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In this episode I’ll:
1. Discuss an article about valproic acid protein binding.
2. Answer the drug information question “How long after starting an ACE inhibitor does angioedema occur?”
3. Share a resource I use for writing notes.
The article for this episode recently appeared in a weekly literature digest for members of my Critical Care Pharmacy Academy. Every week I send Academy members a summary of the most important critical care pharmacy articles, including my analysis of where the article fits in practice. The literature summary is brief, relevant, and presented in audio and video format. You can find out more at pharmacyjoe.com/academy.
Article
Lead author: Richard R. Riker
Published online in Pharmacotherapy February 2017
Background
Valproate is highly protein bound just like phenytoin. In healthy patients, the free fraction is about 5-10%, but only a few case reports exist in the literature that describe how this protein binding varies in critically ill patients. The authors of this study sought to evaluate the range of valproate plasma protein binding in ICU patients.
Methods
The study was an observational study of consecutive ICU patients. 15 patients were studied, and the average dose was 3 grams daily. All patients were critically ill and had an albumin level less than 4 g/dL.
Results
Total and free concentrations showed poor correlation and were concordant in only 2 patients. No patient had a valproate free fraction of 5-10%; the median was 48%, and the range was 15-89%. Free valproate was poorly predicted by an equation correcting for albumin. Adverse drug events occurred in 10 patients: hyperammonemia in 7, elevated transaminases in 2, and thrombocytopenia in 5.
Conclusion
The authors concluded:
Protein binding of valproate is highly inconsistent in this cohort of ICU patients, and total valproate concentrations did not predict free concentrations, even when correcting for albumin. Additional research to define best practice for dosing and monitoring valproate and the relationship between free valproate concentrations and clinical or adverse effects in ICU patients is needed.
Discussion
The only active drug is the free drug. Based on the variable protein binding of valproate in critically ill patients, if you see signs of valproate toxicity despite normal levels, check a free valproate level. The previously published formula for estimating the free fraction of valproate is:
Free fraction (%) = Ae^-BX, where X = albumin concentration (mmol/L), with constants A = 130.69 and B = 4.96 x 10^-3.
Given the results of this study, the formula appears to be inaccurate in critically ill patients.
Drug information question
Q: How long after starting an ACE inhibitor does angioedema occur?
A: Two-thirds of patients who experience angioedema after starting an ACE inhibitor have it in the first 3 months.
This is according to a retrospective, observational, inception cohort study of over 1.8 million patients. If you encounter a patient with ACE inhibitor angioedema, remember the first and only priority is to protect the patient’s airway. I discuss angioedema treatment in episode 60.
Resource
The resource for this episode is the perfect writing instrument. I can’t believe I’ve been a pharmacist since 2000 and only in the last year did I discover the best kind of pen to use. Ball points are always skipping on my progress notes and post-its. What works best is a fine point, felt-tipped pen.
The Bic Intensity Fine Point and the Sharpie Pen Fine Point are two brands that work equally well. They don’t skip or bleed, and are about $1 per pen when you buy them in bulk. If you already have the perfect pen but aren’t sure how to best write your note, check out episode 19 where I discuss when and how to write pharmacy progress notes.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
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