INTRODUCTION

For decades, lipid management focused on treating lipoprotein numbers. The 2026 guidelines instead emphasize individualized cardiovascular risk, earlier intervention, and lower low-density lipoprotein (LDL) targets for patients at highest risk. Patient Nick Smith is a 68-year-old male recently seen by the cardiologist. He currently takes several medications: metformin, empagliflozin, metoprolol succinate, sacubitril/valsartan, rosuvastatin, and loratadine. He has a past medical history of type 2 diabetes mellitus, hyperlipidemia, hypertension, heart failure with reduced ejection fraction (38%), and seasonal allergies. He is also a current smoker with a 15-pack-year smoking history. He has no history of myocardial infarction, ischemic stroke, peripheral artery disease, or coronary revascularization. Reviewing the cardiologist’s notes, his LDL-C is 91 mg/dL and his PREVENT Score is 10.2%.

Nick’s prescriber reviews the new guideline and pauses. Nick has several cardiovascular risk factors, but has never had an ASCVD event. Is this primary or secondary prevention? Does he need a coronary artery calcium (CAC) scan? Does his heart failure change the classification?  And is the statin dose sufficient? Rather than guess, the prescriber calls clinical pharmacist George Johnson and requests a complete lipid-management assessment.

Atherosclerotic Cardiovascular Disease  

Atherosclerosis, or the buildup of plaque within an artery, is a leading cause of death in the United States.¹ In 2023, cardiovascular disease caused 1 in 3 deaths nationwide.² As plaques grow, they progressively occlude arteries and can eventually rupture. Plaque rupture triggers local platelet-rich thrombus (clot) formation, leading to acute coronary syndromes (unstable angina or myocardial infarction [heart attack]), and sudden cardiac death. In cerebral circulation, atherosclerosis can reduce blood flow or promote thrombus formation, leading to ischemic stroke.³Two considerations guide lipoprotein management.³ The first consideration is determining if patients have established atherosclerotic cardiovascular disease (ASCVD), and the second is establishing individualized lipid goals based on the patient’s cardiovascular risk. This risk-based approach allows clinicians to tailor lifestyle interventions and initiate lipid-lowering therapy (LLT) to reduce the likelihood of future cardiovascular events. Strong evidence supports cholesterol management as the preferred method to reduce mortality and preventable cardiac deaths and improve quality of life.³

High LDL can cause catastrophic cardiovascular events and stroke later in life. Unfortunately, patients do not experience bothersome symptoms until the damage is done. New evidence suggests that higher LDL-C values starting earlier in life are strong predictors of ASCVD events in adulthood.⁴ So, screening patients early and periodically, minimizing modifiable risk factors, and initiating aggressive early lipid-lowering interventions are important.⁵ After an ASCVD event, secondary prevention is imperative to reduce the risk of another event.

Cholesterol Screening Blueprint

When clinicians examine lipid panels for patients, they need to use standardized methods for measuring lipoprotein levels.³ Total cholesterol is the sum of high-density lipoprotein (HDL, also called the good cholesterol), LDL, and the very-low-density lipoprotein (VLDL) component of triglyceride (TG) levels.⁶ The 2026 American College of Cardiology/American Heart Association (ACC/AHA) guidelines define high total cholesterol as levels greater than 200 mg/dL. LDL is considered high above 100 mg/dL. HDL should remain above 40 mg/dL in men and 50 mg/dL in women. Non–HDL is calculated by subtracting HDL from total cholesterol or adding together the LDL and VLDL, with values above 130 mg/dL considered high. Non-HDL is important in determining other lipoproteins besides LDL that can contribute to atherosclerosis.

The guidelines also recommend measuring lipoprotein(a), a cholesterol-carrying lipoprotein, at least once. Its normal levels are less than 75 nmol/L with intermediate levels between 75 and 125 nmol/L. Levels above 125 nmol/L independently increase the risk for ASCVD.⁷ Genetics heavily influences lipoprotein(a) levels, and levels remain relatively unchanged after age 5, meaning testing once is often sufficient.⁸

LDL-C measurements may underestimate the number of circulating atherogenic particles. In patients who are taking lipid-lowering therapy (LLT) and have high TG levels, cardiometabolic disease, or diabetes despite LDL-C at goal, apolipoprotein B (ApoB) is useful to determine if therapeutic intensification is warranted.³,⁹,¹⁰ ApoB is the main structural protein found in LDL, VLDL, intermediate-density lipoprotein (IDL), and lipoprotein(a) particles. Elevated ApoB at therapeutic LDL levels suggests persistent atherogenic particle burden that may increase residual ASCVD risk. Many patients with diabetes who have normal cholesterol levels also have elevated ApoB concentrations.¹¹ ApoB is a useful adjunct to traditional lipid measurements to determine if clinicians should intensify LLT.³

TGs should be below 150 mg/dL.³ While high TG levels contribute to ASCVD risk, LDL is the primary lipid target for risk reduction. However, TG levels above 500 mg/dL increase the risk of pancreatitis. Lipoprotein and TG thresholds may change based on a patient’s cardiovascular risk factors and history, meaning interventions may be appropriate even when lipid values fall below these cutoffs.³

Between 2017 and 2020, nearly 90 million adults aged 20 or older had elevated total cholesterol (200 mg/dL or greater).¹² Increasing age, comorbidities, and established ASCVD are factors that call for increased screening frequency. Additionally, one in five adolescents had an LDL above 130 mg/dL.¹³ Pediatricians should screen children between the ages of 9 and 11 at least once, and again between the ages of 17 and 21.¹² Children with obesity or diabetes may need more frequent screening. Diabetes, heart failure, hypertension, current or former smoking history, or consistently high LDL levels warrant more frequent testing. Clinicians should order lipid panels for patients with established ASCVD every 4 to 12 weeks after initiating or titrating LLT, and then every 6 to 12 months thereafter. ³

PAUSE AND PONDER: Can LDL values be too low?

Defining ASCVD, Calculating PREVENT Scoring, and Personalizing Primary Prevention Goals

Determining if patients are at risk for ASCVD (and the level of risk) or have experienced an ASCVD event is critical. Whether or not a patient has established ASCVD greatly impacts their risk for future cardiovascular events, and their treatment goals. In short, the best predictor of a future event is a past event in this case.

Because atherosclerosis affects the body systemically, clinical ASCVD can manifest in the heart and in other vascular areas.³ Locally, ASCVD can result in myocardial infarction (ST-segment elevation [STEMI] and non-ST-segment elevation [NSTEMI]), unstable angina, or the need for arterial revascularization, such as bypass or stents. Ischemic stroke or a transient ischemic attack (TIA) can result if clots embolize and travel to the brain. Finally, plaque buildup in lower extremity arteries leads to peripheral artery disease (PAD). Heart failure, hypertension, and atrial fibrillation do not, by themselves, constitute clinical ASCVD. Patients with these conditions who have no established ASCVD and should not receive lipid-lowering therapy for secondary prevention.

Before clinicians can establish an individualized LDL-C target, they must first calculate the patient’s Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) score.¹⁴ For patients aged 30 to 79 with an LDL-C of 70 to 189 mg/dL, the PREVENT score gauges patients’ 10- and 30-year ASCVD risk to determine optimal LDL-C targets and whether LLT is warranted. (The AHA provides an online calculator here: https://professional.heart.org/en/guidelines-and-statements/prevent-calculator.) The scoring system estimates an individual’s percentage risk of cardiovascular disease using age, systolic blood pressure, total cholesterol, HDL, estimated glomerular filtration rate, and body mass index (BMI).¹⁴ These factors guide LLT initiation. Clinicians can also input comorbidities such as diabetes, current smoking, or patients’ current use of lipid-lowering or antihypertensive medications. The scoring system breaks patients into four categories.³

• Low-risk patients have a 10-year risk of less than 3%.
• In borderline-risk patients who have a 3% to less than 5% risk, clinicians should discuss the risks versus benefits of initiating LLT with the patient.
• For intermediate-risk patients (5% to less than 10%), LLT is indicated, with moderate-high intensity statins preferred.
• High-risk patients with a 10% or greater PREVENT score should start a high-intensity statin or optimize LLT with other medications.

In patients who have not experienced an ASCVD event, primary prevention strategies focus on reducing cardiovascular risk using less intensive interventions with higher LDL treatment thresholds. Primary prevention targets also depend on patient-specific risk factors. Risk factors include

• Age 65 years or older
• Chronic kidney disease
• Current smoker
• Diabetes
• Heart failure
• Heterozygous familial hypercholesterolemia
• Hypertension
• LDL value above 100 mg/dL despite optimized LLT

For patients who do not have these risk factors, an LDL goal of below 100 mg/dL is adequate to reduce their risk of ASCVD. For patients at high risk for ASCVD (PREVENT score 10% or higher), clinicians should target an LDL goal of below 70 mg/dL.³ Prior guidelines favored less stringent goals for primary prevention, but lower LDL levels have been consistently linked to decreased ASCVD risk.

Personalizing Secondary Prevention of ASCVD

In patients with established ASCVD, the new ACC/AHA guidelines recommend aggressive lipid management—these patients are at the highest risk of additional ASCVD events. Secondary prevention targets also depend on defining patients as very high risk for another ASCVD event or not. Very high risk is defined as

• 2 or more previous major ASCVD events, or
• 1 major ASCVD event and 2 or more high-risk conditions (defined in primary prevention)

The target for those at very high risk is an LDL of less than 55 mg/dL.³ The guidelines also indicate that an LDL goal of less than 70 mg/dL is acceptable for patients without high-risk factors for another ASCVD event. However, most patients require lower LDL targets. Evidence suggests that there is no clear lower LDL threshold at which LDL reduction harms patients. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) and Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trials demonstrated that patients with LDL-C values below 30 mg/dL experienced the lowest rates of cardiovascular events without an increase in adverse safety outcomes.¹⁵,¹⁶ So, clinicians can intensify LLT to achieve very low LDL levels without increasing safety concerns.

For all patients, a TG level of below 150 mg/dL is optimal, but slight elevations contribute less to ASCVD risk than LDL-C elevations do. Figure 1 depicts primary and secondary prevention cholesterol goals.

Figure 1. Cholesterol Targets for Primary and Secondary Prevention of ASCVD

George begins by confirming that Nick has no established ASCVD. Although diabetes, hypertension, HFrEF, and smoking increase his cardiovascular risk, none converts his treatment to secondary prevention. So, Nick is receiving LLT for primary prevention. A PREVENT score of 10.2% puts him in the high-risk category, for which the LDL goal is below 70 mg/dL.

SIDEBAR: When to Reclassify with Coronary Artery Calcium (CAC) Scoring?¹⁷,¹⁸

Coronary Artery Calcium (CAC) refers to calcium deposits within the heart’s arterial walls. This noninvasive imaging test performed with a noncontrast cardiac scan is specific to atherosclerotic plaques, meaning it is a precise way to detect early cardiovascular disease. CAC at any level indicates subclinical coronary atherosclerosis, but it does not transform the patient into someone with clinical ASCVD or automatically place everyone into the same treatment category. CAC is principally a selective risk-reclassification tool when the treatment decision remains uncertain.

Coronary artery calcium (CAC) is specific to atherosclerotic plaques and strongly predicts ASCVD risk. It can help refine risk estimates. In adults without established ASCVD who have a borderline or intermediate 10-year PREVENT-ASCVD risk (3% to less than 10%), CAC measurement may be considered when uncertainty remains about whether to initiate lipid-lowering therapy. CAC also guides treatment in asymptomatic men aged 40 years and older and women aged 45 years and older previously not receiving LLT. In patients with CAC scores greater than 0 Agatston Units (AU; a score that reflects both the area and density of calcified plaque in the coronary arteries) who are at borderline risk, clinicians should initiate LLT.

Interestingly, elite endurance athletes can have increased CAC scores without significant risk for atherosclerosis.¹⁹,²⁰ However, increased plaque calcification may serve a cardioprotective role, as calcified plaques are more stable and less likely to rupture and cause thrombosis than lipid-rich, vulnerable plaques. Further research is needed to clarify this association. Athletes with elevated CAC scores should not stop exercising, as exercise is cardioprotective.²⁰

The prescriber asks if a CAC scan would reclassify Nick’s ASCVD risk. George explains that a scan is unlikely to change how Nick is treated. Nick’s PREVENT score, age, and concurrent conditions are clear indications for LLT. A CAC scan is useful if providers are uncertain about initiating LLT, not if patients are already indicated.

Special Population Lipid Targets

Many patients’ concurrent conditions influence recommended lipid goals. For example, primary ASCVD prevention for adults with diabetes has an LDL goal of below 100, or below 70 in the presence of high-risk factors or a PREVENT score of 5% or higher.²¹ Diabetes significantly increases the risk of ASCVD, warranting early guideline-directed risk assessment and lipid-lowering interventions by clinicians.²² Chronic kidney disease, heart failure, and HIV also warrant early LDL lowering, targeting levels under 100 mg/dL if patients have no additional risk factors and under 70 mg/dL in higher-risk patients.³

Patients older than 75 may require individualized lipid management rather than strict adherence to LDL targets. LLT still reduces the risk of major cardiovascular events, but data are limited on lower lipid levels for patients in this age group.²³ While LLT is safe and effective in this population, evidence supporting very low LDL targets is more limited. Poor functional status, frailty, and polypharmacy put these patients at an increased risk for adverse effects and potential injury. Clinician-based decision-making is essential to weigh the cardiovascular benefits of stringent lipid targets against the potential negative impact on patients’ quality of life.²⁴ In patients with limited life expectancy, the risk of a major cardiovascular event is low. So, if patients experience negative effects from aggressive lipid management, clinicians should consider less intensive management.

In pregnant patients, cholesterol targets increase with each trimester of gestation. Maternal lipid levels progressively increase as the fetus grows, with triglycerides demonstrating the largest increase. Consequently, standard lipid goals are not applicable to this population, so the need for LLT is clinician-guided and only warranted in very high-risk individuals.²⁵

Current evidence has not established a lower LDL threshold at which treatment becomes harmful. Patients at very high ASCVD risk may benefit from LDL levels below 30 mg/dL, provided therapy is clinically indicated, tolerated, and monitored. All clinicians need to remember that “lower is better” does not mean “lower everyone’s cholesterol levels indiscriminately.”

PAUSE AND PONDER: Which lipid-lowering medications bypass hepatic metabolism and may offer advantages in select patients with hepatic or renal dysfunction?

