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 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 weary when patients complain of abdominal pain or attempt to purchase multiple OTC products to treat their symptoms; they should relay specific disease- and drug-related questions to the pharmacist on duty. GBD is a common and highly manageable condition, and patients can live normal and healthy lives once symptoms are properly controlled and treated.

 

 

Download CE Activity

INTRODUCTION

Fiery inflammation in the bowel can be due to several conditions. In inflammatory bowel disease (IBD), gastrointestinal (GI) tract inflammation episodes are common. Crohn’s disease (CD) and ulcerative colitis (UC) are two IBDs differentiated by location and bowel involvement.¹ That’s a point to remember: that IBD is an umbrella term that includes CD and UC. In 10% to 15% of patients, the features of CD and UC are so similar that it is impossible to differentiate between them and misdiagnosis may result.^1,2 Besides the GI tract, both CD and UC also may be accompanied by symptoms outside the intestine, called extraintestinal symptoms.

 

DIFFERENTIATING CD AND UC

CD results in patchy ulceration of any portion of the GI tract (see Figure 1) from the mouth to the anus. It frequently affects the terminal ileum and colon, and bleeding is uncommon. Typically, patients experience pain in the lower right abdomen.³ UC, this continuing education’s primary focus, involves inflammation of the colon mucosa. UC often affects the rectum, referred to as proctitis, and bleeding during bowel movements is common. Typically, patients experience pain in the lower left abdomen. It may extend into the left (sigmoid) part of the pelvis or beyond the sigmoid, or include the entire colon, referred to as pancolitis.⁴ In UC, inflammation leads to edema, ulcers, bleeding, and electrolyte losses.

Figure 1. The Gastrointestinal Tract

UC is a chronic idiopathic relapsing/remitting condition (meaning it waxes and wanes) with interactions between the environment, immune system, gut microbiome, and a genetic predisposition to the disease suspected as causes.⁵  UC’s incidence and prevalence is increasing worldwide.⁶ From 1990 to 2017, its incidence increased from 3.7 million individuals to 6.8 million affected individuals worldwide.⁷ UC is incurable, so treatment goals aim to achieve rapid resolution of symptoms, mucosal healing, and clinical and endoscopic remission. An additional goal is to improve a patient’s quality of life (QoL).^6.

 

Individuals with this complex condition have a high level of disability and high healthcare resource utilization. Beyond medical management, 15% to 20% of patients with UC will require surgery. Compared to adults without IBD, adults with IBD experienced $11,029 higher direct costs per patient per year according to one report.⁸ Documenting this diagnosis in the pharmacy’s profile can help pharmacists and technicians screen for potential problems more efficiently.

 

Differentiating the two forms of IBD drives treatment. Both CD and UC present as similar repetitive episodes of GI inflammation and create significant patient burden. In CD, inflammation or ulceration commonly occurs in the ileum and colon.⁴ Outside of the intestine, CD may affect the esophagus, duodenum, or stomach, and gallstones may occur. In UC, extraintestinal manifestations may appear most commonly as inflammatory arthropathies (joint disease) and bile duct inflammation and scarring, but may include bone, eye, and skin involvement.^9,10 Although IBD’s incidence peaks at age 15 to 29 years, 10% to 15% of new diagnoses occur among adults aged 60 years or older.¹¹ Both forms of IBD are more prevalent among non-Hispanic White people than among people in other racial/ethnic groups.¹²

 

PAUSE AND PONDER: What support can you provide to a patient who tells you that wherever they go, their first action is to scan for the closest bathroom?

 

UC’S PATHOPHYSIOLOGY AND ASSESSMENT

 

The normal colon is five or six feet long and three inches wide. Its layers of circular and longitudinal muscles and tissues contract to move food and liquid forward. It wraps around the outside of the small intestine, has segments, and looks somewhat flat. A seam runs vertically down the middle so the segments bulge on either side of the seam. As UC becomes chronic, the colon becomes more rigid and short, leading to a pipe-like appearance.⁹

 

The most important risk factor for UC is a family history of IBD in a first-degree relative.¹⁴ Patients with disease extension to the left side of the colon, or extensive colitis, are more likely to need medication, undergo colectomy (removal of a portion of the colon), and develop colorectal cancer.¹⁵  Risk factors for colorectal dysplasia (abnormal that are not cancerous but can sometimes lead to cancer) or cancer include disease duration and extent, active inflammation, presence of a stricture (inelastic narrowing of a section of the GI tract), polyps, and family history of colorectal cancer. The bile duct may also become diseased in 3% to 7% of patients with UC.^15,16

 

UC’s pathophysiology involves defects in the epithelial barrier, defective immune response, the presence of leukocytes, and microflora imbalance in the colon.^17,18 UC’s inflammation deteriorates the epithelium, and exposure to certain intestinal microbes worsens the inflammation.⁹ Other immune-related factors that affect UC’s pathophysiology and the body’s response include tumor necrosis factor-alpha (TNF-alpha), numerous interleukins, and elevated immune globulin levels.¹⁷

 

Two measures are recognized in UC. Gastroenterologists and researchers tend to use the erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) components of the Truelove and Witts criteria. Researchers frequently measure ESR and CRP before and during treatments as outcome measures. The prescribing information for anti-TNFs, JAK inhibitors, and IL-12/23 antagonists also include ESR and CRP measures. Table 1 illustrates UC disease severity measured by assessment in the modified Truelove and Witts criteria.¹⁵

 

 Table 1. Modified Truelove and Witts Criteria¹⁵

Parameter	Mild	Moderate	Severe
Bloody stools/day (n)	<4	4-6	>6
Pulse (beats/minute)	<90	≤90	>90
Temperature (T) °C (T°F )	<37.5 (<99.5)	37.5 – 37.8 (99.5 – 100.4)	>37.8 (>100.4)
Hemoglobin (g/dL)	>11.5	11.5 – 10.5	<10.5
ESR (mm/hr) [or CRP mg/l]	<20 (normal)	20 – 30 (<30)	>30 (>30)

°C=degree Celsius; CRP = c-reactive protein; ESR = erythrocyte sedimentation rate; °F = degree Fahrenheit

 

In the clinical setting, the simpler Mayo score (see Table 2) is used more widely than Truelove and Witts criteria.¹⁹ It reflects stool frequency, rectal bleeding, a physician’s global assessment, and a measure of mucosal inflammation at endoscopy, with a maximum score of 12. Clinical response in UC is defined as¹⁹

• a reduction of Mayo score by at least 3 points and a decrease of 30% from the baseline score, or
• a decrease of at least 1 point on the rectal bleeding subscale or
• a total rectal bleeding score of 0 or 1

 

Table 2. Mayo Score for Ulcerative Colitis^15,20,19

	Points
Mayo Variables	0	1	2	3
Stool frequency	Normal	1-2/day more than normal	3-4/day more than normal	5/day more than normal
Rectal bleeding	None	Streaks of blood with stool <50% of the time	Obvious blood with stool most of the time	Blood passed without stool
Mucosa (endoscopic subscore)	Normal or inactive disease	Mild disease (erythema, decreased vascular pattern, mild friability)	Moderate disease (marked erythema, lack of vascular pattern, friability, erosions)	Severe disease (spontaneous bleeding, ulcerations)
Physician’s global assessment	Normal	Mild disease	Moderate disease	Severe disease

Mayo score = sum of scores for each of the four variables (maximum score 12)

 

 

Beyond clinical response, clinical remission is a desired objective and is defined as a Mayo score of 2 or less and no individual subscore exceeding 1.¹⁹ Mucosal healing is defined as a mucosa subscore of 1 or less. Disease activity is a measure used to decide what treatments to prescribe. Mild disease activity is defined as scores of 3 to 5. Moderate and severe disease activity are defined as scores between 6 and 10 and 11 and 12, respectively.¹⁹

 

The clinician’s patient assessment must be global (all encompassing).²¹ During patient interviews, clinicians should inquire about extraintestinal symptoms, which may include joint, mood, ocular, oral, or skin changes. They should order laboratory evaluation for anemia and liver function abnormalities. Clinicians should explore QoL issues, such as impact on school, work, or personal relationships. Treatment plans should incorporate patients’ unmet needs and preferences. Exploring the need for social and emotional support, financial resources, and adequacy of patient education regarding their disease are important.²¹

 

Throughout treatment, it’s important to assess the patient’s clinical response and remission periodically. Clinicians should monitor cross-sectional imaging, specifically MRI, CT and ultrasound, and surrogate markers, such as fecal calprotectin (FCP; type of white blood cell that migrates to inflamed tissue) and CRP.^15,22 A sigmoidoscopy or colonoscopy is recommended within three to six months of initiating treatment to determine the level of suppression of the inflammation, treatment response, or the need to modify the treatment.²²

 

THE PATIENT’S JOURNEY

The journey through symptoms, diagnosis, and treatment to quell the fiery inflammation associated with UC can be long and difficult. In one study, one in four individuals with IBD reported GI symptoms to their primary care physician more than six months before receiving a diagnosis.²³ Of these individuals, 10.4% reported symptoms five years before receiving a UC diagnosis. Delayed diagnosis often results in disease progression, worsening tissue, and mucosal damage, surgery, colectomy, or colitis-associated cancer.  Patients with a previous diagnosis of irritable bowel syndrome or depression were less likely to receive a timely specialist appointment.²³

 

UC is vastly heterogeneous. Table 3 presents two cases with distinct disease journeys.

