (diphenhydramine) on steroids, but that really applies to Seroquel (quetiapine) and Zyprexa (olanzapine), as they are several hundred times more potent in their antihistamine effect than Benadryl11. Powerful antihistamines are also mean powerful weight gain. Antihistamines are also used to treat anxiety-spectrum disorders and to prevent nausea. Thorazine (chlorpromazine) and other early APs were originally developed to be potent antihistamines to deal with the anxiety and nausea associated with surgical anesthesia. And, yes, there drugs that have a positive effect on histamine. Provigil is one.
Gamma-aminobutyric acid (GABA) is mostly associated with benzodiazepines, anxiety, and feeling wonderfully relaxed. Anyone who lives and/or works with epilepsy associates it with not having seizures. Most non-benzodiazepine AEDs12 directly or indirectly affect GABA as well.
Glutamate is one of the excitatory amino acid neurotransmitters.13 It is mostly concern mostly of AEDs and lithium, but is currently being researched more and more for use in new APs to treat schizophrenia as well as bipolar.
Your entire body is saturated with acetylcholine (ACh). It is involved with learning, memory, and carrying instructions from your brain to your muscles. Medications that affect it are used to treat, among other things, Alzheimer’s, Parkinson’s and assorted movement disorders. ACh receptors come in two flavors that you’ll probably recognize. The first is muscarinic, named for the stuff you find in Amanita muscaria mushrooms:
The second is nicotinic. You’re born with nicotinic receptors, so it doesn’t matter if you’ve never smoked a day in your life, they’re still there. Blocking nicotinic (N), but mainly muscarinic and (M) receptors are responsible for the anticholinergic side effects common to APs, as well as tricyclic antidepressants (TCAs) and assorted other crazy meds. Based upon little more than my own experience with eating the wrong mushroom, and the medications proven to be most effective in ending episodes of severe ultradian rapid cycling (shifting several times an hour between being extremely manic, extremely depressed, and mixed states where you’re both) - Zyprexa (olanzapine) and Clozaril (clozapine) - that the M1 and M3 receptors are involved in that particularly hellish aspect of bipolar disorder.
Corticotropin-releasing factor/hormone (CRF) has been recently studied as something responsible for why medications of many different classes work and, unfortunately, make you fat as well.
This hormone you can buy OTC is used not only for sleep but also as an antidepressant.
AEDs, for the most part, impede electrical signals. They act as resistors. In the radio metaphor, epilepsy and migraines are like radios, or any other home appliance, that isn’t wired correctly and gives you a hell of a shock when you touch it. Hook up a few resistors to the correct part of the circuit board and you won’t have to keep going down to the basement and resetting the circuit breakers.
- Your brain controls your body via electrical impulses sent down your nerves and excitatory neurotransmitters like glutamate and inhibitory ones like GABA15
- It receives feedback in the form of electrical and chemical signaling
- All of your thoughts are mostly electric in origin 16
- Seizures = power surges
- AEDs = surge protectors
AEDs act as cerebral resistors / surge protectors by regulating the ion channels (sodium and calcium being the most popular) where your thoughts, sensory input, commands to move your fingers, and autonomic function signals like those that tell your heart to keep beating in a nice, steady rhythm are conducted. They also work on the neurotransmitters GABA and glutamate. As to how an AED like Lamictal works for bipolar disorder or one like Topamax works for a migraine - now you’re getting into territory where it’s all hypotheses and perhaps a theory or two. Mainly because genetically-engineered mice with mood disorders are a recent commodity, as are fancy brain scanners with the accuracy and detail required to pinpoint where stuff happens. For decades the only way to attempt to determine how and where a drug worked, when it actually did work, was to induce mania in rats using amphetamines, or infer depression from behavioral tests. Only recently discovered bits and pieces of migraine symptoms (e.g. light sensitivity, or photophobia) in lab rats have brought some aspects of migraine research into the late 20th century.
The converse to AEDs are medical devices that zap your brain with various strengths (think dosages) of electromagnetism. There are all sorts of ways to reset your brain with a good jolt:
- Traditional electroconvulsive therapy (ECT), which is nowhere near as horrible as TV makes it out to be.
