INTRODUCTION

Dolly is a pharmacist in an independent pharmacy working 9 to 5 (what a way to make a living!). Her technician, Miley, calls her to the front to talk with Carol, a 60-year-old woman who consistently wears her smartwatch. Miley tells Dolly, “You have to hear this!” Carol reports that while walking her dog, she tripped and landed face down on the pavement. Carol says her smartwatch called out, “It looks like you’ve taken a hard fall,” and asked if it should call 911. Carol didn’t need emergency services, but she was grateful that the watch detected her fall and could help if necessary. If Carol had been unresponsive, the watch would have called 911 automatically. When Carol left, Miley said, “You know Dolly, I am really concerned that artificial intelligence (AI) is going to replace me.” Dolly nodded and said, “I know. I have some concerns, too. It's enough to drive you crazy if you let it.” Dolly realizes she needs to look into AI and its possibilities.

AI is a technology that learns, reasons, and performs tasks to mimic humans.¹ A 2022 Pew Institute survey of 11,004 Americans found that while 55% use AI frequently, awareness of its presence and capabilities varies.² Only 30% of participants demonstrated high AI awareness, with factors such as education level, income, and Internet use influencing their familiarity.² Despite growing adoption, public engagement is mixed, with concerns about AI’s impact fueling debate.

Recently, many media outlets have published articles about AI, and many of those pieces have generated public debate and concern.^3-5 Public engagement in ethical debates about AI’s use and limitations is only reasonable and well advised if individuals understand its strengths and limitations. Despite the widespread adoption of AI technologies among Americans, another Pew Research Center survey reported that only 15% express more excitement than concern about its increased use in daily life, 38% express more concern than excitement, and 46% are mixed, containing both excitement and concern.⁶ Nonetheless, AI’s adoption and market value increases annually. Researchers estimated the AI market size at $40 billion in 2022 and expect it to grow to $1.3 trillion by 2032.⁷

Americans rely on AI in their everyday lives for web searches, task automation, and more—often without even realizing it. Engineers have seamlessly integrated AI into technologies like Siri, Alexa, and Google Home, making everyday tasks more convenient. With almost limitless possibilities, AI continues to evolve and grow, including in the healthcare field.

PAUSE & PONDER: Take a moment and look at this list. Which of the following are AI powered? You can find the answers at the end of this activity (after the CONCLUSION).

• Air conditioners
• Automatic washing machines
• Basic calculators
• Customer service chatboxes
• Email services
• Facial recognition technology
• Playlist recommendations
• Purchase recommendations
• Refrigerators
• Social media
• Television remote controls
• Voice assistants
• Wearable fitness trackers

Defining AI

AI systems predict, recommend, and make decisions using machine-based algorithms. Programmers design these systems with a set of rules and human-defined objectives to accomplish a variety of tasks.^8,9 As Table 1 implies, no single definition fully captures AI’s complexity, and its applications are broad.¹

AI Models

AI system designs vary based on the AI model used. Common algorithms include machine learning, neural network, deep learning, natural language processing, and rule-based expert systems. Neural network and deep learning fall under the broader category of machine learning. Table 2 describes how developers tailor each model to accomplish specific tasks in unique ways.¹⁰ It also captures common AI models used in healthcare with examples for their application.

After some research, Dolly was ready to determine the model AI uses to detect falls. She found that smartwatches rely on machine learning models, including deep learning, to identify falls. Specifically, the technology uses accelerometer (an instrument that detects and measures speed and directional vibrations) and gyroscope (an instrument that detects and measures angular momentum) data from the watch to detect abrupt movements and shifts in motion that could signal a fall.¹⁶

PAUSE & PONDER: How can healthcare professionals and leaders integrate AI models into healthcare?

AI IN DISEASE MANAGEMENT

Integrating AI into healthcare can transform patient care and streamline workflows.¹⁰ A recent survey reported that 80% to 90% of forecast panelists believe that AI will improve care, simplify patient referrals, and facilitate prior authorizations.⁸ Also, 63% of participants indicated that it is very or highly likely for health systems to adopt AI for pharmacist documentation. AI can specifically help document patient information in electronic health records (EHR).⁸ Some physicians and advanced practice providers are already using AI to improve patient documentation.⁸

Generative AI uses machine models to analyze data patterns and create content like images and text. In healthcare, it enhances patient care and supports whole-person health.⁸ This technology can assist with medical image interpretation, inform disease diagnosis, identify care gaps, personalize treatment plans, enable remote patient monitoring, and support early intervention and preventive care.^8,17 In her research, Dolly found a number of applications that could improve patient care.

Diabetes Management

By 2050, statisticians expect that 1.31 billion Americans will have diabetes.¹⁸ Diabetes management requires frequent follow-up and comprehensive examinations to monitor blood glucose levels and detect complications.¹⁹ Medical resources are unevenly distributed across the United States (U.S.). Physicians are often concentrated in wealthier and suburban areas, leaving rural regions with limited access to primary and specialty care. Yet, rural populations have a 16% higher prevalence of type 2 diabetes (T2DM) and a 20% higher T2DM-related hospital mortality rate compared to urban populations.²⁰

Effective diabetes management requires a collaborative approach involving endocrinology, nutrition, nephrology, ophthalmology, pharmacy, and podiatry. Since primary care alone is insufficient to handle this complex condition, rural areas face significant challenges in diabetes management.¹⁹ By 2034, researchers estimate a shortage of 124,000 doctors in the U.S., with the majority of loss in primary care.²¹ If this prediction is accurate, individuals in rural areas will face growing challenges accessing healthcare. Given the uneven distribution of healthcare resources across various regions, AI advancements may enhance efficiency in diabetes care while diminishing overall health expenditures.^10,19

To achieve better care for all people, clinicians may use predictive models to assess disease progression in T2DM, forecast blood glucose levels, and detect diabetic retinopathy.²²

AI technology may prevent diabetes onset in high-risk patients by ensuring early medical intervention.¹⁹ AI technologies may use non-invasive, cost-effective methods capable of early identification and classification of diabetes.

An emerging theory is that machine learning using facial texture features and tongue color analysis could predict diabetes onset and identify those at high risk. In patients with diabetes, skin manifestations are common.²³ These manifestations range from acanthosis nigricans (demarcated plaques with grey to brown pigmentation), to dermopathy (spots on the front of lower legs), to skin thickening.²³ The pathophysiology of these conditions is not entirely understood. However, aging and diabetes causes increased collagen interlinking. Consequentially, skin changes like thickening and hardening may occur.²³

In Chinese Medicine, practitioners believe face regions reflect the health of internal organs.²⁴ Asian researchers postulated that tongue discoloration, such as a yellow coating, is linked to diabetes, with studies showing a connection between tongue features and glucose metabolism.^25,26 In 2017, researchers conducted a study to determine which model analyzes facial texture and color to detect diabetes most accurately.²⁴ They took facial images, divided them into regions, characterized regions by textures, and analyzed them using eight different models.²⁴ In 2019, Chinese researchers collected tongue images from 570 patients and analyzed their color and texture using AI models. The results demonstrated that these models may effectively associate tongue images with diabetes, but these studies remain preliminary.²⁵

In 2024, 8.7 million Americans or 3.4% of all U.S. adults met laboratory criteria for diabetes but were not aware that they had this condition.²⁷ Delayed diagnosis is a common concern in diabetes, with about 45% of adults worldwide undiagnosed.¹⁸ Current diabetes diagnostic tests include hemoglobin A1C, fasting plasma glucose, 2-hour plasma glucose, and oral glucose tolerance test (OGTT). These four tests are invasive as they require venipuncture.²⁴ Non-invasive diagnostic methods, such as analyzing facial images and tongue color, could help identify diabetic patients who are unaware of their condition.

Dolly is fascinated by this information, but aware that these findings are very preliminary. Recently, one of her favorite patients, Lily, had gained weight rapidly in the early trimesters of pregnancy. Her obstetrician ordered an OGTT. Before the test, Lily fasted, then drank a sugary solution and had her blood sugar levels measured at specific intervals. This process was challenging for Lily, as the sight of blood and having her blood drawn nauseates her. Dolly wishes that non-invasive methods were currently available.

In primary care, AI technologies may create personalized diet and exercise plans for people with diabetes. These plans could align with clinician recommendations and contribute to effective diabetes management.¹⁸

Despite the promise of AI technology in diabetes management, predicting blood glucose levels remains challenging because food and subcutaneously administered insulin absorption rates vary. AI technologies are increasingly embedded into continuous glucose monitoring (CGM) systems to predict blood glucose levels. CGMs track patients’ blood glucose levels in real time and eliminate frequent finger pricks. CGMs provide regular and accurate blood glucose data, offering greater convenience than traditional finger sticks. Regardless, errors may still occur.

CGM may report blood glucose levels that differ from actual values by roughly 9%. Differences in actual blood glucose level measurements may be an important consideration for individuals with diabetes and their healthcare providers.

Another obstacle is when clinicians’ recommendations differ from those generated using AI, as both may be correct. To resolve discrepancies, AI may serve as a tool to support human decision-making. Last, AI technology is designed based on the data it receives. Data quality is important for accurately predicting and managing diabetes.^19,22

Cardiac Care

Like diabetes, heart failure (HF)—the inability of an individual’s heart muscle to pump enough blood—is becoming more prevalent. Common symptoms include shortness of breath, fatigue, and swelling of the legs, ankles, or abdomen.³⁰ Worldwide, approximately 60 million individuals live with HF.³¹ Managing HF requires accurate diagnoses and treatments tailored to individual patients. AI technologies may help diagnose, predict outcomes, classify, and optimize treatment strategies in HF.³²

Researchers have published much information on HF, and information on the use of machine learning to analyze this data is increasing. AI algorithms address challenges like data noise (large amounts of unwanted data that make analysis difficult), false correlations (no relationship between two variables), and statistical power issues (a study’s inability to detect accurate results or effects). By streamlining data analysis, AI complements traditional statistical methods to gather insights into HF.³²

Researchers have created an AI-based diagnostic algorithm for HF. The study enrolled 600 patients with and without HF. The results demonstrated a diagnostic accuracy of 98% and surpassed non-specialist clinicians, who had an accuracy of 76%. In regions with limited access to HF specialists, these AI technologies could be beneficial.^32,33

Patients with HF also face high 30-day readmission rates. Decreasing HF hospital admissions and readmissions is important considering the financial penalties that the Centers for Medicare and Medicaid Services (CMS) impose. CMS reduces hospital payments by a percentage following unplanned 30-day readmissions for patients with HF.³⁴ The hospitalization rate has improved from about 367 hospitalizations per 100,000 adults in 2016 to 350 hospitalizations in 2020. However, Healthy People 2030’s target is 330 per 100,000, meaning more improvement is needed.³⁵

Deep learning AI models may help lower hospital readmissions for patients with HF. In a 900-patient cohort study, these technologies outperformed traditional techniques in predicting readmission rates. This AI algorithm used heart sounds, respiratory rate, tidal volume (the amount of air that moves in and out of the lungs during a normal breath), heart rate, and patient activity to make predictions.³²

The rising use of remote monitoring and wearable devices is likely to expand AI’s effectiveness in managing HF. AI-powered smartwatches programmed with electrocardiography features demonstrate acceptable accuracy in detecting HF with reduced ejection fraction. These technologies allow continuous data streams, better prediction in hospital readmission rates, and earlier HF identification.^31,32

Dolly finds that smartwatches can also be useful for patients who have or are at risk for atrial fibrillation (AFib). Carol, the patient whose smartwatch detected a fall, has been worried that she might develop AFib, which causes irregular heartbeats. Last week, the watch detected an episode of AFib. When Carol visited her provider, she brought the printed electrocardiogram showing the episode. This enabled the provider to make informed decisions about next steps, supported by AI technologies.

Sepsis Identification

Globally, sepsis—a life-threatening response to an infection—is a leading cause of illness and death.³⁶ Patients with sepsis present with varying degrees of severity, ranging from mild sepsis to septic shock. It can lead to tissue damage, organ failure, and death. Sepsis’s variable presentation makes early detection challenging. However, prompt recognition of sepsis is critical, as every hour without treatment increases the risk of death.³⁶

AI technologies may predict sepsis hours before its onset. Through machine learning and predictive algorithms, AI improves the accuracy of sepsis detection in a clinical setting.^36-38 Researchers conducted a prospective, multi-center study of 590,736 patients across five hospitals, with 6,877 included in the analysis.³⁸ During the study, researchers used the Targeted Real-time Early Warning System (TREWS) as a sepsis alert system for providers.³⁸ TREWS is a machine learning-based algorithm that notifies providers when a patient is at high risk for sepsis.

TREWS integration enabled early intervention from providers and reduced the hospital mortality rate by 5.1% when providers responded to the alert within three hours.³⁸ The TREWS intervention group also saw a 4.5% decrease in overall mortality compared to patients whose providers did not respond within three hours. Patients flagged as high risk also experienced reductions in organ failure severity.³⁸ A critical point is provider response time. It is possible that providers who responded more quickly simply had better resources or teams at their disposal.³⁹

This study’s major limitation was the predetermined alert settings, which may have influenced the alerts and their associations with clinical outcomes.³⁸ TREWS notified providers when patients exhibited significant findings related to sepsis. This constraint limits the study’s generalizability, as variations in alert settings may lead to significant differences in the timing of alerts and, potentially, patient outcomes. Future implementation may adopt a less restrictive model, allowing earlier warnings by identifying patients with fewer sepsis-related criteria.³⁸

Alert fatigue—healthcare provider desensitization to safety alerts—may also limit this study’s applicability to clinical practice.³⁸ Alert fatigue often causes individuals to not respond properly to safety alerts and warnings.⁴⁰ TREWS integration may contribute to the alert fatigue phenomenon that plagues the healthcare industry.

Despite this study’s promising results, few large, randomized controlled trials (RCTs) have evaluated AI-based alerts for patients with sepsis.³⁷

Acute Kidney Injury Alert

Acute kidney injury (AKI; a decline in the kidney filtrate rate) impacts approximately 18% of inpatients and greater than 50% of patients in intensive care units.⁴¹ Like managing HF and diabetes, early detection is critical.^41,42 Two studies have examined AI in AKI.

Chinese researchers led a double-blind RCT to evaluate the impact of electronic alerts on adults with AKI.⁴¹ They randomized more than 2,000 hospitalized patients to determine whether an AKI alert combined with management strategies improves care and clinical outcomes. The data showed that alerts did not improve kidney function or overall patient outcomes. However, the alerts influenced treatment approaches. Patients in the alerts group received more intravenous fluids (82.6% vs 61.8%), fewer nonsteroidal anti-inflammatory drugs (5% vs 11%), and more AKI documentation at discharge (49.9% vs 27.3%).⁴¹

Another double blinded, multicenter RCT enrolled more than 6,000 patients. Researchers concluded that the AKI alerts did not reduce the risk of AKI progression, dialysis initiation, or death within 14 days of randomization.⁴²

Both studies found that integrating their specific AKI alert algorithms into EHR did not improve patient outcomes.^41-43 However, pairing these alerts with management strategies influenced providers’ treatment decisions. These findings suggest that while changes in treatment strategies may not directly benefit patients, they may help avoid medications that can contribute to AKI.^41,42

Image Interpretation

Beyond its use in facial recognition for social media and security, AI also has the proven potential to analyze medical images. Specifically, AI technologies show promise in oncology for identifying and categorizing cancers, and in managing diabetic retinopathy.

Oncology

Researchers are developing AI models for cancer imaging, aiming to improve tumor detection, characterization, and monitoring.^10,44 These tools identify various cancers and predict patient outcomes very accurately.⁴⁵ They can help minimize oversights and serve as an initial screen to reduce omission errors.

AI tumor characterization involves tumor segmentation (outlining and identifying boundaries of the tumor in images), diagnosis, and staging. AI-driven automated segmentation has the potential to enhance the efficiency, reproducibility, and quality of tumor measurements.⁴⁴ It may also improve the ability to monitor changes in tumors over time. Despite these promising advancements, challenges remain in ensuring accurate detection, characterization, and monitoring.⁴⁴

Diabetic Retinopathy

AI models can detect diabetic retinopathy, a complication of diabetes that progressively impairs vision over time. AI identification of diabetic retinopathy is facilitated through retinal fundus imaging, which has demonstrated high sensitivity and selectivity, as defined in the SIDEBAR.^22,46,47

In 2017, researchers enrolled 521 participants across 10 U.S. centers. Each patient underwent a dilated ophthalmoscopy (an eye exam). The AI algorithm accurately identified 36 of 37 positive cases (97% sensitivity) and 162 of 184 negative cases (88% specificity).⁴⁶ The researchers concluded that the AI system detects mild diabetic retinopathy more effectively than general ophthalmologists or retina specialists. This tool may offer a low-cost solution for diabetic retinopathy screening and help reduce the burden of diabetic eye screenings.⁴⁶

Electronic Health Records

Approximately 80% of clinically relevant healthcare information is unstructured data.⁴⁸ Applying a natural language processing (NLP)-based algorithm to the EHR may help hospitals identify patients who need a clinical pharmacist’s review. NLP models possess the ability to engage in speech recognition, text analysis, and translation, with goals centered around language processing. One example of its use is transcribing patient interactions, which may be helpful for medication reconciliation. Similarly, NLP-based systems can prepare reports, such as patient notes within the EHR, and analyze these notes.¹⁰ By analyzing notes, the system can also identify patients requiring extensive medication interventions and categorize them as high risk. This classification enables pharmacists to dedicate their efforts to patients most likely to benefit, ultimately enhancing their impact on patient care.⁴⁸

AI models may also detect and alert providers when an ordered medication deviates from its typical use pattern. AI captures information on standard dosages and indications, aiding drug selection, dose recommendations, drug-drug interaction detection, and order entry.⁴⁹ This tool supports pharmacists and other healthcare providers in clinical decision-making to minimize medication-related errors and improve patient outcomes.⁴⁹

Generative AI models may streamline providers’ documentation processes. Clinicians spend approximately 35% of their time documenting patient data and notes.⁵⁰ AI technologies may reduce this workload, allowing providers to focus more on patient care. However, before integrating AI into documentation, leaders must set clear guidelines. For effective use, these guidelines must address concerns such as data security, accuracy, reliability, ethical considerations, and the need for ongoing evaluation of AI programs to ensure regular maintenance and optimization.⁵¹

The possibilities for AI integration in EHR are endless. With proper use, these resources help streamline workflow and increase time providers spend on direct patient care.

PAUSE & PONDER: What are the opportunities and challenges for AI integration into healthcare?

AI CHALLENGES

A major challenge is AI’s inability to explain how it arrives at its conclusions, referred to as model transparency. Predictive modeling and deep learning procedures are difficult to adopt in clinical environments. The algorithms behind these models often lack transparency and experimental context.^8,22

For clinicians to accept AI, they must understand how models generate recommendations. By detailing internal decisions, behaviors, and actions, AI’s developers can build trust among healthcare providers. Developers must equip clinicians with sufficient information to understand each event’s causes. Subsequently, providers can determine how to incorporate AI recommendations into their clinical decision-making processes.^8,22

Another barrier arises from EHRs’ limitations. Since EHR data is not publicly available, AI technologies may struggle to generate comprehensive recommendations. Also, healthcare organizations often restrict data access to internal use, leaving predictive modeling without sufficient information.²² To address this challenge, some experts propose federated learning. This allows institutions to contribute to a global model while keeping sensitive data within their respective systems.¹⁰ However, as AI processes large volumes of data, the risk of data breaches and unauthorized access increases. Protecting databases from security threats remains a challenge.⁸

Bias presents another obstacle. If data used in AI models is homogenous, the results may be skewed. Developers must ensure that training datasets include a wide range of patient demographics and conditions to prevent biased outcomes.⁸

Cost inhibits widespread adoption of AI. Institutions allocate resources for AI differently. Smaller, rural hospitals may struggle to implement these technologies due to financial constraints.⁸ Also, demonstrating a clear return on investment for AI integration is difficult. The limited cost avoidance data per intervention and impact on patient outcomes makes it challenging for hospital executives to justify AI investments.⁸

Legal and ethical considerations further complicate AI acceptance. Mistakes are inevitable with AI technologies. Who will be held accountable for errors, especially when they impact patient outcomes? Healthcare providers may be reluctant to adopt AI technologies if responsibility for potential AI errors is unclear.^8,10 This also calls into question regulatory compliance. If AI becomes the standard of care, providers who choose not to use these tools may face legal and regulatory consequences.^8,10

Before implementing AI in clinical practice, healthcare institutions must thoroughly test and validate each model. A designated committee containing diverse healthcare professionals should lead the approval process to ensure safe and effective implementation of AI models. This approval process and integration into daily practice may take years.¹⁰

After looking at how AI is used currently, the research underway, and AI’s challenges, Dolly feels confident that she can discuss changes in the workplace and pharmacy processes with Miley.

TAILORING AI TO PHARMACY PRACTICE

Many healthcare providers already recognize the implications of AI integration in healthcare. A recent survey asked pharmacists, “How likely is it the following will occur by the year 2029 in the geographic region where you work?”⁸ Table 3 displays the findings on AI integration in pharmacists’ documentation and medication histories.⁸

As healthcare professionals acknowledge AI’s expanding function, they must develop a strong understanding of these technologies. Pharmacists and pharmacy technicians, in particular, need a basic knowledge of AI.⁴⁸ With this foundation, pharmacists can assess AI models’ strengths and limitations and determine when and how to use them effectively.

To establish a baseline understanding of AI technologies, institutions must integrate education and didactic experiences into training for pharmacy technicians, pharmacy students, and pharmacists.^52,53 This will equip healthcare providers with the basic skills needed to evaluate AI models and understand its responsibility in improving patient care.

AI and the Pharmacy Workforce

Like Miley, may pharmacy personnel worry that AI may replace pharmacists and pharmacy technicians. In the United Kingdom, researchers estimate 35% of all jobs—including some pharmacy-related positions—could be automated in the next 10 to 20 years.¹⁰ However, they also predict job losses will amount to less than 5%. This is because of factors like cost of automation technologies, labor market dynamics, and regulatory and social acceptance. These circumstances create major barriers in the widespread adoption of AI across industries and may mitigate actual job loss.¹⁰

In healthcare, similar trends are expected. To date, AI has not eliminated jobs.¹⁰ Pharmacy student enrollment is unlikely to rise, and researchers predict that 20% of first year post-graduate residency spots will remain unfilled after the match. As a result, they anticipate the pharmacy workforce will decline.⁸ This projected reduction has led to expectations that AI will assist with repetitive pharmacy tasks, allowing pharmacists and technicians to focus on responsibilities that require human expertise.

With the integration of AI into healthcare, pharmacists are expected to expand their scope of practice into areas where they can use their skills more and influence outcomes.^8,10 These include managing high-cost medications, bridging gaps in primary care, applying empathy and persuasion, and taking a big-picture approach to patient care. While AI is designed to mimic certain human actions, it is not human. It lacks interpersonal skills and the ability to build relationships. Ultimately, AI will complement pharmacists by streamlining repetitive tasks, addressing workforce shortages, and enabling them to use their unique human intelligence abilities.^8,10

Adverse Drug Reactions

A primary responsibility for pharmacists in medication management is to mitigate patients’ risk of adverse drug reactions (ADRs). EHR systems use AI for ADR prediction and detection. For example, if a prescriber orders amiodarone for a patient who is already taking warfarin, the system is designed to alert healthcare providers that the combination leads to high bleeding risk. Current systems already deliver this alert, and an AI-assisted system may recommend providers decrease the patient’s warfarin dose empirically by 30% to 50%.⁵⁴ However, like any test or algorithm, false positives and negatives can occur, meaning these systems are not foolproof. It is crucial that clinicians and pharmacists do not rely solely on these alerts for detecting ADRs or sending notifications. Instead, they should apply clinical decision-making and rely on their expertise.

A recent study involving 412 patients used a machine learning algorithm to predict the likelihood of ADRs in neonates.⁵⁵ Researchers designed the algorithm to associate a risk score to predict and prevent ADRs, rather than simply display a warning as is done currently for certain medications. The model displayed high predictive accuracies, successfully detecting ADRs in patients with allergic, renal, central nervous system, and hepatic ADRs 78.9% to 90.2% of the time.^49,55 These models illustrate AI’s broad application in ADR detection which supports clinical decision-making.

