INTRODUCTION

Hepatorenal syndrome (HRS), a type of kidney injury unique to patients with advanced liver disease, carries a grim prognosis. Therapies such as volume resuscitation (e.g., crystalloids or albumin) and vasoconstrictors (e.g., norepinephrine or terlipressin) focus on restoring blood flow to the kidneys before they are irreparably injured. Pharmacists and pharmacy technicians can play a crucial role in helping select and monitor therapies for treatment of this syndrome, and perhaps more importantly, by helping patients avoid developing HRS in the first place. By educating patients to avoid certain over the counter (OTC) medications that can worsen the condition (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]), and teaching patients to monitor their diuretic use by weighing themselves daily and monitoring their blood pressure, engaged pharmacists and pharmacy technicians can make a large difference in their patients’ clinical outcomes.

 

HRS: A Complication of Cirrhosis

Cirrhosis, an advanced state of liver disease, is increasingly common and an important cause of mortality.¹ Globally, in 2017 the estimated incidence of people living with compensated cirrhosis was 112 million. In 2019, cirrhosis was associated with 2.4% of deaths worldwide.² Classically, cirrhosis in developed countries is most commonly due to hepatitis C infection and alcohol misuse.¹ However, over the past decade, the incidence of non-alcoholic fatty liver disease (NAFLD) has increased dramatically with improvement in diagnostic criteria and screening. At the same time, treatment improvements for hepatitis B and C infections have decreased viral hepatitis-related deaths in some areas of the world. The COVID-19 pandemic has also had significant impact, with data collected from multiple countries showing a substantial increase in alcohol consumption, and an increase in alcohol-associated cirrhosis deaths.^2,3 Testing and treatment rates for hepatitis B and C declined internationally between January 2019 and December 2020,⁴ and treatment delays are predicted to lead to excess liver-related deaths.^2,5

PAUSE AND PONDER: How will the new hepatitis C direct-acting antivirals (e.g., elbasvir, glecaprevir, ledipasvir, pibrentasvir, sofosbuvir, velpatasvir, and voxilaprevir) change the landscape of HRS?

Although the causes of cirrhosis may be shifting, the transition from chronic liver disease to cirrhosis is generally the same. Chronic inflammation of the liver leads to fibrosis and scarring, causing structural and hemodynamic changes within the liver (Figure 1). One of the main consequences is development of portal hypertension. Portal hypertension results because the scarring of the liver makes it more difficult for blood to flow through it, leading to increased blood pressure in the portal vein as blood is delivered from the splanchnic organs (stomach, small intestine, colon, pancreas, and spleen) (Figure 2). The obstruction of blood flow through the portal vein additionally results in dilation of the splanchnic circulation as a compensatory mechanism aimed at restoring blood flow. In turn, increased blood flow to the splanchnic circulation worsens portal hypertension.¹  

Figure 1. Stages of Liver Disease.

 

Figure 2. The splanchnic circulation. The splanchnic circulation describes blood flow to the abdominal organs. Blood from these “splanchnic” organs is delivered to the portal vein, and accounts for the majority of the blood flow to be processed by the liver.

 

Pathophysiology of HRS

Portal hypertension and the changes in blood flow that result are the main drivers of several consequences of cirrhosis. These complications include the development of ascites, espophageal varices, and HRS.

 

Ascites is fluid accumulation in the peritoneal cavity that commonly appears as abdominal swelling or bloat. A patient with significant ascites will often test positive for a “fluid wave.” That is, when a patient is lying flat and someone applies pressure to the abdominal midline, a clinician can tap one flank sharply, and an impulse or “shock wave” will travel through the fluid in the abdomen. The clinician will be able to be feel the tap on the other side.

 

Esophageal varices are enlarged veins in the esophagus that can lead to bleeding that commonly presents as “coffee ground” looking emesis (or vomitus) that is a result of the blood being digested in the stomach then regurgitated through the esophagus. In the case of HRS, the portal hypertension and splanchnic vessel dilation mean that blood tends to pool in the splanchnic circulation, decreasing effective arterial volume (i.e., a decreased amount of blood effectively perfusing organ tissue, including the kidneys). Additionally, the body activates various compensatory mechanisms aimed at increasing blood volume (e.g., the renin-angiotensin system and the sympathetic nervous system). This action is an attempt to restore effective blood volume, which leads to vasoconstriction of the kidney arterioles and further hypoperfusion of the kidney (Figure 3).⁶

Figure 3. Changes in blood flow with cirrhosis. The image on the left represents normal splanchnic and portal blood flow. The image on the right shows blood flow to a cirrhotic liver. Blood from the splanchnic organs meets increased resistance in the portal vein, leading to portal hypertension. The splanchnic arteries vasodilate which worsens portal hypertension and leads to decreased blood flow to the kidneys.

ABBREVIATIONS: ADH: antidiuretic hormone, IMA: inferior mesenteric artery, RAAS: renal angiotensin aldosterone system, RBF: renal blood flow, GFR: glomerular filtration rate, SMA: superior mesenteric artery

Prevalence and Prognosis

HRS is a type of acute kidney injury (AKI) that is unique to patients with decompensated cirrhosis. HRS occurs in the absence of hypovolemia or any structural changes to the kidney—in fact, the kidneys often function normally following liver transplantation.⁷ HRS is common in patients with cirrhosis, and risk of development increases as the severity of cirrhosis and the duration with which the patient has had it increase. In one study of patients with cirrhosis and ascites, the incidence of HRS increased from 18% at one year to 39% after five years.⁸ The development of HRS is unfortunately associated with a very poor prognosis, and often the only way to reverse the kidney failure is to receive a liver transplant.⁷

 

Classification and Diagnosis

Two distinct forms of HRS have been described. According to the American Association for the Study of Liver Diseases (AASLD) guidelines⁹

• Type 1 HRS is a rapid increase in creatinine (0.3 mg/dL or greater) within 48 hours or an increase in serum creatinine to levels that are at least 50% higher than the most recent baseline value measured within three months. It often has a precipitating factor, such as a bacterial infection, gastrointestinal bleeding, or over-diuresis. This type of HRS is more common and more severe, making up 75% of cases and having a median survival of one month.
• Type 2 HRS takes a longer time to develop and is defined as an estimated glomerular filtration rate of less than 60 mL/minute/1.73m² for three months or more in the absence of other (structural) causes. This is the same definition used for all patients with chronic kidney disease (CKD). Type 2 HRS often co-occurs with other complications of cirrhosis (i.e., refractory ascites) and has a median survival of about seven months.⁸

 

In recent years the nomenclature has been updated so that type 1 HRS is referred to as HRS-AKI and type 2 is called HRS-CKD.^6,9

 

Sometimes it is hard to know that a patient with end-stage liver disease is in kidney failure. These patients may have decreased muscle mass, are prone to malnutrition, and may take diuretics to control volume status. All three of those factors make serum creatinine an unreliable surrogate measure of kidney function.¹⁰

In patients with cirrhosis and ascites who meet the criteria for AKI, the diagnosis of HRS-AKI becomes one of exclusion. Clinicians must attempt to rule out hypovolemia, shock, medication-induced AKI, and structural kidney injury. In the absence of these alternative causes for AKI, a diagnosis of HRS-AKI can be made, and treatment commenced as soon as possible, as early intervention is key to decreasing mortality.⁹

 

Sidebar: Why is serum creatinine unreliable in advanced liver disease?

In clinical practice, clinicians often estimate kidney function by measuring a patient’s serum creatinine and inputting the value into a kidney function estimating equation. Creatinine is a byproduct of creatine, an amino acid produced by the liver and released into the circulation to reach target tissues, such as muscle. Creatinine is released during normal muscle metabolism. It is used in kidney function estimates because the glomerulus filters it freely, and so theoretically the rate at which the kidneys clear creatinine should be similar to the glomerular filtration rate itself.

 

However, a patient’s serum creatinine value is not affected by glomerular filtration rate alone. A malfunctioning liver may produce lower amounts of creatinine’s precursor, creatine. Additionally, patients with cirrhosis may have decreased oral intake due to nausea, ascites, and/or ongoing alcohol use. This means they consume less creatine is consumed from the diet as well. Finally, since creatinine is a product of muscle tissue breakdown and patients with cirrhosis tend to have significantly reduced muscle mass, they may generate less creatinine from the creatine. The end result is a serum creatinine that is normal or even lower than that seen in healthy individuals.

 

Hence, kidney function estimates that rely on creatinine tend to overestimate kidney function in these patients and even small absolute increases in creatinine could represent an acute kidney injury.

PAUSE AND PONDER: Is there a better way to measure true kidney function in patients with end-stage liver disease?

