Clinically, if drug-induced diarrhea is suspected, the simplest approach is to switch to an alternative medication or treat with an antidiarrheal agent. Novel approaches for certain drug-associated diarrheas have been shown to be effective in treatment. In some cases, diarrhea may resolve with continued use.

Thus, for most examples of drug-induced diarrhea, therapeutic trials are not relevant. Only where there are no satisfactory alternatives, as is the case for some anti-cancer therapies, is there sufficient impetus to understand the mechanisms of drug-induced diarrhea. Thus, there probably has been more significant and novel evidence in drug-induced diarrhea obtained in the field of oncology.

Watery diarrhea

Watery diarrheas have been classified as either secretory or osmotic to explain underlying pathophysiology. However, the clinical utility of this classification has not been rigorously tested.

Osmotic diarrhea

Osmotic diarrheas can occur from intentional use of a drug as part of its mechanism of action, or unintentionally. Poorly absorbed solute traps fluid in the lumen, and these unabsorbable solutes account for osmotic activity of stool water [2].

The most common medications associated with osmotic diarrhea are magnesium containing salts and laxatives such as sodium phosphates and long-chain polyethylene glycols, e.g. Miralax (Schering-Plough, Kenilworth, NJ) used for treatment of constipation, and for pre-colonos-copy colon purging [3, 4]. Their cathartic action results from poor absorption in the gastrointestinal tract, leading to osmotically mediated water retention, stimulating peristalsis [4]. The usual dose of magnesium salts produces 300 to 600 ml of stool within six hours [4]. Sodium phosphates cause osmotic diarrhea, but without producing an osmotic gap [5].

Used for constipation and for the treatment of hepatic encephalopathy, lactulose is a synthetic non-absorbable disaccharide that is known to cause diarrhea through this mechanism. Poorly-absorbed fructose, found in fruit juices and carbonated beverages, and non-absorbable sorbitol and mannitol, found in sugar-free candies and gums, may not cause diarrhea until 24 to 48 hours after ingestion. Acarbose and miglitol, used for the treatment of diabetes, prevent the breakdown of carbohydrates to monosaccha-rides by inhibition of intestinal alpha-glucosidase, causing diarrhea. In a multicenter RCT of 286 patients comparing acarbose to placebo, tolbutamide and tolbutamide-plus-acarbose in NIDDM, 27% of patients taking acarbose and 35% taking acarbose + tolbutamide complained of diarrhea in comparison to 6% of patients taking placebo or tolbutamide (p < 0.05) [6]. Diarrhea is minimized by starting therapy at low doses (50 mg three times daily), and tends to decrease with time [7]. In the large-scale, multinational study investigating different doses of acarbose (from 25 mg tid to 200 mg tid) good patient tolerability and compliance was observed, even at the highest dose [8]. The study also confirmed the marked tendency for adverse effects to decline after 4–6 weeks.

Interestingly, in a post-market surveillance study of almost 20,000 patients (both NIDDM and IDDM, only 3.2% of those taking acarbose complained of diarrhea [9]. What can explain this difference between the surveillance study and the RCT? During RCT, there may be more attention directed toward minimal changes in signs and symptoms. Acarbose-associated diarrhea is most common in the early phase of treatment. Finally, surveillance generally separates out those subjects who had already discontinued acarbose because of diarrhea.

The prebiotics fructo-oligosaccharides and inulins, available in nutritional supplements and in functional foods, have been used for treatment of antibiotic-induced diarrhea at dose ranges of 4–10g per day [10]. When given to healthy volunteers, doses higher than 30 g daily of these prebiotics caused significant gastrointestinal discomfort (flatulence, cramping, diarrhea) through fermentation in the colon and production of an osmotic effect in the intestinal lumen [11, 12]. If the dosage is split this usually alleviates the symptoms. Diagnosis can usually be made by checking fecal pH; a pH less than 6 is highly suggestive of carbohydrate malabsorption.

Some formulas for enteral nutrition are hypertonic and may induce osmotic diarrhea by a mechanism similar to dumping syndrome. Changing to an isotonic formula or slowing the infusion rate usually resolves the diarrhea [4].

Once recognized, the treatment of osmotic diarrhea is simple. Removal of the osmotic agent usually resolves this adverse effect. Loperamide or tincture of opium can be added, especially in the case of enteral nutrition. Dose reduction or dose splitting can also help. In some cases, such as acarbose, the diarrhea usually resolves over time with continued use.

