Tuesday, January 10, 2017

The MOAs of AEDs

One of the many questions that always came up every time one of Mira's neurologists recommended a new AED (anti-epileptic drug) was how does it actually work chemically and neurologically in helping control seizures? What is the mechanism of action (MOA) and how is going to potentially impact my child's seizures? Mira has tried many different medications, unsuccessfully, so many of the details have escaped me over the years. I can however, remember the sedating ones like ethosuximide, the horrible ones, like felbamate, and the rest simply by name, but overall, medications overall have done nothing for Mira in terms of seizure control. Researching the MOAs of these medications has been eyeopening. Simply reading through the medication product literature of many popular AEDs, the overwhelming majority of them read very similarly, and in the case of Lyrica, which Mira is currently taking, it states:

 'The exact mechanism of action of Lyrica (pregabalin) has not been fully elucidated. The current findings are based on preclinical animal models. The clinical significance in humans is unknown.'

Not exactly the sentence you want to read as you are signing your child up for one of these medications. As I have said many times before, I am certainly not anti-pharmaceuticals, as there are many out there that provide effective relief for many suffering from epilepsy. There is the right medication or combination of meds that works for that particular individual and it's refreshing to hear those stories. However, there are some meds that can have harmful, damaging, and often permanent side-effects. This list of these side effects are typically listed with the medication pamphlet, along with the MOAs. I would encourage everyone in becoming familiar with the side effects at a minimum - recognizing these effects is critical. For instance, when Mira was prescribed Lamictal (lamotrigine) we were warned by her neurologist at the time, that in rare cases, users can have a potentially fatal skin reaction called Stevens-Johnson Syndrome or in the case of Sabril (vigabatrin), there is the looming threat of permanent retinal toxicity - basically it can cause you to go blind.

Buried with all of the side-effect warnings, clinical trial data, and other relevant user information, usually is an explanation of the supposed MOA(s) of the medication. Most pharmaceutical MOAs revolve around the following actions or potentials:

GABA receptors
Voltage-gated calcium channels (VGCC)
Voltage-gated potassium channels (VGPC)
Voltage-gated sodium channels (VGSC)
NMDA receptors
Glutamate receptors

There is a decent article that can be accessed here, that offers a charted breakdown of 20+ AEDs and their assumed MOA. The only medication Mira has ever had a positive reaction to is Lyrica, thus it is part of the reason she is still on it and has continued to take it for the last 8+ years. Mira's seizures subsided for almost 6 months, within a week after starting Lyrica in 2007, which was miraculous at the time. We attributed her seizure freedom to Lyrica, but the reality is, her EEG never improved in that 6 months and eventually, the seizures came back in full force and have stayed ever since, despite numerous dosage increases and modifications. Nonetheless, I went on a research endeavor back then, trying to dig up as much information on the MOA and history of Lyrica, going so far as to contact the person who actually 'invented' the chemistry behind the drug. I emailed with him numerous times and found the process and method in which a formula ultimately reaches the end user, disconcerting. It is fairly easy to discover the supposed MOA for Lyrica is assumed to be through voltage-gated calcium channels (VGCCs), a claim which is buried in the 55 pages of prescribing information, that can be found here. The MOA and pharmacology can be located in section 12.1.

Every single medication that enters the marketplace should be offering this information to the consumer and of course, the health care professional who is prescribing it. It may seem exhausting to read, but I can assure you, the publicly available information regarding pharmaceuticals will be nothing but enlightening, if not frightening. For a more exhaustive article of the MOAs and the neuropharmacology of commonly prescribed AEDs, can be accessed here, through one of my favorite resources, the NCBI Bookshelf.

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