 

 

Table 3. Two Distinct Patient Journeys^24,25

UC Patient Case 1		UC Patient Case 2
9-year-old girl diagnosed after ileocolonoscopy reveals diffuse moderate inflammation		UC since age 18
Moderate clinical disease activity, Mayo score = 8		Symptoms included bleeding, severe pain and swelling in lower abdomen, gas, and nausea
Low hemoglobin, low vitamin D		Lifestyle: Undergraduate, lifeguard, swim coach
Oral corticosteroids started followed by dose tapering dose and mesalamine started		Daily regimen of oral medication, rectal suppositories, nightly enemas
At week 4, active disease remained		Symptoms worsened so → ED
IFX started at 10 mg/kg at 0, 2, and 6 weeks		Barely able to eat or drink, covered with rash and inflamed eyes
At 26 weeks with IFX, she remained in clinical remission		Incontinence in street, bus, and post office
At 1 year, she remained in remission		Acute diarrhea with each BM → became homebound
Follow-up flexible sigmoidoscopy demonstrated mucosal healing		At age 29, married → then 10 weeks of hospitalization without remission
		Agreed to surgical colectomy → difficult recovery, diarrhea, and intestinal blockages
		Finally exercising, back to work, and monitoring the quantity, texture, and timing of food. Remained on pre-surgical medications.

BM = bowel movement; ED = emergency department; IFX = inFLIXimab

 

UC affects many distinct populations. In the pediatric population with UC, unlike in adults, the clinical condition can present atypically with a more severe, early onset and continuous inflammation of the rectum and colon.^26,27,28 In these patients, clinicians should assess disease location and severity. One study indicated 62% of pediatric patients with UC from birth to age 5 years had extensive pancolitis, and 38% and 31% from ages 6 to 11 and from ages 12 to 18, respectively, had pancolitis.²⁷   Children can also experience rectal sparing (a normal/unaffected rectum) and limited distal disease.^26,28

 

To optimize management, enhance QoL, and minimize complications in all patients, continued patient engagement is important.²⁹

 

GOALS OF UC MANAGEMENT

 

The UC treatment guidelines recommend goals of therapy to include²⁹

• induction and maintenance of clinical and endoscopic remission
• maintaining steroid-free remission
• improving QoL, and
• preventing complications, hospitalizations and surgery.

Pursuing these goals can also contribute to minimizing cancer risk.^21,30,31 Long-term mucosal healing may reduce the risk of dysplasia.³¹

 

The Treat-To-Target Approach                                                         

UC is considered relapsing/remitting because it presents as relapses of symptoms and then periods of symptomless response and remission. Beyond symptom remission, a treat-to-target (T2T) approach focuses on^32,33

• minimizing disease activity
• reducing futures risks and
• reducing future relapses or complications such as ileal strictures (narrowing), fistulas, functional impairment, or colon cancer.

 

In 2015, the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative recommended that UC treatment goals should address two targets: clinical and endoscopic outcomes.³² IBD experts recommend using measures of inflammation such as FCP.³²  FCP detects GI inflammation sensitively and is used to monitor disease activity and predict relapse.

 

PAUSE AND PONDER: Which UC treatments do you see in your practice location most often?

 

UC’s treatment options are plentiful and evolving. Pharmacy team members can collaborate with multidisciplinary professionals regarding patient care for UC. (See SIDEBAR). Pharmacists’ drug therapy and disease management expertise can promote individualized treatment decisions for these complex patients.

 

 

SIDEBAR: Working with the Multidisciplinary Team

Team collaboration can increase patient and provider education, enhance quality of care, and reduce disease burden, and morbidity. Many pharmacists don’t know how to introduce themselves to or work with multidisciplinary teams. Sometimes, team members from other disciplines will call with questions or concerns, and the call opens the door for regular communication. Often, however, pharmacy staff will need to take the initiative and introduce themselves. Here are four tips to working better with the UC care team.

• Ask patients if they are seeing a nutritionist, primary care provider, gastroenterologist, or behavioral health provider (for stress support). If UC is severe, inquire if they have a surgeon or know their radiologist. Record these providers’ names in the patient record and contact them when questions or concerns arise.
• Make the patient your ally and be your patient’s ally. When you educate patients well and show them your capabilities, they will report back to their clinicians.
• When you work with a patient who has UC, let the professional team members know. Sending a quick note to say that, for example, the patient’s adherence was poor and you discussed ways to improve it with the patient sheds light on possible non-response. It also makes clinicians aware that you have skills and you’re not afraid to use them!
• Don’t be afraid to make team members aware of issues like cost or availability of less expensive options. Often, prescribers have no idea that patients experience sticker shock when they fill their prescriptions.

 

TREATMENT

Medication is a mainstay of treatment for patients with UC. Prescribers may combine, dose-escalate, reduce, or discontinue medications, depending on the patient’s disease severity.

 

Traditional Treatments

When a patient presents with mild to moderate UC, the expert consensus is to start treatment with an oral 5-aminosalicylate (5-ASA; sulfasalazine, mesalamine, and diazo-bonded 5-ASA [the prodrugs, balsalazide and olsalazine, which convert to mesalamine]³⁴) with or without a rectal 5-ASA.^34,35 In many cases, rectal dosing improves symptoms; using a suppository, enema, or rectal foam applies the medication exactly where needed. Sulfasalazine, balsalazide, and mesalamine are similarly effective and safe.³⁴ Some patients will respond inadequately and may need to escalate therapy to systemic corticosteroids, immunomodulators (IMM), biologics, or other agents. If symptoms persist, it is important to rule out infection, optimize adherence, increase the oral dose, and add rectal 5-ASA if not yet prescribed.^34,35

 

Comparative efficacy studies are helpful to clinicians. One technical review of multiple drugs in mild to moderate UC compared rectal 5-ASAs (5-ASA enemas 1 to 4 g/day or 5-ASA suppositories 1g/day) to rectal corticosteroids (hydrocortisone enema 100mg/day, prednisolone enema 25–30 mg/day, budesonide enema 2 mg/day, beclomethasone 3 mg/day or comparable foam) in 13 trials.³⁶ In mild to moderate ulcerative proctosigmoiditis cases treated for two to eight weeks, rectal 5-ASAs were superior to rectal corticosteroids for induction of clinical remission.³⁶

 

Table 4 lists the broad categories of medications for mild, moderate, or severe UC and dosing information.

 

Table 4. Medications for UC^22,37-42

Category	Substance	Dosage
5 – ASA	Mesalamine     Balsalazide   Olsalazine   Sulfasalazine	2 – 4.8 g/day (oral) 1 – 2 g/day (rectal)   6.75 g/day (rectal)   1 g/day (oral)   2 – 4 g/day
Corticosteroids	Budesonide   Budesonide MMX   Prednisone   Hydrocortisone   Methylprednisolone	2 mg/day (rectal)   9 mg/day (oral)   0.75 – 1 mg/kg/day   100 mg IV 4 times/day   125 mg IV/day
Thiopurines Immunosuppressives	Azathioprine   6-mercaptopurine	2 – 2.5 (max 3) mg/kg/day   1 – 1.5 mg/kg/day
Calcineurin inhibitors	Cyclosporine   Tacrolimus	2 mg/kg/day IV   0.2 mg/kg/day
Anti-TNF agents	Adalimumab       Golimumab       Infliximab	160 mg wk 0, 80 mg wk 2, 40 mg wk 4, then 40 mg every 2 wks; may ↑ to 40 mg/wk SUBQ   200 mg wk 0, 100 mg wk 2, 50 mg wk 4, then 50 mg every 4 wks; may ↑ to 100 mg if pt>80 kg SUBQ   5 mg/kg wk 0, 2, 6, then every 8 wks IV
Adhesion molecule inhibitors (anti-integrin)	Vedolizumab	300 mg wk 0, 2, 6, then every 8 wks IV
Janus kinase inhibitor	Tofacitinib               Upadacitinib	5 – 10 mg/day (oral) First 8 wks: 10 mg twice/day 10 mg twice/day for 8 more wks if partial response Then 5 mg twice/day or 22 mg XR/day for 8 weeks; then evaluate   45 mg/day for 8 wks then 15 mg/day (oral)
Interleukin 12/23 antagonist	Ustekinumab	250 mg to 55 kg IV 390 mg if >55 kg – 85 kg IV 520 mg if >85 kg IV Then 90 mg SUBQ every 8 wks
Sphingosine 1-phosphate receptor modulator	Ozanimod	0.23 mg days 1-4, 0.46 mg days 5-7, then 0.92 mg/day (oral)

G = grams; IV= intravenous; kg=kilogram; mg= milligrams; MMX = Multi-Matrix System technology drug release; SUBQ=subcutaneous; wk= week

 

Sulfasalazine

If sulfasalazine is prescribed, 4 g provides approximately 1.6 g of 5-ASA equivalence.³⁴ Typical doses are 2 tablets 4 times a day.^37,43 In some cases, prescribers may initiate therapy with a smaller dose, (e.g., 1 to 2 g daily) to reduce possible GI intolerance and slowly increase as tolerated. They may also try enteric-coated sulfsalazine.^37,43 Sulfasalazine is commonly prescribed for individuals with UC and rheumatologic comorbidities.⁴³ Periodic monitoring of complete blood counts (CBC) and liver function tests (LFT) is recommended.

 

Sulfasalazine may be poorly tolerated due to adverse effects such as headache, nausea, diarrhea, and rash.⁴³ Additional adverse events with sulfasalazine include folate metabolism interference, male infertility, and rare cutaneous side effects such as Stevens-Johnson syndrome. Anemia, leukopenia, or thrombocytopenia are also possible. Pneumonitis and hepatitis have been reported.⁴³  Sulfasalazine is contraindicated if a patient has a sulfa allergy. Sulfasalazine tablets are a yellow/orange color; individuals who take it may notice an orange tinge in urine, tears, and sweat that can stain clothing and contact lenses. Auxiliary labels and counseling should emphasize drinking plenty of fluids, taking the drug on an empty stomach, and avoiding antacids.

