Prepping Pharmacist Preceptors on the Pharmacists’ Patient Care Process (PPCP)

The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

Preceptors often work with students to review patient cases in an organized way. Experts developed the Pharmacists’ Patient Care Process (PPCP) in 2014 to provide a template that is consistent and concise, but also comprehensive. Using this process, students and licensed pharmacists develop SOAP notes to document the subjective and objective data they need to complete an assessment, and ultimately make a plan. PPCP stresses an important point: follow-up is critical and a well-written SOAP note can be extremely helpful in the follow-up process. This continuing education activity uses a case study to demonstrate how the PPCP process should work and emphasize areas where preceptors can provide tangential learning. It includes PRO TIPS for preceptors when they supervise students who are attempting to complete PPCP. It highlights the most common errors and suggest ways that preceptors can work with students to improve their experiential education.

INTRODUCTION: A PATIENT CASE

JM, an 8-year-old white male presents to your clinic. It’s a pediatric care clinic located in an area where many financially challenged families live. After talking with his parents, you learn he was recently diagnosed with central precocious puberty (CPP). His endocrinologist recommends initiating therapy and would like to know what treatment you recommend. His parents also have questions.

Your spry pharmacy student jumps at the opportunity to write a SOAP note using the “PPCP.” To you, PPCP sounds like an illegal drug that was abused in the 1980s. She explains that the Pharmacists’ Patient Care Process (PPCP) is a standardized model for collaborative medication management. She clarifies what it entails and how to apply the process in a clinical setting.

PPCP’s Importance

Schools of pharmacy have taught the PPCP for the past few years. Preceptors who are unfamiliar with the process may find it helpful to review the PPCP as many students will take this approach when addressing clinical problems in the workplace.

PPCP: THE DETAILS

Teamwork in healthcare has achieved major goals for many patients (although we have room for improvement): accessible, affordable, and high-quality care. In addition to the many healthcare team members, pharmacists are critical contributors to care plans. Medication expertise equips pharmacists with the knowledge to reduce drug adverse events, prevent medication errors, and provide invaluable input for decision-making.¹

In 2014, the Joint Commission of Pharmacy Practitioners (JCPP) developed a standardized process for medication management that could be used across interdisciplinary teams and dubbed it PPCP. JCPP’s members developed the approach using principles of evidence-based practice. The five steps—collect, assess, plan, implement, and follow-up—are tied together with careful communication and documentation.²Pharmacists can remember the steps as the pneumonic “CAP-IF.”

SOAP Notes

The subjective, objective, assessment, and plan (SOAP) note provides a method of documentation for the collect, assess, and plan steps of the PPCP. SOAP notes are probably familiar to most preceptors, as clinicians have used them for roughly 50 years.³ Table 1 highlights the key components of SOAP notes.

Table 1. Components of a SOAP Note¹

Objective Information	Subjective Information
· Current medication list (prescription and nonprescription) · Medical history · Physical assessments (i.e., blood pressure, heart rate, weight, height, respiratory rate, etc.) · Laboratory results	· Chief complaint · Symptoms · Patient lifestyle habits, preferences, and beliefs · Patient goals for care · Socioeconomic factors
Assessment
· Problem: statement highlighting the chief complaint or main medication-related problem · Rationale: the reasoning for the intervention cited from guidelines and supporting evidence from the collected information · Goals of care: possible barriers to adherence, socioeconomic considerations, and desired outcome of intervention
Plan
· Specific recommendation or intervention based on practice guidelines (i.e., initiation of drug therapy, referral to another provider, or non-pharmacologic lifestyle modifications) · Plan for upcoming sessions, specific monitoring parameters, and progress indicators

Collect

Thorough collection of the right information supplies pharmacists with tools to make safe, effective decisions. A combination of objective and subjective information paints a more complete picture of a patient’s clinical status. If possible, pharmacists should obtain and verify their information across multiple sources. Past medical records, active medication lists, and laboratory results are great places to start.

When soliciting subjective information, pharmacists should use open-ended questions. Prompting patients with questions formatted to avoid “yes” or “no” answers allow providers to obtain more information in less time, prioritize chief complaints better, and minimize implicit assumptions.⁴

Back to the Case

Your head is spinning trying to sort all the “P’s” in PPCP, CPP, and JCPP, but your student assures you that she will start with collecting relevant clinical information. First, you and your student perform a physical assessment of JM including taking his height and weight. JM takes no medication except an occasional antihistamine, but if he took other chronic medications, this would be the time to direct your student to perform a medication reconciliation. Next, you prompt JM’s parents with open ended questions, and they recall JM’s past medical history. You should ask your student if JM needs to be involved in the discussion (see SIDEBAR). After meeting with JM and his parents, here is the relevant information your student jots down:

Subjective information

At age 5, JM frequently soaked through his underarm clothing with pungent perspiration, so since then, he uses a strong deodorant
He is starting to develop pubic and underarm hair
He has some acne on his face and upper back
JM occasionally tells his parents he feels “different” than his classmates because he is so much bigger and taller
He has no past surgeries or hospitalizations
Takes OTC multivitamins daily and loratadine for allergies in the spring

Objective Information

Height = 4’8” inches
Weight = 102 pounds
DHEA Sulfate = Tanner stage III - 60 ug/dL (N = < 28 ug/dL)
Clinical exam findings = testicle size indicates puberty
X-ray bone age hand and wrist = greater than 2 standard deviations, 156 months (expected = 108.9 months)
Luteinizing hormone (LH) = 0.4 units/L (N = < 0.3 units/L)

SIDEBAR: Pediatric Involvement in Healthcare Decisions^5,6

In pediatric cases, clinicians may choose to consult only parents when making decisions regarding their child’s medical care. However, this practice, which is rooted in legal precedence, should shift to involve affected children to some extent. The American Academy of Pediatrics advocates that adolescents actively participate in decisions based on their ability and maturity.⁵ While research is lacking on how exactly to assess a child’s aptitude to participate in decision making, some studies show that children can participate as young as age 5.⁶Regardless, it doesn’t hurt to ask children if they have questions or concerns. In the case, JM is 8 and has voiced his concern previously about his height and size. Therefore, including him in the conversation is a possibility if his parents agree.

Preceptors can and should provide tangential learning when working with special populations. Reminding students that adolescents, older adults, people who have cognitive decline or dementia, and people for whom English is a second language will need careful counseling. Pharmacists and pharmacy staff will also need to select their words carefully and accommodate these patients’ needs. Assigning students to do some research on the various needs in these populations is an excellent way to help them develop skills and a professional identity.

Upon looking at your student’s notes so far, you assure her she has done well. However, you still have some questions. You remind her that sometimes information like height and weight requires additional evaluation and ask her to calculate JM’s BMI; she finds that it’s 22.9. You ask your student, “How does JM’s height and weight compare to the expected height and weight of boys his age?” To which she replies, “Pediatric growth charts will give us a better idea!” After consulting the growth charts, she determined and documented that JM falls within the 112th percentile for both measurements.

To make learning comprehensive, you could ask the student if the only kind of precocious puberty is central in nature. This will help your student learn to differentiate among different forms of similar diagnoses.

Assessment

An assessment of comprehensive patient information helps prioritize the problems that require attention. Pharmacists should consider all information when identifying the problem, the rationale, and the goals of therapy. Some example questions pharmacists can consider include¹

Medication appropriateness

What is the indication for each medication?
What is the correct dosing?
What are the common adverse effects?
What are the possible drug interactions?

Factors that impact access to care

What cultural factors create barriers to care?
What socioeconomic factors impact the patient?
What is the patient’s level of healthcare literacy?
What goals does the patient or his parents have?
What barriers impact patient adherence?

Additional services

What preventive care measures does the patient qualify for?
Which immunizations has the patient received?
What other concerns does the patient have?

THE CASE RESUMED...

After compiling the objective and subjective information on JM, the student finds guidelines in the Journal of Clinical Endocrinology for the management of CPP.⁷ Due to JM’s symptoms and lab values showing consistencies with CPP, the guidelines recommend initiating a gonadotropin releasing hormone (GnRH) analog. Depending on JM’s and his parents' preferences, the endocrinologist can choose either an injectable (leuprolide) or long-acting implantable device (histrelin) provided the insurance covers it or the cost is manageable.

Once again, you should have some questions for your student. For example, asking the student to list the search terms and search engines she employed can shed light on her process. Another question might be, “Are these the only guidelines available?” You can show her that you used PubMed, as she did, but when you used Google Scholar, you found an excellent review article that lists five other publications. You suggest she look at them since expert recommendations can vary. She might also contact the endocrinologist and ask if he plans to follow the guidelines she identified, and if not, why not.

The endocrinologist messages back saying he agrees leuprolide and histrelin are both reasonable options to consider for first-line therapy. However, he also cites a 2019 update published on Hormone Research in Paediatrics. These guidelines recommend a third U.S. Food and Drug Administration (FDA)-approved option for the treatment of CPP, triptorelin.⁸ He says the student should consider this choice as a potential treatment for JM as well.

After reading the endocrinologist’s note, you emphasize to your student the importance of citing multiple guidelines when drafting an assessment. In this case, the FDA approved an additional treatment, triptorelin, in 2022. You walk through your student’s process of finding clinical information to identify more ways she can improve next time. Furthermore, you point out how the endocrinologist’s insight exemplifies the importance of interdisciplinary care.

Simultaneously, you and your student read through all three monographs and discuss the major differences you’d like to share with his parents. You ask the student to practice her delivery of the information, and she says, “Leuprolide is a long acting injectable administered intramuscularly (IM) or subcutaneously. Your doctor will administer the IM formulation every month, three months, or six months. “Triptorelin is similar to leuprolide, but is only available as a six month IM formulation. The other option is for your doctor to administer the subcutaneous formulation every six-months.⁹ On the other hand, histrelin comes as a long-acting 1¼ inch implant surgically placed into the upper arm every 12 to 24 months. For the first 24 hours after the surgery, JM should avoid swimming or bathing. As long as JM avoids heavy play or exercise for the first week, he will not have to worry about any further restrictions after that. The implant also requires surgical removal.”¹⁰

Now, you prompt the student to recall that JM’s parents expressed concern about what would happen if JM experienced an adverse reaction to the long-acting implantable device. They asked, “What is the procedure like?” and “If JM has a reaction to the implant, must he continue to wear it for 12 months or can the doctor remove it easily before then?”

The student does more research and says she will assure JM’s parents that this outpatient procedure lasts only 10 minutes, though the appointment may last 60 to 90 minutes. Most surgeons will just numb the area; however, children may undergo sedation if necessary. The surgeon will insert the narrow implant into a small approximately 5 mm opening made in the skin on the inner surface of the arm. With this option, JM can return to school the same day. The student plans to mention that complications don’t commonly occur, but minor discomfort and bruising may.¹¹The student plans to continue, “The implant may be removed immediately if JM presents at any time a severe allergic reaction or adverse effect. However, this is not common.”

Before you and the student document the assessment section of your SOAP note, the student indicates she will ask JM if he has questions. He shares that he “HATES needles” but is also scared of the surgery hurting.” The student plans to tell him not to worry because he won’t feel any pain during the operation. He can also choose to sleep during the surgery if he prefers.

Here, the preceptor should step in with gentle corrections about patient-appropriate language. First, most Americans have no idea what a 5 mm incision will look like. You ask her to calculate its length in inches and explain it by comparing it to something the child will recognize, like the size of small dice or a stack of 20 playing cards. Next, it’s critical to remind the student that we must never tell patients that something won’t hurt. This is a lesson students should learn during immunization training and creates an opportunity for cross training (applying this principle to other areas of pharmacy) that applies regardless of patient age. Healthcare professionals should never say, “This will not hurt a bit!” or anything similar. People have different pain thresholds making it impossible to predict whether it will hurt. Student pharmacists need to develop language they are comfortable with and use it. A good response if people ask if it will hurt is, “It may hurt or sting a little but just for a minute or two.” In this case, the preceptor suggests saying, “The doctor will numb the area.”

Finally, the preceptor may point out that “operation” can be a scary word for children. The student needs to use a word like “procedure” or find a way to avoid either of those words.

The preceptor should also point out that JM’s parents had also said they were worried about two things: (1) potential side effects and (2) the cost of care. They heard on the news that expenses associated with these medications can add up quickly. The cost of care and determining what the patient’s insurance will cover is probably foremost in the endocrinologist’s mind, too.

In terms of potential side effects, your student says that both GnRH analogs have similar side effect profiles. From the pediatric studies she read on GnRH adverse effects, she shares that signs of puberty may increase transiently with therapy before growth velocity eventually slows down. Some children experience weight gain, changes in appetite, body aches, headaches, gastrointestinal (GI) symptoms, or signs of a common cold. Parameters like physical growth and bone mass density may decrease during treatment but usually return to normal one year after treatment discontinuation.^{9, 10}

Before selecting JM’s treatment option, it’s critical to evaluate insurance coverage since it’s on the forefront of everyone’s concerns. The student needs to determine if they have insurance and what the plan covers. She starts by finding information on ballpark cost. She reports a histrelin implant costs around $40,000. If the patient requires mild sedation when the doctor inserts the implant, the cost may increase. However, in some cases, the implant may be used for up to two years. Leuprolide’s median annual cost ranges from $20,000-$40,000 depending on the formulation.¹² A single injection of triptorelin costs roughly $19,000, making the annual cost nearly $40,000 as well. Then says she will remind JM’s parents that while this may give them an idea, the cost may vary outside of that range.

Plan

Following the assessment, pharmacists work to develop a personalized patient care plan in collaboration with other healthcare professionals. The plan should reflect recommendations from the most recent evidence-based clinical practice guidelines. Pharmacists should focus on optimization of care in a safe, effective, and cost-effective manner.

Address medication-related problems and optimize medication therapy
Set specific, measurable, achievable, realistic, and timed (SMART) goals in the context of the patient’s healthcare goals and access to care
Involve patients to engage in education, empowerment, and self-management
Support non-pharmacologic interventions as appropriate

SMART Goals. When creating an action plan for patients, pharmacists should aim to set goals that are SMART.

Specific instructions provide other clinicians with accurate information about the patient.
Measurable outcomes provide clinicians the ability to evaluate the patient’s progress and whether the plan requires adjustments
Achievable and realistic goals
A timeline for the plan ensures healthcare providers routinely follow up with their patient

A PLAN FOR JM

After you document JM’s main problem, rationale, and goals for care in the assessment section, you move on to create his plan. Following careful consideration of the assessment, you and your student decide to recommend starting histrelin to treat his CPP since his insurance will cover it once the endocrinologist completes prior authorization forms. (Here, you suggest that the student find the prior authorization forms and volunteer to complete as many sections as she can for the endocrinologist. You explain that she can expedite the process and this is a skill she can apply to many different pharmacy practice locations.) Choosing histrelin is also a needle-free option, which may make JM happy. You remind your student that the plan should also include scheduling necessary appointments and follow-ups with JM’s other providers in addition to counseling on the specific adverse effects of the medication detailed in Table 2.

Table 2. Example SOAP note for JM⁷

Name: JM Age: 8 DOB: 10/02/14 Allergies: Seasonal allergies, NKDA
Chief Complaint: Patient referred to clinic by endocrinologist for medication therapy; patient was recently diagnosed with central precocious puberty (CPP)
Subjective Information JM is an 8-year old white male presenting to the clinic. He recently met with his endocrinologist on 6/28/23 and has been referred to the clinic for drug therapy to treat CPP. His parents confirm JM’s use of deodorant to combat excessive perspiration and body odor since the age of 5. He has also developed pubic and underarm hair in addition to acne on his face and upper back. His parents are concerned regarding JM’s reported insecurities at school due to his larger size.
PMH: no surgeries or hospitalizations			Medications: daily multivitamin, OTC loratadine (prn for allergies)
Objective Information Clinical exam findings = testicle size indicates puberty 112^th percentile for weight and height Relevant Labs: Bone age of 13, LH 0.4 units/L, DHEA sulfate 60 ug/dL
Height: 55 in	Weight: 102 lbs	BMI: 22.9	BP: 110/61 mmHg	HR: 75 bpm	Temp: 98.6 ℉	RR: 15
Assessment Problem: Patient requires medication therapy for untreated indication. Rationale: According to the Journal of Clinical Endocrinology Practice Guidelines for Central Precocious Puberty, JM requires hormone suppression therapy. Symptoms of rapid linear growth, advanced skeletal maturation, and basal LH levels > 0.3 units/L require treatment with GnRH analogs until the normal age of puberty. Goals of Care: The goal of treatment is to reduce signs of premature pubertal progression while ensuring therapy is well tolerated and medication side effects are minimized. Patient’s parents would like to choose an option that is cost effective and safe.
Plan Initiate histrelin 50mg SQ implant to be administered by JM’s surgeon every 12-24 months depending on safety and efficacy parameters evaluated at follow up appointments Schedule surgery appointment with JM’s surgeon at earliest convenience Schedule follow up in 3 months to evaluate pubertal progression, growth velocity, skeletal maturation, and tolerability Counsel JM/JM’s parents on possible adverse effects including weight gain, changes in appetite, initial flare of puberty symptoms, GI symptoms, body aches/pains, and signs of common cold Counsel JM’s parents on providing support to make JM feel good about himself. Children who are undergoing rapid development at this age may feel different when comparing themselves to other children their age.

Implement

During the implementation phase, pharmacists set the action plan into motion. This may include the administration of vaccines, initiating or discontinuing a medication, or scheduling the next follow-up appointment. Pharmacists, primary care physicians, or caregivers work together to provide care based on the goals made in the planning step.¹

Follow-up and Monitor

The pharmacist in collaboration with other health care providers should follow-up with the patient as recommended in practice guidelines and referring back to the SOAP note. Continuous monitoring of medication appropriateness, adherence, safety, laboratory results, and patient concerns will indicate if the plan requires revision. Routine medication reconciliations, check-ups, or conversations with patients improve outcomes and help to achieve goals of therapy.

Putting it All Together

Upon completion of the SOAP note, you send the endocrinologist your recommendations. You contact JM’s parents to discuss scheduling a follow-up appointment in three months with the endocrinologist and counsel on histrelin.

IMPLICATIONS FOR PRECEPTORS

The Benefits. The PPCP model creates a reproducible framework that demonstrates clinical pharmacists’ contributions to medication-related outcomes.¹³ In addition to improving the quality and completeness of patient medical records, SOAP notes give pharmacists a place to start when working up a new patient. As students practice developing SOAP notes, preceptors should emphasize how the lessons they learn in one case can apply to future cases.

The Drawbacks. As more pharmacy programs integrate PPCP into their curriculum, new students will have access to courses that teach the model. But because the PPCP model is relatively new, many licensed pharmacists have not yet familiarized themselves with the process. Extracting the necessary information to write quality SOAP notes can also be time consuming. Depending on the setting, pharmacists may not have enough time to walk through every step with students. Finally, the PPCP method does not encompass all clinical situations. The framework relies on pharmacists to exercise clinical judgment and reasoning to modify the model as needed.

Uncomfortable Topics. Students often have little exposure to difficult topics. These may include end-of-life issues, psychiatric diagnoses, cultural or ethnic differences, drug abuse/misuse, and gender-related topics. In this case, students may feel strong discomfort in discussing matters related to sex and sexual development. Preceptors need to help students reduce their hesitancy when communicating with you and the patient because improper communication can lead to poor collection of relevant information. Keep in mind strong note-writing skills facilitate good care. Two things help: (1) practice, and (2) finding resources designed to help with difficult topics. The Conversation Project (https://theconversationproject.org/resources/healthcare/) is one such resource that can help students become more comfortable with difficult topics.

In addition, students may have implicit and explicit biases for uncomfortable topics such as the use of hormone blockers, which may bring to mind their use in transgender children. Creating a safe place for your student to share opinions provides a great opportunity for you to teach students how to avoid these biases. Preceptors need to remember that learning—especially if it changes a student's perspective or points out a student's mistake—can be threatening, and students can feel vulnerable while learning. It’s an emotional experience.⁶

To help guide students through these experiences, the SIDEBAR provides 10 additional tips preceptors can use when supervising the PPCP.

SIDEBAR: PRO TIPS for Preceptors Who Supervise the PPCP

(1) Don't let the acronym scare you! This is a new name for a process you've probably used knowingly or unknowingly for years.

(2) Encourage independence. Hand over the problem to the student once you've described the problem and fielded the student's questions. Establish a time for the student to be prepared to discuss it but check in periodically to see if the student is having trouble.

(3) Rescue when necessary. Some students will need more support than others. If a student is clearly flummoxed, spend more time and provide more direction.

(4) Promote interdisciplinary communication. Having students discuss a clinical problem with another clinician, either with you or on their own, fosters interdisciplinary care. Students will also learn from the other clinicians, which will lighten your load!

(5) When students present findings, always ask them to describe things like the search terms and search engines they used or the obstacles they encountered. Help them refine their processes to reduce barriers or find more appropriate resources.

(6) Consistently prompt students to determine if the case is typical or unusual. Asking questions based on a modification of the case can help students learn more globally.

(7) Don't "stay in your lane"! In this CE, the practice site is an ambulatory care location specific to pediatrics. The lessons a student learns in this rotation, if they go beyond pediatrics, will be invaluable. Helping students develop communication skills or analyze how disease states present or are treated in adults or other special populations will increase their clinical acumen in future rotations.

(8) Address implicit biases or misconceptions. Students may not know that an attitude or opinion is biased, incorrect, or simply rude.

(9) Debrief. After the PPCP is done, provide feedback, ask others who may have been involved to provide feedback, and ask the student to perform a self-assessment.

(10) Appreciate reverse mentoring. Remember that students often teach us new things!

Common Sources of Error

Collecting too little information. Not all the information pharmacists need to collect will be obvious. In the patient case, the student collected important objective information like height and weight. However, without something like growth charts to evaluate JM’s height/weight compared to other kids his age, the information does not help in the assessment. Preceptors can aid students who are new to documenting SOAP notes when they are required to dive deeper into collected information. Students should not make assumptions as to what other clinicians know off the top of their heads. In this case, other areas where the preceptor helped the student included directing her to seek other expert opinions like the endocrinologist. That puts the “inter” in “interdisciplinary” care!

Collecting too much information. Pharmacists and students should collect information worthy of appraisal. In other words, only collect the necessary information that will contribute to the identification, prevention, and resolution of either the chief complaint or medication-related problems. If pharmacists/students do not actively use collected information to make the assessment or plan, they should omit it in the note. Documenting more information does not equate to better information. This leads to overly lengthy or confusing SOAP notes. Here, as in the previous error, preceptors should ask students to examine and explain their processes.

Not verifying information. All information should be verified across multiple sources like when performing traditional medication reconciliations. This prevents possible errors in note-taking that may arise from outdated documentation.

Sourcing one guideline. Depending on the disease state, the frequency in which guidelines are updated can vary. Preceptors should emphasize the importance of looking for multiple guidelines and paying attention to their publication dates. Occasionally, the FDA may approve new treatment options after the release of clinical guidelines or updates. In this case, the student completely missed an additional treatment option as a result of sourcing a single guideline from 2013. Similar to how preceptors should encourage students to verify collected information across multiple sources, preceptors should also encourage students to cross-check sources that aid in their assessment.

The assessment lacks evidence. As mentioned above, the assessment should communicate the assessor’s thought process. The information collected by the pharmacist/student should justify why the problem is a problem. If there is no subjective or objective information to back up the assessment, the assessment has no basis.

Forgetting recommendations on current medications. Pharmacists/students should not forget to include instructions for the patient’s current medications, not just the newly prescribed medications.

Forgetting non-pharmacologic recommendations. The plan section also encompasses non-pharmacologic interventions such as referral to another provider, ordering additional laboratory tests, education, or counseling on lifestyle interventions. Pharmacists/students should remember that not all patients require initiation of a new medication.

Being vague. When initiating new therapy appropriately, pharmacists/students should always provide specific recommendations with the drug name, dose, and frequency. Vague instructions such as “Initiate hormone blocker therapy” are unhelpful. Similarly, instead of “monitor for side effects,” pharmacists/students can list the specific symptoms that present most commonly.

Poor communication. Errors due to poor communication directly hinder the PPCP. Furthermore, clinicians with experience are not necessarily better communicators. Therefore, pharmacists should engage in education/training to constantly improve communication skills. SOAP notes should effectively communicate the pertinent information used to create a plan and document important details for the patient’s medical record.

Setting it and forgetting it. The PPCP is not a linear process. While this framework provides clinicians a place to start and a checklist of sections to complete in order, pharmacists should remember to review and revise all sections at any given time. For example, pharmacists may identify new information they should go back to collect as they work on their assessments. Preceptors should encourage their students to occasionally step back and evaluate the completeness and coherence of the SOAP note. Sometimes patient cases will require students to revise sections of the SOAP note they already completed.

And a New Case

Just before the end of the month, the endocrinologist sends yet another patient with precocious puberty to you. The patient LD is a 9-year old Hispanic female. Her endocrinologist recently diagnosed her with idiopathic precocious puberty and wants to know which treatment you recommend. Her parents also want to know why this is happening to their daughter. Before taking LD’s family from the clinic waiting room, you decide to let your student take charge of this case while you supervise. You ask your student “Now that you have practiced writing SOAP notes and know a little about this disease state, how will you approach the PPCP this time?”

The student says to you...

“I stored all my notes from the last case on precocious puberty from earlier this month. I have a document containing the guidelines from the Journal of Clinical Endocrinology along with several updated publications that cite all additional first-line medications approved after the original guideline’s release. I will start with the collection of subjective information such as LD’s symptoms and medical history followed by objective information, specifically pertaining to her growth statistics. I should calculate BMI and her height/weight percentiles since precocious puberty is usually associated with accelerated growth. Next, I will examine her relevant lab values. Since the patient is female, I will be looking out for progesterone levels this time. If possible, I shall cross-reference all of the information I collect across multiple sources.”

“Before I move onto making an assessment, I understand LD’s parents may feel very concerned about their daughter's condition. I don’t want to forget to address their question. I will explain that idiopathic precocious puberty does not have a definitive cause. To help them better understand, I’ll mention that idiopathic cases may result from anything ranging from a head injury in childhood to exposure to certain chemicals. Regardless of the cause, I will assure them there are several treatment options that may be appropriate for LD at this time. I can walk them through the pros and cons of all the available options.”

“Next, I would prompt LD’s parents with open-ended questions to learn more about their major concerns, potential barriers to medication therapy, and insurance eligibility. I know these are important considerations for my assessment. It would also be appropriate for me to engage with LD using appropriate language for a 9-year-old girl. I realize the topic may be uncomfortable to discuss, but without taking initiative of the discussion I may forget to include pertinent details in my SOAP note.”

“Finally, using the information I collected about the family’s preferences and LD’s medical history, I will draft the chief complaint, rationale for treatment, goals of therapy, and eventually a completed plan. The plan will include which treatment I recommend along with the dose, frequency, and which adverse effects are most common. I will write when I recommend a follow-up with her endocrinologist and make note of which lifestyle modifications may support her specific treatment. If the endocrinologist is on board, then we can collaboratively implement and follow-up with the patient as appropriate.”

You are overjoyed to hear that your student has taken what she learned from the previous case and applied it to this case as well. Although some of the parameters were different, such as the patient’s sex, she was able to anticipate how the changes may impact her SOAP note this time. While you identify a few areas in which she can improve, you are happy that she is continuing to expand her clinical pharmacy knowledge.

Conclusion

The PPCP model can be applied to any healthcare setting in which pharmacists practice. This comprehensive approach to patient-centered care has established a streamlined method of documenting patient information to be shared among healthcare teams. As the PPCP continues to grow in clinical settings, practicing pharmacists should become familiar with its methods and applications.

