topiramate pharmacodynamics (mechanisms/methods of action). What Topamax does and how it does it.

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Pharmacokinetics & Noted Drug-Drug Interactions | TopamaxPagesIndex | Comments
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1.  Working Theory

When you read about the mechanism of action, or how it works, in Topamax’s PI sheet, it’s almost as vague as how likely it will work. Pretty much every beginning paragraph of the mechanism of action section for every crazy med (and many other non-crazy meds) is a variation on “We don’t know exactly how Panacea, or other drugs like it, works to treat whatever you take it for. In various studies, mostly on rats and other animals, we’ve determined that it does the following…” What you read in the PI sheet is often, but not always the original theorized mechanism of action, or what they thought it does when they started testing the drug for whatever it is now used for1.

After researchers who aren’t being paid by the manufacturer get their hands on med it’s just one study after another, in humans and animals, that supports the original theory. Or determines a precise area in the brain where stuff takes place. Or finds an additional thing the med does. Or finds that it doesn’t do something they originally thought it did. Or finds out that everyone was completely wrong in the first place and the method of action is radically different. That last one does happen. Neurontin (gabapentin) was originally thought to be a synthetic form of GABA that could cross the blood-brain barrier. Turns out that it’s just like every other anticonvulsant and works on voltage channels. Except that it’s unique in that it affects a part of your brain that nothing else touches. Except for Lyrica (pregablin), and a few meds under development (e.g. PD-210714). Still, some people are calling those parts of your brain some people are calling those “gabapentin receptors”, along the lines of benzodiazepine receptors. There supposedly were citalopram receptors as well, but that turned out to be a myth. Ironically gabapentin doesn’t directly affect GABA.

Every day a new peer-reviewed journal is published somewhere adding to our knowledge about how a particular med works, or making us crazier with more contradictory data.

It would be nice if we could break things down into neat parameters like we can with pharmacokinetics, but we can’t. The best we can do is tell you what they originally thought it did, let you know if there are any meds with similar mechanisms / methods (the terms are interchangeable) of action, and give you our best guess as to what it really does based upon more recent research.

2.  How Topamax (topiramate) Works

2.1  What the PI Sheet Says

Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate (GABA) at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.
Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.the Topamax PI sheet

In English: Topamax prevents migraines and specific types of seizures by reducing the excessive electrical activity being transmitted through sodium ion channels, inhibits the excitatory (i.e. seizure-inducing and/or crazy-making) neurotransmitter glutamate, helps your brain in using soothing, calming GABA, and inhibits carbonic anhydrase (CAI) to make soda taste like ass and give you kidney stones. They don’t know yet how carbonic anhydrase is related to some forms epilepsy, just that it is.

2.2  What Topamax (topiramate) Really Does

as far as we can tell
Topamax inhibits the voltage-gated (dependent) sodium and calcium channels, inhibits glutamate and carbonic anhydrase, and promotes the reception of GABA and/or increases the amount of GABA, depending on the location in your brain and the study you read. Topamax may also affect voltage-sensitive sodium channels, modulate voltage-gated potassium channels, and modulate voltage-gated calcium channels instead of merely inhibiting them.

In English: Topamax doesn’t just reduce the electrical activity being transmitted through sodium ion channels, but also calcium channels. Additionally it modulates potassium and calcium channels, so it smooths the peaks and valleys as well. Topamax doesn’t just help you use the GABA you have, it also increases the amount of GABA available. GABA = mellow and tipsy, less glutamate = less seizurey.

Topamax’s neuroprotective / antikindling effect is due to its positive GABAergic actions, particularly with GABAA1, and being an antagonist at specific glutamate receptors. Again, when it comes to epilepsy more GABA is good, less glutamate is better. For bipolar more GABA is tricky, and can result in mania.

Originally discounted as having any effect, being a CAI (mainly at CA2 & CA4) is an important part of topiramate’s MOA after all.

Topamax may have an effect on your 5HT-2C receptors. Working on serotonin explains lots of things, from being God’s gift to migraineurs to affecting mood in a positive or negative fashion.

Subunit selectivity of topiramate modulation of heteromeric GABA(A) receptors. In English: YMMV.

Functional MRI reveals declined prefrontal cortex activation in patients with epilepsy on topiramate therapy. Or: pretty pictures of Topamax = me feel toopid.