AI also offers opportunities to improve patient adherence. It can trigger patient-specific message alerts, such as medication renewal reminders for both the pharmacist and the patient. This ensures timely prescription refills, helps maintain a consistent medication supply, and supports better medication adherence for improved health outcomes. Wearable devices like smartwatches and smartphones also integrate AI technology that may encourage behavioral changes and enhance adherence.¹⁰ For example, some smartwatches offer a time-to-stand reminder. If individuals have not moved within the first 50 minutes of an hour, the watch will remind them to stand. Simple alerts like these increase movement and encourage behavior changes.

Beyond clinical applications, AI has the potential to transform pharmacy operations. AI technology may request and process prior authorizations (something of great interest to Dolly and Miley), manage the supply chain, optimize pharmacy revenue cycles, and track financial performance.⁸

CONCLUSION

AI technologies are likely to revolutionize healthcare by enhancing clinical decision-making, improving patient outcomes, and streamlining workflows. Through automation of routine tasks and data analysis, AI can help healthcare providers deliver more efficient care. However, significant barriers including algorithm transparency, bias, cost, and accountability concerns must be addressed before AI is widely adopted. Overcoming these challenges requires collaboration among healthcare providers, policy makers, and AI developers. Establishing clear guidelines and validation procedures will help ensure AI technologies are safe and used properly. With proper implementation and education, AI is a powerful tool that enhances healthcare professionals’ abilities. Dolly and Miley now appreciate that it cannot replace human skills like empathy, critical thinking, and personalized communication.

PAUSE & PONDER: Take a moment and look at this list. Which of the following are AI powered? These are the answers to that we promised to provide!

• Air conditioner
• Automatic washing machine
• Basic calculators
• Customer service chat box
• Email services
• Facial recognition
• Playlist recommendations
• Purchase recommendations
• Refrigerators
• Social media
• Television remote control
• Voice assistants
• Wearable fitness trackers

Download CE Activity

Download CE Activity

INTRODUCTION

Let’s start this continuing education (CE) course with a story. A 13-year-old adolescent, Emily, had asthma exacerbations that were impacting her life. In addition to sitting out at her soccer games, she was having difficulty waking for school because her asthma exacerbations kept her up a few nights a week. Her physician prescribed a budesonide/formoterol (Symbicort) prescription for maintenance and reliever. When she and her mom went to pick up the prescription, their pharmacist told them this prescription was “inappropriate” and “dangerous” at the pick-up counter. This pharmacist likely frightened the patient and her mother. The patient would have been rightfully hesitant to take the prescription as the physician prescribed.

Although the guidelines did not recommend using this combination for reliever and maintenance before 2020, the pharmacist was mistaken. This pharmacist didn’t know about new NHLBI guidelines for SMART therapy. This continuing education activity will explore a recent change to the asthma guidelines that helps aspiring soccer players like our Emily score a goal with their asthma. Staying up to date on guidelines is the only way pharmacists will keep their place as trusted healthcare professionals.

BACKGROUND

All pharmacy team members need to know about asthma because it is a common chronic disease in both children and adults. The Center for Disease Control (CDC) estimates that around 8% of the population has asthma. As a chronic disease affecting the airway and lungs, asthma is characterized by airway inflammation, bronchospasm, and mucus hypersecretion. These findings cause symptoms of difficulty breathing, wheezing, coughing, and chest tightness.¹ Asthma’s symptoms can range from mild to severe and they fluctuate. Symptom worsening is called an asthma attack, flare, or exacerbation.²

Asthma is often diagnosed in childhood but affects people of all ages. It is diagnosed more commonly in males during childhood, but its prevalence is equal in males and females by adulthood.¹ Asthma seems to have a hereditary component, although many genes probably contribute to asthma.³ Family history and the presence of eczema are both risk factors for asthma.¹ Other risk factors include exposure to environmental tobacco smoke, air pollutants, or allergens, such as pollen, dust, or workplace chemicals (see the SIDEBAR for information about household pests).¹ Risk factors for asthma are often present in childhood. For example, exposure to cigarette smoke in the womb increases the probability infants will develop asthma. Young children with allergies or who have respiratory infections are also more likely to develop asthma.¹

Asthma Pathophysiology

The bronchial tree is the branched system of cartilaginous tubes responsible for conducting gas to alveoli, the small air sacs that allow gas exchange, in the lungs. The word “tree” is an apt description because the lungs look like an upside-down tree, where the trachea is the trunk, and the bronchioles are the smallest terminal twigs. The bronchioles are the smallest bronchi and they facilitate gas exchange with alveoli, the air sacs in the lungs that exchange gas with the blood.⁴ Each layer of the bronchi has a smaller diameter than the one it stems from and has more smooth muscle fibers, just like the branches of a tree.⁵ Asthma primarily affects airways including the smooth muscle of the bronchi, where inflammation decreases the airway’s size, in turn increasing the work it takes to breathe.³

In allergic asthma, an asthma exacerbation consists of an early phase and a late phase. IgE antibodies are responsible for the first phase.³ Environmental triggers cause plasma cells to release IgE antibodies, which bind to mast cells and basophils. Mast cells release cytokines, histamine, prostaglandins, and leukotrienes.³ Ultimately, smooth muscle contracts and the airway tightens, causing bronchoconstriction.⁶ Th2 lymphocytes sustain the inflammation by producing additional cytokines and maintaining the communication between cells.³ The late phase occurs over the next few hours as inflammatory cells localize to the lungs and cause bronchoconstriction and inflammation. The cells involved in this second phase include basophils, eosinophils, helper and memory T-cells, and neutrophils.³ These cells cause inflammation and further edema. Mucus worsens airway obstruction and difficulty breathing. Successful management of an asthma exacerbation requires recognition of both phases.

Hyperresponsiveness of the bronchi is another mechanism of asthma’s pathophysiology. Hyperresponsiveness is excessive bronchoconstriction after inhalation of or exposure to triggers.⁷ Triggers can include smoke, exercise, emotion, cold temperatures, humidity, animals with fur, infections, and non-steroidal anti-inflammatory drugs.^8-11 This mechanism of excessive inflammation involves histamine and increased free intracellular calcium that increases smooth muscle contractility.¹² Disease severity and therapeutic intervention are related to bronchial hyperresponsiveness.

Rodent and Cockroaches Sidebar^13-15

The prevalence of asthma is highest in developed countries, especially in urban areas. In urban areas, up to 1 in 4 children may have asthma. Urban areas increase the risk of exposure to cockroaches and rodents, increasing allergen sensitization in these areas, ultimately leading to asthma. Mouse Mus m 1, mouse urinary protein (MUP), rat N 1, and cockroach (Bla g 1 and Bla g 2) are the responsible allergen proteins. Tests have confirmed high levels of these proteins in houses, schools, and daycares in urban locations.

Multifamily homes, high population density, lower socioeconomic status, and poor physical condition of buildings are all settings that foster cockroach and rodent infestation. Sensitization to cockroaches and rodents is associated with wheezing and severe asthma morbidity. Most research done to date has been in children.

Like people, pests need food, water, and shelter to live. They prefer to live in dark and damp areas. Pest mitigation strategies can decrease the likelihood of exposure to rodent and cockroach proteins:

• Do not leave food containers open or dirty dishes out in the open.
• Do not leave pet food and water out overnight.
• Clean regularly. Pick up garbage, crumbs, and clean liquid spills.
• Use trash cans with lids, bags that resist breaking, and do not allow them to overflow.
• Check for plumbing leaks and moisture problems and fix any issues right away.
• Seal cracks and openings around doors, windows, and foundations.
• Use bait gel in cracks and traps rather than pesticides.

Structural changes occur in the airway due to chronic inflammation and airway muscle hyperreactivity. This is known as airway remodeling. An asthmatic bronchiole is narrower than a normal bronchiole. Increased swelling, chronic inflammation, and mucus buildup from persistent airflow obstruction cause the narrowing.³ The narrowing of the lumen disrupts the normal replication of epithelial cells, compromising the layer’s structure and function.¹⁶ The hyperresponsiveness of the bronchioles leads to hypertrophied smooth muscle, disrupting the basement membrane. Irreversible obstruction of airflow is a consequence of airway remodeling.¹² Effective treatment of asthma can prevent or delay airway remodeling.

ASTHMA DIAGNOSIS

The first step in diagnosing asthma is a focused medical history and physical examination. Symptoms consistent with asthma include episodes of cough, wheezing, difficulty breathing, and chest tightness. It is also notable if these symptoms worsen at night and awaken the patient, as they did for our patient Emily.¹⁷ The physical exam may show use of accessory muscles when breathing, sounds of wheezing during normal breathing, increased nasal secretion with mucosal swelling, or atopic dermatitis/eczema.¹⁷ Noting patient allergies or a family history of asthma helps establish a diagnosis.

Spirometry can be used to evaluate asthma and monitor disease severity; it can also be used to monitor response to therapy in patients aged 5 and older.  Of note, it is not common to find many five-year-olds who are capable of reliably performing the test.¹⁷ Spirometry measures the air a patient breathes in and out. Specifically, spirometry measures the forced expiratory volume in 1 second (FEV₁) and the forced vital capacity (FVC).¹⁸

• FEV₁: maximum amount of air a patient exhales in one second.
• FVC: maximum amount of air exhaled when blowing out as fast as possible

Comparing results against values normalized by age, height, weight, gender, and race is the only way to interpret them. An easy way to interpret results is based on the percent predicted; however, most pulmonologists now use z-scores to interpret spirometry.¹⁹ Physicians may have the patient repeat spirometry after taking a bronchodilator to evaluate for airway reversibility.

Clinicians also use spirometry to evaluate if current therapy is controlling asthma effectively. The results of patients’ spirometry tests while on treatment guides doctors to increase or decrease the dose of asthma medications.¹⁸

Airway hyperresponsiveness is measured using a methacholine test. The clinician uses spirometry to find the patient’s FEV₁. The patient then uses a nebulizer and inhales increasingly larger doses of methacholine. The physician takes the FEV₁ before and after each dose. The test is positive if the FEV₁ drops 20% or more from the baseline FEV₁. The test is negative if the maximum methacholine dose does not decrease the FEV₁ by at least 20%.²⁰ Regardless of asthma control and response to therapy, most people with asthma would have a positive methacholine challenge test.

The 2020 NHLBI guideline update includes the conditional recommendation to use fractional exhaled nitrous oxide (FeNO) as a test to diagnose asthma.²¹ Nitric oxide (NO) is a gas produced by cells involved in inflammation. The higher the NO level, the more inflammation in the body. This test is plausible to use as an adjunct for patients aged 5 and older whose asthma diagnosis is uncertain using history, clinical course, and spirometry. Our patient in this CE case would not be a candidate for a FeNO test, as her asthma diagnoses are apparent without one. One should also note that most commercial insurances no longer cover this test.

Asthma Severities

The NHLBI classifies asthma as intermittent, mild persistent, moderate persistent, or severe persistent. Asthma symptoms before treatment determine the classification, but the patient’s classification may change over time. Patients are diagnosed with the asthma classification in which their most severe symptom falls.¹⁷ As you look at these classifications, think about Emily and decide where her asthma would fall.

• Intermittent Asthma
  • Symptoms occur fewer than two days a week and do not interfere with normal activities
  • Nighttime symptoms occur fewer than two days a month
  • Lung function tests are normal when the patient is not having symptoms
• Mild Persistent
  • Symptoms occur more than two days a week, but not every day. Attacks interfere with daily activities
  • Nighttime symptoms occur three to four times a month
  • Lung function tests are normal when the patient is not having symptoms
• Moderate Persistent
  • Symptoms occur daily and interfere with daily activities
  • Nighttime symptoms occur more than once a week, but not daily
  • Lung function tests are abnormal
• Severe Persistent
  • Symptoms occur daily and severely limit daily activities
  • Nighttime symptoms occur multiple times weekly
  • Lung function tests are abnormal

The severity of asthma drives the treatment recommendations. Asthma classification can change over time. From our case, Emily likely has moderate persistent asthma. She is kept up a few times weekly by nighttime symptoms, interfering with her sleep. She also needs to sit out of soccer games and was having trouble in school due to her lack of sleep. Her symptoms limit her daily activities.

Pause and Ponder: How would asthma attacks occurring nightly affect a patient’s quality of life?

TREATMENT

With the revision to the guidelines in 2020, several things have changed, and pharmacy staff need to be aware of the changes.

Medications

People can manage asthma with appropriate medications. Table 1^22-26 provides additional detail on the mechanism of action, pharmacology, and adverse events associated with preferred medications used to treat asthma. Inhaled corticosteroids (ICS) are the cornerstone of asthma therapy, and this has not changed with the updated guidelines, although use of biologic agents to control asthma is more prominent.²³ ICS may be dosed once or twice daily but more often during symptomatic periods.²⁴ Beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, and mometasone are all commonly used ICS.²² When dosed at equipotent doses, all corticosteroids are equally effective, but some individuals respond better to certain ICS than others.²⁴ The dose of ICS can be titrated for symptom relief and spirometry response, but the dose response is relatively flat after moderate doses.²⁵ A flat dose response is like continuing to eat when you are already full. When you are full, you likely have gotten all the calories you need from a meal, and now you are just increasing your chances of bellyache. Increasing the dose of ICS past moderate strengths does not continue to provide additional relief of asthma symptoms as before, and the risk of side effects increases. Some patients with severe asthma do escalate to high dose ICS.

Table 1. Preferred Medications for Asthma Therapy^22-26

Patients use oral systemic corticosteroids for severe exacerbations or if they have a history of severe exacerbations or difficult-to-control asthma.²¹ Oral corticosteroids have many unfavorable adverse events that need to be considered by prescribing physicians.²⁷ An increase in the release of cortisol from the adrenal glands through a negative feedback loop on the hypothalamus-pituitary-adrenal (HPA) axis causes many of these adverse effects.²⁷

Systemic corticosteroid adverse events differ by duration of therapy²⁷:

• Short term: hyperglycemia, leukocytosis, mood alteration, sodium and fluid retention, increased weight gain, nocturnal enuresis
• Long term: growth retardation, osteoporosis, skin thinning, impaired wound healing, bruising, cataracts, glaucoma, Cushingoid feature, increased weight gain, and immunosuppression

ICS have little systemic absorption and are preferred for asthma control over oral corticosteroids. Patients taking higher doses of ICS have increased risk of systemic absorption and adrenal suppression. It is important to titrate to the lowest effective dose of ICS to avoid systemic absorption and adverse events. Corticosteroids have a dose-response relationship to adverse events.²⁷ Clinicians must monitor for systemic side effects to determine the risk and benefit balance of both oral corticosteroids and ICS.

While corticosteroids treat the inflammatory component of asthma, additional medications are needed to address airway hyperresponsiveness and can be either short or long-acting medications. “Quick-relief” and “relief” medications are common ways to refer to short-acting medications.²² Short-acting beta-agonists (SABAs) and inhaled short-acting muscarinic antagonists (SAMAs) are the two classes of relief medications. Patients use SABAs and SAMAs when experiencing symptoms or before exposure to triggers.

SABAs are highly effective bronchodilators but have short durations of action.²² Typically, all patients with asthma are prescribed SABAs as a “relief” inhaler.²² Albuterol metered-dose inhalers (MDI) are the most used relief inhaler. Albuterol is dosed at one to two puffs every four to six hours as needed to control an asthma exacerbation.²⁸ SABA use is changing in clinical practice. Newer research shows that SABAs are more effective when followed by an ICS.²⁹ Even in patients with infrequent symptoms, a prescription for daily low-dose ICS reduces asthma symptoms and risk. Increased SABA use is associated with worse outcomes. A patient is at risk of severe asthma exacerbations and asthma mortality if they pick up three or more albuterol inhalers a year from the pharmacy, the equivalent of 1.6 puffs per day.²⁹

SAMAs can be used in place of SABAs but are less effective. SAMAs will be used if SABAs are not tolerated as relief therapy. Ipratropium is a commonly used SAMA. Emily, our patient in the CE case, does not have a SAMA prescription because she receives symptom relief when using albuterol. The APPENDIX describes the different types of inhalers and points that technicians can emphasize when patients pick up refills.

Long-acting medications include long-acting beta-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). LABAs are never used alone in asthma therapy but are companions to inhaled corticosteroids (ICS).²² Patients should take these medications even when asthma symptoms are not present because they are maintenance therapy. All LABA medications have a boxed warning cautioning about the potential for severe asthma exacerbations. Some severe exacerbations, when using LABA monotherapy, have led to death.²² LABAs do not have the same association with severe exacerbations and death when used in a combination with ICS. Salmeterol and formoterol are the most frequently used LABAs.²² The two LABAs differ in their time of onset. Formoterol and salmeterol have an onset of 15 minutes and 45 minutes, respectively. Patients aged 6 and older can use tiotropium as an add-on LAMA in maintenance therapy.³⁰ Table 2^28,30-46 gives an overview of the current inhaled therapies available in the US to treat asthma. You will find details about Emily’s long-acting therapy in the section where SMART is explained.

Table 2. Asthma Inhalers ^28,30-46

Many patients require multiple medications for asthma management. Clinicians prescribe combination inhalers—inhalers that have two medications—to increase efficacy, patient adherence and ease of inhaler use. Patients experience less confusion about when and how to use their inhalers when using fewer products. Clinicians can assess patient adherence and correct use of medications when a patient is on combination products. With this information, clinicians can determine if the patient needs education or an increased medication dose. Table 3 ^47-52 shows the many combination products on the market.

Think back to our case. This patient's prescription was for budesonide/formoterol. This therapy is an ICS and LABA combined therapy. The patient previously used a fluticasone inhaler once daily and albuterol as a relief inhaler. This new therapy would give the patient only one inhaler to control her asthma, avoiding inhaler confusion.  Also, as patients cannot exactly “feel” the inhaled corticosteroid inhaler making a “difference,” but patients can always feel a change with SABA/LABA therapy—the combination inhalers help patients to experience a positive effect while taking chronic medications.

Table 3 Combination Products ^47-52

The 2020 NHLBI Guidelines for Asthma Management list the following medications as alternatives to the preferred therapies: leukotriene receptor antagonists (LTRA), cromolyn (Intal), theophylline, and immunotherapies. The guidelines list nedocromil (Tilade) as an alternative therapy, although the FDA has discontinued this medication. ^21,53

LTRAs include montelukast and zafirlukast. These medications antagonize the effects of pro-inflammatory chemicals called leukotrienes. LTRAs work to decrease the inflammatory component of asthma.²² Montelukast is indicated in patients aged 1 and older, is only dosed once a day, and does not have many drug interactions.⁵⁴ Montelukast use is discouraged because of side effects and limited efficacy. Montelukast’s labeling includes a boxed warning because of potential neuropsychiatric adverse events.⁵⁴

Cromolyn is a nebulized solution approved for asthma prophylaxis. The approval is for patients aged 2 and older. It inhibits release of histamine and leukotrienes from mast cells.⁵⁵

Theophylline is an oral medication rarely used as maintenance therapy for asthma.  It has many side effects and requires titration via blood tests. It is a phosphodiesterase inhibitor and adenosine antagonist. Theophylline ultimately relaxes smooth muscles in the bronchial airway.²²

Immunotherapies are injectable monoclonal antibodies reserved for patients with severe and treatment-resistant asthma. Currently, omalizumab (Xolair) is the only biologic approved for asthma in patients as young as 4 years old. ²¹ The NHLBI 2020 guideline update does not contain specific recommendations for the use of biologics. The systematic reviews the panel examined to update the guidelines did not include the use of biologics. Anti-IgE (omalizumab), anti-IL5 (mepolizumab [Nucala], reslizumab [Cinqair]), anti IL5-R (benralizumab [Fasenra]), and anti-IL4 (dupilumab [Dupixent]) are other biologic treatments for asthma. Insurers typically require prescribers to document the patient’s allergen sensitization and phenotyping before approving immunotherapies. Patients will have to try other therapies and either be unresponsive or intolerant of them before trying biologics. Specialist supervision is needed.²²

Step Therapy Rationale

The NHLBI Guidelines recommend a stepwise approach to the treatment of asthma. The recommendation guides initial asthma treatment based on the asthma severity and subsequent therapy if symptoms persist despite changes in asthma therapy.²¹ Table 4 represents a combination of the stepwise therapy recommendations across all age groups in the NHLBI Guidelines.²¹ For simplicity, the figure only shows the preferred medication recommendations. The full step therapy recommendations can be found in the full version of the NHLBI 2020 Update to the Asthma Management Guidelines.

Table 4. Stepwise Approach to the Preferred Treatment of the Management of Asthma ²¹

In Step 1—which addressed patients with intermittent asthma—patients only use a reliever inhaler to control intermittent asthma symptoms, meaning the patients will only use an inhaler when experiencing symptoms or for pre-treatment before exercise. A clinician would initiate ICS therapy in a patient with mild asthma on Step 2.¹⁷ A patient with moderate asthma would start therapy on Step 3 or Step 4.¹⁷ A patient with severe asthma would start therapy on Step 5 or Step 6.¹⁷

Once treatment has started, a clinician should reassess the patient every two to six weeks to ensure control of asthma symptoms.²¹ If symptoms persist and asthma is uncontrolled, this would be an appropriate time to step-up therapy. Questioning patients about how frequently they use their reliever inhalers, or how many times they forgot to take their inhaler in the past week may help guide clinicians.¹⁷ More frequent use of the SABA, including using a reliever inhaler more than two days a week, would favor stepping up therapy. Appropriate use of asthma inhalers is critical to achieving control. Adherence to the regimen and proper technique are required to determine if the patient is using the medication correctly.²¹ Pharmacists can play an integral role in educating patients in proper inhaler technique.

Objective measures, like spirometry, can also be used to assess control. Improvements in spirometry readings indicate better control of a patient’s asthma.²¹ Increased healthcare utilization, like emergency room visits for an exacerbation, is another way to determine if a patient’s asthma is under control.¹⁷ An increase in patients’ healthcare utilization suggests poorly controlled asthma. Mitigating the risk of severe exacerbations is another goal of achieving good asthma control.¹⁷ Any patient on step 3 or higher should consult with an asthma specialist for treatment.²¹

If a patient has well-controlled asthma after three consecutive months on a medication, the patient also may step down on therapy.²¹ A patient would always only go down one step of treatment. A clinician would schedule follow-up in the same two-to-six-week timeframe to ensure a patient still has asthma control.¹⁷ The benefit of stepping down therapy is to lower the patient’s systemic ICS and LABA dose exposure, decreasing the risk of potential adverse events.

2020 NHLBI Asthma Management Guideline Updates

The 2020 NHLBI Guideline update focused on six select topics: intermittent ICS (e.g. SMART), LAMAs, indoor allergen mitigation, immunotherapy in the treatment of allergic asthma, FeNO testing, and bronchial thermoplasty (BT). A major update to the guideline that is changing clinical practice is SMART.

Time to be SMART

The 2020 NHLBI Asthma Management Guidelines recommend SMART in patients with moderate persistent asthma ages 4 and older. Keeping a patient's current regimen would be appropriate if asthma symptoms are well controlled. SMART employs a single ICS+formoterol combination inhaler product dosed daily and as needed for asthma exacerbations. This is a significant change, and all pharmacy staff need to be aware of it! SMART medications are FDA-approved in patients 12 and older. SMART is recommended off label in children aged 4 through 11.

Before the 2020 update, patients with moderate persistent asthma would be on Step 3 or Step 4 therapy. Therapy consisted of a daily ICS inhaler for maintenance and a SABA inhaler for relief—two separate inhalers. If a patient was uncontrolled on ICS, a physician added a LABA to the regimen. SMART potentially transitions patients from three inhalers to one inhaler. An ICS+LABA combination has never been a reliever option before; the only option was SABA. The drastic change in recommendations is why the pharmacist in the CE case, unaware of this change, was hesitant to fill the prescription. It is an extreme change in therapy and based on outdated information, and he was understandably uncomfortable.

It would be reasonable to switch patients who are uncontrolled on their current regimens or have had an exacerbation in the past year.²¹ It is also reasonable to discuss with patients or families who want to streamline their treatment regimens or those with difficulty adhering to their current regimens. Patients with uncontrolled moderate asthma should switch to SMART on the same treatment step they are currently on before moving up. For example, Emily in the CE case was on Step 4 of the 2007 guidelines, a medium-dose ICS and a LABA.¹⁷ After being transferred to SMART, her regimen includes a medium-dose ICS-formoterol. This is Step 4 of therapy in the 2020 guidelines.