Prepping Pharmacist Preceptors on the Pharmacists’ Patient Care Process (PPCP)
Post-test
Learning Objectives
After completing this continuing education activity, preceptor-pharmacist will be able to
• Describe the PPCP model and its uses
• Apply the PPCP when students address clinical problems in the workplace
• Identify areas where pharmacy students need the most guidance when using the PPCP
POST TEST
1. Which of the following correctly lists the steps of the PPCP process in order?
A. Collect, plan, assess, follow-up, implement
B. Collect, assess, plan, implement, follow-up
C. Plan, collect, assess, follow-up, implement
2. Which of the following best describes the JCPP’s reason for developing the PPCP?
A. To establish a more efficient method of medical documentation
B. To provide an opportunity for pharmacists to expand their clinical role
C. To create a reproducible method of managing patient medications

3. Which of the following examples is a common error pharmacy students make when using the PPCP?
A. Avoiding discussion involving uncomfortable topics such as those sexual in nature
B. Spending too long counseling the patient as opposed to documenting the SOAP note
C. Omitting recommendations to follow up with the patient’s primary care provider
4. Which of the following is a common source of error with the PPCP?
A. Using a single clinical guideline for recommendations
B. Spending the most time documenting the assessment section
C. Cross-referencing medication lists against too many sources
5. A nurse practitioner calls your clinic and would like you and your student to work up a patient with stage II hypertension. The patient is a 64-year-old African American male who is currently taking amlodipine 2.5 mg and chlorthalidone 6.25 mg. His blood pressure was 150/90 mmHg at his last doctors appointment. Which of the following would be an appropriate first step?
A. Increase the dose of his medications. The SOAP note does not need to be performed as his blood pressure remains elevated due to subtherapeutic dosing.
B. Ask the patient about his/her medication adherence recently. This information will dictate how you decide to approach the patient.
C. Contact the patient’s local pharmacy for a complete list of active medications. This will be valuable information to collect prior to assessing the patient.
6. A student working on a SOAP note cites a 2012 guideline from Europe. The preceptor notices the student forgets to consider a first-line treatment option that was approved in 2022. What should the preceptor do at this point?
A. Call the physician to get his/her opinion on the newly approved medication
B. Discuss the importance of citing multiple sources with the student
C. When the student finishes the note, add in the missing information
7. Laboratory values belong under which of the following sections of the PPCP?
A. Assessment
B. Objective information
C. Subjective information
8. Your student is counseling a patient who has dementia. When you ask him to practice how he would counsel the patient, he looks puzzled and asks “What for? He has dementia and he won’t understand anyway.” How do you proceed?
A. Ask the student to find guidelines on how to determine when and how dementia patients should be counseled.
B. Tell him it was a trick question and that he is correct that dementia patients should never be counseled.
C. Explain pharmacists are legally required to offer counseling and he should be prepared if the patient requests it.
9. A preceptor and student are working in an ambulatory care clinic. A patient presents to the counter and says she has been experiencing terrible adverse effects from one of her medications. The patient places a bottle of sertraline on the counter. She believes this is the medication causing her persistent insomnia. After talking with the doctor, she has switched to taking it in the morning, but she claims it does not help. How should the preceptor advise the student to continue?
A. Advise the student to counsel the patient on ways to manage this adverse effect of sertraline. The student may consult the monograph or other recent guidelines.
B. Remind the student that persistent insomnia is a flag to contact the provider. The psychiatrist can handle this as it isn’t in the scope of the preceptor’s practice.
C. Advise the student to start by evaluating the patient’s past medical history and evaluating her medications before sending her back to see her doctor.
10. A general practitioner refers a patient with mild asthma to your clinic. He has recommended the patient to start SMART therapy and would like you to supply your recommendations through a SOAP note. Under your supervision, the student finishes collecting the necessary objective and subjective information and has begun a draft of the assessment as follows:
“The patient needs medication therapy for an untreated indication. According to the GINA guidelines, the patient should initiate a low dose inhaled corticosteroid plus a long-acting beta agonist combination in low doses as needed.”
Which of the following best describes the feedback the preceptor should give the student when applying the PPCP model?
A. The student has done a good job so far. However, the assessment should also consider patient concerns such as insurance coverage.
B. The student has done a good job so far. The student should provide specific doses and monitoring parameters for completeness.
C. The student has done a good job so far. The student should call the provider to check if they follow the GINA guidelines, and if not, why.

References

REFERENCES
1. Joint Commission of Pharmacy Practitioners. Pharmacists’ Patient Care Process. Published May 29, 2014. Accessed June 21, 2023. https://jcpp.net/patient-care-process/
2. Cooley J, Lee J. Implementing the Pharmacists' Patient Care Process at a Public Pharmacy School. Am J Pharm Educ. 2018;82(2):6301. doi:10.5688/ajpe6301
3. Podder V, Lew V, Ghassemzadeh S. SOAP Notes. [Updated 2022 Aug 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 January. https://www.ncbi.nlm.nih.gov/books/NBK482263/
4. Takemura Y, Sakurai Y, Yokoya S, et al. Open-ended questions: are they really beneficial for gathering medical information from patients?. Tohoku J Exp Med. 2005;206(2):151-154. doi:10.1620/tjem.206.151
5. Taub S. Learning to Decide: Involving Children in their Health Care Decisions. Virtual Mentor. 2003;5(8): virtualmentor.2003.5.8. pfor3-0308. Published 2003 Aug 1. doi: 10.1001/virtualmentor.2003.5.8.pfor3-0308
6. Elnicki DM. Learning with emotion: which emotions and learning what?. Acad Med. 2010;85(7):1111. doi:10.1097/ACM.0b013e3181e20205
7. Fuqua JS. Treatment and outcomes of precocious puberty: an update. J Clin Endocrinol Metab. 2013;98(6):2198-2207. doi:10.1210/jc.2013-1024
8. Bangalore Krishna K, Fuqua JS, Rogol AD, et al. Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium. Horm Res Paediatr. 2019;91(6):357-372. doi:10.1159/000501336
9. Lexicomp. Wolters Kluwer Health, Inc. Updated June 20, 2023. Accessed June 21, 2023. https://online-lexi-com.ezproxy.lib.uconn.edu/lco/action/doc/retrieve/docid/pdh_f/129683?cesid=afdPrd0aazi&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dleuprolide%26t%3Dname%26acs%3Dfalse%26acq%3Dleuprolide#rfs
10. Lexicomp. Wolters Kluwer Health, Inc. Updated June 6, 2023. Accessed June 21, 2023. https://online-lexi-com.ezproxy.lib.uconn.edu/lco/action/doc/retrieve/docid/pdh_f/128793?cesid=4Ds6TlNfgKm&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dhistrelin%26t%3Dname%26acs%3Dfalse%26acq%3Dhistrelin
11. Supprelin LA (Histrelin) Subcutaneous Implant Procedure. Children’s Hospital of Philidelphia. Published May 4, 2021. Accessed June 21, 2023. https://www.chop.edu/treatments/supprelin-la-histrelin-subcutaneous-implant-procedure
12. Kaplowitz P, Hoffman, R. Precocious Puberty Medication. Medscape. Updated January 24, 2022. Accessed June 21, 2023. https://emedicine.medscape.com/article/924002-medication
13. Harris IM, Phillips B, Boyce E, et al. Clinical pharmacy should adopt a consistent process of direct patient care. Pharmacotherapy. 2014;34(8):e133-e148. doi:10.1002/phar.1459
14. Silverman LA, Han X, Huang H, Near AM, Hu Y. Clinical characteristics and treatment patterns with histrelin acetate subcutaneous implants vs. leuprolide injections in children with precocious puberty: a real-world study using a US claims database. J Pediatr Endocrinol Metab. 2021;34(8):961-969. Published 2021 Jun 21. doi:10.1515/jpem-2020-0721

Patient Safety: Fad Diets: Do They Deserve the Hype?

After completing this application-based continuing education activity, pharmacists will be able to

1. Describe the prevalence of fad diets in society

2. Outline the components of different types of fad diets

3. Explain the effect different fad diets can have on the body

4. Recognize situations in which fad diets present safety concerns for patients

After completing this application-based continuing education activity, pharmacy technicians will be able to

1. Describe the prevalence of fad diets in society

2. Outline the components of different types of fad diets

3. Explain the effect different fad diets can have on the body

4. Recognize situations in which fad diets present safety concerns for patients

In the United States, being overweight or having obesity are two leading causes of health issues, and these rates have increased in recent years. Enter the concept of fad diets. People often turn to diets or tools advertised as promoting quick weight loss without considering the diet’s sustainability and their bodies’ reaction. Fad diets’ one-size-fits-all approach is usually not the cure-all solution people hope it will be. Overall healthy nutrition and lifestyle choices are more beneficial. Due to fad diets’ popularity, it is essential to understand their components and their affect within the body to reduce health risks. This continuing education activity discusses intermittent fasting, ketogenic (“keto”) diets, pay-for-food systems, paleolithic (“paleo”) diets, and the Atkins diet. It identifies patients for whom fad dieting can be dangerous.

INTRODUCTION

Fad diets have always existed but have been on the rise in recent years due to the explosion of social media in the 21^st Century. A fad diet is a popular diet followed to achieve fast results or fix long-term problems associated with eating, specifically weight.¹ Fad diets are labeled as fads for a reason. These short-lived trends with wide popularity disregard for the rationale behind or quality of the approach itself.^3,4

People who choose fad diets are often trying to fix ongoing problems including overweight or obesity, inadequate nutrition, sedentary behaviors, and failure to maintain overall healthy habits.² Individuals who follow fad diets adhere to a mainstream concept of dieting without acknowledging individual health needs and restrictions. Health consequences may arise as a result of adhering to a diet ill-suited to an individual's nutritional needs and ability to sustain the associated effort. In addition, certain diets may influence medication interactions and disease outcomes. For this reason, fad diets can undermine patient safety.

This continuing education activity summarizes popular fad diets to inform pharmacy teams of their benefits and risks. It will allow teams to make recommendations for patients, understand how medications interact with the diets, and help prevent health complications.

The History of Fad Diets

Fad diets have existed throughout history in different forms. For example, in the 1920s, the Cigarette Diet was popular. Lucky Strike, a cigarette company, promoted the cigarette diet. They claimed that cigarettes would suppress appetite to boost sales using the tagline “Reach for a Lucky instead of a sweet.” Promoters advertised that people would lose weight successfully while following the diet.⁶ The 1940s saw the rise of the Master Cleanse. This juice cleanse consisted of a meal replacement drink consisting of hot water, lemon juice, maple syrup, and cayenne pepper. Its popularity stemmed from promises of cleansing the body of toxins while providing very few calories. It reached new levels of popularity in 2006, when superstar Beyoncé claimed to lose 20 pounds in two weeks using this method⁶ In the 1960s, The Drinking Man’s Diet made an appearance. The recommendation was to consume high-protein and low-carbohydrate foods while drinking as much alcohol as desired. An example meal may have included a large serving of steak, salad or vegetables, and several alcoholic beverages. The Drinking Man’s Diet’s supporters considered alcohol a good carbohydrate and allowed indulgence. This diet was marketed toward the male population.⁶

People have always been interested in quick fixes for weight loss and appearance without considering how they will feel or how to keep the weight off indefinitely.¹ This approach to choosing a diet or making nutrition decisions ignores tactics that sustain weight loss. Fad diets are inherently unsustainable options that often lead to weight regain. These outcomes prove many fad diets are unreliable (if not dangerous).

With the creation and explosion of modern social media in the early 2000s, fad diets surged in popularity. Social media often fosters a community of misinformation regarding fad diet composition, how to follow the specific diet, and the diet’s benefits.⁵ Much of the information on social media regarding fad diets lacks reputable, verifiable sources. Fad diet promoters use scientific jargon loosely and inappropriately to make information convincing when describing seemingly miraculous diets. However, the information could just be the opinion of an individual or a promotional company sponsorship.⁵ Unless diet information is published by a credible source, it should be regarded as untrustworthy.

Pause and Ponder: How many times a week do you see diet-related content on social media?

Fad Diet Prevalence

Approximately 45 million Americans (about 14% of the total population) go on a diet each year.⁷ Of these diets, 50% are fad diets.⁷ According to the United States (U.S.) Weight Loss & Diet Control Market, the weight loss industry is one of the most advertised with investors spending $66 billion annually.⁷ More people than ever are overweight or obese and using diets as a solution. Table 1 summarizes obesity’s prevalence, which is rising each year in the U.S.

Table 1. Obesity Prevalence in the U.S. Population⁸

Age (years)	% of Population
Adults aged 20 and up	41.9%
Adolescents aged 12-19	22.9%
Children aged 6-11	20.7%
Children aged 2-5	12.7%

According to the Centers for Disease Control and Prevention (CDC), individuals who are overweight or have obesity are at elevated risk for many health issues. These include elevated cholesterol, stroke, heart disease, hypertension, cancer, type 2 diabetes, mental illness, low quality of life, and mortality, among others.⁹ While many factors can influence weight, individuals can adapt their diets to meet nutritional needs and make long-term differences to improve health outcomes.

TYPES OF FAD DIETS

As the definition implies, fad diets’ popularity increases and decreases with current trends. This section discusses some of the most popular current fad diets.

Intermittent Fasting

Individuals following an intermittent fasting diet alternate eating and fasting (not eating or drinking anything) on a cyclic schedule. This diet focuses more on eating during specific periods of time than restricting meal components. Various intermittent fasting schedules exist, but popular versions include alternate-day and time-restricted fasting.^10,11 Alternate-day fasting means fasting every other day, while time-restricted fasting involves eating within set time windows during the day. Individuals should consult a doctor and choose the type of intermittent fasting that best fits their health needs (but most do not). Studies show following intermittent fasting schedules leads to decreased body weight, body mass index (BMI), and waist circumference.¹¹ Studies also show improved blood glucose and triglyceride levels following this diet.¹⁰

The body uses ingested calories—specifically carbohydrates, sugars, and nutrients—as fuel.¹⁰ If people eat continuously throughout the day, the body uses ingested calories as fuel to perform necessary bodily functions. The body stores unused ingested calories in the form of fat where they become an energy reserve.^10,12

When the period between meals lengthens and the body lacks a constant supply of calories for fuel, it turns to the fat reserve to burn fat stored in the body. The theory is that the longer a person goes without eating, the more the body will use its fuel reserve. The more reserve is used, the more fat is burned.¹⁰ As more of the reserve is used for energy while intermittent fasting, more weight is lost through fat burn.

Intermittent fasting regulates eating times without restricting foods or food groups. Dieters must make conscious choices to include foods beneficial to health. This includes fruits, vegetables, plant proteins or lean meats, whole grains, superfoods (see Sidebar: Superfoods), and low-fat dairy options.¹² Healthy choices also include limiting processed foods and sugars.

Sidebar: Superfoods¹³

Superfoods are nutrient-rich and high in important dietary components including antioxidants, vitamins, minerals, fiber, and healthy fats. These help keep the body functioning, reduce disease risk, and improve well-being. Some examples of superfoods are

Avocados → These include potassium and healthy fats to lower the risk of heart disease.
Chia seeds → These include fiber, protein, antioxidants, vitamins, and minerals. They are also easy to add to recipes.
Dark and leafy greens → All greens are good greens, but these are especially nutrient dense, including vitamins A, C, and E. They also contain vitamin K, which promotes bone health.
Ginger → This includes vitamin C, magnesium, and potassium. It also helps reduce pain and aid nausea.
Salmon → Fish is high in omega-3 fatty acids, which can help reduce heart disease.
Yogurt → This includes calcium and protein to help with bone health, cancer prevention, and immune health. It is also a good source of probiotics to support gut health.

Pause and Ponder: Do patients ask about superfoods when discussing dietary information or supplements? Do you know which to recommend?

Pros and Cons

Like most diets, intermittent fasting has benefits and drawbacks. Following intermittent fasting correctly boosts memory, improves blood pressure, induces fat loss while maintaining muscle mass, helps prevent obesity, improves type 2 diabetes by reducing insulin resistance, and improves tissue health.^12,14 Intermittent fasting also regulates the body’s 24-hour cycle to improve physiological functioning and metabolic health. As a result, gastrointestinal (GI) microbiomes, energy levels, and sleep may improve.¹⁵

Drawbacks of this diet include issues with long-term maintenance/adherence, leading to regaining weight.¹⁰ It is difficult and tiring for individuals to maintain fasting for extended periods. In addition, until the body is accustomed to fasting periods, symptoms such as headaches, nausea, or dizziness may occur. Some individuals may feel an initial decrease in energy levels when starting this diet.¹⁰

Keto Diet

The keto diet, also known as the ketogenic diet, is centered around depriving the body of carbohydrates.¹⁶ Researchers originally developed the ketogenic or keto diet in the 1920s as an epilepsy treatment, especially for resistant pediatric cases.¹⁷ The rise of effective antiepileptic drugs and treatments decreased use of the ketogenic diet for this purpose. As originally designed, total daily calories were composed of high fat intake (70% to 80%), moderate amounts of protein (10% to 20%), and low carbohydrate intake (5% to 10%).¹⁶ An iteration of this diet has gained more traction since the 1990s, as people realized its effectiveness for quick weight loss.¹⁶

The keto diet helps with weight loss through the processes of gluconeogenesis and ketogenesis. Under normal circumstances, carbohydrates produce energy for the body.¹⁶ When insufficient carbohydrates are available, insulin secretion is reduced and glucose is less available. The body then exploits gluconeogenesis, using lactic acid, glycerol, and amino acids to produce glucose as an energy source.¹⁶

If carbohydrate levels drop further, the body enters ketogenesis and secretes ketone bodies as an alternative energy source.¹⁶ As insulin secretion levels remain low and ketone bodies are used for energy, fat and glucose storage falls significantly. This can cause other fats to break down, leading to bodily fat loss.¹⁶

To remain in ketogenesis, the body needs constant carbohydrate deprivation.¹⁶ The longer it is deprived of carbohydrates, the more fat is burned in the ketotic state. This is known as nutritional ketosis and is considered safe, as opposed to the metabolic state of ketoacidosis (an accumulation of ketones that increases the blood’s acidity), which can be life-threatening.¹⁶

During ketoacidosis, ketone bodies are produced in large amounts and can acidify the blood pH.¹⁶ Acidic blood pH reduces the amount of oxygen blood delivers to cells leading to cell death and life-threatening complications. Insulin keeps the production of ketone bodies at bay, so sometimes people with type 1 diabetes develop ketoacidosis due to decreased insulin production. Taking diabetes-related medication correctly reduces the risk of ketoacidosis in people with diabetes. Following a low carbohydrate diet for a prolonged amount of time can also lead to ketoacidosis.¹⁷ To reiterate, ketogenesis is the production of ketone bodies in response to carbohydrate and glucose depletion. Low concentrations of ketone bodies are generally regarded as a safe, as opposed to high concentrations caused by ketoacidosis (which is a medical emergency).¹⁶

What to Eat and Avoid

Given the strong emphasis on high-fat foods, healthy fats comprise the largest part of this diet.¹⁶ Foods such as seeds and nuts, coconut, avocados, poultry fat, and plant fats (e.g., olive or coconut oils) are encouraged. In addition, some dairy products—including butter, hard cheese, and yogurt—are allowed, but people on a ketogenic diet should avoid cream, ice cream, and full-fat milk given their natural sugar content.¹⁷ Individuals following this diet should consume a moderate amount of protein, ideally meats high in omega-3 fats.¹⁶ This includes grass-fed beef, free-range poultry, wild-caught fish, and pork. Nuts, seeds, tofu, and eggs are also acceptable protein sources.¹⁷

Adhering to a diet with less than 10% of calories from carbohydrates can be challenging, especially since this diet requires individuals to calculate “net carbs” (See Sidebar: What are “Net Carbs”?).¹⁶ Vegetables lacking high starch contents (e.g., cauliflower, broccoli, onions, leafy greens, bell peppers, garlic, mushrooms, cucumber, summer squash) are encouraged. Small portions of fruit are also allowed, and fruits with a lower net carb content (e.g., berries) are preferred. Other acceptable carbohydrates include dark chocolate, herbs, spices, unsweetened tea, coffee, vinegars, and mustards.¹⁷

Sidebar: What are “Net Carbs”?¹⁷

The body cannot digest or metabolize some carbohydrates because of their molecular structures. For example, fruits, vegetables, whole grains, and sugar alcohols contain insoluble fibers that are indigestible. Insoluble carbs have no energy value or blood sugar impact, so they are allowed when following the keto diet. The keto diet requires dieters to calculate “net carbs,” the amount of carbohydrates taken in by the body that are digested and metabolized and thus contribute to calories. However, it is important to note that the total calorie level does not change even when “net carbs” are calculated.

Individuals calculate net carbs by subtracting the number of ingestible carbohydrates from the food’s total amount of carbohydrates. For example, food containing 24 total carbohydrates and 21 ingestible carbohydrates equals 3 net carbs. Ingestible carbohydrates can typically be found by subtracting the amount of fiber from the amount of carbohydrates in the food item, but it can be more complicated. A number on online net carb calculators are available to help.

Net carbs are also known as “impact carbs.” Food manufacturers use both terms as marketing strategies, but governing bodies do not regulate use of these phrases.

Foods containing added sugar, whole or refined grains, and flour products are restricted.¹⁷ Starchy foods are also not allowed, including some high-starch vegetables such as corn, potatoes, and winter squash. Fruits with a high net carb content and fruit juices are restricted. Most keto programs also advise against alcoholic beverages due to their carbohydrate content and added sweeteners.¹⁷

Pros and Cons

The keto diet may be beneficial for weight loss, as it uses ketone bodies for energy to deplete glucose and fat storage abilities. Decreasing sugar intake lowers the risk of developing diabetes, obesity, and metabolic syndrome.¹⁶ Following this diet may reduce cholesterol, blood sugar, and blood pressure, and decrease insulin resistance.¹⁷

Diet restrictions may cause short-term adverse effects such as nausea and vomiting, fatigue, headaches, dizziness, and insomnia.¹⁶ This is known as the “keto flu.” Symptoms usually resolve once the body adjusts to the diet after a few weeks. Fluids and electrolyte replenishment can help alleviate discomfort during this period.¹⁶

Documented long-term adverse effects include increased uric acid levels in the blood, increased risk of kidney stones, and osteoporosis.¹⁷ This is due to the diet’s restrictive nature and omission of necessary components to sustain a healthy diet. Nutrient deficiencies can occur as a result of following this diet.¹⁷

People struggle to adhere to the ketogenic diet due to strict regulation of fat, protein, and carbohydrates.¹⁷ Dieters must carefully monitor their adherence to intake limits and meet target levels. This can be difficult for individuals to maintain long-term and lead to low adherence to the diet.¹⁷

Pay-for-Food Systems

Pay-for-food diets are meal prep services or meal delivery services with pre-portioned ingredients, pre-cooked meals, or meal replacement options. Diets focus on weight loss and are designed for convenience. These options take the guesswork out of planning meals and make it easier to track eating.

Nutrisystem

The Nutrisystem meal service claims its diets help with weight loss through a high-protein and low glycemic approach.¹⁸ Nutrisystem expects users to lose one to two pounds a week by managing blood sugar and controlling hunger to avoid overindulgence. Dietitians design meals to include healthy options and relieve the stress of planning.¹⁸

Meals are pre-portioned to fit an individual’s needs and tastes.¹⁸ The meals’ composition of lean protein, healthy fat, and smart carbohydrate ingredients is supposed to curb hunger. Protein shakes and bars are options to supplement plans. Nutrisystem claims deprivation is too restrictive and allows for some deviation from the plan or healthy alternatives to “bad foods.” In addition, dieters can track their progress and calories using Nutrisystem’s app. This system promotes prizes and special offers to keep individuals motivated.¹⁸

Prices vary by plan type but can range from $9.99 to $15.18 a day. Nutrisystem has plans designed specifically for men, women, partners, and people with diabetes.¹⁸

SlimFast

When SlimFast originated, the system promoted meal replacement shakes to lose weight.¹⁹ The company has since expanded to include drink mixes, snacks, and meal replacement bars. The products are grouped into categories such as calorie control, high protein, keto, and intermittent fasting. The website also contains a recipe section for dieters to use in their meal planning.¹⁹

SlimFast plans are based on individuals’ goals and preferences, including the Favorite Foods Plan, Keto Plan, High Protein/Low Carb Plan, Original Plan, and Intermittent Fasting.¹⁹ Dieters purchase SlimFast products to supplement or replace parts of their current diet. Plans themselves are not priced because individuals buy their own groceries and supplement with SlimFast products associated with the plan of their choice. The company also has an app to use for weight management tracking and a private Facebook group to communicate with other individuals on the diet to offer support or guidance.¹⁹ SlimFast claims their plans and products promote and maintain weight loss and encourage people to make better food choices.¹⁹

Jenny Craig

The Jenny Craig company has recently gone out of business after 40 years in the industry. Some experts indicates that one reason has been the availability of weight loss medications and increased competition in this market space. This system emphasized one-on-one coaching mixed with healthy foods to lose weight quickly.²⁰ The company claimed dieters could lose up to 18 pounds in the first four weeks. Coaches designed meal plans to be unrestrictive and included an individual’s favorite foods. Meals focused on low-fat foods with high fiber and protein. This program also emphasized physical activity and occasional intermittent fasting to aid the weight loss process.²⁰

Plans consisted of meals from the program, two snacks, and supplemental grocery items daily to promote weight loss and increase metabolism.²⁰ One snack included Jenny Craig’s Recharge Bar, used when intermittent fasting. The program claimed the Recharge Bar helped dieters lose weight faster, feel less hungry, and maintain fasting. Jenny Craig coaches designed plans and provided guidance for the duration of the program.²⁰

Food was delivered weekly or biweekly. Depending on the type of plan, individuals paid $13.99 to $21.99 per day. Prices were based on the number of meals, membership length, and amount of coaching support included. Promotional offers and meal bundles were available.²⁰

Pros and Cons

Pay-for-food diets can be intriguing as they promote healthy choices, weight loss, and convenience.^18-20 They reduce mental load and stress surrounding dieting by making the choices easier or eliminating the need to choose altogether. Some services also provide support groups or coaches for accountability and guidance. In addition, if dieters can adhere to these plans, meal kits promote portion control and reduce overeating.^18-20

A major con associated with these diets and meal kits is adherence. As people lose weight on these diets, they may stop using them, gain weight back, and become discouraged about trying again. This can reverse improved health outcomes.^18-20 Another con is cost. Individuals may be discouraged by the prices associated with pay-for-food systems. The cost may not be viable or sustainable options for all individuals.^18-20

Studies have shown these diets to be ineffective. Attrition rates (percentages of people leaving a program) are 30% or greater, and 37% of dieters who complete programs lose less than 5% of their initial body weight.²¹Other studies failed to produce significant results for how these pay-for-food diets affect weight loss when compared to educating or counseling individuals on weight.²² High attrition rates and insignificant weight loss results suggest these diets are unsustainable and unreliable.²¹

Paleo Diet

The paleo diet goes by many names, including the Paleolithic, caveman, or Stone-Age diet. It consists of (allegedly) eating like humans of the Paleolithic era did, mixed with modern components to supplement the diet. The Paleolithic era occurred from roughly 2.5 million years ago to 1,200 B.C. Diet supporters believe current body function is similar to how it functioned during this era and eating foods available or comparable to this time will improve health.²³ Introduced in 2002 by Dr. Loren Cordain, a scientist specializing in nutrition, this diet has surged in popularity in recent years due to weight loss claims.²⁴

Due to disagreements about which foods were available in the Paleolithic era compared with today, many diet plans are dubbed “paleo.” They differ in specific foods allowed. All plans emphasize high protein, healthy fats, low or moderate carbohydrates, low sugar and sodium, and high fiber to meet weight loss goals.²³ The term “paleo” will be used to describe this model. The paleo diet consists of consuming mostly lean meats, fruits, vegetables, nuts, seeds, and fish, in line with what researchers believe was consumed during the Paleolithic age.²³ It also emphasizes reducing intake of dairy, grains, and carbohydrates.²⁵

Weight loss can occur through several pathways using the paleo diet.²³ Like the keto diet, ingesting fewer carbohydrates forces the body to use fat for fuel. In addition, replacing highly processed foods, added sugars, and large amounts of carbohydrates with healthier options can aid weight loss. Eating more protein and less calorically dense food (i.e., few calories in a large volume of food) also helps curb hunger and leave individuals more satisfied.²³

Less calorically dense foods—including vegetables, fruits, low-fat or fat-free dairy, and egg whites—can be eaten in larger quantities. These foods help with weight loss as they allow individuals to eat a larger volume and feel full, without ingesting large numbers of calories.²⁶ This reduces snacking and overall food intake.²³

Conversely, calorically dense foods are high in calories and eaten in small amounts. These contribute weight gain as individuals who eat a small volume consume high numbers of calories.²⁷ Examples of calorically dense foods include²⁷

Proteins: fish, beans, eggs, cheese, yogurt, fats including nuts, avocados, nut butters
Carbohydrates: potatoes, brown rice, whole grains

Overall, the paleo diet works by breaking down the diet into basic components and making healthier choices. Cutting out foods leading to high glucose or carbohydrate storage also aids in eating healthier and inducing weight loss.²⁸

What to Eat and Avoid

Allowed foods emphasize fresh and healthy choices to remain consistent with foods found in the Paleolithic age.²³ This includes lean meats, fish or shellfish, fruit, vegetables, honey, nuts or seeds, and olive or coconut oils. Frozen fruits and vegetables are allowed as they contain the same nutrients as the fresh variety and may be more convenient. Omega-3 fats are important for the body and can be found in fish, grass-fed beef, avocado, olive oil, some nuts (e.g., walnuts, almonds, pistachios), and seeds. Root vegetables such as cassava and sweet potatoes are highly nutritious and are allowed in moderation.²³

Restricted foods have little nutritional value or a high glycemic index unsuitable for the paleo diet.²³ For example, white potatoes and processed foods are off limits. Other restricted foods include whole or refined grains, cereals, refined sugar, refined vegetable oil, legumes, dairy products, alcohol, coffee, and salt. Canola is a refined vegetable oil and is not allowed. Restricted legumes include peanuts, beans, and lentils.²³

This diet emphasizes eating healthy and portioning fats, proteins, and carbohydrates to enhance health.²³ Calorie counting and general portion control are deemphasized in this diet. Some plans also allow for “cheat meals” (those consisting of food not beneficial to health) in the early stages of the diet to increase adherence.²³

Pros and Cons

Components of this diet including fiber, potassium, and antioxidants aid bodily functions and reduce disease risk. Reducing the intake of highly processed foods with little nutritional value also helps improve overall health.²⁵ Short-term benefits may include weight loss, improved blood pressure and cholesterol levels, and increased insulin sensitivity.²³ One study documented improvements in metabolic levels, specifically glucose control and lipids, in people with diabetes.²⁸

Unfortunately, restricting or excluding foods altogether for long periods of time can lead to nutritional deficiencies and health complications. For example, limiting dairy intake leads to deficiencies of calcium, vitamin D, and B vitamins.²³ These deficiencies can increase risk of osteoporosis and bone injuries.²⁴ Dairy-related nutrient deficiencies are not specific to the paleo diet, but can occur due to its food restrictions. Restricting grains in the diet also deprives the body of nutrients, which increases risks of diabetes and heart disease. In addition, increased meat consumption (especially red meat) contributes to saturated fat intake and increases risks of cardiovascular problems and diabetes.²³ It may also be difficult for people to adhere to a diet that restricts certain categories of foods.

