Month: June 2013

It’s Time to Begin

by Nadia I. Awad, posted in EM PharmD Blog

When I was a little kid, I was always asked the question, “So what do you want to be when you grow up?” I would answer emphatically, “That’s easy- a journalist.”

Why? I have always found the profession to be quite fascinating. The work that it entails- researching and writing to deliver a news story to be shared with an audience of readers, listeners, and viewers- is right up my alley. Even as a kid, I enjoyed reading and writing and engaging an audience with a good story. Through the past decades, several individuals have emerged as prominent leaders in the world of journalism, and I aspired to be just like them. It amazed me how they were able to ask the right questions when it came to “getting the real dirt” on a story, and even after the delivery, I would be left to wonder more about it. 
Then I got a little older, and I began to understand and realize the amount of passion and hard work that went into the profession and to me, it seemed to be a tough industry to break into. At around the same time, I discovered my love for science, particularly chemistry, and with that, I decided to pursue a career along that track. I chose pharmacy, and how I got there is another story for another day.
Fast forward more than 10 years to 2011, at which point I have graduated with my Pharm.D., and I am setting out to begin my pharmacy career as a PGY-1 pharmacy resident. I was excited and when I first started out, I had plans of pursing a PGY-2 specialty residency in critical care and eventually becoming a specialist in critical care pharmacotherapy.
By chance, I had to make a minor adjustment in my schedule of rotations, and it was requested for me to have my emergency medicine (EM) elective rotation in October instead of February. I was agreeable to this change, and so October rolled around and I started my five-week rotation in the emergency department. I selected EM as an elective because I thought that it would be a pretty decent experience, even though I was informed that not many residents pick EM as an elective because of the blood and guts, fast pace, and somewhat high-stress environment of the emergency department (ED). I was ready for a challenge, and I figured that even if I did not like it, I knew that it would come to an end in five weeks’ time. And so I began and spent the first week of my rotation with our evening shift EM pharmacist. 
And I soon realized that I was wrong…very wrong. About my career plans, that is. 
What happened? I fell hard in love with the ED. 
For me, EM encompassed everything that I was interested in learning more about, from critical care to ambulatory care to infectious diseases to everything else in between, and applying that knowledge directly to the acute care of patients. I was able to appreciate the contributions that I could make as a pharmacist in the emergency department, and I felt that my work was valued. 

Simply put, I saw my work come to life. Anyone who practices in the ED knows what I mean and can definitely corroborate this statement. 
Even though EM was previously nowhere on my radar, I knew that by the third week of the rotation, I was going to have to change gears and pursue a career as an EM pharmacist. However, a five-week rotation in the ED was not enough, and I applied for and later accepted the position for the PGY-2 specialty residency in EM at the same institution. 
During my first week of residency, my program director sent me links to a number of EM and toxicology websites and blogs to follow, as the content found on these sites would help guide my way during the first couple of months of the residency. These websites and blogs proved to be critical to my training for the entire year. 
In my third month of the residency, my program director started this blog, which I thought was pretty neat, since it put a different spin on the websites and blogs that I was already following, as the goal was to provide an outlook of things related to EM from the perspective of the pharmacist. I was invited to write about the role of the pharmacist in the emergency department for a blog post after an interesting discussion. I wrote it, and I instantly became hooked. Finally, after many years, I was able to hone my interest in writing in such a way that held true to my original aspirations of becoming a journalist andwas still related to my experiences in the emergency department. 
After a few weeks, I became a regular contributor to this blog and I simultaneously started a Twitter account to share my residency experiences and pearls that I have gained along the way. One by one, I began interacting with EM physicians, pharmacists, students, and other practitioners from all over the country and world that I never imagined to be possible. Through Twitter, I learned about FOAMed, and with the sharing of knowledge through this medium, I was able to enhance my own learning throughout the residency. I cannot even begin to fathom my residency experience without FOAMed. In addition, FOAMed has also inspired me to write about a number of topics on this blog, and I have had a number of requests through both Twitter and from clinicians at my hospital for topics to be written about as well. Researching and writing about these topics has not only provided me with a mechanism to sharpen my writing skills, but it has also supplemented my learning experiences. And just to sweeten the deal, I have been able to meet some of my Twitter “peeps” in person at conferences, which has been pretty amazing. 
Fast forward a few more months, and the day has inevitably arrived- that is, my final day as a resident. I have worked with awesome EM attending physicians and residents this past year and my residency program director, preceptors, and mentors have facilitated my training with plenty of guidance and support along the way, for which I am truly thankful. I am grateful for the educational opportunities I have been afforded throughout my residency and the connections I have made with members of the FOAMed community through Twitter. FOAMed has encouraged me to ensure that I am up to date with the latest in EM, which I hope to maintain as I begin my transition from EM pharmacy resident to an “attending EM pharmacist”, as some have put it. No worries- I am not going too far, and I will certainly continue to post my EM pharmacy-related musings on this blog. 
There have been some whisperings that have turned into discussions on Twitter and other blogs regarding the educational impact of FOAMed and the recognition of FOAMed outlets as scholarly activity, and ways in which we can allow for this to come to fruition. I anticipate that this will become a worldwide community effort, and I am excited and curious to see how this will unfold.
It’s time to begin.