 

Current and Emerging Therapies for HRS

Therapies used to treat HRS aim at removing the precipitating factor and increasing blood flow to the kidneys. First, clinicians must identify and treat the potential etiology leading to the decline in kidney function (e.g., antibiotic therapy in the treatment of an infection of ascites fluid called spontaneous bacterial peritonitis [SBP], proton pump inhibitors, and endoscopic intervention to stop a gastrointestinal bleed). Removing the cause is one of the most important factors in ensuring that the change in kidney function is not permanent.

 

Fundamentally the kidney receives insufficient blood flow secondary to a decrease in effective arterial blood flow, so initial therapy’s main goal is to improve the patient’s mean arterial pressure as soon as possible. The most common goal cited is to increase the patient’s mean arterial pressure (MAP) to greater than 65 mmHg to improve perfusion to target end organs, specifically the kidney.^11,12 The goal is to improve kidney function and give the patient additional time to secure a liver transplant or stabilize the end stage disease and decrease mortality. This continuing education activity will review the agents used to improve kidney function in the setting of HRS. Table 1 summarizes guideline recommendations for initial management of patients with HRS-AKI.

 

Table 1. Summary of Society Guidelines for Initial Management of HRS-AKI in the ICU9,22,23,32,33
Society	HRS-AKI Definition	Volume expander	Vasopressor of choice	Target
American Association for the Surgery of Trauma 2022	Increase in SCr > 0.3 mg/dL within 48 hours or > 50% increase in SCr in preceding 7 days in patients with cirrhosis/ascites without another cause	Lactate ringers or Plasmalyte over Normal Saline; albumin 20-25% 1 gm/kg/day x 48 hours	Norepinephrine, Terlipressin	MAP > 65 mmHg, increased urine output
American Association for the Study of Liver Disease 2021	Increase in SCr > 0.3 mg/dL within 48 hours or > 50% increase in SCr in preceding 7 days in patients with cirrhosis/ascites without another cause; use SCr values for the last 3 months prior to event to evaluate baseline	Albumin 1 gm/kg on day 1, then 40 to 50 gm daily while receiving vasopressor therapy	Terlipressin,* Norepinephrine 0.5 mg/h ; max 3 mg/h	Increase MAP by at least 10 mmHg above pre-treatment baseline or urine output >200 mL over 4 hours; albumin to maintain CVP between 4-10 mmHg; Continue treatment until SCr back to baseline up to 14 days; if SCr remains at or above pre-treatment values after 96 hours stop vasopressor therapy
European Association for the Study of the Liver 2010	Kidney failure in the setting of liver disease unexplained by another cause	Albumin 1 gm/kg/day (max 100 gm/day)	Terlipressin 1 mg every 4 to 6 hours in combination with albumin, if SCr does not improve by at least 30% in 72 hours increase dose to 2 mg every 4 hours	Increase in MAP by at least 5 mmHg by day 3
American Gastroenterological Association 2022	Increase in SCr > 0.3 mg/dL within 48 hours or > 50% from baseline or urine output is <0.5 mL/kg/hr for > 6 hours	Albumin 1 gm/kg/day x 48 hours, if no improvement continue 1 gm/kg x 1 day then 20 to 40 gm daily while receiving vasopressor therapy	Terlipressin 1 mg every 4 to 6 hours; increase to 2 mg every 4 to 6 hours if reduction in SCr < 25% by day 3 if available up to 14 days, alternative norepinephrine or midodrine/octreotide	Increase MAP by at least 10 mmHg or urine output by at least 50 mL/h for at least 2 hours, maintain priority for liver transplant if survive
*not approved in US at the time of guideline construction
ABBREVIATIONS: CVP = central venous pressure; MAP = mean arterial pressure; SCr = serum creatinine

 

 

 

PAUSE AND PONDER: When might these interventions be considered “too late?” What would you do then?

 

Crystalloids

Initial evaluation of patients includes an assessment of their effective arterial blood volume status. Early cessation of home medications that impact blood pressure or volume status, such as diuretics (e.g., spironolactone, furosemide) will allow a more accurate determination. If the patient’s effective arterial blood volume is not optimized, inadequate blood flow to the kidney can precipitate acute kidney injury in the setting of cirrhosis.

 

Crystalloids, such as normal saline and Lactated Ringer’s, stay within the intravascular space and provide appropriate initial fluid replacement. However, clinicians must provide fluid replacement (also referred to in this case as fluid resuscitation) carefully and with appropriate monitoring as patients can become volume overloaded. Patients with end stage liver disease have low albumin levels and tend to lack the oncotic pressure (a type of osmotic pressure induced by plasma proteins, especially albumin) required to keep crystalloids within the intravascular space. Even minimal resuscitation can produce significant peripheral edema and pulmonary edema, and worsen ascites.¹³

Pharmacists should provide support in appropriate monitoring of volume status and ensuring serum electrolytes are frequently obtained. Fluids may need to be stopped abruptly in response to volume overload to prevent hypervolemic hyponatremia (low sodium levels).¹⁴ Appropriate understanding of the patient’s intravascular volume status will determine if using albumin during resuscitation is appropriate.

 

Albumin

Patients with end-stage liver disease typically have reduced or low albumin levels because the liver is no longer able to manufacture these proteins. Reduced albumin decreases the circulating oncotic pressure which yields fluid leakage from blood vessels into other areas of the body (e.g., peritoneal space), reducing the arterial blood volume going to the kidney. This becomes especially apparent when a precipitating event such as a hemorrhage or infection occurs, which further decreases circulating blood volume. Clinicians often administer concentrated albumin (e.g., 25% or 25 grams/100 mL) every six to eight hours to increase the intravascular circulating blood volume. Albumin allows fluid to move from the interstitial spaces back into the blood stream and keeps exogenously administered crystalloids in the vessels, thereby increasing blood flow to the kidneys.¹² Clinicians should reserve concentrated albumin for patients with baseline low serum albumin (e.g., less than 3 mg/dL) who are also volume overloaded and limit them to just the amount that restores hemodynamic stability.¹⁵

 

Patients who have inadequate total body volume or those who have capillary leak (e.g., septic shock) may benefit from less concentrated (e.g., 5%) albumin infusions. A recent single center open-label, randomized study evaluated hypotensive patients with end-stage liver disease and compared volume replacement with albumin to normal saline.¹⁶ The primary outcome was to determine which approach could reverse a mean arterial pressure less than 65 mmHg more effectively within the first hours of resuscitation. Of note this trial excluded patients who needed immediate interventions, such as variceal bleed or vasopressor agents.¹⁷ The researchers randomized patients to receive 250 mL of 5% albumin over 30 minutes followed by 50 mL/hr for three hours or normal saline 30 mL/kg over 15 to 30 minutes followed by 100 mL/h over three hours. Albumin was more effective than normal saline in improving mean arterial pressure above 65 mmHg in the first hour (25.3% albumin vs 14.9% normal saline, p = 0.03) of resuscitation. The benefit continued over the next three hours (p < 0.001) and survival was also better in patients resuscitated with albumin than those treated with saline (43.5% vs 38.3%).^16,18 The researchers note that results are predicated on appropriate management of the underlying causes of hypotension (i.e., sepsis).

 

Albumin is expensive, can be and has been subject to shortages. It should be used with stewardship in end stage liver disease and HRS; however, the evidence for benefit is robust especially when combined with other modalities.¹⁶ It is important to understand the patient’s volume status and hemodynamic goals to select the appropriate concentration and frequency.^19,20 The AASLD Guidelines for the Diagnosis, Evaluation and Management of Ascites, Spontaneous Bacterial Peritonitis and HRS suggest that patients who present with HRS should receive 1 gram/kg albumin on day 1 and then 40 to 50 grams per day until kidney function improves and other therapies are no longer needed.^9,15 The daily dose may be reduced (e.g., 20 to 40 grams/day) if given in combination with vasopressor agents with a goal to maintain adequate volume. Clinicians sometimes use a surrogate measure of volume using a central venous catheter to measure central venous pressure (CVP), which reflects the amount of blood in the patient’s anterior vena cava and venous tone. In this case, a CVP goal between 10 and 15 mmHg is targeted.^10,21 Unfortunately CVP can be unreliable when ascites is present and clinicians may need to employ other invasive methods along with close monitoring for the development of pulmonary edema.^9,22,23

 

Ensuring albumin is available for patients with HRS is necessary. Some ways to aid centers in managing their supplies when shortages occur include limiting scheduled orders to 24 hours (e.g., 1 gram of 25% every 8 hours for 24 hours). Limiting “evergreen” orders to 24 hours will ensure clinicians assess patients appropriately before administering additional albumin and may prevent unappreciated volume overload. Also, standardized order sets will prevent use of partial vials, larger than needed vials (e.g., 250 mL or 500 mL) and inappropriate ordering of the incorrect concentration (e.g., 5% versus 25%). Teaching hospitals may also benefit from limiting albumin orders to certain clinical situations or diagnoses to avoid ubiquitous use for volume resuscitation in patients (e.g., trauma) who can be resuscitated with crystalloid.