- Repetitive transcranial magnetic stimulation (rTMS) is like a low-voltage version of ECT. It’s is essentially getting an MRI in one location, but since it’s not taking a picture, nowhere near a much hardware is required.17
- Vagal nerve stimulation (VNS) - the original “pacemaker for the brain” - is a device implanted in your body that sends a regular pulse along the vagal nerve to your brain in order to prevent a seizure and/or ward off depression. Just like a pacemaker, only it’s a further from its target.
- Deep brain stimulation (DBS) - the new “pacemaker for the brain” - consists of a bunch of electrodes implanted in your brain with wires connected to an external device similar to a VNS. The technology is still being developed and, while used for everything, is not approved to treat anything.
- The Cefaly - a Logan’s Run-esque anti-migraine tiara - is like an external VNS that works on the trigeminal nerve instead of the vagal nerve, and you use it for only 20 minutes a day.
As with AEDs these devices work to correct communications errors in the electrical signaling system. Whereas AEDs are fairly subtle, even rTMS is a brute-force attack in comparison. The next step up the intensity ladder is neurosurgery. Sometimes psychiatric symptoms are caused by a brain tumor or the presence of something else that doesn’t belong in your brain, like a bullet. Neurosurgery is usually for truly severe epilepsy that refuses to respond at all to medication18. Even then you might still need to take meds.
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2 Although the latest generation of prescribing information, especially those European EPARS that can be over 200 pages long, are approaching novel length.
3 The genetic mutation that results in being much more receptive to some neurotransmitters raise all sorts of uncomfortable questions when you combine case reports of people with positive symptoms of schizophrenia, string theory, and recent discoveries of accelerated evolution.
4 No, really, many forms of heart arrhythmia are actually neurological disorders. They are treated with drugs called calcium channel blockers, and most of the commonly-used AEDs do just that to some extent. Some of which, like verapamil, are used off-label to treat bipolar disorder like practically every AED on the planet developed after 1950.
5 Great for someone like me, as I never took chemistry in high school and was both a shortwave radio geek and spent nearly half of my life, at that time, working with communications networks.
6 If you're a fossil like I am you can think of your thought process as watching TV in the days before cable, etc., when everything was over-the-air analog and the signal was affected by weather to an extent far greater than home satellite dishes are today.
7 Stahl has recently begun to use the radio metaphor, but to a lesser extent. When discussing the treatment of schizophrenia he writes about adjusting the signal-to-noise ratio (S/N or SNR), an expression of how clear information is transmitted or expressed that was originated, or was first widely used, in early 20th century radio.
8 At least that's where we have found most of them so far. There are also plenty of them in your pancreas and the rest of your digestive system. We're finding more and more of them in your brain as well, which presents some clues to solving a few pharmacokinetic & pharmacodynamic mysteries, such as why Effexor and Pritiq and both so effective and have such horrific withdrawal symptoms when they are two of the weakest, and poorly absorbed and distributed crazy meds on the planet.
9 Technically an antagonist is on the agonist spectrum, in the same slot as malfunctioning receptor, between partial agonist and inverse agonist.
10 Yup, the same stuff you can buy in a vitamin store. And it will go to your brain. And it may be enough to fix what you have. Assuming what you buy is what the label claims to be. And you need more everywhere and not less in specific places.
11 As I write all over the place, potency is not the same as efficacy. And they way the raw power of a drug is measured, even when they use cloned human brain tissue, doesn't always match how it will act by the time it reaches your brain.
12 Or: anti-epileptic drugs. While technically AEDs, most benzos aren't used for epilepsy, and only pedantic assholes like myself insist on reminding everyone that benzos are AEDs. The convention is that AED generally refers to non-benzodiazepine AEDs.
13 See what I mean about all the different classifications?
14 Thanks to all the lab rats who gave their lives and were usually…you probably don't want to know. Anyone who loves animals more than epileptic children, or just likes animals in general, should never read one of the hundreds of research papers I have.