Atkins Diet

The Atkins diet promotes low carbohydrate intake while allowing as much protein and fat as desired. Robert C. Atkins, a heart specialist, developed this diet in the 1960s as a method for weight loss and maintenance.³⁰ Although it is a low-carb diet, the Atkins program acknowledges that eating right is always better than eating less.³¹ This diet is ever evolving to be current with updated nutritional expertise.³⁰

Like the keto diet, Atkins emphasizes low carbohydrate intake of less than 20 g per day to start.³⁰ Unlike the keto diet, consumption of fat and protein is less restricted. Carbohydrates are claimed as the problem without regulating the intake of other food groups. Diet supporters believe the sugars found in carbohydrates cause health issues such as blood sugar imbalances and weight gain.³⁰

Hypothetically, eating fewer carbohydrates lowers dietary sugar leading to greater satiety, increased energy, less stored fat, and higher metabolism.³¹ When the body lacks glucose and carbohydrates to use as energy, it turns to fat to keep the body functioning through ketogenesis. The more fat a person burns, the more weight they lose.

Fat and protein comprise the remainder of the diet. As carbohydrates are viewed as the source of health issues, intake levels of fat and protein are less restricted. Calorie counting and portion control are unnecessary, besides keeping track of carbohydrate intake to stay below the allowable limit.³⁰

The Atkins diet is split into phases with specific allowable limits of carbohydrates (see Table 2). The diet’s phases adjust to reflect changes in body function and weight. As carbohydrate levels fluctuate in each phase, protein and fat levels change to achieve satiety.

Table 2. Atkins Diet Phases³¹

Phase	Instructions
Phase 1: Induction	3 regular sized meals or 4-5 small meals, vitamins/supplements, 8 oz. glasses of water, 20 g net carbs per day
Phase 2: Ongoing weight loss	Can add net carbs in 5 g increments weekly, vitamins/supplements, 8 oz. glasses of water, no more than 40 g a day after adding extra carbs, introduce Atkins food products
Phase 3: Pre-Maintenance	Maintaining previous stages, can add net carbs in 10 g increments weekly to find the perfect balance until the goal weight is reached, maintain carb intake of goal weight
Phase 4: Maintenance	Maintaining Phase 3 carb level, reducing fat intake as carb intake increases, managing cravings and weight

While phases differ in carbohydrate intake levels, they include similar food groups overall.³⁰ Allowed foods include vegetables, oils, fats, and protein (e.g., eggs, cheese, fish, meat and poultry). Dieters can introduce berries, nuts, seeds, starchy vegetables, and whole grains in the third phase, provided they are still losing weight. Dieters can also eat Atkins’ commercial selection of products during and after phase two. Most fruits, alcohol, baked goods high in sugar, bread, pasta, and nuts are restricted in phase one. Some fruits and grains are added by phase three.³⁰

Pros and Cons

Benefits of the Atkins diet include weight loss; decreased blood pressure; and lower incidence of heart disease, metabolic syndrome, and diabetes.³⁰ This diet can also improve blood sugar and cholesterol levels. These benefits are attributed to low carbohydrate intake and subsequent weight loss.³⁰

Reducing carbohydrate intake may initially cause symptoms such as headache, weakness, fatigue, and dizziness.³⁰ Unrestricted fat intake can be unhealthy. In addition, using fat as the body’s energy source for too long may lead to ketoacidosis if dieters misuse the plan.²⁹ Nutrient deficiency can also occur on this diet as a result of restrictions.³⁰

Weight loss pursuant to this diet is difficult to maintain due to its deficiencies and restrictive nature. Following the carbohydrate limit for long periods of time is difficult and unsustainable for some people.³⁰ Cardiologists warn this diet puts oxidative stress (disproportionate levels of oxygen reactive species overwhelming the ability of body systems to detoxify them) on organs and can cause serious heart problems or fatal complications.²⁹ Some long-term studies have shown the Atkins diet is no more effective than other fad diets. In addition, these studies show that most people who lost weight while following the Atkins diet regained it.³⁰

IMPLICATIONS FOR PHARMACY TEAM

Fad dieting can compromise patient safety, and certain patients are at elevated risk for problems. Pharmacy teams are responsible for advising patients about drug-diet interactions and concerns. Table 3 describes conditions and their associated medications that impact the use of fad diets.

Table 3. Implications for Pharmacy Teams^{10,16,23,30,32-40}

Diet	Patient Conditions and Associated Medications That Can Be Contraindications with Diets
Intermittent Fasting	· Age younger than 18 years · Pregnancy or breastfeeding · Type 1 diabetes o Insulin, blood pressure medication, cholesterol-lowering medication · History of eating disorder
Keto	· Diabetes o Insulin, blood pressure medication, cholesterol-lowering medication · Hypoglycemia o Glucagon or other forms of glucose · Pancreatitis o Pain medication · Liver failure · Fat metabolism disorders o Cholesterol-lowering medication · Primary carnitine deficiency o L-carnitine supplements · Carnitine palmitoyltransferase deficiency · Carnitine translocase deficiency · Porphyrias o Hemin · Pyruvate kinase deficiency o Mitapivat (Pyrukynd), folic acid supplements, iron chelators
Pay-For-Food Systems	· Contraindications and associated medication will depend if it is an individually designed plan or the service’s version of intermittent fasting, keto, etc.
Paleo	· Cardiovascular related issues o Anticoagulants, ACE inhibitors, cholesterol-lowering medications, diuretics, etc. · Diabetes o Insulin, blood pressure medication, cholesterol-lowering medication · Nutrient deficiency disorders
Atkins	· Diabetes o Insulin, blood pressure medication, cholesterol-lowering medication · Taking diuretics o Thiazide, loop, potassium-sparing diuretics or a mix of types · Severe kidney disease o Blood pressure medication, anemia medication, cholesterol-lowering medication, supplements · Pregnancy or breastfeeding

Nutritional Myths

As mentioned, misinformation surrounding diets has always existed, and social media has magnified the problem. Some myths are more harmful than others, but knowing the facts is essential to correctly informing others.³² Examples of nutritional myths that pharmacy teams can debunk for their patients are found in Figure 1.

Dieting is not a one-size-fits-all solution. When pharmacy teams advise patients, they must work with patients to consider health factors . Factors to consider include a patient’s medications, lifestyle choices, and known health issues.³³ Pharmacy teams should advise individuals that fad diets are not necessary and following a generally healthy diet is usually sufficient to lose weight. They should make healthy swaps and find strategies that work best for them as individuals. For example, they can cut back on processed foods, consume more fruits and vegetables, and be conscious of fat or carbohydrate intake to ensure healthy sources. These choices are effective ways to achieve the long-term goals without employing fad diets that promote quick fixes.³³

CONCLUSION

Fad diets are undeserving of the positive hype they receive. They are short-term solutions that sometimes work for people looking to lose weight or make changes quickly. However, benefits are outweighed by their unsustainability and poor post-diet maintenance planning. Fad dieting also starts a cycle of yoyo dieting (see Sidebar: Yoyo Dieting). The best option for health is to find strategies that work individually and stick with them. Ditch the fad diets and make long-term healthy choices for better, lasting results.³³

Sidebar: Yoyo Dieting

Yoyo dieting, or weight cycling, occurs when people achieve their goal weight through dieting, stop dieting and return to unhealthy habits, gain the weight back, diet again for a period, gain the weight back, and repeat the cycle. Yoyo dieting is not only a conscious choice. Physiological mechanisms related to energy intake and expenditure, genetics affecting weight control processes, and the interaction between genes and the environment also affect the cycle.³⁴

Yoyo dieting lacks substantial or sustainable changes to lifestyle or nutrition to keep weight off and instead focuses on quick fixes.³⁴ These quick fixes ultimately fail when weight is regained, and the cycle continues. Most weight lost is gained back within the first two to three years after dieting ceases. However, if dieters keep weight off for two years, the likelihood of gaining it back decreases.³⁵

Pause and Ponder: Do you think fad diets are helpful or harmful?

Resources for Pharmacists and Pharmacy Technicians

CDC Resources - Healthy Weight, Nutrition, and Physical Activity ³⁶
- https://www.cdc.gov/healthyweight/tools/index.html
USDA - Healthy Living and Weight³⁷
- https://www.nutrition.gov/topics/healthy-living-and-weight

Fad Diets: Do They Deserve the Hype?

Pharmacist Post-test

After completing this continuing education activity, pharmacists will be able to

● Describe the prevalence of fad diets in society
● Outline the components of different types of fad diets
● Explain the effect different fad diets can have on the body
● Recognize the value of the pharmacist/pharmacist technician’s role in understanding this information

1. Of the 45 million Americans who go on a diet each year, what percentage are fad diets?
A. 66%
B. 50%
C. 14%

2. What makes fad diets appealing to millions of dieters?
A. They are a good way to stop the cycle of yoyo dieting
B. They are considered safe for individuals with health complications
C. They promote quick weight loss results

3. Which of the following fad diets mainly focus on low carbohydrate intake?
A. Keto and Atkins
B. Keto and intermittent fasting
C. SlimFast and Atkins

4. Which types of fad diets claim to improve blood pressure?
A. Intermittent fasting, pay-for-food diets, and Atkins
B. Intermittent fasting, keto, paleo, and Atkins
C. Paleo and Atkins

5. What causes ketoacidosis?
A. Prolonged extreme carbohydrate restriction***
B. Prolonged extremely high carbohydrate intake
C. Low-level ketone body production

6. Why should individuals taking cardiovascular-related medications such as ACE inhibitors or cholesterol-lowering drugs avoid the Paleo diet?
A. Nutrient deficiencies caused by the composition of the diet lead to increased risk of cardiovascular issues.
B. Reduced grain intake and high meat or fat consumption leads to increased risk of cardiovascular issues.
C. These medications cause sensitivity to foods included in the Paleo diet.

7. A patient with type 1 diabetes mentions that she plans to start following the keto diet because she knows that carbohydrates spike her blood sugar. Which of the following is the BEST response?
A. It is the best way for people with diabetes to lose weight quickly and keep it off long-term
B. It will be difficult for you to follow long-term, so the Atkins diet is more appropriate
C. It is not a safe option for you because you are at increased risk of ketoacidosis

8. Why is it important for pharmacy teams to understand contraindications and health implications of fad diets?
A. To identify signs of diabetes based on how the body reacts to certain fad diets
B. To advise patients about drug-diet interactions and how fad diets can impact their health
C. To direct patients to an appropriate fad diet based on their current medications

9. What general nutrition information should people follow instead of fad diets?
A. Cut all dairy, gluten, and fat from the diet and eat only protein and carbohydrates
B. Decrease fats and carbohydrates in the diet and increase red meat intake
C. Limit processed foods and make overall healthy choices like eating more superfoods

10. A patient comes to the pharmacy to pick up medication and you advise him to avoid diets involving fasting and calorie restrictions. His condition and associated medication indicate fasting and restricting calories would be harmful to his health. Which fad diets does this warning pertain to?
A. Intermittent Fasting, Keto, Atkins
B. Keto, Paleo, Atkins,
C. Intermittent Fasting, Paleo, Atkins

Fad Diets: Do They Deserve the Hype?

Pharmacy Technician Post-test

After completing this continuing education activity, pharmacy technicians will be able to

1. Of the 45 million Americans who go on a diet each year, what percentage are fad diets?
A. 66%
B. 50%
C. 14%

3. Which of the following fad diets mainly focus on low carbohydrate intake?
A. Keto and Atkins
B. Keto and intermittent fasting
C. SlimFast and Atkins

4. Which types of fad diets claim to improve blood pressure?
A. Intermittent fasting, pay-for-food diets, and Atkins
B. Intermittent fasting, keto, paleo, and Atkins
C. Paleo and Atkins

5. What causes ketoacidosis?
A. Prolonged extreme carbohydrate restriction
B. Prolonged extremely high carbohydrate intake
C. Low-level ketone body production

6. Why should individuals taking cardiovascular-related medications such as ACE inhibitors or cholesterol-lowering drugs not follow the Paleo diet?
A. Nutrient deficiencies caused by the composition of the diet lead to increased risk of cardiovascular issues.
B. Reduced grain intake and high meat or fat consumption leads to increased risk of cardiovascular issues.
C. These medications cause sensitivity to foods included in the Paleo diet.

10. You are checking out a customer at the pharmacy counter and notice she is picking up some over-the-counter items along with her prescriptions. Which of the following groups of items would prompt you to refer an individual to the pharmacist?
A. Metformin (for diabetes), Atkins snack bars, and Dramamine (for dizziness)
B. Sertraline (for depression), SlimFast shakes, and a bottle of water
C. Lisinopril (for blood pressure), a gallon of ice cream, and a bottle of soda

References

REFERENCES
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2. Tahreem A, Rakha A, Rabail R, et al. Fad Diets: Facts and Fiction. Front Nutr. 2022;9:960922. Published 2022 Jul 5. doi:10.3389/fnut.2022.960922
3. Foxcroft L. Introduction: 'The Price of a Boyish Form'. In: Calories and Corsets: A History of Dieting over Two Thousand Years. Profile Books; 2011:1-8.
4. British Dietetic Association (BDA). Fad diets: Food fact sheet. September 2021. Accessed January 16, 2023. https://www.bda.uk.com/resource/fad-diets.html
5. British Dietetic Association (BDA). Fad diets and Instagram – friend or Foe? March 2019. Accessed January 16, 2023. https://www.bda.uk.com/resource/fad-diets-and-instagram-friend-or-foe.html
6. Gans, K. Fad diets through the decades. U.S. News. December 23, 2019. Accessed January 17, 2023. https://health.usnews.com/health-news/blogs/eat-run/articles/fad-diets
7. Johnson J. Fad diets are bad diets. American Council on Science and Health. July 2, 2018. Accessed January 20, 2023. https://www.acsh.org/news/2018/07/02/fad-diets-are-bad-diets-13134
8. Centers for Disease Control and Prevention. Obesity and overweight. Updated January 5, 2023. Accessed January 20, 2023. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm
9. Centers for Disease Control and Prevention. Health effects of overweight and obesity. Updated September 24, 2022. Accessed January 20, 2023. https://www.cdc.gov/healthyweight/effects/index.html
10. Johns Hopkins Medicine. Intermittent fasting: What is it, and how does it work? Accessed January 23, 2023. https://www.hopkinsmedicine.org/health/wellness-and-prevention/intermittent-fasting-what-is-it-and-how-does-it-work
11. Chair SY, Cai H, Cao X, Qin Y, Cheng HY, Ng MT. Intermittent fasting in weight loss and cardiometabolic risk reduction: A randomized controlled trial. J Nurs Res. 2022;30(1):e185. doi:10.1097/jnr.0000000000000469
12. UC Davis Health. Intermittent fasting: Benefits, how it works, and is it right for you? February 4, 2022. Accessed January 23, 2023. https://health.ucdavis.edu/blog/good-food/intermittent-fasting-benefits-how-it-works-and-is-it-right-for-you/2022/02
13. Cleveland Clinic. What is a superfood, anyway? November 10, 2021. Accessed January 23, 2023. https://health.clevelandclinic.org/what-is-a-superfood/
14. de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-2551. doi:10.1056/NEJMra1905136
15. Patterson RE, Laughlin GA, LaCroix AZ, et al. Intermittent fasting and human metabolic health. J Acad Nutr Diet. 2015;115(8):1203-1212. doi:10.1016/j.jand.2015.02.018
16. Masood W, Annamaraju P, Uppaluri KR. Ketogenic Diet. In: StatPearls. Treasure Island (FL): StatPearls Publishing; June 11, 2022. Updated June 11, 2022. Accessed January 24, 2023. https://www.ncbi.nlm.nih.gov/books/NBK499830/
17. Harvard T.H. Chan School of Public Health. Diet Review: Ketogenic diet for weight loss. May 22, 2019. Accessed January 24, 2023. https://www.hsph.harvard.edu/nutritionsource/healthy-weight/diet-reviews/ketogenic-diet/
18. Nutrisystem. Accessed January 25, 2023. https://www.nutrisystem.com
19. SlimFast. Accessed March 9, 2023. https://slimfast.com
20. Jenny Craig. Accessed January 25, 2023. https://www-prd.jennycraig.com/how-it-works
21. McEvedy SM, Sullivan-Mort G, McLean SA, Pascoe MC, Paxton SJ. Ineffectiveness of commercial weight-loss programs for achieving modest but meaningful weight loss: Systematic review and meta-analysis. J Health Psychol. 2017;22(12):1614-1627. doi:10.1177/1359105317705983
22. Chaudhry ZW, Doshi RS, Mehta AK, et al. A systematic review of commercial weight loss programmes' effect on glycemic outcomes among overweight and obese adults with and without type 2 diabetes mellitus. Obes Rev. 2016;17(8):758-769. doi:10.1111/obr.12423
23. Harvard T.H. Chan School of Public Health. Diet Review: Paleo diet for weight loss. October 28, 2019. Accessed January 26, 2023. https://www.hsph.harvard.edu/nutritionsource/healthy-weight/diet-reviews/paleo-diet/
24. The Paleo Diet. Accessed January 26, 2023. https://thepaleodiet.com/
25. UC Davis Health. Paleo diet: What it is and why it's not for everyone. April 27, 2022. Accessed January 26, 2023. https://health.ucdavis.edu/blog/good-food/paleo-diet-what-it-is-and-why-its-not-for-everyone/2022/04
26. Weight loss: Feel full on fewer calories. Mayo Clinic. March 22, 2022. Accessed January 26, 2023. https://www.mayoclinic.org/healthy-lifestyle/weight-loss/in-depth/weight-loss/art-20044318
27. Cleveland Clinic. High calorie foods and snack ideas to gain weight. September 15, 2020. Accessed January 26, 2023. https://my.clevelandclinic.org/health/articles/16555-snack-ideas-for-weight-gain
28. Masharani, U., Sherchan, P., Schloetter, M. et al. Metabolic and physiologic effects from consuming a hunter-gatherer (Paleolithic)-type diet in type 2 diabetes. Eur J Clin Nutr 69, 944–948 (2015). https://doi.org/10.1038/ejcn.2015.39
29. Parmar RM, Can AS. Dietary Approaches To Obesity Treatment. In: StatPearls. Treasure Island (FL): StatPearls Publishing; October 3, 2022. Accessed January 27, 2023. https://www.ncbi.nlm.nih.gov/books/NBK574576/
30. Atkins diet: What's behind the claims? Mayo Clinic. May 12, 2022. Accessed January 27, 2023. https://www.mayoclinic.org/healthy-lifestyle/weight-loss/in-depth/atkins-diet/art-20048485
31. Atkins. Accessed January 27, 2023. https://www.atkins.com/how-it-works
32. Type 1 diabetes. Mayo Clinic. Accessed March 10, 2023. https://www.mayoclinic.org/diseases-conditions/type-1-diabetes/diagnosis-treatment/drc-20353017
33. American Diabetes Association. Hypoglycemia (low blood glucose). Accessed March 10, 2023. https://diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hypoglycemia
34. Natesan V, Kim SJ. Lipid Metabolism, Disorders and Therapeutic Drugs - Review. Biomol Ther (Seoul). 2021;29(6):596-604. doi:10.4062/biomolther.2021.122
35. Health Resources & Services Administration. Primary carnitine deficiency. Accessed March 10, 2023. https://newbornscreening.hrsa.gov/conditions/primary-carnitine-deficiency
36. Porphyria. Mayo Clinic. Accessed March 10, 2023. https://www.mayoclinic.org/diseases-conditions/porphyria/diagnosis-treatment/drc-20356072
37. Cleveland Clinic. Pyruvate kinase deficiency. Cleveland Clinic. Accessed March 10, 2023. https://my.clevelandclinic.org/health/diseases/23419-pyruvate-kinase-deficiency
38. American Heart Association. Types of heart medications. Accessed March 10, 2023. https://www.heart.org/en/health-topics/heart-attack/treatment-of-a-heart-attack/cardiac-medications
39. Cleveland Clinic. Diuretics. Accessed March 10, 2023. https://my.clevelandclinic.org/health/treatments/21826-diuretics
40. Mayo Clinic. Chronic Kidney Disease. Accessed March 10, 2023. https://www.mayoclinic.org/diseases-conditions/chronic-kidney-disease/diagnosis-treatment/drc-20354527
41. Egan S. 10 Nutrition myths experts wish would die. The New York Times. January 19, 2023. Accessed February 3, 2023. https://www.nytimes.com/2023/01/19/well/eat/nutrition-myths.html
42. Haspel T. Weight-loss diets boil down to one thing, and it's not science jargon. The Washington Post. January 23, 2023. Accessed February 4, 2023. https://www.washingtonpost.com/food/2023/01/23/weight-loss-diets-fasting-keto/
43. Contreras RE, Schriever SC, Pfluger PT. Physiological and epigenetic features of yoyo dieting and weight control. Front Genet. 2019;10:1015. Published 2019 Dec 11. doi:10.3389/fgene.2019.01015
44. Johns Hopkins Medicine. Maintaining Weight Loss. August 8, 2021. Accessed February 6, 2023. https://www.hopkinsmedicine.org/health/wellness-and-prevention/maintaining-weight-loss
45. Centers for Disease Control and Prevention. Weight Loss and Management. March 19, 2021. Accessed February 6, 2023. https://www.cdc.gov/healthyweight/tools/index.html
46. USDA. Healthy Living and Weight. U.S Department of Agriculture. Accessed February 6, 2023. https://www.nutrition.gov/topics/healthy-living-and-weight

Patient Safety: Ketogenic Diet: Fad Weight Loss or True Medical Benefits?

After completing this application-based continuing education activity, pharmacists will be able to

Describe the components and mechanisms of the ketogenic diet for medical purposes.

List disease states in which the ketogenic diet has been proven to help

Use this information to counsel patients who are interested in the ketogenic diet’s medical benefits

After completing this application-based continuing education activity, pharmacy technicians will be able to

Describe the components of the ketogenic diet for medical purposes

List disease states in which the ketogenic diet has been proven to help

Identify situations in which patients need referral for additional information

The ketogenic diet, despite its current popularity, was initially developed to address seizure disorders. Its reliance on high fat, moderate protein, low carbohydrate intake can make it a challenge for patient adherence. By maintaining a constant state of ketogenesis from eating fatty foods, patients on the ketogenic diet change their natural fuel source from glucose to ketone bodies. Its medical uses include obesity, glaucoma, diabetes, seizures, and other neurode-
generative disorders. A key concept is that patients must strive for ketosis (notketoacidosis) and monitor medical conditions closely. It is contraindicated in patients with liver failure, pancreatitis, inborn disorders of fat metabolism, primarycarnitine deficiency, carnitine palmitoyl transferase deficiency, carnitine translocase deficiency, porphyria, and pyruvate kinase deficiency. People who have type1 diabetes or who are pregnant should not follow this diet. Some people develop the “keto-flu,” a slang term for symptoms indicative of carbohydrate withdrawal. Numerous reliable resources are available for patients and healthcare providers.

INTRODUCTION

Did you know that the ketogenic diet was NOT initially created for weight loss? Recently, the “keto” diet has become another fad diet for people trying to lose weight. Since 2000, more researchers have started to study the ketogenic diet, causing an increase in dieters who are employing this diet.¹

For decades, various entities have promoted fad diets as a way to lose weight and accrue other health benefits, with no data to back them up. The ketogenic diet began to reach the public’s consciousness in the 1970s, gained popularity in the early 2010s, and by 2017, it was a frequent topic in national news media. Google searches for the ketogenic diet (sometimes called the paleo diet, which is similar but not identical) quadrupled that year; questions about this diet were in the top 10 health questions.² Many people started using the ketogenic diet without understanding how it works or its associated benefits and risks. In 2014, celebrities like Lebron James, Kim Kardashian, and Megan Fox started using the ketogenic diet during its fad weight loss phase. In 2020, around 6% of Americans were consuming a ketogenic, high fat diet.³

In the 1920s, researchers noticed that some patients with epilepsy experienced benefits during fasting, so they discovered a way to mimic fasting to treat the disease.¹ Soon, physicians began to use the ketogenic diet for its antiepileptic properties.¹However, in the next decades, researchers introduced antiepileptic medications and the ketogenic diet’s popularity faded. Treatment for epilepsy still includes some of the first antiepileptic medications: phenobarbital and phenytoin.⁴ Although physicians began using phenobarbital in 1912 for epilepsy, the U.S. Food and Drug Administration did not approve phenytoin for use in epilepsy until 1938.⁵ In the 1940s, clinicians used troxidone, but its toxicity profile was unacceptable. Ethosuximide, approved in 1958, replaced it. Approval of carbamazepine and valproic acid in the 1960s made the ketogenic diet unnecessary and obsolete for the most part.⁵

Although pharmacists are the medication experts on the clinical team, they must understand all types of treatment, including nonpharmacologic interventions. During a ketogenic diet, patients eat a limited number of carbohydrates so the body will enter ketosis. Because of the diet’s intensity, pharmacists and technicians need to understand how the diet works to ensure patient safety. When patients start or are on the ketogenic diet, pharmacists need to counsel patients to ensure no drug interactions occur. Pharmacists also need to counsel patients who may have started the diet by themselves about its benefits and the risks. Also, remember interested dieters might embrace a New Year's resolution regarding ketogenic dieting, because National Keto Day is January 5th!

This continuing education activity summarizes knowledge of the ketogenic diet, the diet’s mechanism and its positive and negative effects, current medical uses for patients with epilepsy, diabetes, polycystic ovary syndrome (PCOS), and others, and recommendations for patient education and counseling.

KETOGENIC DIET

The ketogenic diet alters how the body burns energy, from carbohydrates to lipids. The traditional food pyramid places fats in the smallest section at the top, with carbohydrates in the largest bottom section. The ketogenic diet flips the pyramid, so most recommended foods are fats and very few are carbohydrates.

According to the Dietary Guidelines for Americans, 25% to 35% of an adult’s diet should come from fats, 45% to 65% from carbohydrates, and 10% to 30% from protein.⁶ In a 2000 calorie day for ketogenic diet patients, fat should account for 70% to 80% or 165 g of daily caloric intake.⁷

Although an exact timeframe is unknown, researchers believe that it can take the body up to four weeks to adapt to the ketogenic diet and ketosis.⁸ Patients initiating the diet could try daily exercise to force the body to break down fats, but its efficacy for reducing time to ketosis is unknown.⁸

Ketogenesis

The ketogenic diet uses ketosis and ketogenesis. When people eat carbohydrates, the body uses cellular respiration to produce energy from breaking down glucose molecules. However, if no carbohydrates are available, which would be the case during extended exercise or fasting periods, the body will naturally enter ketosis. Ketosis is a state of elevated ketone bodies, which include beta-hydroxybutyric acid, acetoacetic acid, and acetone in the blood.⁹ When the body needs energy, ketogenesis occurs to produce these ketone bodies, which can be used as an alternative energy source.

In normal cellular respiration, acetyl-CoA is condensed with oxaloacetate to begin the citric acid cycle. Beta-oxidation of fatty acids can produce acetyl-CoA, similar to the production of acetyl-CoA from glycolysis of glucose. In times of reduced glucose (i.e., fasting, extended exercise, ketogenic diet), the body diverts the acetyl-CoA produced from the fatty acids into ketogenesis.