 

Mesalamine and Balsalazide

Low dose mesalamine may be prescribed initially at less than 2 grams per day(g/d). Some patients need 2 to 3 g/d. Higher doses of 3 g/d or more may be required to induce remission.³⁶ Combining oral and rectal therapy may deliver a higher effective dose of 5-ASA to the involved area and lead to higher rates of induction and maintenance of remission. This approach may avoid escalation to corticosteroids or other agents.³⁶

 

Mesalamine and balsalazide are associated with rare idiosyncratic worsening of colitis.²² Rare interstitial nephritis may also occur. The prescribing information recommends periodic renal function monitoring. Olsalazine is generally less well tolerated than either mesalamine or balsalazide. Headache, nausea, diarrhea, leukopenia and hepatitis are possible. 5-ASA treatments should be avoided in pregnancy.²²

 

Steroids and Other Traditional Treatments

Corticosteroids, such as budesonide, are generally prescribed for a short duration or for induction of remission.³⁴ Some experts suggest prescribing oral mesalamine, balsalazide or olsalazine over budesonide because hepatic first-pass metabolism lowers budesonide’s systemic activity.^34,44 As the patient’s condition improves, withdrawing the steroids and reaching steroid-free remission (SFR) is important. Long-term corticosteroid use may lead to infection, diabetes mellitus, weight gain, insomnia, osteoporosis, or glaucoma.⁴⁵ Mood changes, cataracts and delayed wound healing are possible.⁴⁵

 

Thiopurines and Cyclosporine

Thiopurines, including azathioprine and 6-mercaptopurine, may improve inflammation in patients with UC. They inhibit the proliferation of lymphocytes and are used to maintain remission. Their dosing is weight-based and their onset of action can be slow, taking up to three months.²² They are often used in combination with biologics. Monitoring for drug interactions is necessary. Allopurinol interactions with thiopurines are especially important because allopurinol inhibits thiopurine metabolism.⁴⁶ The dose of mercaptopurine or azathioprine may need to be reduced to one-third or one-quarter of the normal dose if allopurinol is also prescribed. Prescribers determine dose reductions based on therapeutic response and toxicity.⁴⁷

 

Even though thiopurines and cyclosporine have been prescribed for many years, remaining aware of their side effects is important. Possible adverse events of thiopurines include nausea, vomiting, fever, leukopenia, thrombocytopenia, pancreatitis, and hepatotoxicity. Rare adverse events may include non-Hodgkin lymphoma. Individuals prescribed calcineurin inhibitors, such as cyclosporine, may experience hypertension, nephrotoxicity, hyperkalemia, infection, lymphoma, or diabetes mellitus.³⁷

 

Additional therapies include biologics and newer small molecules (tofacitinib, ozanimod). Before discussing newer therapies, a short review of step-up and step-down approaches is reasonable. If a patient presents with moderate to severe ulcerative colitis, philosophies differ among gastroenterologists regarding beginning with a step-up versus a step-down approach.^36,48

• The step-up approach begins with the traditional therapies mentioned above and followed by biologics and IMM if symptoms persist, if remission is not achieved, and the patient is considered high-risk. Extensive inflammation and the need for repetitive use of corticosteroids are examples of high-risk status.
• The step-down approach occurs when prescribers begin with a more intensive treatment with biologics and IMM and then step down to the medications mentioned above if patients improve.

 

Step Up or Step Down?

A 2021 study (N = 1891) examined UC’s clinical presentation in the five years before starting biologic therapy. The researchers analyzed patients’ experiences, comorbidities, morbidity, and treatment burden over time. Figure 2 summarizes participants’ health burden, disease progression, medication burden, and increased comorbidities. Across the study period, the need for treatment with oral corticosteroids, 5-ASA, and other non-biologic immunomodulators (IMM) increased progressively. Due to the increasing burden, the researchers supported early use of biologics (a step-down approach) rather than gradual step-up after failing conventional therapies for adult patients with moderate to severe UC.³⁰ 

 

Figure 2. Treatment and Health Experience Beginning Five Years Before First Biologic³⁰

5-ASA = 5-aminosalicylates; ED = emergency department; OC = oral corticosteroids; Pts = patients

 

 

Anti-TNF agents

 

Anti-TNF agents are commonly prescribed for moderate to severe UC due to their effectiveness, length of time on the market, and healthcare professional comfort prescribing them.⁴⁴ The U.S. Food and Drug Administration (FDA) has approved many anti-TNFs, but has approved only adalimumab, golimumab, or inFLIXimab for treating UC. Usually, prescribers use anti-TNFs after 5-ASA and corticosteroids in patients with mild to moderate severity and the step-up approach to treatment. Prescribers may prescribe the step-down approach, using biologics earlier, in some cases.³⁸ They often employ concomitant IMM to decrease immunogenicity seen with anti-TNFs.^38,47

 

Because biologics like anti-TNFs are made with living cells, patients may develop an unintended immune response (immunogenicity) in the form of anti-drug antibodies; if they develop, these antibodies may render the anti-TNF medication less effective. The antibodies may bind to the anti-TNF, interfere with its mechanism of action, reduce the anti-TNF’s serum concentration, increase its clearance, and lead to loss of effectiveness. Antibodies may also occur upon restarting an anti-TNF if a patient starts and stops an anti-TNF over time. It is unknown why some people develop anti-drug antibodies and others do not. The presence of antibodies and reduced response often prompt prescribers to switch the anti-TNF to regain effectiveness, and doing so often works. The addition of an IMM can suppress the antibodies which may reduce the risk of switching therapies or avoiding an anti-TNF dose increase.⁴⁷

 

Pharmacy team members should remain diligent about look-alike, and sound-alike names of the anti-TNF agents and should remember that doses of anti-TNF agents vary by indication.

 

SIDEBAR: TECH TALK about Look-alike, Sound-alike medications

Medications with names that look-alike and/or sound alike are classified as high-alert medications.

• Know that inFLIXimab had been confused with riTUXximab, so the Institute for Safe Medication Practices recommends using TALL Man lettering.
• Prevent medication errors between therapies for UC, such as adalimumab and golimumab, ustekinumab and upadacitinib, or vedolizumab and ustekinumab or adalimumab. Segregate the medications in different locations or consider stickers or other alert methods prior to medication dispensing.

 

 

An Anti-integrin

Integrins are adhesion receptors that mediate cell-to-cell and cell-to-extracellular adhesion. Vedolizumab is a humanized monoclonal antibody that binds to the α4β7 integrin, blocks the interaction of α4β7 integrin, and inhibits lymphocyte migration into inflamed GI tissue.⁴⁹ With fewer lymphocytes in the GI tract, vedolizumab helps reduce inflammation and UC symptoms. Vedolizumab can be referred to as a B-anti-integrin and an adhesion molecule inhibitor. Patients with steroid-dependent disease have treatment options, including treatment with thiopurines, anti-TNF agents (may be combined with azathioprine or 6-mercaptopurine), or vedolizumab.³⁸

 

Prescribers and patients may ask about outcomes in clinical trials. A vedolizumab study enrolled patients with an inadequate response or intolerance to IMM therapy (i.e., azathioprine or 6-mercaptopurine) and/or an inadequate response, loss of response, or intolerance to an anti-TNF.⁴⁹ Participants received IV vedolizumab 300 mg or placebo at week 0 and week 2. Concomitant stable dosages of 5-ASA, corticosteroids (prednisone dose of 30 mg/day or less or equivalent), and IMM (azathioprine or 6-mercaptopurine) were permitted through week 6. The percentage of patients achieving a clinical response at week 6 was 47%. The researchers also measured remission and found 17% of participants achieved remission at week 6. Those with a clinical response at week 6, or receiving open-label vedolizumab, were invited to enter a 52-week study with every 8-week dosing. At week 52, 42% of participants achieved clinical remission.⁴⁹

 

JAK inhibitors

 

Tofacitinib and upadacitinib are referred to as small molecules because their molecular structure is smaller and simpler than the biologics’, which are large three-dimensional structures. The JAK inhibitors are dosed orally and require a loading dose. JAK inhibitors are indicated for adults with moderately to severely active UC who responded inadequately or couldn’t tolerate one or more anti-TNF agents.³⁹ Many individuals are willing to visit an infusion suite for treatment; however, younger patients and those with very busy lifestyles or heavy travel schedules may prefer the small molecule oral drugs for their convenience.

 

When prescribing JAK inhibitors, pretreatment screening should include assessment for hepatitis B and tuberculosis. When patients start biologics or JAK inhibitors, their immune response may decrease, increasing risk of certain infections, such as hepatitis B or tuberculosis. If patients have active hepatitis B or tuberculosis, they need treatment to eradicate those infections before beginning biologics or JAK inhibitors. A risk of bacterial, viral, and herpes zoster infections exists, so prescribers must assess vaccination status before treatment. CBC and lipid panel monitoring is recommended. Prescribing tofacitinib in combination with biologics for UC or with potent IMM, such as azathioprine and cyclosporine, is not recommended.⁴⁰

 

 

IL-12/23 antagonist

Interleukin 12 (IL-12) and IL-23 are proteins that can cause inflammation. Ustekinumab is a human monoclonal antibody against the shared p40 subunit of IL-12 and IL-23 cytokines. Ustekinumab disrupts inflammation by blocking IL-12/23.⁴¹ The FDA has approved this biologic for adults with various forms of psoriasis, CD, and UC. (It is also approved for children 6 and older for various forms of psoriasis.) In UC in adults, it is typically administered as an IV induction dose, followed by subcutaneous maintenance dosing every eight or 12 weeks. Clinicians should screen for hepatitis B and tuberculosis and monitor CBC every six months.⁴¹ To minimize the risk of medication errors, pharmacy staff should double-check the prescribed route (IV or subcutaneous). They should also be alert for look-alike, sound-alike issues, to prevent prescription transcribing errors or other confusion between ustekinumab and the JAK inhibitor upadacitinib.