 

Vasopressors

Vasopressors are given in combination with resuscitation, specifically albumin. The exogenous albumin facilitates adequate oncotic pressure to keep fluid in the vasculature, allowing vasopressors to constrict the vessels, increase mean arterial pressure, and supply fluid to the kidney. Vasopressors will be ineffective and can make kidney function worse if fluid in the vasculature is insufficient. Therefore, prescribers should only institute vasopressors along with or after volume resuscitation. The main adverse effects associated with any vasopressor therapy are related to ischemia (poor blood flow) in the peripheral limbs/tissues (e.g., fingertips, skin), gastrointestinal tract, or heart.⁹ Limited head-to-head trials exist to identify which agent or combination is the most effective in reversing HRS beyond early implementation of therapy in combination with albumin volume expansion. Table 2 summarizes the pros, cons, and considerations related to vasopressor agents used in the treatment of HRS.

 

Table 2. Vasopressor Agents Pros, Cons and Considerations
Medication	Pros	Cons	Considerations
Norepinephrine	Frequently used in the ICU setting, team comfort with monitoring for adverse effects and ease/experience with titration	May be less effective in hypothermia, pH dysregulation, continuous infusion	May require ICU setting, especially for acute titration; may require a central line
Terlipressin	Does not require a central line, or continuous infusion	Requires additional monitoring for ischemia which may require ICU level care to ensure safety	Requires monitoring for ischemic events
Octreotide	Can be given outside the ICU	Slow response, IV or subcutaneous administration	May be continued as an outpatient
Midodrine	Available as an oral agent, can be given outside the ICU	Slow response, only available as an oral agent; frequency of dosing	May be provided on discharge to help maintain blood pressure in the setting of hypotension

ABBREVIATIONS: ICU = intensive care unit; IV = intravenous

 

Norepinephrine

Norepinephrine is an exogenous catecholamine that targets alpha-1-adrenergic receptors which helps improve peripheral vascular resistance.²⁴ Norepinephrine has been used consistently in the United States (U.S.) for many years and has been the agent of choice until the recent approval of terlipressin. Norepinephrine’s limitation is that it can be less effective, as are other catecholamines, if patients have temperature or pH dysregulation. Appropriate resuscitation and correction of these variables can improve norepinephrine’s efficacy. A meta-analysis comparing the effectiveness of norepinephrine and terlipressin suggests that norepinephrine is as effective in increasing mean arterial pressure and reversal of kidney dysfunction.²⁴ The most frequent doses of norepinephrine cited in terlipressin head-to-head trials were between 0.5 to 3 mg/hour and/or 0.05 to 0.7 mcg/kg/minute titrated to increase mean arterial pressure 10 mmHg above baseline or increasing urine output to more than 200 mL/hour.²⁴ Clinicians must monitor norepinephrine administration carefully to prevent complications of vasoconstriction, such as cardiac or digital ischemia and therefore it is often restricted to the intensive care unit (ICU).²⁴

 

Terlipressin

Terlipressin is a prohormone of lysine-vasopressin, causing extended release of lysine-vasopressin and activation of V1 and V2 receptors allowing intermittent administration.²⁴ V1 receptors are predominantly located in the smooth muscles of the arterial vasculature in the splanchnic region. Activating V1 receptors constricts the splanchnic vessels (reducing delivery of blood flow to the portal vein, lowering portal pressure) which subsequently may improve blood flow to kidneys. Additionally, activation of the V2 receptors causes reabsorption of water in the kidney.^24,25 Terlipressin has been evaluated in several prospective, placebo-controlled clinical trials evaluating its efficacy in improving kidney function in HRS.¹⁸ Specifically, a recent prospective, randomized, double-blind controlled trial evaluated the effectiveness of terlipressin against placebo in combination with albumin in reversing HRS-AKI.²⁵ Terlipressin was more effective than placebo in reversing HRS (32% vs 17%, p < 0.006), but did yield more respiratory failure.²⁵ This trial was an impetus for U.S. Food and Drug Administration (FDA) approval of terlipressin in 2023.

 

The FDA approved terlipressin for rapid reduction in kidney function in the setting of cirrhosis with no other etiology, or reversal of HRS at a dose of 1 mg administered by intravenous bolus every six hours.¹⁰ If the patient’s serum creatinine fails to improve or increases within the first 96 hours then prescribers should discontinue terlipressin. If improvement is marginal (e.g., less than 30% from baseline) the dose can be increased to 2 mg every six hours.¹⁰ Therapy should be continued until the patient’s serum creatinine is 1.5 mg/dL or less for two days or a maximum of 14 days. Prescribers should use terlipressin with caution in patients with a history of ischemic conditions (e.g., cardiac, mesenteric).¹⁰ Terlipressin should not be used in patients who have a serum creatinine exceeding 5 mg/dL, in patients who are hypoxic (SpO₂ less than 90%), or in patients who develop ischemia.^10,23

 

Terlipressin is often given outside the ICU and does not need continuous cardiac monitoring, which may make it desirable for longer term administration.¹⁰ Initial clinical trials compared norepinephrine continuous infusion (1 mcg/kg/minute increased every four hours to increase MAP by 10 mmHg) to terlipressin (1 mg every four hours; increased to 2 mg every four hours after three days) combined with albumin to maintain a CVP between 10 and 15 mmHg. These trials defined a complete response as an improvement in serum creatinine by at least 30% from baseline within 14 days of therapy. There was no difference in responders between norepinephrine and terlipressin (70% and 83%).^21,26,27 Therefore terlipressin’s benefit may lie in its intermittent dosing and ability to be administered outside the ICU.

 

Terlipressin’s most common adverse reactions (≥10%) include abdominal pain, nausea, respiratory failure, diarrhea, and dyspnea. Terlipressin does have some additional considerations. It also has a boxed warning for possible serious or fatal respiratory failure, and clinicians need to monitor patients’ oxygen saturation carefully.²⁸

 

Terlipressin is supplied as a single dose 0.85 mg vial that must be stored under refrigeration and protected from light. Vials are reconstituted with 5 mL of sodium chloride and if not used, must be refrigerated and expire after 48 hours. The initial dose based on the approved labeling is one vial (0.85 mg) every six hours; which can be increased to two vials (1.7 mg) every six hours.²⁸

 

Midodrine and Octreotide

Midodrine and octreotide in combination have been a staple in the treatment of acute HRS for the last two decades in the U.S. Midodrine, an oral tablet, is like norepinephrine and produces vasoconstriction through alpha-1-adrenergic receptors.²⁴ Octreotide injection is a somatostatin analogue that decreases the release of vasodilatory substances and glucagon leading to vasoconstriction of the splanchnic circulation.²⁴ Because norepinephrine must be administered in the ICU, some healthcare facilities favor the combination of midodrine and octreotide. They also use midodrine/octreotide if they have not added terlipressin to their formularies.²³ Unfortunately, patients tend to respond slowly to the combination and the combination requires an extended duration for full benefit.²³ Octreotide cannot be given without midodrine but midodrine may be continued long-term (e.g., post-discharge) to maintain blood pressure in patients who are persistently hypotensive.^23,29

 

Researchers recently published a single center experience with standardizing administration of midodrine and octreotide for treatment of HRS at their center.²⁹ They wanted to standardize the use and dosing of albumin in combination with midodrine dosed at 2.5 to 10 mg three times daily and octreotide 50 to 100 mcg subcutaneously three times daily for 14 days and compare it to previous unstandardized prescribing. The goal was to obtain a full response: a serum creatinine within 0.3 mg/dL of baseline within seven to 14 days. Use of the standardized protocol was more effective in producing a full response than the historical unstandardized practice (25% vs 10%, p = 0.07).²⁹ Additionally, the researchers also found that fewer patients in the protocol group required kidney replacement therapy. Guidelines suggest initiating midodrine at a dose of 7.5 mg three times daily and titrating it to 12.5 mg three times daily in combination with octreotide.²³ The combination may still be in favor because it is a cost-effective alternative to terlipressin outside the ICU.

