Thursday, March 28, 2013

"Clinical Pharmacist": What's In a Name?

Let us take a trip down memory lane.

The year: 2011
The month: January
The event: Onsite interview for a PGY-1 pharmacy residency program
The place: Swanky office of the residency program director

It was very early in the morning, and I had a full day ahead, with back-to-back meetings with various preceptors and residents of the pharmacy residency program. It was my very first interview of several, and so I was understandably very nervous. For the past few days, I had gone through a comprehensive list of potential questions that I thought the folks interviewing me would ask, and I had all my answers down to a T. I was ready, but still a little anxious for some of the possible curveball questions that I would get asked.

I was asked to sit in the office of the program director, and I waited a few minutes for the program director to come by. My heart was racing, and I placed both of my hands on my lap to try to minimize the sweat being generated from my palms. I looked around and marveled at the size of the office and all the certificates and awards displayed on the walls. "Fancy," I thought to myself. "Maybe I can achieve that one day."

In walked the program director, and I braced myself of the interview. The first question that was asked was the simple yet ever-so-challenging question of "tell me about yourself." I gave my ready-at-the-helm answer, and I was quite pleased with my response.

Here was the next question I was asked:

"What does the term 'clinical pharmacist' mean to you?"

Now, I had done my homework with this question. I had read several articles on the topic, including this article here, which defines the term 'clinical pharmacist' very succinctly. The term was not foreign to me; in fact, throughout my didactic and experiential learning experiences, I heard the term constantly. It encompassed everything that I aspired to be.

But for some reason, when that question was asked, something came over me. All the definitions and descriptions of the term that I had read about regarding the role of the 'clinical pharmacist' literally flew out the window. I just couldn't bring myself to answer the question the way I had originally prepared. I am still not sure as to why it never dawned on me before. Regardless of the reason, the moment of realization conveniently happened to be during the interview at that very moment, and I provided the following response:

"I think that all pharmacists are clinical, regardless of their practice setting."

I still firmly hold to this belief. The sheer number of pharmacists who practice in the profession is much less compared to physicians and nurses. Yet, with our profession as small as it is, why is there a distinction between 'clinical' and 'non-clinical' pharmacists? And where did it originate from?

It all goes back to the early 1960s, when the practice of pharmacy in the hospital setting began to evolve. During this time period, technologies for compounding pharmaceutical formulations as well as the provision of medications advanced. In addition, the number of pharmaceuticals being discovered, developed, and available for the treatment of complex disease states dramatically increased. There was a recognized need for expanding the role of the pharmacist to become more integrated into the healthcare team in managing the safe and effective use of medications for patients to improve health outcomes while minimizing the potential for adverse events. At around the same time, post-graduate residencies began to develop to further educate and train pharmacists and even allow for specialization within specific areas of medicine such as critical care, internal medicine, infectious disease, pediatrics, and emergency medicine.

We have come a long way since then. The profession has continued to evolve and the role of the pharmacist has expanded across all settings to such an extent that nowadays, many healthcare teams have come to rely upon pharmacists to a great extent in managing complex medication regimens. We have witnessed collaborative relationships between pharmacists and other healthcare professionals that was never before imaginable. As part of the curriculum for pharmacy education, there are dedicated courses to educate and train student pharmacists in becoming effective communicators as well, which is essential for providing therapeutic recommendations to healthcare providers on behalf of patients and for providing counseling to patients regarding their medication regimens in order to ensure comprehension and full adherence to therapy. In addition, there have been a number of legal cases that have shown us the importance of screening for drug interactions and contraindications to therapy and intervening on behalf of our patients to ensure patient safety.

Yes, there are those who have had the extra training and certification to practice in a niche area, and I believe that the title of 'specialist' is well-deserved and justified for those pharmacists. The same holds true for physicians as well, as there are 'general practitioners' and 'specialists' in the field of medicine.

Pharmacy happens to be a profession where there exists a vast amount of environments that one can practice in, which include the community, hospital, and managed care settings, just to name a few. The day-to-day duties of the pharmacist across these different settings may vary, but the essential responsibilities of managing medication therapies and providing direct patient care is the tie that binds us all. The pharmacist practicing in the community setting is as every bit responsible for these activities as those who practice in the institutional setting (if not even more so, as there is greater accessibility of the pharmacist to patients in the community setting).

So my response to those people who meet me for the first time when they ask me about my profession: "I am a pharmacist." My practice setting just so happens to be in the emergency department, and I could go on to describe my residency training, my typical workday, and the types of patients that I encounter. But just as it is with any other healthcare professional, the 'clinical' aspect happens to be part of the package that comes with practicing as a pharmacist.

Thursday, March 21, 2013

Methylene Blue: A Wash in Septic Shock?

Even with all the therapies available for the management of septic shock, there still remains a great incidence of morbidity and mortality associated with this condition. One therapeutic agent that has been advocated for refractory septic shock is methylene blue (MB). Yes, you read that right...the same agent used as an antidote for the treatment of methemoglobinemia.