Secretory diarrhea

Secretory diarrhea, on the other hand, produces voluminous stools that persist despite fasting. Drug-induced secretory diarrhea results from a medication either increasing the active secretion of ions and thus pulling fluid into the lumen, or from decreasing the absorption of large amounts of water and electrolytes in the gut lumen. In secretory diarrhea, a minimal osmotic gap is found. Specifically, drugs induce a secretory diarrhea by two main mechanisms: the inhibition of Na⁺ absorption and the stimulation of Cl-/HCO3^– secretion. These changes may occur through either a direct effect on the transporter or changes in intracellular second messengers that alter the function of the transporter.

The Na⁺ pump (Na⁺, K⁺-ATPase) is the final common pathway for Na⁺ absorption; inhibition of the Na⁺ pump blocks Na⁺ (and fluid) absorption and this may cause diarrhea. Digoxin’s therapeutic target is the cardiac Na⁺, K⁺-ATPase. However, inhibition of intestinal or colonic Na⁺ pumps may cause diarrhea, most frequently at superthera-peutic drug levels, especially in elderly patients [3]. In fact, digoxin was the second commonest cause of diarrhea in a study of 100 elderly patients [13]. Similarly, auranofin, used previously for rheumatoid arthritis, caused diarrhea in up to 74% of patients, requiring discontinuation in 14% of them [3]. By reducing K⁺ conductance and inhibiting calcium channels, the class I antiarrhythmic drugs quini-dine and propafenone impede transepithelial Na⁺ and water absorption causing diarrhea in 8–30% of patients [14]. Lubiprostone was initially developed as a treatment for constipation, specifically because of its properties as a ClC2 channel opener; however, it is still unclear what specific role the ClC2 channel has in intestinal secretion.

Olsalazine, used in the treatment of ulcerative colitis, causes diarrhea in 12–25% of patients through the stimulation of bicarbonate and sodium chloride secretion in the ileum [1, 15]. Similar azo compounds sulfasalazine and mesalazine may also cause diarrhea, but less frequently. The mechanism is unclear, but may involve a direct effect on anion transporters, rather than an anti-inflammatory action [16].

Some drugs cause a secretory diarrhea by altering intra-cellular signaling cascades, increasing cyclic AMP, cyclic GMP or calcium. The phosphodiesterase inhibitor, theo-phylline, causes diarrhea by increasing cyclic AMP, opening chloride channels and increasing secretion [17]. In our hypercaffeinated society, coffee is used as a “drug” by many, causing “Starbucks® diarrhea” through this similar mechanism. Caffeine administration in amounts ordinarily contained in many beverages and medications (75 to 300 mg) resulted in striking net secretion in the jejunum and in the ileum [18]. Prostaglandin analogs can cause diarrhea through many pathways, including altered permeability, motility, electrolyte transport and by affecting peptides that stimulate secretion [17]. Misoprostol specifically stimulates epithelial Cl- secretion through cyclic AMP, resulting in intraluminal fluid accumulation and diarrhea, which usually occurs within the first two weeks of treatment [3].

A secretory type of diarrhea limited the clinical use of chenodeoxycholic acid, a bile acid initially used to dissolve cholesterol gallstones. Early studies showed that the mechanism of secretory diarrhea in chenodeoxycholic acid therapy was due to a rise in intracellular cyclic AMP levels. However, recent in vitro studies using much lower doses of bile acids suggest a mechanism involving activation of luminal K⁺ channels and Cl- secretion mediated through increased intracellular Ca⁺⁺ levels [19, 20]. Another dihy-droxy bile acid, ursodiol causes diarrhea much less frequently. Presumably this difference is due to the alternative configuration of the hydroxyl groups compared to chenodeoxycholic acid. However, there are some reports of ursodiol causing diarrhea. A meta-analysis of ursodiol and its adverse effects revealed that diarrhea was the single most frequent adverse drug event in patients treated for gallstone disease, with an incidence of 2–9% [21]. If and when ursodiol is associated with diarrhea, there are two possible mechanisms: an increase in the secretion of all bile salts including chenodeoxycholic acid and/or luminal conversion of ursodiol to chenodeoxycholic acid by intestinal bacteria (Alan Hoffman, personal communication). In primary biliary cirrhosis patients, on the other hand , diarrhea was rarely reported, in five large-scale randomized trials. No report of ursodiol-induced diarrhea was found in the largest placebo-controlled randomized study of its use in primary sclerosing cholangitis [21].

These conflicting data highlight some of the challenges of evaluating adverse events of RCTs.