Along with an ICS, formoterol, a LABA, is being used as the reliever component of the regimen. Using formoterol is entirely different than our previous approaches where SABAs and SAMAs were the reliever medications. Formoterol’s onset is two to three minutes.⁵⁶ Its duration of action is up to 12 hours, creating quick and durable smooth muscle relaxation.⁵⁶ Formoterol is also an ideal drug because patients can use it more than twice daily. The maximum dosage of formoterol varies by age. Each inhalation of SMART will deliver 4.5 mcg of formoterol. Patients aged 4 to 11 can use eight puffs of formoterol daily (36 mcg).²¹ Patients aged 12 and older can use twelve puffs of their inhaler per day (54 mcg).²¹

The two ICS currently used in SMART inhalers are budesonide and mometasone.⁵⁷ A patient using a SMART inhaler as needed will also receive the long-term anti-inflammatory effects of an ICS with each use. SMART therapy aims to provide enough long-acting preventive medicine when symptoms occur to prevent them from recurring.⁵⁷

This treatment will be prescribed as one to two puffs once or twice daily for maintenance with one to two puffs as needed every five to 10 minutes for asthma symptoms. Age, asthma severity, and ICS dose in the inhaler determine the dosage and frequency a clinician prescribes.²¹ Pharmacists should ensure the maximum puffs on a patient’s prescription do not exceed the limit for their age.

SMART reduces asthma exacerbations and decreases healthcare utilization while increasing quality of life and asthma control.²¹ SMART therapy also decreases patients’ systemic corticosteroid use. Patients who decrease their use of oral corticosteroids and maintain lower doses of ICS reduce the risk of corticosteroid-associated adverse events.⁵⁷

SMART may make asthma treatment easier for patients and families. Patients appreciate this one inhaler approach with a single prescription to refill and pickup.⁵⁷ Having a single inhaler decreases confusion about which inhaler is responsible for maintenance and reliever. It also ensures the patients always have the correct inhaler in their possession. SMART may be especially beneficial for patients who regularly skip their maintenance inhaler when they do not have symptoms.⁵⁷ These patients rely on their reliever inhalers. With SMART, if patients only take their reliever inhaler, they still receive anti-inflammatory medication.

Costs, insurance formulary considerations, and intolerance are all reasons SMART may not be appropriate for some patients.²¹ Patients who overuse their SABA reliever inhalers may not be good candidates for SMART. Some patients use their reliever inhalers when they are anxious or feel short of breath, even when this is not asthma related.⁵⁷ These patients are at risk of receiving ICS doses that are too high. Patients who use ICS-salmeterol as their maintenance should not use it as SMART.²¹ Patients using both inhalers will expose themselves to higher and potentially dangerous LABA & ICS doses.

Pharmacists are responsible for reminding patients to use only their maximum daily puffs and to contact a physician if their asthma symptoms require them to exceed this maximum. The pharmacist should also consider the supply a patient will need using the medication for both maintenance and relief doses. Patients may need to pick up multiple inhalers monthly for adequate supply.²¹

Pharmacy technicians will prevent errors if they can recognize SMART. These prescriptions will contain directions for daily use and as-needed use in the same inhaler. An example prescription is budesonide/formoterol 80/4.5, inhale 2 puffs twice daily and 1-2 puffs every 4 hours as needed for asthma exacerbations (maximum 12 puffs daily). Current evidence only recommends formoterol as the LABA in SMART. Knowing this, a technician can be on the lookout for the look-alike sound-alike medication salmeterol in combination inhalers which are not safe to use for SMART. A patient on SMART therapy will likely need all other prescriptions for asthma therapy put on hold. Let’s emphasize this point: Patients with automatic refills of a SABA or other maintenance medication will be at risk of over-treatment if they continue to take their old inhalers with SMART. If a patient with a SMART prescription comes into the pharmacy, it is important for the technician to recognize this to help prevent medication errors.

Pause and ponder: Who makes the ideal candidate for SMART therapy?

Additional Guideline Updates

Intermittent ICS²¹

The NHLBI organized the recommendations for the use of intermittent ICS by age. This update includes SMART.

The guidelines recommend that from birth to age 4, children with recurrent wheezing related to respiratory tract infections (RTI), not currently on asthma therapy and with no symptoms between infections should use a seven-to-ten-day course of daily ICS when the RTI begins.²¹ It recommends combining ICS with as-needed quick-relief SABA therapy. This recommendation aims to decrease exacerbations, systemic corticosteroid use, and healthcare utilization.²¹ Healthcare utilization declines when caregivers have clear instructions for initiating ICS.

Individuals aged 4 to 12 with mild to moderate persistent asthma who are currently taking daily ICS should not increase their regular daily ICS dose for short periods.²¹

Individuals aged 12 and older with mild persistent asthma have two preferred treatments recommended as Step 2 of therapy²¹: either a daily low-dose ICS and as-needed SABA or an as-needed SABA and ICS delivered concomitantly, one after the other.²¹ SMART therapy is the preferred treatment in patients with moderate to severe asthma in patients 4 and older.²¹

LAMAs

The 2020 NHLBI guideline update changed the recommendation for LAMA use in patients 12 years and older with asthma not controlled by ICS therapy. The next appropriate step is to add a LABA to ICS rather than a LAMA, unless the patient is unable to tolerate, has a contraindication, or has an adherence barrier to a LABA.²¹ A prescriber may still add a LAMA onto the ICS+LABA combination for improved symptom control and increased quality of life.²¹ A patient on ICS+LABA and LAMA will require the use of multiple inhalers.

Indoor Allergen Mitigation

Some patients have an identified allergen component of their asthma. Patients may use mitigation strategies like air purifiers, impermeable pillows, mattress covers, and HEPA filters to reduce their risk of allergen exposure.²¹ The 2020 NHLBI guideline update recommends patients use multiple mitigation strategies, as one strategy alone likely will not improve outcomes.²¹ The guideline recommends integrated pest management in patients' homes who are allergic and exposed to rodents and cockroaches.²¹ If an individual does not have an allergy to indoor substances, the 2020 Update does not recommend home mitigation strategies.²¹

Immunotherapy in the Treatment of Allergic Asthma

Immunotherapy includes subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). The 2020 NHLBI guideline update recommends SCIT as an adjunct treatment in patients with demonstrated sensitization to allergens, but not when patients are experiencing asthma symptoms or have severe asthma.²¹

FeNO Testing

The 2020 NHLBI guideline update recommends FeNO measurement in patients older than 4 years with an uncertain asthma diagnosis after a medical examination, complete history, and spirometry testing.²¹

Bronchial Thermoplasty

BT is a procedure that removes muscle tissue from the airway using heat. The benefits in this procedure are small, the risks are moderate, and long-term outcomes are uncertain.²¹ The 2020 NHLBI guideline update conditionally recommends against this procedure.²¹ Patients who may consider BT must have a risk-benefits conversation with their provider.

Conclusion

The update to the 2020 NHLBI Asthma Management Guidelines offers new guidance to clinicians treating patients with asthma. Patients need to go to the pharmacy and pick up their evidence-based treatment without unnecessary intervention—or incorrect and possibly frightening information—from the pharmacist. Pharmacists should expect to see prescriptions of ICS-formoterol written for SMART. The patient case in this CE is an avoidable situation. Staying up to date with the current guidelines is a pharmacists’ responsibility. Technicians should work with patients and pharmacists to put outdated medication prescriptions on hold to avoid further medication errors.

Pharmacy Technician Sidebar: Education on DPI/ MDI/ Nebulizer

Proper inhaler technique is an essential aspect of asthma control. It may seem like a silly statement, but there are different kinds of inhalers and devices. Each inhaler requires patients to use specific inhalation techniques that deliver medications effectively. Some patients may have multiple inhalers, complicating their regimen and increasing the chance for error. Understanding the different types of inhalers highlights the importance of pharmacist counseling for patients who use inhalers. Below are explanations of the differences between using, cleaning, and storing a metered-dose inhaler (MDI), a dry powder inhaler (DPI), and a nebulizer. Pharmacy technicians can point out that every inhaler has an information sheet where patients can find specific and additional instructions. Technicians should encourage patients to read them.

DPI⁵⁸

The DPI contains preset doses of medications in powder form. The medicine is released into the airways with deep, fast breaths. The DPI may be easier than the MDI for patient use.  However, patients with really low lung function or small children may not be able to generate enough inspiratory flow to effectively get the medications. Patients do not need to coordinate breathing and using the inhaler with a DPI .

• Instructions for use:
  • Open the cover. Hold the inhaler as shown on instructions.
  • Load a dose of medicine as shown in your instructions. Do not tip or shake the inhaler.
  • Stand or sit up straight.
  • Holding the inhaler away from your mouth, breathe out completely to empty your lungs.
  • Place the mouthpiece of the inhaler in your mouth. Close your lips around it to form a tight seal.
  • Take a fast, deep, forceful breath in through your mouth. Take as big of a breath as possible.
  • Hold your breath and count to 10.
  • Take the inhaler out of your mouth. Breathe out slowly.
  • If you need more than one puff, wait 1 minute between puffs. Repeat steps 2-8 for each puff.
  • When you finish close the cover. Store in a cool, dry place.
  • If the medicine is an inhaled corticosteroid, rinse your mouth with water and spit it out. This helps prevent infection.
  • Some multi-dose DPI have a built-in counter to tell you how many doses are left. When the counter gets to “0,” throw it away. Arrange your refill pick-up before it gets to 0.
• Instructions to clean the DPI
  • Wipe the mouthpiece at least once a week with a dry cloth
  • Do not use water to clean to DPI

MDI⁵⁹

The MDI is a canister of medication placed into an actuator inhalation mouthpiece. Every use of the MDI delivers the correct amount of medication.

• Instructions for use:
  • Take off the cap, shake the inhaler. Prime the inhaler (if needed)
  • If a spacer* is used, place the inhaler in the rubber ring on the end of a spacer
  • Stand or sit up straight
  • Breathe out completely to empty your lungs
  • Place the mouthpiece in your mouth and close your lips around it to form a tight seal
  • While breathing in, press down firmly on the top of the canister to release one “puff,” or dose of medication. Take as big of a breath as possible, breathing in slowly for 3-5 seconds.
  • Hold your breath and count to 10.
  • Take the mouthpiece out of your mouth. Release your breath.
  • If you need more than one puff, wait 1 minute between puffs. Repeat steps 3-8 for each puff.
  • Put the cap back on the inhaler.
  • If the medicine is an inhaled corticosteroid, rinse your mouth with water and spit it out.This helps prevent infection.
• Important cleaning instructions:
  • Do not put the medicine canister in water
  • Do not brush or wipe the inside of the inhaler

A “spacer” is a tube or chamber that adds distance between the mouth and the canister of medication. The device increases the ease of administering medication.

Nebulizers⁶⁰

Nebulizers change liquid medication into an aerosol. Nebulizers come in both home and portable sizes. Nebulizers need a power source. They plug into a wall, have chargers, or need batteries replaced. Nebulizers take longer to use than MDI or DPI. They are also more laborious to use and store.

• Instructions for use:
  • Wash hands well.
  • Put together the nebulizer machine, tubing, medicine cup, and mouthpiece or mask as shown in instructions.
  • Put the prescribed amount of medicine into the nebulizer cup.
  • Place the mouthpiece in your mouth and close your lips around it to form a tight seal. If a child wears a mask, make sure it fits in snugly around the child’s face and covers their mouth and nose.
  • Turn on the nebulizer machine. You will be able to see a light mist coming from the back of the tube or from the mask.
  • Take normal breaths through the mouth until the medicine cup is empty or the mist stops. This should take about 10 minutes.
  • Take the mouthpiece out of your mouth (or the child’s mouth) and turn off the machine.
  • If the medicine is an inhaled corticosteroid, rinse your mouth with water and spit it out. This helps prevent infection. If a child uses a mask, wash the face as well.
• How to clean and store:
  • After each treatment
    • Wash hands well.
    • Wash the medicine cup and mouthpiece/ mask with warm water and mild soap.
    • Do not wash tubing.
    • Rinse well and shake off excess water.
    • Air dry parts on a paper towel.
  • Once a week:
    • Disinfect nebulizer parts to help kill any germs. Use the instructions that come with your device.
    • Do not wash or boil the tubing.
    • Air dry parts on a paper towel.
  • Between uses:
    • Store nebulizer parts in a dry, clean plastic storage bag.
    • If the same machine is used by more than one person, keep each person’s medicine cup, mouthpiece or mask, and tubing in a separate, labeled bag to prevent the spread of germs and medication errors.
    • Wipe surface with a clean, damp cloth as needed.
    • Replace parts as stated in the instructions or when they appear damaged.

“When you’re riding in a Chevy and you feel something heavy.

When you’re sliding into home and your pants are full of foam.

When you’re sitting in the bath and you feel something splash.”¹

No one likes to talk about it, but everyone knows what it is. Some call it "Montezuma's revenge," "the runs," or worse. Although diarrhea is one of the most commonly managed medical conditions in the outpatient setting, it can also be one of the most serious if treated inappropriately. In addition, concerns with older approaches to acute diarrhea have led to several new practice recommendations. The novel coronavirus disease-2019 (COVID-19) pandemic is also associated with a significant gastrointestinal (GI) component. In one early United States (U.S.) study of patients with COVID-19, one third reported GI symptoms prior to the onset of fever or respiratory symptoms.²

Another challenge is the escalating opioid crisis. Patients addicted to opioids are now abusing over-the-counter (OTC) antidiarrheal medications, such as loperamide, to help manage withdrawal symptoms. The purpose of this activity is to highlight several recent changes in diarrhea management and provide an overview of commonly used OTC antidiarrheal agents and other treatment strategies.

The classic definition of diarrhea is passage of loose or watery stools. Some have defined it as the passage of three or more watery stools per day, but it is difficult to define absolute limits. Acute diarrhea typically lasts one to two days (starting with the first loose stool, not when treatment starts). Patients and caregivers should raise concerns whenever stool patterns deviating from the norm are accompanied by other signs of illness, not just based on the stool frequency or water content. Table 1 summarizes the most common symptoms associated with acute diarrhea.

Table 1. Symptoms Associated with Acute Diarrhea³

• Abdominal pain
• Cramping
• Fecal incontinence
• Fecal urgency
• Nausea
• Three or more loose, watery stools daily

In the U.S., approximately 179 million cases of acute diarrhea occur annually.⁴ The following sections describe its many causes. In immunocompetent individuals, the primary etiology of infectious diarrhea includes foodborne pathogens and norovirus outbreaks.⁵

Numerous factors predispose patients to developing acute diarrhea (see Table 2). Providers should not confuse acute diarrhea with chronic diarrhea (i.e., diarrhea lasting more than two weeks). In many instances, the etiology of acute diarrhea is unknown and it resolves without treatment. Acute diarrhea is most commonly infectious in nature or related to a medication adverse effect.

Table 2. Causes of Acute Diarrhea

COVID-19 = coronavirus disease-19

INFECTIOUS CAUSES OF DIARRHEA 

Viral Gastroenteritis

Acute infectious diarrhea is often viral, resulting in more than 1.5 million outpatient visits in the U.S. annually.⁵ Typically, patients with viral diarrhea experience low-grade fevers and watery, non-bloody diarrhea lasting one to two days. Rotavirus used to be the most common cause of diarrhea in the U.S., but as rotavirus vaccination rates have increased, norovirus has taken over this title. Infant rotavirus immunization starts as early as six weeks of age but no later than 15 weeks.⁶ Healthcare providers should administer the final dose in the immunization series by eight months of age. Infants infected with rotavirus prior to receiving the full vaccine course should still initiate or complete the recommended schedule, as initial infection confers only partial immunity.

Norovirus-induced diarrhea is less severe than rotavirus, especially in children. More commonly known as the “cruise ship virus,” norovirus is now one of the leading causes of foodborne disease and a common cause of traveler’s diarrhea.⁷ Vomiting often accompanies diarrhea. In most cases, symptoms appear 12 to 48 hours after exposure and last one to three days, although the virus can continue to be shed in stools up to two weeks after resolution. Interestingly, not everyone is susceptible to norovirus infections. Individuals with type O blood are more prone to norovirus infections, while those with type B blood are least likely to contract them.⁸

Bacterial Gastroenteritis

It is sometimes difficult to distinguish between viral and bacterial gastroenteritis. Unlike viral gastroenteritis, bacterial infections associated with diarrhea have the potential to be more severe and are often associated with high fevers (exceeding 104^oF), abdominal pain, and bloody stools.⁵ Vomiting is less common. The most common causes of bacterial gastroenteritis in the U.S. are non-typhoidal Salmonella and Campylobacter species.⁵ These usually occur after eating raw or undercooked poultry or something that came in contact with it. Reptiles, such as pet turtles, can also carry Salmonella in their stool and easily transmit the bacteria to their shells, tank water, and anywhere else they live and roam.⁹

Bacterial gastroenteritis is usually mild and self-limiting, but infants younger than three months of age may experience severe complications that can result in hospitalization.⁶ In an otherwise healthy individual, bacterial gastroenteritis can resolve without any treatment. Antibiotics are reserved for treating diarrhea in immunocompromised patients, infants younger than three months of age, and patients who appear septic or toxic.^5,6

COVID-19-Related Diarrhea

Since the onset of the COVID-19 pandemic, respiratory symptoms have been the most common presentation of this viral illness. A growing number of patients, however, experience GI symptoms (e.g., anorexia, diarrhea, nausea, vomiting), sometimes without respiratory symptoms. COVID-19-induced diarrhea can last one day to as long as two weeks.² Although the mechanisms involved in the pathogenesis of COVID-19-related diarrhea are still unknown, the virus is likely altering intestinal permeability resulting in enterocyte malabsorption.¹⁰

Foodborne Disease

Produce—especially leafy green vegetables—is the most common source of diarrhea due to foodborne pathogens.¹¹ Spinach and lettuce purchased from grocery stores often come from developing countries where water contamination is common and produce does not undergo agricultural inspection. Diarrhea-producing E. coli or Salmonella are common pathogens. Contaminated poultry is associated with the highest proportion of diarrhea fatalities (19%), mainly due to Salmonella or Listeria infection.¹¹

To reduce this risk, consumers should soak leafy greens in water and rinse them thoroughly before eating. They must also use care when handling raw poultry. To prevent cross-contamination, cooks should prepare raw poultry separately from other foods. They should also clean food preparation surfaces and utensils (e.g., counters, cutting boards, forks, knives) and their hands with hot, soapy water after handling raw poultry. Finally, they must cook all raw poultry thoroughly. Updated weekly, the Centers for Disease Control and Prevention (CDC) provides extensive information on foodborne outbreak investigations on their website: https://www.cdc.gov/foodsafety/outbreaks/index.html.

Traveler’s diarrhea—commonly caused by consuming contaminated food or drinking water in foreign countries—often appears within 10 days of travel to an area with poor public hygiene.¹² In most cases, traveler’s diarrhea is not serious. However, in some instances, this type of diarrhea may last longer than usual due to infections with parasites and requires treatment with an antiprotozoal agent.¹³ Although it can occur anywhere, the areas of greatest risk are in Africa, Asia (except Japan and South Korea), Central and South America, Mexico, and the Middle East.¹⁴ The CDC publishes notices for travelers about potential health implications (e.g., disease outbreaks, gatherings, natural disasters) for destinations around the world, sorted by disease or country.¹⁵

NON-INFECTIOUS CAUSES OF DIARRHEA

Medication-Associated Diarrhea

Many medications can cause diarrhea as a side effect, usually because they affect gut motility or microbe balance.

Antibiotic-associated diarrhea

Antibiotic-associated diarrhea (AAD) results from an imbalance of intestinal bacteria where opportunistic bacteria like C. difficile are allowed to thrive.¹⁶ AAD happens during a course of antibiotics or shortly afterward. The most commonly implicated antibiotics include clindamycin, macrolides, and other broad-spectrum antibiotics, but any antibiotic can disrupt the balance of non-pathogenic bacteria flora within the intestines.

Pharmacy staff may field questions about fecal transplants (also known as “poop pills” or “poop with a purpose”). The formal name for this is fecal microbiota transplant (FMT), which entails transferring stool from a healthy individual to a patient infected with C. difficile. The goal is to restore the balance of bacteria in the infected patient’s gut. In patients with recurrent C. difficile infections, FMT may be more effective and significantly less expensive than a course of vancomycin.¹⁷ It is not an approved therapy, but the FDA does allow clinicians to use it investigationally to treat C. diff infections. It is not without risk, and patients have developed life-threatening infections from FMT contaminated with other pathogenic organisms.¹⁸

PAUSE AND PONDER: How can Halloween candy and fruit juices predispose children to diarrhea?

Table 3 lists drugs that can cause acute diarrhea. Pharmacists should refer patients to their prescribers to discuss therapeutic alternatives without diarrheal adverse effects. For example, magnesium-containing OTC antacids may cause diarrhea, but calcium carbonate and aluminum hydroxide do not, making them suitable alternatives. Likewise, herbals, such as St. John’s wort, aloe vera juice, and lobelia, have been linked with diarrhea.

Table 3. Drugs Associated with Acute Diarrhea¹⁹

Laxative-Associated Diarrhea

Laxative-associated diarrhea is a specific form of medication-associated diarrhea.²⁰ Excessive intake of laxatives could be accidental (e.g., not understanding the directions) or intentional (e.g., child abuse, bulimia, anorexia nervosa). For example, there are cases reports of parents hiding laxatives in children’s food and/or medication as part of an ill-advised prank or an abusive gesture, resulting in serious harm.^21,22 A person buying multiple types and/or large quantities of laxatives or asking inappropriate questions about their use may be misusing them. Obtaining a thorough history and encouraging patients and caregivers to seek medical care is just as, if not more, important than recommending an antidiarrheal agent. When possible, pharmacy team members may want to discuss their observations regarding unusual laxative use with the patient’s PCP.

Toddler Diarrhea

Toddler diarrhea—also known as functional diarrhea or non-specific diarrhea of childhood—often occurs when children drink considerable amounts of hyperosmolar fluids, such as fruit juices. According to the American Academy of Pediatrics, toddlers between one and three years of age should limit their juice intake to no more than four ounces per day.²³ Toddler diarrhea management involves reducing the volume of fruit juices or other osmotically-active carbohydrate beverages that contain sorbitol or fructose. Similarly, children may develop self-limiting “Halloween diarrhea” after ingesting sorbitol- and fructose-rich candies.²⁴

Lactase Deficiency or Food Intolerance

The brush border of the small intestine produces the enzyme lactase. It is necessary for breaking down lactose (“milk sugar”) to digest milk.​ Lactase deficiency can occur when an enteric (intestinal) infection causes mucosal (lining) injury. Approximately 68% of the world's population has some form of lactose malabsorption.²⁵ Lactase deficiency is more prevalent in Asia and Africa, while it occurs less frequently in northern Europe where many people carry the gene that codes for lactase.²⁶ About 36% of Americans have some form of lactose malabsorption.

When lactose malabsorption occurs with a case of acute viral gastroenteritis, it tends to be mild and self-limiting. Regardless of the cause, when patients have inadequate lactase, ingested lactose is malabsorbed and gut bacteria use it as an energy source and to produce gas. Moreover, undigested lactose has an osmotic effect and pulls excessive water into the bowel, resulting in diarrhea.²⁵ Patients experience abdominal pain, flatulence, or diarrhea within several hours of ingesting a significant lactose load, and it resolves after several days of avoiding lactose-containing foods.

Other forms of food intolerance can also cause diarrhea. Drinking overly salted beverages and ingesting excessive fiber (e.g., sunflower seeds) can cause diarrhea.²⁷ Hot peppers (e.g., jalapeño peppers, cayenne peppers, and some chili peppers) contain the chemical irritant capsaicin (responsible for the “burn") which can trigger diarrhea.²⁸ Similarly, onions and large amounts of spices, fruits, and vegetables can also predispose patients to dietary diarrhea.²⁷ Avoiding the causative food is the best approach to managing symptoms.

PAUSE AND PONDER: How does an antidiarrheal alter the symptoms associated with diarrhea?

DIARRHEA TREATMENT AND PREVENTION

Some recommendations for diarrhea are the same across the board, while others are on a case-by-case basis. In cases of infectious diarrhea, all pharmacy staff should emphasize the need for good hand hygiene, especially after using the bathroom or performing diaper changes to protect others from becoming infected. People should wash their hands with soap and water for at least 15 to 30 seconds paying special attention to the fingernails, between fingers, and wrists. Alcohol-based hand sanitizers are ineffective at preventing all types of diarrhea (i.e., norovirus, Clostridiodes).²⁹ People must also use soap and water to wash visibly soiled hands. In cases of COVID-19 infection, experts recommend using an alcohol-based rub that contains at least 60% alcohol in addition to soap and water.³⁰ Pharmacy teams should be prepared to help patients and caregivers select appropriate diarrhea treatments.

