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

 

Table 1. Risk Factors for Developing Gallbladder Disease2,8,14-16

Demographics ·       Ethnicity (American Indians, Chilean and Mexican Hispanics) ·       Family history ·       Female gender (10:1 female:male) ·       Older age   Diet ·       High fat, calorie, and refined carbohydrate intake ·       Low fiber and unsaturated fat intake ·       Total parenteral nutrition   Lifestyle ·       Pregnancy and multiple pregnancies ·       Persistent fasting or very low-calorie diet ·       Rapid weight loss (i.e., bariatric surgery) ·       Sedentary   Medications ·       Estrogen therapy or oral contraceptives ·       Some hypoglycemic medications (GLP-1RAs) ·       Chronic use of gastric acid suppressants (H2RAs, PPIs) ·       Ketamine abuse   Heath Conditions & Other Factors ·       Alcoholic liver cirrhosis ·       Dyslipidemia (elevated triglycerides and low HDL) ·       Gallbladder motor dysfunction ·       Gastrointestinal surgery ·       Metabolic syndrome, gallbladder, or intestinal stasis ·       Short bowel syndrome ·       Type 2 diabetes mellitus

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

 

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

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

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

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

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

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

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

TREATING GALLBLADDER DISEASE

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

Surgical Intervention: Cholecystectomy

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

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

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

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

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

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

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

Pharmacologic and Other Non-Surgical Interventions

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

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

Gallbladder Cancer²⁰

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

 

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

 

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

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

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

 

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

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

POST-OPERATIVE CONSIDERATIONS AND THE PHARMACY TEAM

Post-Cholecystectomy Syndrome

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

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

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

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

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

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

 

Table 3. Bile Acid Sequestrants^26,27

Drug	Dosage	Administration
Cholestyramine (Prevalite, Questran)	2-4 g daily as a single dose or divided, increase by 4 g weekly based on response and tolerability, maximum 24 g/day	Mix dose in 60-180 mL of any beverage, soup, or pulpy fruit, should not be sipped or held in mouth for long periods*   Take with meals, administer oral medications ≥1 hour before or 4-6 hours after dose
Colestipol (Colestid)	Granules: 5 g once or twice daily, increase by 5 g in 1-2 month intervals, maintenance dose 5-30 g once daily or in divided doses   Tablets: 2 g once or twice daily, increase by 2 g in 1-2 month intervals, maintenance dose 2-16 g once daily or in divided doses	Administer other medications ≥1 hour before or 4 hours after dose   Granules: do not administer in dry form to avoid GI distress or accidental inhalation, should be added to at least 90 mL of any beverage, soup, or pulpy fruit   Tablets: administer one at a time; swallow whole; do not cut, crush, or chew

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

 

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

Medication: Treatment Goals

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

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

The Pharmacy Team’s Role

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

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

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

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

CONCLUSION

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

The pharmacy team should take an active role in GBD management, especially following cholecystectomy. Pharmacy technicians should be 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

Category	Systolic BP (mm Hg)	Diastolic BP (mm Hg)
Normal	<120	<80
Elevated	120–129	<80
Stage 1 Hypertension	130–139	80–89
Stage 2 Hypertension	≥140	≥90

 

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)

Population	Recommended Target	Special Considerations
General adults (<65 yrs)	<130/80 mmHg	If tolerated, emphasize lifestyle + pharmacologic therapy
Older adults (≥65 yrs)	SBP <130 mmHg	Watch for orthostatic hypotension, frailty
Diabetes	<130/80 mmHg	Prioritize ACEi/ARB if albuminuria present
CKD	<130/80 mmHg	Individualize, avoid overly aggressive lowering if symptomatic
CCD	<130/80 mmHg	Beta-blocker and ACEi/ARB preferred first line for compelling indications
Pregnancy	<140/90 mmHg	Labetalol, nifedipine, methyldopa; avoid ACEi/ARB
ABBREVIATIONS; ACEi = angiotensin-converting enzyme inhibitors; ARB = angiotensin II receptor blockers; CCD = chronic coronary disease; CKD = chronic kidney disease; SBP = systolic blood pressure

 

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.

 

Table 3. Pharmacologic Classes in Hypertension (Adapted from 2025 AHA/ACC/ASH Guidelines)
Class	Example Agents	Pharmacist Pearls	Technician Notes
Thiazide diuretics	HCTZ, chlorthalidone, indapamide	Chlorthalidone preferred for potency and duration	Look-alike risk: HCTZ vs hydralazine
ACEi	Lisinopril, enalapril, benazepril	Avoid in pregnancy; monitor for cough, angioedema, hyperkalemia	Sound-alike: lisinopril vs lamictal
ARBs	Losartan, valsartan, olmesartan	Similar efficacy to ACEIs; fewer adverse effects	Patient confusion: losartan vs loratadine
CCBs (DHP)	Amlodipine, nifedipine ER	Useful in Black adults and elderly; risk of edema	Confusion: nifedipine vs nicardipine
CCBs (non-DHP)	Verapamil, diltiazem	Use in arrhythmias; avoid in HFrEF	Always double check ER vs IR formulations
Beta-blockers	Metoprolol, carvedilol, atenolol	Use in CAD, HFrEF, arrhythmias	Watch for mix-ups: metoprolol tartrate vs succinate
Other agents	Hydralazine, clonidine, minoxidil	Adjunct only; significant adverse effects	Clonidine patches: monitor removal/application dates
ABBREVIATIONS: ACEI = angiotensin-converting enzyme inhibitors; ARB = angiotensin II receptor blockers; CCB = calcium channel blocker; DHP = dihydropyridine; non-DHP = nondihydropyridine; CAD = coronary artery disease; HFrEF = heart failure with reduced ejection fraction; ER = extended-release; IR = immediate-release; HCTZ = hydrochlorothiazide

 

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.

 

Download CE Activity

 

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

Common Name of Animal	Source	Allergen	Family
Dog	Dander, saliva, hair	Can f 1 (major allergen) Can f 2 Can f 4 Can f 6 Can f 3 Can f 5 Can f 7 Can f 8	Lipocalin Lipocalin Lipocalin Lipocalin Albumin Arginine esterase (kallikrein) Epididymal secretory protein E1 or Niemann Pick type C2 protein Cystatin
Cat	Sebaceous, anal, and salivary gland	Fel d 1 (major allergen) Fel d 2 Fel d 4 Fel d 7 Fel d 3 Fel d 5w Fel d 8 Fed d 6w	Uteroglobin Albumin Lipocalin Von Ebner gland protein Cystatin Cat IgA Latherin-like IgM
Horse	Dander, sublingual, submaxillary salivary glands, and urine	Equ c 1 (major allergen) Equ c 2 Equ c 4 Equ c 3 Equ c 6	Lipocalin Lipocalin Latherin Albumin Lysozyme
Chinchilla	Epithelia, saliva, urine	Chi La Chi Lb	Protein kinase inhibitor Lipocalin
Guinea pig		Cav p 1 (major allergen) Cap p 2 (major allergen) Cap p 3 Cap p 4 Cap p 6	Lipocalin Lipocalin Lipocalin Serum albumin Lipocalin
Gerbil	Epithelial, salvia, urine, sleep bed	Mer un 23kDa Mer un 4	Lipocalin Serum albumin
Siberian hamster	Epithelial, saliva, urine	Phod s 1	Lipocalin
Rat		Rat n 1 (major allergen) Rat n 4 Rat n 7	Lipocalin; alpha-2u-glubulin Serum albumin Immunoglobulin
Mouse		Mus m 1 (major allergen) Mus m 2 Mus m 4 Mus m 7	Lipocalin; urinary prealbumin Unknown Serum albumin Immunoglobulin
Rabbit		Ory c 1 Ory c 2 Ory c 3 Ory c 4	Lipocalin Lipocalin Secretoglobin Lipocalin
Ferret		Mus p 17 Mus p 66	Unknown Serum albumin
Pig	Meat	Sus s 1 Sus s 5 Sus s 6	Serum albumin Lipocalin Serum albumin

 

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

Medication	Mechanism of Action	Adverse Effects	Notes
Antihistamines
1st generation (nonselective, more sedating):* diphenhydramine, chlorpheniramine, clemastine 2nd generation (less sedating, less drowsiness): cetirizine,* desloratadine,* fexofenadine,* levocetirizine,* and loratadine* Azelastine has nasal spray* and eye drop formulations. Epinastine and olopatadine* are formulated as eye drops.	Blocks histamine and its binding to receptors, prevents histamine-caused redness, swelling, itching, and changes in secretions during an allergic response	·       Drowsiness ·       Fatigue ·       Headache	The 2nd generation antihistamines are preferred over 1st generation based on safety and efficacy data.
Corticosteroids
Available as tablets, liquids, nasal sprays, topical creams for skin allergies, topical eye drops for conjunctivitis.   Some steroids include: beclomethasone, ciclesonide, fluticasone furoate,* mometasone, budesonide,* triamcinolone,* dexamethasone ophthalmic, prednisone, etc.	Anti-inflammatory effect	Short-term use: Weight gain, fluid retention, high blood pressure   Long-term use: Growth suppression, diabetes, cataracts of the eye, osteoporosis, muscle weakness   Side effects of inhaled steroids: Cough, hoarseness, fungal infection of the mouth	Highly effective for allergies but must be taken regularly. It may take 1 to 2 weeks before the full effect.
Decongestants
Available as nasal sprays, eye drops, liquids, and tablets   Some decongestants include: pseudoephedrine,* phenylephrine,* and oxymetazoline* nasal sprays	Shrinks swollen nasal tissues and blood vessels to relieve the symptoms of nasal swelling, congestion, mucus secretion, and redness	·       Increased blood pressure ·       Insomnia ·       Anxiety, feeling nervous, restlessness	Relieve congestion and are often prescribed with antihistamines for allergies.   Contraindicated in patients with severe coronary artery disease, severe hypertension, and who concomitantly use monoamine oxidase inhibitors   Short-term use only (~5 days). Long-term use can make symptoms worse.
Combination Allergy Drugs
Some combination drugs include: cetirizine/pseudoephedrine,* fexofenadine/ pseudoephedrine,* diphenhydramine/ pseudoephedrine,* loratadine/pseudoephedrine,* pseudoephedrine/triprolidine* for nasal allergies, and naphazoline/pheniramine* for allergic conjunctivitis	Effects from each component	Side effects from each component	Use with caution due to increased risk of adverse effects
Anticholinergic Nasal Spray
Ipratropium bromide nasal spray to control nasal discharge	Antisecretory properties in the nasal mucosa	·       Bitterness of the mouth ·       Dry nose, nosebleeds, or irritation ·       Dizziness ·       Headache ·       Sore throat ·       Respiratory tract infection	Some patients may feel better right away. For others, it may take 1 to 2 weeks before the medicine helps. It is important for patients to continue use of this medication as instructed.
Mast Cell Stabilizers
Available as eye drops for allergic conjunctivitis and nasal sprays for nasal allergy symptoms   Some mast cell stabilizers include cromolyn sodium,* iodoxamide-tromethamine, nedocromil, pemirolast, etc.	Prevents histamine release from mast cells	·       Throat irritation, coughing, skin rashes ·       Eye drops may cause blurred vision, stinging, and burning	For mild to moderate symptoms Not as effective as steroids
Leukotriene Modifiers
Montelukast: Indicated for adults and pediatric patients six months or older with perennial allergic rhinitis. May be less effective than loratadine or cetirizine for reducing daytime nasal symptoms	Montelukast binds to leukotriene receptors in the human airway (smooth muscle cells and macrophages), preventing airway edema, smooth muscle contraction, and other respiratory inflammation	·       Stomach pain or upset ·       Headache ·       Stuffy nose ·       Cough ·       Fever ·       Rash ·       Irritability	Warn patients to report behavior changes, including suicidal ideation or suicidal behavior Avoid concomitant use of aspirin or NSAIDs in aspirin-sensitive patients
*Indicates over-the-counter (OTC) medication

 

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

Organ system	Therapeutic category	Illustrative examples	Recommendations
Central nervous system	Antidepressants with strong anticholinergic activity, alone or in combination	TCA •       Amoxapine •       Clomipramine •       Desipramine •       Doxepin > 6 mg/day •       Imipramine •       Nortriptyline   SSRI •       Paroxetine	Avoid   •       Highly anticholinergic, sedating. •       May cause orthostatic hypotension   Exception: Low-dose doxepin 6 mg/day or less is comparable to placebo
	Antiparkinsonian medications with strong anticholinergic activity	•       Benztropine (oral) •       Trihexyphenidyl	Avoid   Treatment of drug-induced EPS: Not recommended for prevention or treatment of EPS due to antipsychotics   Treatment of Parkinson disease: More effective medications are available for the treatment of Parkinson disease
ABBREVIATIONS: EPS = extrapyramidal symptoms; SSRI = selective serotonin reuptake inhibitors; TCA = tricyclic antidepressants

 

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

Contraindicated in patients with

•       Urinary retention •       Moderate or severe hepatic impairment •       Gastric retention •       History of hypersensitivity to xanomeline or trospium chloride •       Untreated narrow-angle glaucoma

Clinical Considerations

•       Risk of urinary retention: can cause urinary retention. •       Biliary disease: Assess liver enzymes and bilirubin prior to initiating and as clinically indicated (with caution). •       Symptoms of gallbladder disorders, biliary disorders, and pancreatitis should be assessed as clinically indicated during treatment. •       May decrease gastrointestinal motility: Use with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. •       Risk of use in patients with narrow-angle glaucoma: Use only if benefits outweigh the risks and with careful monitoring. •       Increases in heart rate: May increase heart rate (monitor)

 

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

Bob’s medication list	ACB score currently	Action	Alternative	ACB score recalculated
Oxybutynin for urinary incontinence	3	Choose alternative	Mirabegron	0
Quetiapine for psychosis	3	Choose alternative	Brexpiprazole	0
Acetaminophen with Diphenhydramine for insomnia and arthritis pain	0   3	Choose alternative	Plain APAP   Ramelteon for sleep onset insomnia	0     0
Tamsulosin for BPH	0	No change		0
Total ACB score	9			0
ABBREVIATIONS: ACB = anticholinergic burden, BPH = benign prostatic hyperplasia

 

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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INTRODUCTION

Imagine you’re working a late shift at your local pharmacy when a mother rushes in with her child, whose hands are red and covered in small, weeping lesions. The child says they itch constantly, and the mother explains the pediatrician mentioned “contact dermatitis,” but mom’s unsure how to help. She didn’t know who else to turn to but hopes you could provide some suggestions on what products can help her child.

 

While skin conditions aren’t necessarily the pharmacy staff’s bread and butter, your expertise can still make a difference. You can scrutinize the affected area and ask some guided questions to decide what products may help the child.

 

PAUSE AND PONDER: What questions may help determine the best remedy for this child?

 

Before recommending products, it’s important to first understand what contact dermatitis is, how it develops, and the most effective treatment options.

 

WHAT IS CONTACT DERMATITIS?

Contact dermatitis is a form of eczema (a group of inflammatory skin conditions that cause dry skin, itchiness, rashes, scaly patches, blisters, and skin infections) that occurs when a substance comes into contact with the skin and causes irritation or an allergic reaction.^1,2 Contact dermatitis occurs in 15% to 20% of people. Contact dermatitis is the most common form of reported occupational skin disease accounting for approximately 90% to 95% of cases.^1,3 Although contact dermatitis has no cure, patients can manage symptoms effectively with topical treatments and by identifying and avoiding the triggering substance.

 

It's important to note many different clinical patterns of contact dermatitis exist. Some common patterns include^4-10

• Erythema multiforme—lesions present as macules (flat, distinct spot on the skin that's a different color than the surrounding area but doesn't impact the skin's texture or thickness), papules (red bumps), bullae (blisters filled with clear fluid), or urticarial eruptions (itchy welts), often demonstrating a characteristic 'target lesion' pattern predominantly affecting the extremities
• Urticarial papular plaques—skin lesions that appear as itchy papules and raised patches, often appearing in lines or clusters
• Lichen-planus—presents as shiny red, purple, gray, or brown bumps that may merge into plaques, commonly on wrists, arms, legs, or lower back; may cause mild to intense itching
• Purpuric petechial reactions—skin or mucous membrane discoloration as a result of hemorrhage from small blood vessels. Lesions are often 1 mm to 2 mm across
• Pustular reactions—a rash consisting of small pustules (bumps) less than 5 mm to 10 mm that are filled with pus
• Pigmentation disturbances
• Pemphigoid—present as large fluid-filled blisters that rupture and form crusted erosions

 

Types of Contact Dermatitis

Contact dermatitis has two main presentations: irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD). Table 1 provides more information on these two presentations.

 

PAUSE AND PONDER: How does ICD differ from ACD?

 

Table 1. The Main Types of Contact Dermatitis and their Characteristics.^1,2-4,11-14

Irritant contact dermatitis	Allergic contact dermatitis
●      Makes up approximately 80% of contact dermatitis cases. ●      Mechanism: Involves a chemical or substance causing damage and inflammation to the skin. Damage occurs over time and with repeated exposure to the irritant. ●      Reaction type: Non-immune mediated reaction. Damage is limited to the place where the chemical or substance is absorbed. ●      Onset: Reactions occur within minutes to hours. ●      Defining characteristics: Occurs as a dose-dependent inflammatory reaction. Harsher agents or more vigorous abrasions produce more severe injury. ●      Clinical manifestations: Clinical features of acute ICD include erythema (redness), vesicles (small fluid filled bumps), edema, bullae, and oozing. Patients often experience burning, stinging, and pain. Clinical features of chronic ICD include erythema, lichenification (hyperpigmentation, skin thickening), scaling, hyperkeratosis (skin thickening), and fissuring (small cracks in dry, thickened skin). Patients often experience burning and pain more than itchiness. ●      Causative factors: ○      Highly irritating chemicals (e.g., acids, bases, oxidizing or reducing agents) ○      Mild irritants (e.g., water, detergents, weak cleaning agents, soaps)	●      Makes up approximately 20% of contact dermatitis cases. ●      Mechanism: Involves the body producing an allergic reaction to a chemical or allergen the skin has absorbed. ●      Reaction type: Immune mediated reaction. ●      Onset: Can be a delayed reaction that occurs more than 24 hours past exposure. ●      Defining characteristics: Improves more slowly than ICD and recurs faster when exposure is re-established. ●      Clinical manifestations: Acute ACD has clinical features including thin, erythematous, scaly, and eczematous plaques. Lesions may also be vesicular (small bubble-like sacs formed when fluid is trapped under the epidermis) or bullous (hive-like welts or large, fluid-filled blisters). Chronic ACD has clinical features including indurated and scaly lesions. Over time, the skin may become lichenified. Other features of the rash are sensations of burning, redness, stinging, swelling, oozing, crusting, and flaking. ●      Causative factors: ○      Poison ivy and other plants ○      Commercial chemicals (e.g., toluene-2,5-diamine sulfate, panthenol, cetrimonium chloride and bromide, chlorphenesin) ○      Industrial compounds (e.g., metals, epoxy, acrylic resins, rubber additives) ○      Agrochemicals (e.g., pesticides, fertilizers)
ABBREVIATIONS: ICD, irritant contact dermatitis; ACD, allergic contact dermatitis

 

Apart from these two main types of contact dermatitis, other less common presentations can develop. Photoallergic and photoirritant contact dermatitis are reactions primarily affecting sun-exposed areas including the face, back of the hands, arms, upper chest, and lower legs.¹¹

 

Photoallergic contact dermatitis requires ultraviolet radiation to activate the allergic agent to trigger an allergic reaction. The most common causative agents are chemicals found in sunscreens. Benzophenones (most commonly oxybenzone) are common sunscreen components and chemical triggers. Other agents include ethylhexyl methoxycinnamate (octinoxate), butyl methoxydibenzoylmethane (avobenzone), ethylhexyl dimethyl (padimate O), and octocrylene. A less common cause implicated in photoallergic contact dermatitis reactions is ketoprofen, a topical nonsteroidal anti-inflammatory drug.¹¹

 

Photoirritant (phototoxic) contact dermatitis requires ultraviolet radiation to activate the irritant and cause cellular damage. It occurs after contact with plants that contain furocoumarins or psoralens (e.g., lime, lemon, parsnips, parsley, celery, hogweed, rue [Ruta graveolens], meadow-grass, fig tree). Due to its association with limes and sunlight, photoirritant contact dermatitis is commonly referred to as “Margarita dermatitis.”¹¹

 

Protein contact dermatitis is caused by exposure to high-molecular-weight proteins often found in foods, latex, and other biologic material. Common foods involved include vegetables, animal proteins, spices, wheat, and milk. Most cases are occupation-related with food handlers frequently developing this form of dermatitis.¹¹

 

Systemic allergic contact dermatitis, also known as hematogenous contact dermatitis, occurs when an individual who has been previously sensitized to an allergen through skin contact later encounters the same substance through a systemic route (e.g., ingestion, injection, inhalation, implantation, or suppository use). Common triggers include metals (most commonly nickel); medications (e.g., aminoglycoside antibacterials, corticosteroids, and aminophylline); chemicals (e.g., parabens, formaldehyde, and propylene glycol); certain foods (e.g., soy, chocolate, nuts, and spices); and plants. Common plant sources include those in the Compositae family (known as the “daisy” family such as dandelions, sunflowers, and ragweed) and Anacardiaceae family (known as the “cashew” family and such as cashews, mango, and sumac), garlic, and balsam of Peru.^11,13,15-17

Pathogenesis of Allergic Contact Dermatitis

The difference in mechanism between ACD and ICD results in their distinct pathogenic pathways. See the SIDEBAR for definitions on the immune cells involved in contact dermatitis’ pathogenesis.