Lifestyle Interventions

Multimodal lifestyle modifications are the backbone of any lipid-lowering regimen, and prescribers should initiate them in all patients who meet the criteria for intervention.³ Dietary modifications emphasize consumption of fruits, vegetables, legumes, whole grains, fiber, and foods with low saturated fats and high mono- and poly-unsaturated fats. To examine the optimal diet to lower LDL, researchers compared the Mediterranean diet to a vegan diet.²⁶ At 16 weeks, patients on a vegan diet decreased their LDL by an average of 15 mg/dL, while the Mediterranean diet failed to show a statistically significant decrease. These data are limited by small sample size—only 62 participants—so more data is needed.²⁶ However, many patients prefer diets that include meat and meat products, rendering vegan diets unsustainable. Any nutritional intervention that lowers LDL and weight is beneficial, provided patients adhere to the diet indefinitely. When coupled with other lifestyle modifications, dietary modifications can lower LDL and reduce the risk of developing ASCVD. Triglyceride-lowering diets decrease added sugars, refined carbohydrates, saturated fats, and alcohol—these modifications can lower TG levels by over 70%.²⁷

Weight loss significantly decreases LDL and TG levels as well. A meta-analysis of 73 randomized controlled trials with more than 32,000 participants discovered that for every kilogram (2.2 pounds) of weight lost, LDL decreases by up to 1.3 mg/dL and TG levels decrease by 4 mg/dL.²⁸ The AHA recommends 150 minutes or more of moderate- to high-intensity aerobic exercise with resistance training to reduce the likelihood of cardiovascular events.³ A meta-analysis conducted by the AHA demonstrated that weekly moderate-intensity exercise decreased the risk of cardiovascular mortality by 23%.²⁹ The analysis followed 3.4 million patients over 12 years, and found that 150 minutes of moderate-intensity aerobic exercise per week yielded a mortality benefit and a 17% decrease in new cardiovascular disease. Combining interventions can drastically lower LDL levels and, rarely, eliminate the need to initiate LLT altogether.²⁹

Lipid-Lowering Medications—Statins

Medications augment lifestyle modifications when lifestyle modifications fail to decrease cholesterol below accepted thresholds. Statins are the backbone of LLT due to their robust ability to decrease LDL.⁶ Low-, moderate-, and high-intensity statins decrease patients’ LDL values by 30%, 30-49%, and 50% or more, respectively. Figure 2 depicts statin intensity categories, available drugs, and equipotent statin doses.³⁰

Figure 2. Statin Intensity Classifications and Equipotent Daily Doses

Statins reduce LDL by competitively inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme, the rate-limiting enzyme in hepatic cholesterol synthesis.³¹ Statin-induced enzyme inhibition decreases hepatic cholesterol synthesis, meaning less LDL circulates throughout the body. After the initial LDL reduction achieved with the starting dose, each subsequent statin dose doubling lowers LDL by an additional 6% to 8%.³² Statins also decrease inflammation through antioxidant properties and stimulate the immune system. The liver primarily metabolizes statins. The liver cytochrome P450 (CYP) 3A4 enzyme metabolizes atorvastatin, simvastatin, and lovastatin, whereas CYP2C9 metabolizes fluvastatin and rosuvastatin to a lesser extent. Statins are eliminated through both hepatic and renal pathways, although the extent of renal excretion varies by agent. Therefore, statin dose adjustments may be necessary in patients with liver or kidney impairment. Statins are contraindicated in patients with active liver disease. Simvastatin is strictly contraindicated with CYP3A4 strong inhibitors, and has a maximum daily dose of 10 mg with diltiazem, verapamil, and dronedarone.³³ The maximum simvastatin daily dose for patients taking amiodarone, amlodipine, and ranolazine is 20 mg. Technician recognition of new drug interactions is crucial to prevent adverse effects and decreased efficacy. Pharmacy technicians can identify new statin drug interactions by reviewing medication profiles, recognizing interaction alerts, and promptly notifying pharmacists of suspected interactions to prevent adverse effects. Clinicians should dose adjust statins in patients taking CYP enzyme inducers or inhibitors.

Common Strong CYP3A4 inhibitors include:

• Ritonavir
• Itraconazole
• Ketoconazole
• Cobicistat
• Grapefruit Juice

Common Strong CYP3A4 and CYP2C9 inducers include:

• Rifampin
• Carbamazepine
• Phenytoin
• Phenobarbital

Common Strong CYP2C9 inhibitors include:

• Sulfamethoxazole/Trimethoprim
• Amiodarone
• Fluconazole

Statin-associated muscle symptoms (SAMS) are the most commonly reported adverse effects associated with statin therapy.³¹ SAMS manifests as muscle aches, pain, and soreness primarily in the larger muscle groups of the body—the thighs, hips, and shoulders. High statin doses, advanced age, decreased thyroid function, diabetes, fibromyalgia, and CKD contribute to a patient’s risk of developing SAMS. The incidence of SAMS increases greatly with concurrent fibrates, which are medications that reduce high TGs. Gemfibrozil is contraindicated with some statins (e.g., simvastatin) and should generally be avoided because it increases the risk of SAMS. ³⁴

As noted above, strong evidence suggests that most muscle symptoms are not attributable to statins.³⁵ Authors of a meta-analysis of 19 trials and 35,000 patients concluded that up to 90% of muscle symptoms attributed to statin therapy were not due to the medication.³¹ Instead, underlying conditions and advanced age played a large role in the misinterpretation. To classify a patient as statin intolerant, clinicians should rechallenge with at least two statins at the lowest approved dose.³⁵ Additionally, switching from statins that are highly lipid-soluble like atorvastatin and simvastatin to a highly water-soluble statin like rosuvastatin could decrease muscle symptoms, but data are inconsistent.³⁶ When initiating statins, clinicians should inform patients that the risk of statin-associated adverse effects is small and the cardiovascular benefits far outweigh the negative aspects of the medication. If patients experience severe muscle symptoms, creatine kinase measurements should be taken to rule out rare, life-threatening muscle breakdown like rhabdomyolysis.³¹

Other rare adverse effects include mild nausea, diarrhea, or constipation, and small increases in blood sugar.³¹ Advising patients to take the medication with food and in the evening alleviates stomach discomfort. For statins with shorter half-lives (simvastatin and lovastatin), evening administration is traditionally recommended because hepatic cholesterol synthesis is greatest overnight. However, statins with longer half-lives, such as atorvastatin, and rosuvastatin maintain therapeutic activity throughout the day and may be taken at any time. Figure 3 summarizes statin administration instructions and counseling.

The prescriber discusses doubling Nick’s rosuvastatin dose to 10 mg. George points out that rosuvastatin 5 mg and 10 mg are both moderate-intensity doses, and because Nick’s LDL remains above his goal, his dose should be increased to a high-intensity dose. George recommends increasing to rosuvastatin 20 mg, granted Nick agrees with the plan and has no contraindications. George also recommends obtaining a repeat lipid panel in 4 to 12 weeks to monitor adherence and response.

Nonstatin Lipid-Lowering Medications

A staple of oral nonstatin therapy, ezetimibe (Zetia) does not decrease cholesterol synthesis—instead, it inhibits intestinal absorption of dietary cholesterol by blocking the Niemann-Pick C1-Like-1 (NPC1L1) transporter. ³⁷ Ezetimibe decreases LDL levels by 13% to 20%, making it a useful adjunct to statin therapy, or as monotherapy for less intensive lipid lowering.³⁷ Prescribers should not use ezetimibe in people who have moderate and severe hepatic impairment, but the medication is generally well tolerated. Limited adverse effects include headache, congestion, and sore throat—a rarity for the majority of patients.

For patients who require drastic reductions in LDL with or without statin therapy, subcutaneous proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor injections decrease LDL-C by 45-65%.³ The medication blocks PCSK9 enzymatic activity, raising levels of LDL-receptors in the body, allowing the liver to remove more LDL from the bloodstream. When the ACC/AHA published cholesterol guidelines in 2018, clinicians lacked sufficient evidence to determine the long-term effects of the monoclonal antibody PCSK9 inhibitors evolocumab (Repatha) and alirocumab (Praluent).⁶ Today, more recent studies demonstrate that evolocumab and alirocumab significantly reduce heart attack, stroke, and cardiovascular death over a five-year period.³⁸,³⁹ Injected into the abdomen, thigh, or upper buttock once every few weeks, these medications offer less frequent dosing than any other lipid-lowering medication. Patients rarely experience significant adverse effects; injection-site reactions and hypersensitivity reactions occur most frequently.⁴⁰

Additionally, the 2018 AHA/ACC cholesterol guidelines did not include inclisiran (Leqvio), a novel small-interfering RNA PCSK9 inhibitor that blocks production of the PCSK9 protein in the liver.⁶ The Lancet Diabetes & Endocrinology published data demonstrating the twice-yearly injection provided sustained LDL reductions and medication tolerability in patients over a four-year period.⁴¹ The updated 2026 AHA/ACC guidelines recommend inclisiran as an alternative to monoclonal antibody PCSK9 inhibitors, but high cost and absence of completed cardiovascular outcome evidence are barriers for initiation. ³ Another difference between inclisiran and the monoclonal antibody PCSK9 inhibitors evolocumab and alirocumab is that a healthcare professional must administer inclisiran. For patients who want less frequent administration or prefer not to inject their medication themselves, inclisiran is a useful alternative.

PCSK9 inhibitors excel in older adults. Researchers at the Erasmus MC Cardiovascular Institute concluded that patients older than 70 taking evolocumab and alirocumab had medication safety and efficacy profiles similar to those under 70.⁴²

In July 2026, the FDA approved the first oral PCSK9 inhibitor, enlicitide (Lipfendra), but the guidelines do not address the medication because it received approval after they were published.⁴³ Decreasing LDL by 56% over 24 weeks, the medication has similar efficacy to injectable PCSK9 inhibitors, but is roughly half the out-of-pocket cost of injectables at $315 per month.⁴⁴ PCSK9-targeting therapies have demonstrated efficacy in lowering LDL-C regardless of formulation, including injectable monoclonal antibodies, injectable small interfering RNA (siRNA), and oral agents.

Clinicians can confidently prescribe PCSK9 inhibitors or ezetimibe as an adjunct or alternative to traditional statin therapy due to their robust reductions in LDL and low adverse effect profile.

The 2026 AHA/ACC guidelines added bempedoic acid (Nexletol), an adenosine triphosphate citrate lyase (ACL) inhibitor, as an alternative for statin-intolerant patients, or an alternative medication.⁴⁵ Bempedoic acid acts two enzymatic steps upstream from statins and reduces LDL by around 20%.⁴⁶ However, bempedoic acid is metabolized via glucuronidation and not a CYP enzyme, but data regarding dose adjustments is limited. Adverse effects include cold or flu-like symptoms, muscle spasms, back and stomach pain. In CLEAR Outcomes, which enrolled 13,970 statin-intolerant patients, bempedoic acid reduced the relative risk of major adverse cardiovascular events by 13% over a median follow-up of 40.6 months. The trial included patients at high risk for ASCVD or with established ASCVD who reported being unable or unwilling to receive statins due to adverse effects. After treatment with bempedoic acid, LDL values dropped from an average of 139 mg/dL to 107 mg/dL, a 30 mg/dL decrease compared to placebo.⁴⁵ Bempedoic acid is also available with ezetimibe as a once-daily fixed-dose combination tablet (Nexlizet; bempedoic acid 180 mg/ezetimibe 10 mg).⁴⁷

Finally, bile acid sequestrants—colesevelam, colestipol, and cholestyramine—are members of a lipid-lowering medication class that decreases LDL without being systemically absorbed, making them a viable option for pregnant patients.³ At full doses, they lower LDL by 15% to 30%.⁴⁸ Gastrointestinal adverse effects like nausea, vomiting, constipation, and bloating prevent some patients from reaching higher doses. Bile acid sequestrants should generally be avoided with TG levels above 300 mg/dL, but contraindications vary by agent. Dosage formulations may also contribute to intolerance. All three available agents come as oral powders for suspension which some patients describe as having a chalky texture or bitter aftertaste. However, colesevelam and colestipol have tablet formulations. Patients with partial biliary obstruction and those who are pregnant or planning to become pregnant may benefit from this medication class. However, more effective therapies are preferred for most other patients.

Administration instructions, storage, and patient counseling points can be found in Figure 3.

Figure 3. Lipid-Lowering Therapy Quick Guide³

Triglyceride Lowering Medications

Statins remain the foundation for TG-lowering therapy.³ While fibrates, niacin, and prescription-strength omega-3 fatty acids have been shown to reduce TG levels, they fail to reduce the risk of cardiovascular events and ASCVD.⁴⁹ The Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT) trial demonstrates that icosapent ethyl (Vascepa) is beneficial in certain patient populations with high TG but normal LDL.⁵⁰  In patients with TG levels surpassing 1,000 mg/dL, the apolipoprotein C-III (apoC-III) inhibitor reduces TG levels and the risk for pancreatitis by 63%.⁵¹

Eight weeks later, Nick reports no adverse effects from rosuvastatin 20 mg daily. His repeat LDL has decreased to 78 mg/dL—closer to his goal but still above 70 mg/dL. The prescriber calls George again to ask what the next steps should be. George tells the prescriber that because Nick only needs modest additional LDL lowering, ezetimibe 10 mg is warranted. Ezetimibe is a once-daily pill that can be taken at the same time as Nick’s statin, is generally well-tolerated, and can lower LDL-C by an additional 13% to 20%.

PAUSE and PONDER: If a patient who has an LDL of 53 mg/dL on a moderate-intensity statin has had a heart attack, is a high-intensity statin warranted?

Lipid-Lowering Therapy Treatment Algorithm

With defined lipid targets, initiating or optimizing LLT is crucial to reduce patients’ risk for ASCVD.

For patients without established ASCVD and an LDL of 70 to 189, the 2026 AHA/ACC guidelines recommend using the PREVENT scoring system to estimate ASCVD risk.³ The guidelines recommend initiating a statin in patients with an intermediate risk (5%) or above, while those with borderline risk (3% to less than 5%) should engage in shared decision-making with their clinician regarding treatment initiation. The guidelines support moderate-intensity statin initiation in intermediate risk patients, with high-intensity statins indicated in higher risk patients. Unlike previous guidelines, which emphasized percent LDL reduction from baseline, the 2026 recommendations incorporate individualized LDL targets.⁶ If maximally tolerated statin therapy fails to reduce a patient’s LDL target, additional therapy—ezetimibe or a PCSK9 inhibitor—is necessary to reduce all-cause mortality and CV events.^52,53,54 Bempedoic acid is a possible alternative, but ezetimibe and PCSK9 inhibitors alongside statins provide greater LDL reductions and are better tolerated.³

The 2026 AHA/ACC cholesterol guidelines recommend initiation or titration to a high-intensity statin for all patients with established ASCVD, regardless of comorbidities, risk factors, or baseline LDL.³ As previously discussed, if patients remain above the LDL goal of 55 mg/dL, clinicians should add ezetimibe, a PCSK9 inhibitor, or bempedoic acid.³

Age and PREVENT score guide statin therapy for patients with diabetes who do not have established ASCVD.³ The 2026 AHA/ACC guidelines recommend initiating at least a moderate-intensity statin, regardless of PREVENT score or LDL. For patients aged 30 to 39 years with PREVENT scores greater than 3%, clinicians should discuss cardiovascular risk reduction before considering moderate-intensity statin therapy. Beyond 75 years old, clinicians should engage in benefit-risk discussions with patients regarding statin therapy.³

Several lipid-lowering medications should be avoided in pregnant patients or patients who wish to become pregnant. Technician and pharmacist recognition of potentially harmful medications to the fetus, known as teratogens, is vital to prevent birth defects, premature births, and fetal harm. Because lipid management goals change with each trimester, lifestyle management is the safest option and can effectively manage high LDL and TG levels throughout pregnancy.³ Women should stop statins one to two months before attempting to become pregnant or as soon as pregnancy is discovered. Some studies suggest statins decrease birth weights, and increase the risk of preterm birth, eclampsia, and preeclampsia.^55,56 Newer data suggests that statin exposure during pregnancy is not associated with major fetal defects, and that spontaneous abortion rates could reflect other confounding factors like maternal comorbidities.⁵⁶

More data is needed to make definitive conclusions, but in 2021 the FDA revised statin warnings, indicating high-risk pregnant patients with established ASCVD could continue statin therapy when appropriate.⁵⁷ Statins should still be avoided when breastfeeding. Clinicians should continue statin therapy only after conducting an individualized risk assessment and engaging in shared decision-making with the patient. Limited evidence for alternative lipid-lowering therapies leaves bile acid sequestrants (BAS) as the only evidence-based medication class for cholesterol reduction during pregnancy because they are not systemically absorbed.³ Unfortunately, BAS can impair fat-soluble vitamins (vitamin A, D, E, K) and folic acid, which can impact the fetus, maternal health, and milk production.⁵⁸ To address TG levels above 500 mg/dL, fibrates and prescription-strength omega-three ethyl esters (DHA and EPA) can be initiated after the first trimester.⁵⁹

Dialysis status determines the optimal lipid-lowering therapy for patients with chronic kidney disease (CKD).³ Guidelines support primary prevention with a moderate-intensity statin with or without ezetimibe for patients 40 to 75 years old with an LDL of 70 to 189 mg/dL for patients not on dialysis. In contrast, statins have not demonstrated cardiovascular outcome benefits in patients receiving dialysis.⁶⁰  

Finally, patients with human immunodeficiency virus (HIV) are at heightened risk for ASCVD, particularly heart attack.⁶¹ Moderate-intensity statins reduce ASCVD risk in this population. However, many antiretroviral medications strongly inhibit CYP3A4, requiring clinicians to monitor for drug interactions and statin-related adverse effects.