Ketosis begins with fatty acid oxidation and the production of acetyl-CoA. Using the enzyme 3-ketothiolase, acetyl-CoA is converted into acetoacetyl-CoA. Then, the enzyme HMG-CoA synthase converts acetoacetyl-CoA to HMG-CoA.⁹ Low glucose levels during starvation or a high fat diet—a signal that the body needs to produce an alternative energy source for the brain—trigger this step of ketogenesis.¹⁰

The last step of energy production during ketosis is the conversion of HMG-CoA to the ketone bodies acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB). Using HMG-CoA lyase, AcAc and 3HB are cleaved from HMG-CoA.⁹By being in a constant state of ketogenesis from eating fatty foods, patients on the ketogenic diet change their natural fuel source from glucose to ketone bodies.

Ketone Bodies

The 3 main types of ketone bodies are AcAc, 3HB, and least commonly, acetone. The liver produces AcAc, 3HB, and acetone in a 78:20:2 ratio, respectively, during fatty acid oxidation.¹¹ Acetone is produced the least because it’s the byproduct of the uncommon and spontaneous decarboxylation of 3HB.¹¹ Ketone bodies are the only non-glucose derived energy source for the brain.¹⁰ The brain cannot process fatty acids, so they must be converted into ketone bodies first. They provide energy to the brain because both AcAc and 3HB can diffuse across blood brain barrier.⁹

During a normal day, ketone bodies account for only 2% to 6% of an individual's energy requirements. However, after a three- to four-day fast, ketone bodies account for 30% to 40% of the body's energy source.⁹ The liver can produce 185 grams of ketone bodies daily, which is enough to satisfy a person’s daily energy needs.⁹

By using ketone bodies, patients can avoid breaking down carbohydrates as an energy source, similar to how the body naturally functions during fasting. Ketone bodies are thought to have a direct beneficial mechanism, which will be discussed later, in disorders like epilepsy.

Effects of Insulin and Glucagon

Insulin and glucagon are important in ketosis and ketone bodies. Low insulin levels trigger steps in the ketosis process. Insulin, also called the antiketogenic hormone, decreases 3HB production, whereas glucagon, the ketogenic hormone, increases 3HB production.¹²

When humans consume carbohydrates and blood glucose levels rise, the pancreas releases insulin to absorb the blood sugar for energy storage.¹³ Insulin inhibits hormone-sensitive lipase and HMG-CoA synthase, enzymes that take part in fatty acid breakdown. It also stimulates acetyl-CoA carboxylase, causing the conversion of acetyl-CoA to malonyl-CoA, and blocking fatty acid transport into the mitochondria.¹⁰ As a result, insulin decreases the need for fatty acid oxidation and ketone bodies are decreased. The ketogenic diet requires patients to avoid carbohydrates to diminish insulin production and promote these mechanisms.

Glucagon does the opposite of insulin. The body uses epinephrine and glucagon to stimulate adipose (fat) tissue to produce more fatty acid.⁹ Glucagon triggers phosphorylation of hormone-sensitive lipase and HMG-CoA synthase, thus promoting ketogenesis.⁹ The body releases fatty acids from triglycerides, so they can be broken down by the newly activated enzymes.

A successful ketogenic diet requires a high glucagon/insulin ratio, similar to that experienced during fasting and by patients with diabetes. The high ratio increases fatty acid production and oxidation. Ketogenesis will follow.

Foods Consumed

Most foods for a ketogenic diet will have moderate amounts of proteins, no carbohydrates, with many fats. To prevent heart disease, physicians and pharmacists can counsel patients to eat healthy fats. Table 1 describes some examples of foods that are common in the ketogenic diet.

Table 1. Food Options Commonly Used in the Ketogenic Diet¹⁴

Fish and Seafood	- Full of protein - No carbs - Associated with positive cardiovascular and health benefits
Poultry and Meat (Chicken, beef)	- Rich in protein - No carbs - Limit processed meats
Nuts (Almonds, walnuts, pecans, cashews)	- High in fiber, protein, and unsaturated fats - Very low carbs - Antioxidants
Non-starchy Vegetables (Broccoli, green beans, bell peppers)	- Include other vitamins and nutrients - Antioxidants
Cheese	- No carbohydrates - High in fats, protein, calcium - Too many saturated fats
Avocados	- Potassium, unsaturated fats - Most carbohydrates in avocados are fiber

Patients on the ketogenic diet must understand how to track their nutrition to diet properly, calculating proteins, carbohydrates, and fats daily. Patients must calculate carbohydrates to account for dietary fiber because fiber is not digested with other carbohydrates.¹⁴ When tracking nutrition, patients on the ketogenic diet must track net carbohydrates, which can be found by subtracting the dietary fiber content from the total carbohydrates. The total carbohydrate level reported on nutrition labels does not accurately reflect the carbohydrate content the patient has consumed.

Most of the foods mentioned in Table 1 are high in fat. Fish, seafood, meat, poultry, and eggs are main staples. Processed meats, like bacon, should be eaten more sparingly compared to non-processed meats, like chicken and beef.¹⁴ Patients can eat chicken and fish more frequently because they promote cardiovascular health, unlike red meat. Many people believe that berries are not allowed on the ketogenic diet, but strawberries, raspberries, and blackberries have very low net carbohydrates. The total carbohydrates in berries may appear high, but their high fiber content allows berries to have a low net carbohydrate content.

A vegetarian ketogenic diet is a possibility, even though options are more limited. Vegetarian options with high protein and low carbohydrates include nuts, tofu, and seitan (a meat substitute made from the gluten in wheat).¹⁵ These dieters can also enjoy peanut butter-based desserts for more proteins. Seeds are high in fat and have high dietary fiber. For higher calorie meals, eggs and dairy (hard cheeses and plain yogurt) are an important fat option. Eggs have many fats, but essentially no carbohydrates.¹⁵

Any food that is high in net carbohydrates will disrupt the body's ketosis. These are foods like starchy vegetables, juices, syrup, chips, and crackers.¹⁴ Foods high in carbohydrates will give the body enough energy to not oxidize fatty acids and prevent the production of ketone bodies.¹⁴

PAUSE AND PONDER: Would a fasting patient reach ketosis quicker than a patient who is not fasting?

WHO BENEFITS FROM THE KETOGENIC DIET?

Obesity

Obesity, a leading risk factor for many chronic health conditions, continues to rise in the United States. According to the CDC, the prevalence of diabetes has increased to 41.9% from 2017 to 2020.¹⁶ Many have adopted low-carbohydrate, high fat lifestyles to lose weight. A 2016 meta-analysis of 11 randomized control trials assessed the efficacy of the ketogenic diet. Among the 1369 participants, those on the ketogenic diet experienced greater weight loss than those who participated in a low-fat diet.¹⁷ After six months to two years of intervention, patients experienced significant weight loss, HDL cholesterol increase, and triacylglycerol (TAG) reduction. The studies were limited by moderate to high heterogeneity and possible publication bias. A 2021 study evaluated the efficacy of the ketogenic diet using a mobile health application in comparison to a calorie restricted, low-fat application.¹⁸ Of the 155 participants, those using the ketogenic diet app experienced greater weight loss (12.3 pounds) at 12 weeks. Hemoglobin A1c (HbA1c) and liver enzymes also improved for the ketogenic diet group. This study was limited by operating fully remotely via the application. Patients could have benefited from in-person counseling or on-site visits to promote adherence.¹⁸

Another meta-analysis of 13 randomized controlled trials showed that participants on the ketogenic diet benefited from greater weight loss than those on a low-fat diet proving that the ketogenic diet can be used for obese patients. The low-fat diet group consisted of 787 patients while the ketogenic diet group consisted of 790. Patients that were part of the keto group lost approximately 3.6 pounds (1.6 kilograms) more than the low-fat group.¹⁹ Patients saw a greater increase in HDL and a more significant reduction in TAG in the keto group.

Type 2 Diabetes

Patients with type 2 diabetes (T2D) sometimes benefit from the ketogenic diet through improved glycemia and reduced insulin resistance. A study of 28 patients with T2D following a ketogenic diet showed that blood glucose and HbA1c improved. The ketogenic diet could potentially help patients with T2D reduce the number or dose of medications.²⁰ Another comparative study showed that obese patients with T2D had improvement in blood glucose profiles, insulin sensitivity, and HbA1c when adhering to the ketogenic diet for two consecutive weeks.²¹ However, the study was limited by short duration and small sample size.

Polycystic Ovary Syndrome

Similar benefits seem to apply to patients with polycystic ovarian syndrome (PCOS). Patients with PCOS experience hyperandrogenism, insulin resistance, and ovulatory dysfunction.²² Current treatment options include metformin, clomiphene, and letrozole; the ketogenic diet may provide good results for these women through insulin reduction.

In addition to the symptoms listed above, women with PCOS tend to gain weight, develop acne, and experience hirsutism.²³ Physicians recommend lifestyle modifications and hormonal contraceptives as first line interventions, but often, these interventions are insufficient, and symptoms persist.²³

Researchers have conducted many studies to evaluate the benefits of the ketogenic diet for women with PCOS, yet the studies are greatly limited by sample size. For example, a 2019 study consisting of 14 women with PCOS struggling with their weight assessed changes in body weight, BMI, fat body mass, lean body mass, HDL, and several other parameters. At 12 weeks, participants saw a 9.43-kilogram (20.7 pound) reduction in body weight, 3.35 reduction in BMI, and an 8.29-kilogram (18.2 pound) reduction in fat body mass.²³

A pilot study consisting of five women tested the ability of the ketogenic diet to reduce PCOS symptoms. Researchers provided the women with low-carbohydrate diet books and handouts alongside group meetings to test the ketogenic diet’s efficacy for PCOS. Participants consumed fewer than 20 grams of carbohydrates per day for six months. To test participants’ adherence, researchers measured ketones and body weight. Throughout the 24-week period, participants lost weight with a mean BMI decrease of four kilograms (approximately 8.8 pounds) which was a 14.3% total reduction in body weight.²⁴ The study resulted with clear reductions in testosterone, fasting serum insulin, and an overall improvement of PCOS symptoms.

Additionally, an eight-week crossover study involving 30 women with PCOS demonstrated various benefits. On average, weight loss ranged from 1.3 to 1.6 kg (2.8-3.5 pounds). When compared to baseline, the results of this study highlight the relationship between decreases in testosterone and fasting insulin.²⁵ Overall, improvements in insulin resistance, testosterone levels, and weight loss, the ketogenic diet may help patients with PCOS.

Epilepsy

The original use for the ketogenic diet was as an antiepileptic therapy in children.¹After the discovery of antiepileptic medications, the need for the ketogenic diet diminished. However, researchers are bringing the ketogenic diet back to help treat patients who are refractory to modern antiepileptic medications.

In combination with medications, researchers have seen up to a 50% reduction in the number of seizures patients are having, with 10% to 15% becoming seizure free.²⁶ Co-administration with antiepileptics is possible for some medications. However, most patients are children and maintaining this strict diet is difficult.

During a retrospective study, researchers compared the effects of the ketogenic diet to modern anticonvulsant medications in 150 children. At one year, 55% of patients remained on the diet, and 27% of the patients who remained in the trial had a greater than 90% decrease in seizure frequency.²⁷ The diet allowed children to reduce their medication burden (patients averaged having 6.2 anticonvulsant medications before the trial), and proved to be more effective than many medications. More studies in larger patient populations are needed over longer periods of time to make stronger conclusions.

Research attributes the ketogenic diet’s anticonvulsant properties to an increased seizure threshold. Mitochondria in the brain have healthier biogenesis and density, leading to increased resistance to metabolic stress.²⁸ Another way the diet increases seizure threshold is through decreased glucose consumption and production of glycolytic ATP.²⁸ Subsequently, potassium channels remain open and hyperpolarize the neuronal membrane.²⁸

Researchers have found that ketone bodies produced from fatty acid oxidation have their own anticonvulsant effects. Although different ketone bodies have different effects, researchers have found that they can alter various neuronal membrane transporters to decrease excitability. Ketone bodies can inhibit transporters like the vesicular glutamate transporter and neuronal potassium channels. Inhibition of these transporters prevents signal transmission and causes decreased excitability of neuronal cells.²⁹

Other Neurodegenerative Disorders

In addition to epilepsy, promising evidence shows that the ketogenic diet has favorable effects for other neurodegenerative disorders. As the incidence of Alzheimer’s disease (AD) increases, few treatment options are available. The ketogenic diet may reduce deposition of amyloid beta (Aβ) plaques in patients with AD. With the addition of D-β-hydroxybutyrate (an enantiomer of the ketone body 3HB) to the ketogenic diet, ketones were able to increase neuron survival by reversing Aβ (1-42) toxicity.³⁰ By increasing ketone production in the liver, the ketogenic diet can reduce the production of reactive oxygen species.³¹ Ketone bodies also work to block histone hyper-acetylation initiated by histone deacetylases (HDACs), increasing antioxidant levels. The ketogenic diet can improve metabolic efficiency which improves ATP concentrations resulting in further protective effects.³¹

Ketones’ neuroprotective effects can potentially help patients with Parkinson’s disease by reducing oxidative stress, maintaining energy supply, and modulating deacetylation and inflammatory responses.^31,32 Because they can reduce inflammation and inhibit the glutamate excitatory synapse, infusions of ketone bodies like 3HB may lead to small improvements in Parkinson’s symptoms.³²The use of the ketogenic diet for Parkinson’s is still controversial, thus further research is necessary.

Glaucoma

Glaucoma is the second leading cause of vision loss in the world.³³ Because ketone bodies are the major source of energy when participating in the ketogenic diet, mitochondrial dysfunction in the retina and optic nerves associated with glaucoma may be decreased.^32,34 A 2020 observational study assessed the benefit of the ketogenic diet in 185,638 adults with glaucoma from three studies between 1976 and 2017. Results showed that following a low carbohydrate diet was associated with 20% lower risk of developing primary open-angle glaucoma with initial paracentral visual field loss.³⁵ However, evidence is still lacking, and researchers need to investigate more to prove the ketogenic diet’s efficacy for glaucoma.

Colorectal Cancer

According to the American Cancer Society, colorectal cancer is the third leading cause of cancer-related deaths in men and women in the United States.³⁶ A 2022 study suggests that the ketone body, 3HB, can suppress colorectal cancer.³⁷ In one experiment, investigators evaluated the ability of the ketogenic diet to prevent tumor growth and development in mice.

They discovered that 3HB could suppress tumor growth by reducing proliferation of colonic crypt cells.³⁷ 3HB induced positive changes in tumor growth through the upregulation of the homeodomain-only protein X (HOPX). The HOPX protein inhibits cancer organoid growth when overexpressed.³⁷ Mice fed the ketogenic diet showed elevated levels of HOPX specific to the colonic tissue.

Overall, mice assigned to the ketogenic diet experienced improved long-term survival rates. To test the efficacy of the ketogenic diet for existing tumors, after two cycles of dextran sodium sulfate, researchers introduced the diet to the mice. After exposure to the diet, tumor growth decreased. When researchers discontinued the ketogenic diet from the mice, tumor development proceeded.³⁷

This discovery led to further testing, this time in human organoids. Organoids are tissue cultures derived from stem cells.³⁸ In the right environment, they are used to replicate organs. They are an essential tool to monitor disease development. Findings mimicked the results from the mice in 41 patients with colorectal cancer. This suggests that the ketogenic diet may be used for the prevention and treatment of colorectal cancer in the future.³⁷

PAUSE AND PONDER: How do you think patients would feel using the ketogenic diet as a primary treatment for neurodegenerative diseases in the future?

Contraindications to the Ketogenic Diet

Some patients should not follow the ketogenic diet. It is contraindicated in patients with liver failure, pancreatitis, inborn disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyl transferase deficiency, carnitine translocase deficiency, porphyria, and pyruvate kinase deficiency.^39,40

Because of the high risk of developing diabetic ketoacidosis (DKA), patients with type 1 diabetes on SGLT2 inhibitors should not participate in the ketogenic diet.⁴¹ DKA occurs when the body produces a dangerously high level of ketones at a rapid pace. Feeling extremely thirsty and frequent urination are early symptoms of DKA. Later symptoms of DKA include dry skin and mouth, flushing, fatigue, stomach upset, and pain. Another notable warning sign of DKA is a fruity odor on the patient’s breath. Acetone is responsible for the sweet scent and indicates high levels of ketones in the body.⁴² If left untreated, DKA can further develop, ultimately leading to death.

Pregnancy is also a contraindication. The CDC recommends 340 additional calories per day during the second trimester of pregnancy and 450 additional calories per day during the third trimester.⁴³ The CDC also recommends a well-balanced diet for women who are expecting. Losing weight during pregnancy is not safe and can be harmful to a patient’s baby.⁴³ Folic acid and iron supplementation is pivotal in a fetus’ development. The World Health Organization recommends daily iron and folic acid supplements to reduce the risk of low birth weight.⁴⁴ If a pregnant woman were to go on the ketogenic diet, she would need to ensure she consumes the suggested dose of 120 mg elemental iron and 2800 µg (2.8 mg) folic acid daily.⁴⁴ Overall, no evidence indicates that the ketogenic diet is safe for pregnant women.

KETOGENIC DIET SAFETY AND COUNSELING

Although several studies suggest the ketogenic diet can be effective for weight loss, limited literature is available concerning its long-term effects. Long-term effects include hepatic steatosis, hypoproteinemia, kidney stones, and vitamin and mineral deficiencies.⁴⁰

Currently, no guidelines address the ketogenic diet specifically, and other guidelines do not include the ketogenic diet for the treatment of the previously mentioned diseases. Researchers must complete longer term studies with larger patient populations to prove the ketogenic diet’s benefits and elucidate any long-term risks. Pharmacists and other healthcare providers should keep this in mind when recommending the diet to patients.

The Keto-Flu

A common adverse effect of the ketogenic diet is the “keto-flu.” The symptoms are indicative of carbohydrate withdrawal that can create symptoms like brain fog, fatigue, nausea, vomiting, constipation, and muscle soreness.^{40, 39} Symptoms usually begin within one to two days and resolve within a week or less. Pharmacists can counsel patients on proper hydration, light exercise, rest, and starting the diet slowly to try to prevent the keto-flu.

Cardiovascular Effects

As research has previously shown, the ketogenic diet shows short-term benefits for obesity and cholesterol. Due to the overconsumption of fats, researchers wondered about the longer-term effects. In rodent studies, the ketogenic diet led to the development of hepatic inflammation and nonalcoholic fatty liver disease.⁴⁵ Limited research has been done for nonalcoholic fatty liver disease in humans and more study is needed.

Other Adverse Effects

While on the ketogenic diet, patients may experience constipation. The healthcare team should implement a bowel regimen for the patient including an agent like polyethylene glycol 3350 (MiraLAX^®) that’s sugar-free, meaning it adds no additional carbs. Other notable side effects are kidney stones and a decrease in bone density. To prevent kidney stone occurrence, pharmacists can counsel patients on drinking large amounts of liquids.. Patients can reach out to their providers to ensure they check bone health routinely. Several advisory groups recommend bone mineral density screening for women aged 65 and older and men aged 70 and older, and for other patients who are at high risk. Patients participating in the ketogenic diet are no exception, and could be considered high-risk if they do not consume enough calcium and vitamin D. Pharmacists can counsel patients to monitor their calcium and vitamin D intake and supplement it if necessary. Upon screening, providers may also recommend calcium and vitamin D supplementation for patients who experience a decline in bone mineral density.⁴⁶

What Can Health Professionals Do?

Pharmacists can counsel patients on ketone testing to prevent occurrences of DKA. When a patient’s blood glucose exceeds 240 mg/dL, testing ketone levels every four to six hours is warranted.⁴⁷ Ketones can be monitored through the urine and blood. A urine stick test is the most common and changes color depending on the ketone level. Although urine tests are convenient, blood ketone tests from finger sticks are more accurate because they measure 3HB and/or AcAc in the blood.⁴⁸ If ketone tests indicate high levels, the patient is at moderate or high risk for ketoacidosis and patients should seek medical attention. Table 2 shows normal ketone levels, the optimal state of nutritional ketosis, and the level for ketoacidosis.

Table 2. Ketone Levels⁴⁸
Normal Ketone	≤ 0.5 mmol/L
Nutritional Ketosis	1 - 3 mmol/L
Ketoacidosis	≥ 20 mmol/L

Patient adherence to long-term regimens always becomes challenging. Counseling patients on the importance of sticking to their diet and other medications will increase the likelihood of desired results.

PAUSE AND PONDER: On average, how long do you think a patient can remain adherent to the ketogenic diet lifestyle?

Medication management is a vital component of patient safety. To ensure that starting the ketogenic diet is safe, a healthcare professional should perform a complete medication reconciliation. Pharmacists, with an interdisciplinary team, should then develop a plan for medication adjustments (including OTCs) and carbohydrate intake. The use of medication package inserts, institutional databases, and manufacturer helplines can assist the team in determining carbohydrate content of drugs to make the process more seamless.⁴⁶ The following oral suspensions contain high carbohydrate contents:⁴⁹

Amoxicillin
Nystatin
Levetiracetam
Midazolam
Phenobarbital
Phenytoin
Baclofen
Ibuprofen

Making patients aware that they must inform the healthcare team of any new medications is equally as important.

Some medications are of concern with the ketogenic diet.

Patients taking SGLT2 inhibitors should not participate in nutritional ketosis due to the increased risk of diabetic ketoacidosis.
Clinicians need to monitor patients taking the anticonvulsant valproate (a fatty acid) and might need to adjust their doses since the ketogenic diet increases metabolic efficiency and valproate can be burned by cells for energy.⁵⁰ Patients may feel as though valproate is not as effective after starting the ketogenic The dose, in this case, may need to be increased temporarily.
A case study showed that topiramate can increase blood pH, inducing metabolic acidosis and kidney stones.⁵¹ This may become hazardous if patients are already in nutritional ketosis.
Patients may experience hypotension while taking antihypertensive agents and following the ketogenic They should monitor blood pressure frequently.

Pharmacists and other health professionals should inform patients to stay hydrated to reduce the risk for kidney stones and eat low salt food items.

MYTHS AND FACTS

The ketogenic diet has become increasingly popular over the years. Halle Berry, Vanessa Hudgens, Kourtney and Kim Kardashian are a few of many celebrities that have tried the ketogenic diet and have seen incredible results. MTV’s Jersey Shore star, Vinny Guadagnino, also known as the Keto Guido, is no stranger to the diet and has even written a keto cookbook. Seeing such drastic transformations all over tabloids and social media, without a doubt leaves people wondering “Why not? If they can do it, so can I,” while others think, “This can’t be real.”

Many misconceptions create skepticism among patients from the abundance of information available on the internet. Pharmacists can alleviate patient worries by staying informed and referring patients to reliable resources. Table 3 below dispels common myths.

Table 3. Myths and Facts About the Ketogenic Diet⁵²
MYTH	FACT
The ketogenic diet is bad for your health.	The ketogenic diet has several health benefits including: ● Weight loss ● Improved brain function ● Reduction of seizures ● Blood sugar management ● Improvement of PCOS symptoms Side effects may include nausea, vomiting, constipation, or other common side effects.
All I have to do is consume any type of fat while going keto.	Patients should eat healthy fats like avocados, nuts, seeds, and fish. Healthy fats lower LDL levels and raise HDL levels. Unhealthy fats saturated and trans fatty acids (e.g., fried foods, pastries, butter, and cream) raise LDL levels.
If I go keto, I will get ketoacidosis.	Ketosis and ketoacidosis are different conditions. The ketogenic diet induces ketosis. ● In ketosis, the body burns fat since carbohydrates are unavailable. Nutritional ketosis is a normal response. ● Ketoacidosis is a complication seen primarily in patients with T2D where the blood becomes acidic. It can be life-threatening.
I will have no energy if I start a ketogenic diet.	Some people may experience an adjustment period while beginning the ketogenic diet. They may experience temporary fatigue, brain fog, or the “keto-flu.” Eventual ketone production fuels the brain with energy and resolves symptoms.
The ketogenic diet is only useful for weight management.	The ketogenic diet has proven effective in patients with diabetes, PCOS, metabolic syndromes, Alzheimer’s disease, and obesity.
I can’t drink any alcohol while on the ketogenic diet.	Various low-carb alcoholic beverages can be substituted. Light beer, vodka, gin, and rum are a few examples, but patients should keep intake low-moderate. Patients should avoid sweet drinks and cocktails to prevent high sugar intake.

Another common misinterpretation is that any low-carbohydrate food is considered keto. No food item has the same benefit as the other. The healthcare team must work with patients to create dietary plans that are more feasible for them. With a tailored diet plan, patients are more likely to feel structured and reach their goals. Overall, providers should conclude that patient education is necessary to certify patient trust and safety.

PATIENT RESOURCES

Reliable resources for patients are hard to find. Table 4 describes some resources that pharmacists can provide to patients for more information.

Table 4. Resources About the Ketogenic Diet for Patients

Cleveland Health Clinic	- Discusses what patients eat on the ketogenic diet - Small tidbits on benefits and risks - Includes information on populations that could benefit from the diet - https://health.clevelandclinic.org/what-is-the-keto-diet-and-should-you-try-it/
Harvard University Health	- Discusses key-takeaways from a ketogenic diet review - Gives food examples - Easy-to-understand - Discusses health implications for certain patient populations - https://www.health.harvard.edu/blog/ketogenic-diet-is-the-ultimate-low-carb-diet-good-for-you-2017072712089
Academy of Nutrition and Dietetics	- Popular nutrition website that presents findings on various health topics - Discusses populations that the ketogenic diet would not be safe in - Gives background on the diet - https://www.eatright.org/health/wellness/fad-diets/what-is-the-ketogenic-diet
Everyday Health	- Discusses risks and benefits of the diet - Provides food substitutions and daily meal plans - Discussion potential supplements and vitamins that may be beneficial to dieters - Discusses other nutrition techniques for other topics - Articles are peer-reviewed - https://www.everydayhealth.com/diet-nutrition/ketogenic-diet/comprehensive-ketogenic-diet-food-list-follow/
EatingWell	- Brief explanation about the ketogenic diet - Provides variety of food options for dieters - Easy-to-understand and discusses other nutrition techniques - Peer reviewed and gives background on all authors/editors - https://www.eatingwell.com/article/290697/ketogenic-diet-101-a-beginners-guide/

CONCLUSION

Following a low-carbohydrate, high fat diet that uses ketone production to fuel the body requires a large selection of foods if patients are to maintain this diet. This is the challenge of the ketogenic diet. Pharmacists and technicians need a good understanding of what this diet is—and what it is not—so they know when prescribers are likely to use it for diseases. Pharmacists, as they screen for contraindications, should identify the signs of ketosis and counsel patients on managing safe ketone levels.

Patient education is the key to reaching patient goals. Pharmacists must be ready to address patient questions and concerns regarding the ketogenic diet in conjunction with current medications. When pharmacists are a part of the care process, outcomes improve.

Ketogenic Diet: Fad Weight Loss or True Medical Benefits?

PHARMACIST POST TEST QUESTIONS

LEARNING OBJECTIVES
After completing this continuing education activity, pharmacists will be able to:
- Describe the components and mechanisms of the ketogenic diet for medical purposes.
- List disease states in which the ketogenic diet has been proven to help
- Use this information to counsel patients who are interested in the ketogenic diet’s medical benefits

1. Which of the following statements is a MYTH regarding the ketogenic diet?
a. The ketogenic diet benefits patients wanting to lose weight from PCOS.
b. A patient starting the ketogenic diet will have ketoacidosis.
c. The ketogenic diet does not prevent patients from alcohol consumption.

2. James is a 46-year-old male with type 1 diabetes with a BMI of 28. His current medications include insulin-glargine, empagliflozin, and hydrochlorothiazide. He would like to start the ketogenic diet to lose weight. Would you recommend James start the ketogenic diet?
a. Yes, James should start the ketogenic diet right away. It has proven to be efficacious in patients with type 1 diabetes.
b. No, James is currently on an SGLT2 inhibitor. He is at an increased risk of developing DKA.
c. James needs to contact his primary care physician for more information.

3. Which of the following chronic conditions needs more information for the ketogenic diet to be a proven treatment?
a. PCOS
b. Epilepsy
c. Glaucoma

4. Mary is an obese 34-year-old female who comes into the pharmacy with a concern. She recently started the ketogenic diet and is experiencing fatigue, nausea, and brain fog. What advice can you give Maria?
a. Inform Maria that she should stop the ketogenic diet immediately and contact her doctor.
b. Inform Maria that this is completely normal, and she may be experiencing the keto-flu.
c. Recommend Maria take over-the-counter acetaminophen for her nausea. Her symptoms will resolve in a few days.