 

SIDEBAR: Overview of Immunomodulatory Cells Involved in the Pathogenesis of Contact Dermatitis^18-22

• T-effector cells: Activated T-cells that migrate to infection sites to eliminate pathogens. These cells develop through antigen recognition (following presentation by antigen-presenting cells), leading to T-cell proliferation and differentiation to effector cells.
• T-memory cells: Form of activated T-cells that become long-lived memory cells. These cells rapidly expand and mount a stronger immune response upon re-exposure to the same antigen.
• Interleukin-1 alpha (IL-1α): A pro-inflammatory cytokine found in most cell types, especially barrier tissues. It’s released during cell injury or stress to trigger local inflammation, recruit immune cells, and promote tissue repair.
• Interleukin-1 beta (IL-1β): A pro-inflammatory cytokine produced by activated immune cells that requires inflammasome processing (enzymatic activation of an inactive precursor by intracellular immune complexes) to become active. It mediates systemic inflammation, fever, and leukocyte recruitment.
• Interleukin-1 receptor antagonist (IL-1RA): A natural inhibitor that blocks IL-1α and IL-1β from receptor binding, preventing excessive inflammation and maintaining immune balance.
• Interleukin-10 (IL-10): An anti-inflammatory cytokine that suppresses pro-inflammatory cytokine production and limits tissue damage by controlling immune cell activation.
• Interleukin-6 (IL-6): A multifunctional cytokine produced during infection or stress that activates immune cells, induces acute-phase responses, and contributes to systemic inflammation and metabolic changes.
• Tumor necrosis factor-alpha (TNF-α): A key inflammatory cytokine—secreted mainly by macrophages—that regulates immune responses, promotes inflammation, and influences metabolism and tissue repair.
• Chemokine ligand 20 (CCL20): A chemokine that binds CCR6 (C-C chemokine receptor type 6) to attract lymphocytes and dendritic cells to inflamed or infected tissues. It plays a central role in Th17-driven inflammation and autoimmune disease.
• Chemokine ligand 21 (CCL21): A chemokine that binds CCR7 (C-C chemokine receptor type 7) to direct T-cells and dendritic cells to lymphoid organs, supporting immune cell organization and adaptive immune responses.
• Chemokine ligand 8 (CXCL8)/Interleukin-8 (IL-8): A chemokine that binds CXCR1 (C-X-C motif chemokine receptor 1) and CXCR2 (C-X-C motif chemokine receptor 2) to recruit neutrophils to infection sites, contributing to inflammation, angiogenesis, and tissue remodeling.
• Intercellular adhesion molecule 1 (ICAM-1): An adhesion molecule on endothelial cells and leukocytes that mediates immune cell attachment and migration during inflammation and supports T-cell activation.

 

Pathogenesis of ACD can be broken down into three stages: sensitization, elicitation, and resolution.¹³

 

Sensitization occurs during initial allergen exposure. The skin absorbs the allergen (antigen) which then binds to dendritic cells (immune cells that present antigens to T-cells and help drive adaptive immunity) and migrate to lymph nodes.²³ In the lymph nodes, these allergens trigger the development of allergen-specific T-cells. The T-cells then differentiate into T-effector cells and T-memory cells and recirculate into the blood and skin. This process may take up to 15 days. Patients may not develop active dermatitis during this phase.¹³

 

Elicitation occurs upon allergen re-exposure. The allergen binds to the dendritic cells and is presented to the antigen-specific T-cells. This triggers a rapid inflammatory response cascade that releases pro-inflammatory cytokines and recruits inflammatory cells. This process occurs hours to days after the exposure and manifests as an itchy rash at the contact site. The dermatitis response can last days to weeks following exposure.¹³

 

Resolution occurs post-exposure. A large population of T-memory cells replace T-effector cells. This ensures that if individuals experience subsequent exposures, the immune reaction to the allergen is of increasing intensity. As a result, patients may experience a worsening severity of symptoms with repeated exposures due to the increasing population of T-memory cells in the skin.¹³

 

Pathogenesis of Irritant Contact Dermatitis

ICD’s pathogenesis is less clearly understood than ACD’s pathogenesis; however, experts have determined a few key mechanisms involved. These mechanisms include disruption of the epidermal barrier (the stratum corneum) and the loss of lipids, damage to keratinocyte cell membranes, cytotoxic effect on keratinocytes, inflammatory cytokine release from keratinocytes, and activation of innate immunity.¹²

 

Previous experimental studies show that disruption of the epidermal barrier  by occlusion or by physical/chemical irritation results in increased skin permeability, transepidermal water loss, and reduced natural moisturizing factor. These steps are considered the initiation event of ICD. ICD’s pathogenesis also varies depending on whether the condition is acute or chronic.¹²

 

In acute ICD, studies using both human and animal models show that acute damage to the epidermal barrier (such as that caused by sodium lauryl sulfate, a surfactant used in many cleaning and hygiene products) triggers the release of preformed cytokines from keratinocytes, including interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. IL-1α and TNF-α serve as key mediators, initiating the release of additional pro-inflammatory cytokines (e.g., CCL20, CCL21, CXCL8) that recruit mononuclear and polymorphonuclear cells to the irritation site. TNF-α stimulates the expression of ICAM-1 on keratinocytes, facilitating leukocyte migration to the epidermis. Concurrently, the body produces anti-inflammatory mediators such as IL-10 and IL-1RA in response to irritant exposure, helping to regulate and resolve the inflammatory process.¹²

 

Researchers don’t fully understand the underlying mechanisms of chronic ICD yet. One proposed theory suggests repeated exposure to mild irritants or persistent wet work (occupations that involve frequent or prolonged contact with water or other liquids; e.g., healthcare, hairdressing, or construction). Continuous exposure leads to downregulation of the inflammatory response while promoting keratinocyte proliferation and differentiation. Studies comparing normal skin with areas repeatedly exposed to irritants, such as sodium lauryl sulfate, have shown decreased levels of pro-inflammatory cytokines (IL-1 and TNF-α) and increased levels of IL-1RA in chronically affected skin.¹²

 

Additionally, ICD appears to involve unique gene expression changes within the skin that distinguish it from ACD. Some individuals develop a tolerance to chronic irritant exposure, a process referred to as the “hardening phenomenon.” Although the exact mechanisms remain unclear, structural and biochemical adaptations—such as epidermal thickening (acanthosis [patches of thickened, velvety, darkened skin that appear within body folds and creases] and hyperkeratosis), alterations in stratum corneum lipid composition, changes in barrier permeability, and modulation of inflammatory mediator expression may contribute to this adaptive response.^12,24

 

Risk Factors

Risk factors for contact dermatitis are a mix of circumstantial and inherent traits. For example, a circumstantial trait is cosmetic preference. A woman partial to perfumes or jewelry has a greater risk of contact dermatitis than a woman who is not. An example of inherent risk is skin type; individuals with thin skin, for instance, are at an increased risk of contact dermatitis. Table 2 describes additional risk factors.

 

Table 2. Common Risk Factors of Contact Dermatitis.^4,11,25

Characteristic	Those at Increased Risk
Age	●      Young children and infants. Contact dermatitis affects close to 20% of children.
Occupation	●      Occupations with more exposure to irritants ○      Cleaners ○      Construction/metal work ○      Cosmetology/hairdressing ○      Electronic industry ○      Farming ○      Food production/handling ○      Forestry/landscaping/florists ○      Healthcare ○      Mechanics
Skin type	●      People with red hair or thin skin (e.g., reduced thickness of epidermis/dermis, reduced keratinocytes, increased risk of skin tearing).
Comorbidities	●      Other skin conditions, such as atopic dermatitis or psoriasis. ●      Genetic factors, such as the TNF-α (-308 G/A) single nucleotide polymorphism or loss-of-function mutations in the FLG gene.
ABBREVIATIONS: TNF-α, tumor necrosis factor-alpha; FLG, filaggrin

 

In addition to these risk factors, higher dermal absorption may increase an individual’s risk for contact dermatitis.²⁶ Factors that impact dermal absorption include skin integrity, absorption location, the chemical’s physical and chemical properties, chemical concentration, absorption time of the chemical, and the surface area of skin that absorbs the chemical.¹

 

Signs and Symptoms

Signs and symptoms of contact dermatitis depend on whether the reaction is acute or chronic. An acute reaction, such as contact with poison ivy, can cause the skin to appear red and swollen and may have small vesicles. However, a chronic reaction caused by repeated reactions is more akin to a presentation of eczema with a rash that appears to thicken, scale, or crack.^3,13

The symptom location will also vary depending on the substance’s contact location. For example³

• A reaction to a skin care product’s ingredient may be localized to the face or eyes
• A reaction to poison ivy may be localized to the legs or hands
• A reaction to jewelry may be centralized around the neck or wrists

 

Common symptoms of contact dermatitis include^1,2

• Dry, flaking, scaly skin (may crack, ooze clear fluid, or crust)
• Inflamed skin (may look pink, red, brown, purple, or gray depending on skin tone)
• Itching (may lead to intense scratching and even bleeding)
• Pain
• Redness
• Small blisters or wheals (itchy, red circles that have a white center)
• Swelling

 

PAUSE AND PONDER: What over-the-counter products are appropriate to suggest to a patient with a poison ivy rash?

 

Diagnosis

Contact dermatitis often resolves once patients identify the trigger and avoid the substance going forward. With acute examples such as poison ivy, symptoms may resolve prior to a doctor’s visit.

 

However, for persistent symptoms that warrant an office visit, clinicians diagnose contact dermatitis by evaluating symptoms based on appearance and duration. They consider factors such as occupation and hobbies and use patch testing to confirm allergens.²⁶ Clinicians can perform skin biopsies to rule out additional skin conditions such as psoriasis and seborrheic dermatitis among others.²

 

During testing, clinicians apply small amounts of diluted allergens to the patient’s back under paper tape patches. After 48 hours, they remove the patches and evaluate the skin for signs of a reaction; the evaluation is repeated 72 to 96 hours later. A patch test helps identify chemicals or substances a patient is allergic to so they can be avoided in the future. The baseline patch test (baseline patch testing panels vary by geographic location, depending on the allergens available in each region ) finds approximately 70% of allergens.^2,3,28

 

The American Contact Dermatitis Society (ACDS) updated their “Core Allergen

Series” in 2020 to increase the chances of finding the responsible agent in contact dermatitis cases. This series is a patch-test panel designed to provide clinicians a tool to identify clinically relevant allergens beyond the standard baseline series.²⁹

 

Since job-specific allergies are common, patch testing is available for certain industries. For example, dermatologists and allergy specialists can use patches specific for florists or dental technicians. This expanded patch testing finds approximately 80% of allergens. Additional series may be applied based on the site of dermatitis, the suspected allergen exposure, and if patients bring their own products to be tested (may require dilution).^27,28

 

Reactions to patch testing are graded for each allergen on a spectrum as seen in Table 3.

 

Table 3. Grading and Interpreting Results to a Patch Test^28,30,31

Symbol	Reaction	Presentation
-	Negative	No reaction
?	Doubtful	Faint erythema only
+	Weak positive reaction	Mild reaction: erythema, infiltration, and possible papules
++	Strong positive reaction	Strong reaction: erythema, infiltration, papules, and vesicles
+++	Extreme positive reaction	Very strong reaction: intense erythema, infiltration, blisters, and coalescing vesicles
IR	Irritant reaction	Irritant reaction of different types

 

Positive reactions can be further classified based on their relevance or potential risk. A current relevance reaction indicates the identified allergen explains the patient’s present dermatitis. A past relevance reaction reflects an allergen responsible for a previous episode but not the current one. A future relevance reaction suggests sensitization to an allergen the patient is likely to encounter again. An uncertain relevance reaction identifies an allergen whose significance remains unclear until further investigation or inspection of the patient’s personal care or occupational exposures. Finally, a potential cross-reaction indicates that sensitivity to one allergen may cause a reaction to related substances.²⁸

 

TREATMENT OF CONTACT DERMATITIS

Pharmacologic Treatment

Currently, no cure for contact dermatitis exists. However, a variety of over-the-counter (OTC) and prescription products can provide patients with symptom relief.

 

Clinicians tailor treatment based on contact dermatitis type, location, severity, and classification (acute versus chronic). Clinicians classify cases as extensive, severe, or disabling if they involve over 20% of the total body surface area or involve the face, hands, feet, or genitalia.³²

 

While pharmacologic treatment provides rapid symptom control, prevention is the mainstay of management for both ACD and ICD. ACD treatment usually involves topical corticosteroids or tacrolimus with added emollients, while ICD treatment focuses on consistent emollient use and topical corticosteroids (when necessary to control irritation).^12,32

 

Providers must recognize that while topical corticosteroids may be used in ICD, evidence supporting their ability to restore the epithelial barrier remains limited. However, they may be prescribed for their anti-inflammatory properties. In ICD, ointments are generally preferred over creams as they are more occlusive. Formulations of products ordered from most to least occlusive are ointment, creams, lotions, and oils.^12,33 See the SIDEBAR for information on the uses and products that fall under each corticosteroid group.

 

SIDEBAR: Groups of Corticosteroids³⁴

Topical corticosteroids are grouped into seven classes based on their potency, ranging from superpotent (Group I) to least potent (Group VII). Potency affects both therapeutic efficacy and risk of adverse effects, making appropriate selection essential for safe and effective treatment.

• Group I (superpotent): used for thick, resistant plaques (e.g., clobetasol propionate 0.05%, halobetasol propionate 0.05%).
• Group II to III (high to medium-high potency): commonly used for less severe lesions or shorter treatment courses (e.g., betamethasone dipropionate 0.05%, fluocinonide 0.05%, triamcinolone acetonide 0.5%).
• Group IV to V (medium potency): appropriate for most body areas and moderate conditions (e.g., triamcinolone acetonide 0.1%, mometasone furoate 0.1%).
• Group VI to VII (low to least potent): preferred for sensitive areas such as the face, groin, or intertriginous areas (e.g., hydrocortisone 1%, desonide 0.05%).

 

For acute, localized ACD affecting the hands, feet, and nonflexural areas (areas of the body that do not naturally bend; e.g., the torso), treatment is a group I to III corticosteroid used once or twice daily for two to four weeks (treatment may be shorter if symptoms resolve).³²

 

For acute, localized ACD affecting the face or flexural areas (areas of the body that naturally form folds; e.g., the elbow or knee joints), treatment is a group IV to VI corticosteroid used once or twice daily for one to two weeks and then tapered off over two weeks. If treatment duration must be longer than two weeks, topical tacrolimus is used twice daily until improvement and is then tapered off. If the contact dermatitis is resistant to other treatments, topical ruxolitinib is used once daily until symptom resolution.³²

 

For extensive, severe, or disabling ACD, treatment is systemic corticosteroids. Prednisone is dosed at 0.5 mg/kg per day (or an equivalent dose, with a max daily dose of 60 mg/kg) for seven days. This dose is then reduced by 50% for five to seven days and then tapered off over two weeks.³²

 

For chronic ACD localized to the hands, feet, and nonflexural areas, treatment is a group I to III corticosteroid once daily for seven to 10 days, then once every other day.

 

For chronic ACD localized to the face and intertriginous (area where two skin areas may touch or rub together e.g., between digits or the armpit) areas and resistant to topical corticosteroids, treatment is topical tacrolimus used once or twice daily until symptom resolution. If it is resistant to other therapies, topical ruxolitinib is used once daily until symptom resolution.³²

 

Last, for chronic ACD that is resistant to topical treatments, phototherapy (bath psoralen plus ultraviolet A photochemotherapy or narrowband ultraviolet B has demonstrated clinical improvement in chronic hand eczema cases), or systemic immunosuppressive medication (such as oral methotrexate, cyclosporine, mofetil, azathioprine, mycophenolate) are used.³²

 

For mild, non-facial ICD, treatment is a group II or III corticosteroid that is used once or twice daily for two to four weeks. For severe, non-facial ICD, treatment is a group I corticosteroid used once or twice daily for two to four weeks. For facial or flexural ICD, treatment is a group IV to VI corticosteroid used once or twice daily for one to two weeks. Last, for chronic ICD with lichenification, treatment is petroleum jelly with or without a medium potency (group IV to V) corticosteroid overnight (under occlusion) for a few days.¹²

 

Over-the-Counter Treatment

In addition to prescription products, patients can use several OTC options to manage ACD or ICD. OTC products are chosen based on the symptoms the patient wants to treat.

 

Cold compresses or antihistamines (such as cetirizine, diphenhydramine, or loratadine) may reduce itching. Pharmacists and pharmacy technicians can recommend calamine lotion or aluminum acetate to dry oozing lesions. Alternatively, patients can take oatmeal baths; this is helpful in cases where the lesions are widespread over the body. Emollients and moisturizers effectively reduce irritation and improve the skin barrier. Additionally, hydrocortisone cream or ointment can decrease inflammation.^3,4,12

 

While people use the terms emollients and moisturizers interchangeably, knowing the distinction can prove useful when recommending products. Moisturizers help hydrate and maintain the skin’s moisture balance. Emollients help soften and smooth the skin by forming a protective layer that reduces water loss. Often, emollients can be used as an ingredient in the formulation of a moisturizer.³³

 

The two main types of emollients are occlusives and humectants. Occlusives create a lipophilic (“water-repelling”) film on the skin’s surface that acts as a barrier, helping to prevent moisture from evaporating from the outermost layer of the epidermis. Occlusives help skin retain moisture, but don’t provide additional moisture. Examples of occlusives include petroleum jelly, lanolin, oil (mineral or vegetable), beeswax, ceramides, and liquid paraffin.^12,33,35 However, some patients may experience “lanolin allergy,” which is a separate condition from contact dermatitis. Lanolin was the ACDS’s 2023 “Allergen of the Year” and some patients should avoid this ingredient.³⁶

 

Humectants are hydrophilic (“water-attracting”) and draw in and hold moisture within the stratum corneum, functioning in a way similar to the skin’s natural moisturizing factors found in corneocytes. Examples of humectants include glycerin, hyaluronic acid, urea, sorbitol, and propylene glycol.^12,33,35

 

Consistent application throughout the day improves the efficacy of emollients. Reapplication after handwashing and before bedtime especially help maintain the skin barrier and prevent flare-ups.¹²

 

Moisturizers reduce skin dryness, scaling, and transepithelial water loss which helps maintain skin integrity, flexibility, and barrier function.³³ Moisturizers are primarily comprised of emollients, occlusives, and humectants but may contain additional ingredients such as fragrances, surfactants (cleansers), and preservatives. Some special formulations may include ingredients with antimicrobial, anti-itch, and anti-inflammatory functions.

 

Choosing the ideal product for a patient depends on the target allergies, the skin’s condition and characteristics (inherent risk factors), and personal preference. Patients using a combination of prescription and OTC products may see symptom resolution within as early as one to two weeks.

 

Prevention

Prevention is the mainstay treatment for both ACD and ICD. Patients can take several actions to help prevent contact dermatitis.