 

Research has documented outcomes for this monoclonal antibody, too. A ustekinumab clinical trial assessed efficacy and safety in adults with UC; the primary endpoint was clinical remission at week 8.⁴¹ The researchers randomized participants to a single IV dose of ustekinumab of approximately 6 mg/kg, 130 mg (a lower dose than recommended), or placebo at week 0. Enrollment required previous inadequate response to corticosteroids, IMM, or at least one biologic. At week 8, 19% of participants successfully reached clinical remission.⁴¹

 

S1P Modulator

Ozanimod is an oral sphingosine 1-phosphate receptor (S1P) modulator indicated for the treatment of moderately to severely active UC in adults.⁴² It is also approved for relapsing forms of multiple sclerosis, and the pharmacy team may field questions about this medication’s various indications. Ozanimod binds with high affinity to S1P receptors 1 and 5. It blocks lymphocyte trafficking from lymph nodes, reducing the number of lymphocytes in peripheral blood. Ozanimod may transiently decrease heart rate and cause atrioventricular conduction delays, so a low-dose starter titration pack is available. Prescribers should escalate the dosing slowly to avoid rare but significant bradycardia. Progressive multifocal leukoencephalopathy, a disabling, sometimes deadly adverse event, is rare but possible. Pharmacy teams should counsel patients regarding the need for effective contraception to prevent pregnancy; patients should use contraceptives for three months after discontinuing ozanimod.⁴²

 

An ozanimod clinical trial assessed efficacy and safety using a primary study endpoint of clinical remission at week 10.⁴² It enrolled adults with moderately to severely active UC if they had an inadequate response, or were intolerant, to specific other treatments. The treatments included oral 5-ASA, corticosteroids, IMM (e.g., 6-mercaptopurine and azathioprine), or a biologic (e.g., anti-TNF and/or vedolizumab). The proportion of patients reaching clinical remission at week 10 was 18% with an ozanimod dose of  0.92 mg once daily. Those achieving a clinical response were invited to be re-randomized to a 52-week study extension. The primary endpoint was the proportion of patients in clinical remission at week 52. The proportion of patients with an ozanimod dose of 0.92 mg once daily with clinical remission at week 52 was 37%.⁴²

 

MEDICATIONS IN DEVELOPMENT

Etrasimod is a once-daily, oral S1P receptor modulator in development for the treatment of UC. Results from the phase 2 OASIS trial and open-label extension study revealed patients with moderately to severely active UC who received etrasimod showed improvements in clinical remission and symptom relief beginning as early as week 2. In the phase 3 ELEVATE UC 52 study, 27% of patients in the etrasimod group achieved clinical remission compared with 7% of patients in the placebo group at 12 weeks.⁵⁰ Use of etrasimod in UC is not FDA-approved and regulatory authorities have not yet evaluated its safety and efficacy.

 

Risankizumab-rzaa is an IL-23 inhibitor that is FDA-approved for psoriasis and Crohn’s disease. It is in development for treatment of individuals with UC. In the INSPIRE trial, 20.3% of participants with intolerance or inadequate response to conventional or advanced therapies (biologics, JAK inhibitors, and S1P receptor modulators) achieved clinical remission at week 12.⁵¹ The FDA has not approved risankizumab in UC or evaluated its safety and efficacy.

 

Considerations for Medications in Therapy

Decision-making regarding UC treatment requires consideration of many factors, including

• disease and inflammation location, severity, and extent
• comparative effectiveness and long-term safety of available treatments
• treatment availability
• product labeling
• guideline recommendation
• prior treatment successes or failures
• cost, and
• patient preferences

Since some prescribers may dose escalate to an off-label (higher) dose or off-label shorter dosing interval, pharmacy teams need to remain alert regarding insurance policies that may impact treatment decisions.

 

Safety Information

Each medication’s full prescribing information includes comprehensive safety and efficacy details. The information in this section is not all-inclusive. It’s critical to keep in mind that all UC treatments have limitations. Because most infusions have similar adverse events, Table 5 summarizes select safety information and limitations regarding newer agents used in UC.

 

 

Table 5. Newer Agents: Select Safety Information and Limitations ^{37,41,42,49,52}

Limitations and Safety Considerations	Anti-TNF agents	Anti-IL-12/23 Agents	JAK Inhibitors	Anti-integrin	S1PR modulator
Immuno-suppression	√	√	√	√	√
Infection	√	√	√ (herpes zoster)	√ (upper respiratory)	√
Venous thrombo-embolism			√
Psoriasis	√	√
Major CV adverse event	√		√
Infusion/ injection site reaction	√	√	√	√
Malignancy	√	√	√	√	√
Tuberculosis	√	√	√	√
Worsen CHF	√
Lymphoma	√ (if combine with thiopurines)		√	√
Lymphocyte abnormalities			√
Anemia	√		√
Elevated lipids			√
Headache	√	√	√	√	√
Nausea	√		√	√	√
Fatigue	√	√	√	√	√
Liver function test elevations			√	√	√
Contra-indication if post-MI within 6 months, or unstable angina, stroke or TIA					√
Contraindicated if severe untreated sleep apnea					√
PML				√	√

MI = myocardial infarction; PML = progressive multifocal leukoencephalopathy; TIA = transient ischemic attack

 

Identifying drug interactions is a key skill for pharmacists. Of note, JAK inhibitors can interact with CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) and CYP2C19 inhibitors (e.g., fluconazole, omeprazole).⁴⁰ Drug interactions may be a concern with the use of ozanimod and concurrent IMM, tyramine, antiarrhythmics, beta blockers, or calcium channel blockers.⁴²

 

ACG and AGA Guidelines for the Management of Moderate-to-Severe UC

The American College of Gastroenterology (ACG) and the American Gastroenterological Association (AGA) published comprehensive treatment guidelines and interventions for UC.^31,44 Both guidelines cover achieving a response, induction of remission, and maintenance of remission. Select highlights presented below are not all-inclusive.

 

For remission induction, ACG recommends the following options³¹:

• In moderately active UC, oral budesonide MMX
• In moderately to severely active UC, oral corticosteroids
• In moderately to severely active UC, anti-TNF therapy
• When inFLIXimab is used as induction therapy for patients with moderately to severely active UC, it should include a thiopurine
• In moderately to severely active UC, or if failed anti-TNF, vedolizumab
• In moderately to severely active UC, tofacitinib 10 mg orally twice a day for 8 weeks
• For induction of remission in moderately to severely active UC with previous failure of anti-TNF therapy, tofacitinib

 

For maintenance of remission, ACG recommends the following options³¹:

• For previously moderately to severely active UC in remission due to corticosteroid induction, thiopurines
• Continue anti-TNF therapy after anti-TNF induction in patients with previously moderately to severely active UC
• Continue vedolizumab in previously moderately to severely active UC now in remission after vedolizumab induction
• Continue tofacitinib in previously moderately to severely active UC now in remission after induction with tofacitinib

 

The AGA provides the following recommendations for response and remission⁴⁴:

• Current evidence supports use of inFLIXimab, adalimumab, golimumab, vedolizumab, and tofacitinib for remission induction and maintenance in moderate-severe UC
• Thiopurine monotherapy should not be used for induction of remission but may be considered for remission maintenance
• Meta-analysis suggests that inFLIXimab and vedolizumab may be preferred first-line therapy in biologic-naïve patients, rather than standard-dose adalimumab or golimumab
• In patients with prior inFLIXimab exposure, particularly those with primary non-response to induction therapy, vedolizumab or tofacitinib may be preferred over adalimumab or golimumab
• Combination of a biologic agent with an immunomodulator is more effective than monotherapy with either agent
• In patients with moderate-severe disease activity, at high risk of colectomy, biologic agents with or without an IMM, or tofacitinib, should be used early rather than gradual step-up therapy after failure of 5-ASA
• Patients in remission with biologic agents and/or IMM, or tofacitinib, after prior failure of 5-ASA, may discontinue 5-ASA

 

PAUSE AND PONDER: What patient support questions may uncover a patient’s adherence challenges?

 

Patient Education Pearls for Patient Counseling

 

Pharmacy teams have numerous opportunities to provide UC patient education. Because the condition appears differently in affected individuals, conversations should align with the individual patient’s situation. Supportive patient education pearls addressing inflammation and advancing opportunities to remission should be individualized from these topics⁵³:

• UC’s exact cause is unknown
• UC affects people differs widely
• UC is a chronic condition and symptoms wax and wane
• Medications are available to control UC
• The number of people with UC has been increasing
• It can occur at any age and in any racial or ethnic group
• Symptoms will occur in the intestine and may occur outside of the intestine
• Ulcers in the intestine lining that bleed may lead to low red blood cell count (anemia)
• Ask the doctor what tests are needed
• Diet and nutrition plans differ for each patient
• Managing stress is important
• Have supportive friends and family
• Locate restrooms when outside the home
• Carry extra underclothes, toilet paper or moist wipes
• Ask for school or work accommodations

 

SIDEBAR: OTC and Alternative Therapies for Patient Discussion^34,35,44,54

 

Patients with UC may use these OTC products:

• Patients with UC may eat less, thinking it will decrease diarrhea. However, they need proteins, water, vitamins, and minerals to promote healing. Patients need vitamin D and calcium for bones if reduce their dairy intake.
• Bismuth subsalicylate (Pepto Bismol) is an antidiarrheal liquid, chewable tablet, and also swallowable tablet. It helps reduce inflammation in the intestinal lining. Remind patients that it darkens stool and the tongue. That darkening is not a medical concern.
• Simethicone (Gas-X) is an anti-flatulent that helps form gas bubbles in the digestive tract, making them easier to pass and relieving gas pain.
• Loperamide (Imodium) should be taken with caution. It slows digestion. Occasional use may be effective, but patients should consult healthcare providers if they contemplate ongoing use.
• If mild disease persists, such as seen with a Mayo score of 1, the AGA guidelines and some advocacy web sites mention curcumin (a phytochemical from turmeric) or suggest adding curcumin and probiotics for some individuals suffering with UC.
• Patients with severe disease, frequent bleeding, anemia, or abnormal laboratory results may need folic acid. The usual folic acid dose is 1 mg/day. Asparagus, broccoli, and spinach are also foods that contain folate or folic acid.

Patients who have UC should avoid these OTC products:

• Patients should consult their healthcare providers whether to avoid aspirin, nonsteroidal anti-flammatories (ibuprofen, naproxen), lactose, sugar substitutes, or preservatives.
• Patients who take sulfasalazine or mesalamine should not take them with antacids.

 

Many institutions, hospitals and healthcare providers have created UC resources. Table 6 lists  examples of supportive options that can be shared with individuals with UC.