5. Which neurodegenerative disorder has substantial evidence that the ketogenic diet may be beneficial?
a. Refractory epilepsy
b. Dementia
c. Parkinson’s Disease

6. Which of the following best describes ketogenesis?
a. The process of producing ketone bodies for energy, an alternative pathway to normal metabolism
b. The last step in the creation of ketone bodies, when AcAc and 3HB are cleaved from HMG- CoA
c. The process that breaks down fatty acids acetyl-CoA, so the body can enter the citric acid cycle

7. Which of the following disorders was seen in animal models after long term use of the ketogenic diet?
a. Hematoma
b. Non-alcoholic fatty liver disease
c. Major rashes

8. What was the ketogenic diet originally created for?
a. Weight loss
b. Type 2 Diabetes
c. Epilepsy

9. Becky comes into the pharmacy and is asking for help for recommendations on starting a ketogenic diet. If she is consuming 2000 calories per day, how many fats should you recommend for Becky to consume each day?
a. About 100g of fats daily, which is around 50% of her daily calories
b. About 165g of fats daily, which is around 70% of her daily calories
c. About 30g of fats daily, which is around 15% of her daily calories

10. What are the general effects of insulin and glucagon on ketosis?
a. Insulin and glucagon are both anti-ketogenic
b. Insulin is pro-ketogenic, and glucagon is anti-ketogenic
c. Insulin is anti-ketogenic, and glucagon is pro-ketogenic

Ketogenic Diet: Fad Weight Loss or True Medical Benefits?

TECHNICIAN POST TEST QUESTIONS

LEARNING OBJECTIVES

After completing this continuing education activity, pharmacy technicians will be able to:
- Describe the components of the ketogenic diet for medical purposes
- List disease states in which the ketogenic diet has been proven to help
- Identify situations in which patients need referral for additional information

2. James is a 46-year-old male with type 1 diabetes and is 156 lbs. He is currently taking empagliflozin (an SGLT2 inhibitor). He would like to start the ketogenic diet to lose weight. From what you learned, why should James avoid the ketogenic diet?
a. James is not overweight. He does not need the ketogenic diet to lose more weight.
b. James is currently on an SGLT2 inhibitor. He is at an increased risk of developing DKA.
c. James needs to contact his primary care physician to see if he is a candidate before starting the diet.

3. Which of the following chronic conditions needs more information for the ketogenic diet to be a proven treatment?
a. PCOS
b. Epilepsy
c. Glaucoma

4. Mary is an obese 34-year-old female who comes into the pharmacy with a concern. She recently started the ketogenic diet and is experiencing fatigue, nausea, and brain fog. What is Maria experiencing?
a. Maria is experiencing withdrawal from not being adherent to the diet. She should create a new care-plan with her provider.
b. Maria is experiencing the “keto-flu.” Refer her to the pharmacist so she can further explain the adverse effect.
c. Maria is ketoacidotic. Ask Maria if anyone has mentioned that her breath smells fruity.

5. Which neurodegenerative disorder has substantial evidence that the ketogenic diet is beneficial for their condition?
a. Epilepsy
b. Parkinson’s Disease
c. Dementia

6. A patient comes into the pharmacy after beginning a new ketogenic diet. The patient is worried because she read online that long term effects of the diet could cause a “fat liver.” What is the best response to the patient?
a. Refer the patient to the pharmacist for additional information.
b. Describe the many long-term effects of the ketogenic diet
c. Describe a study about non-alcoholic fatty liver with long term dieting

7. What was the ketogenic diet originally created for?
a. Weight loss
b. Type 2 Diabetes
c. Epilepsy

8. Becky comes into the pharmacy and is asking for help for recommendations on starting a ketogenic diet. If she is consuming 2000 calories per day, how many fats should Becky consume each day?
a. About 100g of fats daily, which is around 50% of her daily calories
b. About 165g of fats daily, which is around 70% of her daily calories
c. About 30g of fats daily, which is around 15% of her daily calories

9. Which of the following best describes ketogenesis?
a. The process of producing ketone bodies for energy, an alternative pathway to normal metabolism
b. The last step in the creation of ketone bodies, when AcAc and 3HB are cleaved from HMG- CoA
c. The process that breaks down fatty acids acetyl-CoA, so the body can enter the citric acid cycle

10. What is the best response to a patient who is wondering how to count carbohydrates for her ketogenic diet?
a. Use any carbohydrate counting app, all you must do is enter the amount of carbohydrates on the nutrition label.
b. Subtract the fiber carbohydrates from the total carbohydrates to get net carbohydrates and record that number.
c. Record only the carbohydrates from fiber. Other types of carbohydrates do not count because they are not digested the same.

References

RE FERENCES
1. Wheless JW. History of the ketogenic diet. Epilepsia. 2008;49 Suppl 8:3-5. doi:10.1111/j.1528-1167.2008.01821.x
2. Howard J. 10 health questions that had you Googling this year. CNN Wire Service, Atlanta. December 14, 2017.
3. 2020 Food & Health Survey. (n.d.). Accessed July 20, 2022. https://foodinsight.org/wp-content/uploads/2020/06/IFIC-Food-and-Health-Survey-2020.pdf
4. 5 Treating Epileptic Seizures in Children, Young People and Adults. NICE. (n.d.). Accessed July 20, 2022. https://www.nice.org.uk/guidance/ng217/chapter/5-Treating-epileptic-seizures-in-children-young-people-and-adults
5. Brodie MJ. Antiepileptic drug therapy the story so far. Seizure. 2010;19(10):650-655. doi:10.1016/j.seizure.2010.10.027
6. Home of the Office of Disease Prevention and Health Promotion. Accessed July 25, 2022. https://health.gov/sites/default/files/2019-09/2015-2020_Dietary_Guidelines.pdf
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8. Ketogenic Diet FAQ. Diabetes UK. (2020, March 6). Accessed July 25, 2022. https://www.diabetes.co.uk/keto/ketogenic-diet-faqs.html
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28. Ułamek-Kozioł M, Czuczwar SJ, Januszewski S, Pluta R , et al. Ketogenic Diet and Epilepsy. Nutrients. 2019;11(10):2510. Published 2019 Oct 18. doi:10.3390/nu11102510
29. Zhang Y, Xu J, Zhang K, Yang W, Li B, et al. The A nticonvulsant Effects of Ketogenic Diet on Epileptic Seizures and Potential Mechanisms. Curr Neuropharmacol. 2018;16(1):66-70. doi:10.2174/1570159X15666170517153509
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32. Gough SM, Casella A, Ortega KJ, Hackam AS, et al. Neuroprotection by the Ketogenic Diet: Evidence and Controversies. Front Nutr. 2021;8:782657. Published 2021 Nov 23. doi:10.3389/fnut.2021.782657
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The revised USP 795 becomes official in November 2023. What’s new?

In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

Christina Anglieco and Laura Nolan do not have any financial relationships with ineligible companies and therefore have nothing to disclose.

Robin Bogner acts as a consultant for Biontech. There is no conflict of interest.

Compounding of drug preparations requires training and knowledge in the science underlying pharmaceutical compounding. Altering the original drug product can change the drug’s stability and clinical efficacy. The United States Pharmacopeia (USP) is an independent non-profit organization of knowledgeable volunteers who set the standards for pharmaceutical compounding to ensure patient safety. State regulating bodies oversee and enforce these standards at compounding pharmacies to ensure compounded preparations are up to quality and purity standards. Since the field of pharmaceutical compounding is constantly changing, USP revises its standards regularly. The USP recently revised General Chapter <795> Pharmaceutical Compounding – Nonsterile Preparations with revisions enforceable on November 1, 2023. To make this transition easier, this continuing education activity outlines the most significant changes made to USP <795>. USP changed General Chapter <795> Pharmaceutical Compounding - Nonsterile preparations to mimic those of USP General Chapter <797> Pharmaceutical Compounding – Sterile Preparations. Overall, the revision elevates nonsterile compounding’s quality and sanitary standards to improve patient safety by reducing common safety errors seen across the United States.

Introduction

The original “little blue pill” was created in the 1860s and was a popular cure for everything from toothache to tuberculosis.¹ Pharmacists compounded “blue mass syrup” and “blue pills” based on their own recipes or on one of several widespread recipes. Its name probably derives from the use of blue dye or blue chalk (used as a buffer) in some formulations. Blue mass’s ingredients varied, as each pharmacist prepared it himself, but they all included elemental mercury. One recipe for blue mass syrup consisted of¹

33% mercury (measured by weight)
5% licorice
25% Althaea (a root extract, possibly from hollyhock or marshmallow)
3% glycerol
34% rose honey

Pharmacist-compounders produced blue pills by substituting milk sugar or chalk for the glycerol and rose oil for the rose honey. Each pill contained one grain (64.8 milligrams) of mercury and was prescribed two to three times a day, which today we know causes heavy metal poisoning, since the dose is more than 100 times more than the limit set by the Environmental Protection Agency.¹Products were made without fancy definitions or regard to cleanliness. Times have changed.

Pharmaceutical compounding is the act of manipulating a drug product to create a new drug formulation.² Pharmacists and pharmacy technicians still compound drug preparations for a specific patient or group of patients when no drug product exists on the market, or as seen more recently, when the drug product is backordered with no therapeutic alternative(s). It is also interesting to note what the United States Pharmacopeia (USP; described below) does NOT consider to be compounding. Preparing a powdered antibiotic bottle with distilled water per manufacturer’s directions is not considered compounding. Splitting tablets and repackaging is also not considered compounding, nor is preparing a single dose for a single patient to be used within four hours. In other words, making one dose of blue mass syrup and giving it directly to a patient is not compounding. (OK, maybe no one makes blue mass syrup anymore, but crushing a tablet and placing it in a liquid for immediate use is still not a compounded preparation.)

Pharmaceutical compounding has two categories: sterile compounding and nonsterile compounding.²

Sterile compounding is creating a new drug preparation that must be sterile (completely free of pathologic microorganisms) and includes preparations that are primarily infusions, injections, eye drops, and many irrigations.
Nonsterile compounding is creating a new drug product that is not required to be sterile (although these products should be as “clean” as possible) and are mostly used for oral or topical administration. Nonsterile compounding is often employed for pediatric and veterinary preparations where patients need very small or very large doses. Some examples are medicated creams for neuropathic pain, and anesthetic mouthwashes for oral sores and pains.

The USP is an independent non-profit organization of knowledgeable volunteers who set the standards for pharmaceutical compounding to ensure patient safety.³ The USP also distinguishes guidelines for hazardous and non-hazardous compounding. Both sterile and nonsterile compounding can involve manipulation of hazardous drugs. This continuing education activity focuses on non-hazardous nonsterile compounding. More information on hazardous compounding can be found in General Chapter <800> Hazardous Drugs – Handling in Healthcare Settings. Access to the USP Compounding Compendium costs $250.00 for a 12-month membership. There are also various plans for multiple users. Many institutions have a contract with USP. (Readers should check with their designated person or supervisor, as they may already have access to this service.)

The origin of nonsterile pharmaceutical compounding in the U.S. cannot be pinned down to one exact date, but historically, the 1800s saw immense growth in not only population but also in disease states as people traveled and settled to new areas. Between 1840 and 1850, it is estimated that more than 1.5 million persons immigrated to the United States. Backyard herbalists became highly regarded apothecaries seemingly overnight.⁴

Unfortunately, there were no established compounding standards until 1820 when a small group of physicians raised concerns about the high prevalence of poor-quality medicine across America and the USP was formed. By 1863, during the height of the Civil War, the USP had become the most trusted source for information about medicines.^3.

The USP continuously strives to improve the quality of drugs, including compounded preparations. Today we know that the quality of a compounded preparation depends as much on handwashing, gloving and cleaning, as checking the pH of the product itself. These steps are necessary to safeguard the preparation that a pharmacist or pharmacy technician compounds, and ultimately, safeguard the patient.

The USP sets standards for pharmaceutical compounding but has no regulatory authority, so it does not enforce the standards it sets. Each state is responsible for regulating pharmaceutical compounding, but the Food and Drug Administration (FDA) is also authorized to regulate all aspects of drugs, including compounding. Both state regulating bodies and the FDA can inspect compounding in pharmacies and take legal action and can amass fines if compounders do not uphold USP standards. However, this action only applies to states that write USP standards into their laws. Depending on the situation’s severity, legal action could result in a loss of license for the pharmacy or pharmacist.

The USP sets standards for sterile and nonsterile compounding through General Chapter <797> and General Chapter <795>, respectively. (Here’s a PRO TIP: chapters numbered from 1 to 1000 are enforceable by state and federal agencies). More recently, the FDA has been inspecting compounding pharmacies to ensure they meet General Chapter <797> standards, but it is only a matter of time before these agencies turn their attention to General Chapter <795>.

In November 2022, the USP published a revised General Chapter <795> Pharmaceutical Compounding – Nonsterile Preparations. Going forward, we will call these standards the newly revised standards. This revision now includes a designated person (the individual assigned to be accountable and responsible for the compounding facility’s operation, performance, and personnel) requirement to mimic General Chapter <797>. With the implementation of a designated person for nonsterile compounding under proposed General Chapter <795>, when the facility is not up to code, State boards of Pharmacy and the FDA hold the designated person responsible, creating a risk of loss of license. The revised standards will be official in November 2023. Major changes include

garbing
cleaning
training
beyond-use dating and
a designated person requirement

The focus here is on how to implement the major changes made to the currently enforceable General Chapter <795>, which was revised and reissued in 2020. Going forward, we will call these standards the current standards. Once readers are familiar with this summary of the major changes in the newly revised standards, they are encouraged to review the full text of the proposed chapter <795> to address additional minor changes.

So, to repeat, the standards that were revised and reissued in 2020 and are currently enforceable will be called the current standards. The revision that will be adopted in November 2023 will be called the newly revised standards.

Garbing

The newly revised standards put greater emphasis on garbing procedures for nonsterile compounding than the current standards do. Pharmacy personnel who compound sterile preparations are well acquainted with garbing, however, garbing is a foreign concept to many who prepare nonsterile preparations. Think back to the past. How often did you go to the back of the store, push some items on the counter aside, and start mixing a magic mouthwash? You probably made it wearing a shirt and tie or more formal dress, while possibly wearing a lab coat, unless it was a really hot day. You might even have washed your hands if you just came back from lunch. Conversely, many hospital pharmacies mix magic mouthwash in so much garb, that you might think that it is a toxic preparation. The SIDEBAR explores this topic in greater detail.

TECH TALK SIDE BAR⁵

Have you noticed that many pharmacists and pharmacy technicians no longer wear white lab coats? Physicians began to wear white coats in the late 1800s as doctors started to recognize the color white’s effectiveness. It is easier to see dirt and soil that prompts the wearer to launder it, and frequent laundering helps reduce pathogens. Soon all medical professionals adopted the practice. White coats were worn not only to protect one’s clothing, but they were seen as a sign of prestige and respect.

Today, white coats are rarely used, because according to Dennis Miller, “White coats cause white coat syndrome” (hypertension) and they “increase the distance between the pharmacist and the customer.” Few states regulate pharmacy technician attire. Many institutions and most large retail chains require pharmacy technicians to wear uniform “scrubs.” Restricting white coats to professional staff may reduce some customer confusion, but in certain situations, scrubs might imply the wearer is a nurse or other hospital professional, which is also confusing. One of this CE’s authors says, “I can’t even tell you how many patients and families would ask if I was a nurse.”

Recently, some hospitals have banned pharmacy technicians from wearing scrubs, forcing them to wear civilian clothing. Unfortunately, that makes technicians look like pharmacists again. Of course, some pharmacists like to wear scrubs to work; are they secretly wishing they were technicians? Doubtful. Business attire has certainly gone downhill lately. So, if we can’t wear a white coat and we can’t wear scrubs, what are we to wear?

THE ANSWER (which is required by law in many states): A name tag that indicates your position!

The current standards state that personnel involved in compounding should garb “as needed for personal protection and to prevent contamination” of the compounded nonsterile product (CNSP) prior to preparation.⁶ For example, compounding staff don two pairs of gloves for personal protection when preparing cytotoxic CNSPs for their own safety. More information on hazardous compounding can be found in General Chapter <800> Hazardous Drugs – Handling in Healthcare Settings. The current standards also state compounding personnel are responsible for maintaining good hand hygiene and wearing appropriate clothing to prevent contamination of the CNSP.⁶ These statements give compounding personnel some latitude when they make decisions. For example, currently, some compounders don gloves to make magic mouthwash, while many others prepare it with ungloved hands in their practice. Nonsterile gloves will become mandatory on November first.

The newly revised standards now specify hand washing and garbing procedures and provide guidance on personnel who should NOT prepare a CNSP. Compounding personnel are to remove all “garments that cannot be easily cleaned” before entering the designated compounding area. So compounding personnel must now remove personal outer garments (such as jackets, sweaters, hats, and scarves), hand and wrist jewelry, anything that might hinder the use of gloves, and headphones must be removed before compounding something as simple as magic mouthwash. Compounding personnel must wash their hands for at least 30 seconds and dry with one-time use paper towels before compounding as well. After handwashing, personnel must don nonsterile gloves and inspect the gloves for holes, rips, or tears. Compounding personnel should wipe or replace gloves in between different preparations and must remove these gloves before leaving the designated compounding area.⁶These proposed standards are analogous to the procedures required for sterile compounding. In fact, the format of and definitions within the revised <795> aligns with the revised <797> for sterile products much more closely than in the past.

The current standards still require personnel to be in good health and fit for compounding, but the revisions are considerably more specific. Personnel who have new tattoos, oozing sores, open wounds, conjunctivitis, rashes, or active respiratory infections are not considered fit to compound due to risk of contamination of the CNSP. The newly revised standards hold the designated person responsible for deciding if personnel are fit for compounding or not.⁶

Cleaning the Designated Compounding Area

Do I need to create an area for compounding? Yes. The newly revised standards describe a designated compounding area in detail. Some readers are thinking, “My pharmacy is small. Can I use the area for tasks other than compounding?” The designated compounding area is a space with a marked perimeter that is required to be clean, orderly, sanitary, well-lit, and have low foot traffic, and no other activities can occur in this space simultaneously. You may perform other duties there if there is no compounding going on as long as someone cleans the area before compounding again. The newly revised standards suggest the designated compounding area be uncarpeted for easier cleaning, which in one of this CE’s author’s opinion should be changed to a must, since carpets tend to harbor dust and dander, and can be very difficult to clean. (Have you ever dropped and broken a bottle on the carpet in your pharmacy? It’s not pretty.)

The compounding area must be used in a manner that prevents cross contamination of CNSPs from other areas of the pharmacy. For compounding to be completed in the most efficient manner possible, all equipment in the designated compounding area must be arranged in a way that prevents errors. Last, the facility’s standard operating procedures (SOPs) must always include this information and be available to staff.

The current standards simply state that compounding equipment “shall be clean, properly maintained and used appropriately.”⁶ This statement allowed compounding personnel to decide on their own standard of clean when preparing a CNSP and their own definition of when or if they should clean. The newly revised guidelines strengthen the minimum requirements for cleaning the designated CNSP compounding area. The USP dedicates an entire section to cleaning procedures, representing a major change in the standards. The new standards indicate that personnel must clean the perimeters—walls and ceilings—when visibly soiled, after spills, and when surface contamination occurs.⁶ Readers will see that visible soil, spills, and surface contamination form a frequent theme in the newly revised standards!

The new standards also establish a routine cleaning schedule. The section, “Cleaning and Sanitizing” states pharmacy personnel must clean work surfaces at the beginning and end of each shift at a minimum, between each CNSP, and again if spills or surface contamination occurs. The standards add that personnel must clean floors daily on days when compounding occurs, and again if spills or surface contamination occurs.^6.Personnel must clean storage shelves every three months, after spills, and when surface contamination occurs. Personnel qualified to clean can be defined as any staff member who has been properly trained and observed in a facilities cleaning procedures. That means that pharmacy staff can train housekeeping staff to complete the cleaning.

Personnel need to clean and sanitize, and if two separate products are used—one to clean and one to sanitize—cleaning is done first, followed by sanitizing second. Selecting appropriate cleaning products requires careful attention. They should be (1) compatible, (2) effective, and (3) leave minimal residue. Finally, daily documentation is essential on days when compounding occurs.⁶ An old adage applies here: cleaning is not truly done unless it is documented. High tech organizations commonly complete this documentation using an online platform integrated with other daily documentation requirements such as daily temperature monitoring, but a simple sign off sheet is also acceptable. A best practice is to include any cleaning and its documentation into the compounder’s daily workflow, so it is not forgotten. Daily and or weekly task charts can be created to include all activities that need to be performed.

PAUSE AND PONDER: How were you originally trained to compound? Were you told to watch how it was done and then you were on your own?

Training

Another major area of change is the training of compounding personnel. The current standards state that compounders must be “proficient in compounding” and suggest that compounders should pursue knowledge by attending seminars or studying literature related to compounding. It also states that compounders must be conversant on General Chapter <795> and familiar with General Chapter <797>. With standards this vague, and no required number of CE credits on this subject, how often do you think compounding personnel previously searched for compounding topics? Also, the current standards simply require at a minimum compounding personnel to be trained and capable of the compounding duties assigned to them, and for someone to document the training. Compounding duties include verifying critical processes like weighing and mixing that occur frequently during compounding.

The newly revised standards will require a more structured training program for compounding personnel. All compounding personnel must complete this training program initially before being allowed to compound and every 12 months thereafter. The newly revised standards require compounding personnel to repeat compounding procedures “independently while under the supervision of the designated person or assigned trainer for completion of the training program.”⁶ The organization’s designated person will be responsible for designing the training program, which must include

the required training, meaning a detailed description of the training
the frequency of training, and
the process used to evaluate competency.

Table 1 lists the training program’s required topics. It is interesting to note that pharmacists who do not compound but complete in-process checks, verification, or dispensing also must complete the CNSP training program before completing checks, verification, or dispensing. A training program may include an online portion of reading or videos teaching concepts with quizzes to evaluate understanding, and a physical portion to evaluate measuring, mixing, and overall compounding. The designated person or assigned trainers can train personnel, and of course, they must document the completion of the training program.⁶

Table 1. Proposed General Chapter <795> Required Topics for Training⁶

Training programs must teach compounding personnel the following:

· cleaning and sanitizing

· documentation such as Master Formulation Records and Compounding Records

· hand hygiene and garbing

· handling and transporting CNSPs and their components

· measuring and mixing

· proper use of compounding equipment and devices

· understanding General Chapter <795>

· understanding safety data sheets

· understanding procedures to complete compounding duties

It is important to note this table only lists the minimum requirements, additional requirements may be necessary according to each facility’s needs.

The Designated Person

The necessity to designate a person who has oversight and full responsibility for compounding practices now in General Chapter <800> is included in proposed General Chapter <795> and <797>. The current standards again broadly describe the requirements. The chapter states that compounding personnel are responsible for adhering to the general principles of compounding outlined in the current standards. It specifies several responsibilities, which include training, selecting ingredients for compounding, labeling, and cleaning. However, since the compounding process may include many people, the ultimate accountability is unclear.

To clarify accountability, the proposed General Chapter <795> requires each organization to designate one or more persons to be responsible and accountable for nonsterile compounding. The designated person’s responsibilities include ensuring the organization develops written formal quality control and quality assurance procedures and reviews them annually. The designated person must monitor and observe compounding, identify areas of error, and take corrective action if needed. The designated person has several other responsibilities. These include⁶

establishing, documenting, and monitoring SOPs within the CNSP compounding area to include component handling and storage
ensuring that all staff members follow all SOPs
reviewing complaints
determining if potential issues are likely with CNSPs
selecting components to be used in compounding

Beyond Use Dates

The final major difference is the establishment of beyond-use dates (BUD) for CNSPs. The current standards hold compounders responsible for establishing BUDs based on their observation of the drug during compounding. Compounders (not a designated person) are held responsible for noticing signs of instability and using their education and experience to assign a BUD to the final preparation.⁶ The current standards also recommend assigning BUDs based on three categories: non-aqueous, water-containing oral, or water-containing topical. The new guidelines are based on the activity of water (a_w) in each product.

Table 2 compares the current and proposed BUD recommendations.⁶

Table 2. A Comparison of BUD Requirements^6,7

Description	Minimum BUD requirement
	Current USP <795>	Proposed USP <795>
Aqueous non-preserved	14 days in refrigerator	14 days in refrigerator
Aqueous preserved	14 days in refrigerator	35 days controlled room temp or refrigerator
Aqueous topical (Cream, lotion, shampoo, nasal spray, gel, rinse, foam, etc.)	30 days	35 days if preserved 14 days if non-preserved See activity of water chart
Nonaqueous oral (Oil or powder filled capsule, glycol or oil based oral solution, compressed tablet, powder for inhalation, troche, lollipop, etc.)	6 months	90 days
Nonaqueous (Medicated stick, ointment, suppository, etc.)	6 months	180 days (6 months)

Proposed General Chapter <795> determines BUDs based on a preparation’s water activity (a_w,see SIDEBAR), which is more clearly defined as aqueous and non-aqueous by the following distinction:

CNSPs with an a_w ≥0.6, considered aqueous dosage forms
CNSPs with an a_w<0.6, considered non-aqueous dosage forms

SIDEBAR: Activity of Water^7-10

The water in a preparation can “participate in chemical, biochemical, or physicochemical reactions.” However, it is not the water content (such as % water in the CNSP), but rather the activity of water that determines the water’s availability to participate in degradation reactions and allow microbial growth. Therefore, compounders must determine a BUD by considering the preparation’s water activity and not the preparation’s water content.

Water activity is roughly equivalent to relative humidity, except that relative humidity is expressed in terms of percent and water activity is expressed as a fraction. So, a water activity of 0.6 is roughly equivalent to 60% relative humidity. If the dosage form with a water activity of 0.6 were to be sealed in a package, any surrounding space would eventually have a relative humidity of 60%. Compounders can measure water activity for a specific preparation by the procedures outlined in General Chapter <922> Water Activity. However, the proposed General Chapter <795> provides an easy classification system (see Table 3).

The a_w cut-off of 0.6 established in USP comes from various studies showing no microbial growth of any kind in foods below this value. Although the water activity determination was constructed using food, it is also the basis of USP <1112> Water Activity Determination and is the foundation for the BUD rationale in the proposed <795>. A product with an a_w greater than or equal to 0.6 has been shown to have increased bacterial, fungal, and other microbial growth. However, in products with an a_w below the threshold of 0.6, no microbial growth was found.

The newly revised standards recommend adding antimicrobial agents to any CNSP with an a_w at or exceeding 0.6 when assigning a BUD of 35 days. Even components as simple as ascorbic acid can help extend the BUD. As always, careful research must be done to determine suitable preservatives for each product and if an extended BUD date is assigned, the preparation must be tested for antimicrobial effectiveness. Consider one formula for magic mouthwash, which might have an a_wof 0.73 and contains no preservatives. With no USP monograph, one would refer to Table 3 to determine that the BUD should be limited to 14 days when stored in the refrigerator. We are sure that pharmacists compounding blue mass syrup could have cared less about the activity of water in their concoctions. We wonder if they would have viewed mercury as a preservative.

Compounders can assign non-aqueous dosage forms with an a_w less than 0.6 a maximum BUD of 90 days for an oral liquid and 180 days for alternative routes.

While the newly revised standards provide strong guidance on determining a CNSP’s BUD, compounders should only use its tables if no other stability information is available. The designated person is responsible for searching for stability information for each CNSP and determining if a CNSP can have a BUD beyond that specified in Table 2. If the designated person finds an extended BUD appropriate, compounding staff must test it for antimicrobial effectiveness. However, if compounding staff is following a United States Pharmacopeia- National Formulary (USP-NF) monograph for CNSP preparations, the BUD must not exceed that which is indicated in the monograph. Last, the CNSP’s components should drive the overall expiration date, which is not a change from the current standards.

Table 3. Proposed General Chapter <795> classification of commonly compounded dosage forms as non-aqueous or aqueous partial list.

Nonaqueous Dosage Forms a_w<0.6

Aqueous Dosage Forms a_w ≥0.6

- Animal treat, oil based

- Capsule: oil filled or powder filled

- Oral solution: glycol based or oil based.

- Glycol based gel

- Stick or lip balm

- Tablet compressed or triturate

- Sorbitol based lollipop

- Ointment: hydrophilic petrolatum polyethylene and mineral oil based

- Oral suspension: fixed oil

- Powder for inhalation

- Suppository: polyethylene glycol base or fatty acid base

- Troche or lozenge: gelatin based or glycol based

- Animal treat

- Foam

- Shampoo

- Cream: oil in water emulsion, emollient cream, petrolatum, and mineral oil gel: alcohol free aqueous or hydroxypropyl methylcellulose gel

- Lotion

- Nasal spray

- Rinse

- Oral solution: water based, low sucrose syrup vehicle

- Oral suspension

CONCLUSION

Compounders face many of the same challenges today as they did in the 1800s. They were faced with a limited drug list, similar to a closed formulary in today’s world. They searched for alternative therapies, and they did, as we still do, face many drug shortages. The main difference is that we have advanced knowledge to make better products to keep patients safer.