Oral Rehydration Solutions

Provided they are able to drink, most patients with mild-to-moderate dehydration should use oral rehydration solutions (ORSs) to manage diarrhea symptoms. Although ORSs do not treat diarrhea, they help prevent dehydration and electrolyte losses. ORSs are safer, inexpensive alternatives to intravenous fluids. They contain dextrose and electrolytes to replace fluid and electrolytes. The dextrose in ORSs enables the intestine to absorb fluid and salts more effectively.³¹ Table 4 describes commonly-used ORS products. Breastfed infants should continue to drink breastmilk during the bout of diarrhea.

Table 4. Comparison of Oral Rehydration Solutions^31,32

G2 = G2 Gatorade; ORS = oral rehydration solution; WHO = World Health Organization

*as rice base

Pharmacy staff should advise patients to avoid tea, rice water, fruit juice, or gelatin as ORS substitutes, as they contain insufficient electrolytes and may be too hypertonic which could worsen diarrhea. Given the widespread availability of premixed products, people should not try to prepare their own ORS. Pharmacy staff should caution patients to avoid using sports drinks as ORS, as these products contain significant amounts of sugar and can exacerbate diarrhea. Furthermore, if the patient is experiencing significant vomiting or diarrhea, sports drinks contain inadequate amounts of electrolytes, such as sodium, and cannot effectively replace losses.

In the event a commercial ORS product is unavailable, some have recommended adding table salt to G2 Gatorade (not regular Gatorade) to increase its sodium content to match traditional ORSs.³² This option, however, is prone to error and adding too much salt is just as detrimental as not adding enough. Some errors in making homemade ORS have been fatal.³³

Dietary Measures

The practice of holding solid foods and dairy products for the first 24 hours after acute diarrhea onset has come under scrutiny.³⁴ In patients who are adequately hydrated, food is allowed. Caregivers can provide bland, easily-digestible foods and beverages for the first 24 hours after diarrhea onset in patients with nausea or vomiting. Pharmacy teams should advise patients and caregivers to withhold food if antiemetics are unable to control vomiting.

Individuals may read they should eliminate specific foods while they have diarrhea. Patients should avoid foods rich in fructose (e.g., fruit juices), as they are often difficult to digest.³⁵ Similarly, sugar-sweetened drinks can worsen diarrhea, cramping, and flatulence. Most juices also contain little fiber and, in comparison to whole fruits, offer no nutritional advantage. Because they may stimulate bowel function, patients should avoid foods containing roughage (e.g., beans, Brussels sprouts, cabbage), as these may exacerbate diarrhea. Instead, during a bout of diarrhea, patients should follow a low-fiber diet limiting dietary fiber intake to 10 grams/day.³⁶ Table 5 describes foods that are appropriate during episodes of diarrhea and foods to avoid.

Table 5. Foods that Should Be Avoided or Allowed During Bouts of Diarrhea^{35, 36}

Some people use astringent herbs and teas rich in tannins (e.g., blackberry, raspberry teas) as a treatment for diarrhea. When treating diarrhea, only dried berries or juice are recommended, as fresh berries may actually exacerbate symptoms.³⁷ Moreover, patients should be aware that in large doses, blackberry tea might cause more GI upset and trigger nausea and vomiting. Pregnant women should use raspberry and raspberry leaf preparations with caution as they may stimulate contraction of uterine tissue.³⁸

BRAT Diet

This diet is intended to manage diarrhea by providing a bland diet that may improve diarrhea symptoms. However, its low nutritional content has resulted in its abandonment.³⁹ Similarly, only providing clear liquids for several days can potentially prolong the duration of diarrhea, a condition often referred to as “starvation stools.”⁴⁰ This form of diarrhea is green and watery. The green bile is excreted into the stool when there is no food to digest. It is not harmful and management simply entails increasing food intake.⁴¹ Pharmacy teams should not recommend the BRAT diet to patients with diarrhea, as it is outdated.

Probiotics and Prebiotics

To prevent or treat antibiotic-associated diarrhea, healthcare providers often recommend probiotics (see Table 6 for examples). Probiotics—microorganisms that replace colonic bacteria—suppress pathogenic microorganisms’ growth thus restoring normal intestinal function. The most commonly used probiotics to decrease the duration and severity of diarrheal episodes include Saccharomyces boulardii, Lactobacillus GG, and Lactobacillus acidophilus. Some foods contain naturally-occurring probiotics, but probiotic supplements are also available.

Table 6. Examples of Probiotics⁴⁴

One meta-analysis showed probiotic use may prevent antibiotic-induced diarrhea in adults but was not effective in those older than 65 years of age.⁴² To be most effective, patients should start probiotics early when signs of diarrhea first appear. Patients who are also receiving antibiotics should separate probiotic administration by at least two hours from the antibiotic dose. Evidence supporting probiotic use in managing viral diarrhea is mixed.⁴³

Typically used in combination with probiotics, prebiotics are oligosaccharides that stimulate growth of commensal intestinal bacteria (i.e., naturally-occurring flora that induce protective responses to prevent pathogen invasion and colonization). Data supporting the use of prebiotics to reduce severity or duration of diarrhea is weak, and they are not universally recommended.⁴⁵ Currently, prebiotics are only available in combination products containing a probiotic.

Bismuth Subsalicylate

Patients use bismuth subsalicylate (Pepto-Bismol) to treat mild, nonspecific diarrhea. It has anti-secretory, anti-inflammatory, and antimicrobial properties.⁴⁶ Developed more than 100 years ago by a physician to treat cholera, it was originally called Mixture Cholera Infantum.⁴⁷ Despite its cheery pink color, pharmacy staff should remind patients and caregivers that bismuth subsalicylate can darken the stools and tongue with repeated use. Typical dosing for patients older than 12 years of age for acute diarrhea is 524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed for up to 2 days (maximum: 4,200 mg/24 hours).^46,47  Most patients will experience relief within 30 to 60 minutes of a dose. Children and adolescents who have or are recovering from influenza or chicken pox should not use bismuth subsalicylate due to the association of Reye syndrome.^46,47

Patients with histories of salicylate allergy, coagulopathy, or ulcers should not use bismuth subsalicylate. Patients receiving anticoagulants or medications for gout or arthritis (e.g., allopurinol, colchicine, ibuprofen, indomethacin, naproxen) should also avoid it. It can bind with tetracyclines and may also interfere with GI contrast studies. Use of bismuth subsalicylate during a contrast study can potentially cause misinterpretation of images and decrease the test's sensitivity.⁴⁸ Because it is hyperdense liquid, it can mimic the appearance of an acute GI bleed, which may lead to potential diagnostic errors. Patients taking bismuth subsalicylate must also stop using this product if they develop ringing or buzzing in the ears (i.e., tinnitus) because it indicates salicylate toxicity.

Loperamide

Loperamide (Imodium A-D) is an opioid-receptor agonist that inhibits peristalsis (muscle contractions in the GI tract) by acting directly on the musculature of both the small and large intestine.⁴⁹ It has been available OTC since 1988. Typical OTC dosing is 4 mg, followed by 2 mg after each loose stool.⁴⁹ At the Food and Drug Administration (FDA)-recommended OTC maximum dose of 8 mg per day, it does not predispose patients to the usual side effects associated with opioid use (e.g., euphoria, lethargy, nausea, vomiting). Patients should limit use to fewer than two days unless they are receiving medical supervision. Most patients will see improvement in symptoms within one hour after a dose.⁴⁹ Caregivers should not give loperamide to children younger than three years old, as there are case reports associating it with toxic megacolon (severe swelling of the colon) and ileus (intestinal obstruction).⁴⁹

When taken at recommended doses, loperamide does not cross the blood-brain barrier or yield the “high” seen with other opioids. However, at extremely excessive doses (i.e., more than 100 to 200 mg/day), loperamide enters the central nervous system and produces effects similar to those associated with centrally-acting opioids like heroin, hydrocodone, or morphine.⁴⁹ Some individuals withdrawing from opioids use loperamide to ameliorate their symptoms, or simply to induce euphoria.

Loperamide overdoses have been associated with serious cardiac complications, including arrhythmias, loss of consciousness or fainting, and myocardial infarction. Moreover, even standard doses of loperamide may interact with medications that can cause QT prolongation such as azole antifungal drugs and macrolide antibiotics. In response to these concerns, in September 2019, the FDA approved changes to OTC loperamide products. These changes limit each container to no more than 48 mg of loperamide and require the tablets and capsules to be individually packaged (i.e., unit-dosed).⁵⁰

Supplements

Many patients prefer to use OTC supplements to prevent or treat diarrhea. For this indication, a variety of natural products and enzyme supplements are used.

Lactase Enzymes

For individuals prone to diarrhea due to lactose intolerance, lactase enzymes are beneficial for prevention.⁵¹ Most lactose intolerant individuals do not have to give up all dairy products, as they can manage their symptoms by using lactase supplements or lactase-fortified products. There are several ways to provide lactase, and Table 7 lists commonly available products. The typical dose of lactase supplementation to prevent diarrhea in intolerant individuals is 6000 to 9000 international units at the start of a lactose-containing meal.⁵¹ Some patients prefer to add lactase supplementation to milk. In this case, patients mix 2000 international units of a lactase solution into 500 mL of milk immediately before drinking.

Table 7. Common Lactase Supplements

Zinc

Zinc supplements reduce the duration of a diarrhea episode by 25% and are associated with a 30% reduction in stool volume.⁵² Zinc is available in a variety of salt forms, including zinc-gluconate, -acetate, -ascorbate, -chloride, and -sulfate. Providers may use zinc to manage acute diarrhea in children older than six months of age, but evidence supporting its efficacy is mixed. According to the World Health Organization, patients should start zinc supplementation in conjunction with ORS at the first sign of diarrhea, as it may shorten the duration and severity of episodes and prevent subsequent episodes.⁵³ In infants younger than six months of age and children, providers sometimes use doses of 20 mg elemental zinc once daily for 10 to 14 days. The most common adverse reactions associated with oral zinc include dysgeusia (altered taste), mouth irritation, nausea, and vomiting.

Goldenseal/Berberine

Capsules of dried goldenseal appear to kill many bacteria that cause diarrhea, including E. coli. The key component in the herb is berberine. In addition to its antimicrobial effects, berberine may reduce diarrhea by enhancing sodium and water absorption by the intestinal lumen.⁵⁴ In animal models, berberine appears to slow GI motility by activating opioid pathways.⁵⁵

Doses of goldenseal used in studies vary considerably, from 250 mg to 1 g administered three times daily.⁵⁶ Studies of berberine taken alone used doses of 300 to 500 mg three times daily.⁵⁷ Typically, patients take goldenseal capsules daily until diarrhea improves. Patients should be aware that, although rare, very high doses of goldenseal may cause anxiety, depression, nausea, paralysis, or seizures.⁵⁸ Goldenseal may also affect the cytochrome P450 system and may alter patient response to medications metabolized by those enzymes.

Psyllium

Ground psyllium seeds are found in the flowering plant of the plantago genus absorb excess fluid in the intestines. Patients often use psyllium to treat constipation, so patients may be unaware that it can help with diarrhea too. Typical doses are one to three tablespoons mixed in water each day, but the product is also available as capsules and wafers.⁵⁹ When taken concurrently, psyllium may bind with some medications (e.g., carbamazepine, lithium) and may decrease blood glucose levels, so caution is advised in patients taking antidiabetic agents. Adverse effects associated with psyllium use include bloating, flatulence, indigestion, nausea, and vomiting.

PAUSE AND PONDER:  Why are sports drinks not used for fluid and electrolyte replacement in patients experiencing diarrhea?

UNSAFE OR INEFFECTIVE TREATMENTS

Complementary and alternative medicine refer to those medical products that are not standard of care. Many patients will use “home remedies” to manage their symptoms, employing special diets or supplements to manage bouts of diarrhea. In many instances, insufficient evidence exists to support their safety or efficacy. Pharmacy teams should be aware of the more commonly used remedies in their geographic locations (as they vary by population) and understand their limitations.⁶⁰

Wood-Tar Creosote

Some alternative medicine circles use wood-tar creosote (found in a product called Seirogan) as an antidiarrheal treatment. Wood creosotes come from the resin of the leaves of the creosote bush and beechwood.⁶¹ In its classic form, it is a dark brown round pill, but a sugar-coated tablet is also available that masks its bitter taste and distinct medicinal odor. It is not a benign therapy, as ingesting high levels of creosote may cause burning in the mouth and throat or gastritis. Moreover, creosote may be carcinogenic with long-term use. Pharmacy teams should communicate these risks to patients seeking to use wood-tar creosote and encourage them to use a safer alternative.

Attapulgite

Attapulgite is a naturally-occurring, orally-administered clay named for the U.S. town of Attapulgus, Georgia, where it is abundant.⁶² It is a non-absorbable medication that adsorbs large numbers of bacteria and toxins and thereby reduces fluid loss.⁶³ Its binding action reduces the frequency of bowel movements and improves the consistency of stools. Attapulgite can absorb eight times its weight in water. It used to be present in Kaopectate, but in 2003, the manufacturer reformulated the product and replaced attapulgite with bismuth subsalicylate as the active ingredient. The FDA did not include attapulgite as a monograph ingredient, citing that efficacy data was inadequate.⁶⁴ Attapulgite is still used as a veterinary drug in the U.S. and is available in many countries as an OTC antidiarrheal.

“RED FLAGS” TO REFER PATIENTS FOR MEDICAL ATTENTION

Fluids and OTC antidiarrheal products cannot manage all cases of acute diarrhea. Cases accompanied by fever or excessive mucus in the stool suggest evaluation by a primary care provider (PCP) is necessary. Dehydration is another concern, especially in cases where patients report weight loss or decreased urine output (i.e., more than six hours since last urination, decreased number of wet diapers). If patients fail to improve despite oral rehydration, they should seek medical attention.

Patients with a history of recent travel to an undeveloped country, backcountry camping, or consumption of processed meat may develop infectious or parasitic diarrhea. Children in daycare or using community swimming pools may also be at risk for contracting bacterial diarrhea, such as giardiasis. These patients should see their PCPs for further evaluation, as antimicrobial therapy might be necessary.

Toxic exposures to contaminated food, plants, and other substances can cause diarrhea. Obtaining a good history and knowing when to refer patients to their PCPs or hospital is an important step in managing care. For example, profuse diarrhea that occurs with excessive salivation or tearing may be suggestive of organophosphate ingestion.⁶⁵

Although most acute diarrhea cases are self-limiting, children younger than three years of age and adults older than 60 with multiple co-morbidities should seek immediate medical care.⁶⁶ Table 8 highlights other “Red Flags” that warrant immediate medical attention.

Table 8. “Red Flag” Symptoms Indicating Patients Experiencing Diarrhea Should Seek Immediate Medical Attention³

CONCLUSION

There is no “one size fits all” approach to diarrhea treatment, and pharmacy teams should be prepared to assist patients in selecting the most appropriate approach to manage symptoms. Acute cases of diarrhea usually resolve on their own without treatment, but preventing dehydration is crucial. Before recommending an antidiarrheal agent, pharmacists should obtain a good medication history to avoid potential drug interactions and identify red flags. It is important to remind patients that anti-diarrheal treatments do not necessarily cure the diarrhea, but they help to lessen its severity and duration. Just as important as assisting patients in selecting the best therapy, pharmacy staff can identify when prompt medical attention is necessary. Abuse of antidiarrheal agents is possible, and pharmacists and technicians should be vigilant if they encounter unusual purchasing patterns involving these products.

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INTRODUCTION

“My heart feels like it is pounding out of my chest.”

Dan Reeves, a 79-year-old white male, makes this statement to the pharmacy technician at the counter while waiting to pick up his prescriptions for flecainide and apixaban. He has his hand over his chest and states he feels tired and short of breath when doing any activity. The pharmacy technician requests help from the pharmacist, who notes that Daniel is showing signs of an arrhythmia. A check of his records shows that he is two weeks late for his refill of flecainide, a medicine to treat atrial fibrillation (AFib). Upon questioning by the pharmacist, Dan says the doctor has told him how important it is to take the medication properly. However, he admits that he sometimes forgets to take the second dose at bedtime.

AFib is the most common type of sustained heart rhythm disorder, also called an arrhythmia.¹ It occurs when the heart's electrical activity is abnormal or irregular, usually resulting in a fast heart rate.¹ If the rate does not return to normal, it can lead to stroke, heart failure, or other medical problems.² AFib is a leading cause of stroke.¹

An estimated 2.3 million people in the United States have AFib, according to the most recent data available.³ Given the association between advanced age and AFib occurrence, an estimated 5.6 million will experience AFib by the year 2050.³ It affects fewer than 1% of people under the age of 60 to 65 but 8% to 10% of those older than 80.³ It happens more often in males and Caucasians.¹

Risk factors for developing AFib include the following¹:

• Advancing age
• Chronic Inflammation
• Congenital heart disease
• Endocrine disorders
• Genetic factors
• High blood pressure
• Increased alcohol consumption
• Neurological disorders
• Obstructive sleep apnea
• Underlying heart and lung disease.

Athletes who overtrain in intense cardiovascular sports, like competitive bikers and marathon runners, also are at an increased risk of developing AFib (see SIDEBAR).

SIDEBAR: IS OVERTRAINING TO BLAME FOR AFIB IN ATHLETES?

According to studies, the prevalence of AFib in athletes is about 2 to 10 times higher than in the general population.⁴ Most cases occur in endurance athletes, such as marathoners, and may result from overtraining. In one study, a group of middle-aged men who ran marathons had a higher incidence of AFib than their sedentary counterparts.⁵ The disease also occurs five times more often in aging cyclists (average age of 66 years old) who continue training.⁶ The duration and intensity of exercise correlate to the development of paroxysmal AFib.⁴

Reports cite “irrational” regimens involving overtraining as the primary factors, along with obesity and diabetes.⁴ Treatment consists of removing the physical stress and prescribing flecainide or propafenone.⁷ Athletes may return to training in four to six weeks but should remain on a beta-blocker to prevent recurrence.^8,9 Providers should consider the cardioselectivity of the beta-blocker and the athlete’s sport when choosing a therapy.⁴ Prevention and treatment of future episodes may include a “pill-in-pocket” approach or cardiac ablation.⁷

AFib occurs when electrical impulses in the heart’s upper chambers, called the atria, come from multiple foci, rather than just the sinoatrial (SA) node. The atrial and ventricular depolarization rate becomes rapid and chaotic rather than their normal, consistent firing and propagation (called normal sinus rhythm).^10,11 When different atrial defibrillation waves collide, they cancel each other out meaning no one pacemaker exists. This causes the atrial chambers to quiver, or “fibrillate” instead of contracting in a normal manner from the top of the atria to the bottom. As a result, blood pools in the left atrial appendage (a tissue sack attached to the left atria) which can lead to blood clots. The clots may dislodge from the left atrial appendage, travel to the brain, and cause embolic strokes.¹¹

The atrial depolarizations bombard the atrioventricular (AV) node separating the atria from the ventricle with approximately 300 depolarization stimuli per minute. The AV node tries to prevent some of these depolarizations from reaching the ventricles, but the resulting ventricular contractions become faster than normal and irregularly spaced.¹¹

PATHOGENESIS

In a normal heart, electrical impulses travel in a coordinated way through the heart’s pacemaker, the SA node, through the atrial tissue, and to the AV node.¹³ The AV node slows the impulse before it travels to and depolarizes the ventricles.¹⁴ When the SA node in a normal heart initiates a depolarization wave, it spreads across the atria from top to bottom. Once the cells depolarize, it cannot depolarize again for a while, and this is called the effective refractory period. Immediately after the refractory period, the tissue is in a vulnerable period because the electrical charge of the cells is normalized but the amount of sodium in the cell is too high and the potassium inside the cell is too low. If another depolarization stimuli hits tissue in the vulnerable period, fibrillation occurs. However, this is rare in normal hearts because it is impossible for the wave of depolarization to circle behind the effective refractory tissue to hit other tissue in the vulnerable period. However, when there is a mixing of electrically active and inactive cells together, the single wave of depolarization becomes fractionated into multiple wavelets in three-dimensional space and one of the wavelets can emerge and hit tissue in the vulnerable period.

AFib originates in the pulmonary vein-atrial border 95% of the time because the pulmonary vein contains electrically active atrial cells and inactive pulmonary vein cells that are intermingled.¹² However, in people with longstanding AFib, the stress kills atrial cells, which are replaced by electrically inactive connective tissue, and the anatomic milieu is created to have AFib generated in the body of the atria itself. Patients with AFib may present to healthcare providers with or without symptoms.¹ Patients may experience chest pain, palpitations, a fast heart rate, shortness of breath, nausea, dizziness, sweating, or general fatigue when they have symptoms.¹ The ventricular rate for a patient with AFib is 110 to 140 beats per minute (BPM).¹

When AFib occurs, the heart can usually quickly abolish it on its own but as periods of AFib continue to occur, subsequent AFib episodes last longer and longer until eventually AFib just continues.

Providers classify AFib into five types¹:

• Paroxysmal AFib will revert to normal sinus rhythm in less than seven days with no antiarrhythmic medication or electrical cardioversion.
• Persistent AFib occurs and then persists, requiring intervention with antiarrhythmic medication or electrical cardioversion.
• Long-standing persistent AFib exists for longer than 12 months, either due to failure to attempt cardioversion or failure of cardioversion.
• Permanent AFib is unresponsive to antiarrhythmic medication or electrical cardioversion and continues for the rest of the patient’s life.
• Non-valvular occurs without rheumatic mitral valve disease, mitral valve repair, or prosthetic heart valves.

AFib can be viewed on an electrocardiogram (ECG), which will show an “irregularly irregular” pattern with no discernable P-waves and irregular RR spacing during rest (see SIDEBAR).¹ Failure to detect paroxysmal AFib on an ECG doesn’t preclude having the arrhythmia because normal sinus rhythm can intersperse between the arrhythmic episodes. In that case, a patient may wear a Holter monitor (a small portable ECG machine) continuously for a few days or a patch monitor with 30-day readouts to detect the arrhythmia.^10,15

SIDEBAR: ECG Interpretation 101^16,17

An ECG is a visual representation of the heart's electrical activity. For a 12 lead ECG, six electrodes are placed on the chest and four on the limbs before connecting them to an ECG machine, which produces a readout. A normal ECG consists of a small P-wave, a large and narrow QRS complex, and a T-wave. The P-wave is a small, positive, smooth wave that reflects atrial depolarization, which precedes contraction of the atria. The QRS complex represents depolarization of the ventricles which precedes ventricular contraction. The T-wave follows the QRS complex and reflects rapid repolarization.¹⁷ Abnormal results from an ECG are a sign of potential heart problems like arrhythmias, ischemia or infarction, or even ventricular hypertrophy.

TREATMENT OF AFIB

The goals for treating AFib include reducing symptoms, preventing clots, and reducing the risk of heart failure and other cardiac complications.¹⁰ According to the 2023 American Heart Association/American College of Cardiology/American College of Chest Physicians/Heart Rhythm Society (multi-society) guidelines, patient-specific factors direct the choice of antiarrhythmic agent.² Among those factors is heart failure, cardiovascular disease, or other health conditions. Treatment also varies based on where providers discovered the AFib: in the inpatient or outpatient setting.²

PHARMACOLOGIC AGENTS

The multi-society guidelines divide the agents for treating AFib into rate control and rhythm control medications.² Rate control agents control the ventricular rate when patients are in AFib for better symptom management.¹⁸ Rhythm control medications restore and maintain normal sinus rhythm.¹⁰

PAUSE AND PONDER: What medications treat AFib symptoms most effectively?

Providers may choose from a wide range of medications, with the treatment choice often determined by the patient’s clinical picture and the setting in which the AFib occurs.