 

Table 6. Patient and Clinician Resources to Support Individuals with UC

Resource	Contact
American College of Gastroenterology	https://gi.org/topics/ulcerative-colitis/ ·       Describes symptoms, tests, diagnosis, risks, surgery and treatments
Cleveland Clinic: Butts and Guts podcast	https://my.clevelandclinic.org/podcasts/butts-and-guts ·       Covers a wide range of gastrointestinal issues including management and surgery ·       Use the search term “ulcerative colitis”
Crohn’s and Colitis Foundation (CCF)	Help Center (referrals, insurance info) https://www.crohnscolitisfoundation.org/ info@crohnscolitisfoundation.org 1-888-MY-GUT-PAIN (888-694-8872- extension 8) Signs and Symptoms https://www.crohnscolitisfoundation.org/sites/default/files/legacy/assets/pdfs/living-with-ulcerative.pdf Spanish Help Center https://www.crohnscolitisfoundation.org/es/home School Accommodation Suggestions https://www.crohnscolitisfoundation.org/justlikeme/living-with-crohns-and-colitis/school/school-accommodations
Mayo Clinic	https://www.mayoclinic.org/diseases-conditions/ulcerative-colitis/symptoms-causes/syc-20353326 ·       Includes a video and written materials on diagnosis, symptom management, and treatment
Downloadable Mobile Apps ·       Download from the App Store or Google Play	My IBD Care: tracks symptoms, flares, medical appointments, BMs, medications Bathroom Scout: Identifies 1.3 million public toilets MyPlate: Monitors calories, the nutrition content of food MyColitis: Health tracking of bowel movements, medications, moods, symptoms, tests

 

CONCLUSION

UC is a debilitating chronic IBD that usually requires long-term treatment to control symptoms and prevent disease-related complications. Many treatments are available; however, the effectiveness, safety, and durability of response and remission vary, and careful assessment of these factors must drive a personalized approach to care. Pharmacy teams must recognize that every patient’s disease is different, and results in diverse manifestations. Pharmacists and pharmacy technicians are ideally positioned to collaborate with multidisciplinary teams to support strategies tailored to each patient to optimize care and to help patients maintain a positive outlook.

 

Many unanswered questions remain about UC. Researchers will continue to evaluate treatment advances and explore disease management opportunities while pharmacy teams encourage patients suffering from UC to have routine doctor visits, adhere to their medication regimen, and maintain a healthy lifestyle.

 

 

 

 

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 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 United States, 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 (e.g., mouse, rat,) 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, 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:

• 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.
• Consider the labor and time involved in bathing a pet often, safely, and well.
• 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 above, 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 formulation. 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 spray, 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   For 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 over the counter.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 antihistamine 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. 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 United States, 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 dosing. 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 1000 to 4000 BAU range.⁴²

SCIT 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.

Download CE Activity

INTRODUCTION

Asthma and chronic obstructive pulmonary disease (COPD) are common conditions that affect many individuals’ daily functioning. Worldwide, roughly 340 million people have asthma, and 390 million people have COPD.^1,2 It’s well-known that patients often have suboptimal inhaler technique, and numerous professional organizations have advocated for more counseling at every point in the healthcare system.^3,4 Although several new and improved pulmonary inhalation devices are available, inhaler use skills have lagged.⁵

 

Two systematic reviews analyzed studies of inhaler technique among patients and healthcare professionals from 1975 to 2014.^5,6 Each review divided the studies into an earlier (1975 to 1994) and a later (1995 to 2014) period to assess changes over time. The review of 54,354 patients over 144 studies found that approximately 30%, 40%, and 30% percent of patients had correct, acceptable, and poor technique, respectively. There was no significant difference in inhaler use skill between the earlier and later time periods.⁵ The review of 6,304 healthcare professionals over 55 studies found that correct inhaler technique among healthcare professionals declined from around 20.5% in the earlier time period to just 10.8% in the later time period.⁶

 

Using inhalers correctly is essential to disease control. A systematic literature review found an association between inhaler use errors and worsened disease outcomes for patients with asthma and COPD in almost all included studies.⁷ Longitudinal studies found that reductions in inhaler use errors improved disease outcomes.

 

Ultimately, most patients receive their inhalers from a pharmacy. Research shows that community pharmacists can positively impact inhaler technique, asthma control, quality of life, and medication adherence with educational interventions.⁸ Pharmacy personnel are strategically positioned to improve outcomes for people with asthma and COPD by

• Being familiar with the various inhalers available, understanding how to use them, and knowing the counseling points for each
• Recognizing patient-specific factors that could impact inhaler administration
• Understanding the importance of educating and evaluating patients on inhaler technique, and planning how to best deliver this care
  

Medication Classes Found in Inhalers

Several pharmacologic classes of medications (and combinations of these classes) are available in inhaler products:

• Short-acting beta-agonists (SABA) and long-acting beta-agonists (LABA) relax airway smooth muscles by stimulating beta_2-adrenergic receptors.⁴ Patients with asthma and/or COPD can use beta agonist medications as needed for relief of acute symptoms, and on a regular schedule for symptom prevention.^3,4
• Short-acting muscarinic antagonists (SAMA) and long-acting muscarinic antagonists (LAMA) cause bronchodilation by inhibiting muscarinic receptors in the airway smooth muscles.⁴ Patients with COPD can use SAMA and LAMA medications as maintenance therapy.^4,9 Patients with asthma who are already using a LABA and an inhaled corticosteroid (ICS) can add on a LAMA maintenance medication if needed.³
• ICS reduce airway inflammation and are used as daily maintenance medications to prevent asthma exacerbations.³ Patients with COPD may also use ICS in combination with LABA or LABA plus LAMA as a daily maintenance medication. Prescribing information for corticosteroid inhalers advises patients to rinse their mouths with water after inhalation and to spit the water out afterward to reduce the risk of fungal infection in the mouth and pharynx.^10-12

 

TYPES OF INHALER DEVICES

 

Pressurized Metered Dose Inhalers

A pressurized metered dose inhaler (pMDI) has two components: a plastic actuator with mouthpiece, and a pressurized canister which may contain^13,14

• the active medication
• a spray-generating propellant to move the medication out of the inhaler
• co-solvents to allow the inhaler ingredients to mix well
• surfactants to stabilize the mixture and prevent drug particles from clumping together or sticking to the canister

The propellant is typically hydrofluoroalkane (HFA), a replacement for the chlorofluorocarbon (CFC) propellants used in many early inhalers.¹³ The Montreal Protocol of 1987 called for phasing out CFCs due to their ozone-depleting properties. The liquid inside a pMDI canister may be formulated as a solution or as a suspended micronized powder. Each time a patient actuates the inhaler (i.e., presses the button to release a spray), a metering chamber in the canister measures the correct liquid volume for that dose. The device releases large particles (about 45 micrometers) from the mouthpiece in a cloud of vapor, and particle size decreases to between 0.5 and 5.5 micrometers as the aerosol evaporates.

 

Pause and ponder: How do you think the ban on chlorofluorocarbons impacted the inhaler market?

 

To maximize lung deposition of medication from a pMDI, patients should take a slow, deep breath lasting about four to six seconds and actuate the inhaler at the start of (or immediately after starting) this breath.¹³ If patients mistime the actuation or inhale too quickly, medication is more likely to deposit on the tongue or the back of the throat and patients will swallow it instead. This phenomenon—also known as oropharyngeal deposition—can reduce the effective medication dose and increase adverse effects (e.g., oral thrush and hoarseness with inhaled corticosteroids).¹³ Table 1 lists the medications available as pressurized metered dose inhalers.

 

Table 1. Pressurized Metered Dose Inhalers^9,10,15-24

Class	Medication (Trade name[s]/generic availability)	Dose/actuation
SABA	albuterol HFA (Ventolin HFA, ProAir HFA, Proventil HFA, generic)	90 mcg
	levalbuterol HFA (Xopenex HFA, generic)	45 mcg
SAMA	ipratropium HFA (Atrovent)	17 mcg
ICS	ciclesonide HFA (Alvesco)	80 mcg 160 mcg
	fluticasone HFA (Flovent HFA, generic)	44 mcg 110 mcg 220 mcg
	mometasone HFA (Asmanex HFA)	100 mcg 200 mcg
ICS/LABA	fluticasone/salmeterol HFA (Advair HFA)	45 mcg/21 mcg 115 mcg/21 mcg 230 mcg/21 mcg
	budesonide/formoterol HFA (Symbicort, generic)	80 mcg/4.5 mcg 160 mcg/4.5 mcg
	mometasone/formoterol HFA (Dulera)	50 mcg/5 mcg 100 mcg/5 mcg 200 mcg/5 mcg
LAMA/LABA	glycopyrrolate/formoterol HFA (Bevespi Aerosphere)	9 mcg/4.8 mcg
ICS/LAMA/LABA	budesonide/glycopyrrolate/formoterol HFA (Breztri Aerosphere)	160 mcg/9 mcg/4.8 mcg

HFA = hydrofluoroalkane; ICS = inhaled corticosteroid; LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist; SAMA = short-acting muscarinic antagonist

 

Spacers and Valved Holding Chambers

A spacer is a tube or bag, often made of plastic, that a patient connects to a pMDI before use.²⁵ Medication particles traveling through these devices slow down before reaching the mouth. This also allows the aerosol propellant more time to evaporate, leaving smaller particles to be inhaled. Lower velocity and smaller particle sizes reduce oropharyngeal deposition, so more medication reaches the lungs. However, patients still need to time inhalation with actuation, and they should avoid exhaling into the spacer to prevent dilution (weakening) of the dose.

