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.

 

 

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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.

 

 

 

 

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