 

First, patients should identify and avoid known allergens and irritants to prevent possible reactions. Making lifestyle choices such as selecting hypoallergenic jewelry, changing hair or skin care products, and putting cloth covers on metal fasteners (e.g., a jean button) can minimize reactions.^13,37

 

Patients can also improve and protect their skin barrier by continuously moisturizing and hydrating their skin. Various OTC products with different formulations allow patients to find a regimen that works best for their skin.^12,37

 

Patients should wash skin exposed to the allergen or irritant immediately after exposure to remove the irritant (e.g., poison ivy, poison oak) that cause the reaction. Products like Tecnu cleanser, Zanfel cleanser, and Cutter scrub effectively remove urushiol oil (the component of poison ivy and poison oak that causes the red, itchy rash patients experience). Urushiol oil binds to skin proteins within 10 to 15 minutes so immediate use of these products is vital.^13,37,38

 

Patients should also be mindful of pets. Sometimes, allergens can be carried from outside into the house by clinging to a pet’s fur. If patients suspect their pet encountered an allergen (such as poison ivy), they should bathe the animal to reduce the risk of spreading it to people.^13,37

 

Wearing gloves or protective clothing provides an excellent alternative for patients to avoid contact with irritants. This is especially vital for many occupational contact dermatitis cases. Barrier creams are another alternative that function to protect skin from irritants. Barrier creams prevent penetration of hazardous materials into the skin. These products contain compounds such as glycerin, silicones, ceramides, squalene, petrolatum, and other water repelling compounds. Barrier creams should be applied to exposed skin two to three times per day.^12,37

 

ALLERGENS IN CONTACT DERMATITIS

Common Causes of Allergic Contact Dermatitis

ACD is caused by a variety of common chemicals and substances. Common causes include^{11,13,32,37,39-43}

• Excipients (propylene glycol, lanolin)
• Fragrances (limonene, linalool, fragrance mix 1, fragrance mix 2)
• Glues (acrylates)
• Hair dyes and hair care products (toluene-2,5-diamine sulfate, para-phenylenediamine, cetrimonium chloride, cetrimonium bromide)
• Latex (balloons)
• Medications (antibiotics, glucocorticoids, topical antihistamines)
• Metals (nickel, cobalt, and gold); commonly used in jewelry, buckles, claps, buttons, etc.
• Personal care products such as body washes, cosmetics, and skin care products (panthenol, chlorphenesin, parabens, balsam of Peru, colophony [rosin])
• Plants (Toxicodendron genus is the most common; includes poison ivy, poison oak, and poison sumac)
• Preservatives (benzisothiazolinone, formaldehyde, methylisothiazolinone, quaternium-15)
• Surfactants (cocamidopropyl betadine, decyl glucosides)

This list is not exhaustive but serves as a strong starting point for identifying products or substances that may trigger ACD. As new cases are reported, experts continue to identify potential allergens, reflecting evolving exposure patterns and improving diagnostic awareness. Notably, toluene-2,5-diamine sulfate, a chemical commonly used in hair dye, was named the 2025 Allergen of the Year, highlighting its emerging significance in contact dermatitis.³⁹

Common Causes of Irritant Contact Dermatitis

ICD can be caused by a range of common chemicals and substances. Common causes include^11,12,37,40

• Acids and alkalizing agents (sulfuric acid, sodium hydroxide, ammonia)
• Adhesives
• Bleach, detergents, and solvents (benzene, toluene)
• Cosmetics
• Dust
• Fertilizers and pesticides
• Hair products
• Oxidizing agents (sodium hypochloride)
• Paints and varnishes
• Perfumes
• Personal care products
• Plant parts (thorns)
• Plastics
• Rubber gloves
• Soap
• Water

 

Pharmacy staff should recognize that certain products, such as hair and personal care items, can cause both ACD and ICD reactions. However, the underlying mechanisms and nature of the reactions differ between the two conditions.

 

ALLERGEN ALTERNATIVES

Once an allergen has been identified, the most effective management strategy is avoidance. Because many ingredients appear under multiple names, careful review of product labels is essential. For example, balsam of Peru has several names including, but not limited to, Balsamum peruvianim, Black balsam, China oil, Indian balsam, Myroxylon pereirae Klotzsch resin, Myroxylon pereirae Klotzsch oil, and Toluifera Pereira balsam.⁴⁴

 

Patients may need guidance selecting products that provide the desired symptom relief while avoiding their allergens. Many items contain suitable substitute ingredients and pharmacy staff can support patients by reviewing product labels for potential allergens.

 

For example, toluene-2,5-diamine sulfate is frequently used in hair dyes as a primary intermediate (main reactive dye precursor).⁴⁵ An alternative to this chemical is paraphenylenediamine.³⁹ Other strategies include replacing nickel-containing jewelry with sterling silver or titanium; selecting products preserved with phenoxyethanol or benzyl alcohol instead of chlorphenesin or parabens; choosing formulations that minimize preservatives through plant-derived alternatives or hydrosols; and opting for fragrance-free products to avoid balsam of Peru.^46,47

 

It is also important that pharmacy staff understand various terminology used to describe products that would be better suited for patients with allergies. Currently, no Food and Drug Administration regulated definition for the term “hypoallergenic” exists.⁴⁸ Therefore, terms such as “fragrance-free,” “noncomedogenic,” and “dermatologist-tested” are indicators of products that may be better suited for patients with allergies. Pharmacists and pharmacy technicians should notify patients that products with these terms may be more expensive. These products are often placed on lower shelves as they tend to sell slower compared to other popular, branded items.

 

Additionally, pharmacy staff can recommend swatch testing new products before use to minimize risk of a reaction. Patients can apply a quarter-sized amount of the new product on a spot of their skin where the product won’t be washed away or rubbed off, such as the underside of the arm or the bend of the elbow. Patients should follow the instructions of the product to determine how long the product would normally stay on the skin (if the product [e.g., a cleanser] has no specific instructions, leave on the skin for five minutes). The product should be applied to this test spot twice daily for seven to ten days. If there is no reaction after this period, the patient can safely use the new product.⁴⁹

 

Common Allergen-Free Over-the-Counter Products

Finding allergen-free products or brands can be tricky, however online resources can alleviate this burden.

 

One helpful resource is the Contact Allergen Management Program (CAMP) created by the ACDS. CAMP is a web-based tool designed to help patients manage ACD and find personal care products that are safe for them to use. However, CAMP is an exclusive tool for ACDS members and their patients, so access may be limited for some healthcare providers.

 

In addition to using this resource, pharmacists and pharmacy technicians should counsel patients to always read and scrutinize product labels. One tool to navigate product labels and ingredients is skinsafeproducts.com. This website allows patients, providers, and pharmacy teams to scan barcodes or search products to determine if they contain ingredients a patient would react to. It’s important to note this website does not have a filter for every possible allergen.

For example, consider Alvin, a 35-year-old man allergic to parabens and various fragrance mixes. He asks for help finding an aftershave and body lotion. Using the SkinSAFE website (skinsafeproducts.com) you identify that “Clubman Pinaud Reserve Aftershave, Whiskey Woods” is paraben-free and “Minimalist Body Lotion, Niacinamide 0.5%” is fragrance-free.

 

Pharmacy staff should always consider recommending a switch in product. For instance, if a patient has a small cut, pharmacists and pharmacy technicians can recommend petrolatum over bacitracin. Bacitracin was named the Contact Allergen of the Year for 2003 by the ACDS and patients have an increased risk of reaction with this product.⁵⁰ Pharmacy staff have the unique opportunity to help patients make safe and informed product changes.

 

One thing to keep in mind is that formulations change! A product may be safe the first time a person uses it, but it may not be safe the next time. It’s essential to ensure healthcare providers and pharmacy staff always verify the accuracy of all information they provide to each unique patient!

 

CONCLUSION

Now that you’ve reviewed the key concepts of contact dermatitis, let’s revisit our opening case.

To start, ask the patient clarifying questions such as, “When did the rash appear?”, “Have you done anything out of the ordinary recently?”, and “Has the child started any new products?” You then discover the family went camping over the weekend. When this information is combined with the child’s current symptoms, poison ivy is the likely culprit. Suggesting OTC products such as calamine lotion (for lesions) and a cold compress or antihistamine (for itching) can help the manage the patient’s symptoms. However, it’s important to advise the mother to bring her child to the pediatrician if symptoms persist or worsen.

 

By identifying likely triggers, recommending appropriate symptomatic relief, and knowing when to refer the patient to seek additional medical attention, pharmacy staff can improve outcomes for patients with contact dermatitis.

Download CE Activity

INTRODUCTION

It’s been a stressful week for Lance. Lance Sugarman, a 49-year-old male with a history of poorly-controlled type 2 diabetes (T2D), arrives at the emergency department (ED) with complaints of abdominal pain, pain and burning while urinating, and severe dehydration. Connie—his wife—shares with staff that he has become increasingly confused and disoriented over the last three days. In the ED, Lance discloses that he recently lost his health insurance coverage. As a result, he began to ration his insulin glargine by taking less than his prescribed amount (10 units once daily). His last dose was four days ago. Paramedics report that the patient has a peculiar, fruity smell. Point-of-care (POC) testing also notes several laboratory abnormalities (see Table 1). Based on these laboratory results and the patient’s presentation, Lance is admitted to the intensive care unit (ICU). Most importantly, the team has a diagnosis in mind and is prepared to initiate therapy.

 

Table 1. Lance Sugarman’s (MR1234567) Laboratory Findings
Test	Results (normal range)
Blood glucose	442 mg/dL (70-110 mg/dL)
Venous pH	6.72 (7.31-7.41)
Urine ketone strip	4+ (< 2+)*
β-hydroxybutyrate	5.2 mmol/L (< 0.5 mmol/L)
Serum bicarbonate	12 mmol/L (21-28 mmol/L)
Serum osmolality	282 mOsm/kg (275-295 mOsm/kg)
Serum potassium	3.1 mmol/L (3.5-5.0 mmol/L)
*A urine ketone of less than 2+ is consistent with the absence of ketosis or the presence of mild ketosis, which is considered normal.

 

PAUSE AND PONDER: What laboratory markers are you concerned about? What would be a part of your differential diagnosis?

 

Clearly, Lance’s blood glucose (BG) is dangerously elevated. Hyperglycemic crises—an umbrella term for diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS)—are life-threatening medical emergencies associated with uncontrolled diabetes mellitus (DM).¹ Since 2009, hospital admission rates in the United States (U.S.) for DKA and HHS have increased, and this trend is present globally as well.^2,3 Increasing rates of DKA and HHS can be attributed to higher medication costs, particularly insulin, and the rise in DM incidence, which increased from 200 million cases in 1990 to 830 million cases in 2021.^3,4

 

Patients with DKA and HHS present with severe hyperglycemia (elevated BG).⁵ HHS has markedly higher BG levels than DKA; BG levels can reach 600 mg/dL in DKA compared to 1,000 mg/dL in HHS.^5,6 Each diabetic emergency has specific defining criteria outside of hyperglycemia. DKA is characterized by an increased concentration of ketone bodies (metabolites of fatty acids) in the blood or urine and metabolic acidosis (a buildup of acid in the body).^5,7 HHS, on the other hand, is defined by hyperosmolarity (a higher than normal concentration of dissolved substances in the blood or other bodily fluid) and the absence of ketoacidosis (a buildup of ketones in the body).⁶

 

Many signs and symptoms of DKA and HHS overlap, such as dehydration in the setting of an elevated BG, making the clinical work-up and distinction difficult.⁶ To make matters more difficult, 27% of hospital admissions for hyperglycemic crises are for a mixed DKA-HHS presentation.⁵ Patients with a mixed DKA-HHS presentation have both ketoacidosis and hyperosmolarity.⁸ For the sake of simplicity, this continuing education will focus on DKA and HHS as separate entities. The interdisciplinary team should, however, be aware that mixed DKA-HHS exists. It is critical that the healthcare team—including pharmacists and pharmacy technicians—possesses the knowledge to differentiate between DKA and HHS to appropriately treat and manage patients.

 

BACKGROUND

Prevalence and Risk Factors

DKA and HHS make up approximately 1% of all hospitalizations in people with DM; hospital admission rates have increased by 55% over the last decade. ^5,9 DKA and HHS are complications of DM, but they do not occur at the same rate in both type 1 diabetes (T1D) and T2D. Prevalence of hyperglycemic crises in the U.S. is higher in patients with T1D (44.5 per 1,000 person-years) compared to patients with T2D (3.2 per 1,000 person-years).¹⁰ Moreover, DKA occurs most often in those aged 18 to 44 years with T1D compared to HHS, which commonly impacts an older subset of patients aged 45 to 64 years with T2D.⁵  Interestingly, DKA is the initial presentation—the clue that an undiagnosed patient has T1D—for around 6% to 21% of patients with T1D.⁵

Increasing technological advancements for monitoring BG and managing insulin regimens may be associated with decreased incidence or prompt recognition of hyperglycemic crises.⁵ Additionally, accurate monitoring helps prevent recurrent episodes.⁵ However, real-world data to corroborate this idea is still needed. The SIDEBAR discusses options for BG monitoring.

 

 

SIDEBAR: Sweet Surveillance^5,11-17

Early detection of DKA and HHS—via warning signs and urine or blood checks—allows patients or clinicians to start preventive measures or treatment promptly. The American Diabetes Association and European Association for the Study of Diabetes (ADA/EASD) recommend patients with T1D use a continuous glucose monitor (CGM) as the monitoring method of choice; patients with T2D may also use CGM.

 

CGMs are automated devices that can continuously estimate a patient’s glucose level at any time. With three parts—a small sensor inserted into the skin, a transmitter, and a receiver (which is often a SmartPhone)—a CGM provides real-time updates, allowing patients to take preventive measures for hypo- or hyper-glycemia. A blood glucose meter (BGM), on the other hand, is not inserted into the skin. Instead, a BGM uses blood samples collected from fingerstick devices (known as lancing devices or lancets) to calculate BG. CGMs, however, are often preferred due to portability and, thus, convenience.

 

Other tests to consider for DKA, specifically, are ketone concentration tests. Ketones can be measured by urine dipsticks (which measure acetoacetic acid) or blood samples (which measure β-hydroxybutyrate, the predominant ketone in DKA). Blood ketones provide real-time measurements. Urine ketones, instead, lag the concentration of blood ketones due to the shift of acetoacetic acid to β-hydroxybutyrate that occurs during early DKA. Thus, urine ketones may underestimate a patient’s current level of ketonemia (presence of ketone bodies in the blood) and are not preferred for diagnosing or monitoring DKA.

 

Testing for BG and/or ketones allows patients to contact their providers or an emergency call service in a timely manner; this, according to the Centers for Disease Control and Prevention and ADA/EASD, can reduce DKA or HHS admissions.

 

 

Mortality is higher among those with HHS compared to DKA (5% to 20% compared to less than 1%, respectively).^18,19 Several factors are attributed to HHS’s higher degree of mortality, including precipitating factors, age, and complications. Vascular complications, such as stroke or peripheral arterial and venous thrombosis, contribute to HHS’s high mortality rate.²⁰

 

Pathophysiology

In the U.S., 38 million (or one in 10) adults have DM, a group of metabolic diseases resulting from defects in insulin’s action, secretion, or both.^21,22 Insulin’s major action is reducing BG levels by driving glucose into cells.²³ When insulin becomes dysregulated (i.e., in DM), a patient’s blood sugar may rise. An elevated blood glucose is referred to as hyperglycemia. Though both T1D and T2D can lead to hyperglycemia, the preceding mechanism is different. To explain simply^24,25

• T1D is caused by the autoimmune destruction of β cells in the pancreas, leading to insufficient insulin secretion or absolute insulin deficiency.
• T2D is caused by a non-immune mediated process resulting in insulin resistance (or the body’s lack of response to insulin) which, over several years, may lead to relative insulin deficiency.

Insulin dysregulation leads not only to the development of diabetes, but to the development of hyperglycemic crises.

 

Insulin insufficiency and an increase in counterregulatory hormones—including cortisol, epinephrine, glucagon, growth hormone—are hallmarks of both types of hyperglycemic crises. The degree of the insulin deficit, however, plays a role in distinguishing between DKA and HHS; DKA is characterized by severe insulin deficiency compared to HHS, where less severe insulin deficiency is present.⁵

 

Glucagon is the primary counterregulatory hormone in DKA. It should be known, however, glucagon alteration is not essential for DKA to develop.^5,7 In DKA, changes to the glucagon-to-insulin ratio can lead to alterations in glucose synthesis, regulation, and utilization, resulting in hyperglycemia.⁵ Simultaneously, the severe insulin deficiency in DKA, along with the irregular counterregulatory hormones, results in release of free fatty acids (FFAs). Excess FFAs are oxidized to ketone bodies—acetone, acetoacetate, and β-hydroxybutyrate—leading to ketonemia and metabolic acidosis.^5,7,19

 

Ketoacidosis does not occur in HHS. Unlike DKA, sufficient insulin is present in patients with HHS, which prevents ketoacidosis from developing.⁵ Glucose production and use in the patient’s body, however, is still impacted, leading to hyperglycemia.⁵ HHS is also characterized by osmotic diuresis. Osmotic diuresis is increased urination due to the presence of certain substances (i.e., glucose) in the fluid filtered by the kidneys, creating a pressure imbalance between solutes and water in the kidneys. This process prevents water reabsorption and, instead, promotes water excretion in the form of urine. Osmotic diuresis occurs from reduced fluid intake (often caused by a precipitating event) and leads to HHS’s characteristic hyperosmolar state alongside severe dehydration and cognitive impairment.^5,7,18

 

PAUSE AND PONDER: What risk factors might you consider red flags for identifying these hyperglycemic crises in your pharmacy setting?

 

Precipitating Events and Risk Factors

Patients with DM present with hyperglycemic crises for several reasons, including^5,7

• difficulties in managing insulin therapy, such as omission or non-adherence
• metabolic stress
• intercurrent illness (a disease that occurs during the course of another disease) or infection

Challenges with therapy management is the most common cause of a hyperglycemic crisis in the U.S. (41% to 59.6% of patients). Worldwide, however, the predominant precipitating factor of a hyperglycemic crisis (occurring in 14% to 58% of cases) is intercurrent illness or infection. Common infectious causes include pneumonia and urinary tract infections (UTIs).^7,26

 

Several clinical and non-clinical factors put patients at risk for hyperglycemic crises. General risk factors for both DKA and HHS include^5,9,26

• socioeconomic status (e.g., low income, low educational achievement)
• history of previous hypo- or hyper-glycemic crises
• comorbid chronic health or behavioral health conditions, such as DM-related conditions (e.g., neuropathy), kidney disease, eating disorders, and depression
• alcohol and/or substance use
• certain medications, such as sodium-glucose cotransporter-2 inhibitors (SGLT2i; e.g., canagliflozin, dapagliflozin, empagliflozin) and anti-psychotics (e.g., clozapine, olanzapine, quetiapine, risperidone)
• elevated hemoglobin A1c (HbA1c)

 

Understanding risk factors and events that may trigger hyperglycemic crises is important for preventing both DKA and HHS. Counseling is important in these patient populations, specifically regarding monitoring (e.g., signs, symptoms, ketones, and BG) and self-management.⁹

 

CLINICAL PRESENTATION AND DIAGNOSIS

Signs and Symptoms of DKA and HHS

With both crises, patients may present with a variety of symptoms, with some overlapping. The differences in presentation, outlined in Table 2, can help pharmacy technicians determine when an individual may require pharmacist intervention and guide pharmacists to recommend appropriate treatment.

 

Table 2. Characteristic Features of DKA and HHS5,7,20,27,28
	DKA	HHS
Epidemiology	·       T1D ·       Younger	·       T2D ·       Older
Onset	·       Rapid, hours to days	·       Slow, days to a week
Cognitive function	·       Mild-to-moderate confusion	·       Severe confusion, seizures, or coma
Compensation	·       Kussmaul respirations	·       None
Symptoms	·       Abdominal pain ·       Mild dehydration ·       Mild weight loss ·       Nausea ·       Polydipsia ·       Polyuria ·       Vomiting	·       Higher degree of dehydration ·       Higher degree of weight loss ·       Polydipsia ·       Polyuria
Additional signs	·       Tachycardia ·       Tachypnea	·       Poor skin turgor
ABBREVIATIONS: DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state; T1D, type 1 diabetes; T2D, type 2 diabetes

 

When any patient presents with typical symptoms of hyperglycemia, such as polydipsia (excessive thirst), polyuria (excessive urination), and a change in cognitive state, clinicians should consider DKA or HHS in their differential diagnosis.⁹ However, it is important to be aware that not all patients present with these common signs; for example, patients with euglycemic DKA secondary to SGLT2i therapy often present with less polyuria and polydipsia.⁷ The SIDEBAR provides more information on euglycemic DKA.