The time has come to designate your area, designate your person, and train your staff, including pharmacists who may not actually be compounding! Keep the designated area clear for compounding use only, if possible, and remove any unnecessary items before entering. Set up a cleaning routine for the entire space, including floors, walls, and shelving, and incorporate the routine into the daily workflow so it is never forgotten. Train your staff well to the new standards and reevaluate every 12 months. Look into the literature to determine the best BUD for each CNSP and when information is not available, use USP guidance for assigning a BUD date. Choose a designated person wisely, as they need to be responsible and organized with taking responsibility and accountability for all nonsterile compounding occurring in the facility.

Remember, improvements in non-sterile compounding standards will make for higher quality and safer compounded non-sterile products for our patients and are enforceable come November 1, 2023.

After completing this continuing education activity, pharmacists and pharmacy technicians will be able to

1. Describe recent changes to USP <795>
2. Identify the designated person’s responsibilities
3. Recognize areas of nonsterile compounding that could be improved

1. The USP made major revisions to General Chapter <795> in the newly revised standards. What topics are affected?
a. Cleaning, training, purchasing, designated person, and verification processes.
b. Garbing, training, sanitizing, designated person, purchasing.
c. Garbing, cleaning, training, designated person, and BUDs.

2. When will the proposed General Chapter <795> become enforceable?
a. It is already enforceable
b. July 1, 2023
c. November 1, 2023

3. Which of the following conditions would make compounding personnel unfit for compounding at the discretion of the designated person?
a. Recent placement of a temporary (water-removable) tattoo
b. Cough, runny nose, and upper respiratory congestion
c. All of the above.

4. Who must create and enforce a new training program under the newly revised standards?
a. Only staff who will perform compounding
b. All personnel involved in compounding verification and dispensing
c. The designated person or the designated person’s designee

5. How often must the training program and reevaluation of competency be completed?
a. Once prior to compounding, and then every 12 months
b. Once after November 1, 2023, and then biannually
c. Once only, since compounding never changes

6. Sally is about to enter the compounding area. She is wearing makeup, a set of bangle bracelets, and sterile gloves. Which item is not allowed when compounding a CNSP?
a. Makeup
b. Wrist jewelry
c. Gloves

7. Which of the following must the designated person complete personally (that is, not train or delegate to others)?
a. Cleaning the compounding area twice daily
b. Identifying BUDs for all compounded products
c. Ensuring staff follow all operating procedures

8. The FDA visits your pharmacy after several patients develop infections related to a CNSP compounded in your facility. They find that the BUD was incorrect and the product was contaminated. Who will ultimately “take the fall” for this issue?
a. The designated person.
b. The entire pharmacy department.
c. The compounder who prepared the CNSP.

9. Which of the following CNSP properties now restricts the maximum BUD?
a. Activity of water
b. Time till it reaches the patient
c. Duration of treatment

10. Your supervisor tells you it’s time to improve your organization’s compounding. You need to find the best area for compounding. Which of the following is the best option for a designated compounding area?
a. The farthest corner of the pharmacy provided that customers cannot see it and housekeeping staff indicates it is clean
b. A carpeted section of the pharmacy next to the employee refrigerator that has easily cleanable countertops and shelving.
c. A well-lit, uncarpeted area with easily cleanable countertops that is segregated from countertop space used for daily activities

After completing this continuing education activity, pharmacists and pharmacy technicians will be able to

1. Describe recent changes to USP <795>
2. Identify the designated person’s responsibilities
3. Recognize areas of nonsterile compounding that could be improved

2. When will the proposed General Chapter <795> become enforceable?
a. It is already enforceable
b. July 1, 2023
c. November 1, 2023

9. Which of the following CNSP properties now restricts the maximum BUD?
a. Activity of water
b. Time till it reaches the patient
c. Duration of treatment

References

Massae Pilularum—pill masses, Henriette’s Herbal Homepage. Accessed June 2, 2023. https://www.henriettes-herb.com/eclectic/kings/massae-pilu.html
Watson, C.J., Whitledge, J.D., Siani, A.M. et al. Pharmaceutical Compounding: a History, Regulatory Overview, and Systematic Review of Compounding Errors. J. Med. Toxicol. 17, 197–217 (2021). https://doi.org/10.1007/s13181-020-00814-3
USP Timeline. www.usp.org. Accessed March 21, 2023. https://www.usp.org/200-anniversary/usp-timeline#:~:text=1820&text=Concerned%20about%20the%20dangers%20of
Sprowls, Joseph Barnett, Lewis W. Dittert, and Rufus Ashley Lyman. Sprowls' American Pharmacy: An Introduction to Pharmaceutical Techniques and Dosage Forms. Lippincott Williams & Wilkins, 1974. page 3.
Miller D. Are those white coats really necessary? Accessed June 3, 2023. https://www.drugtopics.com/view/dear-pharmacists-are-those-white-coats-really-necessary
USP. Pharmaceutical Compounding - Nonsterile Preparations <795>. In: USP-NF. Rockville, MD: USP; May 1, 2020.

DOI: https://doi.org/10.31003/USPNF_M99595_05_01

USP. Pharmaceutical Compounding - Nonsterile Preparations <795>. In: USP-NF. Rockville, MD: USP; November 1, 2023.

DOI: https://doi.org/10.31003/USPNF_M99595_06_01

USP. Applications of Water Activity Determination to Non-sterile Pharmaceutical Dosage Products <1112>. In: USP-NF. Rockville, MD: USP; 2013

DOI: https://doi.org/10.31003/USPNF_M402_01_01

USP. Water Activity <922>. In: USP-NF. Rockville, MD: USP; May 1, 2021.

DOI: https://doi.org/10.31003/USPNF_M12475_02_01

Sikorski ZE. Fennema's food chemistry (fifth edition) edited by SrinivasanDamodaranKirk L.parkin CRC press, Boca Raton, Florida, 2017. 1107 pp. ISBN 9781482208122. J Food Biochem. 2018;42(2):e12483-n/a. doi: 10.1111/jfbc.12483.

Patient Safety: Social Media Sensation: Semaglutide

After completing this application-based continuing education activity, pharmacists will be able to

· Recall the mechanism of action and dosing schedule of GLP-1 receptor agonists

· Classify adverse reactions most commonly associated with GLP-1 receptor agonists

· Discuss GLP-1 receptor agonists indications for use

After completing this application-based continuing education activity, pharmacy technicians will be able to

· Identify the different formulations of GLP-1 receptor agonists

· Classify storage requirements for GLP-1 receptor agonists

· Review GLP-1 receptor agonists indications for use

Recently, it’s a rare day when the national news outlets and social media platforms don’t discuss medication-assisted weight loss. Semaglutide has become a social media sensation for its ability to help people–even people who do not have diabetes (its approved indication) lose weight. With celebrities reporting significant weight loss with off-label use of glucagon-like peptide-1 (GLP-1) receptor agonists, pharmacy teams are fielding questions and juggling prescriptions to deal with drug shortages. This continuing education activity provides basic facts about using GLP-1 receptor agonists for weight loss.

INTRODUCTION

Lifestyle modifications have been the mainstay of weight management for years. We’ve all heard the advice: Exercise more, eat less, limit fried foods and sugary drinks, and the weight should slowly disappear. As the weight comes off, you might have some setbacks but just keep tracking your foods and your success is right around the corner.

If only it was that easy!

Scroll any social media platform today and search the term, “#ozempicweightloss” and a plethora of joyful testimonials appear. Some videos have reports of people losing 17 pounds in 3 months or 64 pounds in a year with no cravings for food. “I can eat whatever I want!!” cried a satisfied user. It is as if the golden ticket has been found in all the candy bars ever produced and everyone is going to the candy factory!

Although the recent media emphasis has been on semaglutide, and the Ozempic product primarily, other glucagon-like peptide-1 (GLP-1) receptor agonists have also been associated with weight loss to varying degrees. This continuing education activity’s primary focus is to clarify misinformation, highlight specific GLP-1s’ risks and benefits when used for weight loss, and answer frequently asked questions.

WHAT ARE GLP-1 RECEPTOR AGONISTS?

Major breakthroughs in the physiology of the pancreas occurred in the early 1900s.¹At that time, physiologists thought the nervous system had exclusive control of all bodily functions. That idea changed when two scientists, William Bayliss and Ernest Starling, discovered a chemical compound they named secretin. Released from intestinal mucosa, secretin stimulated the pancreas.²Shortly after the discovery of the hormone insulin in 1921, research being conducted at the time primarily stimulated the pancreas to produce insulin by administering glucose via the intravenous route. However, when glucose was administered orally (allowing nutrients to travel to gastrointestinal areas), insulin levels improved substantially. This observation was known as the incretin effect. As a result, two insulinotropic hormones were later identified as incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) discovered in 1971 and glucagon-like peptide-1 (GLP-1) discovered in 1985.^1,2

Analyzing the venom of the Gila monster (Heloderma suspectum) in 1990, endocrinologist Dr. John Eng discovered a peptide that stimulated insulin release from the pancreas.³ Named exendin-4, this peptide was similar in structure and function to GLP-1 found in humans. One problem with GLP-1 was that when it is released into the body, dipeptidyl peptidase-4 (DPP-4). quickly inactivated it. Researchers then developed the DPP-4 inhibitors to allow GLP-1 to remain active for a longer period of time. However, synthetically producing GLP-1 receptor agonists (GLP-1RA) directly has extended the peptide’s life. Initial development resulted in twice daily and then daily administration (half-life of 13 hours) of GLP-1RAs. However, when researchers combined semaglutide with a free fatty acid side chain that was tightly bound to albumin, its half-life was increased substantially. The resultant half-life of 165 hours led to an advantageous injection administration schedule for semaglutide: once weekly.^3,4,5

Mechanism of Action

As a class of medications, all GLP-1RAs share common mechanisms of action in the treatment of diabetes: stimulate the pancreas to secrete insulin, suppress the action of glucagon, and decrease gastric emptying.⁴ Scientists previously studied the effects of GLP-1 and noticed that the protein, when injected in rats, decreased appetite quickly.⁵Once clinicians began using GLP-1RAs to treat diabetes in humans, they also observed weight loss due to decreased appetite, increased feelings of fullness, and reduced caloric consumption.⁴

Researchers determined that the brain contained GLP-1 receptors. Weight loss was due to GLP-1RAs ability to travel to these receptors and influence specific areas of the hypothalamus that are key to controlling appetite, calorie consumption, satiety, and body weight.⁴Among GLP-1RAs, semaglutide and liraglutide stimulate the highest amount of weight loss success.

Comparison of GLP-1 drugs

Table 1. GLP-1RAs for Weight Loss

Medication

Dosing

Counseling points

Supplies needed for injection

Semaglutide (Wegovy)

Adult and pediatric patients aged 12 and older, starting dosage at 0.25 mg injected subcutaneously once weekly.

Weeks 1-4: 0.25 mg

Weeks 5-8: 0.5 mg

Weeks 9-12: 1 mg

Weeks 13-16: 1.7 mg

Weeks 17 & forward: 2.4 mg maintenance dose once weekly.

If adverse reactions occur during the upward titration period, consider delaying increase in dosage for four weeks.

Consider discontinuing the drug if patients do not lose at least 5% of baseline body weight within 3 months

1 alcohol swab or soap and water

1 gauze pad or cotton ball

1 sharps disposable container for used Wegovy pens

Liraglutide

(Saxenda)

Adults and pediatric patients aged 12 and older, starting dosage at 0.6 mg injected subcutaneously once daily. (NOTE: This is a DAILY dose)

Week 1: 0.6 mg

Week 2: 1.2 mg

Week 3: 1.8 mg

Week 4: 2.4 mg

Week 5 & forward: 3 mg maintenance dose daily.

If adverse reactions occur during upward titration period, consider delaying dose increase for approximately one additional week.

Patients can continue on maximally tolerated dose if goal weight loss achieved on that dose.

Soap and water

Pen needle: 8 mm

(Novofine or NovoTwist)

1 sharps disposable container for pen and needles

Adverse Drug Reactions and Boxed Warning

GLP-1 agonists all have similar and common gastrointestinal adverse effects (nausea [~15–30%], vomiting [~10-15%], diarrhea [~5-10%], abdominal pain, constipation).^6,7,8 Patients can use some strategies to possibly mitigate these adverse effects^6,7,8:

Increasing the GLP-1 agonist dose slowly
Staying hydrated and increasing fiber
Avoiding high-fat foods and alcohol
Stopping eating when full (and eating only when hungry)
Spacing meals appropriately
Using short-term proton pump inhibitors or H₂ blockers if needed

Patients may also experience headache, fatigue, dyspepsia (gastrointestinal upset), dizziness, abdominal distension, eructation (burping), hypoglycemia in patients with type 2 diabetes, flatulence, gastroenteritis, and gastroesophageal reflux disease.⁷ Clinicians should evaluate patients for gallbladder disease if cholelithiasis (gallstones) or cholecystitis (an inflamed gall bladder) is suspected.

Reports of patients experiencing hair loss have surfaced recently from news and social media. Listed as an adverse reaction for Wegovy, but not for Ozempic, the Wegovy dose is much higher for treatment of weight loss.⁹ Some clinicians think that the rapid loss of weight triggers the body to conserve calories consumed for essential functions.⁹ Since patients eat less while taking the medications, their diet may consist of lower amounts of protein and minerals important for hair growth. Clinicians have seen hair growth resume once the body reaches a plateau in weight loss, therefore the loss of hair is not permanent.⁹

These drugs also share a boxed warning for risks of pancreatitis and medullary thyroid carcinoma (cancer in the thyroid gland in its medulla, the calcitonin-producing area), which is rare.⁶ Patients with a personal history of pancreatitis or a personal or family history of medullary thyroid carcinoma must avoid these drugs.⁶

These drugs also required an FDA approved Medication Guide whenever GLP-1RAs are dispensed. Pharmacy technicians can be very helpful to pharmacists if they check the patient’s bag and make sure that the Medication Guide is in it.

Recent Shortages of GLP-1 Receptor Agonists

The sensation of weight loss success for some has caused serious problems for other patients who have diabetes and are struggling to find medication at local pharmacies. Staff in community-based pharmacy practice are well aware of the semaglutide shortages that have occurred in the past year. Pharmacists and technicians should be able to explain the current drug shortages, adverse reactions, and FDA approved or off-label use to patients and other healthcare providers.

“Ozempic face”

As social media and now news media have reported the success of dramatic weight loss, some users bemoan weight loss woes associated with use of GLP-1 agonists. The term, “Ozempic face,” introduced by a dermatologist in New York, describes the typical female patient who has lost a significant amount of weight on semaglutide but now needs (or wants) dermal fillers for her sagging facial structures.¹⁰ Patients complain about sagging skin and a gaunt appearance, two problems that follow the loss of facial fat after any harsh weight loss.

Facial fat loss is common when patients lose weight, and when the weight loss is significant, patients will look older. Skin wrinkles and loosens—hallmarks of aging. Similar to weight loss from old-fashioned dieting, fat loss while taking GLP-1 agonists affects the entire body (not just the face). But patients on GLP-1 agonists for cosmetic weight loss fail to understand that they can’t just lose weight where they’d like to lose weight. The facial fat loss is distressing to them.¹⁰ Pharmacy teams need to know that “Ozempic face” is a slang term, and GLP-1 agonists don’t specifically target the face.¹¹

Weight Loss Blockbuster or Fad

Over the past two years, celebrities and social media influencers have posted successful weight loss stories while using semaglutide and as a result, catapulted its popularity as a weight loss miracle.¹²Questions remain as to how long the weight loss effect will last and if patients will gain the weight back once stopping the treatment. Novo Nordisk, semaglutide’s manufacturer, indicates weight loss can be sustained with long-term use. However, the data collected is limited by a time span of two to three years. Since people who pay out-of-pocket for semaglutide will pay around $1200 per month and some insurance companies may not cover the medication, pharmacists should counsel patients that once the medication is discontinued, weight gain is likely to occur and the weight gain might exceed the original amount lost.¹²

FDA APPROVED AND OFF-LABEL USE

In December of 2017, the FDA approved semaglutide (Ozempic) for the treatment of diabetes. As significant weight loss was observed, the Semaglutide Treatment Effect in People with obesity (STEP) studies produced promising weight loss data.¹³ As a result, the FDA approved semaglutide for an additional indication, weight loss, in June 2021 under the brand name Wegovy.

Diabetes

In patients with type 2 diabetes mellitus (T2DM), semaglutide is used in combination with diet and exercise to reduce blood sugar levels.¹⁴ In patients with T2DM who additionally have established cardiovascular disease, liraglutide and semaglutide are indicated to help lessen the risk of major cardiovascular incidents. Dulaglutide, liraglutide, and semaglutide also have beneficial effects on chronic and diabetic kidney disease.⁶ Patients who have a history of pancreatitis should avoid any member of the GLP-1RA class and they are not to be used as treatment for patients who have type 1 diabetes.

Dosing semaglutide for the treatment of diabetes requires a period of time for dosage escalation to minimize adverse effects. The FDA has approved both subcutaneous and oral semaglutide (Rybelsus) dosage forms, but only the injectable version is approved for weight loss. Subcutaneously, semaglutide is initially dosed at 0.25 mg once weekly, and after four weeks the patient should increase to 0.5 mg weekly for four weeks. Doses of 1 mg and 2 mg are optional if glycemic control has not been achieved, however the 1 mg dose should also be used for a minimum of four weeks before increasing to the maximum 2 mg strength.⁶ Dosed on the same day of the week, injections can be dosed at any time of the day with or without regard to meals. Patients sometimes miss or forget their scheduled dosing day. If this occurs, patients should inject the dose within 5 days of the missed dose.⁶

Patients who have diabetes and currently use metformin, sulfonylureas, thiazolidinediones, or insulin can use semaglutide in combination. However, patients can administer semaglutide and insulin injections at the same time and in the same areas of the body, but not close together; they must never mix them together in the same syringe.¹⁴ Hypoglycemic episodes are possible when using a sulfonylurea and/or insulin with semaglutide. Pharmacists therefore should remind patients of the signs and symptoms of hypoglycemia when these drugs are used together. Prescribers may need to adjust the dose of insulin and/or a sulfonylurea when starting semaglutide.⁶

Obesity and Weight Management

Affecting 70% of American adults, obesity and being overweight contribute to a variety of complications and have reduced quality of life.¹⁵ Debilitating and expensive disease states associated with obesity include: T2DM, cardiovascular disease, osteoarthritis, sleep apnea and cancer.^13,15 Since obesity has roughly tripled worldwide from 1975 to 2016, investigating the reasons for the rise in prevalence and finding solutions is of utmost importance to prevent and treat obesity.¹⁶

The access and ease of inexpensive prepared high caloric foods, limited physical activity, and sedentary life styles are factors that have contributed to the rise of obesity.¹⁷ As mentioned, treatment typically has concentrated around the modification of these lifestyle habits.¹⁸ Although the weight reduction is usually moderate in magnitude, it is recovered over time (yes, that means that people gain the weight back!).¹³

Anti-obesity medications have been added to lifestyle modifications. Discouraged by adverse drug reactions, contraindications, cost, and moderate weight loss results with weight that is regained over time, many patients and prescribers are hesitant to consider these treatment options.¹⁶

Maintaining weight loss has proved equally difficult due to the regulatory centers in the brain that control appetite. Increased hunger and abnormal satiety signals controlled by neuroendocrine pathways have been discovered in the hypothalamus.¹⁶ Researchers have also identified levels of hormones that regulate weight in the hypothalamus. These hormones (leptin, ghrelin, peptide YY, and GIP) play a role in counteracting weight loss after dieting and lead to regain of weight.^{17, 16}

Once semaglutide was approved for the treatment of diabetes, clinical trials focused on weight loss. The STEP trials were phase 3 studies implemented to evaluate the safety and efficacy of semaglutide 2.4 mg subcutaneously once weekly injections for 68 weeks. Patients enrolled in the studies were adults with obesity or overweight, a mean age of 46.2 to 55.3 years, mean BMI of 35.7 to 38.5 kg/m², and were mostly female (mean: 74.1% to 81.0%) for five of the trials.¹³All studies included lifestyle interventions at varied intensities.^{13, 18}In one of the larger studies that compared semaglutide with placebo, semaglutide was associated with a 12.4% loss of body weight.¹⁵As a result of the ≥ 5% in weight loss exhibited in the studies, the FDA approved semaglutide for chronic weight management.^18,15 The approval came in June of 2021, and the manufacturer marketed semaglutide as Wegovy.

The STEP 8 trial compared once-weekly semaglutide to once-daily liraglutide and enrolled 338 adult patients with 126 receiving semaglutide 2.4 mg, and 127 participants receiving liraglutide 3 mg. Participants were overweight or obese, without diabetes, had a mean BMI of 37.5, and most had 0-2 comorbidities with dyslipidemia and hypertension being the most frequent.^{19, 18} The primary results at 68 weeks reported an estimated mean change in body weight at -15.8% with semaglutide, and -6.8% with liraglutide.¹⁹ Based on data from this STEP study, the researchers concluded semaglutide is far superior to liraglutide when used for weight loss and had significantly improved cardiometabolic risk factors.^{19, 18}

The most frequent adverse side effects reported in the STEP studies were gastrointestinal disorders. Most gastrointestinal side effects were considered mild or moderate in severity and usually were most prominent during the dose titration phase.¹⁹ In the STEP 8 study, semaglutide (84.1%) reported a higher occurrence of gastrointestinal events than liraglutide (82.7%).¹⁹ Other side effects reported were hypoglycemia, acute pancreatitis, gallbladder disorders that generally resulted in cholelithiasis (gall stones), malignant neoplasms (cancer), change in pulse and injection site reactions.^{18, 19}

SIDEBAR: Alcohol use disorder potential

As patient use of semaglutide has expanded over the past several years, a side effect has emerged that is surprising many clinicians. Patients have reported an abrupt loss in the desire to drink alcohol, almost to the point of repulsion for some patients. GLP-1RAs are known to decrease the desire, enjoyment, and consumption of fatty foods in humans, but observations that patients began to decrease alcohol consumption was unexpected. Although studies to date have observed a reduction of alcohol in rats, mice, and monkeys when receiving GLP-1RAs, reliable researchers avoid extrapolating results from animal studies directly to humans, especially since humans tend to consume more alcohol than animals.²⁰ Since several patients have reported decreased intake of alcohol and data from animal models reflect these results, researchers are starting to investigate GLP-1RAs effect on patients who have alcohol use disorder (AUD).

Existing studies on GLP-1RAs effect on AUD in humans are minimal. A recent study published from Denmark compared the use of a different GLP-1RA, exenatide 2 mg versus placebo in patients with AUD. Researchers were looking to determine if exenatide reduced the amount of heavy drinking days. At the same time, functional MRI brain scans were also completed during the study that focused on areas involved in addiction and reward centers of the brain. Administered once weekly to 127 patients along with cognitive behavior therapy for 26 weeks, exenatide failed to show a decrease in heavy drinking days.²¹ However, in a subgroup of obese patients (BMI > 30 kg/m²) heavy drinking days and total alcohol intake was reduced.²¹ Brain scans revealed weakened alcohol cue reactivity and lower dopamine transporter availability for those patients in the exenatide group.²¹

Ongoing phase two clinical trials are studying the effects of semaglutide on patients with AUD.²² Since semaglutide usage and availability have increased with approved indications for diabetes and obesity, researchers are continuing to investigate this drug class for potential promising new therapies.

Product information

When used for chronic weight management, semaglutide (Wegovy) is approved in addition to a reduced calorie diet and increased physical activity.^{7, 15} Semaglutide is indicated for patients who meet one of the following criteria: BMI of 30 kg/m² or greater, or patients who have a BMI of 27 kg/m² with at least one comorbid weight related condition (cancer, cardiac disease, diabetes, dyslipidemia, obstructive sleep apnea).^{7, 15} Available in a prefilled pen that contains one dose, semaglutide is a clear and colorless liquid that can be injected into the upper arm, lower stomach or upper thigh.⁷Semaglutide should be stored in the refrigerator between 36°F to 46°F (2°C to 8°C).⁷ If the pen has been frozen, exposed to light, or heat above 86°F (30°C), the pen should be discarded. The pen remains stable and active for 28 days once removed from refrigeration. Each pen contains the exact dose to be delivered with the needle located inside each pen, therefore each pen should be disposed of in a sharps container.⁷

Drug shortages, alternatives for therapy

Shortly after marketing Wegovy, the facility hired by Novo Nordisk to fill syringes was cited by the FDA for issues with current good manufacturing processes.^{23, 24} As a result, deliveries and manufacturing of Wegovy was halted in December of 2021.²⁴ At the same time, staggering demand for the drug was reported by the manufacturer mainly due to news and social media platforms announcing the success of several celebrity weight loss stories. As a result of the Wegovy shortage, prescribers started to write for Ozempic off label in an effort to treat obesity and therefore depleted the supplies of Ozempic.²⁴At the end of 2022 and early 2023, Novo Nordisk announced that supply issue resolution for Wegovy was on the horizon and that production of the drug was being increased. Due to residual and increasing demand though, some supply issues might continue sporadically but over time distribution centers and pharmacies should receive more drug product in the months ahead.²⁵

CONCLUSION

Probably the first drug to be considered a social media sensation, semaglutide’s entrance into the realm of prescription weight loss treatments has been filled with anticipation, fame, demand, intrigue, and acceptance. Lifestyle management will continue to play a role in losing and maintaining weight loss, with or without a GLP-1RA used in treatment for weight management. Long term use of semaglutide seems to be necessary to maintain a healthy weight but more research is necessary. Gastrointestinal side effects are seen as the most prevalent adverse effect, leading some patients to discontinue the drug. As availability of semaglutide increases due to resolution of the issues that halted production, price, and lack of coverage by insurance plans continues to be problematic for some patients. This is an area where pharmacy technicians can help by looking for coupons or patient assistance programs.

Researchers continue to investigate the various effects seen as a result of usage of semaglutide. Investigators are hopeful of finding new treatments for patients that are struggling with alcohol use disorder and addictive behaviors. GLP-1RAs will continue to be in the headlines for years to come. Pharmacists and technicians hold the golden ticket of information by helping patients and providers understand this unique class of medication’s history, mechanism of action, dosing, side effects, storage requirements, pricing and potential treatments being investigated.

Pharmacist Post-test

After completing this continuing education activity, technicians will be able to
• Recall the mechanism of action and dosing schedule of GLP-1 receptor agonists
• Classify adverse reactions most commonly associated with GLP-1 receptor agonists
• Discuss FDA approved and off-label therapeutic uses of GLP-1 receptor agonists

1. What are the GLP-1RAs’ common mechanisms of action in the treatment of diabetes?
A. Stimulate central glucose receptors to secrete insulin, suppress the action of glucagon, and decrease gastric emptying
B. Stimulate the pancreas to secrete insulin, suppress the action of glucagon, and decrease gastric emptying
C. Suppress the pancreas so insulin secretion decreases, increase the action of glucagon, and speed gastric emptying

2. Why do patients who take GLP-1RAs eat less?
A. GLP-1RAs influence specific areas of the hypothalamus that are key to controlling appetite
B. GLP-1RAs influence specific areas of the medulla that are key to controlling appetite
C. GLP-1RAs influence specific areas of the GI tract that are key to controlling appetite

3. Which of the following is a common adverse reaction associated with GLP-1RAs?
A. Vasovagal reaction
B. Blurred vision
C. Gastrointestinal upset

4. Joey is a 44 year-old-man who comes to the pharmacy and says that he is experiencing flatulence and burping ever since he started his GLP-1RA. Which of the following do you
suggest as a way to mitigate this adverse effect?