RATE CONTROL MEDICATIONS

Rate control medications slow the impulses through the AV node, reducing the rate of contraction of the ventricles.¹⁸ While the number of ventricular contractions per minute decrease (allowing for better ventricular filling with blood during diastole), the RR spacing remains irregular. This irregularity coupled with the loss of atrial contraction in AFib reduces the cardiac output versus normal sinus rhythm. The goal is better symptom control with limited adverse effects. (See Table 1.)¹⁰

Table 1. Rate Control Medications in AFib

Beta-Blockers

Beta-blockers inhibit the activity of the beta-1 adrenoceptor at the AV node, slowing conduction (negative dromotropic effect).¹⁸ Providers may choose from various options, including atenolol, bisoprolol, carvedilol, metoprolol (succinate and tartrate), and propranolol. Atenolol, bisoprolol, and metoprolol are the cardioselective beta-blockers, which means they less potently block the beta-2 adrenoceptors in the lungs.¹⁹ While all beta-blockers can cause drops in the Forced Expiratory Volume in 1-second (FEV-1) in asthmatic patients, the cardioselective agents do so to a lesser extent. Their effects are readily reversed with standard dosing of inhaled beta-2 agonists. All beta-blockers control the ventricular rate, and the multi-society guidelines consider them first-line therapy.²

Non-Dihydropyridine Calcium Channel Blockers

The multi-society guidelines also list non-dihydropyridine calcium channel blockers dilTIAZem and verapamil as first-line for treating AFib.² They block the L-type calcium channel to produce their negative dromotropic effects and like the beta-blockers have negative chronotropic and inotropic effects, meaning they slow the SA nodal firing rate and decrease the force of muscle contraction, respectively.¹⁸ They provide reasonable rate control and improve AFib-related symptoms compared to beta-blockers.² The multi-society guidelines note that dilTIAZem and verapamil are contraindicated in patients with pre-existing heart failure.¹⁸ However, if the signs and symptoms of heart failure are solely due to the AFib and no other underlying diseases, verapamil and dilTIAZem can be used.

The Institute for Safe Medication Practices lists the generic name dilTIAZem on the look-alike sound-alike list due to the potential for confusion with diazePAM.²⁰ The organization recommends the use of TALLman lettering to distinguish the two drugs.²⁰

Digoxin

Digoxin provides a negative dromotropic and chronotropic effects but does not provide a negative inotropic effect. The inotropic effect can be neutral at serum concentration below 1.2 nanograms/mL but can be positive at higher concentrations.¹⁸ Since digoxin slows AV nodal conduction through enhancing the parasympathetic nervous system, it does not work as well in times of higher sympathetic outflow like exercise or stress. The multi-society guidelines indicate providers may use digoxin with other rate control medications because it will not augment the negative inotropic effects of beta-blockers or non-dihydropyridine calcium channel blockers.² The guidelines also recommend digoxin in patients who do not tolerate or have an inadequate response from other rate control agents.^2,18 It is a narrow therapeutic index medication, with the recommended serum digoxin level for AFib being <1.2 nanograms/mL.² Providers should use digoxin cautiously with verapamil, since verapamil is a P-glycoprotein inhibitor and the combination may therefore increase digoxin levels (see SIDEBAR).¹⁸ However, digoxin may be a good initial choice for acute rate control in heart failure patients with AFib since the negative dromotropic effects of beta-blockers and nondihydropyridine calcium channel blockers could induce decompensated heart failure.² If patients start with low dose beta-blockers and digoxin in heart failure patients, as the beta-blocker dose is increased to therapeutic levels (doubled every two weeks until therapeutic doses are achieved) the digoxin level can be reduced.  

SIDEBAR: DIGOXIN IN AFIB: FRIEND OR FOE?

Digoxin is the oldest medication used today in AFib, with records of its use as early as 1250 AD.²¹ Dr. William Withering first described its good and bad effects in 1785.²² Providers still prescribe it today; however, its use has decreased in the 21st century.²³ In AFib, the multi-society guidelines recommend it as a rate control agent.² The guidelines suggest using it with either beta-blockers or non-dihydropyridine calcium channel blockers or as a standalone medication if the other rate control options are not tolerated.²

Digoxin has a wide variety of adverse effects triggered by toxicity. These include arrhythmias, GI symptoms like anorexia, fatigue, and nausea, and central nervous system issues like mental status changes and visual disturbances.²⁴ Elevated drug levels cause the most toxic effects, often triggered by drug interactions. Other antiarrhythmics like amiodarone, dronedarone, flecainide, non-dihydropyridine calcium channel blockers, propafenone, and quinidine may block P-glycoprotein and increase digoxin blood levels as a result.^25,26 Antibiotics like macrolides and tetracyclines may have similar effects.²⁵

According to reports, toxicity occurs in about 13 to 25 percent of digoxin patients.²⁵ It happens more often with blood levels greater than 2.0 nanograms/milliliter.²⁵ While providers may stop digoxin and provide supportive therapy in milder cases, severe cases require digoxin-specific antibody fragments (digoxin-fab).²² Derived from sheep, digoxin-fab is an intravenous medication that works in 30 to 45 minutes to reverse digoxin toxicity.²⁷ According to reports, providers use it in about 20% of cases of digoxin toxicity.²⁸

Other Rate Control Options

The multi-society guidelines recommend amiodarone, dronedarone, and sotalol for rate control, but only in extreme circumstances. Providers sometimes order amiodarone as a last resort in a hospital setting. Still, it should be used sparingly due to its many drug interactions and adverse effect profile.² Dronedarone has a chemical structure similar to amiodarone, except that it does not contain iodine, making it safer.¹⁰ However, the guidelines do not recommend its use in patients with heart failure or permanent AFib due to the risk of death.^2,18 Sotalol is both a beta-blocker and a potassium-channel blocker that also exerts rhythm control properties.¹⁸ While it is a negative dromotropic agent, it can also prolong the QTc interval on the ECG, which may lead to a life-threatening arrhythmia called Torsade de Pointes.¹⁸

In Torsade de Pointes, the ventricles beat in a fast, irregular manner.²⁹ Torsade de Pointes means “twisting of the points” in French. It refers to a characteristic twisting pattern of QRS complexes around the ECG baseline.²⁹ QRS complexes are specific waves or deflections on the ECG, representing electrical activation of the ventricles.¹⁴ Symptoms of Torsade de Pointes may include dizziness, fainting, or palpitations, or it may not present with symptoms.²⁹ The syndrome can be short-lived and self-limiting or life-threatening.²⁹

RHYTHM CONTROL MEDICATIONS

The Vaughan Williams classification system divides commonly prescribed rhythm control agents into two classes.¹⁰ Miles Vaughan Williams, a British pharmacologist and fellow at Hertford College in Oxford, created the classification system in 1970.³⁰ Medications in Class Ic block sodium channels in the heart.¹⁰ Class III medications alter potassium channels.¹⁰ (see Table 2.)

Table 2. Rhythm Control Medications in AFib

Flecainide

Flecainide, a Class 1c agent, is effective in treating paroxysmal AFib in patients without heart disease.¹⁰ However, it can trigger other arrhythmias; the multi-society guidelines recommend ECG monitoring at initiation and dose changes.² Providers should avoid flecainide in patients with structural heart disease or enlarged left ventricles.¹⁰ Given twice daily for chronic use, it also may serve as a “pill-in-pocket” option at a larger, loading dose to convert an AFib episode to normal sinus rhythm.¹⁰

Providers sometimes give patients “pill-in-pocket” prescriptions, which may be taken at the time of an acute AFib episode to return the heart rate to normal sinus rhythm.² Typically, the approach is first tested under the supervision of a provider before the prescription is written for the patient. Providers instruct the patient to carry the dose with them and take it if and when symptoms occur.²

Propafenone

Providers use propafenone, another Class 1c agent, in paroxysmal and sustained AFib.¹⁰ It blocks sodium channels and has weak calcium channel-blocking and beta-blocking properties.¹⁰ Like flecainide, it can cause arrhythmias, and the multi-society guidelines recommend ECG monitoring at initiation, dosing changes, and periodically during treatment.² Providers prescribe propafenone every 8 to 12 hours as a chronic medication. They may prescribe larger doses in a “pill-in-pocket” approach to convert recent-onset AFib to normal sinus rhythm.¹⁰

Dofetilide

Dofetilide is a Class III agent that blocks IKr, a key potassium channel in the heart.¹⁰ It limits the maximum frequency of electrical impulses without slowing conduction through the AV node.¹⁰ It can cause dangerous arrhythmias, including Torsade de Pointes.² As a result, the multi-society guidelines recommend providers place patients under observation with ECG monitoring for three days when starting this medication.² The initial period requires a hospitalization that lasts at least 12 hours after the patient converts to normal sinus rhythm.² The guidelines indicate providers should monitor potassium and magnesium blood levels due to the risk of arrhythmia.² Providers must dose dofetilide based on kidney function.¹⁰

Sotalol

Sotalol, another Class III antiarrhythmic, is a beta-1 and beta-2 blocker.¹⁰ It prolongs the length of electrical impulses to control heart rhythm.¹⁰ Like dofetilide, it can cause dangerous arrhythmias, including Torsade de Pointes.² The multi-society guidelines recommend three days of inpatient ECG monitoring for patients who start sotalol. The guidelines also suggest regular monitoring of potassium and magnesium levels.² Providers must dose sotalol based on renal function.¹⁰

Amiodarone

While amiodarone is more effective at preventing recurrent AFib episodes than sotalol, dotetilide, and dronedarone, the multi-society guidelines recommend these other options preferably for most patients, although it is a first line option (along with dofetilide) in heart failure.² Amiodarone is a Class III drug that blocks both IKr and IKs potassium channels and exhibits rate control properties.¹⁰ It blocks sodium and calcium channels and displays antiadrenergic properties as well.¹⁰ The multi-society guidelines note that amiodarone has a long list of adverse effects and drug interactions, making it a poor choice for chronic therapy.² The adverse effects include thyroid disorders (see SIDEBAR), lung toxicity, liver toxicity, photosensitivity, blue-green skin discoloration, corneal microdeposits, peripheral neuropathy, and the potential for Torsade de Pointes.¹⁶ However, the balance of IKr and IKs potassium channel blockade means it is less likely to cause Torsade de Pointes than Class III antiarrhythmics like dofetilide and sotalol.² Amiodarone (like dronedarone) blocks many CYP P450 isoenzymes and P-glycoprotein. Notable drug interactions include atorvastatin, calcium-channel blockers, beta-blockers, digoxin, fluoroquinolone and macrolide antibiotics, phenytoin, simvastatin, and warfarin.³⁵

SIDEBAR: THE TROUBLESOME ‘I’ IN AMIODARONE

The antiarrhythmic amiodarone comprises 37% iodine (element ‘I’ on the periodic chart) by weight.³¹ The iodine content and the molecule's shape can cause problems for patients prone to thyroid disorders.³¹ Depending on the patient’s susceptibility, amiodarone may cause low thyroid, called hypothyroidism, or a high thyroid condition, called thyrotoxicosis.³¹

Each 200 mg of amiodarone contains 75 mg of iodine, with 7 mg of free iodine released when enzymes process the medicine.³¹ The free iodine is much more than the recommended daily requirement of 0.15-0.3 mg, which leads to iodine overload.³¹

Iodine is critical in creating and processing thyroid hormones T3 and T4. Excess iodine in patients may lead to an overproduction of thyroid hormone, especially in the short to moderate term. Thyrotoxicosis may also occur due to direct damage to the thyroid, which is called thyroiditis.³³ The consequences of thyrotoxicosis may be severe, including arrhythmias.³³ Treatment of thyrotoxicosis depends on its subtype but may include methimazole, prednisone, or propylthiouracil.^31,34

With longer term use of amiodarone, the thyroid produces similar or slightly higher levels of T4 hormone but this T4 is shunted to reverse T3 (rT3) which is biologically inactive, instead of to T3 which is more potent than T4. It is this reduction in T3 that drives signs and symptoms of hypothyroidism in susceptible patients.³¹ The treatment of hypothyroidism is the use of levothyroxine, following guidelines for its use in low thyroid conditions.³³ In cases in which providers stop amiodarone, thyroid function may return to normal.³¹

Dronedarone

Like amiodarone, dronedarone is a Class III antiarrhythmic that blocks sodium and calcium channels and features beta-blocking properties.¹⁰ It resembles amiodarone in chemical structure but lacks iodine. The absence of iodine makes it safer, removing or reducing thyroid, lung, and liver effects.¹⁰ Dronedarone has shown modest benefits for patients with non-permanent AFib.¹⁰ It is contraindicated in permanent AFib or New York Heart Association Class III to IV heart failure.^2,10,18

CONSIDERATIONS IN CHOICE OF RATE OR RHYTHM CONTROL

Prescribers sometimes face difficult choices between rate control or rhythm control. Many factors affect the decision, including the patient’s clinical picture. How old is the patient? How severe are the symptoms? Does the patient have heart disease?

PAUSE AND PONDER: In what situations would prescribers use rate and rhythm control?

The goals of rate control include treating symptoms, preserving heart function, and improving quality of life.¹⁸ Providers prefer this strategy in older patients (age greater than 80 years) with no or mild symptoms.¹⁸ Rate control also may be the only option if rhythm control fails or the risks of it outweigh the benefits.¹⁸ Finally, rate control is more cost-effective due to the medications' wide availability and low cost.³⁶

However, the correct degree of rate control has been debated. Previous sources have recommended a goal ventricular rate of less than 80 bpm at rest in symptomatic patients, but newer recommendations suggest a more lenient approach of less than 110 bpm.² A recent study showed no difference in outcomes with the more lenient strategy, which the multi-society guidelines currently favor.^2,37 As a general rule, all AFib patients should have a ventricular rate less than 110 bpm; those who can tolerate lower heart rates should get the opportunity to see if this reduces their hemodynamic symptoms during AFib. Once a patient’s ventricular rate is below 80 bpm though, further heart rate reductions are unlikely to provide additional value and they should consider a rhythm control strategy.

Rhythm control is preferred in most cases, even though it hasn’t shown an advantage over rate control in risk of death.^1,10 It prevents stroke and improves quality of life but might increase the risk of hospitalization, especially due to ventricular arrhythmias such as Torsade de Pointes.^38,39 Rhythm control is also the best option in patients with a recent diagnosis and in the case of AFib combined with heart failure.² It reduces symptoms and slows disease progress from paroxysmal AFib to more sustained forms of the arrhythmia.² Remember that rhythm control medication is overlaid upon rate control medication, one does not replace the other.

ANTICOAGULANTS

To reduce the risk of stroke in patients with AFib, the multi-society guidelines recommend the use of anticoagulation in select cases.² Determining the need for anticoagulation involves a risk assessment using a scoring system – the CHA₂D₂-Vasc (see Table 3).² In men, a score of 0 indicates low risk, 1 low-moderate risk, and 2 or more is moderate-high risk.¹ In women, a score of 0 or 1 is low risk, a score of 2 is low-moderate risk, and a score of 3 or more is moderate-high risk.² Providers should start anticoagulation in patients with moderate-high risk and consider it in patients with low-moderate risk.¹ When uncertain about whether the benefits of anticoagulation are greater than the risk of bleeding, providers may use the HAS-BLED scoring system; however, the multi-society guidelines indicate it should not replace clinical judgment.² HAS-BLED considers age, renal and kidney function, stroke history, and other factors to determine the risk of bleeding events with anticoagulation.⁴⁰

Table 3. CHA₂DS₂-VASc Scoring Considerations

Providers prescribe direct oral anticoagulants (DOACs) and warfarin for anticoagulation (see Table 4).^1,2 In patients with AFib and no signs of stroke, providers should start anticoagulation immediately.² The standard for patients with a transient ischemic attack or stroke is the “1-3-6-12” rule. Providers should start anticoagulation in 1 day after a transient ischemic attack and 3, 6, and 12 days after mild, moderate, or severe strokes, respectively.⁴¹ This is because there is an increased risk of cerebral bleeding after a stroke for a short period of time and anticoagulation would exacerbate it.

Table 4. Anticoagulants

DOACs

In most cases, providers prescribe DOACs, including apixaban, dabigatran, edoxaban, and rivaroxaban.² Studies show that each is equal to, if not superior to, warfarin in preventing stroke and has less bleeding.² DOACs have fewer drug and food adverse effects, cost more than warfarin, but do not have INR laboratory costs. Dabigatran binds to thrombin (Factor IIa) in the coagulation cascade, and prevents it from activating coagulation factors.⁴² Apixaban, edoxaban, and rivaroxaban are Factor Xa inhibitors and prevent the cleavage of prothrombin to thrombin.^43-45

Warfarin

Warfarin is a Vitamin K antagonist.² Researchers believe it competitively inhibits the vitamin K epoxide reductase complex 1 (VKORC1), which is important for activating Vitamin K in the body.⁴⁶ Without active Vitamin K, Factors VII, IX, X, and II cannot be activated. Warfarin has long been a standard of anticoagulant therapy, although its many drug and food interactions and the need for regular monitoring make its use challenging for clinicians and patients alike.² However, providers still use warfarin for the treatment of AFib in patients with mechanical heart valves or mitral stenosis.² The goal international normalized ratio (INR) for AFib is 2.0 to 3.0 in most cases, except in the presence of certain mechanical heart valves where the INR is 2.5 to 3.5.¹⁰

CONSIDERATIONS IN THE SELECTION OF ANTICOAGULANTS

The choice of anticoagulant depends on several factors. Despite their high costs, the multi-society guidelines consider DOACs first-line therapy due to their advantages over warfarin.² Compared to warfarin, DOACs have lower bleeding risks, fewer drug and food interactions, no dietary restrictions, and require less therapeutic monitoring.² Providers must adjust DOACs based on renal function.² However, warfarin is the only anticoagulant indicated for patients with mitral stenosis or mechanical heart valves.² Multi-society guidelines do not recommend antiplatelet drugs such as aspirin or P2Y12 inhibitors as a substitute for anticoagulants in treating AFib.²

In patients with both AFib and coronary artery disease, the use of an oral anticoagulant can be used alone to treat both. If the patient requires dual antiplatelet therapy (DAPT), after an acute coronary syndrome or the use of a drug eluting stent, but also has AFib, there is a new recommendation. Instead of 6-12 months of DAPT plus an anticoagulant, they recommend a single month of triple therapy, and then 5 months of the P2Y12 inhibitor + oral anticoagulant followed by the oral anticoagulant alone.

PAUSE AND PONDER: What are the recommendations for reversing anticoagulation with warfarin and DOACs?

Providers must also consider reversal of anticoagulation in the case of bleeding. Removal of the offending drug works in some cases, but providers have options in life-threatening instances. They may reverse warfarin by administering Vitamin K and 4-factor proprotein complex concentrate (PCC) in an acute setting.² Reversal of DOACs occurs in only 2% to 4% of cases.² Providers reverse dabigatran using idarucizumab.² Andexanet-α reverses apixaban, edoxaban, and rivaroxaban.² Providers administer PCC, idarucizumab, and andexanet-α intravenously.

NONPHARMACOLOGIC INTERVENTIONS

Electrical Cardioversion

Providers may attempt electrical cardioversion in emergencies or when medications fail to treat AFib adequately.² The procedure is completed in an outpatient facility. Providers place electrode pads on the patient’s chest and back and connect them to a cardioversion machine.⁴⁷ The patient receives anesthesia, and providers administer a high-voltage shock. The shock resets the heart to its normal sinus rhythm. Providers monitor patients for several hours and then patients may go home if they experience no complications.⁴⁷

The multi-society guidelines recommend anticoagulation therapy three weeks before and four weeks after electrical cardioversion if AFib has been present for more than 48 hours (or an unknown period).² The anticoagulant reduces the risk that a clot may be formed during or after the procedure that can be dislodged and cause medical problems.⁴⁸ Even after the AFib is shocked to normal sinus rhythm, it takes a few weeks for the atria to fully start contracting normally again.

Catheter Ablation

Catheter ablation involves the insertion of small tubes directed through the veins to the heart. The ends of the tubes contain electrodes that damage the diseased heart tissue that is causing abnormal electrical pulses.⁴⁹ Heat (radiofrequency ablation) or cold (cryoablation) from the electrodes destroy the tissue.⁵⁰ As a result, ectopic foci or re-entry circuits are eliminated, and normal electrical conduction resumes. Young, healthy patients are good candidates for catheter ablation and the procedure is much more effective in patients with paroxysmal AFib.¹⁰ The multi-society guidelines recommend catheter abation when antiarrhythmic therapy is ineffective, not tolerated, or non-preferred.² Catheter ablation can be curative of AFib in 70% of cases but may take as many as three attempts to fully resolve the arrhythmia.¹⁰ Providers should continue anticoagulation during and after the procedure unless it is clear that the procedure was curative months down the line.²

Watchman LAA Device and AtriClip

In patients who require anticoagulation, but the risk of bleeding outpaces the potential benefits, there are devices that occlude the left atrial appendage (LAA, the pouch on the left atria where most of the clots form in AFib). The Watchman LAA device is placed inside the atria and then opens like an umbrella to block off the LAA. The AtriClip is a clamp that is applied to close off the LAA from the outside of the heart during open heart surgery. In this case, the clots still form in the LAA but cannot get out in the circulation. If a patient is having nonadherence to oral anticoagulation due to bleeding, this is a potential option that a pharmacist could recommend a patient discuss with their cardiologist.

TREATMENT IN THE ACUTE SETTING

Providers in an acute setting order beta-blockers or non-dihydropyridine calcium channel blockers as the first-line treatment.² If ineffective, digoxin is the next choice. Amiodarone is also an option, but only if the previous treatments fail. Providers should not use dilTIAZem and verapamil in patients with poor left ventricular function or heart failure.²

Providers may attempt electrical or pharmacologic cardioversion in the acute setting, especially in unstable patients.² Providers use one of three intravenous medications in pharmacologic conversion. The multi-society guidelines recommend ordering ibutilide if patients do not have reduced ventricular function or risk for Torsade de Pointes.² Ibutilide is a Class III antiarrhythmic available only in an intravenous form that quickly restores normal sinus rhythm.¹⁰ Providers may also order amiodarone; however, converting to sinus rhythm takes longer than other antiarrhythmics (8 to 12 hours).² The multi-society guidelines suggest procainamide as another option.² It is a Class 1a antiarrhythmic that quickly restores normal sinus rhythm; however, the multi-society guidelines discourage its long-term use due to its many adverse effects.^2,10 Procainamide may cause low blood pressure, nausea, vomiting, and a Lupus-like syndrome.¹⁰ Providers should avoid using it in patients with heart failure, and it can prolong the QTc interval, potentially leading to Torsade de Pointes.¹⁰

LIFESTYLE MODIFICATIONS

The multi-society guidelines recommend lifestyle modifications for patients with factors that may influence the disease course.² Providers should recommend weight loss in overweight and obese patients and moderate to vigorous exercise for all AFib patients. The guidelines also recommend screening for sleep apnea with appropriate treatment if it is found. Finally, providers should counsel patients to reduce or eliminate alcohol and tobacco use.²

AFIB AND HEART FAILURE

Several factors complicate the management of AFib in the presence of heart failure.² Providers should consider the degree of left ventricular dysfunction, which determines the type of heart failure and limits the choice of antiarrhythmic.^2,51

The multi-society guidelines recommend rhythm control over rate control in AFib with heart failure.² However, the multi-society guidelines recommend against certain rhythm control agents—namely, flecainide, dronedarone, and propafenone—in patients with heart failure.² Digoxin may be an appropriate choice for rate control, as it has a role in treating both diseases while non-dihydropyridine calcium channel blockers should not be used.² Beta-blockers can be used, and actually provide enhanced survival in heart failure patients, but need to be started with low doses and then slowly titrated up to therapeutic doses.

Besides treating AFib, an evaluation of the patient should reveal whether their profile meets guideline-directed medical therapy for heart failure.² In the case of heart failure with reduced ejection fraction, this includes one of three approved beta-blockers: bisoprolol, metoprolol, or carvedilol.⁵¹ It also includes mineralocorticoid antagonists like spironolactone, a sodium-glucose cotransporter-2 inhibitor, and either an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or sacubitril/valsartan.⁵¹

DIGITAL HEALTH AND AFIB

Smartphones, smartwatches, and handheld devices show promise for uncovering asymptomatic AFib.⁵² In approximately one-quarter of patients with asymptomatic disease, providers do not discover AFib until patients suffer a stroke.⁵³ In recent years, smart devices have provided a solution – ECG monitors. The devices use a technology called photoplethysmography (PPG) sensor technology.⁵² Reflected light from the device measures changes in blood flow from the irregular heart rate.⁵²

Specific versions of the Apple Watch, the Garmin Venu, and the Samsung Galaxy all use PPG technology to look for irregular heart rhythms.⁵² Fitbit also has PPG capabilities in its Charge and Sense models.⁵² A meta-analysis showed that smartphones detect AFib with a sensitivity of 94% and a specificity of 96%.⁵⁴ Sensitivity means that if a patient is having AFib, the device will detect it 94% of the time. Specificity means that in 4% of cases, when AFib is found, it is due to something other than AFib. PPG technology is equally as effective at detecting AFib as a single-lead ECG.⁵⁴ Another meta-analysis confirmed that smartwatches were not inferior to medical-grade devices.⁵⁵

Some limitations of using smart devices in ECG monitoring include the potential for false positives, disparities in access, and the possibility patients will overload providers with consumer data. ECG monitors may incorrectly indicate positives, especially for young, healthy patients.⁵³ AFib patients older than 65 with a low educational and socioeconomic status often do not own smart devices.⁵⁶ Experts also worry about the possibility of consumer data overwhelming the overworked healthcare system.⁵²

Investigators are examining the possibility that mobile ECG monitoring can reduce stroke risk?⁵². A large initial trial of 75-year-old patients using a Zenicor-ECG device twice daily for two weeks revealed a small but significant reduction in endpoints, which included strokes, at five-year follow-up.⁵⁷

Application stores feature digital apps to help manage AFib.⁵⁸ The apps allow patients to record appointments, feelings, symptoms, and questions for their doctors, among other things. App quality varies, and providers should advise patients to check ratings and reviews and provide recommendations.⁵⁸

PHARMACY TEAM IMPACT ON AFIB MANAGEMENT

Nearly 90% of Americans live within five miles of a community pharmacy.⁵⁹ That fact makes pharmacists one of the most accessible healthcare providers.⁶⁰ Pharmacists and technicians can leverage their familiarity with their customers in several ways.