The 2026 AHA/ACC triglyceride recommendations remain mostly unchanged from the 2018 guidelines.^3,6 LDL management through LLT decreases TG levels concurrently. In most cases, adequate LDL control and lifestyle management maintain healthy TG levels below 150 mg/dL. One major difference is the inclusion of icosapent ethyl (Vascepa) in the 2026 guidelines. The REDUCE-IT trial observed the effect icosapent ethyl had on patients with established ASCVD or diabetes with risk factors for ASCVD. Patients’ TG levels were between 135 and 499 mg/dL and LDL-C values between 41 and 100 mg/dL.⁵⁰ When added to prior statin therapy, twice-daily icosapent ethyl reduced the relative risk of major cardiovascular events by over 20%. The medication also decreased TG levels by 40 mg/dL. So, clinicians can add icosapent ethyl in patients with diabetes and ASCVD risk factors or with established ASCVD already on statin therapy with high triglycerides. In patients with TG levels exceeding 500 mg/dL or familial chylomicronemia syndrome, olezarsen is indicated to reduce the risk of pancreatitis.⁶² Other TG-lowering therapies remain last line and are not recommended in the 2026 guidelines.³

Whether preventing or managing ASCVD, clinicians must individualize lipid goals and consider special populations to reduce cardiovascular events and mortality.³

SIDEBAR: Do patients with heart failure require lipid-lowering therapy? ^3,63,64,65

Heart failure alone is not an indication to initiate statin therapy. Irrespective of ejection fraction, the 2026 AHA/ACC guidelines quantify heart failure as a high-risk cardiovascular condition. Several conditions add to the progression of heart failure, with coronary artery disease being a major contributor. Coronary atherosclerosis restricts blood flow to the heart, increasing the risk of myocardial infarction. The resulting loss of viable cardiac cells triggers compensatory overactivation of the remaining healthy tissue, progressively impairing cardiac function and contributing to the development of heart failure. Lipid-lowering therapy may reduce heart failure-related hospitalizations in some patients with heart failure. However, without another indication for LLT, statins do not reduce sudden cardiac death and major cardiovascular events.

Ten weeks after adding ezetimibe, Nick’s LDL is 65 mg/dL. He reports remaining adherent to his medications and has no new adverse effects. George recommends continuing the regimen and reinforces smoking cessation and lifestyle modifications. The prescriber thanks George for the assessment, as Nick has reached his LDL goals without unnecessary testing or premature initiation of costly injectable medications.

Optimizing Access to New Lipid-Lowering Therapy

The cost of new lipid-lowering medications can prevent patients from receiving guideline-directed treatment. Out-of-pocket costs for bempedoic acid and PCSK9 inhibitors can exceed $700 and $500 per month, respectively.^66,67,68 Inclisiran presents additional coverage challenges because healthcare professionals must administer it in a clinical setting. Patients in low socioeconomic groups can struggle to achieve recommended lipid goals due to cost. Even insured patients frequently encounter stringent prior authorization requirements.⁶⁹ Insurers frequently require medical records, specialist evaluation, and step-therapy requirements with statins before approving PCSK9 inhibitors or bempedoic acid.

Pharmacists and pharmacy technicians can increase medication access by helping patients reduce financial barriers. Many manufacturers offer copay cards that reduce out-of-pocket costs for privately insured patients.⁷⁰ Some manufacturers also provide patient assistance programs that offer free or reduced-price medications.^71,72 These programs often require income documentation and provider approval. Evolocumab’s manufacturer, Amgen, even offers patients a one-time, one-month free trial of evolocumab.⁷³ Coverage for these medications can reduce monthly costs to as little as $50 per month.

Additionally, Medicare Part D has an annual out-of-pocket spending cap of $2,100, meaning covered lipid-lowering therapies cost patients little or nothing after the cap is reached.⁷⁴ Pharmacists and technicians should familiarize themselves with available assistance programs and insurance requirements to identify eligibility and serve patients better. These resources improve medication access, boost adherence, and help patients achieve guideline-directed cholesterol goals to reduce ASCVD risk.

CONCLUSION

The update to the 2026 AHA/ACC Cholesterol Management Guidelines offers new guidance to clinicians on how to optimize lipid-lowering interventions to achieve individualized cholesterol targets. The guidelines equip pharmacists to calculate 10-year ASCVD risk, personalize patients’ estimated risk using the PREVENT-ASCVD equation, reclassify risk with CAC, and reassess treatment success. As newer lipid-lowering therapies are incorporated into standard practice, pharmacists should understand the updated treatment algorithm to improve medication selection and reduce ASCVD events. Pharmacy technicians can enhance patient care through recognition of potential drug interactions, identification of adverse effects, and improvement of medication access.

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INTRODUCTION

On a busy July afternoon, Jillian, a woman in her mid-40s, approaches the pharmacy counter looking tired and jittery. She glances toward the back of the store, as though making sure she knows where the restroom is.  When the pharmacist asks how she can help, she says quietly, "I started having diarrhea more than a week ago." At first, she assumed she had a stomach virus and expected it to resolve in a day or two. Instead, the diarrhea has become more frequent. "It's explosive," she says. "When I have to go, I have to go right now. I haven't been more than a few minutes from a bathroom in days."

She reports having six to eight episodes of watery diarrhea each day, accompanied by cramping, bloating, nausea, and profound fatigue. She has missed three days of work because she is afraid she won't make it to a bathroom in time. She has been drinking plenty of fluids, but feels weak and has little appetite.

She has tried bismuth subsalicylate without relief and wonders whether a stronger over-the-counter medication might finally stop the diarrhea. As the pharmacist asks additional questions, she mentions that she and her husband have been trying to eat healthier. Over the past two weeks, they have eaten several prepackaged salad kits, fresh berries, and homemade smoothies made with fresh basil from a neighborhood farm stand.

The pharmacist considers this history. Acute viral gastroenteritis usually resolves within a few days. Persistent, profuse watery diarrhea during the summer months suggests another possibility.

PAUSE and PONDER: What additional questions should the pharmacy team ask? Which features of this patient's illness warrant referral for medical evaluation?

Seasonal Spotlight: Cyclosporiasis

Cyclosporiasis is a seasonal intestinal infection caused by the microscopic parasite Cyclospora cayetanensis.^1,2 (Table 1 explains how parasites differ from bacteria or viruses.) Although cases occur every year, infections increase during the spring and summer when contaminated fresh produce enters the food supply.³ In 2026, the United States (U.S.) is experiencing a substantial multistate increase in reported cases, prompting investigations by the Centers for Disease Control and Prevention (CDC), the U.S. Food and Drug Administration (FDA), and multiple state health departments.^2-6 The SIDEBAR lists facts every pharmacy employee needs to know.

SIDEBAR: Fast Facts about Cyclosporiasis^1,7-9

• Cause: Infection with the protozoan parasite Cyclospora cayetanensis.
• Transmission: Consumption of food or water contaminated with Cyclospora oocysts—most often in the US via fresh produce.
• Person-to-person spread: Unlike many diarrheal illnesses, freshly shed Cyclospora oocysts require days to weeks in the environment before they become infectious, making direct transmission unlikely.
• Incubation period: Typically about one week (range, two days to two weeks).
• Hallmark symptom: Profuse, watery diarrhea that is often described as explosive.
• Other symptoms: Abdominal cramping, bloating, nausea, fatigue, loss of appetite, weight loss, and low-grade fever. Symptoms may persist for weeks or relapse if untreated.
• Diagnosis: Stool testing specifically ordered to detect Cyclospora. Most commercial laboratories have this as part of their multiplex PCR testing.  Additionally, up to three days of testing is recommended after negative tests, as oocysts shed inconsistently.
• Treatment: Trimethoprim-sulfamethoxazole (TMP-SMX) for 7 to 10 days is the first line treatment. Supportive care includes aggressive fluid replacement. Patients with sulfonamide allergy require alternative management because no highly effective substitute has been established.

This Outbreak Is Different

As of early July 2026, the CDC confirmed domestically acquired cases in at least 37 states, while several affected states reported substantially larger numbers through their own surveillance systems. Michigan has experienced an especially large outbreak, and investigations to identify the contaminated food source remain ongoing. No single food item had been implicated as of July 11, 2026.⁷ Many cyclosporiasis outbreaks are never linked to a single food source because traceback investigations and testing of fresh produce are often difficult.

Although the source of the current outbreak has not been identified, previous U.S. outbreaks have been associated with fresh produce, including^10-12

• Bagged salad mixes
• Cilantro
• Fresh basil
• Raspberries and blackberries
• Romaine and mesclun lettuce
• Snow peas

Identifying Possible Cyclospora Infection

Patients often mistake cyclosporiasis for viral gastroenteritis. The difference is time.¹ Most cases of norovirus, the most common form of viral gastroenteritis, improve within 24 to 72 hours. In contrast, patients with cyclosporiasis often report that their diarrhea has persisted for a week or longer and may even improve briefly before returning. Why? Cyclospora cayetanensis has an unusual life cycle, described in Figure 1, that explains many of the infection's clinical characteristics and public health challenges.

Although first recognized in humans in 1977, scientists spent more than a decade debating this parasite’s identity.^13-15  At various times, the organism was referred to as "coccidia-like bodies," reflecting its resemblance to coccidial parasites, or "cyanobacterium-like bodies," and some investigators even suspected it was a blue-green alga before it was formally identified as Cyclospora cayetanensis in 1993.  Large multistate outbreaks linked to imported Guatemalan raspberries in 1996 transformed Cyclospora from an obscure tropical parasite into a major foodborne pathogen of international public health importance.^13-15

PAUSE and PONDER: Why is person-to-person transmission of Cyclospora cayetanensis not possible?

People become infected by swallowing sporulated oocysts—the environmentally mature form of the parasite—on contaminated food or in contaminated water.^16,17 After ingestion, the parasite infects cells lining the small intestine, where it multiplies and causes inflammation that leads to watery diarrhea and other gastrointestinal symptoms. Infected individuals shed unsporulated (immature) oocysts in the stool.16,17 Freshly passed oocysts are not immediately infectious. Instead, they must remain in the environment for one to two weeks under favorable conditions before they mature (sporulate) and become capable of infecting another person.^3,16

This delay explains two important features of cyclosporiasis^1,3:

• Person-to-person transmission is uncommon because freshly shed oocysts cannot immediately infect another individual.
• Fresh produce is a common vehicle for infection because fruits, vegetables, and herbs can become contaminated in the field or during irrigation, allowing oocysts time to mature before the food is harvested and consumed.

Jillian seems relieved to have a possible diagnosis and a plan to see her primary care provider. Suddenly, she looks worried again. She says, “I feed some raw fruits and vegetables to my dogs! Will they get this?”

Here’s a not-so-fun fact: humans are the only known host for Cyclospora cayetanensis.16 Jillian’s dogs will not become ill from Cyclospora cayetanensis. Contamination of food or water occurs through exposure to human feces rather than infected animals.16 How does human fecal contamination get onto produce? See the SIDEBAR.

SIDEBAR: How Does Human Fecal Material End Up on Fresh Produce?^5,6

Most people picture an obvious sanitation failure, but contamination is usually much less dramatic.^6,18 Fresh produce can become contaminated when irrigation or wash water is contaminated with sewage, when an infected worker harvests or packs produce without adequate hand hygiene, or when toilet or handwashing facilities are unavailable or improperly maintained. Contamination may also occur during harvesting, packing, or processing if proper hygiene and sanitation practices are not followed.^6,18 Food safety is ultimately about human behavior and infrastructure, not just microorganisms.

Because humans are the only known host for Cyclospora cayetanensis, preventing contamination depends on worker health and hygiene, safe water sources, proper sewage disposal, and field sanitation.^6,18 The FDA's Produce Safety Rule requires covered farms to provide toilet facilities, handwashing stations, employee hygiene training, and procedures designed to prevent produce contamination.^6,18

Recognizing Cyclosporiasis: Symptoms and Patient Clues

Jillian’s case is classic. Cyclosporiasis’s hallmark symptom is profuse, watery diarrhea, often described as explosive.8,19 Patients frequently report an overwhelming urgency to reach a restroom and may avoid work, social activities, or travel because they cannot predict when another episode will occur. Other symptoms commonly include abdominal cramping, bloating, nausea, loss of appetite, fatigue, low-grade fever, and weight loss. Vomiting is less common than diarrhea.^8,19

The illness’s prolonged nature places patients—particularly older adults and individuals with underlying medical conditions—at risk for dehydration and electrolyte abnormalities. Although healthy adults usually recover without long-term complications, prolonged diarrhea can lead to dehydration, electrolyte disturbances, and weight loss, particularly in older adults, young children, and individuals who are immunocompromised.^8,19

When a patient asks for help finding an antidiarrheal, ask a few simple questions:

• How long have the symptoms lasted?
• How many episodes do you experience each day?
• Is the diarrhea watery or bloody?
• Have over-the-counter medications helped?
• Have you recently eaten fresh berries, salad, herbs, or other raw produce?
• Have you traveled recently or attended a large gathering where food was served?

A patient like Jillian who says, "I thought it was a stomach bug, but it's been over a week and I'm still having explosive diarrhea," should be referred for medical evaluation.

Pharmacy personnel should encourage patients to seek prompt medical evaluation if they experience

• Watery diarrhea lasting more than 3 to 5 days
• Severe or persistent diarrhea accompanied by dehydration
• Inability to maintain adequate fluid intake
• Fever, bloody stools, or severe abdominal pain
• Significant weight loss
• Symptoms in an immunocompromised patient or other individual at high risk for complications

Diagnosis and Treatment

Diagnosing cyclosporiasis can be challenging because routine bacterial stool cultures do not detect Cyclospora cayetanensis, and many commonly ordered gastrointestinal multiplex PCR panels do not include this parasite. Healthcare providers should ensure that the selected diagnostic test specifically includes Cyclospora when the infection is suspected.^1,8,20 Patients with persistent diarrhea should inform their healthcare provider about the duration of symptoms, recent travel, and consumption of fresh produce. If they don’t, healthcare providers need to ask.

Diagnosis may be made by identifying the characteristic round Cyclospora oocysts (which are round and a size equivalent to one-tenth the width of a human hair) in stool specimens or, more commonly, by using molecular methods such as PCR when the selected test panel includes Cyclospora. Because infected individuals may shed relatively few oocysts—and may not shed them consistently—a single negative stool specimen does not rule out infection. Sometimes, symptomatic patients do not shed a sufficient quantity of oocysts in their stool; these patients, called low level shedders, might need to submit several specimens collected on different days.^5,20 When clinical suspicion remains high, healthcare providers may request stool samples collected on multiple days.