 

Midodrine is supplied in three tablet strengths which include 2.5 mg, 5 mg and 10 mg.³⁰ This allows outpatient tapering or adjustment if the patient experiences tachycardia. Unfortunately, it is short acting and requires three times daily dosing initially. In practice, dropping the middle of the day dose without reducing the strength allows improved adherence once the patient’s blood pressure is stable. Midodrine’s labeling includes a boxed warning for possible marked elevation of supine blood pressure, and clinicians should monitor supine and standing blood pressure regularly.³⁰

 

Octreotide is supplied in single dose ampules or multidose vials that must be stored in the refrigerator and protected from light; multidose vials must be discarded within 14 days. Octreotide is stable for 14 days at room temperature.³¹ Doses of 50 mcg to 100 mcg are administered every eight hours around the clock during the inpatient stay. If patients continue on octreotide as outpatients, the hospital pharmacy often needs to supply the doses. Patients and caregivers need appropriate education on subcutaneous injections and disposal of injection materials. In practice, the dose used in the hospital with success is often continued and not reduced to allow for the shortest duration possible. Octreotide subcutaneous injections on the outpatient side typically require additional insurance approval and preparation so discharge planning early is important.³¹

 

The Role of Pharmacists and Pharmacy Technicians in the Treatment of HRS

Pharmacists and pharmacy technicians can play an integral role in improving outcomes for patients presenting with or who have a history of HRS. Prevention is the key! Patients with end-stage liver disease should avoid medications that can precipitate HRS such as non-steroidal anti-inflammatory drugs and will require appropriate adjustment or discontinuation (if possible) of potential nephrotoxic agents (e.g., certain antimicrobials).

 

Ensuring patients with a history of spontaneous bacterial peritonitis (SBP) are on appropriate antibiotic prophylaxis can prevent subsequent SBP events that decrease blood flow to the kidneys. In the ambulatory setting, careful blood pressure monitoring and adjustment of blood pressure medications commonly used to treat portal hypertension (e.g., carvedilol), can ward off hypotensive events that can precipitate HRS.

 

Table 3 summarizes some lifestyle counseling tips that can help empower patients to play an active role in optimizing their care and preventing HRS episodes. Additionally, general management of concurrent disease states, such as heart failure and diabetes, can aid in maintaining optimal hemodynamics.

Table 3. Lifestyle Counseling Points for Patients with Cirrhosis at risk for HRS35-37
Avoid alcohol	Even if the cause of liver damage isn’t drinking, alcohol use can increase the amount of damage. Patients who cease alcohol can experience dramatic improvements in some of the complications of cirrhosis.
Low sodium diet (especially in patients with ascites)	Limit sodium intake. This can be quite difficult, but if it can be done will help quite a bit with volume management. Patients with ascites are often asked to target ≤2 g/day. (For reference, 1 teaspoon of salt contains 2.3 g!)
Weight loss in patients who are overweight	Even a small amount of weight loss (e.g., a few pounds) can have a beneficial effect in patients with NAFLD or chronic HCV.
Protect yourself from infections	Patients need to stay up to date on vaccinations, wash their hands frequently, and avoid people who are sick.
Organize medication schedule	Patients with liver impairment can take seven to 10 medications a day—some administered multiple times a day. Investing in a strong adherence-enhancing system with alarm reminders or reminders from caregivers can be key.
Use OTC medications carefully	NSAIDs, such as ibuprofen and naproxen, can precipitate acute kidney injury.
Monitor weight daily (if on diuretic treatment)	Patients need to weigh themselves first thing in the morning after urinating. They should report significant weight changes to their providers (e.g., losing 1 pound or more a day or gaining more than 5 pounds in a week).

 

 

SIDEBAR: Did you know…acetaminophen can be a great choice for patient with HRS?³⁴

Imagine a situation where a medical intern is cross-covering in the medical intensive care unit and receives a call from a nurse about a patient with HRS. The patient is experiencing some mild pain and the nurse would like an as-needed medication to help.

 

Or…

 

You are working in the pharmacy and receive an order for oxycodone 5 mg every six hours as needed for mild pain. You are very concerned that this patient has both kidney and liver insufficiency and oxycodone is not a good choice but what else can you recommend?

 

What about acetaminophen?!?

 

Acetaminophen tends to have a bad rap mainly because it is in so many prescription and OTC products. It’s often in the news for causing liver toxicity. Oftentimes patients and providers do not think about the total acetaminophen exposure (the total daily dose of acetaminophen) and that is where the danger can come in. When the amount of acetaminophen’s toxic intermediary N-acetyl-p-benzoquinone imine (NAPQI) exceeds the liver’s glutathione stores, NAPQI starts to stick to hepatocytes (the liver’s main structural component). NAPQI acts like an antigen and stimulates the immune system to attack the liver.

 

Fortunately, it takes a significant amount administered at one time or consistently over several days to expend the glutathione stores. Doses up to 2,000 mg per day are safe and effective in most patients with severe liver insufficiency. (The maximum daily dose in healthy adults is 3900 mg.) Pharmacists and pharmacy technicians can ensure providers and patients with liver disease know they have alternative options. They can also help patients avoid reaching for a NSAID, especially if the patient has had a recent bout of HRS or if the patient is taking other medications that would suggest the presence of liver insufficiency (e.g., lactulose, rifaximin, norfloxacin). Remember prevention of HRS is the key!

 

When a hospital admits a patient, healthcare providers need to understand what the patient was taking at home and stop or continue the appropriate medications at the right doses. For example, prescribers should discontinue medications that could be reducing blood pressure (e.g., beta blockers and alpha beta blockers) on admission.^11,16 They need to consider adjusting home medications for kidney dysfunction and restarting medications needed to manage other complications of end-stage liver disease (e.g., lactulose for encephalopathy).

 

When prompt administration of resuscitation with albumin is needed, the team may need help selecting the appropriate concentration. Patients who are significantly volume overloaded but have fluid in the extravascular space (e.g., in the abdominal cavity) would likely benefit from concentrated (25%) albumin. With the multidisciplinary team, the pharmacy team needs to understand the patient’s volume status and goals of therapy. Helping teams develop protocols to treat HRS can aid in goal-directed therapy and allow quick implementation of pharmacologic interventions to improve blood flow to the kidneys.

 

At discharge pharmacists and pharmacy technicians must ensure that medications are appropriately adjusted for the patient’s current kidney and liver function after the acute event has resolved or stabilized. The pharmacy team should be involved in educating patients on how to organize their new medication regimens, how to monitor their responses to therapy and recognize common adverse effects, and how appropriate lifestyle changes can increase the effectiveness of therapy and help avoid the advanced complications of liver disease.

 

CONCLUSION

HRS is a common complication for patients with advanced liver disease and ascites. Patients are in a state of decreased effective arterial blood flow to the kidneys and other end organs, and kidney injury is easily precipitated by nephrotoxic agents, over-diuresis, or bacterial infection. Acute treatment is aimed at restoring blood flow to the kidneys with the use of volume resuscitation and splanchnic vasoconstrictors. Pharmacists and pharmacy technicians can identify medications that may worsen kidney function, and assist in the appropriate prescribing, monitoring, and stewardship of these agents. Additionally, appropriate patient education—empowering patients to monitor their fluid/blood pressure status and avoiding OTC medications that can worsen their condition or precipitate HRS—is key in optimizing patient outcomes.

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INTRODUCTION

The feeling of grit under the eyelids is uncomfortable, annoying, and frustrating and can pose a serious health issue. This feeling, often accompanied by burning, itching, redness, and visual disturbances, is a symptom of keratoconjunctivitis sicca, otherwise known as dry eye disease (DED). At its simplest, DED is inflammation of the cornea and conjunctiva from tear hyperosmolarity (higher concentration of solutes like salts, sugars, or other dissolved particles) and tissue dryness. Left untreated, DED may result in severe eye inflammation, corneal ulcers, and vision loss.¹

 

DED affects approximately 16.4 million people, or 6.8% of the United States (U.S.) adult population.^2,3 DED is likely underreported and underdiagnosed, with estimates as high as 22.9 million adults experiencing symptoms.² Researchers estimate DED’s global prevalence is as high as 50%.⁴

 

Despite this prevalence, experts began to recognize DED as a disease state only about 30 years ago.^5,6 Initially described as a component of Sjogren’s syndrome (an autoimmune disease involving tear and saliva glands), DED emerged as a separate condition as ocular surface study progressed. The National Eye Institute first defined DED in 1995.¹

 

The Tear Film and Ocular Surface Society (TFOS) is a non-profit organization focused on eye health research and education.⁵ In 2015, the Dry Eye Workshop II (DEWS II), organized by TFOS, examined multiple aspects of DED. The workshop updated the definition, diagnosis, and classification of DED, the disease’s impact, therapeutic management options, and clinical trial design.⁵

 

TFOS DEWS II defines DED as "… a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles."⁵ In simpler terms, DED occurs when the tear film, which keeps the eyes moist, becomes imbalanced, leading to problems like tear film instability, high concentration of substances in the tears, inflammation and damage on eye surface, and abnormal nerve sensations.