For pharmacists, managing and monitoring anticoagulation is the most obvious intervention that can improve outcomes. Providers and administrators often ask pharmacists to dose INRs for warfarin patients in clinics, hospitals, and outpatient settings. Pharmacists may monitor for bleeding complications, both with warfarin and DOACs.

Pharmacist medication review activities may catch meaningful drug-drug and drug-food interactions in AFib patients. Pharmacists can also monitor for the toxic effects of medications like digoxin and amiodarone and report any observations to providers. Even common agents like beta-blockers and calcium channel blockers may cause troublesome interactions in patients with complicated clinical pictures. Pharmacists may catch these problems and intervene with the prescriber.

Pharmacists can collaborate with pharmacy technicians to improve patient adherence to medications. While technicians may coordinate the adherence programs, pharmacists counsel patients on the importance of following providers’ medication orders and communicate nonadherence to the prescriber.

Pharmacists also may counsel patients on lifestyle modifications. If a pharmacy has a smoking cessation program, for example, the pharmacist may refer AFib patients to it. The pharmacist may also counsel on the need for weight loss or exercise and help the patient set goals.

Finally, the advent of portable ECG monitors allows pharmacists to set up screening programs for asymptomatic or suspected AFib. The AliveCor KardiaMobile is a single-lead ECG that connects through a smartphone. Pharmacists may use it to collect ECGs and triage patients. A cardiologist then confirms any positive result and refers the patient for treatment.⁶¹

Pharmacy technicians may also help manage AFib. Technicians often coordinate medication adherence programs, such as automated refill reminders, medication synchronization, and compliance packaging. Pharmacy technicians can then inform the pharmacist of cases of nonadherence.

Technicians may also coordinate filling pill-in-pocket prescriptions for medications like flecainide or propafenone. They can also use TALLman lettering for sound-alike look-alike medications and place dosing labels on shelving for narrow therapeutic index medications like warfarin or digoxin.²⁰

Finally, technicians can inform pharmacists when AFib patients try to purchase inappropriate over-the-counter or herbal medications. Decongestants like pseudoephedrine can increase heart rate, and herbals like St. John's wort and hawthorn can interact with antiarrhythmics.^62,63 Medications like non-steroidal anti-inflammatory medications, aspirin, and herbals like vitamin E supplements, ginseng, and ginkgo biloba may interfere with anticoagulation.^62,631

Finally, pharmacies can foster knowledge and understanding of the disease by hosting community events in coordination with local healthcare providers. For example, a pharmacy could hold an event during AFib awareness month in September. Pharmacy staff could invite representatives from local clinics and cardiologists’ offices.

CONCLUSION

AFib is the most common type of heart rhythm disorder or arrhythmia, and its incidence and prevalence continue to grow as the population ages. Goals for AFib patients include prevention of stroke, control of heart failure symptoms, and improvement in quality of life. Rate and rhythm control antiarrhythmics can treat AFib. The rate control strategies help with symptoms by controlling the ventricular rate. Rhythm control medications restore the normal sinus rhythm, but providers must carefully choose and monitor them due to their side effects and contraindications. Providers prefer rhythm control agents in many patients due to their ability to reduce the risk of stroke and improve quality of life. Anticoagulation is indicated in cases of higher stroke risk; providers should choose DOACs over warfarin in most cases, except for patients with mitral stenosis or mechanical heart valves.

Beta-blockers and calcium channel blockers are the first choices in the acute setting, followed by digoxin. Providers have limited options in both rate and rhythm control in patients with heart failure. Beta-blockers, digoxin, dofetilide, sotalol, and amiodarone provide options. Pharmacists can play essential roles in managing and monitoring anticoagulation, performing drug use reviews and adherence monitoring, and screening patients for asymptomatic cases. Pharmacy technicians can aid pharmacists by coordinating adherence mechanisms, filling pill-in-pocket refills, and notifying the pharmacist of patients' improper OTC or herbal selections.

Now let’s return to our patient case. Dan’s uncontrolled AFib requires a quick call to his cardiologist, who suggests he go to a local emergency room for examination. The pharmacy staff offers to put his apixaban, flecainide, and other medications on a medication synchronization program with refill reminders. They also suggest that he invest in a digital device that monitors ECG. He promises to go straight to the emergency room.

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INTRODUCTION

Practitioners in all healthcare settings need to understand and respect gender diversity. Pharmacists and pharmacy technicians can play a pivotal role in gender-affirming care by using inclusive language and developing comprehensive knowledge of pharmacologic interventions. The scope of gender affirming care ranges from puberty suppression to gender-affirming surgeries to align physical appearance with gender identity. Gender dysphoria is a very serious condition among transgender individuals that can lead to depression and suicide. Gender dysphoria is not solely internally driven and can be exacerbated by external stressors/stigma. This includes external aspects of experience such as distress associated with misgendering and social norms, social isolation, transphobia, etc.^1,2 It may be treated with hormone therapy and can require lifelong treatment. Healthcare professionals in the pharmacy setting can help these patients by creating a supportive environment that promotes adherence to their treatment. The SIDEBAR provides definitions for frequently used terms in transgender care.

SIDEBAR: Terminology^1-6

• Gender expression: External manifestations of gender, expressed through one’s behavior, body characteristics, clothing, haircut, name, pronouns, or voice. Typically, transgender people seek to make their gender expression align with their gender identity, rather than their assigned gender.
• Gender role: Behaviors, attitudes, and personality traits that a society (in a given culture and historical period) assigns as masculine or feminine and/or that society associates with or considers typical of the social role of men or women
• Gender identity/experienced gender: One’s internal, deeply held sense of gender. For transgender people, gender identity does not match their sex assigned at birth. Most people have a gender identity of male or female. For some people, gender identity does not fit neatly into one of those two choices (e.g., nonbinary). Unlike gender expression, gender identity is invisible to others.
• Sex: The best-known attributes include sex-determining genes, sex chromosomes, gonads, sex hormones, internal and external genitalia, and secondary sex characteristics.
• Sex assigned at birth: Sex assigned at birth, usually based on genital anatomy. AFAB refers to "assigned female at birth," and AMAB to "assigned male at birth."
• Transgender (also TGD, trans): An umbrella term for people whose gender identity and/or gender expression differs from what is typically associated with their sex assigned at birth. Not all transgender individuals seek treatment.
• Cisgender: A term for people whose gender identity and/or gender expression is aligned with what is typically associated with their sex assigned at birth.
• Gender dysphoria: The distress experienced when one’s gender identity and assigned gender are incongruent, often worsened by external factors like misgendering, social norms, isolation, and transphobia. Not all transgender people experience gender dysphoria; being transgender on its own is not a medical condition.
• Transition: The process during which transgender people change their physical, social, and/or legal characteristics consistent with their affirmed gender identity. Transgender individuals may initially transition socially and postpone medical transition. This is especially true for prepubertal children.
• Transgender male (also: trans man, female-to-male): Individuals assigned female at birth but who identify and live as men.
• Transgender woman (also: trans woman, male-to female, transgender female): Individuals assigned male at birth but who identify and live as women.
• Non-binary: An adjective describing a person who does not identify exclusively as a male or a female. Non-binary people may identify as being both male and female, somewhere in between, or as falling completely outside these categories. While many also identify as transgender, not all non-binary people do.
• Embodiment goals: Body qualities/characteristics that a patient wishes to have (e.g. shape, feeling, behavior of body).

Guidelines

The World Professional Association for Transgender Health (WPATH) publishes the Standards of Care for the Health of Transgender and Gender Diverse People (SOC),⁷ which is the main guideline used internationally for transgender health. This continuing education activity is based on SOC Version 8.

The Endocrine Society develops the Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline.³ These guidelines establish a framework for the appropriate treatment of individuals and standardize terminology to be used by healthcare professionals. This activity cites these guidelines as well.

Inclusive Language

Everyday language often revolves around the concept of two genders and one sexuality, potentially overlooking diverse identities. Using gender-inclusive language demonstrates respect and acknowledgment of all gender identities while eliminating assumptions. Using they/them pronouns instead of he/his or she/her when unsure of someone's pronouns is best.⁶ Healthcare professionals can demonstrate inclusivity by introducing themselves with their own pronouns and asking patients how they prefer to be addressed. Common pronouns include she/her/hers, he/him/his, and they/them/theirs..⁶ Healthcare professionals should avoid stating that a person is transgender to others unless that is how the person identifies and is comfortable with sharing that information.⁶ Another suggestion is saying “feel free to bring your spouse or partner” instead of “feel free to bring your husband or wife.”⁶

PAUSE AND PONDER: A fellow colleague consistently misgenders a transgender patient despite being corrected. How would you address this behavior while promoting inclusivity and respect in the pharmacy setting?

Physiology

Puberty is the process of an adolescent becoming capable of reproduction. This process involves the hypothalamic-pituitary-gonadal axis. The first biologic sign of puberty is an increase in endogenous gonadotropin hormone-releasing hormone (GnRH).⁷ GnRH produced by the hypothalamus causes the pituitary gland to secrete gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH stimulate gonads to produce sex hormones.⁸ Table 1 compares puberty in individuals with ovaries and those with testes.

Table 1. Patterns of Typical Puberty⁷

ADULTS

Feminizing Pharmacology

The goals of feminizing pharmacology care are the development of female secondary sex characteristics and the minimization of male secondary sex characteristics. Treatments include externally dosed estrogens and antiandrogens. The selection of therapy should include a patient-specific evaluation of patient goals, medical conditions, medication risk/benefit, and economics.⁷

Estrogen promotes feminine features such as breast growth. Antiandrogens diminish masculine features by reducing endogenous testosterone. Examples of antiandrogens include spironolactone, cyproterone acetate, GnRH agonists, and 5-alpha reductase inhibitors.

Estrogen

In gender-affirming care, estrogen (or 17-beta estradiol) used for feminizing treatment is chemically identical to estrogen produced by human ovaries.^3,7 Multiple dosing formulations exist including oral tablets, topical patches, intramuscular injections, and topical gels/sprays. A major safety concern for anyone using exogenous estrogen is the increased risk of thromboembolic events. 17-beta estradiol is generally preferred over synthetic estrogens for the ease of monitoring serum levels and its lower risk of thromboembolic events. For those older than 45 years and those at a higher risk of venous thromboembolism (VTE), the guidelines recommend transdermal formulations. Cardiovascular screening is essential to identify patients at higher VTE risk. Due to multiple Boxed Warnings in the product labeling and potentially significant adverse events, providers should use caution and consider the risks and benefits of estrogen therapy.^3,7

The desired effects of exogenous estrogen include breast development, redistribution of facial and subcutaneous fat, reduction of muscle mass, reduction of body hair, and reversal of scalp hair loss. Exogenous estrogen will not alter voice or height in adults. Table 2 describes available estrogens used in gender-affirming care.^3,7

Table 2. Estradiol for GAHT⁹

Antiandrogens

Antiandrogens, listed in Table 3, can reduce endogenous testosterone levels or its activity and are usually used in combination with estrogen for feminizing effects. While antiandrogens may be employed as monotherapy, combination treatment can help minimize the amount of estrogen necessary for gender-affirming effects and therefore reduce the estrogen-associated risks. General adverse effects of antiandrogen monotherapy may include hot flashes, low mood or energy, and bone loss when used long term.⁷

Table 3. Antiandrogens for GAHT^10-13

Spironolactone is a potassium-sparing diuretic that has many therapeutic uses including in heart failure and hypertension. Spironolactone is also an aldosterone receptor antagonist that can cause positive effects, such as gynecomastia (an increase in breast gland tissue) for transgender women. Gynecomastia is dose and duration dependent, occurring in approximately 10% of patients. The diuretic and antihypertensive effects may become apparent within two to three weeks potentially resulting in excess urination and low blood pressure.^3,14

GnRH agonists (histrelin, leuprolide) work by continuously activating the pituitary gland to make more LH and FSH. This overactivation eventually suppresses sex steroid production. Out of pocket costs for these medications can range anywhere from $10,000 to $50,000 for three months, thereby significantly limiting their use.¹⁶

WPATH does not regularly recommend other drugs like 5-alpha reductase inhibitors, finasteride or dutasteride, as data supporting use in the transgender population is sparse.⁷

Cyproterone acetate is a synthetic progestin that inhibits testosterone synthesis and action. This medication is not approved in the United States but may be used elsewhere.³

PAUSE AND PONDER: A transgender patient presents with concerns about the different formulations of estrogen available for feminizing treatment. How would you explain the advantages and disadvantages of each formulation?

Masculinizing Pharmacology

The goals of masculinizing treatment are the development of male secondary sex characteristics and the minimization of female secondary sex characteristics. Masculinizing GAHT typically consists of testosterone.

Testosterone

Testosterone treatment in transgender patients is used in the same way that it is used for hypogonadism in cisgender male patients. Table 4 illustrates the various testosterone formulations in transgender care, including intramuscular, transdermal, and implantable options. Intramuscular injections may be preferred due to available clinical data, efficacy, patient satisfaction, and low levels of injection pain and local irritation relative to subcutaneous injections. Prescribers and patients should not interchange products without considering pharmacodynamic differences.^7,16

Positive effects of masculinizing hormones include irreversible deepening of voice, increased body/facial hair, and increased lean muscle mass. Patients and care teams should know that masculine hormone therapy will not reverse previous feminine features such as breast tissue. Achieving physiological testosterone levels will usually suppress menses. If testosterone monotherapy doesn’t suppress menses, additional therapies can be used including progestins, GnRH agonists, and aromatase inhibitors. Patients may continue testosterone therapy for life unless medically contraindicated.¹⁶

Table 4. Testosterone Formulations for GAHT ¹⁷

CHILDREN

GAHT is not recommended in children who have not begun endogenous puberty. Healthcare providers should take a non-pharmacologic approach instead for pre-pubertal individuals, including psychosocial gender-affirming care. Patients should continue gender exploration regardless of social transition.⁷

ADOLESCENTS

GAHT’s goal in adolescents is pubertal suppression. Halting progression of puberty allows adolescents to explore gender identity and embodiment goals. Although suppression is reversible, the treatment team should discuss fertility preservation before starting supression.⁷ Current timing and readiness estimates are as follows: pubertal suppression at 12 years old, GAHT at 16 years old, and surgery at 18 years old.

Pubertal Suppression Pharmacology

Healthcare providers employ Tanner staging to track children’s development during puberty. It outlines five specific stages for the physical changes during this period, including genital, breast, and pubic hair development. Patients should reach Tanner Stage 2 before initiating pubertal suppression. In Tanner Stage 2, individuals who are assigned female at birth would experience breast budding while those who are assigned male at birth would experience external genitalia enlargement.⁶ Menstrual suppression is recommended for patients assigned female at birth with gender incongruence, regardless of testosterone therapy.⁷

Pharmacologic Agents

Gonadotropin-Releasing Hormone (GnRH) Agonists

GnRH agonists cause partial regression of secondary sex characteristics and inhibit physical functions, such as menses and erections, by decreasing concentrations of gonadotropin and sex steroid hormones. Supraphysiological doses of sex steroids are not needed with GnRH agonists.⁷

Short-term hypertension is an important counseling point. Individuals who are older than 14 years also have a long-term risk of poor bone health because of the lack of exposure to adequate levels of sex steroid hormone levels. Sex steroid hormone therapy, however, induces rapid recovery of bone mineralization rate.⁶

For feminizing therapy, patients should continue puberty blocking until gonadectomy. Masculinizing pharmacology is covered in the following Hormone Therapy section. If patients have functioning uterus and ovaries, health care providers should counsel on potential breakthrough menstrual bleeding two to three weeks after GnRH agonist initiation.

Progestins

Oral or injection depot progestins are recommended if GnRH agonists are unavailable or cost-prohibitive.⁷

Patients can also receive these progestins if they seek menstrual suppression only⁷:

• Oral progestin-only pills (contraceptive and non-contraceptive options)
• Medroxyprogesterone injection (e.g. Depo-Provera)
• Levonorgestrel intrauterine device (e.g. Mirena, Liletta, Kyleena, Skyla)
• Etonogestrel implant (e.g. Nexplanon)

If a patient continues to have menstrual bleeding after taking progestin and/or is seeking a contraceptive, healthcare providers can consider a combination progestin-estrogen product for amenorrhea and counsel on possible breast development. Combined formulations include oral contraceptive pills, transdermal patches, and vaginal rings. Note that increased breakthrough bleeding is associated with lower dose ethinyl estradiol in combined oral contraceptives.⁷

Hormone Therapy (HT)

The patient’s health care professionals will need to measure hormone levels during gender-affirming treatment. The purpose is to ensure that endogenous sex steroids are falling and the sex steroids administered to the patient stay at appropriate levels. Appropriate levels are determined by (1) the patient’s treatment goals and (2) the patient’s Tanner stage. Timing of pubertal suppression determines sex steroid HT regimen, as shown in Table 5.⁷

Table 5. Sex Steroid Hormone Therapy Regimen Based on GnRH Agonist Treatment Timing⁷

WPATH suggests 12 months as sufficient time for psychological adaptations to physical changes due to GAHT. Healthcare providers should monitor sex steroid levels every three months during the first year of HT or with dose changes. Once the prescriber titrates the patient’s dose to the adult maintenance dose, monitoring one to two times annually is sufficient. As GAHT can activate the hypothalamic-pituitary-gonadal axis, prescribers may need to add a GnRH agonist as adjunctive therapy after GAHT initiation to avoid development of characteristics associated with the patient’s sex assigned at birth.⁷

For masculinizing GAHT, testosterone monotherapy at physiologic doses is typically sufficient to decrease estrogen secretion by the ovaries. Injection, transdermal, and subcutaneous pellets are available androgen formulations. Key counseling points include the possibility of developing androgenic acne or sexual dysfunction.

Patients on GnRH agonists should continue them until they reach maintenance testosterone level. If the patient was not on a GnRH agonist as an adolescent, then no concomitant GnRH agonist is needed. While testosterone usually suppresses menstruation in the first six months of therapy, healthcare providers should make sure to counsel adolescents on possible pregnancy despite amenorrhea because they can still ovulate.⁷

NON-PHARMACOLOGIC INTERVENTIONS

Chest Binders

Chest binding refers to compressing breast tissue to achieve a flatter chest appearance. Research indicates that up to 87% of individuals identifying as transgender males have tried chest binding.⁶ Various methods used for binding include commercial binders, sports bras, layering clothes, elastics, and bandages.⁷

Healthcare providers play a crucial role by making patients aware of chest binding’s potential advantages and risks. Transgender men who bind often report benefits such as increased comfort, enhanced safety, and reduced instances of misgendering.⁷

Negative physical impacts of chest binding include back or chest pain, difficulty breathing, and feeling overheated.⁷ Severe health issues like skin or respiratory infections and rib fractures, which are rare, have been linked to adult chest binding.⁶ Providers can lower the risk by counseling patients on safe binding methods, like binders specifically designed for gender-diverse individuals, to lessen the likelihood of serious health complications. Meanwhile, patients should avoid unsafe methods like duct tape, ace wraps, or plastic wrap due to their potential to constrict blood flow, harm the skin, and restrict breathing.⁶ If negative health effects occur, seeking guidance from medical professionals experienced with transgender and gender-diverse patients is sensible.⁷

Tucking

Genital tucking involves positioning the penis and testes to minimize the visibility of genital bulges.⁷ This can be done by tucking the penis and testes between the legs or placing the testes inside the inguinal canal while pulling the penis back between the legs.⁷ Underwear or specialized garments called gaffs are commonly used to keep the genitals in place.⁷

Research on the risks and advantages of tucking in adults is limited, and no studies conducted specifically address youth.⁶ Previous research has highlighted that snug undergarments might lead to reduced sperm concentration and motility. Moreover, higher scrotal temperatures due to tucking might theoretically impact sperm production and fertility.⁷ However, no conclusive evidence confirms these negative effects. More data is needed to understand the risks and benefits of tucking.

Voice Therapy

Hormone treatment for transgender and gender diverse (TGD) individuals has potential effects on voice and communication. While estrogen treatment does not usually cause measurable voice changes, testosterone treatment can lead to desired shifts in voice pitch and male attributions but may also result in undesired outcomes.⁷

Research indicates that some TGD individuals experience positive effects from testosterone, such as lowered voice pitch and increased satisfaction, aligning with their gender identity. However, a significant portion may face challenges like insufficient pitch changes, vocal quality issues, limitations in singing range, and vocal instability post-treatment.^7,18 A meta-analysis examined about 600 patients across 19 studies to determine the effects of at least one year of testosterone therapy. The patients were all at least 18 years old, with an average age of 35 years. According to the results, approximately 21% of participants did not reach the expected normative frequencies associated with cisgender males. Additionally, a similar percentage reported incomplete alignment between their voice and gender identity, experiencing voice-related challenges or incongruence. Furthermore, 16% of individuals undergoing testosterone therapy expressed dissatisfaction with the changes in their voice.¹⁸

It's essential to provide accurate counseling beforehand to establish realistic expectations and avoid potential disappointment. Referral to voice and communication specialists can address concerns through tailored voice training and assisting those dissatisfied with outcomes or lacking access to hormone treatment.⁷

Electrolysis And Laser Hair Removal

Hair removal is a significant part of transitioning for many transgender women (or females), particularly for those seeking a more stereotypical feminine appearance. The process helps alleviate dysphoria, boosts self-confidence, and enhances overall quality of life.¹⁹ The U,S, Food and Drug Administration recognizes laser hair removal as a permanent hair removal method.¹⁷ It targets melanin in hair follicles using laser light waves.¹⁹ An alternative, electrolysis, also removes hair permanently using a small probe inserted into individual hair follicles to administer an electric current.¹⁷

For individuals undergoing GAHT, healthcare providers need to keep specific considerations in mind. Among transgender women taking estrogen¹⁹

• Estrogen hormone therapy often results in an overall reduction in body hair, except for minimal effects on facial and genital hair.
• The extent of hair removal (complete hairlessness or retaining some hair) depends on personal preference and comfort levels.
• Many transgender women find facial and neck hair removal crucial for increased self-confidence, reduced dysphoria, and a sense of safety in public spaces.
• Those prioritizing gender-affirming lower surgeries like vaginoplasty (vagina construction surgery) require completely hair-free areas for surgery preparation, as hair growth within transformed tissue can cause complications.

For transgender men taking testosterone¹⁹

• Testosterone hormone therapy generally leads to increased body hair growth.
• Preparing for surgeries like phalloplasty (penis construction surgery) often requires completely hair-free skin areas for successful procedures, the specific area depending on the type of surgery planned.
• It is important to note that electrolysis doesn't prevent the growth of new hair follicles activated by testosterone. Therefore, new hair growth might occur in areas previously treated with electrolysis due to testosterone’s effects on stimulating hair follicles.

The adverse effects of hormone therapy may be beneficial for some patients, while being detrimental to others. It is critical for healthcare providers to educate patients on hair removal methods and their impact within the context of hormone therapy, so that patients understand what to expect.