 

Valved holding chambers (VHC) are like spacers, but they have a one-way valve between the chamber and the mouthpiece.²⁵ VHCs trap the aerosols in the chamber, allowing time for patients with poor hand-breath coordination to inhale their medication. The one-way valve blocks exhalations from reaching the aerosols in the chamber, allowing patients to use multiple inhalations or tidal (restful) breathing if needed. For doses requiring multiple medication puffs, healthcare providers should counsel patients to prepare, actuate, and inhale each puff separately rather than spraying multiple puffs into the spacer or VHC at once.¹³

 

Due to gravity, impaction, and electrostatic charge, some medication is lost in a spacer or VHC before reaching the patient.²⁵ Washing a spacer or VHC with detergent (a water-soluble cleansing agent) and letting it air dry before first use can reduce the electrostatic charge and limit drug particle loss to the device walls. Some spacers and VHCs are made with anti-static material, but often come at a higher cost to the patient.

 

The Global Asthma Network (which aims to improve asthma care, particularly in low- and middle-income countries) advises that people can make effective spacers from 500 ml plastic bottles if commercial spacers are unavailable or too expensive.¹ A cost-effectiveness analysis determined home-made spacers (most of which were made from plastic water bottles) to be more cost-effective than commercial spacers in Columbia (a middle-income country).²⁶ The study found lower overall treatment costs and no difference in hospital admission rates.

 

Breath-Actuated pMDIs

A breath-actuated pMDI of beclomethasone dipropionate HFA (Qvar Redihaler) is available to overcome the problem of hand-breath coordination.²⁷ This inhaler is available in 40 mcg/actuation and 80 mcg/actuation. As the name implies, it actuates when the patient takes a breath, but it does not rely on a high inspiratory flow rate to deliver the medication. An inspiratory flow rate of just 20 L/min activates the inhaler, which then uses the HFA propellant to assist with dose delivery. Other breath-activated inhalers (discussed below) require up to 88 L/min for activation, which may be difficult for individuals with asthma or COPD who are already having trouble breathing. Young children and adults have tidal breathing inspiratory flow rates of 8 to 16 L/min and 13 to 18 L/min respectively.²⁷ Therefore, a breath-activated pMDI may require only a bit more inspiratory effort than the patients’ usual breathing.

 

Soft Mist Inhalers

Soft mist inhalers (SMIs) do not contain a propellant.²⁵ Instead, these inhalers use a spring to create pressure and spray the drug solution through a nozzle, forming two jets of liquid that collide to create a slow-moving mist. The mist’s low velocity increases drug deposition in the lungs rather than the oropharynx. An SMI’s aerosol cloud lasts about six times longer than a pMDI’s, increasing the window for effective inhalation in patients who have trouble coordinating actuation and inhalation. Table 2 shows the medications available as soft mist inhalers.

 

Table 2. Soft Mist Inhalers^28-31

Class	Medication (Trade name)	Dose/actuation
SAMA/SABA	ipratropium bromide/albuterol sulfate (Combivent Respimat)	20 mcg/100 mcg
LAMA	tiotropium (Spiriva Respimat)	1.25 mcg 2.5 mcg
LABA	olodaterol (Striverdi Respimat)	2.5 mcg
LAMA/LABA	tiotropium/olodaterol (Stiolto Respimat)	2.5 mcg/2.5 mcg

LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist; SAMA = short-acting muscarinic antagonist

 

Dry Powder Inhalers

Dry powder inhalers (DPI) are breath-actuated and breath-powered inhaler devices. To improve powder flow and accurate dose metering, manufacturers combine the active medication with a carrier powder or formulate it into spherical agglomerates (small sphere-shaped particles).³² Patients’ inspiratory flow and the resistance inside the inhaler generate turbulent energy that disaggregates (separates) the medication. Quick inhalation optimizes this process. The resulting tiny drug particles (less than 5 micrometers) can reach the lungs, while the larger carrier particles land in oropharynx and are swallowed.

 

DPIs typically require an inspiratory flow rate of at least 30 to 60 L/min, which some patients may have difficulty achieving.²⁵ There is also a possibility of decreased medication delivery from a DPI during disease exacerbations (periods of worsening), when patients’ ability to generate a forceful inspiration may be impaired.³² Table 3 lists available dry powder inhalers.

 

Table 3. Dry Powder Inhalers^15,33-46

Class	Medication (Trade name[s]/generic availability)	Dose/actuation
SABA	albuterol (ProAir RespiClick, ProAir Digihaler)	117 mcg
LABA	salmeterol (Serevent Diskus)	50 mcg
ICS	budesonide (Pulmicort Flexhaler)	90 mcg 180 mcg
	fluticasone propionate (Flovent Diskus)	50 mcg 100 mcg 250 mcg
	fluticasone furoate (ArmonAir Digihaler)	55 mcg 113 mcg 232 mcg
	fluticasone furoate (Arnuity Ellipta)	50 mcg 100 mcg 200 mcg
	mometasone (Asmanex Twisthaler)	110 mcg 220 mcg
ICS/LABA	fluticasone/salmeterol (Advair Diskus, Wixela Inhub, generic)	100 mcg/50 mcg 250 mcg/50 mcg 500 mcg/50 mcg
	fluticasone/salmeterol (AirDuo RespiClick, AirDuo Digihaler, generic)	55 mcg/14 mcg 113 mcg/14 mcg 232 mcg/14 mcg
	fluticasone/vilanterol (Breo Ellipta, generic)	100 mcg/25 mcg 200 mcg/25 mcg
LAMA	aclidinium bromide (Tudorza Pressair)	400 mcg
	tiotropium bromide (Spiriva Handihaler)	18 mcg (per capsule)
	umeclidinium (Incruse Ellipta)	62.5 mcg
LAMA/LABA	umeclidinium/vilanterol (Anoro Ellipta)	62.5 mcg/25 mcg
ICS/LAMA/LABA	fluticasone/umeclidinium/vilanterol (Trelegy Ellipta)	100 mcg/62.5 mcg/25 mcg 200 mcg/62.5 mcg/25 mcg

ICS = inhaled corticosteroid; LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist

 

INHALER TECHNIQUE EDUCATION

Consider that participants in most randomized controlled trials receive thorough education on inhaler use, must demonstrate competence to be included, and receive ongoing evaluations of their technique.⁴ This is the context in which inhaler efficacy is established. Ideally, all patients would have access to similar standards of care to ensure maximum benefit of inhaled medications. Inhaler technique support can also improve adherence. If patients are using inhalers incorrectly and not seeing clinical improvement, they may discontinue them due to perceived lack of efficacy.⁴⁷ A survey of patients with COPD found significantly greater adherence and confidence in treatment among patients whose inhaler technique had been checked by a healthcare professional within the past two years.⁴⁸

 

Healthcare providers must consider patient preferences, health literacy, and language barriers when choosing appropriate education methods.⁴⁷ A survey of inhaler-using adults seen at a pulmonary clinic or outpatient pharmacy compared education preferences between English and non-English speakers.⁴⁹ Both groups shared a preference for in-person, active learning methods but had low interest in participating in education sessions outside of regular clinic visits. The aforementioned survey of patients with COPD found that 83% thought a demonstration was “very helpful” for learning inhaler technique.⁴⁸ Only 58% and 34% thought the same about a video or leaflet, respectively.

 

Pharmacists Can Improve Inhaler Use

Pharmacists are best placed to provide in-person, active demonstrations to patients where they already come to pick up their medications. Research shows that pharmacists can provide effective inhaler use education (if and when their workflow allows for it). A 2017 systematic review of critical inhaler errors in asthma and COPD found that pharmacist-led inhaler education interventions produced statistically significant improvements in patients’ inhaler technique in seven out of eight studies.⁵⁰

Published studies of pharmacist-led interventions provide examples of counseling methods that have proven effective. A pre- and post-intervention study of 211 patients with COPD in Vietnam examined the efficacy of face-to-face inhaler training with a pharmacist. Training followed this format⁵¹:

• Patients demonstrated technique on a placebo inhaler device
• Pharmacists corrected each mistake and explained why the correction was important
• Pharmacists demonstrated every step verbally and physically with a placebo inhaler
• Patients performed the technique again
• Patients and pharmacists repeated this process until patients could complete all steps correctly

 

This procedure took about six minutes for initial training and three minutes for follow-up trainings.⁵¹ Pharmacists provided training monthly for three months, once at six months, and once at 12 months. They also included label stickers on inhalers with a summary of the steps for use. The percentage of patients using correct inhaler technique increased by over 40% from baseline to six months but declined somewhat between six and 12 months. Researchers concluded that patients benefit from an initial intensive period of repeated training sessions, followed by long-term follow-up at least every three months.⁵¹

 

Another study of 72 subjects examined the efficacy of different inhaler training methods by assigning patients to do one of the following⁵²:

• Read an MDI package insert pamphlet
• Watch a Centers for Disease Control and Prevention video demonstrating technique
• Watch a YouTube video demonstrating technique
• Receive direct instruction from a pharmacist

 

Only two minutes were allotted for the interventions (to mimic what might be feasible in a community pharmacy setting).⁵² The pharmacist-led counseling sessions were loosely scripted based on a checklist of proper inhaler technique. After a pharmacist explained and demonstrated inhaler use, subjects could ask questions if time permitted. Study investigators (including the pharmacists performing the direct instruction sessions) used a standardized checklist to assess all participants immediately following the training. There was a statistically significant difference between pharmacist-led instruction and each of the other interventions but not between any of the three other intervention groups. More than 70% of patients in the pharmacist-led intervention group demonstrated correct inhaler use after training compared with less than 20% of patients in the other intervention groups.⁵²

 

Pause and Ponder: Why might a live demonstration provide better training than a video demonstration of the same time duration?

 

The 2022 GINA report emphasizes the importance of providing patients with ongoing inhaler technique training and assessment. The report recommends that pharmacists, nurses, and other healthcare workers³

• physically demonstrate using placebo inhalers (and spacers or VHCs, if applicable)
• check against a device-specific checklist as patients demonstrate technique
• supply a take-home handout with steps for inhaler use (ideally including pictures)
• check and re-train patients at every opportunity, as errors frequently recur four to six weeks after training

 

Pause and ponder: In your workplace, would it be feasible to provide two minutes of counseling with every inhaler refill? How might you identify patients who most need inhaler use training?