 

Many risk factors contribute to DED development (Table 1). Women are two to three times more likely to develop DED than men.^3,4 Risk of developing DED increases with age. Adults aged 50 or older are three times more likely to develop symptoms than those 18 to 49 years old.^2,3 However, DED’s incidence is rising steadily in the younger population, possibly due to increased disease awareness.³ Digital device use may also contribute. Studies show that using digital devices decreases blink rate and increases incomplete blinks, leading to ocular surface dryness and, ultimately, DED.^4.7

 

Table 1. Dry Eye Disease Risk Factors^1,4,5

Modifiable	Non-modifiable
Androgen deficiency Computer use Contact lens wear Environment Medications	Age ≥ 50 years Asian race Connective tissue diseases (e.g., rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus) Diabetes Female sex Meibomian gland dysfunction

 

 

DED impacts the American economy significantly. Several factors contribute to DED burden: direct costs of medical care, the impact of lost productivity, and the associated quality of life burden. In the U.S., estimates of direct medical costs exceed $3.84 billion, fueled by healthcare professional visits, pharmacologic therapies, and surgical procedures.^4,8 The cost of lost productivity (i.e., time spent seeking and receiving treatment, avoidance of aggravating work environments, and inability to perform work due to visual changes) is even more substantial. One study estimates that these indirect costs total $11,302 per patient annually.⁸ If more than 16 million people have DED, that totals more than $150 billion annually.^4,8

 

Beyond monetary costs associated with DED, the disease also affects vision-related quality of life (VR-QoL). As DED progresses, visual quality decreases. Individuals with DED are three times more likely to report visual difficulties than those without.⁴ This impacts many daily activities such as reading, driving, watching television, and smartphone use.⁴ DED-associated pain and discomfort, along with difficulty in activities of daily living, impact mental health negatively.⁸ A 2021 study examined self-reported health status and psychological burden in patients with DED. The study associated DED with having a negative self-perception of health status and experiencing increased psychological stress.⁹

 

A Deeper Look at DED

A better understanding of DED requires review of the surface anatomy of a healthy eye (see Figure 1). The eye's surface consists of the ocular surface and ocular adnexa (accessory anatomical parts).¹⁰ The ocular surface includes the cornea, conjunctiva (including goblet cells), and tear film. The ocular adnexa includes the eyelids, lacrimal and meibomian glands, tear ducts, and the connecting muscles and nerves.¹⁰

 

Figure 1. Eye Surface Anatomy and Tear Film Formation

 

Tears lubricate the eye, and the tear film—which provides nutrients and moisture, removes microbes, and smooths the ocular surface—has three layers^10,11:

• Outermost lipid layer, produced by meibomian glands
• Aqueous layer, produced by the lacrimal gland
• Innermost mucin layer, produced by goblet cells

 

Tear film instability, primarily increased tear osmolarity, leads to ocular surface damage in DED.⁷ DED's categorization is based on the mechanism leading to tear hyperosmolarity. In aqueous deficient dry eye disease (ADDE), decreased tear secretion increases tear film osmolarity. Increased evaporation of tears leads to hyperosmolarity in (you guessed it) evaporative dry eye disease (EDE).⁵

 

ADDE is further categorized based on the underlying cause: Sjogren’s Syndrome or non-Sjogren’s syndrome. As mentioned, Sjogren’s syndrome is an autoimmune disease attacking the salivary and lacrimal glands resulting in dry mouth and eyes. Non-Sjogren’s syndrome ADDE has various causes, including lacrimal deficiency, lacrimal gland duct obstruction, and systemic drugs. These mechanisms decrease tear secretion, resulting in tear hyperosmolarity.^5,10

 

Meibomian gland dysfunction (MGD) is the primary cause of EDE.^12,13 Meibomian glands line the inside of the upper and lower eyelid. Lipid secretion by meibomian glands forms a coating on the aqueous layer, impeding tear evaporation and providing protection against environmental irritants. Risk factors for MGD include aging, hormonal changes, contact lens wear, diet, and systemic and topical medications.¹³

 

Separation of DED into ADDE and EDE implies mutual exclusivity, but many patients presenting with DED exhibit characteristics of both. Recent evidence indicates the two classifications co-exist, with more patients presenting with EDE due to MGD. ^6,14,15 Regardless of the subtype or mechanism, the result is a vicious, self-perpetuating cycle of inflammation.^6,16 Tear film hyperosmolarity triggers an innate inflammatory immune response, activating CD4+ T-cells. This leads to conjunctival and corneal cell death and impaired lacrimal gland function, further decreasing tear production.^16,17 This further increases tear hyperosmolarity, which continues the cycle.

 

Diagnosing DED is problematic due to its multi-factorial nature and inconsistent symptom presentation. Exploring differential diagnoses using triaging questions is crucial to exclude diseases that mimic DED, including allergic, bacterial, or viral conjunctivitis; blepharitis; and rheumatic disorders.^5,18 A thorough patient history screens for risk factors such as smoking, contact lens wear, and certain systemic and topical medications. Several questionnaires also exist to help clinicians screen for DED. The Dry Eye Disease Questionnaire (DEQ-5) contains five items asking patients to rate the frequency of eye discomfort, eye dryness, and watery eyes during a typical day.¹⁸ The Ocular Surface Disease Index (OSDI) is another popular questionnaire. The OSDI questionnaire asks a series of 12 questions assessing eye symptoms, vision issues (e.g., reading, driving), and environmental conditions.¹⁸

 

Patients with positive questionnaire results should progress to a more detailed tear film and ocular surface examination. A positive result in any of the following tests is diagnostic of DED¹⁸:

• Tear breakup time (TBUT): There are two methods for measuring TBUT, using fluorescein dye or illumination of the cornea. Both measure how long it takes for tears to break up after a blink. Lower TBUT scores indicate tear instability.
• Osmolarity: Clinicians use a device with a test strip to gain a sample of the tear film from both eyes to check tear osmolarity. An osmolarity of 308 mOsm/L or greater in either eye or a difference of more than 8 mOsm/L between the eyes is diagnostic of DED.
• Ocular surface staining: After applying dye to the lower eyelid’s inner lining, clinicians examine the ocular surface for missing or damaged epithelial cells. Positive scores range from five to nine spots depending on the dye used.

 

Clinicians also commonly deploy the Schirmer test to evaluate the eye’s ability to produce tears. A notched paper strip placed over the lower eyelid stimulates tear production during the test. After five minutes, a length of wetting greater than 10 mm indicates normal tear function. Values less than 5 mm signify tear insufficiency.¹⁸

Pause and ponder: How would vision loss affect your everyday life?

 

Treatment Goals

Treatment goals for DED are to decrease ocular inflammation and restore ocular surface homeostasis (balance). DED's complexity and heterogeneous presentation necessitate an individualized approach. TFOS DEWS II recommendations emphasize identifying the disease’s root cause to determine an appropriate management approach.¹⁴ From there, the report outlines a stepwise, flexible approach to guide treatment based on patient-specific disease etiology and severity.¹⁴ Table 2 briefly summarizes recommended management steps.

 

Table 2. Treatment Steps in DED Management¹⁴

Step 1: ·       Education ·       Environmental modifications ·       Lifestyle modifications ·       Dietary supplementation ·       Eyelid hygiene ·       Medication review ·       Artificial Tears	Step 2: ·       Preservative-free artificial tears ·       Prescription therapy ·       Tear Conservation ·       Overnight treatments ·       In-office treatments
Step 3: ·       Tear stimulation ·       Biological tear substitutes ·       Therapeutic contact lenses	Step 4: ·       Prescription therapy ·       Surgical intervention

 

 

NON-PHARMACOLOGIC TREATMENT

One of the first steps, patient education, is essential for successful disease management.¹⁴ Patient education starts with thoroughly explaining DED’s chronic nature, including the ongoing, often long-term nature of therapeutic management. Discussing the patient’s home and work environment during the session may identify contributing factors.¹⁴ The environment affects overall health and well-being. Air pollution, low humidity, high altitude, and wind contribute to DED development.¹⁴ Adding an air humidifier inside or using protective eyeglasses outside can help mitigate DED symptoms. Other strategies include minimizing exposure to digital screens, cigarette smoke, and air conditioning.¹⁹

 

Proper lid hygiene is important in managing many eye conditions, including DED.¹⁴ Patients can use a cotton swab to scrub the eyelid with a dilute solution of baby shampoo to keep the area free of crusty build-up and environmental contaminants. Warm eye compresses also promote good lid hygiene and help alleviate DED symptoms. Unfortunately, lid hygiene adherence is poor, with estimates of just over 50% adherence at six weeks.¹⁴ Reinforcing the importance of lid hygiene with patients is an important component of DED patient counseling.