 

Kussmaul respirations—a pattern of deep breathing and hyperventilation accompanied by a fruity odor—is a manifestation specific to DKA.^5,29 As previously discussed, patients with DKA have ketoacidosis, unlike HHS. Kussmaul respirations are the body’s compensatory response to the metabolic acidosis present during DKA as an attempt to normalize the disrupted acid-base balance.³⁰

 

 

SIDEBAR: Sweet Lies: Euglycemic DKA^5,9,31,32

DKA is a common complication of DM characterized by ketonemia, metabolic acidosis, and hyperglycemia (serum glucose at or exceeding 200 mg/dL [11.1 mmol/L]). However, 10% of patients present with an uncommon complication of DM and presentation of DKA—euglycemic DKA. Euglycemic DKA occurs without hyperglycemia but rather euglycemia (normal serum glucose of 200 mg/dL [11.1 mmol/L] or less). (PRO TIP: the prefix “eu-” means good or well, and in medicine is often used to mean “normal.”) Patients with euglycemic DKA, like DKA and HHS, have an insulin deficiency.

 

Without clear signs of hyperglycemia present (e.g., polydipsia, polyuria), diagnosis or treatment may be delayed. Patients presenting with euglycemic DKA, therefore, are at risk of increased mortality and morbidity. Common causes of euglycemic DKA include

• alcohol use
• exogenous insulin injection
• liver failure
• pregnancy
• SGLT2i therapy
• starvation

 

Of these, SGLT2i therapy accounts for the greatest number of euglycemic DKA cases. Cases of euglycemic DKA have continued to increase over the last couple of years. This has resulted in changes to the guideline recommendations for diagnosing DKA. The ADA/EASD, Joint British Diabetes Societies for Inpatient Care (JBDS), American Association of Clinical Endocrinology (AACE), and Diabetes Technology Society (DTS) recommend diagnosing DKA with either a blood glucose of greater than 200 mg/dL (11.1 mmol/L; previously 250 mg/dL [13.9 mmol/L]) or any BG level in a patient who presents with a history of DM.

 

 

DKA and HHS Diagnosis

Hiding is not their forte; DKA and HHS give their diagnostic criteria away immediately! Literally. It’s in their names. According to the ADA/EASD/JBDS/AACE/DTS Hyperglycemic Crises in Adults with Diabetes Consensus Report, clinicians diagnose DKA based on the presence of all three of the following criteria^5,9:

1. Diabetes/Hyperglycemia: an elevated BG level OR a prior history of DM regardless of BG level
2. Ketonemia: an elevated ketone body concentration in the blood OR urine
3. Acidosis: a diminished venous pH AND/OR reduced serum bicarbonate level

 

Clinicians diagnose HHS based on the presence of all three of the following criteria:

1. Hyperosmolality: an elevated calculated effective or total serum osmolality
2. Hyperglycemia: an elevated BG level
3. AbSence of ketonemia (ketone body concentration is not elevated in the blood OR urine) AND acidosis (venous pH AND serum bicarbonate are within normal limits)

 

Table 3 lists laboratory markers mentioned in the diagnostic criteria for DKA and HHS. Upon reviewing Table 3, revisit Lance’s laboratory findings (see Table 1) and his clinical picture to determine his diagnosis. His BG clearly demonstrates a hyperglycemic crisis, and these two types are related but not the same.

 

Table 3. Laboratory Markers for Diagnosis of DKA and HHS5
Laboratory marker	DKA	HHS
Glucose	≥ 200 mg/dL (11.1 mmol/L) OR history of DM	≥ 600 mg/dL (33.3 mmol/L)
BHB concentration	≥ 3.0 mmol/L OR urine ketone strip ≥ 2+	< 3.0 mmol/L OR urine ketone strip < 2+
Urine ketone strip
Venous pH	pH < 7.3 AND/OR < 18 mmol/L	pH ≥ 7.3 AND ≥ 15 mmol/L
Serum bicarbonate
Serum osmolality	NA	> 300 mOsm/kg (calculated effective) OR > 320 mOsm/kg (total)

ABBREVIATIONS: BHB, β-hydroxybutyrate; DKA, diabetic ketoacidosis; DM, diabetes mellitus; HHS, hyperosmolar hyperglycemic state

 

Patients and clinicians can measure ketone body concentrations using several methods, including urine, serum, and blood testing. Urine and serum testing measures concentration of acetoacetic acid while blood testing quantifies the concentration of β-hydroxybutyrate, which is preferred due to higher specificity for DKA.⁵ The patient care team should also acknowledge the potential overlaps in presentation. Clinicians diagnose HHS based on the absence of metabolic acidosis, indicated by normal venous pH and bicarbonate levels, and the absence of ketonemia, shown by low β-hydroxybutyrate or negative urine ketones. However, patients with HHS may have mild ketonemia due to modest ketone production, though ketone levels are generally much lower than in DKA.¹⁸ Similarly, patients with HHS may have mild metabolic acidosis resulting from dehydration secondary to the hyperosmolar state, as reduced volume promotes lactic acid production that disrupts the acid-base balance.¹⁸

 

Given his combination of laboratory abnormalities and clinical presentation (i.e., signs and symptoms), Lance from the patient case presented is experiencing a classic episode of DKA.

 

Patients suspected of having DKA or HHS must be referred for emergency evaluation, treatment, and a thorough work-up.⁷ All work-ups should evaluate vital signs and laboratory findings to not only confirm a hyperglycemic crises, but also to narrow down a precipitating event and anticipate complications.^5,18,26 Outside of the parameters listed in Table 3, clinicians must measure blood electrolyte levels and perform an electrocardiogram.⁵ If an infection is the suspected precipitating cause, the ADA/EASD/JBDS/AACE/DTS recommends a urinalysis (urine test) and/or chest X-ray to identify and/or diagnose a UTI or pneumonia, respectively.^5,18 Based on lab results, patient history, and final diagnosis, clinicians initiate disease-specific therapy.

 

Remember the pain and burning sensation Lance reported in the ED? His physician ordered a urinalysis, which found elevated bacteriuria (bacteria in the urine), and a urine culture, which was found to be positive and growing Escherichia coli. Turns out he has a UTI! With this information, the team is prepared to initiate appropriate antibiotics and prepare for complications of UTIs or DKA. This infection is what likely exacerbated his DM and led to this episode of DKA.

 

TREATMENT OF DKA AND HHS

Goals of Therapy

DKA and HHS share several features, including some aspects of treatment and therapeutic goals. Successfully treating hyperglycemic crises requires the following^5,33:

• correction of dehydration
• correction of hyperglycemia
• correction of electrolyte imbalance(s)
• identification and treatment of precipitating event(s)

 

PAUSE AND PONDER: What medications can be used to lower blood sugar? Which should you use first in a hyperglycemic crisis?

 

Dehydration

Intravenous (IV) fluids are first-line therapy for DKA and HHS.^7,34 Treatment with IV fluids restores intravascular volume to perfuse organs and tissue, correct electrolyte abnormalities, and resolve metabolic acidosis and ketogenesis.^5,7,35 Correcting the fluid deficit aids in decreasing BG and regulating counterregulatory hormone levels.³⁴

 

The ADA/EASD/JBDS/AACE/DTS recommend isotonic saline—also known as 0.9% sodium chloride (NaCl) or normal saline (NS)—as the fluid of choice for patients without renal or cardiac compromise.⁵ Use of a balanced crystalloid (e.g., lactated ringers [LR]), however, is an acceptable choice.⁵ During the first two to four hours, the administration rate is 500 to 1,000 mL/hour.⁵ Subsequent fluid replacement (i.e., 0.45% or 0.9% NS) and administration rate is based on hemodynamic stability and the patient’s fluid status.^5,7

 

Balanced crystalloids contain sodium, potassium, and chloride content resembling that of normal extracellular fluid and cause fewer adverse effects on acid-base balance compared to NS.^5,36 A recent systematic review and meta-analysis of eight randomized controlled trials involving 482 patients found that LR shortened the time to DKA resolution and length of hospital stay.³⁶ Patients treated with NS required 3.51 additional hours to recover from DKA and remained hospitalized for nearly an additional day (specifically, 0.89 days).³⁶ LR may decrease costs for patients but may increase costs for hospitals. One liter of LR typically costs more than twice that of one liter of NS, with one source indicating they cost $4.50 and $2, respectively.³⁷ While research suggests LR resolves hyperglycemic emergencies faster, the patient-care team and hospital’s procurement team must weigh the potential increase in clinical benefits against the increase in cost. Therefore, the ADA/EASD/JBDS/AACE/DTS guidelines recommend physicians choose IV fluids based on availability, cost, and patient-specific information.⁵

 

Fluid therapy decreases BG—slowly, but surely. In DKA, for example, a patient’s BG can fall to less than 250 mg/dL in four to eight hours.⁵ Using concomitant insulin compounds the reduction. If not closely monitored, patients become at risk of having a hypoglycemic (low BG) episode. As a result, 5% or 10% dextrose is a recommended addition to the fluid regimen once BG falls to less than 250 mg/dL to maintain BG and allow for ketoacidosis to resolve.^5,38

 

Hyperglycemia

Acute Management

Insulin, like fluid management, decreases BG and regulates ketogenesis.³⁵ However, patients undergoing hyperglycemic crises should never receive insulin in place of or before fluid therapy. Insulin administration shifts fluids from the intravascular space into the cells, which can exacerbate hypovolemia (decreased blood volume) and lead to severe hypotension (decreased blood pressure).³⁹ For this reason, insulin is recommended following initial fluid resusicitation.³⁹

 

Short-acting, IV insulin (e.g., insulin regular [Humulin R, Novolin R]) is the cornerstone of DKA and HHS management and prescribers should start IV insulin as soon as a patient is diagnosed and adequately hydrated.⁵ Rapid-acting insulin (e.g., insulin lispro [Humalog]) is considered for the treatment of mild or moderate DKA but not HHS.^5,19

 

The continuous insulin infusion rate used in DKA depends on a facility’s protocols and the severity of the patient’s condition. Preferred options include a fixed-rate starting at 0.1 units/kg/hour or a nurse-driven protocol (variable rates).⁵ Nurse-driven protocols and algorithms allow nurses to adjust treatment based on laboratory results. Different providers might choose different rates or fluids to treat patients, while a nurse-driven protocol makes sure all patients receive all the same guideline-driven medications, unless otherwise contraindicated.⁴⁰ If obtaining venous access is delayed for any reason, it is recommended to initiate an intramuscular (IM) bolus dose (0.1 units/kg) of insulin.³³

 

HHS treatment depends on the presence of ketosis (metabolic state in which the body burns fat for energy), ketonemia, and acidosis. The ADA/EASD/JBDS/AACE/DTS recommends initiating insulin at 0.05 units/kg/hour in patients with HHS, no ketosis or mild-to-moderate ketonemia, and no acidosis.⁵

 

Regardless of the crisis or regimen chosen, the insulin rate requires adjustment—like with fluid replacement—once BG falls below 250 mg/dL.^5,34  Insulin’s rate should be corrected (based on institution specific protocols) to maintain BG at 150 to 200 mg/dL in DKA or 200 to 250 mg/dL in HHS until resolution (to be discussed later) of either crisis.⁵

 

Maintenance Insulin Therapy

Following resolution of DKA or HHS and when patients can tolerate food and drink, they should transition from IV to subcutaneous insulin. During this transition period, patients are at an increased risk of hyperglycemia, ketoacidosis, and recurrent DKA or HHS.^5,18 IV insulin’s half-life is short, around less than 10 minutes.⁴¹ Thus, to prevent these complications, an overlap between discontinuation of IV insulin and the initiation of subcutaneous insulin must occur over one to two hours.^5,33

 

The treatment team designs the patient’s subcutaneous insulin regimen based on current clinical situation, previous insulin use, and assessment of insulin requirements.⁴¹ The ADA/EASD/JBDS/AACE/DTS recommends that patients with known DM and previous insulin use receive their at-home regimen.⁵ For patients without known DM or prior insulin use, various methods are available to estimate total daily dose (TDD) of insulin. No consensus on a preferred method is available, but approaches often used include^5,41

1. Weight-based calculation: 0.5 to 0.6 units/kg/day for insulin-naive patients; 0.3 units/kg/day for patients with risk factors for hypoglycemia, such as kidney failure
2. Pre-admission insulin requirements: for patients with history of insulin use prior to hospital admission, consider previous TDD of insulin and evaluate outpatient HbA1c levels
3. Hourly inpatient IV insulin requirements: uses the patient’s current in-hospital summation of hourly IV insulin requirements; evaluate a several-hour period (typically six-to-eight hours) during which the patient’s BG remains at goal and the IV insulin rate is stable

 

With TDD calculated, it is time to choose an appropriate insulin regimen. Insulin regimens should be dosed properly to ensure 24-hour coverage.^5,41 Additionally, certain insulin types are preferred over others. The ADA/EASD/JBDS/AACE/DTS recommended therapy is a basal-bolus (basal and rapid-acting) insulin regimen, as it is closely mimics physiologic state and reduces hypoglycemia risk.⁵ Short-acting insulin regimens are an acceptable alternative, but they may require a change in frequency (i.e., from once daily to twice daily) to ensure adequate coverage.⁵ SGLT2is should not be initiated or continued in a hospitalized patient.⁵ Non-insulin agents—excluding SGLT2is—may be considered in a patient with T2D undergoing insulin therapy or if they are ketosis-prone. Non-insulin agents are contraindicated in patients with T1D.⁵

 

Electrolyte Imbalances

Electrolyte disorders—most commonly of potassium—occur in both DKA and HHS. Potassium-associated disorders may result from osmotic diuresis (in HHS) or metabolic acidosis (in DKA).^5,18 Patients may present with low potassium (hypokalemia), normal potassium, or high potassium (hyperkalemia). One-third of patients arrive to the hospital in a hyperkalemic state, while the remaining patients typically present with normal potassium levels.⁴² (Potassium will decline within 48 hours of initiating treatment for DKA or HHS, like insulin therapy, so additional treatments for hyperkalemia are not required.⁵)

 

A small proportion of patients—5% to 10%—have low potassium (less than 3.5 mmol/L) at admission.⁵ In this population, insulin initiation should be delayed. Insulin’s purpose in DKA and HHS management is to decrease BG. However, insulin also stimulates the movement of potassium into the cells, which may result in hypokalemia during infusion.^5,18 Potassium replacement is initiated at 10 mmol/hour in individuals with hypokalemia.⁵ Once serum potassium is greater than 3.5 mmol/L, insulin infusion can begin.

 

During DKA or HHS management, potassium serum levels are maintained at a goal level of 4 to 5 mmol/L.⁵ (Potassium is often presented in mEq/L; 1 mmol/L of potassium is equal to 1 mEq/L of potassium.) If not monitored and maintained at goal, hypokalemia may develop in 55% of patients undergoing insulin and fluid therapy.^5,43 Without replenishment, patients are at risk of life-threatening arrythmias, myocardial infarction, and respiratory muscle weakness.^18,42

 

Upon treatment initiation with fluids and insulin, potassium levels will begin to decrease.⁵ If the team fails to monitor hyperkalemic patients closely, they may develop hypokalemia. Potassium replacement (20 to 30 mmol/L of potassium) is appropriate to add to IV fluids if the serum potassium level falls to 5 mmol/L or less.^5,18

 

Other electrolyte disorders—such as hypomagnesemia (low magnesium), hypophosphatemia (low phosphates), bicarbonate irregularities—are not regularly monitored or treated. It is important, however, to know when repletion is indicated and the available treatment options.^5,18,39,42

 

Hypophosphatemia results from an extracellular shift of phosphate. Severe hypophosphatemia may lead to decreased cardiac function, respiratory failure, rhabdomyolysis, and more.^5,26 Phosphate therapy, however, is not indicated in all patients due to risk of hypocalcemia (low calcium) and hypomagnesmia.^18,26 Patients with DKA and a phosphate level of less than 1 mg/dL or with evidence of muscle weakness (i.e., respiratory or cardiac compromise) are indicated for phosphate replacement.^5,18 Information concerning phosphate replacement for patients with HHS is limited and often extrapolated from data for DKA. The ADA/EASD/JBDS/AACE/DTS recommends using a similar approach in patients with both DKA and HHS.^5,18 If indicated, replacement fluids may be enhanced with 20 to 30 mmol of potassium phosphate.⁵

 

Low serum levels of bicarbonate are a root cause of metabolic acidosis in DKA. Bicarbonate administration is not typically recommended, however, unless the patient develops severe metabolic acidosis or severe hyperkalemia with a decrease in cardiac function.^5,26 Severe metabolic acidosis is defined as a venous pH less than 7.0.⁵ Clinicians may administer 100 mmol of sodium bicarbonate (8.4% solution) in 400 mL of sterile water every 2 hours to replenish bicarbonate until pH is greater than 7.0.⁵

 

Magnesium abnormalities may appear in DKA and HHS but are not commonly treated. Hypomagnesemia may result in arrythmias, which can lead to Torsade’s de Pointes (a life-threatening rapid, abnormal heart rhythm), muscle weakness, and convulsions.^18,39 The ADA/EASD/JBDS/AACE/DTS do not provide a recommendation for magnesium replacement initiation or regimen. The American Academy of Family Physicians recommends starting replacement therapy if magnesium levels are less than 1.2 mg/dL, but they do not provide a treatment regimen.²⁶

 

Returning to the case, Lance’s care team ordered an initial bolus of 1,000 mL/hour of 0.9% NS. After two hours, the team decides to reorder a POC glucose and electrolyte panel, resulting in a glucose drop to 309 mg/dL. Though this is a great initial reduction, Lance is still not at goal. Lance’s physician orders 9.38 units/hour of insulin regular. The pharmacist, however, denies the order. At first the physician believes the order is wrong (it is not; to check yourself, use the patient weight: 93.8 kg). But the pharmacist explains that insulin is currently not indicated since the patient’s electrolyte panel still shows hypokalemia (3.1 mmol/L). Grateful to the pharmacist for a great catch, the physician, instead, orders a potassium replacement regimen. The physician will add insulin to Lance’s regimen once indicated.

 

ONGOING MANAGEMENT OF DKA AND HHS

Monitoring

Patients undergoing treatment for DKA or HHS require continuous monitoring until either crisis is resolved.⁵ Monitoring allows clinicians to assess treatment responses, adjust treatment regimens, and prevent possible complications.

 

Monitoring parameters to be reviewed during the treatment of DKA and HHS include^5,18,26

• serum BG, every hour
• electrolytes (i.e., potassium, sodium), β-hydroxybutyrate, phosphate, renal function (serum creatinine), and venous pH, every two to four hours
• serum osmolality (only in HHS), every two to four hours

 

Resolution

The criteria for determining resolution of DKA and HHS differ, except for serum glucose; even then, the preferred glucose ranges are not the same. Table 4 provides details on the specific metabolic parameters assessed when determining resolution of DKA or HHS.

 

Table 4. Criteria for Resolution of DKA and HHS5,18
	DKA	HHS
Serum glucose	< 200 mg/dL (11.1 mmol/L)	< 250 mg/dL (13.9 mmol/L)
Plasma ketones	< 0.6 mmol/L	NA
Serum bicarbonate	≥ 18 mmol/L	NA
Venous pH	≥ 7.3	NA
Serum osmolality	NA	< 300 mOsm/kg
Urine output	NA	> 0.5 mL/kg/hour
Cognitive status	NA	Improved, return to normal

 

Understanding which parameters indicate DKA resolution is important. Equally as important is knowing which values should not be used. The following parameters are used for DKA diagnosis but not to identify crisis resolution^5,26,16:

• Anion gap: Patients undergoing treatment with large volumes of 0.9% NS (which contains a high chloride content) are at risk of hyperchloremic metabolic acidosis. The excess chloride in 0.9% NS displaces bicarbonate which can offset the acid-base balance leading to a seemingly normal anion gap. This may be misleading in assessing resolution of DKA.
• Urine ketones: These are unreliable in determining resolution due to conversion of β-hydroxybutyrate to acetoacetate (a ketone body excreted in the urine) as acidosis improves, resulting in an increase in urine ketone readings. This may be viewed as DKA worsening when, in reality, blood ketone levels are declining and DKA is resolving.