Gender-Affirming Surgery

Gender-affirming surgery is often a crucial milestone for many, but not all transgender adults.³ Broadly classified into two categories, surgeries (1) directly impact fertility or (2) have no effect on fertility.³ Surgeries that alter fertility involve procedures like the removal of male genitalia (penis and gonads) for transgender women or the removal of female reproductive organs (uterus and ovaries) for transgender men.³ Surgeries that do not affect fertility include chest masculinization or breast augmentation, facial feminization, or facial masculinization surgeries.³

There is a lack of evidence supporting the routine discontinuation of hormone therapy before planned surgeries.²⁰ The majority of evidence advocating for estrogen cessation before surgery is derived from studies involving oral synthetic estrogen regimens (ethinyl estradiol), which are uncommon in transgender patients.¹⁹ WPATH advises maintaining estrogen therapy both before and after surgical procedures in transgender women, particularly in those without specific risk factors such as smoking, family history of VTE, or the use of synthetic estrogens.⁷ If the patient has the previously mentioned risk factors, the prescribing endocrinologist should discuss estrogen therapy cessation in the perioperative setting openly with the patient and make decisions collaboratively.²⁰ Typically, an acceptable timeframe for estrogen discontinuation is two to four weeks before the procedure.²⁰ Anticipated physiological and psychological withdrawal symptoms may include anxiety, autonomic hyperactivity, depression, decreased seizure threshold, and fatigue.²⁰ This comprehensive approach ensures a thoughtful consideration of hormonal factors in the surgical process for transgender women.

Evidence suggests that there is generally no need to discontinue testosterone treatment routinely in transgender men before scheduled or elective surgery despite the concern that testosterone can be aromatized to estradiol, which theoretically could increase the clotting risk.²⁰ A recent systematic review found no association of increased VTE complications after surgery with perioperative testosterone use.^21,22

The decision to undergo these surgeries is deeply personal and varies based on individual needs, preferences, financial access, and dysphoria. Access to comprehensive information, counseling, and support from healthcare professionals helps patients make informed decisions aligned with their gender identity and long-term goals while understanding the potential impact on fertility.³

PAUSE AND PONDER: A transgender patient would like to undergo breast augmentation but has only been on hormone therapy for six months. Is she eligible for the surgery?

Chest or “Top” Surgery

“Top” surgery is either removing breast tissue for a more masculine appearance or enhancing breast size and shape for a more feminine appearance. Breast surgery is a type of gender-affirming surgery with no impact on fertility.³ Since breast size varies among females, it is advisable for transgender women to postpone breast augmentation surgery until they have undergone at least two years of estrogen therapy.³ This is recommended because the breasts continue to grow during this period of hormone therapy.³

Meanwhile, the primary masculinizing surgery for transgender men is a mastectomy, which also has no impact on fertility.³ While breast size only partially regresses with androgen therapy, discussions about mastectomy in adults typically occur after androgen therapy starts.³ However, in some cases where trans-masculine adolescents present after significant breast development, a mastectomy may be considered approximately two years after starting androgen therapy and before the age of 18.³ Treatment decisions should be individualized based on the individual’s physical and mental health status. ³

Genital or “Bottom” Surgery

Genital or “bottom” surgery involves transforming and reconstructing the genitalia. According to The Endocrine Society Clinical Practice Guideline Criteria for Gender-Affirming Surgery, the following factors may influence decisions related to fertility preservation³:

1. Persistent and well-documented gender dysphoria
2. Meets the legal age requirement in the relevant country
3. Use of gender-affirming hormones for a continuous 12-month period, unless there is a medical contraindication
4. Successful in living full-time as a new gender role for the duration of 12 months
5. Well-controlled management of any significant medical or mental health conditions, if present
6. Demonstrated knowledge of practical aspects related to surgery, including cost, required lengths of hospitalizations, likely complications, and postsurgical rehabilitation.

Gender-affirming surgeries for transgender women that affect fertility include procedures like gonadectomy (orchiectomy), penectomy, and the creation of a neovagina.³ In the case of transgender men, surgeries that affect fertility include an oophorectomy, vaginectomy, complete hysterectomy, and the creation of a neopenis.³ Infertility can occur from both the temporary consequences of gender-affirming hormone therapy and permanent effects of gender-affirming surgeries (GAS).⁶ It is crucial to engage in ongoing discussions about infertility risks and fertility preservation options with transgender individuals and their families before and after initiation of therapies and surgeries.⁶

OTHER CARE IMPACTED BY GAHT

Anticoagulation

When assessing the risk of VTE associated with GAHT, it is crucial to consider the alternative—the risk of not providing GAHT.²² Withholding GAHT could lead to adverse mental health consequences that might outweigh the risk of VTE.²⁰ Some individuals may seek hormone therapy outside clinical care settings (that is, from unreliable sources) if healthcare providers refuse to provide it.²²

For transgender individuals experiencing VTE while on GAHT, treatment should align with current therapeutic anticoagulation recommendations for cisgender individuals.²⁰ The American Society of Hematology guidelines recommend direct oral anticoagulants (DOACs) over other options due to a lower risk of bleeding.²² Despite limited data in transgender people, recent case reports suggest DOACs are effective in those with VTE during GAHT. In severe cases threatening limbs, clinicians can consider thrombolysis and recommend it as they would in cisgender individuals.²² GAHT discontinuation during an acute VTE episode is often recommended, especially with above normal hormone levels, but this recommendation lacks extensive data.²² Clinicians and patients should discuss the potential risks and benefits of continuing GAHT during an episode.

Following acute VTE treatment, the decision to resume GAHT becomes complex. Many clinicians continue GAHT, even in patients with previous VTE, along with full-intensity anticoagulation to prevent recurrence.²² Although researchers have not conducted systematic evaluation in transgender patients, this approach was effective in cisgender women on hormone therapy.²² While cisgender patients may reduce anticoagulation dose after initial therapy, it is uncertain if dose reduction is prudent with GAHT. Shared decision-making, emphasizing the risks and benefits, remains crucial in determining the course of GAHT post-VTE treatment.

Estimating Kidney Function

Many healthcare providers are accustomed to using the Cockcroft-Gault equation to estimate kidney function.²³ This formula factors in sex, causing uncertainty as to how to calculate creatinine clearance in transgender patients. Although GAHT affects muscle mass and creatinine, using the duration of therapy is unreliable because the timing and magnitude of effect differ by individual. As such, cystatin C is often more accurate than creatinine. Acknowledging that cystatin C levels are not accessible at all practice sites, some experts suggest using the Cockcroft-Gault-calculated male and female creatinine clearance estimates as a range. Other methods include using vancomycin clearance calculations.²³

Fertility Preservation

Individuals who have transitioned may wish to have biological children for personal reasons, to maintain a genetic connection with their offspring, or to conform with cultural expectations.²² While many transgender individuals may not initially consider having children, their desires can change over time.²⁴ In a survey of 50 transgender men who had undergone gender-affirmation surgery, the majority (77%) had not contemplated fertility preservation before GAHT. An average of 9.9 years after starting testosterone therapy, 54% of participants wanted to have children.²⁵ The study also found that participants with children had a higher quality of life than those who did not have children.²⁵

Fertility preservation through the cryopreservation of sperm and oocytes is a well-established technique, available for pubertal, late pubertal, and adult individuals assigned male or female at birth^.6 Ideally, clinicians should present this option before initiating GAHT.⁷ Clinicians can offer embryo cryopreservation to adult transgender individuals, particularly those who have completed puberty, express a desire to have a child, and have a willing partner.⁷

While research has shown semen parameters may be compromised after the initiation of GAHT, a small study indicated that when treatment was discontinued, semen parameters were minimally altered.²⁶ In regards to oocyte preservation, there is no expectation that assisted reproductive technology (ART) treatments would be different for TGD patients compared to cisgender patients.⁷ The only potential variations are individuals with confounding factors related to infertility.⁷

Barriers to fertility preservation include financial constraints, invasiveness of procedures, and concerns about mistreatment or bias from healthcare providers.²⁴ Some fertility preservation procedures, such as sperm or egg collection, can serve as reminders of their sex assigned at birth and may trigger gender dysphoria.²⁴ Transgender individuals who pursued ART reported mixed experiences. Some have positive encounters with supportive providers who use gender-neutral language. Others experienced misgendering in clinical documentation.²⁴ Patients should be provided with options for future family planning whether they desire biological children or not.

BARRIERS IN PRACTICE

Laws and Legislation

When the Supreme Court tackled the Conservative challenge to the Affordable Care Act (ACA), the focus was on whether it was constitutional to mandate health insurance purchase.²⁷ This overshadowed Section 1557's anti-discrimination provisions protecting transgender individuals. The 2016 Rule, finalized by Health and Human Services, extended Title IX's anti-sex discrimination coverage to include "gender identity," ensuring equitable access to healthcare for transgender patients. The Trump administration attempted to reverse these protections but faced legal obstacles. This led to the Supreme Court's ruling in Bostock v. Clayton County, which affirmed protections for transgender individuals under existing civil rights statutes. Despite the Trump administration's efforts, subsequent legal challenges and judicial actions further emphasized protections for transgender individuals, leading to ongoing debates and policy shifts under the Biden administration.²⁷

The Bostock ruling, initially about employment, now impacts transgender minors' access to gender-affirming care.²⁷ Federal courts often interpret Title VII and Title IX together, meaning they see both statutes as prohibiting sex-based discrimination similarly.²⁵ This means that the Biden Administration can confidently enforce protections for gender identity under Title IX, following Bostock's reasoning.²⁷ Since Bostock's ruling was made under a majority conservative Supreme Court, it's unlikely to be reversed. This leaves opponents of gender-affirming care to explore other tactics, like raising religious objections or labeling such care as "experimental" or "medically dangerous."²⁷ These viewpoints circumvent many physicians’ clinical judgement, thus restricting how they practice medicine.

Over the past 18 months, the number of states implementing laws that restrict or prohibit minors' access to gender affirming care has increased dramatically.²⁸ Currently, the count of states with restrictions increased from just four states in June 2022 to 23 states by January 2024. Among these states, 17 have fully enacted their restrictions, while four face temporary injunctions, and one is permanently blocked pending appeal. The laws vary in complexity, with some focusing on specific aspects of gender affirming care, such as GAHT or gender affirming surgery. Additionally, while these laws primarily target minors' access to care, they often include provisions affecting other groups, such as parents, medical providers, and teachers.²⁸ These laws and policies cause potential harm to the wellbeing of young TGD, thus emphasizing the need for continued advocacy and support for inclusive and affirming practices.

Insurance Coverage

Ensuring comprehensive healthcare for transgender individuals requires access to both gender-affirming care and a wide range of inclusive services. However, numerous barriers have historically hindered access, with lack of health insurance coverage being shaped by intersecting factors at the individual, interpersonal, and structural levels.

Many state Medicaid programs exclude coverage for gender-affirming care, posing a significant concern given the elevated prevalence of poverty among transgender people. In a study utilizing Behavioral Risk Factor Surveillance System (BRFSS) data, gender non-conforming individuals were nearly twice as likely as cisgender women to report unmet care needs due to financial issues.²⁹According to the 2015 United States Transgender Survey, 25% of insured respondents encountered insurance discrimination.²⁹ Experiences included denial of coverage for gender-specific services, such as cancer screenings (13%), for care unrelated to gender affirmation (7%), and for gender-affirming surgery (55%) or hormone therapy (25%).²⁹ TGD individuals (33%) reported negative experiences related to being transgender when seeing a healthcare provider in the previous year, which includes verbal harassment, physical assault, or treatment refusal.²⁹ Additionally, 23% refrained from seeking care when needed in the previous year due to fear of mistreatment.²⁹

A 2019 systematic review revealed that 27% (range, 19% to 40%) of transgender individuals reported outright denial of healthcare.²³⁰ Assessments of provider readiness indicate that many clinicians lack training in transgender clinical and cultural competency, potentially contributing to interpersonal discrimination in healthcare settings.

Assessing Implicit Bias, Addressing Bad Behavior

1. Respect Gender Identity: TGD individuals deserve the same respect as cisgender patients. Address patients by their chosen name and pronouns, reflecting their gender identity. Avoid gossiping or making jokes about patients and treat them with the same respect you would want at work.³¹

2. Recognize Workplace Values: Understand the difference between your personal beliefs and the workplace values of dignity and respect for everyone. While you are entitled to your opinions, professionalism requires setting aside personal views and treating everyone with fairness and courtesy in the workplace.³¹

3.Seek Feedback and Learn from Mistakes: Don't be afraid to ask for feedback from TGD individuals about how you can better support them or avoid inadvertently causing harm. Be open to learning from your mistakes and apologize if you unintentionally offend someone. Additionally, take the initiative to stay updated on evolving terminology and practice recommendations, as ideas/norms about gender are fluid and change over time. Learning from reputable sources, such as The Trevor Project's Guide to Being an Ally to Transgender and Nonbinary Youth, shows a genuine commitment to fostering inclusivity and respect in the workplace.^31,32

4. Support Colleagues with Challenges: If you notice co-workers struggling to adjust to interactions with TGD individuals, offer gentle reminders about using the correct name and pronouns. Help them understand the impact of their behavior on both the TGD individual and the workplace environment. Encourage empathy and understanding to foster a more inclusive workplace culture.³¹

5. Intervene When Appropriate: If you witness blatant inappropriate behavior or discriminatory actions with no remorse towards a TGD individual in the workplace, don't remain silent. Find appropriate ways to intervene, whether it's addressing the behavior directly, reporting it to management, or offering support to the affected individual. Standing up against prejudice and discrimination helps create a safer and more inclusive work environment for everyone.³¹

CONCLUSION

Embracing gender diversity and providing gender-affirming care is essential in healthcare settings, including pharmacies. Pharmacists and pharmacy technicians who employ inclusive language and possess a thorough understanding of pharmacological interventions play a critical role for transgender individuals. Pharmacists can help tailor GAHT regimens to individual patient needs, promoting safety and helping patients achieve their goals towards gender affirmation. Pharmacists and pharmacy technicians can create a more inclusive and safer environment when interacting with patients. As healthcare workers in the pharmacy setting, we can provide patients with the resources they need without judgement.

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INTRODUCTION

Gene therapy is a medical approach to replace missing genes or correct dysfunctional genes in patients with genetic diseases. Gene therapies are best suited for patients who have well-defined, single (monogenic) mutations.^1,2 Many are rare diseases for which there are few, if any, treatment options. Therapeutics to correct gene mutations are biologics with the potential to cure a variety of previously incurable diseases such as muscular dystrophy, hemophilia, cystic fibrosis, and some types of blindness. Scientists are also developing gene therapies to stop cancer-causing genes and boost immune responses against tumors.

The term “gene therapy” encompasses multiple broad strategies that can be separated into two general approaches: in vivo (performed inside an organism) and ex vivo (cells that are removed from the organism, genetically modified, and then returned to organism).³ Within these approaches, multiple techniques and delivery systems are currently used or in development:^4,5

• Viral vectors (in vivo or ex vivo)
• Non-viral delivery particles (in vivo or ex vivo)
• Gene editing (in vivo or ex vivo)
• Cell engineering (ex vivo only)

The entire field of gene therapy is beyond the scope of this activity. This activity’s focus will be in vivo gene delivery via engineered adeno-associated virus (AAV), with some discussion of gene therapy’s basics and background. This is valuable information for pharmacists and pharmacy technicians as this complex biologic class matures and more gene therapies become available to patients.

BASICS OF GENE THERAPY

Gene Therapy Terminology

People outside of the field may be unfamiliar with many terms used to describe gene therapies. Table 1 defines common terms.

Table 1. Common Terms Used to Describe Gene Therapy^6,7,8

DNA, deoxyribonucleic acid.

We have used brand drug names preferentially throughout this activity because generic names for gene therapies are complex (See Sidebar).

SIDEBAR: What’s in a Name? How Are Gene Therapies Named?^9,10

For in vivo gene therapies, the generic names are composed of two words:

• First word corresponds to the gene component
  • Prefix: random element to provide unique identification
  • Infix: element to denote the gene’s pharmacologic class (gene’s mechanism of action)
  • Suffix: element to indicate “gene”
• Second word corresponds to the vector component
  • Prefix: random element to provide unique identification
  • Infix: element to denote the viral vector family
  • Suffix: element to identify the vector type (non-replicating, replicating, plasmid)
  • 4-letter distinguishing suffix: devoid of meaning and attached to the core name with a hyphen

Example:

The Pros and Cons of Gene Therapy 

Patients and/or caregivers considering gene therapy should consider several factors^11-13:

• Duration of efficacy
  • PRO: Potential exists for permanent correction of a disease state. If successful, patients may not need lifelong treatments/medications.
  • CON: Gene therapy is relatively new and long-term efficacy data is lacking. If gene expression wanes over time, patients may need redosing (which may be impossible) or alternative treatments.
• Safety
  • PRO: Regulatory agencies have approved several products, and safety data is available.
  • CON: Complete understanding of adverse effect mechanisms is lacking, and long-term safety information doesn’t exist.
• Cost
  • PRO: A curative gene therapy may be more cost-effective than a lifetime of other medications/treatments.
  • CON: Available gene therapies are very expensive, $2.9 to $3.5 million for the AAV in vivo therapies approved in 2022 and 2023.

The History of Gene Therapy

Gene therapy is a relatively new field. Clinicians ran the first clinical trial in 1990. Scientists made several advancements in the 1990s and early 2000s, and progress has rapidly accelerated since then.¹⁴ (See Sidebar).

ABBREVIATIONS: AAV, adeno-associated virus vector; Ad, adenovirus; ADD, adenosine deaminase deficient; ALL, acute lymphoblastic leukemia; CALD, cerebral adrenoleukodystrophy; CAR T, chimeric antigen receptor; Cas9, CRISPR-associated protein 9; CRISPR, clustered regularly interspaced palindromic repeats; DMD, Duchenne muscular dystrophy; EMA, European Medicines Agency; FDA, Food and Drug Administration; HSC, human stem cells; LV, lentivirus; DLBCL, diffuse large B-cell lymphoma; SCD, sickle cell disease; SCID, severe combined immunodeficiency disorder; SMA, spinal muscular atrophy; TDT, transfusion-dependent thalassemia.

Gene Therapy Systems

Viral Vectors

Prototypical gene therapy is an in vivo approach to curing genetic diseases. It uses a delivery vehicle, such as an engineered virus that encapsulates the gene of interest (GOI) for injection into a patient by various routes, such as intravenous (IV), intraocular, or intrathecal.³⁹ This method takes advantage of a virus’s natural ability to enter mammalian cells efficiently. Once the delivery vehicle enters host cells, the encapsulated gene drives production of the missing or faulty protein. Clinicians use this approach for diseases such as muscular dystrophies, where mutations in the dystrophin gene cause progressive weakness and muscle-wasting, and cystic fibrosis, where mutations in the cystic fibrosis transmembrane conductance regulator gene impair lung function.

Non-viral Delivery Vehicles

Non-viral delivery vehicles, such as nanoparticles, can also deliver genes or gene editing systems in vivo. These particles use biocompatible materials such as polymers and lipids to carry genes or nucleic acids into cells.³ Researchers can customize a particle’s physiochemical properties to target the intended cell types better and evade immune responses. Non-viral particles are less efficient than viruses at entering cells but may have several other advantages. It’s likely that most patients are immunologically naïve to manufactured particles and lack pre-existing antibodies that may prevent successful uptake by cells. Non-viral particles may also be easier to manufacture and purify, making them more cost-effective to produce than viral vectors.⁴⁰

Recent gene therapy clinical trials using nanoparticles or lipid nanoparticles include the following^41-43:

• Reqorsa: contains a tumor suppressor gene encapsulated in a lipid nanoparticle for treatment of several types of lung cancer
• NTLA-2001: contains a gene editing system encapsulated in a lipid nanoparticle for treatment of hereditary transthyretin amyloidosis (a disease which deposits abnormal protein [amyloid] in organs)

Gene Editing Systems

Gene editing systems, which can be in vivo or ex vivo approaches, can provide precise, targeted gene modifications. Gene editors are engineered nucleases (enzymes) that produce double-stranded breaks at a specific target site. These breaks stimulate the cell’s natural DNA repair mechanisms, resulting in the repair of the break by homology-directed repair or non-homologous end joining. With these systems, target-specific DNA insertions, deletions, modifications, or replacements are all possible.^3,44

Many gene editing tools exist, including^3,44

• clustered regularly interspaced short palindromic repeats (CRISPR) Cas-associated nucleases
• transcription activator-like effector nucleases (TALENs)
• zinc-finger nucleases (ZFNs)
• meganucleases (MNs)

Gene editing ex vivo systems are a fast-growing area with many programs in development.⁴¹ In vivo gene editing is rife with challenges, especially those concerning delivery to the intended cells. Gene editing systems are an evolving cutting-edge platform reviewed in much more detail elsewhere.^3,44,45

Ex Vivo Gene Therapy

In ex vivo gene therapy, medical and/or laboratory personnel remove a patient’s cells from the body, genetically modify them (using viral vectors, non-viral delivery particles, or gene editing systems), and then re-introduce them into the patient. Alternatives to the use of a patient’s cells include genetically modified cell lines or cells from another donor. The use of autologous (patients’ own) cells avoids the need to find an immuno-compatible donor. Examples of systems include chimeric antigen receptor (CAR) T cells and engineered hematopoietic stem cells (HSC). CAR T cells are T lymphocytes that are modified to recognize tumor antigens, such as the B lymphocyte antigen Cluster of Differentiation-19 (CD-19) and B-cell maturation antigen (BCMA). Once genetically modified, the CAR T cells bind to cells expressing the tumor antigen and subsequently kill them. HSC have the ability for self-renewal and to differentiate into multiple cell lineages, therefore engineering them to correct genetic flaws such as enzyme deficiencies and hemoglobinopathies (inherited disorders affecting hemoglobin, the molecule that transports oxygen in the blood) makes them a promising approach.

Several products have received regulatory approval in the United States (U.S.)⁴⁶:

• Autologous CAR T cells^47-50
  • CD19-directed autologous T cell immunotherapies for the treatment of various types of B cell lymphomas include the following:
    • Yescarta (axicabtagene ciloleucel) – approved 2017
    • Kymriah (tisagenlecleucel) – approved 2017
    • Tecartus (brexucabtagene autoleucel) – approved 2020
    • Breyanzi (lisocabtagene maraleucel) – approved 2021
  • BCMA-directed autologous T cell immunotherapies for treatment of relapsed or refractory multiple myeloma include the following^51,52:
    • Abecma (idecabtagene vicleucel) – approved 2021
    • Carvykti (ciltacabtagene autoleucel) – approved 2022
• Autologous HSC-based gene therapies include the following^53-56:
  • Skysona (elivaldogene autotemcel) – slows neurological dysfunction in cerebral adrenoleukodystrophy by inducing synthesis of adrenoleukodystrophy protein – approved 2022
  • Zynteglo (betibeglogene autotemcel) – corrects β-thalassemia by adding functional copies of a modified β-globin gene into the patient’s HSC – approved 2022
  • Casgevy (exagamglogene autotemcel) – first FDA-approved CRISPR/Cas9 gene-editing therapeutic; corrects sickle cell disease (SCD) and transfusion-dependent β-thalassemia by adding functional copies of a modified β-globin gene into the patient’s HSC – approved 2023
  • Lyfgenia (lovotibeglogene autotemcel) – corrects SCD by adding functional copies of a modified β-globin gene into the patient’s HSC – approved 2023

CAR T cell gene therapy is an effective treatment for several types of cancers but comes with many challenges to patients, medical professionals, and pharmacy personnel. Product manufacturing, administration, and adverse effect mitigation are more complex than for many other treatment types. Medical, laboratory, and/or pharmacy personal carry out the following key steps at specialized medical centers^47-50:

1. Collect the patient’s white blood cells (leukapheresis)
2. Manufacture the CAR T cells in a laboratory with a typical time frame of two to four weeks
   • Patients may need to travel to and remain near the center while they wait for the cells
   • If the process fails, then personnel must repeat the cell collection and CAR T cell manufacturing
3. Administer chemotherapy to deplete the patient’s lymphocytes, two to 14 days prior to CAR T cell infusion, which makes room for the CAR T cells
4. Administer the CAR T cells to the patient by slow infusion to minimize infusion-related adverse reactions
5. Monitor the patient for at least four weeks, likely requiring the patient to stay at or near the treatment center

This therapy class carries Boxed Warnings:

• CD-19 directed therapies^47-50,57
  • Cytokine release syndrome (CRS): over-activation of the immune system with release of large amounts of cytokines (immune system proteins); this is a common, potentially life-threatening adverse event
  • Neurotoxicity: the mechanism by which this occurs is not well understood, but it is common and can be life-threatening

• BCMA-directed therapies^53,54
  • CRS and neurotoxicity as listed for CD-19 directed therapies
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome: a hyperinflammatory immune response that can be life-threatening
  • Prolonged cytopenia (low numbers of blood cells) with bleeding and infection; can be life-threatening

Ex vivo gene therapy with autologous HSC is also a complex process with multiple challenges and toxicities.^53,54 For these therapies, medical personnel pretreat patients with granulocyte-colony stimulating factor to increase production and release of HSCs from bone marrow. Laboratory staff then collect and purify HSC from the patient’s blood. Staff may need to collect cells more than once to amass the required number of cells or in cases where manufacturing fails. Laboratory staff genetically modify the patient’s HSCs, typically with a lentiviral vector, to express the GOI. The cell manufacturing process can take up to three months. The modified cells require cryopreservation and liquid nitrogen storage conditions, adding to the process’s complexity.