And for the question that is asked at least once a week, how does Topamax make you lose weight? I may finally have an answer for that one. Topamax was initially developed as an oral hypoglycemic to control weight in diabetes 2. It is an inhibitor of gluconeogenesis. As such Topamax is similar to metformin. Being a CAI is also a contributory factor. Serotonin at 5HT-2C is also a factor in weight control, but it’s still not clear if Topamax does anything there at all, much less to what extent.

Zonegran is a CAI and, like Topamax, it’s also a supermodel drug. Diamox (acetazolamide) is used to treat altitude sickness and glaucoma, and is used off-label (in the US) as an AED. Diamox also causes weight loss, but the side effects suck so much more than Topamax and Zonegran combined that no one in their right mind would use Diamox, or any other CAI as a diet pill2. Being a CAI is also why Topamax makes carbonated beverages taste like ass and is responsible for kidney stones and other kidney problems, and metabolic acidosis being potentially serious problems for anyone who takes Topamax and Zonegran.

One more thing: the weight-loss effect is the one thing Topamax may not give you a second chance on. And if it does, it may not work as well. You can stop taking Topamax and try it again for epilepsy, migraines, as an add-on for bipolar, or whatever and most people have reported that it works about as well as it did before. Except for the weight loss.

3.  Functional Equivalence

No two medications will have the exact same mechanisms / methods of action. Sometimes a drug that is developed from the active metabolite of another, essentially inert med e.g. Invega (paliperidone) is a predigested form of Risperdal (risperidone) and is basically the same thing. However there is no good conversion of dosages between the two like there is for Tegretol (carbamazepine) and Trileptal (oxacarbazeine). Like Invega and Risperdal, Pristiq (desvenlafaxine) is the active metabolite of Effexor (venlafaxine), but Pristiq has a somewhat different mechanism of action than Effexor. Mainly it kicks Effexor’s ass when it comes to how potent its inhibition of norepinephrine reuptake is.

All SSRIs are essentially interchangeable, making it possible to work out equivalent dosages so you don’t need to wait until you’ve cleared one drug to start another. But Celexa (citalopram) and Lexapro (escitalopram) are vastly more selective than Prozac (fluoxetine), and so the side effect profiles, and pretty much everything else, are very different when you compare Celexa or Lexapro with other SSRIs, but practically identical when compared with each other. While most people couldn’t tell the difference between Lexapro and Celexa,3 because Lexapro is a derivative of Celexa, a few people will respond differently to the two.

3.1  Drugs with Similar Methods of Action as/That Work Like Topamax (topiramate)

Zonegran (zonisamide).

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4.  References

  1. Topamax (topiramate) Full US Prescribing Information


Pharmacokinetics & Noted Drug-Drug Interactions | Topamax Index | Comments

1 Unlike Lamictal, which was originally thought to be be such a potent folate antagonist that it would work well as a treatment for malaria and similar parasites that took up residence in your brain. Or Topamax, which was originally thought to be an awesome drug for type 2 diabetes, as it looked like it would both control weight and blood sugar.

2 Which is why the FDA has given tentative approval to Qnexa, a combination topiramate and phentermine, and Mayan for "you frelling idiot," to treat obesity. They also gave it a pregnancy category of X to prevent anyone who takes it from further polluting our already disgusting gene pool.

3 The one real difference used to be cost. Now that Lexapro is available as a generic in the US that difference isn't as great as it once was.

If you have any questions not answered here, please see the Crazymeds Topamax discussion board. We welcome criticisms of the articles, notifications of bad links, site problems, consumer experiences with medications, etc. I’m not always able to write back. Hence I never answer questions about meds via e-mail that are answered by this or other articles. Especially if they have been repeatedly asked on the forum. That’s why we write these damn things. Questions about which meds are best for your condition should also be asked on the forum; because this is a free site, so the price of admission is making things easier for somebody else searching for the same answer. We don’t deal with children on the forum or in private because after doing this for ten years I don’t have the emotional stamina to deal with kids who have brain cooties. How to contact Crazymeds. — Jerod Poore, CME, Publisher Crazymeds (

Last modified on Sunday, 25 January, 2015 at 01:06:42 by JerodPoorePage Author Date created Tuesday, 11 January 2011 at 13:43:23
“Topamax (topiramate): a Review for the Educated Consumer.” by Jerod Poore is copyright © 2011 Jerod Poore Published online 2011/01/11
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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.

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