Serotonin Syndrome Risk – A Case Example

When I’ve had students with me, they will often ask about multiple serotonin related drugs and risk of serotonin syndrome.  A classic example of this is a patient on an SSRI and Tramadol.  This combination is used frequently in practice.

Serotonin syndrome is very serious, but extremely rare.  We should never exclude anything, but if I have a patient on Zoloft 25 mg daily and is taking a prn Ultram 50 mg once or twice a week, serotonin syndrome is not going to be the first thing on my radar to say the least.

courtesy sketchymedicine.com
courtesy sketchymedicine.com

Now take this example of a patient on Zoloft 200 mg daily and Effexor 400 mg daily.  My concern for serotonin is obviously much greater and we would need to thoroughly investigate why those high doses (and why this combination) is necessary and if we’ve had to ramp up to these doses on both medications, have they really been effective?  Given the Effexor/Zoloft combo above, my level of concern for Serotonin Syndrome risk would be much higher than simply on a low dose SSRI and Tramadol.  Side effects could also certainly be more prevalent on these higher doses.

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What Would my Wife Say?

Some humor today, because we can’t take life too seriously all the time!  It was a beautiful, quiet afternoon at a LTC facility.  Everything was going smoothly without many issues that day and I was focused.

While reading through some progress notes for a particular resident, I couldn’t help but have that feeling that someone was slowly approaching me from behind and to the left.  Not knowing what was going to happen, I slowly leaned back and to the right.  There was a 90+ year old resident with her lips puckered asking, “Well aren’t you going to kiss me?”

Photo by Chalmers Butterfield
Photo by Chalmers Butterfield

I remember stammering a little bit, looking for the right words.  I threw out this softball for her, “Ah, what would my wife say?”  To which her response was, “We don’t have to tell her”. – Well played.

You truly never know what is going to happen at a long term care facility.

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Gabapentin Induced Edema

87 year old female is having difficulty with tingling and burning in her feet.  She is diagnosed with diabetic neuropathy.  Her current medications include:

  • Hydrochlorothiazide
  • Metformin
  • Glipizide
  • Tylenol as needed
  • Lisinopril
  • Aspirin

The primary provider orders gabapentin 300 mg three times daily to help with the new onset neuropathy.  The symptoms of neuropathy do begin to resolve, but within a few weeks, the patient is complaining of a new problem.

Leg_Edema NSAIDs

She is noticing a significant amount of swelling in her legs that is greatly frustrating her.  She is started on Lasix 20 mg daily to help reduce the swelling.  The Lasix (furosemide) does the job of relieving the edema, but now the patient’s new concern is that she is going to the bathroom constantly.

This is the prescribing cascade in action (treating side effects of one medication with another medication). Gabapentin induced the edema causing the addition of more medications.  We could certainly go further with this example by adding potassium supplementation and maybe an anticholinergic for urinary frequency from the Lasix etc.  In this case, gabapentin was eventually reduced to a lower dose, and this did make the edema less problematic allowing for the discontinuation of the Lasix.  I would’ve made the argument that this is a pretty steep dose of gabapentin to begin with in a patient who is 87.  Kidney function would be another important parameter to check out in a case like this.

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What Could Be Causing My Persistent Angioedema?

A 47 year old African American female came into the emergency room with a chief complaint stating that “my throat was closing.” The patient had also been coughing with multiple episodes of vomiting throughout the night. Twice last month, the patient experienced a similar presentation plus swelling of her lips, face, and upper and lower extremities, which was diagnosed as angioedema. She also experienced urticaria with the previous hospital visits, but there was no mention of urticaria with this admission. She was treated with diphenhydramine, famotidine and methylprednisolone on both previous occasions. This time, the patient was treated with oxygen therapy, racephinephrine 0.5mL nebulized, methylprednisolone 125mg IV, famotidine 20mg IV, ondanestron 4mg IV, diphenhydramine 50mg IM and a liter bolus of normal saline. The patient is currently taking clonidine and hydrochlorothiazide for hypertension and sertraline for depression, none of which are new medications. The patient also admitted that she was not always adherent with her medications because sometimes she could not afford them. The patient does have a history of illicit drug use, including crack cocaine and alcohol abuse. Due to the nature of her condition and its frequent reoccurrence, she was placed in observation for two nights. Once the swelling cleared and she improved clinically, she was discharged on her current medications, a prescription for an Epipen® and no clear explanation of what had caused this reaction.