Clozapine-Induced Agranulocytosis in the Emergency Department

by Nadia I. Awad, posted in EM PharmD Blog

The case: TR is a 55-year-old African American male who is sent to your emergency department after his primary care physician receives the results of recent routine bloodwork performed earlier that day, revealing a white blood cell count (WBC) of 2700 and an absolute neutrophil count (ANC) of 1350. He has a past medical history of paranoid schizophrenia, and for this, he is currently taking clozapine 150 mg by mouth twice daily as an outpatient. He has been on this treatment regimen for nearly 18 months. The EM resident promptly discontinues clozapine, but is unsure of what antipsychotic agent to prescribe in the meantime while waiting for the cell counts to increase to reinitiate clozapine and if any additional therapy is necessary.

Clozapine is a dibenzodiazepine derivative that is classified as an atypical antipsychotic. It is often considered to be a treatment of last resort in the management of schizophrenia, after other agents have failed to manage patients symptomatically or if the adverse effects of other agents become intolerable. One of the major limitations associated with its use is the adverse effect of agranulocytosis. The incidence of agranulocytosis in patients taking clozapine is 0.8% during the first year of treatment (the greatest risk during the first six months), and increases to 0.91% after 18 months. In addition, clozapine is also associated with induction of neutropenia, which occurs in 3% of all patients who are initiated on clozapine. The mechanism by which clozapine induces agranulocytosis has not been clearly delineated, but a number of proposals have been suggested: (1) one of the metabolites of clozapine, N-desmethyl clozapine, may have a direct cytotoxic effect on myeloid precursor cells; (2) bioactivation of clozapine to a nitrenium cation by the enzyme flavin monoxygenase-3 (FMO-3), which has demonstrated to have in vitro activity on neutrophil apoptosis; and (3) an immune-mediated reaction, which has been demonstrated in several cases of rechallenging patients with a history of clozapine-induced agranulocytosis.

Patients who are on clozapine are required to be enrolled in the Clozapine National Registry to ensure that appropriate monitoring and reporting of these adverse effects occur. Guidelines provided in the package insert put forth the following recommendations regarding dose adjustments of clozapine in the setting of these hematological toxicities:

  • Moderate leukopenia or granulocytopenia (WBC < 3000 and/or ANC < 1500):
    • Discontinue therapy
    • Patient may be rechallenged once WBC > 3500 and ANC > 2000
  • Severe leukopenia or granulocytopenia (WBC < 2000 and/or ANC < 1000):
    • Discontinue therapy
    • Patient should not be rechallenged with clozapine

What I did find interesting was the number of studies evaluating the use of lithium in increasing the cell counts that were decreased as a result of clozapine use. Lithium upregulates the activity stimulating factors necessary for leukopoiesis to occur. This will typically occur within the first four weeks of initiating lithium, and blood counts will increase by 30 to 45%. Although this has not been demonstrated to be a dose-dependent phenomenon, serum concentrations of at least 0.4 mEq/L are necessary for this effect to occur. However, this will necessitate the need for monitoring of serum concentrations of lithium to prevent toxicity (particularly seizures and neuroleptic malignant syndrome) in addition to monitoring of complete blood counts to ensure that the dual combination therapy is truly effective.

Some do advocate the use of granulocyte colony stimulating factors in the management of clozapine-induced agranulocytosis. Not only do these agents stimulate the proliferation, differentiation, and functionality of myeloid precursor cells in the bone marrow, but they also appear to decrease the duration of clozapine-induced agranulocytosis by one-half of the expected timeframe. However, a number of case reports have demonstrated that this treatment option is not always successful. It also becomes questionable as to the optimal dosing schedule for this treatment option and whether the use of this therapy should be used over the long-term due to its adverse effects and costs associated with treatment in patients who meet the criteria of rechallenge with clozapine.

If we follow the above recommendations in the case of our patient TR and discontinue clozapine, we would be putting him at risk of rebound psychosis. So what antipsychotic should be prescribed in the meantime to prevent this from happening?

There is really no good answer to this question, as a number of atypical antipsychotics are associated with neutropenia and/or granulocytopenia. One study highlights the mechanisms and several case reports regarding the incidence of these adverse effects among other atypical antipsychotic agents. The authors found that consistent with other studies, olanzapine and quetiapine were more likely to prolong clozapine-induced granulocytopenia in comparison to risperidone and amisulpride. Regardless of what agent is chosen, close monitoring of cell counts is critical during the first two weeks of switching to another agent.

References:
Nooijen PMM, Carvalho F, Flanagan RJ. Haemotological toxicity of clozapine and some other drugs used in psychiatry. Hum Psychopharmacol 2011; 26:112-119.
Nielsen J, Damkier P, Lublin H et al. Optimizing clozapine treatment. Acta Psychiatr Scand 2011; 123:411-422.
Whiskey E, Taylor D. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs 2007; 21:25-35.
Ghaznavi S, Nakic M, Rao P, et al. Rechallenging clozapine following neutropenia: treatment options for refractory schizophrenia. Am J Psychiatry 2008; 165:813-818. 
Cosar B, Taner ME, Esar HY, et al. Does switching to another antipsychotic in patients with clozapine-associated granulocytopenia solve the problem? Case series of 18 patients. J Clin Psychopharmacol 2011; 31:169-173.