Here is the low down. Nitric oxide (NO) is thought to be one of the major culprits for the manifestation of the vasodilatory effects seen in septic shock, as it activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP). Nitric oxide is produced through the activate of nitric oxide synthase (NOS), of which there are two types that exist: (1) constitutive NOS (cNOS) and (2) inducible NOS (iNOS), the latter being activated in the presence of cytokines and endotoxins. The downstream effects of accumulated cGMP include decreased sensitivity to vasopressor therapy, increased permeability within the vasculature, decreased systemic vascular resistance, and depressed contractility of the myocardium. On the flip side, NO may have potential benefits in septic shock with its actions as a free radical scavenger and may help enhance oxygen delivery to ischemic tissue as well as increase the activity of macrophages. Because of this, non-selective suppression of NOS can have harmful effects in the patient with refractory septic shock.

Enter MB, which acts on iNOS to competitively inhibit the activation of guanylate cyclase in the vascular smooth muscle. With this specific inhibition of guanylate cyclase, the theoretical benefits of this process include increased mean arterial pressure and improved vascular resistance, which has been demonstrated in animal studies.

So what about the effects of MB in refractory septic shock in humans? There have only been a couple of controlled clinical trials that have been published regarding this, which are reviewed in the table below:

Other small observational studies have been conducted, and have been reviewed here and here. Based on the results of the studies, MB seems to improve hemodynamic parameters (i.e. "make the numbers look good") but had no real impact in improving clinical outcomes (i.e. mortality). Varying dosing and administration strategies (bolus versus continuous infusion) of MB have been employed in these small studies as well, and with lack of a homogenous patient population across these studies, it may be difficult to determine which patients with refractory septic shock can receive the greatest short-term and long-term benefits from treatment with MB.

In addition, there are some considerations that we need to keep in mind as well. MB may be ineffective in patients with G6PD deficiency, and because these patients are at greater risk of experiencing hemolytic anemia, use of MB is generally not recommended. In addition, discoloration of the skin, bodily fluids, and mucous membranes is a potential adverse effect associated with treatment.

Moreover, in critically patients with refractory septic shock, it is not uncommon to find that continuous renal replacement therapy (CRRT) is used to help manage and prevent further progression of acute renal failure. In fact, an estimated 5% of all critically ill patient will receive CRRT during the course of their hospital stay. What are the implications of CRRT on the efficacy of MB should it be used in such patients with refractory septic shock? Only one case report has been published that has evaluated this, which found that MB is not significantly removed in CVVHDF, and the authors concluded that caution should be used when administering MB for refractory septic shock in patients concomitantly receiving CVVHDF.

The jury for MB in the management of refractory septic shock is still out. Careful consideration of the patient being selected for treatment with MB as well as the dosing strategy and place of MB in the course of the treatment of the patient are important factors to determine whether or not the patient will truly benefit from MB. Bear in mind that although the hemodynamic status may improve in patients being treated with MB for refractory septic shock, the mortality benefits have not been demonstrated.

Kirov MY, Evgenov OV, Evgenov NV, et al. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med 2001; 29:1860-1867.
Memis D, Karamanlioglu B, Yuksel M, et al. The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care 2002; 30:755-762.

Monday, March 18, 2013

Dabigatran Post-Marketing Data

Perspective is everything. Changing your perspective when learning can help gain a higher understanding; likewise in teaching, altering your perspective can help make a point. Take for, example, this recent article in NEJM[1] regarding the true incidence of bleeding associated with dabigatran.  Take a step back from the usual perspective of dabigatran being the spawn of Satan, if only for a moment.

In this article, the authors propose that the reported incidence of bleeding as a result of dabigatran is inflated from what would normally be reported. Going back to RE-LY, the overall incidence of bleeding was lower in patients taking dabigatran compared to warfarin.  When a higher than anticipated number of bleeding events were reported to the FDA adverse event reporting system, further investigation took place. These reports led the authors to conduct their own [albeit flawed] review of the FDA Mini-Sentinel database to find similar bleeding incidences, and note a larger phase II study is on the way. 

Part of the post-marketing safety data of new drugs comes from voluntary reporting systems like Medwatch.  Across the board there is a tendency to under-report adverse events because, well, it’s more work (unless you have pharmacy students looking board).  What seems to be going on with dabigatran and the inflation of adverse event reporting is thought to be a result of the Weber effect. In a nutshell, since everyone is on the bash-dabigatran bandwagon, there is an increased awareness, almost excitement, to report adverse events. When compared to warfarin, there seems to be underreporting of bleeding (I mean, we all see it on a daily basis).

Of course, when bleeding is discussed, several confounding patient factors do need to be considered. With dabigatran, bleeding incidence of bleeding has been linked to inappropriate use of the drug; i.e., normal dosing in patients with impaired renal function.   Not understanding the lack of pharmacokinetic data supporting the renal dosing recommendation is not a reflection of “real-world practice,” it’s poor medicine.  

The perspective I am trying to describe is similar to one I recently heard regarding tPA for AIS: let’s not look for patients with contraindications to tPA, but rather, ask which patients will benefit from tPA.  With dabigatran, lets be aware of the risks of bleeding and the difficulties in reversing the anticoagulant effects, but also identify patients who will benefit from dabigatran and not treat is as a carte blanche replacement for warfarin.

[1]Ross Southworth M, Reichman ME, Unger EF. Dabigatran and Postmarketing Reports of Bleeding. N Engl J Med. 2013 Mar 13

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