 

PAUSE AND PONDER: What complications may you expect to see in DKA or HHS? Which are related to treatment options?

 

Complications

Patients with DKA and HHS are at risk for several complications, including

• acute kidney injury (rapid decline in kidney function)
• cerebral edema (increased fluid content in the brain tissue)
• hyperchloremic non-anion gap
• hypoglycemia
• hypokalemia
• metabolic acidosis
• osmotic demyelinating syndrome (neurologic disorder caused by a rapid increase in sodium)
• thrombosis (blood clot)

 

Hypoglycemia and hypokalemia are common, and previous sections discussed their treatments.

 

Several complications may occur during a hyperglycemic crisis and its management; cerebral edema is the most life-threatening.⁷ Cerebral edema may occur in DKA and HHS within 12 hours of treatment initiation.¹⁹ Though rare in adults, it has a mortality rate of around 30%.^5,26

 

The exact mechanism of development is unknown. In HHS, for example, elevated BG and rapid decrease in BG (from fluid and insulin therapy) can both lead to this complication.¹⁸ Rapid BG decline causes an osmotic gradient (a difference in liquid pressure between different compartments) in the brain, causing water to shift into the brain.¹⁸

 

The treatment team must not delay treatment for cerebral edema, even if results of imaging studies are not yet available.^5,19 Thus, prompt recognition of signs and symptoms is necessary, which may include^26,7

• altered level of consciousness
• altered respiration and heart rate
• incontinence (especially if inappropriate for age)
• new onset or worsening headache
• recurrent vomiting

 

Recommended treatment includes a mannitol infusion with concomitant mechanical ventilation or hypertonic (3%) saline infusion.^5,18,19 Specific regimens vary based on the guideline. Both infusion options result in the shift of water from the intracellular compartment to the vascular compartment.¹⁹ Slow correction of hyperglycemia and hyperosmolality in patients with HHS prevents cerebral edema.^5,18 The decline of hyperglycemia and hyperosmolality should not exceed 90 to 120 mg/dL/hour and 3.0 to 8.0 mOsm/kg/hour, respectively.⁵ Prompt treatment can prevent neurologic deterioration.⁷

 

PHARMACY TEAM IMPACT ON PREVENTION AND MANAGEMENT

Pharmacists and pharmacy technicians are vital members of the interdisciplinary team. Their roles include collaborating with providers to prevent and manage glycemic crises or recognize signs of a crisis.^15,44

 

In the inpatient setting, pharmacists can improve outcomes for patients with DKA and HHS by ensuring clinicians order fluid, insulin, and electrolyte regimens (dose and rate) correctly.⁴⁴ Admission medication reconciliations, acquired by a medication history technician, can help the patient care team determine possible medication use issues at home.⁴⁴ Concerns may include actual medication use, non-adherence, and barriers to adherence.⁴⁴ These details are important for determining a precipitating event and/or preparing a patient-centered discharge plan to avoid future occurrences. Technicians should escalate their concerns to the pharmacist.

 

Community and ambulatory care pharmacists can also assist with management and prevention of hyperglycemic crises. In these settings, pharmacists can detect patients at high risk of DKA or HHS. Pharmacists can review and determine adherence patterns (i.e., missing refills or needing refills too soon), insurance coverage, or other social determinants of health.¹⁵ Community pharmacists can help patients with limited or no insurance coverage acquire insulin and help insured patients navigate their prescription plan coverage.⁴⁵

 

Pharmacists and pharmacy technicians can also leverage their knowledge of hyperglycemic crises to identify at-risk patients in the community setting, acting as an added layer of protection for the community. By recognizing warning signs (“red flags”), technicians can escalate concerns to the pharmacist and pharmacists can recommend immediate referral to the ED. The following signs should prompt immediate medical attention, especially in the setting of a DM diagnosis^9,12,13:

• fruity-smelling deep respirations or hyperventilation
• decreased cognitive function and/or increasing confusion
• elevated BG levels
• elevated urine or blood ketone levels
• inability to tolerate oral hydration
• polydipsia or polyuria
• signs and symptoms of worsening illness

 

All pharmacists—with or without Certified Diabetes Educator credentials—are well positioned to provide medication counseling and patient education at discharge. This includes guidance on new medication and equipment or adjustments to existing at-home regimens.^44-46 Specifically, pharmacists can emphasize the importance of proper medication use, adherence to the prescribed regimen, and consistent monitoring of BG or ketones.⁴⁵ These interventions support safer recovery and can reduce the risk of complications and future admissions.⁴⁶

 

CONCLUSION

DKA and HHS are complications of DM, although their specific prevalence depends on the type of DM and the patient’s age, both are becoming increasingly common. Goals of treating hyperglycemic crises include correction of dehydration, hyperglycemia, and electrolyte imbalances. Fluid resuscitation, insulin infusion, and, potentially, potassium replacement can treat DKA and HHS. Though these goals and treatments appear straightforward, patient care teams—including pharmacists and pharmacy technicians—must pay close attention to the results of continual monitoring. Without attention to detail, patients may receive inappropriate treatment and be at risk of life-threatening complications. Through verifying or correcting orders (like Lance’s pharmacist) and counseling on new medications or BG monitoring at discharge, pharmacists can help treat a hyperglycemic crisis and prevent future episodes. Pharmacy technicians can assist in determining a precipitating event (e.g., non-adherence) and escalate symptom-related or medicinal concerns to pharmacists.

 

Returning to Lance one last time, after his potassium was corrected, he was initiated on the previously ordered insulin NPH dose. Guideline recommended treatment adjustments were followed thereafter (i.e., reducing insulin dose, addition of dextrose). Two days after ICU admission, Lance’s DKA fully resolved. At discharge, a social worker helps Lance enroll in a patient assistance program and the pharmacist counsels him on appropriate treatment and monitoring. Feeling more confident in managing his T2D, Lance is ready continue enjoying his sweet life with Connie by his side.

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INTRODUCTION

Menopause is a natural part of biological aging in women. This phenomenon marks the end of reproductive years, and every woman who lives long enough will experience it.¹ Often beginning in perimenopause—the period of time leading up to menopause—women experience many symptoms and health risks.^1,2

 

Approximately 1.3 million women in the United States (U.S.) enter menopause every year.³ Despite being a natural result of aging, menopause has historically been shrouded in secrecy and seldom openly discussed, but the New York Times reports that high profile women and female celebrities alike are now openly discussing their experience with menopause. It also reports that the market is being flooded with menopause-related beauty products and telemedicine start-ups.⁴

 

With increased interest, a growing movement to increase awareness, and information flooding the Internet, it is important now more than ever for women to receive accurate information from healthcare providers and reputable sources. However, a recent survey revealed that nationally, most obstetrics and gynecology residency programs lack a dedicated menopause curriculum. Most program directors also agreed that their programs needed more menopause education resources.⁵ 

 

Many symptoms and health risks of menopause, if left unmanaged, have an impact on a woman’s quality of life, productivity, and emotional state. Women are living longer, and a woman may live many years after menopause. Globally, a woman aged 60 years in 2019 could expect to live on average another 21 years.¹

 

Years after the National Institutes of Health's (NIHs) Women's Health Initiative, HRT as an option for certain symptoms in postmenopausal women is back in the spotlight. Now, physicians take a nuanced approach to HRT, considering certain individual patient factors.^6,7

 

It is important for women to recognize symptoms, understand the risk of chronic conditions, and generally educate themselves about the menopause transition. Being well-informed about the menopause transition means women can be proactive and lead healthier lifestyles to counter the issues that may arise with menopause such as bone loss and cardiovascular disease. Proper management during this period results in healthy aging and better quality of life. Menopause is a universal female experience, and it is vital that both physicians and women alike be appropriately informed about it.

 

PAUSE AND PONDER: What do you wish you knew about menopause before you or a loved one began the menopause transition?

 

DEFINING MENOPAUSE AND ITS EFFECTS

Perimenopause is the period leading up to menopause and signals the final years of a woman’s reproductive life. This period can last several years, the average being four years.² It begins with irregular menstrual cycles marked by a gradual loss of ovarian follicular function (i.e., ovaries begin to stop releasing eggs for fertilization) and a decline in circulating estrogen and progesterone levels.^1,2 This period may usher in a slew of symptoms, and the hormonal changes and fluctuations are often responsible for them.² A woman can still get pregnant during perimenopause because although menstruation is irregular, the ovaries can still release eggs for fertilization. It is impossible to accurately predict ovulation, and women must use adequate birth control until one full year after the last period to avoid unwanted pregnancy.²

 

Menopause marks the end of the reproductive years for women.^1,2 Menopause occurs or is diagnosed after 12 consecutive months without menstruation in the absence of clinical intervention or other physiologic or pathologic cause.¹ This means that a woman could go 11 months with no menstruation and then have a period in the 12^th month. The clock would then begin all over again. A woman cannot become naturally pregnant after menopause because the ovaries have stopped releasing eggs for fertilization. Importantly, they can still contract sexually transmitted diseases, so experts advise women to use adequate protective measures.²

 

The average age of menopause in the U.S. is 52.² Genetics, lifestyle, and environmental factors influence the age at menopause and the timing of symptoms throughout the menopausal transition. According to the World Health Organization, for women worldwide, natural menopause generally occurs between age 45 and 55.¹ The SIDEBAR lists factors that trigger early menopause.

 

SIDEBAR: Factors That Trigger an Early Onset of Menopause^1,2

• Surgical procedures that involve removing both ovaries
• Medical interventions that cause termination of ovarian function, such as radiation therapy and chemotherapy
• Premature menopause, or menopause before age 40 due to chromosomal abnormalities, autoimmune disorders, or other unknown causes

 

Menopausal Hormone Changes

Years before menopause occurs, ovarian function begins to fluctuate.² This is a progressive process often responsible for many of the symptoms women experience during this period.

 

How this Happens

Ovaries are the primary estrogen source in a woman’s body, with follicles synthesizing and releasing the hormone. An ovary has the greatest number of oocytes (about 1 to 2 million) at birth. Oocytes are the immature cells within a follicle that potentially mature into fully developed eggs. A fully developed egg is  released from the ovary during ovulation and travels down the fallopian tube to be potentially fertilized.^8,9

 

As women age, the number of follicles in their ovaries decrease. During a physiological process known as atresia, ovarian follicles that contain oocytes degenerate and die. This is a normal process that happens in all women. The process ensures that only healthy follicles with oocytes mature and ovulate. During atresia, follicle cells die, eggs break down, and macrophages and other follicular cells resorb the follicle contents. Although ovulation will also decrease the number of follicles, the vast number of follicles are decreased through atresia. At some point the number of follicles and oocytes reach critically low levels in the ovaries. Since these are responsible for producing estrogen, this is when women begin to experience symptoms associated with estrogen depletion.^8,9

 

At various stages during the menopause transition, women may only have a few hundred to a few thousand oocytes left. Estrogen levels decrease and menstrual periods become irregular. As various tissues in the body have estrogen receptors, when estrogen levels decrease or fluctuate, several systems can develop and women experience many of the symptoms of perimenopause and menopause.^8,9

 

Progesterone levels also decrease during the menopausal transition. After ovulation releases the egg from the follicle, the leftover contents of the empty follicle form the corpus luteum, a temporary gland that produces progesterone.¹⁰ Progesterone thickens the endometrium (lining of the uterus) for a fertilized egg to implant and grow. If pregnancy occurs, the placenta takes over the production of progesterone. In the absence of pregnancy, progesterone levels drop, causing the endometrium to shed (causing menstruation). During the menopause transition, the ovaries no longer produce high levels of estrogen and progesterone in the absence of regular ovulation.¹⁰

 

Symptoms of Menopause

Hormonal changes and fluctuations lead to the many symptoms associated with perimenopause and menopause, some more common than others and affecting each woman differently, with varying degrees of severity. Vasomotor symptoms (VMS) like hot flashes are the most recognized and reported symptom of menopause.¹¹ Table 1 describes the symptoms a woman may experience during and after the menopause transition listed in the order in which they typically occur. For less common symptoms of menopause, see the SIDEBAR. Some women may be able to tolerate menopausal symptoms with lifestyle changes alone, while others may require hormonal remedies, non-hormonal remedies, or a combination of both.¹¹

 

Table 1. Signs and Symptoms of Perimenopause and Menopause^2,12-15

Symptom	Description
Irregular periods	Starts the menopause transition Unpredictable ovulation causes changes in menstrual cycle patterns Could be months of missed periods, varying lengths of time between cycles (longer or shorter), and menstrual flow changes
Vasomotor Symptoms ( hot flashes, night sweats)	This is a sudden feeling of heat in the face, neck, and chest that is often accompanied by flushing, perspiration, and acute feelings of physical discomfort. May be followed by cold shivering. This may last up to several minutes. Night sweats are hot flashes that cause sweating during sleep. Vasomotor symptoms can occur before, during, and after menopause.
Genitourinary symptoms	Symptoms include dysuria, urinary incontinence, increased urinary frequency, vaginal and cervical atrophy (thinning, drying, and inflammation of the vaginal walls), sexual dysfunction, and decreased libido. Vaginal dryness presents an increased risk for sexually transmitted diseases.
Weight gain	While weight gain occurs in both men and women with aging, a particular increased deposition of visceral and subcutaneous adipose tissue to the abdomen in women during the menopause transition occurs. For weight gain before menopause, estrogen makes it possible for subcutaneous adipose tissue to deposit in the gluteal and femoral regions. After menopause this deposition moves to the abdominal region due to the decrease in estrogen levels. Abdominal fat distribution carries the risk of cardiovascular and metabolic diseases.
Sleep disruption	Sleep duration changes with advancing age, however during the menopause transition, concurrent changes in women’s reproductive hormone levels influence sleep duration and quality. It may be harder to fall asleep and stay asleep. Night sweats may also disrupt sleep.
Mood changes  depression, anxiety	Estrogen receptors are in the brain including areas involved in mood regulation. Stress, work, and family responsibilities affect mood during this period. Although the exact mechanism is unknown, mood symptoms may additionally be related to fluctuating estrogen levels. Some women may feel irritable or have crying spells. Depression and anxiety may be caused by fluctuating hormones, menopausal symptoms, or both.

 

SIDEBAR: Less Common Symptoms of Menopause¹⁶

Experts are continually learning about menopause’s symptoms. Gradual estrogen loss may be responsible for these less common symptoms of menopause:

• Dry eye syndrome and vision changes
• Easier bruising due collagen changes in the skin
• Return of acne
• Joint pain and stiffness
• Growing rogue hairs on chin or cheeks

The menopause transition can cause a wide variety of symptoms, but other serious conditions can cause these too. It is always important to consult a provider to rule these out.

 

PAUSE AND PONDER: How many symptoms of perimenopause and menopause can you name aside from hot flashes?

 

Chronic Conditions and Long-Term Consequences

Long term complications of menopause are related to low estrogen levels. Two major complications of concern are cardiovascular disease and osteoporosis.

 

Declining estrogen in menopause increases the risk of cardiovascular disease.² Coronary heart disease rates are two to three times higher in those who have reached menopause than those at the same age who have not. Women generally have a lower risk of heart disease than men before the age of 55, but after menopause, women reach the same level of risk for heart disease as men of the same age.²

 

Estrogen deficiency during menopause also causes the typical bone loss or decreased bone density seen in osteoporosis.² Up to 20% of bone loss  can happen  during this period.¹⁷ The consequences of osteoporosis are an increased risk of fractures, pain, mobility issues, and loss of height. Osteoporosis, a progressive condition, can worsen over time.

 

Menopause symptoms also adversely affect women in the workplace. Middle aged women contribute greatly to the global workforce and could potentially face increased health care costs and lost opportunities for career advancement. Mayo Clinic conducted a study to determine the estimated economic impact of menopause symptoms based on missed days from work; hours cut back at work; and quitting, retiring, or changing jobs. Based on missed workdays alone, these researchers estimated an annual loss of $1.8 billion in the U.S. due to menopause-related symptoms.¹⁸

 

MENOPAUSAL HORMONE REPLACEMENT THERAPY

The Ongoing Debate of HRT

Experts have debated menopausal HRT use for decades. Studies in the mid-1970s showed that women who used estrogen alone had an increased risk of endometrial cancer.^19,20 Researchers found that adding progesterone to estrogen provided protection against uterine cancer. Since then, progesterone is added to hormone treatment for women who have an intact uterus.^7,19,20

 

Between 1993 and 1998, the NIH began The Women’s Health Initiative, to study strategies to prevent and control some of the most common causes of morbidity and mortality in postmenopausal women (e.g., cardiovascular disease, osteoporosis, cancer).²¹ Researchers randomized more than 27,000 postmenopausal women aged 50 to 79 in the HRT portion of the trial. Those with a uterus (n = 16,608) received either combined conjugated equine estrogen (CEE 0.625 mg/day) plus medroxyprogesterone acetate (MPA 2.5 mg/day) or placebo. Women without a uterus (i.e., prior hysterectomies) were assigned to CEE alone or placebo.^22,23 The primary outcome was coronary heart disease incidence, and the primary safety outcome was invasive breast cancer incidence. To summarize overall effects, researchers also looked at other risks and benefits of HRT in addition to the primary outcomes. These included colorectal cancer, hip fracture, and cardiovascular risks.^22,23

 

After about five years, results began to show that the risks of HRT outweighed the benefits. HRT was associated with an increased risk of stroke, heart disease, and breast cancer. However, the results also indicated a reduction in osteoporotic fractures and colorectal cancers but no significant cardiovascular benefits. Ultimately, the research team stopped the trial early. Many physicians stopped prescribing HRT, and many women abandoned it altogether.^6,7

 

Despite stopping the trial, researchers continued to follow up with trial participants until 2010.^24,25 They reanalyzed the data based on results from the intervention, post-intervention, and follow-up phases with consideration for the trial participants’ ages. Researchers concluded that the trial findings do not support HRT for chronic disease prevention. They have since noted that HRT may be beneficial for bothersome symptoms among women in early menopause (i.e., women 50 to 59 years of age) or within 10 years of menopause onset. Data do not support HRT for chronic disease prevention in this subset either. These women must have no contraindications and must be interested in taking HRT.^24,25

 

Extensive debate continues, but several groups such as the U.S. Preventive Service Task Force (USPSTF) and the Menopause Society, have published position statements and recommendations for HRT use. The USPSTF is an independent panel of experts in disease prevention and evidence-based medicine that makes recommendations about clinical preventive services. The Menopause Society, formerly known as the North American Menopause Society, is a non-profit organization dedicated to improving women’s health during menopause and beyond, by providing resources for both healthcare professionals and the public.

 

Several organizations have issued recommendations on HRT use in postmenopausal individuals, particularly regarding its benefits, risks, and approved indications. While the general consensus is that HRT is the most effective treatment for VMS and genitourinary syndrome of menopause, its role in preventing chronic conditions such as osteoporosis remains controversial. The U.S. Food and Drug Administration (FDA) and the Menopause Society support HRT for VMS, genitourinary symptom management, and osteoporosis prevention in appropriate candidates, especially women younger than age 60 or within 10 years of menopause onset. In contrast, USPSTF recommends against using HRT solely for the primary prevention of chronic conditions in asymptomatic individuals. Recommendations emphasize shared decision-making and individual risk assessment.^26-28

 

Forms of Hormone Therapy

Menopausal HRT involves the administration of synthetic estrogen and progesterone to replace a woman’s hormone levels to help alleviate symptoms. Women should be educated on the risks and benefits of HRT, consider their personal risk, and be willing to take HRT, before starting treatment.^26-28

 

The current recommendations are for postmenopausal women younger than 60 years or women who are within 10 years of menopause onset and have no contraindications. These women must also be willing to take HRT.^26-28 HRT use is not recommended in women after the age of 60, or in those who are 10 years post menopause. The FDA has approved HRT for VMS, urogenital symptoms, and postmenopausal osteoporosis prevention.