 

Of note, devices exist to evaluate patients’ inspiratory flow and inhalation technique when prescribing, training, or assessing.⁴⁷ Although these may not be feasible to use in most community pharmacy settings (and are outside the scope of this continuing education module), they may be very useful in other settings (e.g., a pulmonary clinic). Devices include the AIM (Aerosol Inhalation Monitor), the In-Check DIAL, and the 2-Tone trainer.⁴⁷

 

Inhaler Administration Counseling

 

pMDIs

Most pMDIs require users to prime (release sprays into the air) before first use (see Table 4).^17-20 When priming a pMDI, users should spray it in the air away from the face. If the inhaler requires shaking, they should also be sure to shake well before each priming spray. Most pMDIs require shaking prior to actuation but some, including Atrovent HFA and Alvesco, do not.^9,10 Patients should always avoid spraying pMDIs into their eyes; the package insert for Atrovent HFA instructs users to close their eyes during inhaler actuation.⁹

 

Table 4. Priming Requirements for pMDIs^10,15-24

Product(s)	Prime before first use and if not used for more than:	Number of Sprays
Advair HFAa	28 days	4 sprays
Proventil HFA Ventolin HFAb	14 days
Bevespi Aerosphereb Breztri Aerosphereb Flovent HFAa	7 days
Asmanex HFA Dulera	5 days
Xopenex HFA	3 days
ProAir HFAb	14 days	3 sprays
Alvesco	10 days
Symbicorta	7 days	2 sprays
Atrovent HFA	3 days

^aAlso need to be primed if dropped; ^bAlso need to be primed after cleaning; HFA = hydrofluoroalkane

 

The following are general administration instructions for pMDIs^17-20:

1. Check for a firm fit of the canister in the actuator
2. Remove cap from mouthpiece and check mouthpiece for any foreign objects
3. If product requires shaking, shake well (typically for 5 seconds)
4. Facing away from the inhaler, exhale completely
5. Holding inhaler upright with mouthpiece down, place mouthpiece in mouth
6. Form a tight seal with lips, keep tongue below mouthpiece, and tilt head back slightly
7. While breathing in deeply and slowly through the mouth, press down on the canister until it stops moving and has released a puff and remove finger from the canister
8. Continue to breathe in as long as possible, then remove the mouthpiece
9. Hold breath as long as is comfortable (up to 10 seconds)
10. Breathe out gently, away from the inhaler
11. Replace cap right away

Patients should never use the canister of one inhaler with the actuator of another inhaler.^9,23,24 Patients should clean pMDIs at least once a week. Cleaning instructions for pMDIs vary by product (see Table 5).

Table 5. pMDI Cleaning Requirements^10,15-24

Product	Cleaning instructions
Proventil HFA	Remove the canister from the actuator; DO NOT let the canister get wet. Remove the cap from the mouthpiece. Run warm water through the top and bottom of actuator for 30 seconds in each direction. Thoroughly shake dry. Check the mouthpiece for remaining medication buildup. Let air-dry completely (overnight if possible).   If not fully air-dried before next dose, shake the plastic actuator as dry as possible, insert the canister, shake the inhaler, and actuate it twice. Repeat the original cleaning procedure after taking the necessary dose(s).
Ventolin HFA
Xopenex HFA
ProAir HFA
Atrovent HFA
Bevespi Aerosphere
Breztri Aerosphere
Flovent HFA	Clean after evening dose. DO NOT remove the canister from the actuator. Use a water-dampened cotton swab to clean the small circular opening where medicine sprays out of the canister, twisting in a circular motion. Repeat with a new damp swab. Wipe the inside of the mouthpiece with a clean, damp tissue. Let air dry overnight.
Advair HFA
Asmanex HFA	DO NOT remove the canister from the actuator. Wipe inside and outside surfaces of the actuator with a dry, lint-free tissue or cloth. DO NOT wash or put any parts in water.   Use a dry folded tissue to wipe over the front of the small hole where the medicine comes out of the Alvesco inhaler.
Alvesco
Symbicort
Dulera

HFA = hydrofluoroalkane

 

All available MDI inhalers have dose counters built into either the canister or the actuator. For most products, the dose counter’s numbers or background will change to red when the inhaler is running low, reminding patients to refill their medication. Healthcare providers should counsel patients not to use inhalers after the dose counter reads zero, even if the canister does not feel empty and still operates. People should not put canisters in water to see if they float as a means of gauging whether medication remains (an old trick that is no longer recommended) or try to alter dose counters. They should also never use a sharp object to unblock an actuator or throw a pMDI into a fire or incinerator. All pMDI inhalers require storage at room temperature, and most should be stored with the mouthpiece down so that the tip of the canister valve is facing down. This keeps the gasket inside of the canister wet so that it does not become brittle and allow outside moisture to enter the canister.⁵³

 

In addition to general counseling for pMDIs, specific counseling points for breath-actuated pMDIs include four points⁵⁴:

• There is no button to press; opening the cap prepares the dose. If patients leave the cap open for more than two minutes, they will need to close and reopen the cap before inhaling their dose.
• Do not shake (especially not with the cap open, as this may actuate the inhaler). Do not prime or use with a spacer or VHC.
• Clean weekly with a clean, dry tissue or cloth
• Do not take the inhaler apart

 

SMIs

To set up an SMI (Respimat inhaler), remove the clear base, label the cartridge with the discard date (three months from first use), and insert the narrow end of the cartridge into the inhaler.^28-31 With the inhaler on a firm surface, push down until the cartridge clicks into place (this often takes more force than patients expect). Replace the clear base so that it clicks into place. Do not take the inhaler apart after assembly. To actuate the inhaler, patients should remember the acronym TOP:

• Turn the clear base half a turn in the direction of the arrows until it clicks
• Open the cap fully
• Press the dose-release button and close the cap.

Before first use, repeat the actuation steps until a mist is visible. ^28-31 Then repeat three more times. To take an inhalation

 

1. Turn the base and open the top
2. Fully exhale away from the inhaler
3. Put mouthpiece in mouth and form a tight seal with lips, keeping mouthpiece above the tongue and pointing towards the back of the throat; be sure not to block air vents with lips or fingers
4. While taking a slow, deep breath through the mouth, press the dose-release button and breathe in as long as possible
5. Remove inhaler from mouth and hold breath as long as is comfortable (up to 10 seconds)
6. Breathe out slowly away from the inhaler
7. Close cap

Pharmacists should counsel patients to prime the device with one puff if not used for more than three days or four visible puffs if not used for more than 21 days. ^28-31 Patients should clean the SMI’s mouthpiece (including the metal part inside) once a week with a damp cloth or tissue. These inhalers have dose indicators and automatically lock when empty. Patients should not spray the device into their eyes or use the SMI with a spacer or VHC. SMIs require room temperature storage.

 

DPIs

To administer DPIs^33-36

1. Open cover or remove cap and check mouthpiece for foreign objects

1. Prepare dose (see Table 6)
2. Fully exhale away from the inhaler
3. Put mouthpiece in mouth and form a tight seal with lips, keeping tongue below mouthpiece; be sure not to block air vents with lips or fingers
4. Breathe in quickly and deeply, generating a forceful breath right from the start of inhalation
5. After breathing in all the way, remove inhaler from mouth and hold breath for as long as is comfortable (up to 10 seconds)
6. Breathe out slowly away from the inhaler
7. Cover mouthpiece

 

Table 6. Preparing and Administering DPI Doses^{15,33-37,39-46}

DPI Type	Dose Preparation and Related Notes
Digihaler	Holding inhaler upright, open cap fully until it clicks (the click can be felt and heard). Built in sensors track adherence and inspiratory flow rates. The inhaler sends information to an application using Bluetooth technology. The inhalers work even if they are not wirelessly connected to the mobile application.
Diskus	Hold inhaler in left hand with thumb of right hand in thumb grip. Push thumb grip away to snap mouthpiece into place. Hold in a level, flat, horizontal position. Slide lever away from mouthpiece until it clicks. Keep holding Diskus level during inhalation. To close after inhalation, patients put their thumb in the thumb grip and pull back towards themselves until the inhaler clicks shut over the mouthpiece. Do not close before inhaling, tilt, play with the lever, or move the lever more than once; doses may be lost.
Ellipta	Open the cover until it clicks. If patients open and close the cover without inhaling the medicine, the dose will be lost inside the inhaler, but patients will not receive a double dose.
Flexhaler	Hold brown grip in one hand and use the other to twist off white cover. Hold inhaler upright with one hand still on brown grip and the other in the middle of the inhaler. Twist brown grip as far as possible in one direction, and then back all the way in the other direction. Priming is required before first use (follow instructions for preparing a dose twice). The inhaler will click in the process of preparing a dose. Do not click the brown grip multiple times without inhaling. The dose indicator will count down with each click. However, it is not possible to receive more than one dose at a time. Do not shake the inhaler after preparing a dose.
Handihaler	Press green button and pull cap away to uncover mouthpiece. Then pull mouthpiece away to uncover center chamber. Remove a capsule from blister packaging (without using sharp instruments) and place it in the center chamber. (Discard unused capsules accidentally exposed to air. Close mouthpiece until it clicks. With mouthpiece pointing up, press green piercing button until flat against base only once, then release. Do not shake. When the capsule is pierced, small pieces of gelatin may be created. These may end up in the mouth or throat and are not harmful. Hold inhaler horizontally when inhaling and inhale twice from the same capsule. The capsule should rattle during inhalation. Do not swallow or manually open capsules.
Pressair	Hold inhaler horizontally with green button on top. Press and release the green button to prepare dose. Do not tilt inhaler. Check that control window changes to green. Do not hold green button down when inhaling. Correct inhalation causes an audible click and control window changes from green to red. Pushing green button multiple times before inhaling does nothing; patients will not lose a dose or get a double dose.
RespiClick	Holding inhaler upright, open cap fully until it clicks (the click can be felt and heard). Always close the cap after each inhalation. Patients will waste the medication if they open and close the cap without inhaling.

