A Pharmacy of Suspects: Drug-Induced Diarrhea's Likeliest Causes

David A. Johnson, MD

Disclosures

May 15, 2017

Common Side Effect in a Highly Medicated Population

Hello. I am Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. Welcome back to another GI Common Concerns—Computer Consult.

Today, I wanted to highlight some of the prevalent problems we see in the spectrum of drug-induced chronic diarrhea. This topic has been covered in a good review[1] recently, which provides us with the chance to revisit some areas that you, as clinicians, need to know.

Patients in the United States currently take 4 billion prescriptions every year.[2] When we think about the common side effects, gastrointestinal (GI) symptoms like heartburn and nausea are often listed. Diarrhea in particular is listed in over 700 individual and combination medicines, making it an incredibly prevalent issue. It may not be uniformly related just to one drug. It may be due to a combination drug, with possibly overlapping mechanisms. In an attempt to identify this, I want you to start to rethink the role of medications when you look at a patient with diarrhea.

Let's first reflect back on the physiology of how you get diarrhea. The small bowel's main function is the resorption of water. In the small intestine's typical day-to-day activity, somewhere in the neighborhood of 7.5-9 L of both ingested and secreted fluid are reabsorbed, whereas in the large intestine it is closer to 1.2-1.3 L. During the desiccation process down to the level of the rectum, approximately 200 mL are left when ultimately the bowel movement is passed. This is a progressive sponge effect, if you will, but the colon's sponge effect is nominal relative to the small bowel.

Classifying Diarrhea

There are a number of ways to define diarrhea. One is to look at three or more unformed stools a day, in addition to some other enteric symptoms such as cramping, or perhaps the passage of 250 g of unformed stools. Regardless, diarrhea should be broken down as to whether it is acute (lasting less than 2 weeks), chronic (greater than a month), or persistent (problematic and somewhere in between).

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Diarrhea should be classified by its mechanisms, based on whether it is osmotic, secretory, inflammatory, or some type of motility or malabsorptive-type disorder. Doing this starts to account for at least part of the clinical history. A secretory diarrhea typically goes on and on and on. One of the first questions I ask is: What happens when you fast or if you have some fasting? Is it something that diminishes the diarrhea, as opposed to an osmotic diarrhea that is typified by more food and more ingestion leading to increased stool volume?

One of my early tasks for a noninfectious type of diarrhea is to look at stool electrolyte patterns (ordering stool sodium and potassium). The summation of that times two, subtracted by an estimated osmolality of stool of 290, gives you a discriminant of secretory vs osmotic. Osmotic diarrhea would typically be over 100, and a secretory diarrhea would be typically less than 50. There are other electrolytes you can order on the stool pattern, but they are virtually never needed except under the most specific circumstances. In pediatrics, chloride can be measured for congenital chlorhydria, a very rare disease in that patient group. You may also start to look at magnesium or phosphate if you are looking for surreptitious diarrhea, but the general rule is just look at sodium and potassium.

In general, we do not measure stool osmolality. The reason is that unless it is processed immediately, there is a fermentation process. The stool osmolality changes very quickly as soon as it is excreted.

One of the rare times when you may want to order a stool osmolality is if you are thinking about surreptitious water addition (ie, patients adding water). In these patients, the stool osmolality will be extremely low. It would be very unusual to have a stool osmolality that was in the area of 0-20, or even a negative osmolality. This certainly tells you about surreptitious water, as you just cannot reach those levels by even the worst case of secretory diarrhea, such as Vibrio cholerae-type infections. The other time you would order a stool osmolality is in patients who may have addition of urine, be it surreptitious or not. Here, the measured stool osmolality would be quite high, greater than 600 mOsm/kg.

Again, it is very rare that you would ever order a stool osmolality. If you do, you want to process it right away.

Drug-Induced Diarrhea by Category

Let us talk about what causes drug-induced diarrhea, by category.

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Secretory diarrhea can occur when drugs bind the specific receptors. In the normal colon, you resorb sodium and excrete potassium, but drugs like digoxin inhibit the sodium-potassium ATPase activity. Digoxin prevents the sodium reabsorption that leads ultimately to a net water loss, as in secretory diarrhea. That is why we see diarrhea in patients on digoxin. Similarly, drugs such as misoprostol are sometimes used therapeutically in our postoperative ileus patients to develop bowel activity. Misoprostol certainly can lead to a secretory diarrhea because it causes a stimulation of epithelial chloride secretion, intraluminal fluid increase, and then diarrhea. These drugs are very commonly listed as causes of secretory-type diarrhea.

Osmotic diarrhea occurs more often with drugs like lactulose. In particular, you want to ask about enteral feeding because a patient who has a relatively hypoalbumic situation—as we commonly see in intensive care unit (ICU) settings—may not be able to achieve oncotic balance. Instead, they can experience body and gut edema—visceral gut anasarca—and the loss of surface areas. They may have decreased ability for the osmotic-type enzyme pathways that allow absorption. The osmotic nature of the enteral feed is key, and you may want to aim for more of a balanced osmotic load. In a severe malnourished patient, think about options like a dipeptide or tripeptide, which are predigested proteins that allow passive absorption rather than having active transport.

Motility is the other area to consider regarding the pathogenesis of drug-induced diarrhea. Certain drugs accelerate the migrating motor complex, the classic example being erythromycin, though cisapride used to do this, and prucalopride has some stimulant effect on the bowel as well. You may also see a deceleration and a predisposition to small intestinal bacteria overgrowth, or potentially even a fecal impaction and an overflow diarrhea, with drugs that have a potentially profound anticholinergic effect. Some of the neurologic drugs or the tricyclics may be predisposing to diarrhea.