When the cells are ready, medical personnel administer lymphocyte-depleting chemotherapy to the patient to remove HSCs that are making the faulty protein and to make room in the bone marrow for the genetically modified HSCs. Next, medical personnel infuse the thawed HSCs to the patient intravenously. After infusion, patients may need to stay at the medical center for several months for recovery and monitoring.

The prescribing information lists toxicities including prolonged cytopenias, serious infections, and an increased risk for lentiviral vector-mediated oncogenesis (development of a new cancer). It recommends patient monitoring for 15 years to life for hematologic malignancies. Skysona and Lyfgenia have Boxed Warnings for hematologic malignancy.^53,56

The overview above describes how the field of gene therapy is broad and encompasses multiple approaches. New and evolving approaches include non-viral delivery, gene editing, and ex vivo cell engineering; they have recently started to become available to patients. This is an exciting and hopeful time for patients with genetically-linked diseases, and it is likely that many more effective and approved therapies will be available soon.

AAV-BASED IN VIVO GENE THERAPY

Although researchers are developing viral vectors based on many types of viruses (e.g., adenovirus, gamma retrovirus, herpes simplex virus, lentivirus) adeno-associated virus (AAV) has emerged as the leading viral vector for in vivo gene therapy with five current regulatory approvals in the U.S. and many more programs under development.^41,46 Its favorable characteristics include not causing human disease, inability to replicate in the host without a helper virus, and ability to elicit a low host immune response relative to many other viruses. Since the expression cassette is typically maintained on an episome, scientists expect AAV-based vectors to have a low frequency of integration into the host genome, conferring a minimal risk of cancer.⁵⁸ In addition, at least one serotype of AAV (AAV9) can cross the blood-brain barrier making AAV a suitable choice for neurologic diseases without invasive local administration of the vectors into the brain. Researchers find AAV-based vectors to be attractive, versatile tools with suitable properties and utility for a wide variety of diseases.

AAV Biology

Naturally occurring AAVs are small, non-enveloped viruses that belong to the Parvovirus family. They have a linear single-stranded DNA genome of approximately 4.7 kilobases, including rep and cap genes that encode for replication and capsid proteins, respectively.³ Figure 1A illustrates the genomic structure of a wild type (naturally occurring) AAV.

In engineered AAVs used for gene therapy, developers remove the rep and cap genes and replace them with an expression cassette, as illustrated in Figure 1B. The expression cassette contains the GOI, regulatory elements (promoter/enhancer), and poly-adenosine tail (to stabilize the messenger RNA and facilitate translation into protein) flanked by inverted terminal repeats (ITRs; required for genome replication and packaging). The expression cassette replaces approximately 96% of the native genome.³

Figure 1. Genomic Structure of Wild Type AAV and Engineered AAV Vector

cap, capsid gene; GOI, gene of interest; ITR, inverted terminal repeat; rep, replicase gene.

AAV capsids in both the wild type AAV and engineered AAV vectors are composed of three viral proteins (VPs) named VP1, VP2, and VP3. Sixty molecules of these proteins, estimated to exist in a 1:1:10 ratio (VP1:VP2:VP3), assemble into each icosahedral capsid (Figure 2). The VP sequences overlap, with VP1 being 137 amino acids longer than VP2, which is 57 amino acids longer than VP3. Differences in VP3 sequences distinguish one AAV serotype from another.⁵⁹

Figure 2. Protein Structure of the AAV Capsid

VP, viral protein.

AAV exists as at least 11 natural serotypes, which share about 51% to 99% sequence identity in their VP3 protein.^60,61 Sequence comparisons between different AAV serotypes identified nine variable regions situated on the capsid surface. The specific amino acid sequences of these regions impact AAV binding to host cell receptors, thus determining cell- and tissue-specific tropism (affinity for a specific tissue or cell type). These variable sequences also function as binding sites (epitopes) for AAV-specific antibodies, thus influencing host immune responses.⁶²

An AAV serotype can be tropic to multiple cell types and tissues, and multiple serotypes can be tropic to the same cells/tissues. Researchers isolate serotypes from non-human primates and develop synthetic serotypes using protein engineering to alter tropisms and/or evade pre-existing AAV-specific antibodies.¹

PAUSE AND PONDER: If your child had a life-shortening genetic disorder and a new AAV9-based therapy became available, how would you feel if your child had a high anti-AAV9 neutralizing antibody titer that excluded them from clinical trials or treatment?

Neutralizing antibodies (NAbs) are naturally occurring antibodies that bind to AAV surface epitopes and block uptake into target cells. NAb binding to the AAV capsid can induce rapid clearance of the gene therapy by the patient’s immune system. Clinical personnel must screen patients for pre-existing Nabs. Trial protocols and prescribing instructions often exclude patients with NAbs specific for the gene therapy’s serotype.

Older children and adults tend to have a high prevalence of pre-existing antibodies against commonly circulating (wild type) AAV serotypes because of previous exposure to these viruses over the course of their lives. For example, studies showed that approximately 40% of humans have NAbs to AAV serotypes 5, 6, 7, 8, and 9.⁶³ Between 6% and 95% of individuals with hemophilia A and B have AAV-specific antibodies based on AAV serotype and assay used.⁶⁴ In addition, due to the high degree of conservation of capsid protein amino acid sequences, pre-existing antibodies to one serotype may cross-react with other serotypes, further limiting the availability of a therapy for a patient. Patients without NAbs prior to gene therapy will develop high titers of NAbs following vector administration, rendering them ineligible for additional rounds of gene therapy with the same vector or a cross-reactive serotype.^1,63-65

Vector Design

To create a vector for a particular disease, drug developers try to target an AAV vector to the specific cell or tissue type where gene correction is needed. The capsid serotype choice significantly influences this decision.

AAV2, AAV5, AAV6, AAV8, and AAV9 account for a majority of the ongoing AAV gene therapy clinical trials.^60,66 Commonly, AAV2 or AAV8 is the choice for ocular therapies; AAV2, AAV8, AAV5, and AAV9 are best for liver targeting; and AAV2 and AAV9 are preferred targeting muscle or the central nervous system. Some researchers are also using AAV serotypes isolated from rhesus monkeys, such as rh74.^60,67 As discussed, AAV9 can cross the blood-brain barrier, allowing IV administration of this serotype to target brain tissue while avoiding invasive intrathecal injections.^60,68 Therefore, AAV9 is a popular vector to treat many diseases affecting the nervous system.

Developers derive the capsids of AAV vectors either from natural AAV viruses or by engineering capsids through rational design, directed evolution, or computer-guided strategies. The impetus to develop AAV vectors with capsids from less common AAV serotypes or novel engineered AAV capsids serves to improve or modify tissue targeting and circumvent immune recognition.⁶⁹

Considerations for vector design include^61,62

• Choosing the best AAV serotype to target the intended cell type or tissue, using the desired route of administration
• Potential for tissue-specific promoters (e.g., targeting the muscle for muscular dystrophy or the liver for hemophilia) rather than constitutive promoters (that will drive gene expression in a wide range of tissues and perhaps result in off-target toxicity)
• Whether an enhancer is needed to boost expression in the target tissue to achieve desired therapeutic effect
• Modifying capsid epitopes to reduce recognition/response from the host immune system

Vector Production and Purification

Once developers choose the best capsid serotype and design the vector, they proceed to the manufacturing step. Gene therapies are complex biologics, and manufacturing and purification are of utmost importance for efficacy, safety, and product stability. Regulatory agencies require good manufacturing practice compliance.⁷⁰

Scientists commonly use mammalian cell lines to propagate engineered AAV vectors and then purify the vectors from cell lysates. Rigorous purification is essential. As the science of gene therapy matures, drug developers continuously improve purification methods. Contaminants from the engineered AAV cultivation process are a potential source of toxicity and can induce unwanted immune responses. Release testing of the final product in the U.S. must comply with a series of FDA-established requirements and predetermined specifications to determine product safety, purity, concentration, identity, potency, and stability.⁷¹ Characterization of the final product includes a determination of the viral genome (vg) titer, infectious titer (potency), product identity (AAV capsid and genome), and therapeutic gene identity (expression/activity).⁷²

Gene therapy developers follow these steps to manufacture AAV-based therapies^73-75:

1. Use conventional recombinant DNA technology in bacterial systems to produce the plasmids
2. Use mammalian cell lines, such as human embryonic kidney 293 cells, or insect cell lines, such as the baculovirus/insect cell system, to produce the vectors
3. Transfect (introduce genetic material into a cell) three plasmids into the cell line
   • a recombinant AAV plasmid containing the expression cassette (see Figure 1b)
   • an adenovirus-based helper plasmid supplying genes needed for virus replication
   • a plasmid containing the essential rep and cap genes needed for virus replication and capsid formation
4. Collect produced vectors from the cells and purify them. Complex purification processes require multiple methods that may be specific for each individual contaminant. Rigorous purification minimizes patient risk (see Sidebar). Examples of purification process steps (and techniques used) include the following:
   • Cells lysis to release the viral particles (detergent, mechanical stress, hypertonic shock, freeze-thawing)
   • Removal of nucleic acids (nuclease treatment), cell fragments and proteins, cell culture contaminants (centrifugation, filtration, chromatography)
   • Separation of full vector particles from empty particles (cesium chloride gradient ultracentrifugation or chromatography)
5. Formulate vectors after purification for administration to the patient. Formulation optimization prior to manufacture is not trivial. Some considerations are:^73-75
   • Formulation chemical composition must be optimized for intended route of administration
   • Formulation must be sterile and have low endotoxin concentration
   • Formulation must minimize product degradation to avoid aggregation and loss of efficacy due to product instability

SIDEBAR: Patient Safety: The Importance of Purification of AAV^69,74

• Non-vector sequences (including plasmid DNA, helper virus DNA, and DNA from the cell line used to produce the vector) can unintentionally be packaged into the capsids. AAV vector genomes can recombine with non-vector DNA, resulting in AAV vectors that contain chimeric (mixtures of DNA from different sources) sequences. The behavior of these unintended sequences is unpredictable in patients.
• Capsids containing the complete intended therapeutic gene, partial sequences, unintended chimeric sequences, or no genetic sequence material at all (empty capsids) are all possible outcomes of vector manufacturing. Administering a mixture of different forms of the therapeutic to patients may result in a partial effective dose, thus lowering potency and necessitating administration of higher overall numbers of AAV particles to achieve efficacy. The higher the number of AAV particles, the higher the risk of toxicities and immune system activation.

Toxicities/Adverse Events

Although AAV gene therapy is generally considered safe, multiple treatment-emergent serious adverse events have occurred following gene therapy administration to patients. These include severe hepatoxicity and thrombotic microangiopathy (TMA). Other potential toxicities and identified risks include myocarditis, neurotoxicity (dorsal root ganglion [DRG] degeneration), oncogenicity, and immunotoxicity.⁶⁹

In general, AAV vectors administered IV first travel to the liver. Liver enzyme increases denoting liver damage commonly occur and corticosteroid treatment is often effective. On occasion, acute serious liver injury, liver failure, and death have occurred. Although the mechanism is not completely understood, more severe liver injury appears to correlate with higher vector doses. Severe liver injury following AAV vector administration for spinal muscular atrophy (SMA) and X-linked myotubular myopathy genetic diseases has occurred.^69,76

TMA is a pathological condition characterized by formation of thrombi (clots) in small blood vessels, following endothelial cell injury. TMA’s clinical presentation often includes complement activation, cytokine release, thrombocytopenia (decreased platelets), and kidney injury/failure. Several cases of TMA have been reported in patients or clinical trial participants following AAV gene therapy for SMA and Duchenne muscular dystrophy (DMD). Treatments for affected patients included hemodialysis, platelet transfusion, and the complement inhibitor eculizumab. As with severe liver injury, TMA development appears to be related to high vector doses.^77,78

Several patients in DMD clinical trials have developed myocarditis, which was fatal in one patient. A hypothesis is that pre-existing inflammation in DMD patients’ muscles, including heart muscle, worsened upon local expression of dystrophin. Steroid treatment successfully resolved myocarditis in some cases.⁷⁹

DRG degeneration/toxicity is an identified potential risk of AAV gene therapy. DRGs are collections of sensory neurons that relay impulses from the periphery to the central nervous system. Researchers have observed AAV vector-induced DRG toxicity mainly in non-clinical studies with pigs and non-human primates. Direct administration of AAV into cerebral spinal fluid and high vector doses were contributing factors. Pathology studies have detected DRG degeneration in autopsy samples from humans who received AAV gene therapy. Scientists do not completely understand DRG toxicity’s underlying mechanisms in animals or the significance of clinical translation to humans.⁸⁰

Oncogenicity due to insertional mutagenesis (introducing foreign DNA into a person’s genome) is a potential risk of gene therapy. Studies in mice that received AAV vectors revealed integration events and hepatocellular carcinoma. Hepatocyte clonal expansion occurred in dogs following AAV vector administration although tumors were not found. AAV vector genome integration into chromosomes has been detected in humans, but so far AAV-associated oncogenesis has not been reported.⁵⁸ Due to the potential risk, regulators expect long-term monitoring after vector administration.^69,81

Although immune responses to wild type AAV are low relative to other viruses, AAV can engage all arms of the immune system and can do so robustly especially when high vector doses are administered. The immune response to AAV gene therapy is complex, and poorly understood, and can contribute to loss of efficacy and adverse effects. Local (rather than systemic) dosing, use of tissue specific promoters, and increasing the vector’s potency (increasing promoter strength/achieving higher levels of expression per AAV particle) may effectively minimize toxicity.^65,76,82,83

Immune responses to AAV gene therapy include the following^65,66,79,82:

• Innate immune responses: may lead to cytokine induction and/or activation of the complement cascade (e.g., toll-like receptor recognition and signaling in response to capsid proteins and nucleic acids)
• Humoral responses: antibody binding to AAV capsid may activate complement and immune cells and remove the vector from circulation before it can reach its target tissue. After gene therapy administration, the body generates new antibodies that can be specific for a capsid or transgene product.
• Cellular immune responses: may lead to inflammation and elimination of the cells producing the disease-correcting protein (e.g., activation/expansion of capsid- or transgene-product-specific cytotoxic T lymphocytes)

APPROVED IN VIVO GENE THERAPIES

As of December, 2023, the FDA approved eight in vivo gene therapies, five of which are AAV based.⁴⁶

Non-AAV-Based Therapies

Three of the FDA-approved in vivo gene therapies are non-AAV based; they are adenovirus (Ad)-based or herpes simplex virus (HSV)-based. None are systemically administered, but instead are administered locally to the skin or bladder.

Vyjuvek (beremagene geperpavec-svdt) is a live, replication deficient HSV type 1 (HSV-1) vector genetically modified to express human type VII collagen. Vyjuvek is indicated for wound treatment in patients with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain gene. Topical application to wounds induces production of the mature form of type VII collagen leading to wound healing.⁸⁴

Adstiladrin (nadofaragene firadenovec-vncg) is a non-replicating adenoviral serotype 5 vector genetically modified to produce human interferon α-2b (IFNα-2b). Adstiladrin is indicated for patients with high-risk Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. Intravesical (within the bladder) instillation results in local expression of IFNα-2b protein that is anticipated to have anti-tumor effects.⁸⁵

Imlygic (talimogene laherparepvec) is a live, attenuated HSV vector genetically modified to replicate within tumors and to produce the immune stimulatory protein granulocyte-macrophage colony-stimulating factor (GM-CSF). Imylgic is indicated for local treatment, by intralesional injection of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Imylgic causes tumor lysis followed by release of tumor-derived antigens, which together with virally derived GM-CSF may promote an antitumor immune response. However, the exact mechanism of action is unknown.⁸⁶

AAV-Based Therapies

Luxturna (voretigene neparvovec-rzyl) is a genetically modified non-replicating AAV2 expressing the human retinoid isomerohydrolase (RPE65) gene approved in 2017. It’s used to treat patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy, a condition causing progressive retinal degeneration and dysfunction, which can lead to vision loss and blindness over time. Retinal pigment epithelial (RPE) cells produce RPE65. Mutations in this gene result in vision impairment, so Luxturna aims to correct these mutations. A clinician administers 1.5 x 10¹¹ vg of Luxturna subretinally (directly into the space beneath the retina) to each eye on separate days, at least six days apart. Patients typically take systemic oral corticosteroids starting three days before its administration and continuing with a tapering dose for 10 days. Preparation of Luxturna for administration is complex and includes thawing, dilution, and preparation of syringes for injection. Warnings and precautions include endophthalmitis (infection/inflammation of the inner structures of the eye), permanent decline in visual acuity, retinal abnormalities, increased ocular pressure, intraocular air bubble expansion, and cataracts. Immune responses to Luxturna were mild in clinical trials, perhaps due to corticosteroid administration.²³

Zolgensma (onasemnogene abeparvovec-xioi) is a genetically modified non-replicating AAV9 expressing the human survival motor neuron (SMN) protein. The FDA approved it in 2019 for treatment of patients younger than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the SMN1 gene. SMN protein is key for muscle development and movement and Zolgensma aims to correct these mutations to treat the disease. After Zolgensma is thawed, a clinician administers 1.1 × 10¹⁴ vg/kg of Zolgensma intravenously by slow infusion. Patients typically take systemic corticosteroids starting one day before Zolgensma administration and continuing for a total of 30 days. Serious adverse effects described in the Boxed Warning include acute liver injury and failure with fatal outcomes. Other warnings and precautions include systemic immune response, thrombocytopenia, TMA, and elevated troponin (a protein involved in muscle contraction).⁸⁷

Hemgenix (etranacogene dezaparvovec-drlb) is a genetically modified non-replicating AAV5 expressing human coagulation Factor IX (Padua variant), under control of a liver-specific promoter. Approved in 2022, it is employed to treat male patients with hemophilia B (congenital Factor IX deficiency). The Padua variant has an 8-fold higher specific activity relative to wild type Factor IX, and Hemgenix would ideally correct the disease by providing circulating Factor IX activity. Clinicians administer 2.0 × 10¹³ gc/kg of Hemgenix by slow intravenous infusion. Hemgenix is a refrigerated suspension that requires dilution into normal saline. The prescribing information recommends corticosteroids, not prophylactically, but only if the liver enzyme aspartate aminotransferase (AST) increases to twice the patient’s baseline value. Warnings and precautions include infusion reactions (including anaphylaxis), hepatotoxicity, and hepatocellular carcinogenicity (theoretical risk if vector DNA integrates into the host cell genome).⁸⁸

Elevidys (delandistrogene moxeparvovec-rokl) is a genetically modified non-replicating AAVrh74 (originally isolated from rhesus monkeys) expressing human micro-dystrophin. The FDA approved it in 2023 for treatment of ambulatory 4- to 5-year-old patients with DMD with a confirmed mutation in the dystrophin gene. The vector’s promoter/enhancer drives transgene expression predominantly in skeletal and cardiac muscle. The dystrophin protein’s micro version consists of selected domains of dystrophin that confer function to muscle cells. After Elevidys is thawed, clinicians administer 1.33 × 10¹⁴ vg/kg by intravenous infusion using a syringe infusion pump. The prescribing information recommends prophylactic corticosteroids following a complex administration and tapering schedule, which is further complicated in patients with DMD already on a corticosteroid regimen. Warnings and precautions include acute serious liver injury, immune-mediated myositis, and myocarditis.⁸⁹

Roctavian (valoctocogene roxaparvovec-rvox) is a genetically modified non-replicating AAV5 expressing the B-domain-deleted form of human coagulation Factor VIII (the smallest active form of Factor VIII) under control of a liver-specific promoter. Approved in 2023 for treatment of male patients with severe hemophilia A, clinicians administer Roctavian after thawing at 6.0 × 10¹³ vg/kg by intravenous infusion using a syringe infusion pump. The prescribing information recommends corticosteroids, not prophylactically, but only if liver enzymes increase to 1.5 times the patient’s baseline or to above the upper limit of normal. Warnings and precautions include infusion reactions (including anaphylaxis), hepatotoxicity, and thromboembolic events.⁹⁰

PAUSE AND PONDER: The prescribing information for Hemgenix and Roctavian do not recommend these gene therapies for women. Why?

A LOOK TO THE FUTURE

As discussed above, the FDA has approved five AAV-based gene therapies, Figure 3 illustrates disease indications being studied in AAV-based clinical trials including 90 ongoing, interventional studies.⁴¹

Figure 3. AAV-based gene therapy clinical trials for different disease indications as a percentage of all AAV-based clinical trials for therapies not yet approved for marketing⁴¹

The percentages of each disease indication were calculated based on the total of current AAV-based interventional clinical trials. Clinical trials were identified using the search terms gene therapy and adeno-associated (for condition/disease) and interventional (study type). Trials designated as recruiting, active – not yet recruiting, enrolling by invitation, and completed were included in the analysis (n = 73). Trials designated as terminated, suspended, or unknown status were not included. Data are current as of April 12, 2024.

Ophthalmology and neurology represent the highest percentage of forthcoming therapies. Within the ophthalmology category, multiple trials are underway for achromatopsia (color blindness), amaurosis (complete vision loss without visible eye damage; typically, an optic nerve disease), and retinitis pigmentosa (progressive vision loss due to retina deterioration), among others. The neurological disease category includes trials for Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and others. Hematological and musculoskeletal clinical trials are highly focused on hemophilia and muscular dystrophies, respectively. The metabolic disease category is diverse containing a few trials each for numerous genetic diseases.⁴¹

Controlling the immune response to AAV vectors is one of the biggest hurdles for future therapeutics. The human immune system is complex and very efficient. Often, it has a back-up plan in case an organism escapes the first round of attack and usually a back-up plan for the back-up plan. It becomes impossible for an AAV vector (a virus in sheep’s clothing) to go unnoticed, especially when the doses are greater than 1 trillion vg/kg of body weight. Thus, a patient’s immune system will go into action starting shortly after receiving gene therapy and mount a multi-pronged attack.

New and improved strategies to control immune responses will greatly benefit patients. Researchers are diligently pursuing strategies (Table 2) that target the vector itself or immune system components.^91-93 Success will probably use a combinations of strategies.

Table 2. Strategies to Control or Circumvent Immune Responses^91-94

AAV, adeno-associated virus; IdeS, immunoglobulin G-degrading enzymes of Streptococcus pyogenes; IgG, immunoglobulin type G; NAb, neutralizing antibody.

Perfection of technologies to remove pre-existing NAbs would allow many more patients to be eligible for gene therapies. Curbing antibody production in the days following the gene therapy may boost efficacy, reduce toxicity, and allow patients to remain eligible for more than one round of AAV gene therapy if needed. Methods to control T cell-mediated responses would prevent destruction of the cells producing the transgene product, increasing the persistence of the curative gene expression.

Early clinical studies took a reactive approach to immune responses to AAV; they used medications such as corticosteroids following observation of increases in liver enzymes or signs of inflammation. More recently, efforts to identify drugs and combinations of drugs that will suppress the immune response prophylactically have accelerated^91,93:

• Corticosteroids (e.g., methylprednisolone): general anti-inflammatory
• Tacrolimus: inhibits T cell proliferation and differentiation
• Rituximab: depletes B cells to block antibody production
• Rapamycin (sirolimus): disrupts cytokine signaling resulting in inhibition of B cell and T cell activation
• Mycophenolate mofetil: inhibits B cell and T cell proliferation
• Eculizumab: complement inhibitor
• Hydroxychloroquine: inhibits toll-like receptor-9-mediated responses to viral DNA an antigen presentation

Researchers must investigate other key variables: the timing of immunosuppression initiation and the requisite treatment duration.

Many clinical trials have employed corticosteroids, but corticosteroids alone are insufficient to control immune responses. Regulators have approved the immunosuppressants listed above for indications other than gene therapy, and their safety profiles are known, making them logical choices to investigate for gene therapy indications. Future work must maximize safety and efficacy of AAV gene therapy while balancing adverse effects of the immunosuppressive regimens.⁹³

SUMMARY

Gene therapy is a relatively new, complex, and evolving field in medicine that offers hope to patients with previously incurable genetic diseases. The information presented here is intended to introduce a topic that pharmacists and pharmacy technicians may not have been previously exposed to, and perhaps inspire them to read more.

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