 

HRT may be given as estrogen alone, progestin alone, or a combination estrogen and progestin. The FDA has approved several formulations, including oral, topical, transdermal, and injectable dosage forms.²⁹ Table 2 lists FDA-approved HRT products.

 

Women with an intact uterus with no other contraindications or risks who are willing to take HRT for menopause may receive estrogen in combination with progesterone. Estrogen therapy alone causes the endometrial lining to grow unopposed. Adding progesterone to the regimen prevents this abnormal growth and thus reduces risk of malignancy.^19,20

 

Women with no other contraindications or risks who have had a hysterectomy and are willing to take HRT may receive estrogen therapy alone. In such cases, progesterone is unnecessary.^19,20

 

Table 2. FDA-Approved Hormone Replacement Therapies²⁹

Generic Name	How Supplied	Brand Name(s)
Estrogen-Only
Conjugated estrogens	Oral	Premarin
	Vaginal cream	Premarin
	Injection	Premarin
Estradiol	Gel	Divigel, Elestrin, Estrogel
	Transdermal patch	Alora, Climara, Menostar*, Minivelle, Vivelle, Vivelle-Dot
	Transdermal skin spray	Evamist
	Vaginal cream	Estrace
	Vaginal ring	Estring
	Vaginal tablet	Vagifem
Estradiol acetate	Vaginal ring	Femring
Estradiol valerate	Injection	Delestrogen
Estropipate	Oral	Ogen
Progestin-Only
Medroxyprogesterone acetate	Oral	Provera
Micronized progesterone	Oral	Prometrium
Combination Therapies
Conjugated estrogen/ bazedoxifene**	Oral	Duavee
Conjugated estrogen/ medroxyprogesterone	Oral	Prempro
Estradiol/drospirenone	Oral	Angeliq
Estradiol/levonorgestrel	Transdermal patch	Climara Pro
Estradiol/norethindrone acetate	Oral	Activella
	Transdermal patch	Combipatch
Norethindrone acetate/ethinyl estradiol	Oral	Femhrt

*Menostar is for osteoporosis prevention only. **Bazedoxifene is not a hormonal therapy.

 

Due to the known risks of menopausal HRT use, all patients need a thorough evaluation—including a detailed medical history and physical examination—for a proper diagnosis and to identify potential contraindications. Providers and patients must also assess whether the benefits outweigh the risks on an individualized basis. Women should use HRT at the lowest possible dose and for the shortest possible duration to achieve symptomatic relief while avoiding adverse effects.³⁰

 

Women should not take HRT if they have²⁹

• problems with vaginal bleeding
• current or past cancers, such as breast cancer or uterine cancer
• current or past blood clot, stroke, or heart attack
• bleeding disorders
• liver disease
• allergy to hormone medicine

 

NON-HORMONAL THERAPIES FOR MENOPAUSE

Risks of menopausal HRT outweigh its benefits for many patients, so additional options are needed. The FDA has approved a few non-hormonal options for women who are ineligible for or uninterested in HRT, and others many opt to use off-label or complementary and alternative medicines.²⁶

 

FDA-Approved Therapies

Fezolinetant

The FDA recently approved an oral medication fezolinetant (Veozah) for the treatment of moderate to severe VMS caused by menopause. Fezolinetant is a neurokinin-3 (NK3) receptor antagonist that binds to and blocks the activities of the neurokinin-3 receptor, which plays a role in the brain’s regulation of body temperature.³¹

 

Fezolinetant is supplied as a 45 mg tablet, taken once daily with or without food. It has been associated with a risk of elevated hepatic transaminases, leading the FDA to add a Boxed Warning about the risk of liver injury more than a year after initial approval.³² Blood work to check for liver damage is required before fezolinetant use and every three months for the first nine months after initiation of therapy.³¹

 

Adverse effects of fezolinetant include abdominal pain, diarrhea, insomnia, back pain, hot flush, and elevated hepatic transaminases. Symptoms relating to liver damage to watch for include nausea, vomiting, and yellowing of the skin and eyes. Patients experiencing these must consult their prescriber immediately. Fezolinetant is contraindicated in patients with cirrhosis, severe renal damage, or end-stage renal disease.³¹

 

Paroxetine

Paroxetine (Brisdelle) is a selective serotonin reuptake inhibitor (SSRI) FDA-approved for the treatment of moderate to severe VMS. It is not an estrogen and its mechanism of action for the treatment of VMS is unknown.³³ The recommended dose is one 7.5 mg capsule daily at bedtime with or without food. This medication contains a lower dose of paroxetine than those used for other indications (e.g., depression, obsessive compulsive disorder) and is not approved for any psychiatric conditions.

 

Paroxetine’s common adverse effects include headache, fatigue, and nausea and vomiting. Paroxetine has a Boxed Warning for the potential of increased risk of suicidal thoughts and behaviors, and serotonin syndrome. The FDA warns prescribers to monitor for worsening and emergence of these severe symptoms. Contraindications include concomitant use or within 14 days of monoamine oxidase inhibitors, use with thioridazine or pimozide, hypersensitivity to any ingredient, and pregnancy. VMS do not occur during pregnancy and paroxetine may cause fetal harm.³³

 

Selective Estrogen Receptor Modulators

Raloxifene and ospemifene are selective estrogen receptor modulators (SERMs) FDA-approved for varying uses during menopause. Bazedoxifene is another FDA-approved SERM, which is found only in a combination tablet with conjugated estrogens.

 

Raloxifene (Evista) is SERM indicated for treatment and prevention of osteoporosis in post-menopausal women.³⁴ Patients take one 60 mg tablet once daily. Common adverse effects include hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, and sweating.³⁴ Raloxifene is contraindicated in women with active or history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. It is also contraindicated for use in pregnancy, as it may cause fetal harm.³⁴ The FDA’s Boxed Warning cautions of an increased risk of venous thromboembolism and death from stroke. Providers must consider the risk-benefit balance in women at risk for stroke. Concomitant use is not recommended or caution should be used when raloxifene is taken with cholestyramine, warfarin, and other highly protein-bound drugs (e.g., diazepam, diazoxide, lidocaine).³⁴

 

Ospemifene (Osphena) is a SERM indicated for the treatment of moderate to severe vaginal dryness and dyspareunia due to menopause.³⁵ Patients take one 60 mg oral tablet once daily with food. Ospemifene acts just like estrogen in some parts of the body but not in others. ³⁵ It has estrogen agonistic effects on the endometrium, which has led the FDA to add a Boxed Warning of a risk of endometrial cancer. With its estrogen agonist/antagonist profile, the FDA has another Boxed Warning of an increased risk of cardiovascular disorders (stroke, coronary heart disease, venous thromboembolism). ³⁵ Ospemifene should be used for the shortest duration consistent with treatment goals and risks for the individual woman.³⁵ Common adverse effects include hot flush, vaginal discharge, muscle spasms, headache, hyperhidrosis, vaginal hemorrhage, and night sweats. Contraindications to ospemifene use include³⁵

• undiagnosed abnormal genital bleeding
• estrogen-dependent neoplasia
• hypersensitivity to ospemifene
• active or history of deep vein thrombosis or pulmonary embolism
• active or history of arterial thromboembolic disease (e.g., stroke, myocardial infarction)

 

Women taking ospemifene should not take estrogen or estrogen agonist/antagonists, fluconazole, or rifampin concomitantly.³⁵

 

Bazedoxifene is a SERM available in combination with conjugated estrogens (Dauvee) indicated for the treatment of moderate to severe VMS and postmenopausal osteoporosis prevention in women with a uterus. Bazedoxefine acts as an estrogen agonist in some estrogen-sensitive tissues and as an antagonist in others (e.g., the uterus). The pairing of conjugated estrogens with bazedoxifene produces a composite effect that is specific to each target tissue. The bazedoxifene component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component.  Patients take one tablet (conjugated estrogens/bazedoxifene 0.45 mg/20 mg)daily with or without food for both indications.³⁶

 

Women taking conjugated estrogens/bazedoxifene should add supplemental calcium and/or vitamin D to their diets if intake is inadequate.

 

Contraindications to conjugated estrogens/bazedoxifene include³⁶

• Undiagnosed abnormal uterine bleeding
• Known, suspected, or a history of breast cancer
• Known or suspected estrogen-dependent neoplasia
• Active or history of deep vein thrombosis and pulmonary embolism
• Active or history of arterial thromboembolic disease (stroke, myocardial infarction)
• Known hepatic impairment or disease
• Hypersensitivity to estrogens, bazedoxifene or any ingredients
• Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders
• Pregnancy

 

Women taking conjugated estrogens/bazedoxifene should not take progestins, additional estrogens, or additional estrogen agonists/antagonists.

 

Adverse reactions include a risk for malignant neoplasms (endometrial cancer, breast cancer, ovarian cancer), cardiovascular disorders (stroke, coronary heart disease, venous thromboembolism), gallbladder disease and hypertriglyceridemia.³⁶

 

Off-Label Therapies

In 2023, The Menopause Society conducted an evidence-based review of the most current and available literature to determine whether to recommend some management options for menopause associated VMS. They recommended some SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and gabapentin.³⁷

 

Researchers have found in large randomized, double-blind, placebo-controlled trials that paroxetine, citalopram, escitalopram, venlafaxine, desvenlafaxine, and duloxetine reduce hot flashes by 24% to 69%. These medications are also first-line therapies for mood disorders such as depression and anxiety. For women with new onset or worsening mood disorders, which are common in menopause, these medications may be beneficial.^38,37 Common adverse effects associated with use of SSRIs and SNRIs include nausea, weight gain, gastrointestinal disorders, headache, and sexual dysfunction. Lower doses are generally used for VMS rather than the higher doses used for mood disorders.³⁸

 

In very small randomized double-blind, placebo-controlled trials, gabapentin was effective at reducing hot flash frequency by 45% to 51% compared to placebo.^39,40 It was also shown to be a well-tolerated treatment for hot flashes.⁴⁰ Gabapentin is also used as treatment for neuropathic pain and epilepsy and may help with sleep when taken at bedtime. Adverse effects include dizziness and coordination difficulties, weight gain, edema, and lethargy. Patients should use the lowest effective dose to minimize these negative adverse effects.³⁸

 

Complementary and Alternative Medicine

Some complementary and alternative medicines (CAMs) make claims about easing menopausal symptoms. Complementary health approaches to menopause may include any or all of the following⁴¹:

• nutritional (e.g., dietary supplements, special diets)
• psychological (e.g., meditation, hypnosis, relaxation therapies)
• physical (e.g., massage therapy, acupuncture)
• combination approaches (e.g., yoga, tai chi [physical and psychological])

 

CAMs are not regulated the same way as FDA-approved medications. Although some dietary supplements have been studied for menopause symptoms, none have been shown to be clearly helpful. Little information is available on long term safety of dietary supplements for menopause and some supplements may have harmful adverse effects or drug interactions.

 

In 2023, the Menopause Society released its position statement on non-hormonal approaches for menopause-related VMS based on an evidence-based review of current literature.³⁷ For CAM, it recommended cognitive behavioral therapy and clinical hypnosis as options for the treatment of VMS. The Menopause Society did not recommend yoga, acupuncture, or any natural products for VMS.³⁷

 

According to the NIH’s National Center for Complementary and Integrative Health, the evidence has not clearly shown that phytoestrogens, herbs, and other dietary supplements; acupuncture; or yoga relieve menopause symptoms.⁴¹

 

Phytoestrogens are substances from plants that have chemical structures similar to those of estrogen. Flaxseed is a phytoestrogen source and the isoflavones found in soy and red clover are also phytoestrogens. Studies on their ability to relieve menopause symptoms have been inconsistent, or no more effective than placebo.  Phytoestrogens may be safe for short term use, but their long-term safety has not been established and may not be safe for women who should not take estrogen.⁴¹

 

Regarding custom-mixed (compounded) bioidentical hormones, the group reports that the evidence does not support claims that they are more effective than conventional HRT. They also warn that compounded bioidentical hormones have not been shown to be safer than other forms of HRT, and that their content may vary from batch to batch.⁴¹

 

PAUSE AND PONDER: In what ways have you made or supported a loved one in making lifestyle changes to adequately prepare for “the change of life?”

 

Lifestyle Modification During and After Menopause^,

To stay healthy during and after menopause, lifestyle changes and modifications (illustrated in Figure 1) are beneficial. Lifestyle changes and modifications may make menopausal symptoms bearable even if symptoms are not completely eliminated. Lifestyle changes may also help prevent the chronic conditions of menopause such as cardiovascular disease, osteoporosis, and insulin resistance. It may also help with mood and sleep and help prepare a woman for healthy aging.⁴²

 

Figure 1. Lifestyle Modifications for During and After Menopause ⁴³

 

At least 30 minutes of physical activity on most days of the week helps women maintain a healthy weight and is good for the bones, heart, and mood. Women should aim for a mix of moderate and vigorous aerobic activities and exercises that build muscle strength, such as weight-bearing exercises.^42,44 Women should obtain advice from their healthcare provider before beginning any physical activity.

 

Eating a healthy diet can help counter some of the symptoms women experience in the menopause transition and prevent chronic illnesses and certain cancers. Essential nutrients to focus on in menopause include vitamins B, C, D, calcium, and protein for energy. A healthy diet also helps with the maintenance of a healthy weight, which improves cholesterol levels, reduces the risk for diabetes, improves blood pressure, and improves daily function.^42,44

 

Good sleep is essential for health and emotional well-being. Insufficient sleep duration and quality may be a problem during this period in a woman’s life. Hot flashes and night sweats are also disruptive to sleep. Getting enough sleep lowers the risks for chronic conditions such as high blood pressure, diabetes, and heart disease. It also improves attention and memory. Regular exercise, a healthy diet, avoiding caffeine and alcohol before bedtime, and going to bed and getting up at the same time each day can improve sleep.⁴⁴

 

Cognitive function at midlife appears to be influenced by the stage of menopause and menopausal symptoms such as sleep difficulties and mood changes. Many life stressors cannot be altered, but coping skills and strategies are beneficial to maintain a balance between self-nurturing and the obligations of work and caring for others. To improve and maintain cognition and mood, women should consider maintaining a social network, remaining physically and mentally active, and following a healthy diet.⁴⁴ Maintaining quality social contacts is beneficial during this period. Actively engaging with friends, family, and the community in positive ways helps improve health and emotional wellbeing.

 

Smoking is damaging to health in many ways. It causes heart disease, reduces bone density, and causes many forms of cancer. Experts advise women to stop smoking and limit alcohol consumption.^42,44

 

CONCLUSION

Discussions about menopause are no longer taboo. While HRT is beneficial and remains an option for women with no risk factors and contraindications, it is not a one-size fits all solution. HRT comes with risks and providers must assess patients carefully before treatment initiation and consider patient preferences. Non-hormonal therapies are available for women who may be unable or unwilling to take HRT. Women are living longer, and a woman may live for several years post-menopause. Lifestyle changes and modifications help counter the chronic conditions that often arise post-menopause and are important and necessary for healthy aging in women.

Download CE Activity

Sjogren’s Disease: How Dry Am I?

 

Author: Kelsey Giara, PharmD

 

Program Goal: To educate pharmacists and pharmacy technicians about emerging theories related to Sjogren’s disease, including use of biomarkers to diagnose and classify patients. This continuing education activity will cover guidelines, evidence-based medicine, and supportive material that the integrated healthcare team can employ to improve quality of life for patients who have Sjogren’s disease.

 

Learning Objectives:

Upon completion of this activity, pharmacists will be able to

1. Discuss current theories postulating how Sjogren’s disease develops
2. Identify biomarkers used in diagnosis and patient classification
3. Interpret guidelines and evidence-based medicine to use best practices to manage Sjogren’s disease
4. Use elements of an integrated approach to care among specialists and other pharmacists

 

Upon completion of this activity, pharmacy technicians will be able to

1. Describe Sjogren’s disease’s basic pathology and symptoms
2. Outline prescription and non-prescription treatments used in Sjogren’s disease
3. Identify when to refer patients to the pharmacists for recommendations or referrals

 

ABSTRACT

Once considered a “dry eye-dry mouth-arthritis” illness, Sjogren’s disease (SjD) is a systemic condition strongly associated with organ-specific and systemic autoimmunity. Systemic SjD is linked to autoimmune dysfunction that may eventually be irreversible. This disease affects about 2 to 4 million Americans, but every patient presents differently and symptoms mimic those of various other conditions, posing a challenge for diagnosis and treatment. SjD’s classic symptoms include sicca (ocular and oral dryness), arthralgia (joint pain), and fatigue. The pathogenesis of the disease is complex and multifactorial, but researchers are looking for a well-defined cause and modern understanding of SjD is improving. The search for biomarkers, therapeutic targets, and disease-modifying treatments for SjD is underway. Health care providers—including pharmacists and pharmacy technicians—who are up to date on current understanding and recently-updated guidelines will be better prepared to make evidence-based recommendations and appropriate referrals to improve care and outcomes for patients with SjD.

 

 

INTRODUCTION

The medical community’s understanding of Sjogren’s disease (SjD) has evolved a great deal since it was first recognized in the late 1800s. A surgeon reported the first clinical case of what is now called SjD in 1888, describing a male patient with painless bilateral swelling of the lacrimal, parotid, and submandibular glands (i.e., the glands that produce tears and saliva).¹ Following a series of case reports over about a century detailing a “dry eye-dry mouth-arthritis” illness, physicians pieced together and named the disease known today as SjD.^1,2

 

Importantly, this disease recently underwent a name change from “Sjogren’s syndrome (SjD).” The name change from Sjögren’s syndrome to Sjögren’s disease was proposed and endorsed by the 2023 International Rome Consensus Task Force, a multidisciplinary panel of international experts and patient representatives.² The name was changed to better reflect its nature as a distinct systemic autoimmune disease, rather than a vague collection of symptoms implied by the term “syndrome.” The change also aimed to eliminate the confusing and potentially misleading distinction between “primary” and “secondary” forms, which does not align with how other autoimmune diseases are classified and was viewed by patients as diminishing the seriousness of their condition.²

 

Epidemiologic data about SjD in the United States (U.S.) is limited. It is estimated to affect about 2 to 4 million Americans, but only about 1 million are definitively diagnosed.^3,4 Women are nine times more likely to have the condition, and it typically emerges around menopause (i.e., after age 50). SjD is the second most common rheumatologic disorder in the U.S. behind systemic lupus erythematous (SLE).⁵ Autoimmune conditions don’t discriminate; many famous people have historically battled them publicly. Selena Gomez postponed a concert tour to undergo treatment for SLE. Kim Kardashian suffers from psoriasis. SjD, as a rarer condition, doesn’t make the news quite as often as other autoimmune conditions, but here are a few people you may recognize who are battling the disease today^6-8:

• Carrie Ann Inaba: In 2021, the 30-season judge of Dancing with the Stars and co-host of The Talk took a leave of absence from television to focus on her health and wellbeing. The chronic pain associated with her SjD, SLE, fibromyalgia, and rheumatoid arthritis forced her to stay in bed three days a week.
• Shannon Boxx: This World Cup soccer player and Olympic gold medalist was diagnosed with SjD in 2002 and suffered from severe fatigue and joint pain. Ahead of the 2007 World Cup, she was put on corticosteroids to alleviate her symptoms and needed specific approval from the U.S. Anti-Doping Agency to take them while competing.
• Venus Williams: While dominating the sport of tennis as the most decorated female tennis player to compete in the Olympic Games, she has also been in a battle against her own body. SjD-related fatigue caused her to pull out of the 2011 U.S. Open, and she was temporarily booted from the top 100 tennis players for the first time in 15 years.

 

As an autoimmune condition, SjD’s cause is unclear. Genetic, environmental, and hormonal factors likely work collaboratively to produce the cardinal symptoms of dry eyes and/or mouth, fatigue, and limb pain. Some patients experience additional manifestations in the lymph nodes, lungs, kidneys, muscles, nervous system, skin, teeth, and brain. Glandular and joint involvement is also possible, and constitutional symptoms (e.g., fever, involuntary weight loss, night sweats) can affect quality of life. Patients with SjD have an elevated risk of lymphoma, about 15 to 20 times higher than the general population.^9,10

 

Clinical Presentation

SjD is a systemic condition strongly associated with organ-specific and systemic autoimmunity. Since it impacts multiple systems in the body, SjD can manifest various ways. Affected patients may have symptoms that cycle between mild and severe. Symptoms also tend to worsen as patients age and the function of the exocrine glands subsides.