A. Reschedule the dose to take it right before bedtime
B. Recommend a probiotic with Lactobacillus
C. Avoid high fat foods and alcoholic beverages

5. Which of the following GLP-1RAs are approved by the Food and Drug Administration for weight loss?
A. Semaglutide and liraglutide
B. Dulaglutide and semaglutide
C. Only semaglutide

6. Which of the following would be considered an off-label use of a GLP-1RA?
A. Weight loss in patients with T2DM, used in combination with diet and exercise to reduce blood sugar levels
B. Weight loss in patients who need to lose 10 pounds quickly to fit into Marilyn Monroe’s size 12 dress
C. Weight loss in patients who have a BMI greater than 27 kg/m² with at least one weight-related comorbid condition

Social Media Sensation: Semaglutide

After completing this continuing education activity, technicians will be able to
• Identify the different formulations of GLP-1 receptor agonists
• Classify storage requirements for GLP-1 receptor agonists
• Review GLP-1 receptor agonists indications for use

1. Which of the following GLP-RA is injected once daily?
A. Semaglutide, (Ozempic)
B. Semaglutide, (Wegovy)
C. Liraglutide, (Saxenda)

2. A patient presents a prescription for Wegovy 0.5 mg. Checking the refrigerator, the place for Wegovy is empty. You notice Saxenda is in stock and you have Ozempic 0.5 mg and 1 mg in stock. What is your best response?
A. We have Ozempic 1 mg pens in stock and I can have the pharmacist check and fill today
B. We have Ozempic 0.5 mg in stock but we need a new prescription for Ozempic from your prescriber
C. We have Saxenda in stock, we can have that ready later today

3. Semaglutide should be discarded when exposed to which of the following conditions?
A. Exposed to light or the pen was frozen
B. Refrigeration between 36-46 °F
C. Room temperature for up to 28 days

4. Sharon calls the pharmacy and informs you that she has used her GLP-1RA pen this morning but wants to know how she should dispose of the pen. What is the correct response?
A. At a drug take-back event
B. In a sharps container
C. In the trash

5. Semaglutide is approved for weight loss in patients who have a BMI of what level?
A. BMI between 27-30 kg/m² with two comorbid conditions
B. BMI less than 25 kg/m² who has depression
C. BMI greater than 30 kg/m² alone or 27 kg/m² with one comorbid condition

REFERENCES

Creutzfeldt, W. The [pre-] history of the incretin concept. Regulatory Peptides. 2005;128:87-91.
Holst JJ, Gasbjerg LS, Rosenkilde MM. The Role of Incretins on Insulin Function and Glucose Homeostasis. Endocrinology. 2021;162(7). doi:10.1210/endocr/bqab065
Exendin-4: From lizard to laboratory...and beyond. National Institute on Aging. July 11, 2012. Accessed April 3, 2023. https://www.nia.nih.gov/news/exendin-4-lizard-laboratory-and-beyond
Nauck M, Quast D, Wefers J, et al. GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Molecular Metabolism. 2021; 46. https://doi.org/10.1016/j.molmet.2020.101102
Blakeslee, S. A Protein Tells Eaters To Stop. The New York Times Jan 4, 1996 Section A, Page 1.
OZEMPIC (semaglutide) injection, for subcutaneous use. Novo Nordisk. October 2022. Accessed March 22, 2023. https://www.ozempic.com/prescribing-information.html
WEGOVY (semaglutide) injection, for subcutaneous use. Novo Nordisk. June 2021. Accessed March 22, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf
Wharton S, Davies M, Dicker D, et al. Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice. Postgrad Med. 2022;134(1):14-19. doi:10.1080/00325481.2021.2002616
Sullivan K, Some people taking weight loss drugs say they're experiencing hair loss. April 22, 2023. Accessed April 27, 2023. https://www.nbcnews.com/health/health-news/weight-loss-drugs-and-hair-loss-rcna79798
Johnson A. ‘Ozempic Face’ Explained: Why It Happens And How To Fix It. February 1, 2023. Accessed February 22, 2023. https://www.forbes.com/sites/ariannajohnson/2023/02/01/ozempic-face-explained-why-it-happens-and-how-to-fix-it/
Speckhard Pasque L. Let’s stop using the term “Ozempic face.” February 10, 2023. Accessed March 22, 2023. https://mcpress.mayoclinic.org/women-health/lets-stop-using-the-term-ozempic-face/
Constantino, A. People taking obesity drugs Ozempic and Wegovy gain weight once they stop medication. March 29, 2023. Accessed April 3, 2023. https://www.cnbc.com/2023/03/29/people-taking-obesity-drugs-ozempic-and-wegovy-gain-weight-once-they-stop-medication.html
Kushner R, Calanna S, Davies M, et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the step trials 1 to 5. Obesity. 2020; (6):1050-1061. doi: 10.1002/oby.22794
Drug Trial Snapshot: Ozempic. US Food & Drug Administration. Published August 20, 2020. Accessed April 12, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-ozempic
FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. U.S. Food and Drug Administration. Published June 4, 2021. Accessed April 18, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
Obesity and overweight. World Health Organization. Published June 9, 2021. Accessed April 18, 2023. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
Ard J, Fitch A, Fruh S, Herman L. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Advances in Therapy. 2021;38(6):2821-2839. doi:10.1007/s12325-021-01710-0
Alabduljabbar K, Al-Najim W, le Roux CW. The impact once-weekly semaglutide 2.4 mg will have on clinical practice: a focus on the STEP trials. Nutrients. 2022;14(11):2217. Published 2022 May 26. Assessed April 20, 2023. doi:10.3390/nu14112217
Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA.2022;327(2):138–150. doi:10.1001/jama.2021.23619
Blum D, Some people on Ozempic lose the desire to drink. Scientists are asking why. February 24, 2023. Accessed May1, 2023. https://www.nytimes.com/2023/02/24/well/eat/ozempic-side-effects-alcohol.html#:~:text=Side%20Effects%3A%20Diabetes%20treatments%20like,can%20also%20take%20a%20toll.
Klausen MK, Jensen ME, Moller M, et al. Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight. 2022. 7(19). doi: 10.1172/jci.insight.159863.
Hendershot C, Semaglutide for alcohol use disorder. NIH Clinical Trials.gov. Indentifier:NCT05520775
Wegovy® supply update, investor conference call. Novo Nordisk. Dec 2021. Accessed: April 25, 2023. https://www.novonordisk.com/content/dam/nncorp/global/en/investors/pdfs/financial-results/2021/conference-call-supply-update-20Dec2021.pdf
Goodman B, As the market for new weight loss drugs soars, people with diabetes pay the price. December 28, 2022. Accessed April 25, 2023. https://www.cnn.com/2022/12/28/health/weight-loss-diabetes-drug-shortages/index.html
Lovelace Jr B, Supply of weight loss drug Wegovy expected to improve in next few months, company says. February 1, 2023. Accessed April 25, 2023. https://www.nbcnews.com/health/health-news/supply-weight-loss-drug-wegovy-expected-improve-months-company-says-rcna68572

The Gall of it All: Gallbladder Disease

After completing this application-based continuing education activity, pharmacists will be able to

1. DESCRIBE the functions of the gallbladder and how it aids digestion

2. RECOGNIZE gallbladder disease based on various presentations

3. EXPLAIN gallstone prevalence, risk factors, and pathogenesis

4. DISCUSS treatment approaches for gallbladder disease and post-cholecystectomy management

After completing this application-based continuing education activity, pharmacy technicians will be able to:

1. DESCRIBE the functions of the gallbladder and how it aids digestion

2.EXPLAIN gallstone prevalence, risk factors, and pathogenesis

3. LIST over-the-counter medications used by patients with gallbladder disease and post-cholecystectomy

4. IDENTIFY when to refer patients with questions about gallbladder disease to a pharmacist

The gallbladder—a member of the biliary system—is responsible for bile secretion into the digestive tract. It was more useful centuries ago when the human diet was largely carnivorous and high in fat, its role in digestion today is less essential. This makes removal of the organ to treat gallbladder disease (GBD) quite commonplace. Although surgery is first line GBD treatment, pharmacy teams should remain involved in care for patients with this condition. Pharmacy involvement is especially important post-gallbladder removal. This continuing education activity describes the function of the gallbladder, risk factors for and pathogenesis of GBD, treatment approaches for GBD, and how to optimize care for patients with the disease and post-gallbladder removal.

INTRODUCTION

Gallbladder disease (GBD; see Sidebar: Types of Gallbladder Disease) is the most common surgical emergency, responsible for 600,000 surgeries per year in the United States.¹ Cholelithiasis, or gallstones, is one of the most common and costly gastrointestinal diseases, affecting more than 20 million Americans annually.²An estimated 115 of every 100,000 of the world’s population will undergo gallbladder removal surgery every year.³

GBD is influenced by genetic and environmental factors, diet, physical activity, and nutrition. The healthcare team should encourage patients to incorporate healthy habits into their lifestyles to reduce the risk of GBD. This continuing education activity will discuss GBD pathology, risk factors, treatment, considerations post-cholecystectomy, and the pharmacy team’s role.

GALLBLADDER DISEASE

The Gallbladder

The gallbladder is the small pear-shaped organ located in the right upper quadrant (RUQ) of the abdomen beneath the liver. It is part of the biliary system, which is a series of ducts in the liver, gallbladder, and pancreas that drain into the small intestine.⁴ The gallbladder acts as a storage pouch for up to 50 mL of bile, also known as “gall.”⁵Gall became a synonym for bile in the Middle Ages and also meant “embittered spirit.”⁵ In the late 19^th century, gall was used to describe a person having boldness or insolence.⁴

Bile is a yellowish-brown alkaline surfactant (substance that decreases surface tension) continuously produced by the liver.^1,2 It is composed of cholesterol, bilirubin, water, bile salts, phospholipids, and ions. The common bile duct carries bile from the liver to the gallbladder. Fatty foods and proteins released from the stomach into the small intestine stimulate the gallbladder to empty bile into the duodenum via the sphincter of Oddi, which facilitates digestion. Bile salts emulsify lipids in the intestines allowing absorption of dietary fats such as cholesterol and fat-soluble vitamins. Unused bile salts return to the gallbladder through the distal ileum and portal circulation.^1,2

The gallbladder was probably more valuable centuries ago.⁵ Primitive humans were carnivorous hunters; meals were large, few, and far between.⁵ The gallbladder would have been crucial for digestion of large, high fat meals. The organ wasn’t considered nonessential until the late 1600s, after two Italian doctors discovered that animals could thrive without it.¹ This discovery was forgotten until a German physician successfully performed the first cholecystectomy (surgical removal of the gallbladder) in a human in 1878.^1,6 Figure 1 describes a brief history of the gallbladder, gallstones, and cholecystectomy beginning in the 15^th century.

Today, the gallbladder assists in digestion of fat-soluble vitamins, proving important even for vegetarians.⁵ People can still live a healthy life after gallbladder removal; however, the risk of hepatic problems increases due to impaired fat digestion.⁵

Sidebar: Types of Gallbladder Disease^2,8

Biliary dyskinesia: gallbladder motility disorder caused by scarring or spasm of sphincter of Oddi, the valve that controls the flow of biliary and pancreatic secretions into the duodenum
Cholangitis: inflammation of the biliary system
Cholecystitis: inflammation of the gallbladder
Choledocholithiasis: common bile duct stones
Cholelithiasis: gallstones
Gallbladder empyma: severe acute cholecystitis, a surgical emergency
Gallbladder pancreatitis: inflammation of the pancreas caused by pancreatic duct obstruction by a gallstone
Gallbladder perforation: a hole in the gallbladder wall
- Acute: generalized biliary peritonitis
- Subacute: acute plus pericholecystic abscess
- Chronic: cholecystoenteric fistula
Gallbladder polyps: overgrowths or lesions in the gallbladder wall

This continuing education activity will focus on gallstones and their complications, which may include cholecystitis, choledocholithiasis, and cholangitis. Cholecystectomy (gallbladder removal) is the treatment mainstay for gallstones and pharmacist intervention is most valuable post-cholecystectomy.

Gallstones and Acute Cholecystitis

The most common gallbladder disease is gallstones.⁷ Gallstones commonly form from imbalances in bile constituents and biliary sludge (solids precipitated from bile) caused by slowed gallbladder motility or altered hepatic cholesterol metabolism. Hardened cholesterol or bilirubin become saturated in bile and crystalize, like rock candy, and can lodge in the common bile duct.⁷ Gallbladder hypomotility leads to delayed emptying, resulting in the formation of biliary sludge and consequently, gallstones.⁷

Bilirubin is a substance found in bile resulting from red blood cell breakdown in the liver. It is normally eliminated through the feces. Gallstones caused by bilirubin, or “pigment stones”, are rare and only account for approximately 10% of all gallstones.⁸ Pigment stones are commonly seen in individuals with blood disorders, such as sickle-cell anemia.⁸ Approximately 75% of gallstones in Western countries contain cholesterol as their major component.⁹

The presence of stones in the gallbladder is called cholelithiasis. Most patients with gallstones are asymptomatic and may not have any attributable symptoms during their lifetime.⁸ Asymptomatic cholelithiasis does not require treatment as the risk of symptom development is only about 10% at five years.⁸

Cholelithiasis becomes acute cholecystitis when gallstones block the cystic duct, causing the gallbladder to become inflamed and patients to become symptomatic. Biliary pain—also known as biliary colic—is the most common symptom of cholecystitis. Epigastric (upper-middle abdomen) pain lasting from 30 minutes to several hours radiates around or through the back and may be accompanied by heartburn, bloating, nausea, and/or vomiting. The sharp, stabbing pain generally follows food intake and peaks after the first hour. It is characteristically steady and is severe enough to interfere with activities of daily living. The pain is not relieved with a bowel movement. Women often describe biliary pain as being worse than childbirth.^2,8

Cholecystitis pain from an acute episode usually subsides over one to five hours as the stone dislodges.^3,10 The likelihood that patients experience repeated symptomatic episodes from their gallstones is approximately 38% to 50% annually.⁸ More than 90% of patients presenting with a single episode of biliary colic have recurrent pain within 10 years.¹³

Ultrasound is the best test for diagnosing gallstones and finds most patients with an average of two to 20 stones. The record-setting number of stones was found in England in 1987; a female patient had 23,530 stones removed.⁵ Computerized tomography (CT) can also be used for diagnosis, but it is less accurate than other imaging methods, detecting approximately 75% of gallstones.² Providers can also diagnose by the presence of Murphy’s sign, or pain upon inhalation when the inflamed gallbladder meets the examiner’s hand.⁸ Other diagnostic markers include elevated liver function tests, white cell count, erythrocyte sedimentation rate, and C-reactive protein.⁸ Patients presenting with acute cholecystitis may have experienced several bouts of biliary colic before diagnosis.

Acute cholecystitis diagnosis typically requires admission for pain management and intravenous (IV) fluid rehydration. Nonsteroidal anti-inflammatory drugs (NSAIDS) like ketorolac, diclofenac or indomethacin combat inflammation and promote speedy recovery.⁸ NSAIDS are generally preferred to narcotic analgesics as they are equally effective with fewer adverse effects.² A study of 324 patients given IV ketorolac or meperidine showed both drugs offered similar pain relief but patients in the NSAID group reported fewer adverse effects.² Patients receive broad-spectrum antibiotics (e.g., ciprofloxacin, cefuroxime) to prevent or treat bacterial infection.⁸

Failure to properly treat cholecystitis can lead to severe inflammation, gangrene, sepsis, and life-threatening gallbladder perforation. Cholecystitis can also lead to gallstone pancreatitis if stones in the sphincter of Oddi are not cleared and block the pancreatic duct.²

Chronic Cholecystitis

Repeated episodes of cholecystitis or chronic irritation from gallstones can lead to chronic cholecystitis.¹¹ Chronic cholecystitis more often presents with cholelithiasis (calculous) but can also exist without gallstones (acalculous). Symptomatic patients usually present with dull RUQ pain that radiates around the waist to the middle back. Most patients are afebrile.¹¹

While acute cholecystitis symptoms are sharp and abrupt, chronic cholecystitis symptoms usually develop and worsen over weeks to months.¹¹ Lab values normally elevated in acute disease may not be in chronic disease and therefore cannot be used in diagnosis. Ultrasound of the RUQ is the best diagnostic tool to evaluate the gallbladder for wall thickening and inflammation. Elective cholecystectomy is the preferred treatment for chronic cholecystitis. Patients who are not eligible for or who prefer not to undergo surgery should be closely monitored. A low-fat diet and other lifestyle modifications can help reduce symptom frequency.¹¹

Pharmacists should recognize the differences between presentations of acute versus chronic cholecystitis and refer patients to the nearest emergency department if symptoms are severe.

Choledocholithiasis and Cholangitis

Choledocholithiasis, or common duct stones, are gallstones that have migrated from the gallbladder to the common bile duct via the cystic duct. Approximately 8% to 16% of patients with symptomatic gallstones will also have common bile duct stones.⁸ Common duct stones can be asymptomatic or may lead to complications such as gallstone pancreatitis or acute cholangitis. Cholangitis is inflammation of the biliary system that causes fever, jaundice, and abdominal pain (Charcot triad).⁸ Charcot triad becomes Reynolds pentad when hypotension and altered mental state are also present.⁸ These symptoms develop due to bile stasis and bacterial infection in the biliary tract.

Cholangitis is most commonly caused by gram-negative (Escherichia coli [25% to 50%], Klebsiella spp. [15% to 20%], Enterobacter spp. [5% to 10%]) intestinal bacteria, and less often by gram-positive bacteria (Enterococcus spp. [10% to 20%]).⁸ Patients require prompt treatment with IV antibiotics such as a broad-spectrum cephalosporin or ciprofloxacin.⁸ Pharmaceutical intervention should be followed by stone removal to prevent septicemia (systemic blood infection), which can be fatal.Most clinicians recommend that common bile duct stones be removed once discovered, even when asymptomatic.⁸

Risk Factors

Several genetic and environmental factors contribute to gallstone development. Patients with first-degree relatives with history of cholelithiasis are at a three times higher risk of gallstones.⁸ Approximately 60% of patients with acute cholecystitis are female, but the illness is generally more severe in males.²Women experience a higher prevalence because of estrogen’s effects on cholesterol metabolism.¹² Estrogen increases cholesterol synthesis and decreases bile acid production.¹² Progesterone in pregnancy decreases gallbladder contractility leading to stasis, making gallstones 10 to 15 times more common in women who have been pregnant.^8,12 Women with history of biliary colic, gallstones, and the like should be aware of how hormones may affect their risk for recurrence. This is valuable information for pharmacists to consider and an appropriate place to intervene and educate.

European and American populations are more likely to develop gallstones, and Black people of African descent are least likely. Prevalence is highest in Native American populations, with 60% incidence in the Pima Indian populace of southern Arizona.⁸ Table 1 summarizes risk factors for GBD.^2,8,13

Table 1. Risk Factors for Developing Gallbladder Disease^2,8,14-16

Demographics

· Ethnicity (American Indians, Chilean and Mexican Hispanics)

· Family history

· Female gender (10:1 female:male)

· Older age

Diet

· High fat, calorie, and refined carbohydrate intake

· Low fiber and unsaturated fat intake

· Total parenteral nutrition

Lifestyle

· Pregnancy and multiple pregnancies

· Persistent fasting or very low-calorie diet

· Rapid weight loss (i.e., bariatric surgery)

· Sedentary

Medications

· Estrogen therapy or oral contraceptives

· Some hypoglycemic medications (GLP-1RAs)

· Chronic use of gastric acid suppressants (H2RAs, PPIs)

· Ketamine abuse

Heath Conditions & Other Factors

· Alcoholic liver cirrhosis

· Dyslipidemia (elevated triglycerides and low HDL)

· Gallbladder motor dysfunction

· Gastrointestinal surgery

· Metabolic syndrome, gallbladder, or intestinal stasis

· Short bowel syndrome

· Type 2 diabetes mellitus

GLP-1RAs, glucagon-like peptide 1 receptor agonists; H2RAs, histamine-2-receptor antagonists; HDL, high-density lipoprotein; PPIs, proton-pump inhibitors.

Glucagon-like peptide 1 (GLP1) receptor agonists (GLP-1RAs) are notable for their glucose control and cardiovascular risk reduction for patients with type 2 diabetes mellitus and more recently, for weight loss. Their link to GBD is controversial as GLP1 inhibits gallbladder motility and delays gallbladder emptying.¹⁴ A recent systematic review and meta-analysis of 76 randomized clinical trials shows an association between GLP-1RA use and elevated GBD risk. The risk for gallbladder or biliary diseases were more prominent with higher doses, longer duration, and when used for weight loss.¹⁴ Clinicians should discuss the benefits of using these hypoglycemics for type 2 diabetes or weight loss and whether they outweigh the risk for GBD. Pharmacists can educate patients initiating GLP-1RAs about their benefits, risks, and implications with past medical history of or additional risk factors for GBD. Multiple GLP-1RAs are available in varying doses and pharmacists should continue to counsel patients as doses are increased over time.

Chronic use of gastric acid suppressants may cause cholelithiasis.¹⁵ These drugs impact gut microbiome and may slow gallbladder motility leading to delayed gallbladder emptying. A recent prospective cohort of 0.47 million participants found that regular use of proton-pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) resulted in increased cholelithiasis risk.¹⁵ Physicians should be aware of this association when prescribing these medications, especially for patients requiring long-term use or those already at high risk for gallstones.Pharmacists should keep these risks in mind when filling prescriptions for their patients on long-term or high-dose H2RAs and PPIs.

Ketamine abuse has been associated with chronic biliary colic. Ketamine was developed in 1962 as an anesthetic.¹⁶ “Street ketamine”, a close analogue of ketamine, is commonly used for its euphoric effects. Ketamine’s onset of action after oral ingestion is about ten minutes and its hallucinogenic effects are short acting, lasting up to two hours. The most common signs of ketamine abuse are hypertension, tachycardia, and abdominal tenderness. Ketamine abuse is also associated with impaired consciousness, dizziness, abdominal pain, and lower urinary tract symptoms.¹⁶ Case reports have shown ketamine abusers presenting with severe bladder dysfunction and recurrent episodes of epigastric pain due to a dilated common bile duct not associated with gallstones.¹⁶ Clinicians should collect detailed drug histories for patients presenting with recurrent abdominal pain, namely biliary colic.

Diets characterized by increased caloric intake with highly refined sugars, high fructose, low fiber, high fat, and consumption of fast food increase the risk of gallstone formation.⁹ Nutrition and lifestyle changes may be beneficial in the prevention of gallstones. Increased physical activity, consuming smaller more frequent meals, and “heart healthy” diets low in cholesterol and fat and high in fiber can reduce risk of cholelithiasis.⁷ Fat should not be completely cut out of the diet as too little fat can also precipitate gallstone formation.

Weight loss can reduce gallstone risk, but rapid weight loss achieved by low-calorie diets (less than 800 kcal/day) or bariatric surgery can cause gallstones.^2,9 Patients should seek professional advice before starting diets promoting very low caloric or high fat intake to achieve rapid weight loss (i.e., Atkins, ketogenic). Pharmacists should be aware of patients who have recently undergone bariatric surgery or are taking drugs or supplements for weight loss. These patients may be at a higher risk for gallstones, especially those with past medical histories of GBD or abdominal colic symptoms.

Some foods and medications seem to be associated with a reduced risk of gallstones:

Statins alter bile cholesterol and thus affect gallstone formation, suggesting a role in prevention. While the relationship between statins and gallstone formation is conflicting, studies report reduction in symptomatic gallstone disease with statin use.¹⁷
Ezetimibe, a selective NPC1L1 inhibitor, has been associated with a reduced incidence of cholesterol gallstones in animal studies.The mechanism involves reduced amounts of absorbed cholesterol, decreasing biliary cholesterol saturation, and in turn, reduced rate of cholesterol gallstone formation.¹²
Vitamin C supplementation has been shown to reduce gallstone prevalence. Researchers have studied vitamin C supplementation’s effects in gallstone formation in guinea pigs; those deficient in vitamin C more often develop gallstones. An observational study of a randomly selected population in Germany (n = 2129) showed a positive correlation between regular vitamin C intake and a reduced gallstone incidence.¹⁸
Coffee consumption may also offer a protective effect against gallstone formation. Studies suggest coffee stimulates cholecystokinin release, enhancing gallbladder contractility, thereby reducing bile cholesterol crystallization. A 2019 observational analysis published in the Journal of Internal Medicine found a 23% decrease in gallstone formation in subjects consuming six or more cups of coffee daily.¹⁹
A small study conducted in Spain shows that regular consumption of olive oil containing monounsaturated and polyunsaturated omega-6 fatty acids may prevent gallstones. Similarly, fish (omega-3 fatty acids) and fish oil may reduce triglycerides and prevent gallstones. A group of participants with hypertriglyceridemia taking fish oil supplements for a seven-week study in the Netherlands experienced improved gallbladder motility and a decrease in triglycerides.¹⁰

TREATING GALLBLADDER DISEASE

Endoscopic retrograde cholangiopancreatography (ERCP) is the most common way to identify and remove common duct stones. ERCP is minimally invasive and carries the risk of acute pancreatitis.⁸ This diagnostic tool may also identify duct strictures at which time stents are placed to reduce obstruction and improve biliary flow.^8,10 Timely stent removal (within three to six months) is crucial to prevent occlusion, stent migration, or cholangitis.²² Cholecystectomy is the definitive treatment for symptomatic gallstones and should commence within 48 hours of symptom onset during the acute inflammatory process, before tissue thickening or scarring develops.^8,10

Surgical Intervention: Cholecystectomy

The first gallstone removal surgery was a coincidence. In the mid-19^th century, a physician was performing investigative surgery on a female patient, and when he cut into her gallbladder, several bullet-like objects spilled out.⁵ The first planned gallbladder removal was performed 15 years later.⁵ Before the early 1900s, the surgery was performed through an incision in the RUQ (Kocher’s incision, named after Emil Theodor Kocher, a Swiss physician and medical researcher who performed the first successful cholecystectomy in 1878).^6,8 This invasive procedure was outmoded a few years after Erich Muhe, a German surgeon, performed the first laparoscopic cholecystectomy in 1985.⁸ Today, surgeons perform more than 98% of cholecystectomies laparoscopically, over 70% of which are outpatient day surgeries.⁸

Cholecystectomy is associated with fewer gallbladder-specific complications and shorter length of hospital stay when surgery is elective or performed as a single emergency visit without previous surgical admissions.³ A population-based cohort study of outcomes following surgery for benign GBD showed poorer outcomes and risk of readmissions with delayed cholecystectomy. Many studies define emergency or early surgical intervention as operations performed within 48 to 72 hours of symptom onset. A study of 14,200 patients in Canada discovered patients experienced fewer complications when surgery was performed within seven days of hospital admission.³ These studies show value in offering emergency surgery over delaying cholecystectomy for patients presenting with benign GBD.³

Antibiotic prophylaxis is not routinely recommended for low-risk patients undergoing elective laparoscopic cholecystectomy.¹³ High-risk patients (age older than 60, type 2 diabetes, acute colic within 30 days of surgery, jaundice, acute cholecystitis, or cholangitis) may benefit. Providers should limit prophylaxis to IV cefazolin 1 g as a single dose one hour prior to surgery.¹³

Several studies suggest that pain management before or during, and after laparoscopic cholecystectomy can reduce post-operative pain. A 2018 review of 258 randomized control trials recommended a basic analgesia technique: acetaminophen plus an NSAID or cyclooxygenase-2 inhibitor with local anesthetic infiltration.²¹ Opioids are reserved for breakthrough pain.²¹

Patients are generally discharged a few hours after surgery. Surgeons should be on alert for early signs of complications if there is divergence from the usual course of rapid recovery post-op. Extreme pain shortly after surgery may indicate intra-peritoneal leakage of bile or bowel contents.⁸ Persistent hypotension (low blood pressure) and pain can suggest bleeding. Re-laparoscopy may be necessary to identify and repair these problems and is preferred to diagnostic imaging.⁸

Removal of the gallbladder will not cause weight loss/gain or vitamin deficiencies. Patients should be able to tolerate foods they couldn’t before surgery, but providers should advise them to add those foods back into their diet very slowly. Following gallbladder removal, the liver will continue to make bile, but instead of storing it in the gallbladder, it will drain into the stomach and small intestines. Patients might experience three to five days of soreness post-op and are expected to fully heal within four to six weeks.⁷

Diarrhea and bloating due to alternation of biliary flow are common short-term occurrences after surgery.²² A small percentage (1% to 2%) of patients will have loose stools each time they eat greasy or high-fat meals.⁷ A cystic duct remnant is also possible, potentially leading to stone formation, causing Mirizzi syndrome. Mirizzi syndrome is characterized by fever, jaundice, and RUQ pain due to common hepatic duct obstruction caused by compression from the impacted stone in the remnant cystic duct.²² Endoscopic removal of the stone may be adequate. In rarer cases, surgical excision of the remnant duct may be necessary to prevent further complications.²²

Pharmacologic and Other Non-Surgical Interventions

Nonoperative methods exist for patients unwilling or unable to undergo surgical intervention. Contraindications for laparoscopic cholecystectomy include^10,13

Absolute: gallbladder cancer (see Sidebar: Gallbladder Cancer), general anesthesia intolerance, giant gallstones, morbid obesity, uncontrolled bleeding disorder
Relative: advanced cirrhosis/liver failure, bleeding disorder, peritonitis, previous upper abdominal surgeries, septic shock

Gallbladder Cancer²⁰

Gallbladder cancer is a rare malignancy but accounts for almost 50% of biliary cancers. Biliary cancers have a poor five-year survival rate and a high recurrence rate. Factors affecting prognosis are stage at discovery, tumor location, operability, response to chemotherapy, and presence and location of metastases. Early-stage gallbladder cancer may be curable with surgical resection.