 

Identifying medications that may contribute to DED is an important task for pharmacy staff. Many medication classes produce drying effects on the body, intentionally or as an adverse effect.^14,19 Table 3 lists examples of medications that may worsen DED. Pharmacists and pharmacy technicians should review patient profiles to identify drying medications, including ophthalmic formulations, as medications for glaucoma (an eye condition causing progressive vision loss) may contribute to DED.¹⁴ Mitigating options to consider include changing the route of administration from oral to topical, substituting with a therapeutic alternative, and adjusting doses.¹⁴

Table 3. Examples of Medications that Worsen Dry Eye Disease^14,19

Drug Class	Examples
Antihistamines and decongestants	Chlorpheniramine Diphenhydramine Fexofenadine Loratadine Pseudoephedrine
Antidepressants ·       TCA ·       SSRI ·       SNRI	Amitriptyline Citalopram Duloxetine Fluoxetine Sertraline Venlafaxine
Anti-Parkinson’s	Levodopa
Antipsychotics	Aripiprazole Perphenazine Quetiapine
Beta-blockers	Atenolol Carvedilol Metoprolol Propranolol
Diuretics	Furosemide Hydrochlorothiazide
Proton pump inhibitors	Omeprazole Pantoprazole
Hormone therapy	Estrogen

DED = dry eye disease; TCA = tricyclic antidepressants; SSRI = serotonin-selective reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor

 

Diet and Nutrition

An emerging body of evidence suggests that certain diet changes and nutritional supplementation may play a role in DED treatment. Dehydration increases tear osmolarity, so maintaining adequate hydration is important to disease control.¹⁴ Lactoferrin is an anti-inflammatory glycoprotein found in natural tears. Studies have found decreased lactoferrin levels in patients with DED leading researchers to the explore lactoferrin topical application and oral supplementation as treatment for the condition. One study found improved dry eye symptoms and tear film stability in patients taking an oral lactoferrin supplement.²⁰ Oral lactoferrin is available as a supplement in many retail locations.

 

Supplementation with omega-3 fatty acids also shows potential in DED. Omega-3 fatty acids block proinflammatory substances and are essential for ocular surface homeostasis.¹⁴ Some studies have found that omega-3 fatty acid supplementation improves TBUT and Schirmer scores.^21,22 Conversely, The Dry Eye Assessment and Management (DREAM) trial reported no difference between groups receiving omega-3 fatty acids and placebo.²³ While oral omega-3 fatty acids show benefit for some patients, further study is necessary. These conflicting results prompted studies for alternative administration routes. Topical application of omega-3 fatty acids shows promise. A systematic review of 10 studies (five in animals and five in humans) showed overall improvement in ocular surface staining and TBUT.²⁴ Further study is necessary to evaluate long-term efficacy and optimize dosage and delivery formulations.

 

Artificial Tears

Patients often attempt self-treatment before seeking healthcare professional assistance. Tear replacement with artificial tear (AT) formulations is essential for patient comfort and a mainstay of initial and ongoing therapy. Global sales of AT reached $2.64 billion in 2019, and experts predict this to reach $4.30 billion by 2027.²⁵ Many AT products line the pharmacy shelves, all touting their ability to lubricate the eye. Faced with the confusing array of products, patients often employ a trial-and-error approach for AT selection, leading to high costs and frustration. Knowing the differences between ATs enhances the pharmacy team’s ability to counsel patients effectively.

 

AT supplementation is generally safe and well tolerated and associated adverse effects are mild, including blurred vision and ocular discomfort.¹⁴ Most ATs are water-based with viscosity-enhancing agents added for lubrication. Osmolarity, viscosity, and pH vary between products. Table 4 describes the components of AT products and their functions.

 

Table 4. Components of Artificial Tear Products^11,14,26

Component	Purpose	Examples
Viscosity-enhancing agents (lubricants)	Aid lubrication Increase tear film thickness Protect ocular surface Promote tear retention Improve goblet cell density	Carbomer 940 (polyacrylic acid) Carboxymethyl cellulose (CMC) Dextran Glycerin Hyaluronic acid (HA) Hydroxypropyl-guar (HP-guar) Hydroxypropyl methylcellulose (HPMC) Polyvinyl alcohol Polyvinylpyrrolidone Polyethylene glycol (PEG)
Lipids	Restore the lipid layer Increase lipid layer thickness Prevent evaporation	Mineral oil Castor oil Flaxseed oil
Osmoprotectants	Balance osmotic pressure	Trehalose Levocarnitine Erythritol Betaine
Preservatives	Prevent microbial growth in multi-dose formulations	Benzalkonium chloride (BAK) Sodium chlorite Sodium perborate
Buffers	Control pH	Sodium borate Sodium citrate Sodium phosphate
Electrolytes	Promote ocular surface homeostasis	Potassium Calcium Magnesium Phosphate

 

 

Viscosity-enhancing agents, or demulcents, are the most common ingredient in AT and typically listed as the active ingredient on product packaging. The higher the viscosity (i.e., the thicker the product), the longer the ocular surface retention time, but differences in viscosity can influence product choice. High viscosity can create visual disturbances and buildup on the eyelid leading to decreased adherence.²⁶ These products are best for nighttime use, and patients should use lower-viscosity products during the day.²⁶ Many products contain multiple viscosity-enhancing agents. Commonly paired agents include carboxymethyl cellulose (CMC) with hyaluronic acid (HA) and hydroxypropyl-guar (HP-guar) with HA.^14,26 Studies suggest that combining viscosity-enhancing components improves symptom control.¹⁴

 

There is significant interest in developing novel formulations to increase the spreading and retention time of applied drops.¹⁴ Lipid-containing eye drops are gaining in popularity as understanding of DED’s pathophysiology progresses.¹⁴ Lipids restore and thicken the lipid layer of the tear film and prevent tear evaporation. Formulated as oil-in-water emulsions, lipid-containing products contain macro-, micro-, or nano-particles. Particle size is important. Macro particles are associated with cloudy, blurred vision. As particle size decreases, blurring decreases.¹⁴

 

Osmoprotectants balance osmotic pressure, as the name implies, to protect and prevent corneal and conjunctival cell death.²⁶ Levocarnitine and erythritol protect cells from hyperosmolar stress and improve DED’s symptoms.²⁶ Clinical trials have shown that trehalose is more effective at improving ocular surface staining than saline.^14,26

 

Multi-dose products contain preservatives to prevent microbial growth, but these can also worsen symptoms in DED. Benzalkonium chloride (BAK), the most common preservative, may cause corneal damage and interfere with tear film stability.¹⁴ Newer “disappearing preservatives” (e.g., sodium chlorite, sodium perborate) have a lower impact on the ocular surface. Exposure to light or the ocular surface breaks down these compounds, minimizing toxicity.^14,27 Even newer preservatives carry risk, making preservative-free drops the best choice, especially in patients with severe DED. Preservative-free AT products are available in disposable single-use units but are generally more expensive.¹⁴

 

The pH of ATs affects product activity, stability, patient comfort, and safety.¹⁴ Adding electrolytes to reproduce the electrolyte profile of the tear film aids osmotic balance. Studies show that hypotonic solutions (i.e., having a lower osmotic pressure) decrease DED signs.²⁶

 

No large-scale, randomized clinical trials have evaluated all currently available AT formulations. Some clinical trials evaluate individual AT products, and a few head-to-head studies exist.^16,28 Several published systematic reviews have concluded that ATs treat DED safely and effectively. One systematic review of more than 60 studies published in 2022 drew the following conclusions²⁷:

• Combination formulations, including the following, may be more effective than single-ingredient products: CMC and HA, HA and trehalose, CMC and glycerin, and HA and coenzyme Q10.
• Formulations containing polyethylene glycol (PEG) may be more effective than those with CMC.
• Preservative-free formulations are preferable.
• Patients with EDE and/or MGD should use drops containing phospholipids.
• Patients should administer AT four times daily for one month to assess efficacy.
• Patience is key; sometimes, it may take up to four months of consistent use to see improvement.

 

Another literature review of 18 studies compared commercially available AT products and concluded that products containing CMC, hydroxypropyl methylcellulose (HPMC), or HA were the most beneficial in improving patient comfort level.²⁹ This study also determined that clinicians should recommend administration three to four times daily for two months to assess patient response before escalating therapy. The use of a preservative-free formulation is preferable.²⁹ If patients choose or clinicians recommend preservative-containing eye drops, administration should be limited to four to six times daily.²⁹ Researchers created a stepwise approach to selecting AT products²⁹:

• Step 1: Start with CMC, HPMC, or HA-based formulations
• Step 2: Move to formulations with PEG or PEG and glycerin
• Step 3: Consider gel or lipid formulations
• Step 4: Progress to ointments, liposomal sprays, or prescription inserts

 

Both studies reached similar conclusions. Adherence and persistence are key to successfully evaluating an individual product, a fact that pharmacy staff should reiterate to patients. While some trial and error may be necessary, following the above recommendations allows patients and providers an organized approach to AT selection. While AT are a mainstay of early symptomatic treatment of dry eye disease, they do not address DED’s underlying causes. Prescription therapies target the underlying inflammatory processes.