PAUSE and PONDER: A patient fills a prescription for TMP-SMX and says the prescriber told him to use “supportive care.” He doesn’t really know what that means. What would you say?

Treatment

The treatment of choice is trimethoprim-sulfamethoxazole (TMP-SMX).8,9 For immunocompetent adults, the recommended adult regimen is one double-strength tablet (TMP 160 mg/SMX 800 mg) orally twice daily for seven to 10 days.  The pediatric dose for children older than two months is 8 to 10 mg/kg TMP and 40 to 50 mg/kg SMX per day, orally, in two divided doses for seven to 10 days. Both Bactrim and ciprofloxacin work similarly on the protozoan parasite as they do on bacteria. Bactrim inhibits its ability for folate synthesis it needs for survival, while ciprofloxacin inhibits its DNA replication. Importantly, it needs a functional immune system for cure; those with immunocompromise, it may result in stasis and secondary prophylaxis is generally recommended.^8,9

Fluid replacement is an essential component of treatment because prolonged watery diarrhea can lead to dehydration and electrolyte imbalances. The pharmacy team should encourage patients to8

• Drink small, frequent amounts of fluid rather than large volumes at one time if nausea is present.
• Use an oral rehydration solution (ORS) (e.g., Pedialyte or other commercially available ORS) when diarrhea is moderate to severe or prolonged. ORS products contain an appropriate balance of water, sugar, and electrolytes to promote intestinal absorption.
• Consume clear fluids such as water, broth, or diluted sports drinks if an ORS is unavailable. (ORS remains the preferred option.)

Some beverages may worsen diarrhea or contribute to dehydration and should be avoided, including^21-23

• Alcohol
• Excessive caffeine (coffee, energy drinks)
• Sugar-sweetened beverages such as regular soda or undiluted fruit juice, which can increase osmotic diarrhea
• Sugar-free beverages containing poorly absorbed sugar alcohols (e.g., sorbitol or mannitol), which may also worsen osmotic diarrhea
• Patients should be recommended to have ORS available at home.

Patients who are unable to keep fluids down, experience dizziness or fainting, produce very little urine, or develop signs of severe dehydration should seek immediate medical attention. Pediatric patients with any level of dehydration should seek medical attention. Patients with diabetes should monitor blood glucose more frequently during diarrheal illness because dehydration and changes in food intake may affect glycemic control. Patients who continue to have diarrhea after completing treatment—or whose symptoms recur—should contact their healthcare provider.³  Relapses are part of the disease.¹²

Over-the-counter antidiarrheal medications, may provide temporary symptomatic relief in otherwise healthy adults but do not eradicate Cyclospora cayetanensis.20 (And note that Cyclospora typically does not cause bloody diarrhea; if a patient has bloody stools or high fever, they may have an invasive bacterial infection rather than cyclosporiasis.) Patients with persistent watery diarrhea lasting more than several days should be referred for medical evaluation rather than repeatedly self-treating with over-the-counter products.²⁰ Antidiarrheals should be avoided in patients with bloody diarrhea or high fever unless directed by a healthcare provider.^8,20

Management becomes more complicated in patients with sulfonamide allergies. Research has yet to identify a highly effective alternative to TMP-SMX.⁸ Depending on the severity of the illness and the nature of the allergy, clinicians may recommend symptomatic treatment, consider an alternative antimicrobial  such as ciprofloxacin, supported by limited evidence, or pursue TMP-SMX desensitization in carefully selected patients.+

Food Safety and Prevention

Fresh produce is the most common source of infection because people often eat it raw. Previous U.S. outbreaks have been linked to cilantro, basil, raspberries, blackberries, and leafy greens.^10-12 However, any fresh fruit or vegetable exposed to contaminated irrigation water or poor sanitation practices may become contaminated. The 1996 raspberry outbreak was so large that it fundamentally changed how public health agencies investigate produce-associated outbreaks. Before then, most people associated foodborne illness with meat, eggs, or dairy—not fresh berries.^13-15

Rinsing produce under running water is recommended because it removes dirt and may reduce contamination, but it cannot be relied upon to remove or eliminate all Cyclospora oocysts.⁶ The parasite's hardy outer shell allows it to survive under environmental conditions that would eliminate many bacteria and viruses. Experts don’t recommend soap, bleach, or commercial produce washes because they have not been shown to eliminate Cyclospora and may leave harmful residues on food. Refrigeration does not kill the parasite. Freezing may reduce viability but should not be relied upon to prevent infection.⁶

PAUSE and PONDER: If washing doesn't work, why bother?

In short, washing reduces contamination, even though it doesn't guarantee safety.

Jillian listens to the information about washing vegetables, and she sighs, “We were eating better. Now we can’t even have a salad.” The pharmacist says, "I understand why you feel that way," and continues, "But I don't want this experience to keep you from eating healthy foods. The answer isn't to avoid salads forever. It's to pay attention to food recalls and practice good food safety." He also tells her, “In otherwise healthy individuals this is not fun, but it is important to continue eating healthy foods.”

Reducing Infection Risk

Although no method completely eliminates the risk of cyclosporiasis, patients can reduce their risk by²⁴

• Washing hands with soap and water before preparing or eating food.
• Rinsing fresh fruits and vegetables under running water before eating, cutting, or cooking them.
• Scrubbing firm produce (e.g., melons, cucumbers, potatoes) with a clean produce brush.
• Refrigerating perishable produce promptly.
• Separating fresh produce from raw meat, poultry, seafood, and their juices to prevent cross-contamination.
• Following FDA recalls and public health advisories during foodborne illness outbreaks.

For most healthy adults, cyclosporiasis is unpleasant but rarely life-threatening. The health benefits of eating fresh fruits and vegetables continue to outweigh the relatively low risk of infection. Patients should follow recommended food safety practices, remain aware of food recalls, and seek medical evaluation promptly if persistent watery diarrhea develops. Individuals who are severely immunocompromised should discuss additional food safety precautions—including avoiding raw produce—with their healthcare providers.

CONCLUSION

Remember Jillian? She didn't come to the pharmacy looking for an antiparasitic medication. She came looking for an antidiarrheal. The pharmacy team's greatest contribution wasn't recommending a product—it was recognizing that her symptoms didn't fit the pattern of a routine stomach virus and ensuring she received appropriate medical evaluation. Tackling outbreaks of this parasitic diarrhea is about recognizing patterns, asking the right questions, and understanding that food safety begins long before food reaches the pharmacy—or the patient.

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INTRODUCTION

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

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

GALLBLADDER DISEASE

The Gallbladder

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

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

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

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

Sidebar: Types of Gallbladder Disease^2,8

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

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

Gallstones and Acute Cholecystitis

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

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

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

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

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

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

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

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

Chronic Cholecystitis

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

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

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

Choledocholithiasis and Cholangitis

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

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

Risk Factors

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

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

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

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

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

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

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

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

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

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

TREATING GALLBLADDER DISEASE

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

Surgical Intervention: Cholecystectomy

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

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

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

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

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

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

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

Pharmacologic and Other Non-Surgical Interventions

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

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

Gallbladder Cancer²⁰

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

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

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

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

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

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

POST-OPERATIVE CONSIDERATIONS AND THE PHARMACY TEAM

Post-Cholecystectomy Syndrome

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

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

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

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

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

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

Table 3. Bile Acid Sequestrants^26,27

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

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

Medication: Treatment Goals

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

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

The Pharmacy Team’s Role

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

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

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

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

CONCLUSION

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

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

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INTRODUCTION

It’s a busy Monday at The Friendly Fill pharmacy. The pharmacy’s certified technician, Olivia, opens the door at 8 A.M. and three patients are waiting. Thomas “Call me Buddy” Thornton says he’s in a hurry because he needs to be at work by nine. Mrs. Lawrence, who walks with a cane, says she’s in no hurry and will sit in the waiting area. Ms. Vasquez slides in next to Mrs. Lawrence, saying, “Don’t you live in my neighborhood?” Olivia determines what each one needs or wants and tells pharmacist Travis, “Brace yourself! It’s already busy and it’s going to be a hypertension haven today!” Travis responds with, “So what’s new?”

Hypertension continues to pose a critical public health challenge. Elevated blood pressure (BP) affects approximately 122 million adults in the United States (U.S.), nearly half of the adult population.¹ Despite the availability of effective therapies, control rates remain suboptimal, with fewer than half of patients achieving recommended targets.² Poor BP control contributes significantly to preventable cardiovascular morbidity and mortality, including myocardial infarction, stroke, heart failure, and chronic kidney disease (CKD) progression.³

Clinical guidelines are essential tools to translate emerging research into actionable practice standards. The 2025 American Heart Association, American College of Cardiology, and American Society of Hypertension (AHA/ACC/ASH) guideline update reflects ongoing reassessment of evidence, integration of trial data, and refinement of treatment algorithms to address persistent gaps in care.⁴ For pharmacists and pharmacy technicians, understanding these updates is vital not only for accurate dispensing and counseling but also to improve patient adherence and safety at every stage of therapy.

By reinforcing this activity’s objectives, pharmacists and technicians can strengthen their ability to detect medication-related problems, identify safety concerns, and improve long-term patient outcomes.

BURDEN OF HYPERTENSION AND RATIONALE FOR FREQUENT UPDATES

Hypertension remains the leading cause of global disease burden, estimated to affect more than 1.4 billion individuals worldwide.⁵ As mentioned, nearly half of the adults in the U.S are living with hypertension, with disproportionately higher prevalence among Black adults and individuals from socioeconomically disadvantaged backgrounds.⁶ The financial burden is equally substantial, with direct healthcare costs and productivity losses exceeding $130 billion annually in the U.S alone, and estimated to continue increasing.⁷

The epidemiology of hypertension reveals two concerning trends. First, prevalence increases with age, affecting more than 75% of adults older than 65 years.⁴ Second, awareness and control rates plateaued or declined over the past decade, with a substantial disparity among older adults, women, and non-Hispanic Black adults.⁸ These realities highlight the need for renewed strategies to drive earlier diagnosis, improve adherence, and address structural health inequities.

Guidelines Change Frequently

Guideline committees such as the AHA/ACC/ASH and international bodies such as the European Society of Hypertension (ESH) or International Society of Hypertension (ISH) frequently update recommendations for several reasons⁹:

• Evolving trial data: Landmark studies such as the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated the benefits of more intensive blood pressure lowering, shifting treatment targets.
• Emerging populations: New evidence informs management for subgroups such as older adults, patients with CKD, and individuals with diabetes.
• Medication landscape: The introduction of fixed-dose combinations, new safety signals, and expanded generics change therapeutic decision-making.
• Health system priorities: Guidelines increasingly emphasize team-based care and health equity to close persistent treatment gaps.

Pharmacists and technicians must stay current, as guideline recommendations directly affect drug selection, dispensing patterns, insurance coverage, and patient counseling.

Pharmacy Team Contributions in Hypertension Care

Pharmacists remain integral to managing hypertension, from initiating therapy in collaborative practice agreements to monitoring adherence and managing adverse effects. Meta-analyses consistently demonstrate that pharmacist-led interventions significantly reduce systolic blood pressure and improve the likelihood of achieving guideline targets.^10-12

Technicians, while not prescribers, provide critical support in ensuring accurate dispensing, preventing medication errors, and identifying red flags. Examples include^13,14

• Detecting look-alike/sound-alike (LASA) medications such as hydralazine and hydroxyzine
• Identifying inappropriate duplication (e.g., patient receiving two ACE inhibitors (ACEi) from different prescribers)
• Recognizing over-the-counter (OTC) or complementary products (e.g., licorice, decongestants) that can worsen blood pressure
• Referring patients to pharmacists when they report elevated readings during in-pharmacy screenings

Together, pharmacists and technicians contribute to earlier intervention, better adherence, and safer therapy.

Given the 2025 update and persistent challenges in hypertension care, it is essential that pharmacy professionals translate guideline recommendations into practical workflows. This is the first major update provided by the ACC/AHA in almost a decade. Its importance cannot be stressed enough with the rise in morbidity and mortality in hypertensive patients.

PAUSE AND PONDER: What are the key reasons that guideline committees update hypertension targets more frequently than in the past? What causes delays?

EVOLVING BLOOD PRESSURE TARGETS

For decades, the definition and treatment thresholds for hypertension have been dynamic. The 2003 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 7 guidelines classified hypertension as blood pressure at or exceeding 140/90 mmHg.^15,16 However, the 2017 AHA/ACC guidelines lowered the BP threshold to at or exceeding 130/80 mmHg, a shift driven by data showing that cardiovascular risk begins at levels previously labeled as “prehypertension.”³

Table 1. Current Blood Pressure Classifications⁴

The 2025 AHA/ACC/ASH update reaffirms the upper threshold of 130/80 mmHg for most adults, while offering nuanced considerations for patient subgroups.⁴ European and international guidelines sometimes recommend slightly higher thresholds, but the global consensus increasingly supports earlier intervention and tighter control in high-risk groups.^16,17 Most clinicians in the U.S. adhere to the AHA/ACC/ASH guidelines but it is important to be aware that the European guidelines exist.

Current Target Recommendations

The 2025 AHA/ACC/ASH update emphasizes risk-based, individualized targets rather than a uniform cutoff. Table 1 summarizes population-specific blood pressure targets and key considerations.

The updated AHA/ACC hypertension guideline emphasizes a shift toward earlier, risk-based, and more individualized care. The PREVENT risk calculator is now central to guiding treatment decisions, replacing prior models and improving risk prediction across diverse populations. A blood pressure target of <130/80 mmHg is recommended for most adults, with pharmacologic therapy initiated based on both BP level and cardiovascular risk. The guideline supports earlier use of combination therapy when appropriate while maintaining thiazide diuretics, ACEis or ARBs, and calcium channel blockers as first-line agents. Additional updates include expanded screening for albuminuria and primary aldosteronism, greater emphasis on standardized and home blood pressure monitoring, reinforcement of team-based care, and continued prioritization of lifestyle interventions.

Table 2. Blood Pressure Targets by Population (Adapted from 2025 AHA/ACC/ASH Guidelines)

The updated guideline places greater emphasis on risk-based, individualized treatment decisions, making the PREVENT risk calculator an essential tool in clinical practice. Unlike prior risk assessment models, PREVENT incorporates a broader range of variables to improve cardiovascular risk prediction across diverse populations. This enhanced stratification allows clinicians to better align patients blood pressure goals and pharmacologic therapy with a patient’s overall cardiovascular risk profile. Familiarity with the PREVENT calculator is critical, as its integration represents a meaningful shift in how hypertension management is approached in the current update.