Oral bile acid dissolution drugs include ursodeoxycholic acid (ursodiol) and chenodeoxycholic acid (chenodiol).²³ Table 2 lists dosing and adverse effects of these medications. Smaller gallstones (0.5 to 1 cm) may be better suited for pharmaceutical intervention but may take up to 24 months to dissolve.² Ursodiol is preferred over chenodiol due to its safer adverse effect profile. Use-limiting adverse effects of chenodiol include dose-dependent diarrhea, hypercholesterolemia, hepatotoxicity, and leukopenia.² Recurrence rate is more than 50% and fewer than 10% of patients with symptomatic gallstones are candidates for this treatment.¹³

Table 2. Oral Bile Acids^2,23,24

Drug	Dosage	Duration	Adverse Effects
Ursodiol (Actigall)	8-10 mg/kg/day given in 2-3 divided doses	Symptom relief after 3-6 weeks, results may take 6-24 months, continue for 3 months after documented dissolution	Dyspepsia (>10%), nausea, vomiting, pruritis, headache, diarrhea, dizziness, constipation
Chenodiol (Chenodal)	250 mg twice daily for 2 weeks, increase dose by 250 mg/day weekly until maximum tolerable dose reached (13-16 mg/kg/day in 2 divided doses)	Discontinue if no response by 18 months, safety not established beyond 24 months	Dose-dependent diarrhea* (>10%), hypercholesterolemia, leukopenia, increased serum aminotransferase

* If diarrhea occurs, reduce dose and restart at previous dose when symptoms resolve.

Extracorporeal shock wave lithotripsy is a noninvasive option for symptomatic patients.¹³ Complications such as biliary pancreatitis and liver hematoma are rare, however stone recurrence is common. Recent studies show this procedure is beneficial for large pancreatic and common bile duct stones with similar pain relief and duct clearance outcomes compared to surgery.¹³

The initial approach for pregnant women with symptomatic gallstones is supportive care.¹³ Meperidine is the choice agent for pain control as NSAIDs are not recommended in pregnancy.¹³ Chenodiol is contraindicated in pregnancy.²⁴ Ursodiol has been used in pregnant patients for intrahepatic cholestasis; safety and efficacy of use for gallstones has not been studied.^13,23 Laparoscopic cholecystectomy, when indicated, is safe in all trimesters.¹³

POST-OPERATIVE CONSIDERATIONS AND THE PHARMACY TEAM

Post-Cholecystectomy Syndrome

Persistent or delayed onset abdominal pain after laparoscopic cholecystectomy may indicate post-cholecystectomy syndrome (PCS).²² Additional PCS symptoms include fatty food intolerance, nausea, vomiting, diarrhea, heartburn, indigestion, flatulence, and jaundice. PCS often occurs in the post-operative period but can present months or years after surgery.²² Cholecystectomy carries a low mortality risk, but approximately 10% of patients undergoing cholecystectomy each year develop PCS.²² The risk increases with urgent surgeries and 20% of patients will develop PCS regardless of choledochotomy (surgical incision of common bile duct).²²

PCS etiologies can be extra-biliary (pancreatitis, pancreatic tumors, hepatitis, esophageal diseases, mesenteric ischemia, diverticulitis, peptic ulcer disease) or biliary (bile salt induced diarrhea, retained calculi, bile leak, biliary strictures, stenosis, sphincter dyskinesia) in nature.²² Pathophysiology is related to alterations in bile flow and bile is the main trigger for patients with gastroduodenal symptoms or diarrhea.

The likelihood of diarrhea post-cholecystectomy ranges from 2% to 50% according to various studies.²⁵ Diarrhea usually improves or resolves over the course of weeks to months. As discussed, in the gallbladder’s absence, bile flows straight from the liver into the small intestine continuously. This redirection of bile flow can overwhelm the ileum’s capacity for reabsorption, leading to increased bile acids in the colon and subsequently cholerheic diarrhea (also known as bile acid diarrhea).²⁵ Patients may respond to treatment with bile acid sequestrants, including cholestyramine and colestipol.²⁵

Bile acid sequestrants release chloride and bind bile acid in the intestines, preventing bile acid reabsorption. The drugs do not leave the gastrointestinal tract and are eliminated in the feces. They are indicated for hypercholesterolemia but patients use them off-label for chronic diarrhea due to malabsorption (Table 3). The most common adverse effect of bile acid sequestrants is constipation, which occurs in more than 10% of patients.^26,27 Clinicians should instruct patients to drink plenty of fluid and increase dietary fiber. Most adverse effects are gastrointestinal-related (e.g., abdominal pain, flatulence, bloating, anorexia, nausea, vomiting, dysphagia), and others include^26,27

Cholestasis and cholecystitis (with colestipol only)
Dental bleeding and caries
Diuresis, dysuria, and burnt odor to urine
Edema
Worsened hemorrhoids

Bile acid sequestrants bind vitamin K and folate so prescribers should monitor for deficiencies of both. Patients should supplement with folate. Patients may supplement with vitamin K; however preexisting coagulopathy is a contraindication. These drugs should be used with caution in patients with renal insufficiency.^26,27

Table 3. Bile Acid Sequestrants^26,27

Drug

Dosage

Administration

Cholestyramine

(Prevalite, Questran)

2-4 g daily as a single dose or divided, increase by 4 g weekly based on response and tolerability, maximum 24 g/day

Mix dose in 60-180 mL of any beverage, soup, or pulpy fruit, should not be sipped or held in mouth for long periods*

Take with meals, administer oral medications ≥1 hour before or 4-6 hours after dose

Colestipol (Colestid)

Granules: 5 g once or twice daily, increase by 5 g in 1-2 month intervals, maintenance dose 5-30 g once daily or in divided doses

Tablets: 2 g once or twice daily, increase by 2 g in 1-2 month intervals, maintenance dose 2-16 g once daily or in divided doses

Administer other medications ≥1 hour before or 4 hours after dose

Granules: do not administer in dry form to avoid GI distress or accidental inhalation, should be added to at least 90 mL of any beverage, soup, or pulpy fruit

Tablets: administer one at a time; swallow whole; do not cut, crush, or chew

^*May cause tooth discoloration or enamel decay. GI, gastrointestinal.

PCS is a temporary diagnosis until further investigation establishes organic or functional diagnosis.²² Misdiagnosis of preexisting conditions is possible. The healthcare team should order a complete blood count and consider patients re-presenting with ongoing or new-onset abdominal pain post-cholecystectomy for CT scan.⁸ Presence of gas and fluid in the gallbladder bed may be normal but fluid or gas build-up elsewhere may indicate a bile leak. Elevated liver function tests may also suggest a bile leak or retained common bile duct stone. The most common cause of PCS is the presence of stones in the biliary tree.¹⁰ ERCP, both diagnostic and therapeutic, is the most common procedural approach to PCS.²²

Medication: Treatment Goals

Pharmacologic treatment goals in GBD are to prevent complications and reduce morbidity.²² Administration of bulking agents like psyllium fiber can help patients with symptoms of irritable bowel syndrome (IBS) and/or diarrhea. Psyllium husk (Metamucil, Benefiber) is an over-the-counter (OTC) option for patients looking to increase fiber intake. It is usually used to treat constipation and works by stimulating intestinal contractility, speeding up the movement of stool through the colon.²⁸ Psyllium can also treat diarrhea by soaking up excess water from the intestines, bulking stool, and promoting regularity.²⁸ Psyllium may reduce absorption and effectiveness of many medications; it is important that patients seek pharmacist counseling before initiating a psyllium fiber regimen.

Antispasmodics (e.g., loperamide) may help patients with IBS symptoms like cramping. Cholestyramine may help symptoms of diarrhea alone. Antacids (Maalox, Mylanta, Tums), H2RAs (e.g., famotidine), and PPIs (e.g., esomeprazole, lansoprazole, omeprazole) can improve gastritis or gastric reflux symptoms by reducing acid production.²² One study showed a correlation between dyspeptic symptoms and gastric bile salt; these patients may benefit from bile acid sequestrants.²² Patients should consult their gastroenterologist for recommended dosing of these drugs, as they may vary depending on clinical presentation and severity of symptoms.

The Pharmacy Team’s Role

Pharmacists and pharmacy technicians are integral members of the healthcare team. Pharmacists can educate patients about GBDs, the risk factors for their development, and how to mitigate them with a proper diet and exercise.

Pharmacy technicians can help by directing patients in the right direction when looking for OTC antacids, fiber supplements, or anti-diarrheal agents. Many patients may not ask questions about OTC products before purchase. Pharmacy technicians are often the patients’ first point of contact in the pharmacy and should ask open-ended questions at the register before or during the transaction.

Patients should use the products as directed by their gastroenterologists. Pharmacy technicians should refer patient questions relating to administration, dosing, adverse effects, and drug interactions to the pharmacist on duty. Consider possible scenarios that may arise in the pharmacy and how pharmacy technicians and pharmacists should approach them:

Mark is a pharmacy technician at XYZ Pharmacy. Jaclyn enters the pharmacy, approaches the pick-up window, and places several OTC items on the counter. She states she would like to pick up a prescription her doctor called in today. Mark retrieves Jaclyn’s prescription and notices it is for omeprazole 40mg. The items on the counter include Tums, famotidine 20mg, docusate sodium 100mg, and lansoprazole 30mg. Mark knows that omeprazole and lansoprazole are in the same drug class. What questions can Mark ask Jaclyn? Should Mark involve the pharmacist?
Jaclyn comes back to the pharmacy a week later to pick up a prescription for cholestyramine. She wants to know if she can take this with omeprazole and famotidine. Mark refers Jaclyn’s question to the pharmacist. How should the pharmacist respond to Jaclyn’s question and what counseling points are important to include?

CONCLUSION

Gallbladder diseases typically occur secondary to cholelithiasis. Most gallstone cases are asymptomatic, but some develop into symptomatic disease. Factors that may increase GBD risk include gender, age, family history, ethnicity, diet, and medical conditions. Surgical gallbladder removal is the most common treatment, but many nonsurgical alternatives exist when surgery is nonpreferred or contraindicated. Additionally, PCS can occur months to years after surgery and treatment should be directed based on specific diagnosis post-examination. Healthcare providers should collaborate to develop the best procedural and/or pharmaceutical treatment plan as each patient’s clinical presentation and symptoms will vary.

The pharmacy team should take an active role in GBD management, especially following cholecystectomy. Pharmacy technicians should be weary when patients complain of abdominal pain or attempt to purchase multiple OTC products to treat their symptoms; they should relay specific disease- and drug-related questions to the pharmacist on duty. GBD is a common and highly manageable condition, and patients can live normal and healthy lives once symptoms are properly controlled and treated.

After completing this continuing education activity, pharmacists will be able to
• DESCRIBE the functions of the gallbladder and how it aids digestion
• RECOGNIZE gallbladder disease based on various presentations
• EXPLAIN gallstone prevalence, risk factors, and pathogenesis
• DISCUSS treatment approaches for gallbladder disease and post-cholecystectomy management

1. How do gallstones form?
A. Fat soluble vitamin deficiency
B. Gallbladder hypermotility
C. Imbalances in bile components

2. Which of the following are risk factors for GBD?
A. Female gender; high fat, high calorie, low fiber diet; and type 2 diabetes
B. Female gender; low fat, high calorie, high fiber diet; and rapid weight loss
C. Male gender; high fat, high calorie, low fiber diet; and type 2 diabetes

3. MB is a 44-year-old female who presents to the emergency department with severe RUQ pain and nausea. She states this is the third time this year that she has presented to the ED with these symptoms. MB is admitted and the hospitalist starts her on IV fluids, acetaminophen, and ketorolac. Which of the following interventions is most appropriate?
A. MB should also receive meperidine to manage her pain
B. MB should undergo cholecystectomy within 72 hours of admission
C. MB is at high risk for infection and should be given IV cefazolin for prophylaxis

4. Gallstone recurrence is common with which of the following?
A. Oral bile acid dissolution drugs
B. Endoscopic retrograde cholangiopancreatography
C. Asymptomatic cholelithiasis

5. Which of the following is FALSE about gallbladder removal surgery?
A. Patients should have higher tolerability for foods they could not tolerate before surgery
B. Patients should supplement with fat soluble vitamins post-cholecystectomy
C. Up to 50% of patients may experience diarrhea following cholecystectomy

6. Why is diarrhea a common complication post-cholecystectomy?
A. Overproduction of bile
B. Vitamin deficiencies
C. Altered biliary flow

7. Which of the following statements is TRUE regarding the use of oral bile acid dissolution agents?
A. They can cause vitamin K and folate deficiencies
B. Chenodiol is preferred in pregnant women due to its safer adverse effect profile
C. Fewer than 10% of symptomatic patients are candidates for treatment

8. AP is a 37-year-old female, weighing 80 kg with symptomatic gallstones. She is not a candidate for laparoscopic cholecystectomy due to previous anesthesia intolerance. AP brings a prescription to the pharmacy for ursodiol 250 mg TID. How long will AP most likely need to take this medication?
A. 3 to 6 weeks
B. 6 months to 2 years
C. 1 to 3 years

9. KM is a 42-year-old female whose gastroenterologist recommends she try psyllium husk twice daily for her chronic diarrhea post-cholecystectomy. She seems confused when you hand her Metamucil because she thought it was used for constipation. What should you tell KM?
A. Psyllium husk treats diarrhea by binding bile acids in the gut and excreting them in the stool
B. Psyllium husk treats diarrhea by soaking up excess water in the intestines to bulk the stool
C. Psyllium husk treats diarrhea by increasing intestinal contractility

10. Which of the following is an appropriate counseling point for bile acid sequestrants?
A. Their most common adverse effects are diarrhea and edema
B. They are contraindicated in patients with uncontrolled bleeding disorders
C. Take other oral medications at least 1 hour before or 4 hours after dose

After completing this continuing education activity, pharmacy technicians will be able to
• DESCRIBE the functions of the gallbladder and how it aids digestion.
• EXPLAIN gallstone prevalence, risk factors, and pathogenesis.
• LIST over the counter medications used often by patients with gallbladder disease and post-cholecystectomy.
• IDENTIFY patient questions that need to be referred to a pharmacist.

1. How do gallstones form?
A. Fat soluble vitamin deficiency
B. Gallbladder hypermotility
C. Imbalances in bile components

3. Gallstone recurrence is common with which of the following?
A. Oral bile acid dissolution agents
B. Endoscopic retrograde cholangiopancreatography
C. Asymptomatic cholelithiasis

4. Which of the following may reduce the risk of developing gallstones?
A. Statins
B. Oral contraceptives
C. Ketogenic diet

5. Why was the gallbladder more essential centuries ago?
A. Humans consumed smaller meals containing less fat
B. Humans consumed larger meals containing more fat
C. Humans consumed meals containing more protein

6. What is cholelithiasis?
A. Gallstones caused by bilirubin
B. The presence of stones in the gallbladder
C. The presence of gallstones in the cystic duct

8. How does psyllium husk help patients with diarrhea?
A. Psyllium husk treats diarrhea by binding bile acids in the gut and excreting them in the stool
B. Psyllium husk treats diarrhea by soaking up excess water in the intestines to bulk the stool
C. Psyllium husk treats diarrhea by increasing intestinal contractility

9. Which of the following patients should pharmacy technicians refer to a pharmacist?
A. A patient holding a container of Metamucil and Fibercon fiber capsules and wants to know which contains psyllium
B. A patient asking for help locating famotidine, which their gastroenterologist recommended for acid indigestion
C. A patient who has failed several OTC therapies wants to know what to try for persistent diarrhea post-cholecystectomy

10. Which of the following statements is TRUE regarding OTC products for patients with GBD and/or PCS?
A. Antispasmodics like loperamide may help patients’ gastritis symptoms
B. Famotidine can relieve gastritis symptoms by reducing acid production
C. Patients can take an antacid like omeprazole to calm IBS symptoms

Division of General Surgery. History of Medicine: The Galling Gallbladder. Columbia University Irving Medical Center, New York, NY; 1999-2022. Accessed April 26, 2022. https://columbiasurgery.org/news/2015/06/11/history-medicine-galling-gallbladder
Afamefuna S, Allen SN. Gallbladder disease: Pathophysiology, diagnosis, and treatment. US Pharm.2013;38(3):33-41. https://www.uspharmacist.com/article/gallbladder-disease-pathophysiology-diagnosis-and-treatment
CholeS Study Group, West Midlands Research Collaborative, et al. Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases. [published correction appears in Br J Surg. 2018 Aug;105(9):1222]. Br J Surg. 2016;103(12):1704-1715. doi:10.1002/bjs.10287
Jones MW, Small K, Kashyap S, Deppen JG. Physiology, Gallbladder. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 8, 2022.
5 surprising truths about the gallbladder. Surgical Consultants of Northern Virginia; Reston, VA. 2023. PatientPopInc. Accessed September 21, 2022. https://www.scnv.com/blog/5-surprising-truths-about-the-gallbladder
De U. Evolution of cholecystectomy: A tribute to Carl August Langenbuch. Indian J Surg. 2004;66(2):97-100.
Haelle T. 10 essential facts about your gallbladder. Everyday Health. August 15, 2015. Accessed September 21, 2022. https://www.everydayhealth.com/news/essential-facts-about-your-gallbladder/
Beckingham IJ. Gallstones. Surgery (Oxford). 2020;38(8):453-462. doi:10.1016/j.mpsur.2020.06.002
Di Ciaula A, Garruti G, Frühbeck G, et al. The role of diet in the pathogenesis of cholesterol gallstones. Curr Med Chem. 2019;26(19):3620-3638. doi:10.2174/0929867324666170530080636
Ahmed A, Cheung RC, Keeffe EB. Management of gallstones and their complications. Am Fam Physician. 2000;61(6):1673-1688.
Jones MW, Gnanapandithan K, Panneerselvam D, Ferguson T. Chronic Cholecystitis. In: StatPearls. Treasure Island, FL: StatPearls Publishing; October 24, 2022. Accessed March 29, 2023. https://www.ncbi.nlm.nih.gov/books/NBK470236/
Di Ciaula A, Portincasa P. Recent advances in understanding and managing cholesterol gallstones. F1000Res. 2018;7:F1000 Faculty Rev-1529. doi:10.12688/f1000research.15505.1
Abraham S, Rivero HG, Erlikh IV, Griffith LF, Kondamudi VK. Surgical and nonsurgical management of gallstones. Am Fam Physician. 2014;89(10):795-802.
He L, Wang J, Ping F, et al. Association of glucagon-like peptide-1 receptor agonist use with risk of gallbladder and biliary diseases: A systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med.2022;182(5):513–519. doi:10.1001/jamainternmed.2022.0338
Yang M, Xia B, Lu Y, et al. Association between regular use of gastric acid suppressants and subsequent risk of cholelithiasis: A prospective cohort study of 0.47 million participants. Front Pharmacol. 2022;12:813587. Published 2022 Jan 28. doi:10.3389/fphar.2021.813587
Al-Nowfal A, Al-Abed YA. Chronic biliary colic associated with ketamine abuse. Int Med Case Rep J. 2016;9:135-137. Published 2016 Jun 2. doi:10.2147/IMCRJ.S100648
Pulkkinen J, Eskelinen M, Kiviniemi V, et al. Effect of statin use on outcome of symptomatic cholelithiasis: a case-control study. BMC Gastroenterol. 2014;14:119. Published 2014 Jul 3. doi:10.1186/1471-230X-14-119
Walcher T, Haenle MM, Kron, M, et al. Vitamin C supplement use may protect against gallstones: An observational study on a randomly selected population. BMC Gastroenterol. 2009;9:74. doi:10.1186/1471-230X-9-74
Nordestgaard AT, Stender S, Nordestgaard BG, et al. Coffee intake protects against symptomatic gallstone disease in the general population: a Mendelian randomization study. J Intern Med. 2020;287(1):42-53. doi:10.1111/joim.12970
Mukkamalla SKR, Kashyap S, Recio-Boiles A, et al. Gallbladder Cancer. In: StatPearls. Treasure Island, FL: StatPearls Publishing; July 10, 2022. Accessed December 20, 2022. https://www.ncbi.nlm.nih.gov/books/NBK442002/
Barazanchi AWH, MacFater WS, Rahiri JL, et al. Evidence-based management of pain after laparoscopic cholecystectomy: a PROSPECT review update. Br J Anaesth. 2018;121(4):787-803. doi:10.1016/j.bja.2018.06.023
Zackria R, Lopez RA. Postcholecystectomy Syndrome. In: StatPearls. Treasure Island, FL: StatPearls Publishing; August 29, 2022. Accessed November 21, 2022. https://www.ncbi.nlm.nih.gov/books/NBK539902/
Ursodeoxycholic Acid, Ursodiol. Clinical Pharmacology. New York, NY: Elsevier Inc.; 1960. Updated August 6, 2018. Accessed October 25, 2022. Available from: http://www.clinicalkey.com
Chenodiol. Clinical Pharmacology. New York, NY: Elsevier Inc; 1960. Updated September, 29 2015. Accessed October 25, 2022. Available from: http://www.clinicalkey.com
Bonis PA, Lamont JT. Approach to the adult with chronic diarrhea in resource-abundant settings. UpToDate. UpToDate Inc.; 1978-2022. Last Updated May 2, 2022. Accessed November 28, 2022. https://www.uptodate.com/contents/approach-to-the-adult-with-chronic-diarrhea-in-resource-abundant-settings
Cholestyramine Resin. Lexicomp. UpToDate Inc.; 1978-2022. Updated November 25, 2022. Accessed November 29, 2022. Available from: https://online.lexi.com
Colestipol. Lexicomp. UpToDate Inc., 1978-2022. Updated October 22, 2022. Accessed November 29, 2022. Available from: https://online.lexi.com
Sruthi M. What does psyllium husk do? MedicineNet. Updated October 7, 2021. Accessed November 29, 2022. https://www.medicinenet.com/what_does_psyllium_husk_do/article.htm

Honey: A Sweet Solution?-RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-0000-23-013-H01-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

HONEY: A SWEET SOLUTION? Dr. Andrea K. Hubbard

Which of the following is correct?

Propolis helps in the maturation of the queen bee.
Royal jelly helps in the development of the king bee.
Honeybees collect nectar and pollen in separate flights.

How have various people used honey or products of bees for centuries?

Treatment of infected wounds
Element in marriage ritual
Food for livestock

What component of honey creates its low pH and antimicrobial activity?

Potassium
Dextrose
Gluconic acid

At what age is it safe to give children honey?

Younger than 1 year of age
Older than 2 years of age
Once they are weaned

Which of the following apitherapy has the FDA-approved?

Propolis
Royal jelly
Honey

Which of the following is a function in honey that is associated with hydrogen peroxide and methylglyoxal?

Vitamin
Mineral
Oxidant

Fill in the blank: Bees lower the water content in honey to _____ through enzymes in their crop, fanning their wings, and keeping their hive at a high temperature.

Ayahuasca and Drug Interaction: The Good, the Bad, the Soul-RECORDED WEBINAR

Learning Objectives

The activity met the following learning objectives for Pharmacists:

· Describe pharmacological properties of harmala alkaloids in ayahuasca

· Define adverse reactions associated with food and dietary interactions with ayahuasca such as hypertensive crisis and serotonin toxicity

· Construct management strategies to avoid adverse reactions from interacting foods and drugs

· Discuss observational, clinical, and toxicologic studies relating to ayahuasca use

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-0000-23-009-H05-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Which of the following is true about harmala alkaloid inhibition of MAO?

Harmalas strongly inhibit both MAO-A and MAO-B
Harmalas are irreversible inhibitors of MAO-A
Harmalas are reversible inhibitors of MAO-A

Which of the following is/are red flags for serotonin toxicity when using psychedelics?

Fever > 101F
Dilated pupils
Hallucination

Which of the following drugs do you predict to be dangerous with MAOIs?

A drug that releases serotonin
A drug that increases GABA neurotransmission
A drug that binds to opioid receptors

A new drug named Seratanin has come to market. You research this compound and find that it works by blocking serotonin reuptake, lacks active metabolites, and has an elimination half life of ~48 hours. Which of the following do you predict?

It could be dangerous with ayahuasca if not avoided for at least 10 days prior
It could be dangerous with ayahuasca if not avoided at least 48 hours prior
It could be dangerous with ayahuasca if not avoided at least 6 days prior

Why is it difficult to analyze calls made to poison control centers concerning Ayahuasca?

Poison control centers have received fewer than 100 calls since they started tracking so any assumption lacks statistical significance
Poison control centers have been unable to verify contents of ayahuasca or other concurrent drugs users were taking
Most of the calls come from older women, reflecting the Baby Boomers propensity to be more accepting of hallucinogens

Evidence Based LDL Lowering Options-RECORDED WEBINAR

Learning Objectives

The activity met the following learning objectives for Pharmacists:

· Describe the role of dietary modification for LDL modification

· Identify how some dietary supplement ingredients mimic the mechanisms of action of prescription drugs

· Describe the magnitude of plant sterols and stanols, red yeast rice, silybum M, berberine, cinnamon, green tea extract, and garlic LDL reduction as monotherapy

· Describe the potential for combination therapy to increase the magnitude of benefit

· Compare and contrast with prescription LDL lowering options

· Describe risks of contamination and adulteration with dietary supplements

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-0000-23-010-H01-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Which of the following fats has the worst effects on the LDL to HDL ratio?
Trans fats
Saturated fats
MUFAs

Which of the following describes the impact of the Mediterranean diet on patients?
It reduces cardiovascular events significantly and LDL by a large amount
It reduces cardiovascular events significantly and LDL to a modest amount
It reduces the need for lipid lowering therapy by a large amount

Which of the following supplements is linked correctly to its likely mechanism of action?
Berberine – Blocks the enzyme HMG CoA Reductase
Red Yeast Rice – Blocks formation of the protein PCSK9
Sterols/Stanols – Block LDL reabsorption and fat absorption

Tobias Whale is a 50-year-old super villain in the series Black Lightening. In addition to killing the innocent and extorting small business owners, he also has a poor baseline diet. He requires a 6% reduction in his LDL to reach his goal. Which of the following natural products are MOST LIKELY to get him to goal?
Cinnamon
Green tea
Red Yeast Rice

What does a USP or NSF seal on a bottle of Red Yeast Rice tell you?
That the product will reduce your LDL by 30% under normal circumstances
That the product will reduce your risk of ASCVD events
That the specified active ingredient is actually in the pills

“I don’t dig your cig” : Strategies for tobacco cessation-RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive 1.0 CE Hour for completing the activity (ACPE UAN 0009-0000-23-011-H01-P), passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Which patient characteristic supports initiation of combination therapy for smoking cessation?
1. Age younger than 65 years
2. Elevated eosinophil levels
3. Heavy smoker with high dependence

When should patients begin varenicline relative to their quit date if they are following an approach with a traditional fixed quit date?
1. 1 week prior
2. 3 days prior
3. The same day

Which of the following treatments for smoking cessation requires a dose adjustment for renal impairment?
1. Nicotine lozenge
2. Bupropion SR
3. Varenicline

Which of the following combinations is the most effective for smoking cessation?
Combination NRT
Bupropion SR + nicotine patch
Varenicline + nicotine patch

Which statement correctly describes the comparative efficacy of first-line smoking cessation monotherapies?
Bupropion SR is more effective than NRT
All NRTs are more effective than varenicline
Varenicline is more effective than NRT or bupropion SR

Why can’t women who are younger than 35 who smoke 15 or more cigarettes per day use estrogen containing contraceptives?
A pharmacokinetic drug interaction decreases contraceptive efficacy and increases risk for adverse effects
A pharmacodynamic drug interaction increases risk of venous thromboembolism, myocardial infarction and stroke
A pharmacokinetic drug interaction increases estrogen levels and also magnifies estrogen-like side effects

Patients should be counseled to avoid eating or drinking 15 minutes prior to the use of which therapies?
Nicotine lozenge, gum and inhaler
Nicotine lozenge and gum
Nicotine nasal spray, gum and lozenge

Which of the following smoking cessation therapies does NOT match with the listed side effect?
Nicotine gum and vivid dreams
Nicotine nasal spray and nasal irritation
Bupropion SR and tremor

Chad is a 55-year-old male patient with a past medical history including diabetes mellitus type 2, hyperlipidemia, hypertension, and chronic obstructive pulmonary disease. He is currently hospitalized due to a myocardial infarction but is now stable Chad recognizes that quitting smoking is critical to his cardiovascular health and wants to try to quit. Which of the following therapies is a first-line recommendation for Chad to initiate while hospitalized, according to the American College of Cardiology?

Pharmacotherapy is contraindicated 2 weeks post myocardial infarction
Combination therapy with Chantix and NRT
Combination NRT

Melissa is a 34-year-old female who has smoked two packs per day since she was 19 years old. She comes to the pharmacy and asks if there is a medication that can help her feel ‘readier’ to quit. She does not feel ready to set a quit date but wants to try and work toward this goal. Which of the following medications can Melissa start now with a goal of reducing smoking?
Chantix or NRT
Any of the first-line medications
Bupropion SR

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