 

Hydroxypropyl cellulose ophthalmic insert (HCOI) is a prescription-only lubricant insert containing 5 mg of hydroxypropyl cellulose. The insert is preservative-free and designed to provide continuous lubrication throughout the day. Patients insert HCOI once daily using an applicator.³⁰ They rinse the applicator in hot water then use the grooved end to pick up the insert. Patients then place the insert in a pocket created by pulling out the outer corner of the eyelid. The HCOI softens and slowly dissolves, stabilizing and thickening the tear film, prolonging TBUT. One study comparing HCOI to using AT four or more times a day found increased TBUT and decreased foreign body sensation with HCOI compared to AT.^30,31 Reported adverse effects include blurred vision, eye irritation, eyelid matting, and light sensitivity.³⁰

 

Pause and Ponder: A patient approaches the pharmacy counter with a plastic bag full of bottles of different brands of artificial tears. Dumping them on the counter, she states, “None of these work! I don’t know what to do next.” What advice would you give her?

 

PRESCRIPTION THERAPIES

Available prescription therapies (outlined in Table 5) target the inflammatory cycle of DED through different mechanisms with varying degrees of success.

 

Table 5. Prescription Therapies to Treat Dry Eye Disease^28,32-36

Drug	Brand Name (Manufacturer)	Formulation(s)	Dosing	Supplied
Cyclosporine A	Restasis (Allergan)	0.05% emulsion	1 drop in each eye BID	Single-use vials
	Cequa (Sun Pharma)	0.09% solution	1 drop in each eye BID	Single-use vials
	Generic (Mylan)	0.05% solution	1 drop in each eye BID	Single-use vials
Lifitegrast	Xiidra (Novartis)	5% solution	1 drop in each eye BID	Single-use containers
Loteprednol	Eysuvis (Kala Pharma)	0.25% suspension	1-2 drops in each eye QID for up to 2 weeks	Multi-dose 10 mL bottle
Perfluorohexyloctane	Meibo (Bausch & Lomb)	100% solution	1 drop in each eye QID	Multi-dose 5 mL bottle
Varenicline	Tyrvaya (Oyster Point Pharma)	0.03 mg/0.05ml solution	1 spray in each nostril BID	Multi-dose nasal spray

ABBREVIATIONS: BID, twice daily; QID, four times daily

 

Cyclosporine A

Cyclosporine A (CsA) is an anti-inflammatory immune modulator approved for use in DED more than two decades ago.¹⁶ Calcineurin activates T-cells, increasing inflammatory cytokine production. CsA inhibits calcineurin to prevent T-cell activation, disrupting the inflammatory cycle in DED.¹⁶

 

Many clinical trials have evaluated CsA’s safety and efficacy in DED treatment.^1,5,14,37 Results consistently show that CsA improves Schirmer test scores, corneal staining results, and goblet cell density. Improvement often takes several months, making patient education key to adherence.^1,5,14,37 Topical CsA alleviates symptoms in approximately 50% of patients.¹ Patients using CsA experience decreases in blurred vision, ocular dryness, foreign body sensation, and watery eyes.^1,14 Treatment often causes stinging and irritation. Other adverse effects include blurred vision, ocular itching, eye redness, and foreign body sensation.³⁷ Pretreatment with an ophthalmic steroid such as loteprednol may decrease CsA’s adverse effects.^1,38

 

As a hydrophobic (water-fearing) substance, CsA is challenging to formulate into an ophthalmic topical formulation. Initially, products used castor oil and corn oil as vehicles, but poor bioavailability and adverse effects preclude their use.¹⁶ The first commercially available CsA product, a 0.05% emulsion, uses a castor oil-in-water emulsion, which reduces but does not eliminate adverse reactions.³⁷

 

Approval of CsA 0.09% nanomicellar solution introduced a novel formulation.^16,37 Clinical efficacy trials found a response as early as day 28.¹⁶At the end of 12 weeks, 17% of study participants receiving CsA 0.09% experienced increased tear production with a Schirmer score greater than 10 mm. Reported adverse effects included mild instillation site pain, eye irritation, blepharitis, and headache.³² Preliminary studies suggest CsA 0.09% is more effective and better tolerated than CsA 0.05%.¹⁶

 

Lifitegrast

Approved in 2016, the novel drug lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist.³³ LFA-1 binds to intracellular adhesion molecule-1 during inflammation, activating T-cell migration and resulting in ocular inflammation. Lifitegrast binds to LFA-1, preventing this interaction and decreasing T-cell-mediated inflammation.³³ The U.S. Food and Drug Administration (FDA) approved this drug based on four randomized, double-masked, 12-week efficacy and safety trials. ^33,39-41 All studies showed a reduction in patient-rated eye dryness scores at the end of 12 weeks. Patients in three of the four studies experienced reduced corneal staining scores.³³

 

The one-year multicenter, randomized, placebo-controlled SONATA study evaluated lifitegrast safety.⁴² Reported adverse effects included burning, reduced visual acuity, dry eye, and taste changes. Researchers observed no serious adverse events and discontinuation rates were 12.3% and 9% for lifitegrast and placebo, respectively.⁴² A 2021 retrospective review of 600 patient charts examined real-world experience with lifitegrast in DED.⁴³ Most patients continued treatment for six months and showed improvement in DED symptoms. Patients also experienced improved quality of life at three and 12 months of treatment.⁴³

 

Perfluorohexyloctane

Perfluorohexyloctane, formerly known as NOV3, reduces tear evaporation from the ocular surface.⁴⁴ The drug’s exact mechanism in DED is unclear. In May 2023, the FDA approved an ophthalmic formulation containing perfluorohexyloctane for treating DED in adults 18 and older based on data from two phase 3 clinical trials: GOBI and MOJAVE.^44,45

 

These trials evaluated efficacy and safety in more than 1,200 patients with DED meeting similar inclusion and exclusion criteria based on tear film break-up time, ocular surface disease scores, and MGD evaluations. Both trials were multi-center, randomized, double-masked, and saline-controlled.^44,45 GOBE and MOJAVE results also consistently showed statistically significant reductions in reported symptoms of DED. Reported adverse events occurred in less than 4% of study participants and included blurred vision, blepharitis, instillation site pain, and conjunctival redness.^44,46 Patients must remove contact lenses before and for at least 30 minutes after administration of perfluorohexyloctane drops.³⁴

 

Perfluorohexyloctane should be available in the second half of 2023.⁴⁴

 

Short-Term Corticosteroids

Corticosteroids are potent inhibitors of inflammatory mediators.¹⁴ Many clinical trials have demonstrated their efficacy in breaking the inflammatory cycle of DED. Unfortunately, long-term therapy is associated with increased intraocular pressure, cataracts, and risk of infection.¹⁴

 

Loteprednol is a synthetic corticosteroid derived from prednisolone. Its rapid breakdown into inactive metabolites reduces risk of adverse reactions.⁴⁷ A retrospective safety study concluded that loteprednol therapy carries a low risk of treatment-related elevated intraocular pressure compared to other steroids.⁴⁸ Several loteprednol ophthalmic formulations are available, but only the 0.25% suspension is FDA approved for the short-term treatment of DED. This formulation uses mucus-penetrating particle (MPP) technology to allow nanoparticle penetration through the mucin layer.^47,49

 

The FDA approved loteprednol 0.25% suspension based on the STRIDE series of trials.³⁶ These trials randomized patients with DED to the drug or a vehicle control four times daily in both eyes for two weeks. All trials reported significant improvements in eye redness and discomfort at the end of two weeks.³⁶

 

One role for topical steroids in DED is pre-treatment prior to topical CsA therapy. A 2014 study compared loteprednol versus AT during a two-week lead-in period to CsA.³⁸ Patients self-administered either loteprednol or AT four times daily for two weeks, followed by CsA twice daily plus either loteprednol or AT twice daily for an additional six weeks. Both groups showed improved ocular staining and OSDI and Schirmer scores. Loteprednol provided more rapid relief of DED symptoms and resulted in a lower CsA discontinuation rate than AT.³⁸

 

Patients with moderate-to-severe DED with adequate long-term control may still experience periodic symptom exacerbation. Short-term pulse steroid therapy (using steroids of a week or two, then tapering and resuming if necessary) can be useful for patients with symptom exacerbations.¹⁴

 

Varenicline Nasal Spray

Pharmacy staff may recognize varenicline as a treatment for smoking cessation, but a newer nasal spray formulation shows utility for treating DED. Tear film production results from stimulating afferent nerves in the cornea and conjunctiva and parasympathetic nerves in the lacrimal gland, meibomian glands, and goblet cells.^50,51 This neural pathway is accessible through central nervous system or peripherally through the nasal cavity. While the drug’s mechanism in DED is not fully understood, experts theorize that varenicline, a cholinergic agonist, activates this pathway to stimulate tear production.^50,51

 