 

 

Patients may or may not taste or feel the powder from a DPI upon inhalation. It is fine if they do, and they should not take an extra dose if they don’t. Patients cannot use spacers, VHCs, or masks with DPIs. Manufacturers formulate most DPIs with lactose powder as an ingredient, so patients with severe milk protein allergies should not use them.

 

Individuals should not wash DPIs. If cleaning is necessary, using a dry tissue or cloth is appropriate. Patients should store DPIs at room temperature and protect them from heat and humidity; they are more sensitive to humidity than are other inhalers. They should not store the Tudorza Pressair inhaler on a vibrating surface.

 

DEVICE SELECTION TO MATCH PATIENT NEEDS

Individualizing delivery device selection is crucial for optimizing outcomes of aerosol drug therapy. Healthcare professionals must consider patient-, drug-, device-, and environmental-related factors. A good starting point may be to observe a patient’s natural inhalation.⁵⁵ For example, if the patient instinctively takes slow, deep breaths, a pMDI or SMI might be a good fit. If the patient tends to inhale quickly and deeply, a DPI may be ideal. Table 7 discusses other important factors to consider.

 

Table 7. Inhaler Suggestions Based on Patient-Specific Factors^25,27,56-58

For people with…	…Consider
Inability to achieve a good lip seal around an inhaler’s mouthpiece (e.g., pediatric, facial weakness, cognitive impairment)	pMDI with spacer/VHC and facemask
Inability to learn and perform specific breathing techniques	pMDI with VHC
Difficulty generating an inspiratory flow rate of at least 30 to 60 L/min (e.g., older age, female gender, airflow limitation, respiratory muscle weakness, lung hyperinflation, history of COPD exacerbations requiring hospitalization)	pMDI; breath-actuated pMDI; SMI
Poor manual dexterity or limited hand strength	Breath-actuated pMDI; SMI (may need help with initial cartridge installation); DPI (one that does not require complicated manipulations for dose preparation)
Difficulty with hand-breath coordination	Breath-actuated pMDI; pMDI with VHC; DPI; SMI
Inability to store inhaler away from heat and humidity	Non-DPI inhaler (particularly sensitive to heat and humidity)

COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; pMDI = pressurized metered dose inhaler; SMI = soft mist inhaler; VHC = valved holding chamber

 

Patients often use multiple inhaled medications for asthma and COPD. Prescribing the same inhaler type for all a patient’s inhaled medications eliminates confusion over varying administration techniques.⁵⁹ Clinicians can also prescribe combination products where appropriate to simplify treatment regimens.

 

Consider the Cost

Affordability is another vital consideration and will depend on the patient’s insurance status. While most inhalers are brand-name only, a few generic inhalers are available (see examples in Tables 1-3). Prioritizing patient preference when selecting inhalers can improve adherence.⁶⁰ Central to patient satisfaction are issues such as simplicity of use, treatment time, comfort, portability, cleaning requirements, taste, and effect on the throat. If a patient remains unable to use a device effectively after several training visits, consider switching to another inhaler type.

 

INHALER USE MISTAKES

A literature review and meta-analysis of inhaler use errors in patients with asthma and COPD found that 50% to 100% of patients made at least one error when using their inhaler. Error rates were higher for patients⁶¹

• using MDIs compared to those using DPIs
• with COPD compared to those with asthma
• with a longer history of device use compared to patients new to inhaler treatment
• using multiple inhalers compared to those using only one inhaler

 

Errors are also common in patients using SMIs. A systematic literature review and meta-analysis of patients with COPD, bronchitis, or emphysema found that nearly 60% made at least one error when using a SMI.⁶² Other factors associated with higher error rates include^50,61

• older age
• lower education level
• female gender
• lower socioeconomic status
• having two or more comorbidities

 

Pause and ponder: In your workplace, would it be feasible to provide training and technique assessment with every inhaler refill? If not, how might you identify and prioritize patients who most need inhaler use training?

 

While perfect inhaler use is ideal, patients often have complex medication regimens and healthcare professionals often have heavy workloads. It’s vital to prioritize the most essential steps in the inhaler use process, including those that have a proven impact on patient outcomes. The CRITIKAL study used data from the iHARP asthma review service (a multicenter cross-sectional study of adults with asthma) to identify inhaler use errors associated with worsening asthma control.⁶³ Investigators used data from 3660 patients to pinpoint these critical errors which included⁶³

• not opening the cover or removing cap from mouthpiece
• insufficient inspiratory effort
• incorrect position of head
• not breathing out before inhalation
• not holding breath after inhaling medication, or holding for less than three seconds
• not sealing lips around mouthpiece
• incorrectly priming, timing, or inhaling the second dose (if needed)

 

Demonstration Devices

Demonstration devices are placebo inhalers, meaning they contain no active medication. They may be available free of charge from device manufacturers. These are ideal for training since the lack of active drug allows for repeated cycles of education and patient demonstration (“teach-back”). Many demonstration inhalers are specifically marked as “only for use by a single patient” to prevent the possible spread of disease.⁶⁴ Keep demonstration inhalers in a separate area of the pharmacy, and do not send them home with patients to avoid any confusion.⁶⁵

 

We collected the following information by calling inhaler manufacturers directly. Typically, anyone in a healthcare provider’s office or pharmacy is allowed to order demonstration devices on behalf of a prescriber or pharmacy. To order demonstration devices

1. Determine the patient population and disease state you will be addressing
2. Generate a list of common devices your patients use
3. Identify the manufacturer of each device and visit the manufacturer’s website or the website for the specific product
4. Obtain the email and phone number for customer service representatives and note days and times available (keep in mind the time zone)
5. Reach out to the company’s local representative or customer care representative to request demonstration devices
6. Provide all information required (generally your full name, title, state license number, phone number, address of the pharmacy or office you plan to have the devices delivered to and the facility’s secondary contact information [e.g., fax, email])

 

When making a demonstration device request, pharmacy staff should allow several weeks for processing and device delivery. The number of devices available also varies. For example, one inhaler manufacturer provides 15 or 20 demonstration devices in response to requests, while another requires a manager review of any request for more than three devices.

 

Appendix 1 provides contact information for the manufacturers of several inhaler devices. Demonstration device availability can change over time; some companies have demonstration devices in stock only periodically and will advise calling back another time. Companies may also stop carrying demonstration devices for their older products. The GOLD report identifies a lack of placebo inhalers as a common barrier to educating patients.⁴ However, if efforts to obtain demonstration devices are unsuccessful, pharmacists can teach patients using their own devices instead.

 

Manufacturers may also provide patient assistance programs and co-pay assistance to help with affordability. Patients with commercial or private health insurance are often eligible to participate in co-pay assistance programs and receive a savings card to help lower the cost of the prescription. Healthcare providers can also request additional educational materials and pamphlets to hand out. Referring patients who may be struggling with affording their medications to the manufacturer for assistance and to investigate the patients’ benefits to determine discounts available is highly recommended.

 

CONCLUSION

Pharmacy personnel are well positioned to help patients maximize the benefit of their inhaled medications. An awareness of available inhalers and the requirements and techniques for their use can help healthcare professionals identify whether patients and their devices are a good match. Recognizing the importance of ongoing training and assessment, pharmacy staff can encourage brief yet frequent counseling sessions with patients as they refill their inhaled medications. Pharmacy personnel should proactively order inhaler demonstration devices from manufacturers (if available) to facilitate patient education.

 

 

Good	Better	Best
1. Be familiar with different inhaler devices, including counseling points and potential barriers to use for each 2. Encourage any patient picking up an inhaler to speak with the pharmacist about technique 3. Provide pictorial instructions for use with every inhaler	1. Obtain inhaler demonstration devices and use them with patients 2. Based on refill patterns, recognize patients who may be over- or under- using inhalers and assess for suboptimal technique 3. Check against a device-specific checklist when assessing patient technique	1. Check and re-train on inhaler technique at every opportunity 2. Explain the reason behind any corrections 3. Repeat the teach-back/correction cycle until patients are confident and competent

 

 

 

Appendix I. Inhaler Manufacturer Contact List (Current as of July 1, 2022)

Company	Products (demo device unavailable)	Business Contact
AstraZeneca	Symbicort HFA Pulmicort Flexhaler Bevespi Aerosphere Breztri Aerosphere	1-800-236-9933 Monday-Friday, 8am-6pm ET   https://www.astrazeneca-us.com/az-in-us/Contact-us.html   Discount card eligibility: https://www.azandmeapp.com/home.html
Boehringer Ingelheim Pharmaceuticals, Inc.	Spiriva Respimat Striverdi Respimat Combivent Respimat Stiolto Respimat Atrovent HFA Spiriva Handihaler	Direct Representative Line: 1-800-243-0127   https://www.boehringer-ingelheim.us/contact-form   Patient assistance program: 1-800-556-8317 or www.bipatientassistance.com
GlaxoSmithKline (GSK)	Breo Ellipta        Ventolin HFA Trelegy Ellipta   Flovent HFA Anoro Ellipta      Advair HFA Incruse Ellipta    Flovent Diskus Arnuity Ellipta   Serevent Diskus                              Advair Diskus	GSK Response Team: 1-888-825-5249 Monday-Friday, 8:30am-5:30pm ET   https://www.contactus.gsk.com/callback/hcp.html   Discount card eligibility: www.gskforyou.com
Organon & Co.	Asmanex HFA Dulera HFA Asmanex Twisthaler	Service Center: 1-844-674-3200   Coupons for patients with private insurance: www.asmanex.com ; www.dulera.com
Mylan	Wixela Inhub	Customer Relations Team: 1-800-796-9526   Discount card eligibility: www.wixela.com
Sunovion	Xopenex HFA	Customer Service (Respiratory): 1-844-276-8262
Teva	albuterol sulfate HFA (generic) ProAir RespiClick levalbuterol tartrate HFA (generic) fluticasone propionate/salmeterol inhalation powder, USP QVAR Redihaler	Clinician Support Line: 1-877-867-3034   Patient assistance program: 1-800-896-5855

HFA = hydrofluoroalkane

All information was obtained by calling companies directly and was up to date as of July 1, 2022.

Download CE Activity