First of all, is this a real difference in that the incidence of diarrhea is truly higher in gallstone disease than in PBC/ PSC. Perhaps bile salt metabolism is different in gallstone disease, where there is an increased conversion of ursodiol to chenodeoxycholic acid which is a potent secretagogue. The gallbladder in patients with gallstones is likely to be hypo-functional and may be altered in its contractility in response to a meal or in its concentrating capacity, thus allowing more bile acid to enter the duodenum per ursodiol dose. In addition, ursodiol may be stimulatory to the inflamed bowel, while neutral or inhibitory to the bowel of patients with gallstones (Roger Soloway, personal communication). Alternatively, the design of RCTs may account for the difference. The definition of diarrhea as an adverse event, the focus on a more serious disease, or an already increased baseline bowel movement frequency in patients with PSC are possible examples of this factor.

Used as an old home remedy, castor oil is hydrolyzed in the small bowel by the action of lipases into glycerol and the active agent, ricinoleic acid, which acts primarily in the colon to stimulate secretion of fluid and electrolytes by increasing cyclic AMP and speeding intestinal transit [22, 23].

Stimulant laxatives such as diphenylmethane derivatives and anthraquinones induce their effect by inducing a limited low-grade inflammation in the small and large bowel to promote accumulation of water and electrolytes and stimulate intestinal motility. This occurs through activation of prostaglandin-cyclic AMP and NO-cyclic GMP pathways, platelet-activating factor production and, perhaps, inhibition of Na⁺,K⁺-ATPase [4]. Anthraquinone laxatives are poorly absorbed in the small bowel, are activated in the colon, and produce giant migrating colonic contractions as well as water and electrolyte secretion. Other laxatives or stool softeners such as docusate (dioctyl sodium sulfosuccinate), can cause diarrhea when taken in large quantities, by stimulating fluid secretion by the small and large intestine [24]. Clinicians should thus be aware that surreptitious use of laxative may be the cause of diarrhea in patients who present with this complaint. Table 15.2 lists a number of commonly used laxatives.

Diarrhea associated with medullary carcinoma of the thyroid suggested that calcitonin may cause a secretory type of diarrhea. Calcitonin in high doses can induce a secretory diarrhea in 1–3% of patients. Studies involving intravenous infusions showed prompt and marked increase in jejunal secretion of water, sodium, chloride and potassium, and reduced absorption of bicarbonate, which was reversed immediately with discontinuation of the infusion [25, 26]. However, in clinical practice, the use of salmon calcitonin for treatment of osteoporosis rarely causes diarrhea (Vassilopoulou-Sellin, R. personal communication) [27]. This paradox highlights the variable and sometimes unpredictable pattern of drug-induced diarrhea.

Table 15.2 Stimulant laxatives.

Colchicine, besides causing secretory diarrhea through the inhibition of Na⁺,K⁺-ATPase activity, is a microtubule inhibitor and may induce diarrhea by interfering with the migration of epithelial cells from the crypt to the villus and/or interfere with intracellular trafficking of specific transport proteins [17].

The biguanide metformin, used in the treatment of type II diabetes, has an effect on the brush border, reducing disaccharidase activity and leading to malabsorptive diarrhea in 10–53% of patients [28, 29].

Animal studies have found that metformin or the older biguanide phenformin inhibits intestinal glucose absorption in a dose-dependent manner through effects on mucosal and serosal glucose transfer mechanisms [30–33]. Based on a systematic review evaluating common adverse events of metformin monotherapy in type II diabetes mel-litus, patients receiving metformin are 3.4 times more likely to develop diarrhea compared to those taking placebo (p = 0.002) [34]. Most cases are transient and mild, but even in severe cases, lowering the dose usually resolves the diarrhea [35]. In clinical trials, only 5% of study participants discontinued metformin because of gastrointestinal side effects [34]. There have also been cases of metformin causing late-onset chronic diarrhea in whom discontinuation of the drug resolved the diarrhea [36]. Larger studies of 405 type II diabetics show that metformin was independently associated with chronic diarrhea with an odds ratio of 3.08 (CI: 1.29–7.36, p < 0.02) [37]. In a diabetic clinic, metformin was found to be the most common cause of diarrhea based on a questionnaire based survey of 285 randomly selected diabetic patients [38]. Diarrhea in a diabetic patient may be related to the disease process itself. However, diabetic diarrhea usually occurs in type I diabetes for which metformin is not a treatment.