The first thought most of the clinicians at the hospital had was “Is this patient on an Angiotensin-converting enzyme (ACE) inhibitor?”.

ACE Inhibitors like lisinopril are always one of the first medications considered when angioedema is present: photo courtesy: NIH
ACE Inhibitors like lisinopril are always one of the first medications considered when angioedema is present: photo courtesy: NIH

Once they were assured she was not taking one, the physicians were at a loss for what could be causing her persistent angioedema. We have become so programed to associate angioedema with ACE inhibitors that we have forgotten about its possible other perpetuators. A very common cause of angioedema is allergies caused by insect stings, foods (eggs, nuts, fish or shellfish), exercise, handling certain plants parts, animal saliva or latex. There are also several medications, other than ACE inhibitors, which can cause angioedema such as antibiotics, nonsteroidal anti-inflammatory agents (NSAIDs), selective serotonin receptor inhibitors (SSRIs) and clonidine. This patient was documented to have an allergy to penicillin, but no reaction was listed, nor was she given it during her hospital visit. Furthermore she was never asked if she took any over the counter products before coming to the emergency room. Her physicians had dismissed her clonidine, sertraline and hydrochlorothiazide as possible causes of angioedema because they were not new medications; however there have been cases of patients developing angioedema after taking ACE inhibitors for years. Both the package inserts for clonidine and sertraline list angioedema as possible side effects and the American Society of Health-System Pharmacists reports that 0.5% of patients develop angioedema with clonidine; angioedema has not been reported with hydrochlorothiazide in these references.

Another possibility is that the angioedema was hereditary. Hereditary angioedema is caused by excessive production of bradykinin possibly caused by a deficiency or dysfunction of C1 esterase inhibitors that play a role in regulating bradykinin. C4 levels (the natural substrate of C1 esterase), C1 esterase inhibitor (C1-INH) quantitative and functional measurements and C1q levels are all diagnostic tests that could have been performed to establish if the patient had hereditary angioedema, however they were not. If all options had been extensively explored, this patient’s angioedema could have been idiopathic, occurring for no reason.

Overall, several factors in this patient’s case could have caused her angioedema, such as possible allergy to an NSAID, a possible contaminant in an illicit drug she had taken, or restarting her medications after a period of nonadherence.  References: Submitted By: 

Viktoriya Kotik, PharmD-PGY 1 Pharmacy Practice Resident in collaboration with Donna M. Lisi, PharmD, BCPS, BCPP

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Drug Interaction: Dilantin and Diflucan

64 year old female with a history of seizures, hypertension, and osteoarthritis was diagnosed with a case of recurrent vaginal candidiasis.  Her current medications included:

  • Dilantin
  • Enalapril
  • Amlodipine
  • Ibuprofen as needed

Her previous labs were unremarkable with a total Dilantin (phenytoin) level of 16 and seizure free for well over a period of a year.  She had not been experiencing any signs of toxicity as well.

Photo courtesy CDC
Photo courtesy CDC

For treatment of the candidiasis, she was prescribed Diflucan (fluconazole) for a period of 14 days.  Approximately halfway through the treatment period, family was concerned with a change in mentation in the patient.  She had also had a fall and was having trouble walking.  Family was questioning if the patient was having side effects from the newly prescribed Diflucan.

Upon investigation, a Dilantin level was checked, and revealed to be 27.  She was diagnosed with Dilantin toxicity.

When I think of fluconazole, I normally think of all the classic CYP3A4 interactions.  Per Lexicomp, Dilantin and Diflucan interaction is likely caused by fluconazole’s ability to inhibit CYP2C9.

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Eric Christianson, PharmD, BCPS, CGP

Interprofessional Medication Education