Jimmy Suh, MD Profile picture
Jan 6, 2022 14 tweets 9 min read Read on X
1/ There’s a lot of AEDs that work great together to tx szs! Unfortunately, Valproic acid (VPA) and Phenytoin (PHT) are two that didn’t get that memo.

Get ready for a fun and educational two-part #tweetorial on the do not miss VPA and PHT interactions w/ @theABofPharmaC
2/ Let’s go back in time.

Valproic acid was first synthesized in 1882 by Burton. It wasn’t until 1963 when its anticonvulsant properties were discovered by Eymard.

Phenytoin was first synthesized in 1908 by Biltz and discovered to have anticonvulsant properties in 1936
3/ VPA works by ⬆️ GABA lvls and blocking Na and Ca channels. It’s broad-spectrum permits its use for various szs types: partial, tonic clonic, myoclonic, and absence.

PHT works solely by inhibiting Na channels and has a narrower spectrum of use: partial and tonic clonic szs
4/ The typical starting dose of VPA is 10-15 mg/kg/day w/ therapeutic range of 50-100 mcg/ml (total) and 5-15 mcg/ml (free). Roughly 10% of the total level = free level.

Adverse rx include hepatotoxicity, hyperammonemia, thrombocytopenia, pancreatitis, and fetal toxicity.
5/ The typical starting dose for Phenytoin PO is 100mg TID (remember to hold tube feeds 1 hr before and after).

If given IV (should really consider fosphenytoin instead), the starting bolus is 15-20mg/kg w/ therapeutic range of 10-20 mcg/ml (total) and 1.0-2.5 mcg/ml (free).
6/ Adverse rx include gingival hyperplasia, ataxia, peripheral neuropathy, hepatotoxicity, and bone marrow suppression. If given IV purple glove syndrome, hypotension and arrhythmia can occur if given too rapidly.
7/ So what’s the big issue using the two together? VPA and PHT are both are highly protein bound to albumin meaning that they both compete for the same “hang out” spot.

VPA is bound to albumin at 90-95% whereas PHT is bound ~90%
8/ VPA displaces PHT from plasma binding sites, which significantly increases the free phenytoin level (i.e. the actual active form) even though the total level may still be the same or even decreased!
9/ What makes this even more complicated is the fact that Phenytoin follows zero-order kinetics.
.
.
.
Wait say what?

Unlike first-order kinetics where elimination is dependent on a constant % of a drug, zero-order kinetics is where elimination is the same constant amount.
10/ This means that after a certain threshold, even small ⬆️ in dosage can cause a significant disproportional ⬆️ in plasma concentration.

This is particularly important in patients with hypoalbuminemia or conditions that cause altered albumin binding (ex: acidosis/uremia).
11/ If that wasn’t complicated enough, clinically significant % alterations of free VPA occurs when total drug concentrations become >80mcg/mL, making the VPA – PHT drug-drug interaction even more complex.

pubmed.ncbi.nlm.nih.gov/121944/
12/ If this is making your head hurt 🤯, thank all the wonderful and spectacular pharmacists who help keep an eye out on all these drug-drug interactions!
13/ So protein binding and zero order kinetics both play a big role when it comes to using both VPA and PHT together, but there’s more vital concepts to consider!

Head over to @theABofPharmaC to continue to part two of this tweetorial!

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More from @JimmySuhMD

Feb 13, 2023
1/ You're finally settled in as an attending and you get a new patient.

They sound brain brain dead.
They clinically look brain dead.
Your team asks if they're brain dead.

Well this turned serious… a quick #tweetorial about 🧠 death
#NeuroTwitter #Neurocrit #MedTwitter
2/ The transfer 📞 you got was a 28 yo with no other history. They were concerned about her being in status epilepticus.

You turn off all sedation. They're still unresponsive.
3/ Clinically, they're intubated and have fixed and dilated 👀. No corneal or cough and not breathing over the vent. No motor response w/ painful stimuli 🤕

You scan their labs - ✅ no significant abnormalities You check their vitals - ✅ looks all good

What should we do next?
Read 20 tweets
Dec 10, 2021
1/ #EmoryNCCTweetorials 🚨

The setup: Neuro ICU at @EmoryNeuroCrit
The pt: John Doe transferred for status epilepticus

You’re told about the pt’s ammonia lvl ➡️ 181 (where's @Capt_Ammonia?!). He’s also on 5 different AED’s...

@MedTweetorials
#MedEd #tweetorial #neurotwitter
2/ On quick review, patient was admitted 5 days earlier at the OSH. Initially admitted for encephalopathy that was then c/b seizures the following day. Initial ammonia was normal. CT/CTA unremarkable. MRI brain w/ contrast shows the following abnormality over the R frontal area
3/ Further hx significant for excessive EtOH (~2-3 glasses of wine/day). Recently in the mountains drinking homemade moon shine. He had nausea and vomited ~24-48 hrs later before becoming encephalopathic. Eventually admitted ~4 days later.
Read 20 tweets
Aug 30, 2021
1/ Alright, time to give this #EmoryNCCTweetorials a swirl!

The setup: Neuro ICU at @EmoryNeuroCrit
The pt: Basilar stroke s/p tPA & MT. Now intubated & undergoing stroke workup

You’re called to the bedside for sats in the 80s!
@MedTweetorials #MedEd #tweetorial #neurotwitter
2/ RN lets you know that the patient just completed their TEE....

O2 is beeping, 88% ➡️87%➡️ 86%
3/ Time to quickly go over your checklist
✅Auscultate breath sounds?
Normal.
✅Change sensor on O2 sat probe?
Still 86%.
✅Check ETT placement?
Unchanged from the day prior.
✅Compliance/Plugging issue?
Normal Peak and Plateau pressure. Nothing clogged.
Read 17 tweets

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