15 Which is why benzos and other drugs with a potent effect on GABA act as muscle relaxants.
16 Which is why the government can eavesdrop on your thoughts using Google's satellites. One of the reasons why I live in my shitty, slowly-imploding, glorified UNABOMBer shack is because its galvanized steel roof blocks not only cellphone and radio reception but also the NRO's psychic eavesdropping. Now who's the crazy one?
17 rTMS was developed after numerous reports of people, especially people with various forms of mood disorders, feeling much, much better after getting an MRI done on their head. It's certainly worth trying, especially if you've had the same thing happen to you.
18 For someone my age surgery requires finding a single focal point, one place in the brain that is the source of seizures. I don't have that, else I'd be more than happy to pay cash to have the fucked-up part of my brain cut out of my head under a local anesthetic. Since the one time I've had surgery I had anesthesia awareness anyway.
Pharmacodynamics Basics by Jerod Poore is copyright © 2013 Jerod Poore
|Last modified on Wednesday, 18 March, 2015 at 13:14:56 by JerodPoore||Page Author: Jerod Poore||Date created: 25 February 2013|
All drug names are the trademarks of someone else. Look on the appropriate PI sheets or ask Google who the owners are. The way pharmaceutical companies buy each other and swap products like Monopoly™ real estate, the ownership of any trademarks may have changed without my noticing.
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Almost all of the material on this site is by Jerod Poore and is copyright © 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, and 2015 Jerod Poore. Except, of course, the PI sheets - those are the property of the drug companies who developed the drugs the sheets are about - and any documents that are written by other people which may be posted to this site will remain the property of the original authors. You cannot reproduce this page or any other material on this site outside of the boundaries of fair use copying without the express permission of the copyright holder. That’s usually me, so just ask first. That means if want to print out a few pages to take to your doctor, therapist, counselor, support group, non-understanding family members or something like that - then that’s OK to just do. Go for it! Please. As long as you include this copyright notice and something along the lines of following disclaimer, I’m usually cool with it.
All rights reserved. No warranty is expressed or implied in this information. Consult one or more doctors and/or pharmacists before taking, or changing how you take any neurological and/or psychiatric medication. Your mileage may vary. What happened to us won’t necessarily happen to you. If you still have questions about a medication or condition that were not answered on any of the pages you read, please ask them on Crazy Talk: the Crazymeds Forum.
The information on Crazymeds pertains to and is intended for adults. While some information about children and adolescents is occasionally presented (e.g. US FDA approvals), pediatric-specific data such as dosages, side effects, off-label applications, etc. are rarely included in the articles on drugs or discussed on the forum. If you are looking for information regarding meds for children you’ll have to go somewhere else. Plus we are big pottymouths and talk about S-E-X a lot.
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1 While there are plenty of books to help you with hypochondria, for some reason there’s not much in the way of websites. Then again, staying off of the Internet is a large part of curing/managing the disorder.
2 Remember kids, Microsloth operating systems are like TOS Star Trek movies with in that every other one sucks way, way more. With TOS Star Trek movies you don’t want to bother watching the odd-numbered ones. With Microsloth OS you don’t want to buy and install the even-numbered ones. Anyone who remembers ME and Vista knows what I mean.
3 Have I mentioned how open source operating systems for commercial applications is one of the dumbest ideas in the history of dumb ideas?* I don’t even need my big-ass rant any more. Heartbleed has made my case for me. And that’s just the one that got all the media attention. The very nature of an open source operating system makes security as much of an illusion as anonymity on teh Intergoogles. Before you flip out too much: the domain Crazymeds is hosted on uses a version of SSL that is not affected by the Heartbleed bug. That’s one of the many reasons why I pay a lot of money and keep this site on Lunarpages.
* Yes, I know I’m using open source browsers. I also test the site using the now-defunct IE and Safari browsers. Their popularity - and superiority - killed IE and Safari, so that’s why I rely on the open source browsers. It’s like brand vs. generic meds. Sometimes the generic is better than the brand.