Key Trial Evidence

SPRINT, published in 2015, was a large multicenter, randomized controlled study designed to evaluate whether more intensive SBP control would improve cardiovascular outcomes compared with standard treatment targets.¹⁸ The trial enrolled 9,361 adults aged 50 years or older with baseline SBP between 130 and 180 mmHg and at least one additional cardiovascular risk factor. These included clinical or subclinical cardiovascular disease (excluding prior stroke), CKD with an eGFR of 20 to 59 mL/min/1.73 m², a Framingham 10-year cardiovascular risk of 15% or greater, or age 75 years and older. Individuals with diabetes, previous stroke, symptomatic heart failure or reduced ejection fraction, polycystic kidney disease, or those residing in nursing facilities were excluded.¹⁸

These researchers assigned participants to either an intensive treatment strategy targeting SBP less than 120 mmHg or a standard treatment target of less than 140 mmHg.¹⁸ Achieving the intensive target required an average of 2.8 antihypertensive medications, while the standard group required 1.8 drugs. The treatment algorithm emphasized the use of thiazide-type diuretics, particularly chlorthalidone, with ACEi or ARBs, CCBs such as amlodipine, and beta-blockers (BB) or loop diuretics when appropriate.¹⁸

The primary outcome (the most important question the researchers are trying to answer) was a composite of myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or cardiovascular death.¹⁸ Intensive therapy resulted in a significant reduction in the primary composite outcome, with a 25% relative risk reduction, and a 27% reduction in all-cause mortality compared with the standard control group. These benefits were consistent across higher-risk subgroups, including adults aged 75 years and older. However, intensive control was associated with increased risks of hypotension, syncope, electrolyte abnormalities, and acute kidney injury, although fall rates did not increase. SPRINT's implications are highly relevant to contemporary practice; intensive outpatient control can provide meaningful cardiovascular benefit in appropriately selected and closely monitored patients. Achieving SPRINT-level targets in inpatient settings is more challenging and may pose added safety concerns due to acute illness, fluid shifts, and frequent medication adjustments. As a result, current recommendations emphasize individualized BP goals and cautious titration, especially in older adults and those with CKD.¹⁸

The Action to Control Cardiovascular Risk in Diabetes Blood Pressure Trial (ACCORD BP), published in 2010, was a major randomized controlled study designed to determine whether intensive systolic BP control would provide additional cardiovascular benefit in adults with type 2 diabetes.¹⁹ The trial enrolled 4,733 participants with diabetes who were at high cardiovascular risk, including individuals with existing cardiovascular disease or multiple risk factors. Researchers assigned participants to either an intensive BP target of less than 120 mmHg or a standard target of less than 140 mmHg. Achieving the intensive goal required an average of three or more antihypertensive medications, commonly including ACEi or ARBs, thiazide diuretics, BBs, and CCBs. Over a median follow-up of 4.7 years, intensive therapy successfully lowered mean SBP levels but did not significantly reduce the primary composite cardiovascular outcome (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death). There was, however, a modest but statistically significant reduction in stroke risk, which remained a secondary outcome benefit.¹⁹

Intensive treatment was associated with higher rates of serious adverse events, including hypotension, syncope, bradycardia, hyperkalemia, and elevations in serum creatinine.¹⁹ Compared with the SPRINT population, ACCORD BP differed in that all participants had type 2 diabetes, a factor believed to influence vascular responsiveness and cardiovascular risk profiles. The ACCORD BP findings contributed to more nuanced guideline recommendations, demonstrating that aggressive systolic BP targets below 120 mmHg may not yield broad cardiovascular benefits in patients with diabetes.^17,19 As a result, prescribers should individualize BP goals in this population based on patient characteristics, comorbidity burden, tolerability, and risk of adverse events

The 2021 Kidney Disease | Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease provided updated, evidence-based recommendations emphasizing more intensive systolic BP control for adults with CKD not receiving dialysis.²¹ KDIGO recommended targeting a standardized office systolic BP of less than 120 mmHg for most patients with CKD, based largely on findings from SPRINT, including its CKD subgroup. The guideline underscored the use of standardized BP measurement techniques, noting that nonstandardized readings, like incorrect cuff size or the patient in improper position, could lead to overtreatment and increased risk of adverse events.

KDIGO continued to support the use of renin–angiotensin system inhibitors, such as ACEIs or ARBs, as first-line therapy for patients with CKD and albuminuria due to their proven renal and cardiovascular benefits. It recommends adding additional medications, including thiazide-type diuretics, CCBs, and BBs, as needed to reach target BP based on individual patient characteristics and comorbidities.

The guideline emphasized lifestyle interventions for all patients with CKD, including sodium restriction to less than 2 grams per day, regular physical activity, weight optimization, and moderation of alcohol intake. Importantly, KDIGO highlighted the need for careful consideration in frail or elderly patients, those at high risk of falls or orthostatic hypotension, and individuals with advanced CKD where volume status and electrolyte abnormalities may complicate aggressive BP management. Overall, the 2021 KDIGO guideline reinforced the value of tighter BP control to reduce cardiovascular events in CKD while stressing individualized treatment goals, standardized measurement, and vigilant monitoring for potential harms.²¹

Technician Perspective: BP Measurement Accuracy

Pharmacy technicians often help patients to measure their BP or guide their use of automated devices. Inaccurate readings may lead to inappropriate treatment changes. Key considerations include cuff size, patient positioning, and device selection. Using the wrong cuff can alter systolic readings by up to 10 mmHg. Crossing legs, talking, or failing to support the patients back/arm can falsely elevate readings. Technicians should recognize that wrist or finger monitors are less reliable than upper-arm devices. Educating patients on proper technique ensures that pharmacists and prescribers base decisions on accurate data.²²

Health Equity and Population Disparities

The updated guideline places a stronger emphasis on health equity, particularly in addressing the disproportionate burden of hypertension among Black adults. Unlike prior recommendations, race-based treatment algorithms have been removed, and management is now guided by individualized risk assessment using the race-neutral PREVENT calculator. The guideline recognizes that Black populations experience earlier onset, higher prevalence, and lower rates of blood pressure control, driven in part by social determinants of health and structural inequities. As a result, clinicians are encouraged to incorporate social context into treatment decisions and to utilize team-based, community-engaged strategies to improve outcomes and reduce disparities. Socioeconomic factors also affect control. Patients with limited access to healthcare often delay diagnosis and treatment.²³ Pharmacists and technicians can bridge gaps by offering screenings, counseling, and referral.

Cost remains one of the most significant barriers to optimal hypertension care, particularly for low income or uninsured patients, who may not be able to afford the out-of-pocket cost. Even when generic options are available, the cumulative cost of antihypertensive medications, office visits, laboratory monitoring, and transportation can be prohibitive. Out-of-pocket expenses often compete with other essential needs such as food, housing, and childcare, leading to medication underuse or discontinuation. Studies consistently demonstrate that patients with limited financial resources are less likely to achieve target BP levels, and cost-related nonadherence directly contributes to worse cardiovascular outcomes.^23,24

Hypertension does not affect all populations equally.²³ Beyond race and ethnicity, geography, socioeconomic status, education, and access to healthcare drive disparities. Rural communities often face reduced access to primary care providers and specialists, resulting in delayed diagnosis and fewer opportunities for BP monitoring or adjustment of therapy. Urban populations may live closer to healthcare resources but face their own challenges, including limited access to safe spaces for physical activity, higher exposure to environmental stressors, and greater difficulty affording fresh, healthy food.²³ Both contexts underscore the reality that where patients live significantly impacts their ability to manage chronic conditions.

Health literacy is another key factor in BP control. Patients with limited understanding of hypertension may underestimate its risks, fail to recognize the importance of daily adherence, or misinterpret instructions on medication labels.²⁴ Cultural differences and language barriers can further complicate communication, or when educational materials are not tailored to their needs.

Pharmacists and technicians can contribute greatly to narrowing these gaps. By using plain language, simplified graphics, or teach-back methods, pharmacy teams can reinforce understanding and empower patients to take ownership of their health. Pharmacists can collaborate with interpreters and community health workers to identify relevant social and cultural factors and provide culturally competent care. Pharmacy technicians, who are often the first point of contact for patients, are well positioned to identify communication barriers and recognize when patients appear confused, disengaged, or overwhelmed. Technicians can then refer these patients to the pharmacist for additional counseling and support.²⁵

Community outreach also offers opportunities to address disparities outside the pharmacy's walls. BP screening events at churches, schools, and community centers allow pharmacists and technicians to meet patients where they are, building trust in populations that may have historical skepticism toward healthcare institutions.²⁵ These efforts, although often requiring additional time and resources, can strengthen relationships, improve early detection, and ultimately reduce long-standing inequities in hypertension care.

By acknowledging and responding to these layers of disparity, pharmacy teams expand their contribution beyond medication dispensing. They become advocates for equitable care, working to ensure that the benefits of updated hypertension guidelines reach all patients, regardless of background or circumstance. Some practical takeaways for pharmacy teams include:

• Strive for less than 130/80 mmHg in most patients, but tailor goals based on age, comorbidities, and tolerance.
• Reinforce accurate measurement and patient self-monitoring.
• Use technician touchpoints (register, OTC aisles, refill calls) to identify patients with uncontrolled BP or medication-related problems.
• Consider social determinants of health when counseling patients and refer for community resources if needed.

PAUSE AND PONDER: When considering initial therapy for a patient with diabetes and hypertension, which classes of antihypertensives are prioritized, and why?

Lifestyle Modification: Foundational Therapy

Nonpharmacologic strategies remain first-line for stage 1 hypertension and are always recommended alongside medication. Pharmacists and technicians can make valuable contributions in guiding patients to realistic modifications to their daily routine.

Major recommendations include^4,20

• The Dietary Approaches to Stop Hypertension or DASH diet: This diet is high in fruits, vegetables, and low-fat dairy, reduced saturated fat.
• Sodium restriction: Aim for less than 1,500–2,300 mg/day (1/4 -1/2 tsp)
• Weight loss: Patients generally experience a 1 mmHg reduction per kg (2.2 lbs) lost.
• Physical activity: Targeting at least 150 minutes/week of moderate activity is best.
• Alcohol moderation: Patients should aim for two or fewer drinks/day in men and fewer than three drinks/day in women. (Standard drink is approximately 12 oz beer, 5 oz wine, or 1.5 oz spirits.)
• Tobacco cessation: Eliminating tobacco reduces cardiovascular risk overall, though not directly antihypertensive.

UPDATED PHARMACOLOGIC RECOMMENDATIONS

Pharmacologic therapy remains the cornerstone of hypertension management when lifestyle interventions alone fail to achieve BP goals. The 2025 AHA/ACC/ASH update continues to endorse four primary classes of antihypertensive drugs as first-line options⁴:

1. Thiazide diuretics
2. ACEis
3. ARBs
4. CCBs

BBs are not considered first-line except in specific populations. Centrally acting medications, direct vasodilators, and alpha-blockers are relegated to adjunctive roles due to safety and tolerability concerns.⁴ Table 3 outlines the key pharmacologic classes further.

Initial Therapy

The 2025 AHA/ACC/ASH guideline recommends antihypertensive medication for all adults with average BP of 140/90 mmHg or higher and for selected adults with BP of 130/80 mmHg or higher who have clinical cardiovascular disease, prior stroke, diabetes, CKD, or a 10-year PREVENT risk of 7.5% or greater. Adults with stage 1 hypertension who have no clinical cardiovascular disease and a PREVENT risk below 7.5% should begin with lifestyle modification alone, with medication added if BP remains at least 130/80 mm Hg after 3 to 6 months. For stage 2 hypertension, the guideline recommends initiating 2 first-line agents of different classes, preferably as a single-pill combination to improve adherence and accelerate BP control.

Combination Therapy

For patients with stage 1 hypertension, monotherapy remains appropriate when pharmacologic treatment is indicated (elevated PREVENT risk or comorbid conditions). However, the guideline reinforces that timely escalation to combination therapy should occur if BP targets are not achieved, rather than prolonged titration of a single agent.⁴

The 2025 AHA/ACC/ASH hypertension guideline places significantly greater emphasis on early combination therapy for patients with stage 2 hypertension. This is evident by the recommendation of routine use of 2 first-line antihypertensive agents of different classes at treatment initiation for most patients, particularly when BP is ≥20/10 mmHg above target.⁴

Importantly, the guideline now prioritizes single-pill, fixed-dose combination therapy over prescribing separate agents. This shift reflects accumulating evidence that fixed dose combinations improve medication adherence, persistence, and speed of blood pressure control, all of which translate to better cardiovascular outcomes.⁴

Pharmacists can help patients weigh risks and benefits, particularly when navigating adverse effects that could reduce adherence (e.g., cough with ACEis, edema with amlodipine, or diuretic-induced electrolyte disturbances). Technicians enhance this process by recognizing early refill gaps or frequent OTC purchases (e.g., NSAIDs) that may worsen BP control.

At The Friendly Fill Pharmacy, technician Olivia is chatting with Buddy Thornton, a 48-year-old man, who is waiting for a refill for lisinopril 20 mg as she takes his blood pressure. He mentions persistent headaches. Olivia recalls seeing him purchase ibuprofen frequently. She slips Travis a piece of paper with the BP reading (145/119), and Travis raises his eyebrows. When reviewing Buddy’s profile, he sees that Buddy’s lisinopril is his only antihypertensive. Travis reviews Buddy’s BP log (Buddy keeps it on his phone), showing persistent readings of roughly 150/95 mmHg. Travis also notes an amlodipine prescription that was picked up once over a year ago but never refilled. Travis counsels Buddy on avoiding frequent use of NSAIDs, discusses combination therapy, and coordinates with his prescriber to add a diuretic (Travis learns Buddy experienced significant edema while on amlodipine). The technician’s vigilance prevented a missed opportunity.

SPECIAL POPULATIONS

Diabetes Mellitus

Patients with diabetes represent a special population in hypertension management because chronic hyperglycemia accelerates microvascular and macrovascular damage, making them particularly vulnerable to renal and cardiovascular complications. The updated guideline emphasizes a risk-based approach using the PREVENT calculator to guide treatment intensity. ACEis and ARBs are preferred because they reduce intraglomerular pressure, lower albuminuria, and slow the progression of diabetic nephropathy when a patient also has CKD. This renal protection is supported by extensive evidence demonstrating reduced proteinuria and improved long-term kidney outcomes with renin–angiotensin system blockade.²⁶ When additional therapy is needed, thiazide diuretics or CCBs are effective second-line options but if CKD isn’t present all are deemed equally efficacious.

Chronic Kidney Disease

In patients with CKD, hypertension both contributes to and results from kidney dysfunction, creating a cycle of progressive decline. ACEis and ARBs are foundational therapies in this population because they reduce proteinuria and slow structural kidney damage through efferent arteriolar vasodilation (widening the small blood vessels that carry blood away from the kidneys). However, dual blockade with an ACEi and ARB is contraindicated because studies such as the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) have demonstrated higher rates of kidney injury, hyperkalemia, and hypotension without added renal benefit.²⁷ Thiazide diuretics are thought to become less effective as CKD progresses and eGFR falls below 30 mL/min, prompting a transition to loop diuretics (furosemide, bumetanide) for adequate volume control. However, recent evidence is beginning to potentially change this viewpoint despite more studies being needed.²⁸ These pharmacologic considerations highlight the importance of individualized therapy based on kidney function, electrolyte profile, and risk of adverse outcomes.

Back at the Friendly Fill Pharmacy, Mrs. Lawrence, a 62-year-old Black woman with type 2 diabetes and stage 2 CKD (eGFR 58 mL/min), is still chatting with Ms. Vasquez but gives technician Olivia her blood pressure log for Travis to see. She is taking HCTZ and amlodipine and is 100% adherent. Travis sees that her current medications include amlodipine 10 mg daily and hydrochlorothiazide 25 mg daily. Her average home BP readings are 156/92 mmHg. Recent labs show persistent microalbuminuria. At pickup, Olivia notes that Mrs. Lawrence refills her medication routinely, but Olivia hears Mrs. Lawrence tell Mrs. Vasquez that she “adds salt to almost everything” because food tastes bland otherwise. She wonders aloud if that’s why her ankles swell. Meanwhile, Travis sees that this patient has three related issues addressed by the guideline update: (1) BP more than 20/10 mmHg above target, and thus uncontrolled, (2) diabetes, and (3) albuminuria. He asks her if it’s OK to call her prescriber, and she says, “Fine, fine, go ahead…” and resumes her chat. Travis explains his concerns to the prescriber and suggests adding an ACE inhibitor or ARB to reduce intraglomerular pressure and provide renal protection. He also asks the prescriber to assess Mrs. Lawrence for CCB-related peripheral swelling or volume status concerns at her next visit.