The randomized, double-masked, vehicle-controlled, 28-day ONSET-1 and ONSET-2 trials evaluated varenicline nasal spray’s safety and efficacy.^50,51 Participants self-administered one spray of varenicline solution or vehicle in each nostril twice daily. Both studies found a significant improvement in tear production measured by Schirmer scores. The most common patient-reported adverse effects included sneezing, cough, throat irritation, and nasal irritation.^50,51 The 2021 MYSTIC study examined varenicline nasal spray's long-term safety and efficacy compared to placebo over a 12-week period.⁵² Patients reported no severe or serious adverse events during the study; sneezing was the most common adverse reaction, occurring in 82% of patients.⁵²

 

Varenicline packaging includes two glass bottles, each containing a 15-day drug supply. Patients must initially prime the bottle by pumping seven sprays into the air away from the face. Re-priming by pumping one spray into the air is necessary after five days of nonuse.³⁵

 

Steps for administration of varenicline nasal spray³⁵:

• Blow nose if needed to clear nostrils
• Remove the cap and clip from the bottle
• Hold the bottle upright, placing one finger on each side of the applicator and thumb on the bottom of the bottle
• Tilt head back slightly
• Insert the applicator tip into one nostril, pointing it toward the ear on the same side of the nostril, leaving space between the tip and the wall of the nostril
• Place tongue on roof of mouth and breath gently while pumping one spray into the nostril
• Repeat in other nostril
• Wipe the applicator with a clean tissue and replace the cap and clip

 

Antibiotics

Clinicians sometimes use oral or topical antibiotics with anti-inflammatory effects off-label to treat DED due to MGD.¹⁴ Many patients experience MGD due to overgrowth of eyelid flora, so reduction of eyelid flora and inflammation improves patient-reported symptoms.⁵³ Oral administration of doxycycline and minocycline in small doses (40 to 400 mg of doxycycline and 50 to 100 mg of minocycline) to treat MGD improves patient-reported symptoms.^1,53 Unfortunately, gastrointestinal adverse effects limit the use of these medications. One study found that azithromycin 1% eyedrops improved eyelid inflammation and tear film lipid layer stability.⁵⁴

 

EMERGING THERAPIES

New and novel therapies are also in the pipeline for DED treatment. Pharmacy staff should be aware of their potential place in therapy and prepared to incorporate them upon approval.

 

Reproxalap

Exploring another causative mechanism in DED, reproxalap is a reactive aldehyde species (RASP) inhibitor. RASP molecules are found at the top of the inflammatory cascade and are elevated in many inflammatory diseases. They bind to and disrupt the function of enzymes and ion channels, which activates pro-inflammatory mediators. RASP inhibition, therefore, decreases pro-inflammatory substances associated with DED.^55,56

 

A randomized, double-masked, phase 2a trial evaluated the efficacy of three formulations of reproxalap: 0.1% and 0.5% solutions and a 0.5% lipid solution.⁵⁵ Participants used the products four times daily for 28 days. The study found a significant improvement in four questionnaire scores, Schirmer test values, tear osmolarity, and tear staining scores. Within one week, patients reported symptom improvement. Researchers concluded that reproxalap could potentially alleviate DED symptoms.⁵⁵

 

A separate randomized, double-masked, phase 2b trial compared reproxalap 0.01% and 0.25% to a control vehicle solution.⁵⁶ Patients self-administered drops four times daily for a total of 12 weeks. The study found statistically significant improvements in ocular dryness and staining over 12 weeks.⁵⁶

 

A 2021 tolerability study compared ocular adverse effects between two formulations of reproxalap 0.25% (one solution, one lipid-based) and lifitegrast 5% solution.⁵⁷ Over seven days, study participants received one dose of each solution with a 3-day washout period between administrations. Researchers assessed adverse effects after 1 hour. Reproxalap formulations were similar to one another and superior to lifitegrast in ocular discomfort, blurry vision, and dysgeusia.⁵⁷

 

Reproxalap offers a novel approach to treating the underlying inflammatory process involved in DED. Preliminary study results show improvements in DED symptoms and better patient tolerability, potentially leading to lower discontinuation rates and improved patient outcomes.

 

Cationic Cyclosporine

A cationic (positively charged) 0.1% CsA nanoemulsion is available in Europe to treat DED.⁵⁸ Experts theorize that a cationic emulsion increases the surface time of CsA on ocular tissues. All FDA-approved products are anionic (negatively charged). Clinical trials are evaluating CsA 0.1% nanoemulsion for FDA approval.⁵⁸

 

PHARMACY TEAMS: FRONT-LINE SUPPORT

Pharmacists and pharmacy technicians are among the most accessible healthcare providers. People routinely turn to neighborhood pharmacies for advice on many health topics. Most people self-treat dry eye symptoms long before seeking professional help. These facts make the pharmacy team essential in supporting people suffering from DED. The SIDEBAR provides basic counseling information about eye products.

 

SIDEBAR: Counseling Tips for Eyedrop and Eye Ointment Administration^59,60

Proper administration of ophthalmic formulations is key to their success. Administration is awkward, and many patients struggle with it. Advising patients on proper technique is a key role for the pharmacy team. General tips for all ophthalmic products include

• Confirm you have the correct product
• Check expiration date
• Read the directions
• Wash your hands
• If using both eyedrops and eye ointment, wait five to ten minutes between drops, and administer the eyedrops at least 10 minutes before the ointment
• Using a mirror may make it easier to see what you are doing

 

Eyedrops:

1. Gently shake the bottle

1. Be sure the eye dropper is clean, and do not let it touch any surface
2. Tilt your head back and look up

4. Pressing your finger gently on the skin just beneath the lower eyelid, pull your lower eyelid down and away from your eyeball to make a “pocket” for the drops
5. With the other hand, hold the eye drop bottle upside down with the tip just above the pocket
6. Squeeze the prescribed number of eye drops into the pocket
7. If you think you did not get the drop of medicine into your eye properly, use another drop
8. Blink a few times so that the medicine spreads across your eye
9. For at least 1 minute, close your eye and press your finger lightly on your tear duct (small hole in the inner corner of your eye) to keep the eye drop from draining into your nose

1. Wash your hands

11. Wait at least 10 minutes before you use other eye products, especially ointments, gels, or other thick eye drops

 

Eye ointment:

1. Be sure the top of the ointment tube is clean, and don’t let it touch any surface, including the eye, eyelid, or lashes. (If it does, call your pharmacy and arrange to get another tube of eye ointment.)
2. Tilt your head back and look up
3. With one hand, pull the lower eyelid down with one or two fingers to create a small pouch
4. With the other hand, position the medicine above your eye
5. Put a thin line of ointment in the pouch. Close the eye for 30 to 60 seconds to let the ointment absorb
6. Wash your hands
7. Eye ointments can cause some temporary blurring of vision

 

Knowledge of risk factors, including precipitating medications (revisit Table 3 for a refresher), aids in identifying patients at risk for developing DED. Technicians are often the first point of contact at the pharmacy counter, routinely fielding questions. Actively listening and asking open-ended questions help gather necessary information. Patients reporting dry eye symptoms or buying AT products may need counseling or a referral to a pharmacist or an eye care professional.

 

Educating patients about avoiding certain environmental factors is important. Remind patients that minimizing exposure to wind or smoke, taking a break from digital screens, and using a humidifier may help alleviate symptoms. Adherence to therapeutic interventions is key in DED treatment. Some interventions, such as lid hygiene, are time-consuming, and many patients stop after only a few days.  Reinforcing the importance of lid hygiene with patients is an important component of DED patient counseling.

 

 

Advising patients on selecting an appropriate AT product decreases frustration and increases overall patient satisfaction. Proper administration of ophthalmic preparations can be difficult for some patients, particularly older individuals. Taking the time to counsel on proper technique sets patients up for successful administration and improved outcomes.

 

Patients with severe refractory DED may not benefit enough from lifestyle modifications and pharmacologic therapy. Many other interventions exist including¹⁴

• Punctal plugs blocking the tear ducts to promote tear conservation
• Pulsed light therapy delivered in office with a handheld flash gun
• Tear stimulation utilizing topical and systemic secretagogues
• Biological tear substitutes utilizing patient-derived serum
• Use of therapeutic contact lenses made of silicone hydrogel
• Surgery to correct any causative physiological abnormalities

Pharmacy staff should recognize when patients with worsening DED symptoms may require escalation of therapy and refer them to an eye care provider when appropriate.

 

Pause and Ponder: Consider your home and work environment. Could you take steps to minimize conditions contributing to developing dry eye?

 

CONCLUSION

You may have noticed a recurring theme throughout this activity: education. Helping patients understand the chronic nature of DED and navigate treatment options improves patient care and outcomes. Education must include the entire pharmacy team. Understanding the roles of each treatment allows for effective management and counseling. Educated pharmacy teams can assist patients with product selection, counsel on the timing and administration of treatments, improve safety, and provide referrals when appropriate.

 

Download CE Activity

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.

 

 

 

 

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.

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