Inflammatory diarrhea involves the flow of luminal contents into the intestine due to inflammation and a loss of the tight junction sanctity. There may also be secretion and a weeping effect. Drug-induced diarrhea from inflammation can occur with a lot of drugs, such as chemotherapy drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), and vascular-compromised drugs like ergotamine or cocaine, where users have a visceral relative hypoperfusion, and an inflammatory process can initiate as well.

Steatorrhea can be precipitated by drugs, in particular those that may predispose to fatty diarrhea, like colchicine or cholestyramine. The antiobesity drug orlistat is used for the purpose of blocking fatty absorption. It is something that by nature is trying to precipitate a block of absorption, but it may also be a culprit here as the diarrhea gets out of control.

The Usual Suspects

The surreptitious use of laxatives also cannot be forgotten as a cause. The majority of laxatives are used in women, which is not a gender disparity but rather just a reality of the reporting. Approximately 90% of the factitious diarrheas occur in women. Healthcare professionals are aware of how these drugs work, as patients can present with 10-20 bowel movements a day. It is important to have a high level of suspicion when looking at these patients. Measuring for the fecal electrolytes and magnesium with magnesium-containing antacids or laxatives may give you at least a first insight into this. Drug screens for things like bisacodyl and PEG-containing products are another option. In women, factitious diarrhea needs to be considered.

NSAIDs can cause a nonspecific colitis, which we see not infrequently. We do a colonoscopy; it may be indistinguishable from inflammatory bowel disease. There may be a higher predisposition in the microscopic colitis population as well. Again, we need to query patients about their NSAID use, known or unknown.

Cardiovascular medications are common within our patient population. Certainly one of the most interesting areas that you need to be aware of is with the antihypertensive olmesartan. This drug is associated with a sprue-like type of enteropathy consistent with the pathologic findings of sprue. This needs to be remembered when you see these patients because olmesartan does have a high likelihood of association with a sprue-like enteropathy.

Antidiabetic drugs are frequently used. The drug metformin exerts an action on the 5-HT3 (serotonin) receptors. I frequently see patients with diarrhea who are on metformin, and it is really just a matter of adjusting their diabetic medications. There are some other 5-HT3 agonists, in particular the chemotherapy drugs cisplatin and dacarbazine, which actually facilitate the release of serotonin from the enterochromaffin cells. These are drugs that may also have a higher likelihood for this type of diarrhea.

Speaking of antineoplastic plastic agents, in gastroenterology we often deal with colon cancer and see drug-related diarrhea, in particular with 5-fluorouracil and irinotecan. These drugs have a proclivity for causing diarrhea. One that I want to really draw your attention to is ipilimumab, the humanized monoclonal immunoglobulin G antibody used in metastatic melanoma. This drug almost always causes diarrhea, which can take very severe forms and actually has led to colon perforations in patients. There are two types of patterns to this. Patients can have a diffused colitis or a segmental colitis. Diffused colitis is particularly associated with watery diarrhea and is managed by steroids. Segmental colitis may also be managed with steroids and is typified by patterns that you need to recognize because they can look like inflammatory bowel disease. Patients from this population who have not responded to corticosteroids after 2 weeks have been successfully treated with infliximab therapy.

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Irinotecan, which we unfortunately have to use in the later stages of colon cancer management, is another chemotherapeutic drug that needs to be considered. As with other chemotherapeutics, it can be quite insidious and unpredictable; it can be acute, or it can be really dose dependent over time. Maintain a high suspicion for drug-induced diarrhea in the antineoplastic-using patient.

The same is true with the immunosuppressive agents used in our transplant population, in particular with the commonly used drug mycophenolate, which is associated with diarrhea. The mechanism is not quite clear. You need to be suspicious of superimposed infection, particularly the cytomegalovirus (CMV)-type viral infections in these patients. These drugs may be associated with a colitis-type presentation, histologic abnormalities, and crypt destruction and may mimic inflammatory bowel disease. Drug withdrawal or dose reduction certainly in the exclusion of CMV needs to be considered.

Many of our patients are also taking psychotropic medications, which are associated with a plethora of GI disorders, not the least of which is diarrhea. The classic here is lithium, where we see a high association with diarrhea and polyuria/polydipsia, probably related to the volume effect loss with the diarrhea.

Although it is not so much a drug, you need to consider the possible role of artificial sweeteners, which in our era seem to be in so many things patients potentially consume, whether they know it or not. Fructose, sorbitol, or mannitol will cause an osmotic diarrhea, as we see in patients taking candy mints or fruits or types of supplements. These may actually cause a significant osmotic diarrhea. I always look at the additives, in particular in the ICU where sorbitol is frequently added. Potassium elixir is a classic example of a way to liquefy the administration of some of these oral agents.

Final Thoughts

When you start to think about diarrhea, do not forget drug-induced diarrhea, which is such a common problem.

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Think about the patterns of diarrhea in response to fasting. Think about who the patients are, in particular for surreptitious diarrhea. Think about the ways that you can approach these patients, perhaps by whether it is bloody vs nonbloody, osmotic vs secretory, and by looking at cases that may be a malabsorptive type of diarrhea. Take a look at everything your patients are taking, including supplements and additive foods. Do not forget to always look at whether the single or additive medications may actually be causing diarrhea. Most of this can be resolved by withdrawal of the medication; but, in some circumstances, we may actually have to treat these patients with steroids or some of the biologic agents like ipilimumab. Nonetheless, these are drugs that can actually precipitate a severe disease.

When you see your next patient with diarrhea, reflect back on what they are taking, take a good history, look at their medication list repeatedly, and ask lots of questions about food additives, supplemental candies, etc.

Hopefully, this will steer you well in your next interaction with the patient with diarrhea. Be it acute, chronic, or persistent, it certainly is a clinical problem that we see every day.

I am Dr David Johnson. Thanks for listening.

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