When he counsels Mrs. Lawrence, Travis explains why he called the prescriber. He also tells her that liberal use of salt may be contributing to increased fluid in her circulation (a patient-friendly way to say “volume expansion”) and poor BP control. He says, “Sadly, people of your ethnicity tend to be more salt-sensitive than other patients. We know that the most you should use is 1,500 to 2,300 mg per day—that’s about one quarter to one half teaspoon.” Olivia reinforces lifestyle messaging during prescription pickup.

Pregnancy

Management of these patients balances maternal risk reduction and fetal safety. Patients within the severe-range (systolic ≥160 or diastolic ≥110 mmHg) should be treated promptly. Patients with persistent readings ≥140/90 mm Hg should be considered for treatment based on maternal risk. First-line agents in pregnancy include labetalol, long-acting nifedipine, and methyldopa, while ACE inhibitors and ARBs are contraindicated because of fetal toxicity. Care should include fetal growth monitoring, assessment of maternal end-organ function, close coordination with obstetrics, and a clear plan for postpartum follow-up.⁴

Post Partum Hypertension

Blood pressure often changes in the first six weeks after delivery, and women with chronic or pregnancy-related hypertension require continued monitoring and management. Check blood pressure frequently in the first 72 hours and arrange early outpatient follow up through six to twelve weeks. Continue or adjust antihypertensive therapy as needed with preferred drugs that are safe for breastfeeding such as labetalol and nifedipine. Enalapril or captopril can be used with counseling about lactation. Watch for delayed onset postpartum preeclampsia up to twelve weeks post-birth and give clear discharge instructions and a plan for follow up.⁴

Elderly

Effective prevention and treatment of hypertension across midlife and later life reduces the risk of cognitive decline and vascular dementia. Older adults require special consideration because age-related changes present additional challenges. This includes progressive arterial stiffness, reduced renal function, and an impaired ability to adjust BP when changing positions, resulting in an increase to both their susceptibility to hypertension and their vulnerability to treatment-related adverse effects. Initiating therapy at low doses and titrating gradually is essential to minimize orthostatic hypotension, dizziness, electrolyte disturbances, and falls. Evidence suggests that intensive BP lowering may reduce cardiovascular events in older adults, but healthcare providers must weigh these benefits against frailty and fall risk, as highlighted by contemporary trials and geriatric hypertension experts.²⁹

Secondary Stroke Prevention

Controlling BP after an ischemic stroke or a transient ischemic attack is proven to reduce the chance of another stroke. Aim for a blood pressure near 130 over 80 mmHg if the patient tolerates it. Start or increase BP medicines as part of the secondary prevention plan. Choose drugs that fit the patient’s other conditions, for example, ACEis, ARBs, and thiazide diuretics which have shown benefit in secondary stroke prevention in RCTs. CCBs have limited data in stroke prevention but can still be used if the patient requires additional control. The care team should monitor for low blood pressure and signs of poor brain perfusion in patients with large vessel disease or a recent large infarct. Work with neurology to set the timing and targets after the acute phase.⁴

Black Adults

Black adults experience a disproportionate burden of hypertension, including earlier onset, higher prevalence, and lower rates of blood pressure control. The 2025 guideline removes race-based treatment recommendations and instead emphasizes individualized, risk-based care using the PREVENT calculator. Antihypertensive therapy should be selected based on comorbid conditions, cardiovascular risk, and patient-specific factors rather than race alone. The guideline also highlights the critical role of social determinants of health, including access to care, medication affordability, and culturally competent education, in driving disparities. Addressing these factors through team-based and patient-centered care is essential to improving outcomes. Combination therapy is often required due to the high prevalence of salt-sensitive hypertension, but treatment selection should remain individualized.

Resistant Hypertension

Resistant hypertension is BP that remains uncontrolled despite the use of three antihypertensive medications, including a diuretic, at optimal doses. Patients with resistant hypertension represent a clinically complex population because they often have underlying physiologic contributors such as excess aldosterone, renal disease, or sympathetic overactivity, a state in which the patient’s “fight or flight” response is overreactive.²⁸ Spironolactone has proven to be an effective fourth-line agent due to its ability to antagonize aldosterone, a key driver of resistant hypertension, as demonstrated in the Prevention And Treatment of Hypertension With Algorithm-based therapy-2 trial (PATHWAY-2)³⁰

Evaluation for secondary causes of hypertension is a critical component of managing apparent resistant hypertension. The guideline recommends a systematic workup for conditions such as primary aldosteronism, renal parenchymal disease, renovascular disease, and obstructive sleep apnea. Early identification and treatment of these conditions can substantially improve blood pressure control. Referral to a specialist is appropriate when a secondary cause is suspected or when hypertension remains uncontrolled despite optimized therapy.⁴

Clinicians should optimize the core antihypertensive regimen before escalation. This includes ensuring use of a long-acting thiazide-like diuretic (chlorthalidone or indapamide) and adding a mineralocorticoid receptor antagonist when blood pressure remains uncontrolled on standard triple therapy. When using mineralocorticoid receptor antagonists, careful monitoring of kidney function and serum potassium is essential.⁴

The guideline does not recommend routine use of loop diuretics solely to offset potassium-sparing effects. However, loop diuretics may be appropriate in patients with reduced kidney function or volume overload, where thiazide-type diuretics are less effective and additional control is needed.⁴

Pharmacist Perspective

Pharmacists can take four steps to optimize care:

• Assess for secondary causes or adherence issues before intensifying therapy.
• Counsel patients on adverse effects (e.g., cough with ACEis, edema with amlodipine).
• Encourage home BP monitoring and medication synchronization.
• Evaluate drug–drug interactions (e.g., ACEi/ARB with potassium-sparing diuretics).

Technician Perspective

Technicians frequently encounter dispensing and OTC-related issues that can affect hypertension management:

• Dispensing errors: Look-alike or sound-alike errors (e.g., HCTZ and hydralazine, losartan and loratadine) are more common than they should be.
• Formulation confusion: Metoprolol tartrate vs succinate (short- vs long-acting).
• OTC interactions: nonsteroidal anti-inflammatory drugs (NSAIDs), decongestants (pseudoephedrine, phenylephrine), and herbal products like ginseng or licorice can raise BP.
• Refill management: Missed refills may indicate poor adherence; technicians can flag for pharmacist follow-up.

By recognizing these issues and starting a discussion with patients or pharmacists, technicians strengthen the pharmacist’s ability to provide comprehensive care.

PAUSE AND PONDER: How can technicians help identify potential errors when dispensing antihypertensive therapy, and how does this support patient safety?

Individualized Patient Care Strategies

Hypertension is not a one-size-fits-all condition. Two patients may share the same BP readings but differ in cardiovascular risk, comorbidities, socioeconomic factors, and treatment preferences. The 2025 AHA/ACC/ASH update underscores tailoring management to the individual to improve both safety and adherence.⁴ Pharmacists and technicians serve integral functions in implementing this approach within the pharmacy setting.

Medication Adherence and Persistence

Up to 50% of patients discontinue their antihypertensive medications within the first year of treatment, a trend strongly linked to poor BP control and increased cardiovascular risk.³¹ Several factors contribute to declining adherence, including bothersome adverse effects, complex medication regimens, high out-of-pocket costs, and limited understanding of the long-term risks associated with uncontrolled hypertension. Many patients also struggle to recognize the importance of daily adherence because hypertension is largely asymptomatic, making the benefits of therapy feel abstract or distant compared with the immediate inconvenience of taking medications.³¹

Pharmacists can help identify barriers and improve patient adherence. Medication synchronization programs can simplify refill schedules and reduce gaps in therapy by aligning all prescriptions to a single pickup date.^32,33 Pharmacists can also counsel patients on managing expected adverse effects, such as peripheral edema from amlodipine, offering reassurance, recommending mitigation strategies, or adjusting therapy in collaboration with prescribers. Motivational interviewing techniques allow pharmacists to explore patient beliefs, correct misconceptions, and support patients in developing intrinsic motivation to their own care.

Pharmacy technicians also make meaningful contributions to adherence efforts. As the team members most frequently interacting with patients at the counter or on the phone, technicians are often the first to notice patterns such as delayed refills, missed pickups, or patient comments indicating confusion or dissatisfaction. They can bring these issues to the pharmacist’s attention for timely intervention. Technicians also assist patients with navigating copay assistance programs if the patient requires certain brand name medications, identifying lower-cost generic options, and coordinating insurance processes, all of which can reduce financial barriers and support sustained adherence. Together, pharmacists and technicians form an integrated support system that helps patients overcome obstacles, understand their therapy, and stay engaged in long-term hypertension management.

Olivia and Travis know about issues related to nonadherence; they see nonadherence often. Mrs. Vasquez is at The Friendly Fill Pharmacy today, and this 60-year-old woman is picking up her lisinopril and HCTZ refills three weeks late. Olivia notices the delay and alerts Travis, who speaks with Ms. Vasquez and discovers that she has been taking her medications inconsistently because she “feels fine” and does not see an immediate need for daily treatment. Travis explains, “Hypertension is often ‘silent,’ meaning you don’t feel any different. When you don’t take daily medicine, you increase your risk of heart attack, stroke, and kidney damage even if you have no symptoms right now.” After reinforcing the importance of consistent daily dosing, Travis consults with the prescriber to ensure her regimen is optimized. As he does, Olivia provides adherence tools such as a pill organizer and works on medication synchronization. Olivia also asks, “When do you take your blood pressure?” and Ms. Vasquez admits she doesn’t have a BP machine and can’t afford one. Olivia says, “I see you in here often. How about you let me take it whenever you’re in the store?”

Integrating Comorbidities

Pharmacists must consider comorbidities that significantly influence antihypertensive therapy selection and monitoring. An ACEi or ARB is specifically recommended in patients with diabetes who have albuminuria or CKD, given their ability to reduce progression of kidney disease and provide cardiovascular benefit. In the absence of albuminuria, other first-line agents may be used as initial therapy, and treatment selection should be guided by patient-specific factors and blood pressure goals rather than diabetes alone.⁴

For individuals with CKD, these same drugs help slow disease progression, although careful monitoring of kidney function and serum potassium is essential. Patients with heart failure benefit most from evidence-based BBs and ACEis or ARBs, while prescribers should avoid non-DHP CCBs (verapamil, diltiazem) due to their negative inotropic effects (decrease in strength of cardiac muscle contraction).⁴ In older adults, heightened sensitivity to adverse effects, increased fall risk, and the prevalence of polypharmacy necessitate cautious use of diuretics and thoughtful regimen simplification to reduce treatment burden and improve safety.⁴

Patient Preferences and Shared Decision-Making

Guidelines highlight patient-centered care. Adherence improves when patients feel heard and are engaged in decisions. Preferences may include once-daily rather than twice-daily dosing, brand as opposed to generic formulations, and avoiding medications that interfere with work (e.g., diuretics in long-distance drivers). Pharmacists can provide education, while technicians reinforce instructions during handoff at the counter, adding another touchpoint every time a patient receives their medications.

Pharmacists in Team-Based Care

Pharmacists increasingly engage in collaborative practice agreements and chronic disease management programs. Evidence shows pharmacist-led interventions can reduce systolic BP by 7 to 10 mmHg.¹⁰ Accessibility and trust equip pharmacists with ample opportunity to benefit the team’s future decision making. Responsibilities include initiating or titrating therapy under protocol, monitoring home BP logs, and conducting medication therapy management (MTM).

Technicians in Workflow and Safety

Technicians’ contributions, while often underrecognized, directly affect hypertension outcomes. Their expertise in preventing medication errors is critical, such as distinguishing between metoprolol tartrate and metoprolol succinate to ensure patients receive the correct formulation. Technicians also help identify potential risks associated with OTC products by noticing when patients purchase medications like pseudoephedrine while taking multiple antihypertensives, prompting timely pharmacist intervention. They support BP screening initiatives by assisting with in-pharmacy BP checks and ensuring that monitoring devices are properly calibrated. Technicians are also well positioned to identify referral triggers, such as encountering consistently elevated BP readings above 180/110 mmHg and guiding patients to speak with the pharmacist or seek emergency care when appropriate.

Social Determinants of Health

The guideline also emphasizes addressing barriers beyond medication.⁴ Pharmacists and technicians can assist patients in overcoming transportation challenges by coordinating mail-order services or arranging prescription delivery. They can support individuals with low health literacy by using pictograms, simplified instructions, or teach-back methods to ensure understanding. Enrolling patients in assistance programs or recommending lower-cost generic alternatives, when appropriate, may mitigate cost barriers. By recognizing and responding to these social and structural influences, pharmacy teams can help improve BP control and reduce disparities in patient outcomes.

Pro Tips

In patients requiring multiple medications, fixed-dose combinations improve adherence and reduce pill burden, but cost and formulary restrictions may be barriers. Pharmacists and technicians should assess insurance coverage and provide alternatives when needed.

Pharmacists should leverage each patient encounter to address medication adherence and reinforce lifestyle goals. Short, structured counseling moments whether at prescription pick up, during BP screenings, or over the phone can make measurable differences in patient outcomes. Technicians should consistently monitor refill histories and OTC purchases to identify potential red flags.

Although pharmacist and technician intervention can improve hypertension outcomes, real-world barriers such as time and staffing constraints often limit implementation. In busy community and health-system settings, pharmacists and technicians may have limited opportunity for extended counseling, follow-up, or collaboration with other providers.

Pharmacy technicians may process several hundred prescriptions per shift, which leaves them little opportunity to flag adherence concerns or discuss OTC risks. These constraints not only contribute to professional burnout but also create gaps in care that disproportionately affect patients with the greatest social and economic barriers. Without adequate time, even the most motivated pharmacy teams may struggle to deliver truly individualized care. Addressing these limitations requires workflow optimization, investment in technician training, and system-level support such as scheduling adjustments, use of synchronization technology, and collaborative practice agreements to ensure guideline implementation remains realistic and sustainable.

Pharmacists should use medication therapy management and collaborative practice agreements to intensify therapy when clinically appropriate. Technicians should flag missed refills, OTC risks, and look-alike/sound-alike errors for pharmacist review. Both pharmacists and technicians should reinforce lifestyle modifications during brief patient encounters.

These real-world applications show how small actions at the pharmacy level can translate into better BP control across entire patient populations. As a staple to many communities, pharmacies, and their workers, are foundational in optimizing outcomes from a population health perspective. In retail settings, friendly, consistent employees go a long way in making patients feel welcome and important.

CONCLUSION

Hypertension remains the most prevalent, preventable driver of cardiovascular morbidity and mortality. The 2025 AHA/ACC/ASH guideline update emphasizes early detection, tighter BP targets, individualized pharmacologic strategies, and comprehensive team-based care.

For pharmacists, these updates demand vigilance in drug selection, patient counseling, adherence monitoring, and clinical decision-making. For technicians, the focus is on dispensing accuracy, recognizing red flags, and supporting patients at the counter. Together, pharmacy professionals form the most accessible layer of hypertension management with an expanding horizon. As frontline providers, pharmacists and technicians hold the power to transform evidence into daily practice. Through ongoing education, vigilance, and patient-centered care, pharmacy teams can meaningfully reduce the burden of hypertension and improve public health outcomes.