 

SjD’s main symptoms are dry mouth and dry eyes (collectively, sicca). More than 95% of patients with SjD present with sicca symptoms, which are irritating and poorly tolerated.¹¹ About half of patients also have dermatologic involvement (i.e., dry skin or rashes).^3,12 Xerostomia (oral dryness) can substantially impact daily life, interfering with eating, speaking, or sleeping.⁴ When patients’ salivary volume decreases, they also lose saliva’s antibacterial properties. This can accelerate tooth decay, infection, and periodontal disease. Patients with dry mouth also report swallowing difficulties, halitosis (bad breath), and burning sensations in the mouth. Using artificial saliva products to manage dry mouth is time-consuming and ineffective for many patients with SjD.¹³

 

Patients with ocular dryness complain of itchy, gritty, sore, or dry sensations in the eyes despite appearing physically normal.⁴ Decreased tear production over time can cause chronic irritation and destruction of conjunctival epithelium that lines the inside of the eyelids and covers the sclera (whites of the eyes).

 

Patients may also experience symptoms elsewhere in the body, including

• Dry cough
• Fatigue
• Joint and muscle pain
• Numbness or tingling of the hands and feet
• Vaginal dryness

 

Patients who develop musculoskeletal symptoms may have difficulty remaining active. About 53% of patients experience arthralgias (joint stiffness) and 22% experience myalgias (muscle pain).⁴ SjD-associated arthralgia occurs primarily in small joints, sometimes asymmetrically. Providers may confuse these symptoms with SLE or rheumatoid arthritis.

 

Disease Classification and Severity

Experts classify SjD as primary or secondary (see Table 1). Primary SjD (pSjD) is an autoimmune disease that causes immune cells to mistakenly attack and destroy healthy cells in the glands that produce tears and saliva. SjD can also be secondary to other autoimmune diseases (e.g., SLE, rheumatoid arthritis, scleroderma), as is the case for about 60% of patients.⁴

 

Table 1. American-European Consensus Group Criteria for the Classification of SjD¹⁴

Primary SjD Criteria	Secondary SjD Criteria	SjD Exclusion Criteria
At least 4 of the following, including at least criterion 5 or 6: 1.   Ocular symptoms (dry eyes for ≥ 3 months, foreign-body sensation, use of tear substitutes > 3 times daily) 2.   Oral symptoms (dry mouth, recurrently swollen salivary glands, frequent use of liquids to aid swallowing) 3.   Ocular signs (Schirmer test* performed without anesthesia [< 5 mm in 5 minutes], positive vital dye staining results) 4.   Oral signs (abnormal imaging of salivary glands, unstimulated salivary flow < 1.5 mL in 15 minutes) 5.   Positive minor salivary gland biopsy findings 6.   Positive anti-SDA or anti-SDB antibody results	In the presence of a connective-tissue disease, symptoms of oral or ocular dryness exist in addition to criterion 3, 4, or 5 for primary SjD.	Any of the following: ·     AIDS ·     Graft versus host disease ·     Hepatitis C virus infection ·     Past head-and-neck radiation ·     Prior lymphoma ·     Sarcoidosis ·     Use of anticholinergic drugs

*Schirmer test is used to determine whether the eye produces enough tears to keep it moist; AIDS = acquired immunodeficiency syndrome; SjD = Sjogren’s disease; SDA = Sjogren's disease A; SDB = Sjogren’s disease B

 

There is a broad range of disease severity in SjD. Some patients experience mild glandular dryness and constitutional symptoms while others have severe glandular involvement and various manifestations throughout the rest of the body, including systemic autoimmune features. Mild SjD has a good prognosis, but patients often have difficulty managing their symptoms and moderate-to-severe disease can severely impact quality of life.¹⁵ SjD symptoms cause considerable psychological distress. About one third of patients with the condition have clinically significant anxiety and half have diagnosable depression.¹⁶

 

Measuring Systemic Disease Activity

The European League Against Rheumatism (EULAR) created a disease activity index for primary SjD (ESSDAI) to measure systemic disease activity.^17,18 The ESSDAI includes 12 domains: cutaneous, respiratory, renal, articular, muscular, peripheral nervous system, central nervous system, hematological, glandular, constitutional, lymphadenopathic, and biological. Each domain is divided into three or four levels of activity, and patients are scored based on that domain’s severity (i.e., 0 indicates no activity and 3 or 4 indicates high activity).¹⁸

 

Each domain’s weight reflects its relative importance to disease activity, and the score for each domain is equal to the level of activity multiplied by the domain’s weight. A final ESSDAI score (i.e., the sum of all the domain scores) could theoretically be between 0 and 123. Patients’ disease activity based on ESSDAI score is as follows^17,18:

• 0 = no activity
• 1 to 4 = low activity
• 5 to 13 = moderate activity
• 14 or greater, or high activity in any domain with a definition of high activity = severe activity

 

Measuring Patient-Reported Outcomes

EULAR also created the SjD patient reported index (ESSPRI) to assess patient-reported outcomes in pSjD.¹⁸ This scale focuses solely on the three major manifestations of SjD: dryness, fatigue, and musculoskeletal pain. Patients rank each of these domains on a scale of 0 to 10, and the total ESSPRI score is the mean (average) of those scores. A “patient acceptable symptom state” is defined as an ESSPRI score of less than 5, and clinicians and researchers define “minimally clinically important improvement” as an increase in ESSPRI score 1 point or more or 15%.¹⁸

 

Recognition and Treatment are Inadequate

SjD’s variable symptoms are not always present at the same time, leading providers—including physicians, dentists, and ophthalmologists—to treat each symptom individually, unaware of the systemic disease’s presence. Patients suffer from SjD symptoms an average of 10 years before obtaining a diagnosis.^4,19 The condition has historically been misdiagnosed because providers consider symptoms minor or vague and they often mimic other diseases. Up to 30% of people 65 years or older, with SjD or not, report dryness of the eyes and mouth.¹⁹ Sicca and/or parotid gland enlargement can result from various other conditions, including¹⁹

• Alzheimer’s disease
• anxiety and depression
• Bell’s palsy
• bulimia
• chronic conjunctivitis or blepharitis (inflammation of the membrane on the eye or the eyelid, respectively)
• chronic pancreatitis
• complications from contact lenses
• dehydration
• diabetes mellitus
• hepatitis C
• Parkinson’s disease
• rosacea
• viral infections (e.g., cytomegalovirus, influenza, mumps)

 

About half of patients with SjD lack a definitive diagnosis, so undertreatment is considerable.⁴ For those who are diagnosed, treatment guidelines have historically been unclear and available treatments are limited and often unsuccessful. Recently, evidence-based treatment guidelines have emerged (discussed below) to help providers make decisions regarding SjD care. SjD is incurable; targeted, disease-modifying therapies are needed.

 

DISEASE MECHANISMS AND BIOMARKERS

pSjD’s pathogenesis is complex and multifactorial. Underlying genetic predisposition, epigenetic mechanisms (i.e., things that cause changes that affect the way your genes work), and environmental factors contribute to disease development.²⁰ There is no identified causal agent for SjD and it presents with multiple organ involvement. This makes the pursuit for defining an etiology and identifying biomarkers all the more important.

 

Researchers historically considered SjD a specific, self-perpetuating immune-mediated loss of exocrine tissue as the main cause of glandular dysfunction.²⁰ Today, with more sophisticated research methods, experts believe this fails to fully explain several SjD-related phenomena and experimental findings.

 

Genetics and Epigenetics

Genetic studies are a powerful tool for discovering new pathogenic pathways. Scientists have made great strides in studying genetic susceptibility to pSjD, but the evidence still does not match that of other autoimmune conditions.²⁰ Several genome-wide association studies in pSjD have shown that the strongest association lies within human leukocyte antigen (HLA) genes.

 

The non-HLA genes IRF5 and STAT4 (relevant to the innate and adaptive immune systems) also show consistent associations but on a smaller scale.²⁰ These genes activate interferon (IFN) pathways as part of the innate immune system. Epigenetic mechanisms (e.g., DNA methylation) also play a role in pSjD pathogenesis by modulating gene expression without altering DNA sequences. This may serve as a dynamic link between the genome and SjD manifestation.

 

Chronic Immune System Activation

Chronic immune system activation is central to SjD pathophysiology. Innate (“nonspecific”) immunity is the defense system people are born with to protect them from all antigens (foreign substances) that enter the body. Unlike the innate immune system, which attacks based on identification of general threats, the adaptive immune system is activated by pathogen exposure. Adaptive immunity uses its “memory” to learn about the threat and enhance the immune system accordingly over time. The adaptive immune system relies on B cells and T cells—otherwise known as lymphocytes—to function.

 

IFNs exert antiviral, antimicrobial, antitumor, and immunomodulatory effects as part of the innate immune system. Literature widely recognizes the SjD-associated “IFN signature,” as increased IFN levels activate multiple IFN-responsive genes involved in immune activities.²¹ Research indicates that type 1 IFN dysregulation is a major pathogenic mechanism in many autoimmune conditions, including SjD.^21,22 It is also suggested that “crosstalk” between the type 1 IFN pathway and B-cell activation causes a vicious cycle of immune activation where type 1 IFNs drive production of autoantibodies (made against substances formed by a person's own body) which further promotes IFN production.²¹ Toll-like receptors (TLRs) also play key roles in the innate immune system.²¹ Research suggests that TLR-dependent IFN expression may contribute to immune system activation and autoimmunity development in pSjD.²¹

 

In patients with SjD, lymphocytes infiltrate the salivary and lacrimal glands and other glands of the respiratory and gastrointestinal tracts and vagina.⁴ T cells in this infiltrate produce interleukin (IL)-2, IL-4, IL-6, IL-1β, and tumor necrosis factor while the B cells cause hypergammaglobulinemia (overproduction of immunoglobulins/antibodies) and produce autoantibodies.⁴ Some of these autoantibodies target cellular antigens of salivary ducts, the thyroid gland, the gastric mucosa, erythrocytes, the pancreas, the prostate, and nerve cells. About 60% of patients with SjD also express non-organ-specific autoantibodies, including rheumatoid factors, antinuclear antibodies, and antibodies to the small RNA-protein complexes Ro/SS-A and La/SS-B.⁴ These processes eventually lead to glandular dysfunction that manifests as dry eyes and mouth and enlargement of major salivary glands.

 

B-cell activating factor (BAFF) may also contribute to pSjD development. BAFF is usually an active part of the innate immune system, but B cells, T cells, and epithelial cells in the salivary glands also release BAFF in response to IFNs.²¹ This suggests that epithelial cells are not only passive victims of pSjD autoimmunity but also contributors to immune system overactivation. This also shows that BAFF serves as a link between the innate and adaptive immune systems in pSjD and could also represent an important therapeutic target in pSjD.²¹

 

Other Theories

Research into a well-defined cause of SjD is ongoing. Additional theories include a potential viral trigger, neuroendocrine abnormalities, and autoimmune epithelitis. Evidence for a viral trigger in pSjD development is conflicting, but studies have been unable to replicate an association between SjD and Epstein-Barr virus, hepatitis C virus, retroviruses, or Coxsackie A virus.²¹ Researchers think that the microbial stimuli driving pSjD development could be diverse or that the initiating viral stimulus is no longer detectable once the disease manifests.

 

The classic triad of symptoms in pSjD is sicca, arthralgia, and fatigue. Pathogenic mechanisms producing fatigue remain unknown, but neuroendocrine dysfunction may play a key role in the process.²¹ Studies show that patients with pSjD have decreased hormone levels (e.g., cortisol) compared with healthy individuals, indicating dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is suggested to promote fatigue and depression in patients with pSjD.

 

The Search for Biomarkers

Disclosing a disease’s etiology allows researchers to identify biomarkers (i.e., a biological molecule in the body that is a sign of an abnormal process) for diagnosis and assessment of disease process and treatment response. It also stimulates discovery of treatment targets. Researchers have been hard at work searching for biomarkers for SjD. Biomarkers can drive more precise diagnosis and may be used to measure disease severity or see how well the body responds to treatment. Scientists have discovered potential biomarkers, but studies have yet to validate their utility in SjD diagnosis and treatment.

 

Novel tissue-specific autoantibodies (TSAs) have been described in the early stages of pSjD, including salivary protein-1, parotid secretory pro­tein, and carbonic anhydrase 6.²³ These are detectable even before the classic autoantibodies Ro/SS-A and La/SS-B. Further studies are needed to determine the utility of TSAs in screening patients with dry eye for SjD.

 

Some researchers hope to look beyond blood for reliable biomarkers for pSjD, more specifically in tears or saliva. They have studied y=tear proteins LACTO and LIPOC-1 as potential biomarkers for pSjD and one study shows they are more accurate indicators than traditional clinical tests for disease detection.²³ Other studies have examined salivary levels of S100A8/A9 as a potential biomarker for lymphoma development in patients with pSjD. Imaging biomarkers are also gaining attention. Salivary gland ultrasounds, for example, are non-invasive and valuable for studying the morphology (structure) of major salivary glands.²³

 

EVIDENCE-BASED TREATMENT STRATEGIES

SjD has no cure, and treatment varies from person to person based on their symptoms. Until recently, guidelines were unavailable to help clinicians manage Sjogren’s disease rationally.

 

In 2019, EULAR released evidence-based guidelines on which to rely, but clinicians may be unaware of its availability.¹¹ Medication is the cornerstone of these recommendations, so pharmacists and pharmacy technicians should be prepared to make evidence-based recommendations and appropriate referrals to improve care for patients with SjD. It is important to remember that no therapy is explicitly approved for SjD disease modification. Rather, providers use therapies indicated for each symptom separately—and some off label (i.e., for a non-FDA-approved indication)—on a trial-and-error basis based on available evidence from small trials that sometimes include a subset of patients with SjD.

 

Sicca

Glandular dysfunction—the cause of sicca symptoms—appears to be stable for long periods of time (up to 12 years) and has a chronic course in patients with pSjD.¹¹ No therapeutic intervention can reverse or slow the progression of glandular dysfunction, so sicca symptoms cannot be cured. EULAR guidelines state that the first therapeutic approach to sicca symptoms should be symptomatic relief using topical therapies (e.g., saliva substitutes, artificial tears).¹¹ This minimizes the risk of adverse effects (AEs) seen with systemic therapies.

 

Finding the optimal lubrication is a matter of trial and error, so pharmacy staff should be prepared to set realistic expectations for patients seeking relief of sicca symptoms. They should also help patients recognize when it may be time to talk to their prescriber about stepping up to pharmacologic treatment.

 

Oral Dryness

Treatment of oral dryness depends on the severity of salivary gland dysfunction (Figure 1).¹¹ No evidence indicates any non-pharmacologic stimulant is better than another, so patients with mild glandular dysfunction should use a trial-and-error approach to find one that works for them. If these therapies don’t help or patients do not wish to use non-pharmacologic stimulants, providers should move on to pharmacologic stimulation. Muscarinic agonists’ main AE is excessive sweating.¹¹ To avert this, EULAR recommends increasing the dose progressively up to 15 to 20 mg/day when possible.

 

Figure 1. Treating Oral Dryness Based on Degree of Glandular Dysfunction¹¹

 

Cevimeline and pilocarpine are cholinergic agents, meaning they activate muscarinic receptors in the parasympathetic nervous system (which controls bodily functions when a person is at rest) to stimulate saliva production. Patients with SjD take cevimeline 30 mg by mouth three times daily or pilocarpine 5 mg by mouth four times daily to treat dry mouth.^24,25 The most common AEs of cevimeline and pilocarpine are excessive sweating, nausea, rhinitis (stuffy nose), and diarrhea.

 

The ideal saliva substitute will have a neutral pH mimicking natural saliva composition and contain fluoride and other electrolytes.¹¹ Gel formulations are ideal for patients with acceptable salivary flow output, especially those with oral dryness at night. However, patients often dislike these formulations due to their sticky mouth-feel. Pharmacists can recommend that patients dilute oral gel formulations to reduce this phenomenon for better adherence. Thinner preparations are preferred for patients with better-preserved glandular function.¹¹

 

Some experts feel that all patients with oral dryness should use salivary substitutes regardless of the degree of glandular dysfunction.¹¹ Whether patients use these formulations or not, all patients with salivary dysfunction should use a neutral pH sodium fluoride gel to prevent extensive caries (i.e., cavities).

 

Ocular Dryness

Reflex tears are the tears we produce when we cry, while we produce basal tears continuously to lubricate the ocular surface (the surface layers of the eye, namely the cornea and conjunctiva).²⁶ While tears may taste like salt water, their composition is more complex. Both types of tears contain water but they also contain mucin, lipids, proteins (lysozyme, lactoferrin, lipocalin, immunoglobulins, and peroxidase), electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, and calcium), growth factors (epidermal growth factor), cytokines, and glucose.

 

Artificial tears and ocular gels/ointments are first line therapies for volume replacement and lubrication for ocular dryness.¹¹ While many people refer to over-the-counter (OTC) drops, gels, ointments, and lubricants as artificial tears, these products lack the biologically active components found in natural tears.²⁷ Their primary role is to supplement the patient’s natural tear production and provide sufficient lubrication to avoid eye complications.

 

Many artificial tear formulations are available, so patients may need assistance navigating the options. Table 2 lists common ingredients in artificial tears and their functions. A major difference between OTC products is the presence of chemical formulations that increase viscosity (thickness/stickiness) and adhesion and facilitate even distribution across the ocular surface.²⁷ As a general rule, drops are the lowest viscosity products, ointments have the highest viscosity, and suspensions fall in between. Lubricants with a polymeric base or viscosity agent are preferred for patients with SjD to¹¹

1. Add volume to the tear lake
2. Increase the time the lubricant remains on the ocular surface
3. Cushion the ocular surface to reduce friction between the eye and the eyelid

 

Table 2. Artificial Tear Ingredients and Their Functions^27-30

Ingredient Class	Function	Examples
Astringent	Precipitate protein to clear mucus from outer eye surface	zinc sulfate
Buffering agent	Maintain normal tear film pH	bicarbonate, phosphate
Demulcent	Protect and lubricate mucous membrane surfaces	carboxymethylcellulose sodium, dextran, gelatin, glycerin, hydroxyethyl cellulose, hypromellose, methylcellulose, polyethylene glycol, polysorbate, polyvinyl alcohol, povidone, propylene glycol
Lipid formulations	Improve gland function and increase tear film stability	castor oil, phospholipids, triglycerides
Preservatives	Prevent bacterial contamination	benzalkonium chloride (BAK), ethylenediaminetetraacetic acid (EDTA), polyquaternium-1, sodium chlorite, sodium perborate

 

Not all artificial tear products are equal, and different products work better for different patients. The optimal artificial tear offers long-lasting, effective symptom relief. It should also have low blur and be comfortable to administer.³¹ Surface tension, pH, viscosity, duration of action, and preservative presence or absence affect these factors.

 

OTC eye drops commonly include preservatives to prevent bacterial contamination. Repeated use of preservative-containing eye drops is associated with ocular allergies and toxicities, which can lead to product nonadherence and worsening symptoms.²⁷ Benzalkonium chloride (BAK)—the most common preservative used in eye formulations—is an epitheliotoxin and a toxic detergent.^28,29 It attracts monocytes and lymphocytes to the conjunctiva, worsening inflammation and thickening the tissue. This effect is cumulative; the more the eye is exposed to BAK, the greater the negative effects.²⁹ As a rule-of-thumb, pharmacists should always recommend products without BAK as a preservative.²⁸

 

EULAR recommends that all patients with SjD who present with ocular dryness use artificial tears containing methylcellulose or hyaluronate at least twice daily.¹¹ They should increase frequency as symptoms reappear as often as hourly. Individuals who use artificial tears four or more times daily should always use preservative-free products. Patients who experience overnight dryness should consider ophthalmic ointments before bedtime, as they remain in the eye longer. These are not recommended for daytime use because they blur vision.

 

Patients who are refractory to artificial tears and ointments—those who do not improve after maximum use—should see an ophthalmologist for prescription treatment. Short-term non-steroidal anti-inflammatory drug (NSAID) or corticosteroid eye drops are indicated for a maximum of two to four weeks.¹¹ This is due to the potential for AEs with long-term use, including

• NSAIDs: corneal-scleral melts, perforation, ulceration, severe keratopathy
• corticosteroids: infections, increased intraocular pressure, cataract worsening or development

 

Cyclosporine 0.05% is another therapeutic option for patients who are refractory to or do not tolerate artificial tears and ointments and those with severe ocular dryness requiring multiple courses of a glucocorticoid eye drop.¹¹ Cyclosporine is a calcineurin inhibitor that prevents T cell maturation.³² This counteracts SjD’s vicious cycle of inflammation. Patients administer the drug in the eyes twice daily, and the most common AEs are eye burning, stinging, and irritation. Of note, a small trial investigating topical tacrolimus showed promising results, but larger trials are needed to confirm the role of this drug for SjD-associated ocular dryness. Some providers also use lifitegrast ophthalmic solution or varenicline nasal spray off-label to treat SjD-associated dry eye, but EULAR makes no recommendation for their use.

 

Serum eye drops are blood-derived eye drops that may be autologous (uses the patient’s own blood) or allogenic (the blood comes from a donor).²⁶ These are compounded; a specialized pharmacy collects the patient’s blood, then clots, centrifuges, and dilutes it with sterile saline. The serum drops also contain increased concentrations of proteins, growth factors, vitamins A and C, antioxidants, and electrolytes found in natural tears.²⁶ This is meant to mimic natural basal tears’ biochemical properties to heal the cells of the ocular surface.

 

Small uncontrolled studies have examined serum eye drops for SjD patients, and results are inconsistent.¹¹ Nevertheless, ophthalmologists may use this option for patients with severe symptoms who are refractory to topical cyclosporine drops. When considering serum eye drops, individuals should consider storage needs, as they should be frozen until use (up to six months) and then refrigerated once opened for up to one week. Contamination during and after the compounding process is also possible.¹¹

 

Studies have investigated the utility of other therapies—hydroxychloroquine, immunosuppressive agents, and rituximab—for SjD-related ocular dryness, but EULAR does not recommend any of them for ocular dryness alone based on available clinical data.

 

Fatigue and Pain

Patients with pSjD often present with general non-inflammatory joint/muscle pain and fatigue/weakness. After ruling out potential concomitant conditions (e.g., osteoarthritis, hypothyroidism, vitamin deficiencies, depression), providers should evaluate whether the patient is experiencing joint pain (arthralgia) or joint inflammation (arthritis, tenosynovitis).¹¹ The ESSDAI score defines low articular activity level as arthralgia in the hands, wrists, ankles, and feet accompanied by morning stiffness longer than 30 minutes, always ruling out concomitant osteoarthritis.¹⁷ Objective inflammation (i.e., redness, heat, and swelling) in one or more joints is considered arthritis, and the ESSDAI score classifies arthritis severity based on the number of joints involved. Management of arthritis is covered under systemic disease treatment, and Table 3 outlines EULAR recommendations for non-arthritis musculoskeletal pain.

 

Table 3. EULAR-Recommended Management of SjD-Associated Musculoskeletal Pain*¹¹

Acute Pain	Frequent Acute Pain	Chronic, Daily Pain
· Acetaminophen or NSAIDs for symptomatic relief for up to 7 to 10 consecutive days · Topical diclofenac may be effective for local pain with fewer adverse effects	· Consider hydroxychloroquine in patients with articular pain based on its evidence for use in other SAD · Off-label use of biologics (even as rescue therapy) is not recommended	· Emphasize non-pharmacologic management (e.g., physical activity) before medications · Goal is to avoid repeated use of NSAIDs or glucocorticoids · Musculoskeletal: antidepressants and anticonvulsants · Neuropathic: gabapentin, pregabalin, or amitriptyline · Opioids are not recommended

*Providers must first rule out concomitant osteoarthritis (i.e., objective inflammation in 1 or more joints); NSAID = non-steroidal anti-inflammatory drug; SAD = systemic autoimmune diseases

 

Systemic Disease

EULAR defines systemic SjD as disease involvement that affects or has affected any of the organs/systems included in the ESSDAI score (i.e., all domains except biological).¹¹ Systemic disease is linked to autoimmune dysfunction that may eventually become irreversible. Providers should limit systemic therapies to patients with active systemic disease following careful evaluation of symptom severity and organ damage. Clinicians should consider systemic therapy on an individual basis, as not all patients with active systemic disease will require it.¹¹

 

EULAR makes a few general recommendations regarding systemic therapy¹¹:

1. Consider systemic therapies for most patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score (i.e., greater than 5).
2. Therapeutic response is considered a reduction of 3 or more points in the global ESSDAI score.
3. Providers should follow a sequential (or combined) use of glucocorticoids, immunosuppressive agents, and biologics to treat organ-specific systemic manifestations.
4. Use glucocorticoids at the minimum dose and duration necessary to control active systemic disease.
5. Use synthetic immunosuppressive agents (e.g., azathioprine, cyclophosphamide, leflunomide, methotrexate, mycophenolate) mainly as glucocorticoid-sparing agents in patients requiring long-term glucocorticoid therapy (i.e., those with severe organ impairments).
6. Consider B-cell targeted therapies (e.g., belimumab, rituximab) in patients with severe, refractory systemic disease.

 

Evidence regarding the use of glucocorticoids for SjD is weak and studies report high rates of AEs.¹¹ Guidelines recommend administering pulses of methylprednisolone followed by doses of 0.5 mg/kg daily or less as induction therapy in patients with severe disease and lower doses in patients with less severe disease. The goal is to withdraw glucocorticoids in patients whose SjD becomes inactive as soon as possible or at least target a maintenance dose of 5 mg daily or less with the aid of steroid-sparing immunosuppressive agents.¹¹ Studies of immunosuppressive agents are lacking, so EULAR does not recommend one agent over another, except in the case of patient characteristics or comorbidities. Dose, route of administration, and duration of treatment are not established given the lack of clinical data, so physicians should follow similar dosing schedules to other systemic autoimmune diseases.¹¹

 

EULAR guidelines also include algorithms for each ESSDAI domain based on available trial data and the clinical experience of the individuals on the EULAR task force.¹¹ Figure 2 summarizes these recommendations, including standard of care, second line, and third line recommendations.

 

Figure 2. EULAR Algorithms for Systemic Therapy Based on ESSDAI Domain¹¹

ABA = abatacept 0, 2, 4 weeks and every 4 weeks; BLM = belimumab 10 mg/kg (0, 2 and 4 weeks and then every 4 weeks); CyC = cyclophosphamide pulses 0.5g/15 day (maximum six pulses); ESSDAI = EULAR Sjogren's syndrome disease activity index; GC = glucocorticoid (recommended dose in mg/kg/day), short-term course whenever possible, consider methylprednisolone pulses in severe cases; G-CSF = granulocyte-colony stimulating factor; Hb = hemoglobin; HCQ = hydroxychloroquine 200 mg/day; ID = immunosuppressive agents, no head-to-

head comparisons available; ivIG = intravenous immunoglobulins 0.4-2 g/kg 5 days; MP = methylprednisolone; NSAID = non-steroidal anti-inflammatory drug; Pex = plasma exchanges; RTX = rituximab 1 g/15 days (x2)

 

 

Considering Comorbidities

More than 20% of people with SjD are older than 65 years, making them more likely to have pulmonary, liver, kidney, or heart-related comorbidities.¹⁹ It is especially important to consider alternative causes of sicca in older patients since many conditions and drugs produce oral and ocular dryness. Older people are nearly twice as likely to suffer from dry eyes than younger individuals.¹⁹ Older age is also associated with decreased salivary flow rate. Dry mouth is more than a bothersome symptom. Addressing dry mouth in older adults is vital because worsening oral health increases risks of malnutrition, social isolation, care dependency, and frailty that tend to affect this population.¹⁹

 

An estimated 45% to 80% of the older adult population reports some pain, most commonly musculoskeletal.¹⁹ Treatment plans for these patients should emphasize non-pharmacologic relief rather than medications as first-line therapy. Also, despite the lack of available evidence, experts suggest that topical NSAID formulations may be effective for local SjD-related pain in older adults with fewer AEs than oral NSAIDs.¹⁹

 

Treating systemic symptoms in this population also requires special considerations. Older adults are more likely to experience AEs from glucocorticoids—including blood clots, osteoporosis, and bone fractures—than younger individuals.¹⁹ Pharmacists should also consider the greater frequency of hepatic and renal impairment in older patients. For example, renal function decline and decreased folate stores may increase methotrexate-related toxicity.¹⁹ Studies suggest that disease-modifying antirheumatic drugs (including some biologics) have similar effects on younger and older patients while maintaining favorable AE profiles.¹⁹ Older people, therefore, should not be excluded from the use of these agents for systemic disease where appropriate.

 

Autoimmune conditions increase the risk of lymphoma, cancer stemming from the lymph nodes.³³ More specifically, pSjD is the autoimmune disease associated with the highest risk of B-cell lymphoma, occurring in 5% to 10% of patients.³³ This risk increases by 2.2% per year of age in this population.³³ In patients with pSjD, chronic stimulation of autoimmune B cells leads to development of B-cell lymphoma. Screening for lymphoma is an important part of a comprehensive treatment plan given the increased risk. Similar to other autoimmune conditions, SjD also increases patients’ risk for atherosclerosis and coronary artery disease.²²

 

Research Continues

Researchers continue to define new therapeutic targets and investigate new treatments for SjD. Targeting B cells appears to be the most promising therapeutic approach for this condition.¹⁸ Studies are evaluating anti-CD20 antibodies and antibodies targeting the BAFF signaling pathway to target B cells and anti-CD40 antibodies to block the crosstalk between T cells and B cells.¹⁸ So far, two agents have met their primary outcome—improvement in systemic disease activity—in pSjD clinical trials: anti-BAFF receptor antibodies and anti-CD40 antibodies.

 

BAFF receptors are exclusively expressed on B cells, so targeting these receptors effectively depletes B cells to blunt the autoimmune response in pSjD. Clinical trials have assessed an anti-BAFF receptor antibody, ianalumab (VAY736) in patients with pSjD with positive results.^34,35 In the phase 2b study, patients experienced improved ESSDAI scores from baseline to week 24 and improvement in stimulated saliva flow rate.³⁵ This is a promising option for a future disease-modifying pSjD treatment, and phase 3 trials are ongoing.

 

The interaction between CD40 and the CD40 ligand (CD40L) is important for B cell development, antibody production, and optimal T cell-dependent antibody responses. Patients with pSjD have increased expression of CD40L compared to healthy individuals, which suggests that CD40-CD40L interactions could be a practical target for pSjD treatment.¹⁸ Phase 2 studies have shown promising results for iscalimab, an anti-CD40 antibody, to treat pSjD. However, the drug’s manufacturer discontinued development of iscalimab, citing a non-competitive risk/benefit profile to other agents.³⁶ A phase 2 trial of another anti-CD40L antibody frexalimab (SAR441344) also shows promise for SjD, but the manufacturer is not currently pursuing this indication.³⁷

 

Additional therapeutic targets under investigation include¹⁸

• Bruton’s tyrosine kinase, an important molecule in B cell receptor signaling
• plasmacytoid dendritic cells, which secrete type 1 IFNs
• downstream type 1 and 2 IFN signaling (using Janus kinase inhibitors)
• IL-12 signaling pathway and induction of T helper 1 cell, which secrete type 2 IFNs (using ustekinumab)

 

MULTIDISCIPLINARY TEAM CARE IS IDEAL

EULAR guidelines recommend a multidisciplinary approach to SjD treatment.¹¹ This is the second strongest recommendation included in the 2020 guidelines, with only a recommendation for patients who develop B-cell lymphoma to receive individualized treatment receiving a stronger grade. SjD’s overall prevalence in the general population is low and the condition presents differently in every patient, making it difficult for any one provider to ensure in-depth expertise in managing it. At minimum, the SjD care team should include a primary care provider (PCP), a rheumatologist, a dentist, and an ophthalmologist. Pharmacy staff should understand the roles and responsibilities of each provider to better recognize their own place on the care team.

 

Rheumatologist

Rheumatologists are usually the “lead” of the medical team for SjD and have the primary responsibility for managing it.³⁸ The rheumatologist should verify the diagnosis, including looking for disease mimics and screening and monitoring for coexisting rheumatologic or autoimmune conditions. They should also screen for lymphoma risk factors and common comorbidities. They may collaborate with the patient’s PCP for comorbidity monitoring and management. Rheumatologists also provide treatment for systemic features of SjD.³⁸

 

Primary Care Provider

The PCP should provider routine, comprehensive health care addressing a wide range of issues, including patients’ mental health.³⁸ They should collaborate with the patient’s rheumatologist to establish who is responsible for overlapping areas of practice (e.g., comorbidities, immunizations, nutrition concerns). Screening for comorbidities—including cardiovascular disease, osteoporosis, sinusitis, and others—is an important task for PCPs, but they may be unaware of the increased risk of these conditions in patients with SjD. Pharmacy teams should encourage patients to advocate for themselves, and direct patients to www.sjogrensadvocate.com for advice on how to do so effectively.³⁸

 

Ophthalmologist

Ophthalmologists are responsible for managing severe dry eye.³⁸ Occasionally, the ophthalmologist is the first provider to suspect SjD and refers patients to rheumatology for general management. They perform diagnostic tests (e.g., Schirmer’s test, ocular staining score, tear breakup time) to determine the severity of SjD ocular symptoms and blood tests to screen for biologic signs of SjD. These clinicians also provide routine dry eye management, including prescription medications/drops and recommendations for OTC therapies.

 

Dentist

Many patients with SjD require extensive dental care exceeding the recommended checkups every 6 months for otherwise healthy individuals.³⁸ Preventative dental visit frequency depends on patients’ level of dryness and decay. At every checkup, dentists should examine the entire oral region, including palpating (i.e., feeling with the fingers) salivary glands, face, and neck for swelling and masses.³⁸ They should also provide dental caries prevention, screening, and treatment.

 

Where Pharmacy Fits In

Most often, pharmacy technicians will encounter patients with SjD at the pickup counter, so they should be prepared to refer patients to the pharmacist when appropriate. Sometimes, patients request assistance finding the eye care aisle for OTC drops. Before pointing them in the right direction, pharmacy technicians should refer patients to the pharmacist for counseling if they indicate they are new to using artificial tears (e.g., asking your opinion about product selection).

 

Technicians can also help patients locate products based on pharmacist recommendations and provide informational handouts about proper administration technique (see Sidebar). While cost in an important factor in therapy adherence, consider recommending name brand products rather than store brand generics whenever feasible. While the active ingredients may be consistent across proprietary and store brand products, the concentration of these components is often less than 5% of each drop.³⁹ The amount of inactive ingredients (i.e., “filler”) differs from brand to brand.

 

Sidebar: Don’t Leave Patients High and Dry^40,41

To provide maximum relief, patients must administer eye formulations correctly. Many patients struggle with this, especially older patients, and joint pain in SjD can make it even more difficult. Counseling patients on proper eye drop and ointment instillation is crucial to improving outcomes.

 

Eye Drop Administration

1. Thoroughly wash hands and areas of the face around the eyes. Remove contact lenses, unless the product is specifically designed for use with contact lenses. If using a suspension, shake well.
2. Tilt head back, gently grasp the lower eyelid below lashes and pull away from the eye to create a pouch.
3. Look up, and administer a single drop into the pouch without touching the tip of the container to the eye.
4. As soon as the drop is instilled, release the eyelid slowly. Close eyes gently for 3 minutes and position the head downward (gravity pulls the drop onto the ocular surface). Minimize blinking or squeezing the eyelid.
5. Use a finger to gently apply pressure to the opening of the tear duct (inner corner of the eye) to prevent medication from draining through the tear duct and increase medication contact time in the eye.
6. If additional ophthalmic therapy is indicated, wait 5 to 10 minutes in between. Also, wait 5 to 10 minutes before reinserting contact lenses, if applicable.

 

Pro-Tip: tell patients, “If you have a hard time deciphering whether you’ve successfully installed eye drops, refrigerate the solution before administration to more easily detect the drops on your eye’s surface. Do NOT use this trick with a suspension.”

 

Eye Ointment Administration

1. Thoroughly wash hands and areas of the face around the eyes. Remove contact lenses, unless the product is designed for use with contact lenses specifically.
2. Tilt head back, gently grasp the lower eyelid below lashes, and pull away from the eye to create a pouch.
3. Look up, and with a sweeping motion, place a strip of ointment ¼ to ½ inch wide inside the lower eyelid by gently squeezing the tube (avoid touching the tube tip to any tissue surface).
4. Release the eyelid slowly and close eyes gently for 1 to 2 minutes.
5. Vision may blur temporarily, so avoid activities that require good visual acuity until vision improves. Also, wait 15 minutes before reinserting contact lenses, if applicable.

 

Clearly, a medication expert needs to contribute to patient and provider education and oversee prescribed and OTC medications. Pharmacists can offer various clinical pearls to help patients with SjD avoid dry eyes, mouth, and skin.

 

Lifestyle modifications⁴²:

• Avoid windy or drafty environments and wear sunglasses outdoors
• Use a humidifier indoors to keep the air moist
• Practice good oral hygiene (e.g., chew sugarless gum, stay well hydrated, see a dentist three times a year)
• Consciously remember to blink when working at a computer or reading extensively
• Avoid wearing eye makeup
• Consider smoking cessation and avoid smoky environments
• After showering, pat dry gently and apply an emollient to damp skin within three minutes

 

Separation and timing^40,41:

• Separate administration of multiple eye drops by at least 5 minutes to ensure the first drop is not flushed away by the second and the second drop is not diluted by the first
• If using multiple products, use them in order of least viscous to most viscous to ensure efficacy of all treatments
• If using drops and ointment, administer drops at least 10 minutes before ointment so the ointment does not create a barrier to the drops’ absorption
• If using a suspension with another dosage form, use the suspension last because its retention time in the tear film is longer

 

Pharmacists and pharmacy technicians should also be aware of medications that could worsen symptoms of dryness (Table 4). Technicians should refer patients with SjD to the pharmacist when they see these at the pick-up counter. They should also stay up to date on available eye care formulations and discuss new products with the pharmacist. Pharmacists should counsel patients with SjD about which OTC products to avoid and offer to contact prescribers to recommend prescription therapy changes.

 

Table 4. Medications That Cause or Worsen Ocular Dryness^19,25,28

Medication/Class	Examples	Rx/OTC	Mechanism for Ocular Dryness
Anticholinergics	benztropine trihexyphenidyl	Rx	Blocking acetylcholine blurs vision and stops the signals that normally tell the eyes to produce tears
Antihistamines (especially first-generation)	cetirizine chlorpheniramine diphenhydramine loratadine	OTC	Dry secretions (including tears) and produce anticholinergic adverse effects
Beta-blockers	atenolol metoprolol propranolol	Rx	Cause the body to make less of a protein present in tears, and can lower pressure in the eyes, affecting the amount of water in the tears
Decongestants	phenylephrine pseudoephedrine	OTC	Decrease nasal/mucosal mucus production (including the eyes), which decreases tear production
Diuretics	furosemide hydrochlorothiazide	Rx	Help the body eliminate water and salt, which can alter tear composition
Hormones	estrogen/progesterone and other hormones used for contraception, infertility, or hormone replacement	Rx	Unknown
Isotretinoin	N/A	Rx	Lessens oil production by certain glands to treat acne, but some of those glands are in eyelids, decreasing oil in tears
Tricyclic antidepressants	amitriptyline amoxapine clomipramine imipramine maprotiline	Rx	Anticholinergic adverse effect stops the signals that normally tell the eyes to produce tears

OTC = over-the-counter; Rx = prescription only

 

CONCLUSION

SjD is a complex, multifactorial condition that impacts patients’ quality of life substantially. Providing optimal care for this disease requires a multidisciplinary team, on which pharmacists and pharmacy technicians provide a link between all providers to ensure continuity of care. Recognizing patients with SjD in the pharmacy is crucial to prevent polypharmacy, ensure patients know how to use eye care formulations, assist patients in finding OTC products to address symptoms, and refer to other providers when necessary. This will improve care and outcomes for patients with SjD.

 

 

 

PAUSE AND PONDER:

1. Why are patients with SjD so difficult to identify and diagnose?
2. How would your daily life change if you had SjD? What hardships might you face?
3. How often do you encounter patients asking for help choosing artificial tear products? What could you improve about your ability to assist them?

 

 

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