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INTRODUCTION AND EPIDEMIOLOGY

The American Pet Products Association (APPA) estimates that approximately 70% of Americans keep pets in their household, equating to 90.5 million homes. Dogs and cats are the most popular and live in around 69.0 and 45.3 million United States (U.S.) households, respectively, followed by 11.8 million households for freshwater fish, 9.9 million households for birds, and 3.5 million households for horses.¹ Public, residential, leisure, and specific occupational environments (e.g., farms, laboratories, pet shops) have high concentrations of pet allergens because of the high prevalence of community pet-keeping and Americans’ tendency to live indoors. Allergic reactions to pets have been recognized for at least 100 years.² Risk factors for developing asthma and rhinitis include allergies to furry animals, especially cats and dogs.³ Direct or second-hand pet exposure increases the likelihood of exacerbating disease in pet-sensitive people. However, evidence also shows that early childhood exposure to dogs or cats before one year of age may have protective effects in preventing allergic sensitization.⁴

Notably, allergies to unusual or exotic pets have increased over the last decade.⁵ In many urban areas, apartment complexes prevent owning large pets or charge a fee for owning cats and dogs, leading to the choice of smaller, more unusual animals. Some examples of uncommon pets are rodents (mice, rats [which allegedly make very good pets], guinea pigs, and other mammals like ferrets, pigs), amphibians (axolotl [a Mexican salamander], dart frogs, and fire belly newts), and reptiles (snakes).⁶ The allergic signs and symptoms or diseases associated with uncommon pets are like those manifested in cat and dog allergies. In addition, patients may present with respiratory symptoms induced by bird allergens and gastrointestinal symptoms after consuming bird eggs; this is called a bird-egg syndrome.⁷

Overall, the incidence of specific allergy to exotic or uncommon pets is unknown because literature only includes isolated cases or small series. In the U.S., an estimated 15% to 30% of people are allergic to their pets.⁸ Among people with pet allergies, a fraction is sensitized to more than one animal. Moreover, according to the Asthma and Allergy Foundation of America, cat allergies are reported twice as often as dog allergies. Animals are also recognized as the third leading cause of allergic asthma, after mites and pollens.⁸ Many people adopt ferrets or rabbits, believing they are hypoallergenic. They are not, and pharmacy staff should be aware of that fact.^9,10 The most frequent allergic reactions result from inhalation, contact, or bites.

This continuing education activity summarizes knowledge of pet allergens, including those from uncommon pets; the allergy reaction mechanism and its signs and symptoms; current advances in diagnosis and treatment methods such as immunotherapy; and recommendations for patient education and counseling.

PAUSE AND PONDER: When patients ask about medication for pet allergies, what kinds of questions should you ask?

PET ALLERGENS

Allergy Mechanisms

Compared with other conditions’ mechanisms, allergy mechanisms are simple and encompass three specific paths: allergic sensitization, allergy, and cross-reactivity.¹¹

• Allergic sensitization is the presence of immunoglobulin E (IgE) antibodies to an allergen.
• Allergy is the occurrence of reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by nonallergic persons and mediated by specific immunologic mechanisms. If no symptoms develop, a person could be sensitizing to a particular allergen but not be allergic.
• Cross-reactivity is the process of IgE antibodies (originally developed against a given allergen) binding to homologous molecules originating from a different allergen source.

Characterizing Pet Allergens

Allergies to pets are common. Pet allergy is an allergic reaction to proteins (allergens) found in animals’ skin cells (dander), saliva, urine, or sweat on their fur.⁵ Allergens within the same protein family can cause cross-reactivity. Most allergens are spread via airborne particles. Dander contains allergens formed in sebaceous gland secretions and saliva. Secretions containing allergens adhere to the hair and stratum corneum of the skin. When an animal sheds, tiny particles disperse into the air and remain buoyant for an extended period of time. After the particles slowly settle onto the floor, furniture, or other items, they can be easily re-dispersed into the air. As a result, pet-sensitive people could experience allergy symptoms in the nose, eyes, and respiratory tract even if the pet is not present.⁵ Additionally, people can carry pet allergens that settled onto their clothing or hair.

For cats and dogs, the primary allergen sources are dander and saliva. Similarly, the primary allergen source in rabbits is saliva. In contrast, the primary allergen source is urine in rodents (mice and rats) and Mustelidae (ferrets and minks).

Rodents are an interesting case study. Most research laboratories experience a very high rate of staff turnover because lab workers develop allergies to rodents. Children who are exposed to rodent urine can develop this allergy, too. Male rodents produce a larger quantity of and more condensed urine than female rodents. This explains why people who commonly come in contact with male rodents are more likely to develop allergic symptoms. Allergy to rodents acts as an occupational hazard for researchers. Mouse urine is the most concentrated of all urines—far more concentrated than any other species.¹² One study showed that 30% of people exposed to mice and 13.7% of people exposed to rats suffered from allergy symptoms.¹² Symptoms range from conjunctivitis to asthma to skin reactions, which makes working with these animals difficult.

Most animal allergens belong to one of three primary protein families. Within the three families, lipocalin-like proteins and the serum albumin family are the two most widely studied. Other identified allergens are considered minor, including gelatins, immunoglobulins, and transferrins presented in secretions and dandruff. Knowledge of these allergens’ allergenicity and cross-activity is essential to improve treatment and prevent allergic reactions. Table 1 summarizes partially characterized pet allergens, including those generated by exotic pets, because not all allergens are fully characterized.⁵

Table 1. Summary of Characterized Pet Allergens^13-22

Lipocalin Superfamily

More than 50% of allergens identified from furry animals belong to the lipocalin superfamily and are found in animal dander, saliva, and urine.²³ Lipocalins are large proteins and can induce IgE production in a large proportion of atopic individuals (people who have enhanced immune response to common allergens) who are exposed to the allergen source.²⁴

Serum Albumin Family

Serum albumin is a globular protein prone to participation in IgE-mediated cross-reactions.²⁴ Serum albumin is commonly found in pet dander and saliva and causes an allergic reaction by inhalation and ingestion.

Secretoglobin Superfamily

Secretoglobins are the most potent allergens in cats (e.g., Fel d 1) and other pets (e.g., rabbit; Ory c 3). Produced by the skin, salivary and lacrimal glands, these proteins have an unknown function. Dried saliva and dandruff are spread as airborne particles and cause sensitization in susceptible people.²⁵

SIGNS AND SYMPTOMS OF PET ALLERGIES

The most frequently observed pet allergies result from inhalation, contact, and bites. The main allergic symptoms are similar across both common and uncommon pet types. They present as rhinitis, conjunctivitis, urticaria (red, itchy welts that result from a skin reaction), and lower and upper respiratory symptoms, which can be mild to severe and rarely cause anaphylactic shock.⁵

Hypoallergenic Pets

“Hypoallergenic” is defined as possessing decreased risk of causing an allergy in people, which means that hypoallergenic animals could still elicit allergies in humans.⁹ To make hypoallergenic animals, breeders or researchers combine breeds that produce less allergen (in dogs, breeders use breeds that shed less than other breeds, or have hair rather than fur). However, animals often have different mechanisms of allergenicity, so infrequent shedding does not solve all allergy problems.

In a dog allergen study, homes that included hypoallergenic dogs had no statistically significant difference in dog allergen levels compared to homes that included non-hypoallergenic dogs. The common allergen in dogs, Can f 1, was reported at similar levels in all groups.²⁵ The frequency of shedding varies in different dog breeds, but all dogs can elicit allergies in humans.

The main allergen in cats, Fel d 1 protein, comes from their saliva and sweat glands. Because of its small size and adhesiveness, Fel d 1 floats around and sticks to everything, making it almost impossible to remove physically. In fact, Fel d 1 measures in at less than one-tenth the size of ribosome; it’s so small, it easily navigates its way deep into the lungs and can precipitate asthma.²⁶ For this reason, making a completely hypoallergenic cat has proven impossible, however vaccines to decrease the production of Fel d 1 protein have been studied; one vaccine is a combination of recombinant Fel d 1, tetanus toxoid protein, and a snippet of the coat of a plant virus.²⁷ Researchers are unsure as to the purpose of Fel d 1 in cats or why levels of Fel d 1 vary.

Ferrets—which are related to otters, minks, and weasels—are considered hypoallergenic because they are less likely to cause an allergic reaction compared to other animals. However, they can still provoke allergies in people. Allergies to ferrets come from their hair, saliva, and urine. Ferret hair and saliva is usually easy to control because they shed infrequently and do not lick people like dogs and cats often do. However, urine is harder to control and can cause allergies when owners clean crates.⁹

Rabbits produce allergens through dander, hair from shedding, and saliva. They tend to shed more often than ferrets, around every three months, so keeping up with cleaning may be difficult. Rabbit hair isn’t naturally allergenic, but when rabbits lick their fur, they transfer a saliva protein that is contaminated with the protein allergen.¹⁰

DIAGNOSIS

Skin Prick Test

Allergists (allergy specialists) use skin prick tests together with medical history and physical examinations to rule out or confirm a suspected IgE-mediated animal allergy.²⁸ Manufacturers prepare skin prick tests by extracting natural allergens from animal hair, dander, and urine. The doctor or nurse will prick the patient’s skin on the forearm or upper back and determine if an allergic reaction occurs within 15 minutes. If a patient develops a red, itchy bump where the pet allergen extract is pricked into the skin, the patient is allergic to that pet allergen. Diagnosticians should first use a skin prick test as it is inexpensive, easy to use, and quick to perform. However, allergen concentrations and components are inconsistent, varying among similar commercial tests from different manufacturers. Healthcare providers should be aware that patients’ test results may be inconsistent if they use different skin prick tests at different times.²⁸

Serum-specific IgE Test

Allergists can use a serum-specific IgE (blood) test when patients’ symptoms and skin test results are contradictory or when patients’ skin conditions prevent a skin test. Serum-specific IgE tests can only determine if a patient is sensitized to a specific pet allergen, but it cannot determine if a patient is allergic to that allergen. Serum-specific IgE tests are highly sensitive, but prone to false-positive results. From this perspective, serum-specific IgE tests may be less accurate than skin prick tests.²⁹

Molecular Diagnosis

Recent scientific advances have allowed molecular diagnosis to differentiate patients who are allergic to a single species or sensitized due to cross-reactivity. This method can aid targeted recommendations for avoidance and assess the choice and composition of immunotherapy.²⁸

PET ALLERGY MANAGEMENT

Pet allergies cannot currently be cured. The treatment goal is to control symptoms and improve patients’ functional status and well-being.

Nonpharmacologic Treatment – Avoid & Minimize Allergen Exposure

Current recommendations for managing pet allergy symptoms start with exposure avoidance. Starting when animals are young, bathing them at least once weekly can reduce allergens and eliminate reactions in humans who are exposed to them (see SIDEBAR).³⁰ Immediate removal of animals from the household will not alleviate symptoms if the owner has carpeting and other pieces of furniture/items that the pet slept or sat on. Mammalian allergens are stable and can persist in house dust for up to six months.³² Additionally, using high-efficiency particulate air (HEPA) filters and mattress encasement, vacuuming, and chemically treating carpet are alternative methods for reducing exposure to contaminated materials, but may not reduce disease severity.³³

PAUSE AND PONDER: When patients have pet allergies, which symptoms are best treated with antihistamines?

SIDEBAR: To Bathe or Not to Bathe…^26,31

Bathing a cat or dog regularly appears to reduce the quantity of allergen harbored by the pet. To effectively lower Can f 1 concentrations, owners need to bathe the animal at least twice every week because Can f 1 concentrations rise rapidly, approaching baseline concentrations within three days after washing. Twice-weekly bathing can reduce the amount of recoverable Can f 1 on dogs by more than 80%, but researchers note that ideally, one would bathe the dog two to three times every week. Airborne Can f levels can fall by ruff-ly 40% but will quickly escalate.

However, the beneficial effects of reducing allergen levels by regular bathing are more likely associated with dogs, because their allergen burden returns faster than that of cats. So, bathing animals reduces the amount of allergen far better than vacuuming.

But should companion animals be bathed so often?

Most cats are notoriously averse to bathing, although some breeds like water (i.e., the Bengal). Dogs vary in the response to bathing—some like it, others do not. People who plan to bathe their cats or dogs regularly should do three things:

1. Check with a veterinarian or a breed advocacy group. The American Kennel Club indicates that how often an owner should bathe a dog depends on the dog’s coat type and presence or absence of an undercoat (in the latter case, frequent bathing can affect a dog’s temperature regulation). Bathing an animal is not just about a human’s allergies, the animal’s health and welfare should be a primary concern.
2. Consider the labor and time involved in bathing a pet often, safely, and well.
3. Start when the animal is young.

An allergen reducing cat food (Pro Plan LiveClear) is now available, and its manufacturer indicates it reduces the number of allergens in cat hair and dander by 47% after three weeks of feeding.³⁴ It is produced using eggs that contain an anti-Fel d1 antibody. When cats consume the food, the egg powder binds to and neutralizes Fel d1 in the cat’s saliva.³⁴

Pharmacologic Treatment

When avoidance and reducing allergens are not enough, depending on the severity of signs, over the counter (OTC) medications like antihistamines or local/topical steroids may provide temporary relief of allergy symptoms.³⁵ Those symptoms include runny/itchy nose or throat, sneezing, and itchy, red or watery eyes. Combination products that contain both an antihistamine and a decongestant or an analgesic are available but should be used with caution due to the increased risk of adverse effects. Other allergy medications, besides the ones mentioned, are used less often, including mast cell stabilizers and leukotriene antagonists. Table 2 summarizes common medications (both OTC and prescription) for treating mild to moderate allergy symptoms.³⁵

Table 2. Medications to Treat Allergy Symptoms³⁶

In general, for conditions eligible for self-care (e.g., allergic rhinitis) patients should start taking OTC allergy medications one week before they expect symptoms from a predictable exposure or as soon as possible before allergen exposure (for episodic exposure).³⁵ Prescribers should tailor the pharmacologic therapy and length of treatment based on symptoms and severity. Usually, complete relief takes two to four weeks. Intranasal steroids control nasal symptoms more effectively than antihistamines, as they inhibit multiple cell types and mediators, and should be recommended for moderate or persistent allergic rhinitis. Decongestants are effective in nasal congestion but have little effect on other symptoms. Intranasal and ocular preparations are available for nasal and eye symptoms. Intranasal cromolyn is the preferred initial choice for pregnant or lactating patients, as the body does not absorb it based on the route of administration. As mentioned in the table, fluticasone and triamcinolone nasal sprays are available OTC.³⁵

If a patient has persistent allergies, allergy medication is more effective when taken regularly.³⁵ For example, if a patient with moderate or severe persistent allergic rhinitis has completed two to four weeks of treatment with intranasal corticosteroids or oral antihistamines and achieved symptomatic control, healthcare providers can optimize the treatment’s effect by reducing the dose and continuing treatment for one additional month. If a patient’s symptoms are uncontrolled after two to four weeks of OTC treatment, pharmacists should assess the patient’s adherence and refer for prescription therapy if necessary.³⁵

PAUSE AND PONDER: Which providers in your area provide allergen-specific immunotherapy? What should patients expect if they take this route?

Allergy Immunotherapy

Allergen-specific immunotherapy has been used in pet allergies for years and has proven efficacy to help control symptoms and prevent disease progression. Allergists will consider allergy-specific immunotherapy when symptoms are uncontrolled by medications and/or avoidance measures, when adverse drug effects are intolerable, or when patients want to reduce long-term use of allergy medications.³⁷

The basis for allergen-specific immunotherapy is gradual reprogramming of the immune system to build a tolerance to allergens. The U.S. Food and Drug Administration (FDA) characterizes allergen-specific immunotherapies as biologics because they are produced from living cells, not synthesized by chemists, and regulated under the Center for Biologics Evaluation and Research (CBER).³⁸ This class comes in three forms:

• Sublingual allergy immunotherapy (SLIT) tablets
• SLIT drops, and
• subcutaneous allergy immunotherapy (SCIT)

As of 2022, the FDA has approved four SLIT tablets to treat allergic rhinitis with or without allergic conjunctivitis caused by ragweed, northern pasture grasses, and dust mites in susceptible individuals; the FDA has not approved SLIT tablets for pet allergies.²²

SLIT drops are made from FDA-approved allergy extracts used to make SCIT shots. However, these extracts are only FDA-approved for injection use under the skin, and they are not approved for use under the tongue. Therefore, SLIT drops are not FDA-approved and are off-label in the U.S., and Medicare or Medicaid does not cover these treatments in most cases. Despite not having FDA approval, patients can still receive SLIT drops from some prescribers who prepare a custom-mixed formulation but must pay out of pocket. Research indicates SLIT is safe and effective.³⁹

The FDA has approved SCIT for cat allergies, but not for other pet allergies. Patients who receive SCIT usually call it “allergy shots.” One systemic review evaluated 88 trials that enrolled 3,459 asthmatic patients and exposed them to SCIT. One case of deterioration in asthma symptoms was avoided for every three patients treated with SCIT (95% CI, 3-5), and one patient would avoid increasing symptomatic medication use for every four patients treated (95% CI, 3-6).⁴⁰ Another study found that SCIT can reduce the need for systemic steroids in allergic rhinitis patients.⁴¹ Usually, the patient receives a solution for injection with 10,000 bioequivalent allergy units (BAUs) per milliliter (standardized extract) of lyophilized cat hair and dander added to glycerol and human serum albumin (0.03%). A clinician administers one to two subcutaneous injections every week starting at low doses (1:10,000 dilution) and titrating up to a seemingly effective maintenance dose. Then, the prescriber extends the injection interval gradually to every 2 weeks to 4 weeks. For cat allergens, the effective maintenance dose usually falls within the 1,000 to 4,000 BAU range.⁴²

S'CIT sometimes can cause treatment-related systemic allergic reactions; however, near-fatal or severe reactions are rare, and most reactions are local and mild (swelling, pruritis, and redness at injection site).⁴³ SCIT should not be recommended to patients who have severe uncontrolled heart problems or asthma if they take beta-blockers, which are associated with more frequent reactions, more severe reactions, and reactions that are refractory to epinephrine. Additionally, allergy shots should not be recommended for pregnant women unless discussed with their obstetricians.⁴³

Both SCIT and SLIT require gradual up-titration of dosages with ongoing and multiple treatments and may take three to five years to reach desensitization. Also, for SCIT, based on its route of administration (subcutaneous injections are invasive), patients will need to visit the doctor's office more frequently and may experience the treatment-associated side effects.

SLIT has been increasingly recommended because of its ability to modify the immune system for the long term while reducing allergy symptoms. SLIT also showed a safer profile, only associated with mild mouth symptoms, and improved adherence compared to SCIT.⁴⁴ When compared to traditional allergy treatments, SLIT tablets showed similar clinical efficacy to nasal corticosteroids and greater clinical efficacy than second-generation antihistamines and montelukast.⁴⁵

What About Cost?

In adherent patients, SCIT and SLIT have proven to be an economically viable option. The annual cost of using SCIT depends on patients’ insurance: Medicare ($1021.70), Medicaid ($758.16), and the commercial average ($1722.24). Yearly treatment costs for SLIT are self-pay because treatment is not FDA approved and costs around $679.25.⁴⁶ Because SLIT drops are administered at home by patients, they tend to be more affordable than the cost of SCIT. Patient preference might be for a once monthly administration, rather than taking oral antihistamines daily.

OTC medications are less expensive than immunotherapy, but costs vary. In a comparison of second-generation antihistamines versus montelukast, levocetirizine (Xyzal) had the best efficacy per cost value. Generic fexofenadine (Allegra), although similar in efficacy, was more expensive than levocetirizine.⁴⁴

CONCLUSION

Healthcare providers should counsel patients about reducing allergen exposure and help patients to choose OTC medications for self-care based on individual patient needs and conditions to optimize treatment effects. Pharmacy staff should refer patients to allergists when necessary to identify the cause of their allergy symptoms. If a patient's allergy does not allow him or her to have pets at home and the patient owns a pet, suggest that the patient ask family members or friends about placement before contacting the local animal shelters.

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INTRODUCTION

Let’s start this continuing education (CE) activity with a case. Bob is a 63-year-old who has had lifelong exacerbations of disabling psychosis. In addition to his psychiatric diagnosis, Bob also struggles to control concomitant medical conditions. These conditions include urinary incontinence, benign prostatic hyperplasia (BPH), and severe constipation that persists from a previous gastrointestinal obstruction and surgical perforation. He has been experiencing breakthrough psychotic symptoms on his current antipsychotic and arrives at the pharmacy today to pick up his new antipsychotic, xanomeline combined with trospium chloride (Cobenfy). Bob mentions to the pharmacy technician he is also having pain and trouble sleeping. He would like to purchase a bottle of over-the-counter (OTC) Tylenol PM (acetaminophen with diphenhydramine). The pharmacy technician recognizes diphenhydramine’s potential conflict with his new prescription and alerts the pharmacist. Staying current with new medications is key to providing optimal care and safety for patients. The pharmacist contacts the prescriber to discuss less complicating anticholinergic options for Bob.

Acetylcholine (ACh) is a neurotransmitter found in the brain and peripheral nervous system. Pharmacologic manipulation of this neurotransmitter has resulted in the advancement of novel pathways to treat conditions ranging from anaphylaxis rescue to treatment of dementia. Unintentional consequences of ACh manipulation include adverse effects associated with anticholinergic burden (ACB). The magnitude of ACB increases with the number of medications with anticholinergic characteristics added to the prescribed regimen. Often overlooked is the added burden of a patient’s OTC medications ranging from sleep aids to antidiarrheals.¹ It is also important to differentiate anticholinergic action from drug-induced fluid depletion, like that expected with diuretics, which have no hallmark muscarinic effects.

Increased ACB results in short-term adverse effects like dry mouth, blurred vision, and urinary retention. It can also cause or contribute to long-term effects including dementia, worsening physical function, and increased risk of falls.¹ The characteristics of anticholinergic reactions are easier to remember when understanding the normal function of muscarinic receptors at different sites in the body. The following symbolic descriptions can help you recall these effects²:

• Mad as a hatter (delirium, cognitive deficits)
• Blind as a bat (eye symptoms, blurry vision)
• Dry as a bone (decreased sweating/dry mouth/dry skin)
• Hot as a hare (elevated body temperature)
• Bloated as a toad (constipation)
• The heart runs alone (tachycardia)
• Full as a flask (urinary retention)
• Red as a beet (cutaneous vasodilation)

Clinicians (including pharmacists and technicians) can rank medications according to their ACB contribution and predict their cumulative effects.

PAUSE AND PONDER: What diagnoses and conditions may be worsened if patients are exposed to anticholinergic medications?

What Does the Beers Criteria Have to Say?
The American Geriatrics Society (AGS) Beers Criteria warns of diminished medication elimination as we age. Using highly anticholinergic medications is riskier in older adults, resulting in exaggerated adverse effects such as confusion, xerostomia (dry mouth), and anticholinergic toxicity. Even younger adults are at risk of long-term cumulative exposure to anticholinergic drugs that can lead to delirium (an acute, fluctuating disturbance in attention and awareness) and dementia (a chronic, progressive cognitive decline).¹ In addition to central nervous system anticholinergics, Beers also recommends avoiding anticholinergic gastrointestinal antispasmodics and skeletal muscle relaxants because of questionable efficacy (Table 1).¹

Table 1. Illustrative List of Potentially Inappropriate Medication Use in Older Adults¹

The Beers Criteria also includes potentially inappropriate medications (PIMS) for older adults that can worsen a condition or syndrome. Anticholinergic medication can exacerbate lower urinary tract symptoms, BPH, and glaucoma. Therefore, prescribers should avoid them in patients with these conditions.¹ Peripheral effects of ACB include constipation, dry mouth, tachycardia, and urinary retention. Central adverse effects include agitation, confusion, delirium, and cognitive impairment. Individuals with serious mental illnesses (SMI) are in a state of chronic cerebral cholinergic depletion and exposure to high ACB can worsen negative symptoms (a reduction or absence of normal behaviors and functions related to motivation and interest, or verbal/emotional expression) leading to further functional and cognitive impairment.³

Anticholinergic medications frequently cause dry mouth, and medication-induced xerostomia can result in discomfort and oral health complications.⁴ Saliva not only facilitates swallowing and digestion, but also promotes the removal of harmful microorganisms.⁵ Medication-induced xerostomia has been reported in twice the number of patients taking anticholinergic medications compared to non-medicated individuals (30% as opposed to 16%, respectively).⁶ Data suggests that patients with dry mouth are 11.5% more likely to develop oral candidiasis, also called thrush, than those without xerostomia.^7,8 More than 95% of dry mouth cases reported in residential long-term care settings for older adults were attributed to medication use and not a natural consequence of aging.^4,9

The development of dementia with long-term anticholinergic use has been well researched. Numerous studies have investigated the potential cognitive impacts of prolonged chronic anticholinergic exposure.^10-14 Epidemiological research has demonstrated that anticholinergic medications’ impact on the development of dementia is significant, with an increased risk of up to 50% among those with high ACB. Researchers have been able to detect risk associated with anticholinergic use up to 20 years before diagnosis.^10-14

PAUSE AND PONDER: What diagnoses and conditions may be affected when using anticholinergic medications? What OTC medications may pose anticholinergic risk?

ESTABLISHING AN ACB ACTION PLAN

Establishing an ACB action plan is as easy as following five steps.

First, the Beers Criteria expert panel recommends routine medication reviews that include consideration of total ACB. Clinicians should calculate ACB risk scores to determine ACB magnitude. Numerous published scales are available to measure ACB. Expert consensus groups develop scales using clinical experience along with research evaluating anticholinergic properties of medications. One calculator that is available is the ACB Calculator, which combines the Anticholinergic Cognitive Burden Scale (ACBS)¹⁵ and the German Anticholinergic Burden Scale (GABS).¹⁶ This calculator is available at https://www.acbcalc.com/.¹⁷ The developers report their source calculators are valid, reliable, and have been used as a pharmacology standard to measure ACB. A score of 3 or greater on the ACBS is associated with significant cognitive impairment and increased mortality.

The second step is to use direct observation and consider patient self-reported adverse effects.

• Clinicians should inquire about physical symptoms associated with anticholinergic toxicity at each patient encounter. They should evaluate ACB in individuals with new or worsening urinary retention, significant constipation, dry mouth, or any of the symptoms described earlier.
• Clinicians should evaluate individuals who report confusion or new or worsening memory impairment for ACB.

Third, the clinical team needs to evaluate the patient’s regimen to determine whether pharmacologic substitution to medications with less ACB is possible.

• Diphenhydramine (Benadryl) or sedating antihistamines for allergies? Individuals seeking relief of allergic symptoms may find less sedating options such as loratadine (Claritin) adequate. For others requiring greater control, exploring intranasal steroids (like fluticasone) used along with loratadine may provide better symptom relief.
• Ask the question, “Can the patient use antipsychotics or antidepressants with less ACB?” Individuals taking antipsychotics report a spectrum of adverse effects and symptom improvement. Clozapine is ranked among the most anticholinergic antipsychotics currently available, however its position also as the most superior antipsychotic prevails for many patients who need it.¹⁸ Clinicians can evaluate potential ACB using established rankings when prescribing antipsychotics. Odds ratios reveal that quetiapine (Seroquel) has one of the highest odds ratios of 4.53, meaning a 4.53 times higher chance of experiencing anticholinergic effects (see Figure 1).¹⁸ While not all antipsychotics are entirely interchangeable, evidence supports relative equivalency for most when given for an adequate duration and at optimal doses. Antidepressants can be ranked for ACB more efficiently by their class effects, with the tricyclic antidepressant class contributing high ACB and selective serotonin reuptake inhibitors (SSRI)/serotonin norepinephrine reuptake inhibitors (SNRI) with low ACB contribution potential. The SSRI paroxetine (Paxil), however, is an exception to the SSRI class benefit because Beers cautions against its use for those at risk of high ACB.¹

Figure 1. Anticholinergic Effects of Commonly Prescribed Second Generation Antipsychotics Ranked by Odds Ratio¹⁸

Fourth, it’s essential to educate patients about OTC medications for sleep and allergies that have anticholinergic properties.^1,19

• Using diphenhydramine in situations such as acute treatment of severe allergic reactions is appropriate, even for older adults. Having diphenhydramine on hand for many families is critical to emergency planning.
• Diphenhydramine and other sedating antihistamines are limited by tolerance that develops when used chronically as a sleep aid. Melatonin is a popular alternative; however the Food and Drug Administration (FDA) regulates it less strictly than other medications, and some formulations contain inconsistent amounts of melatonin. In fact, analysts have found melatonin supplements to contain almost 3.5 times more melatonin than reported on the label. Prescription melatonin agonists like ramelteon (Rozerem), are an option for individuals who prefer a non-controlled, FDA approved intervention for sleep onset insomnia.
• Patients with sleep complaints can try nonpharmacologic interventions before exploring medications that can cause further complications. Interventions include developing a consistent schedule for sleep-wake times, controlling the environment (decreasing noise and temperature), and avoiding vigorous physical activity and caffeine consumption before bedtime. Avoiding blue light from cell phones and other devices is also essential to promote natural melatonin release and facilitate decreased sleep latency.
• Pharmacy technicians can be a great to deliver educational materials with pharmacist review. These materials can include symptom checklists prepared by healthcare professionals. Pharmacists should calculate scores when a patient presents with possible ACB or when conducting a routine medication review. Pharmacists can also check ACB scores technicians calculate for them before they share them with patients. Pharmacy technicians be sure to include OTC purchases and all prescription medications because burden scores should consider the total medication regimen.

Finally, all healthcare providers need to stay current with newly approved medications because these may not be available in an ACB calculator.^1,20

• The AGS Beers Criteria is scheduled for updates every three years. Pharmacists and pharmacy technicians should review the summary tables that highlight anticholinergic agents newly included in the List.
• ACB calculators are limited by the medications they include for ranking. New medications are often not readily available until expert update the calculator.
• Cobenfy’s prescribing information, for example, is not available in the ACBS yet. This “first in class” antipsychotic is a muscarinic combination of xanomeline and trospium chloride. The prominent precautions provided in its labeling are associated with its anticholinergic adverse effects and risks, as reflected in Table 2.

Table 2. Highlights of Xanomeline/Trospium Chloride’s Anticholinergic Warnings²⁰

So, what about Bob? Clinicians skilled in developing ACB action plans determined that with some small changes, as described in Table 3, they could minimize his anticholinergic risks. They continued some of Bob’s current medications that did not contribute to the ACB. More options could be considered in the future if Bob’s symptoms continue or require further intervention. For example, the clinical team chose brexpiprazole because it had the least ACB of available options, but many others could be explored. What changes would you have made?

Table 3. Reducing Bob’s Anticholinergic Burden

CONCLUSION

Clinicians should consider using a calculator, such as the Anticholinergic Burden Calculator, as a clinical support tool for determination during a routine medication review. Many medications with anticholinergic properties are prescribed out of clinical necessity and without an appropriate alternative for certain patients. Calculating ACB is also advisable if the patient presents with symptoms that suggest possible anticholinergic toxicity.

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