Some have speculated that anticholinergic drugs, which most often cause constipation by reducing intestinal motil-ity, as well as the proton pump inhibitor omeprazole, can cause a secretory diarrhea. Although the proposed mechanism for diarrhea is thought to be bacterial overgrowth leading to bacterial deconjugation of primary bile salts to dihydroxy bile acids causing net fluid and electrolyte secretion in the colon, there is no substantial evidence to confirm this explanation [3]. In fact, a Cochrane systemic review showed no statistically significant difference in diarrhea occurrence in patients treated with PPI for reflux disease either at maintenance dose (PPI 1.1%, vs placebo 3.3% , RR 0.34; 95% CI:0.04 to 3.18) or at healing dose for esophagitis (PPI 5.2% vs placebo 2%, p = 0.11) [39]. A recent article suggesting a link between PPI use and small bowel bacterial overgrowth contributing to diarrhea predominant IBS shows that there is a common assumption among gastro-enterologists that PPI can cause diarrhea, that is not necessarily supported by evidence [40].

Diarrhea is a common adverse effect with molecularly targeted agents. Epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, and other tyrosine kinase inhibitors such as sorafenib, imatinib and bortezomib cause diarrhea in up to 60% of patients [41]. Erbitux® (cetuxi-mab), used for the treatment of EGFR-expressing, meta-static colorectal carcinoma and squamous cell carcinoma of the head and neck and Iressa® (geftinib), used for non-small cell lung cancer, can cause diarrhea in 48–67% of patients, depending on dose [42, 43]. EGF can activate PI 3-kinase and the lipid products of this enzyme inhibit calcium-dependent Cl-transport in T84 human colonic epithelial cells [44, 45]. EGF-receptor inhibitors may cause diarrhea by blocking this inhibitory loop and causing secretion. Diarrhea can easily be managed by loperamide, dose reduction or treatment interruptions [41].

Flavopiridol, a cyclin-dependent kinase inhibitor, has undergone several clinical trials as an anti-tumor agent, with secretory diarrhea as a dose-limiting factor. Adding cholestyramine and loperamide as a prophylactic antidi-arrheal treatment allowed for use of higher doses [46]. Diarrhea may be related to flavopiridol binding to the gut mucosa acting as a modest secretagogoue. Cholestyramine, by binding flavopiridol, eases the adverse effect [47]. Pharmacogenomics may play a role in drug-induced diarrhea. For example, those with extensive hepatic glu-corinidation metabolism experienced less diarrhea than others [48]. The hepatic metabolism of the drug decreases the toxic metabolites that causes intestinal secretion. In this clinical study, mild cases of diarrhea were controlled by loperamide, whereas more severe diarrhea was controlled by octreotide infusion and reduction of flavopiridol dosages in subsequent cycles [48].

Disordered or deregulation motility

Although not as elegantly delineated as epithelial transport changes, disordered or deregulated motility can also cause diarrhea. Prokinetic agents reduce intestinal contact time between luminal fluid and the epithelium. The decreased amount of time chyme is exposed to intestinal epithelium can limit absorption, and ultimately lead to diarrhea [2]. Cisapride and tegaserod are 5-HT₄-receptor agonists that stimulate motility and accelerate gastrointestinal transit. However, both of these drugs have been removed from the market due to potential cardiotoxicity.

Cholinergic drugs such as bethanecol, used for urinary retention and neurogenic bladder, have broad muscarinic effects via cholinergic receptors in the smooth muscle of the urinary bladder and the gastrointestinal tract [4, 49]. The effect of acetylcholine on smooth muscle of the gastrointestinal tract is mediated by two types of G protein-coupled muscarinic receptors, M₂ and M₃ in [4]. The activation of the M₃ receptor increases intracellular Ca²⁺ mediated by the G_q-PLC-IP₃ pathway [4, 28]. This results in increased gastrointestinal and pancreatic secretions, as well as increased peristalsis.

Acetylcholinesterase inhibitors, such as those used for Alzheimer’s disease, allow acetylcholine to accumulate in the synaptic and neuromuscular junctions. These drugs enhance contractile effects producing diarrhea in up to 14% of patients [1, 3]. RCTs comparing donepezil to placebo for the treatment of Alzheimer’s disease revealed diarrhea incidence of 15% with donepazil compared to 10% in placebo [50]. The Cochrane Review of the use of donepazil with over 1000 patients revealed that diarrhea occurred more frequently in donepazil treated patients (OR 2.78; 95% CI: 2.10, 3.69) [51]. In another Cochrane Review of the three anticholinesterases (donepezil, galantamine and rivastigmine) used for Alzheimer’s dementia, the odds ratio for diarrhea with the use of anticholinesterases in comparison to placebo was 1.91 (95% CI: 1.59, 2.3) [52].

Neostigmine, used off-label for acute colonic pseudo-obstruction (Ogilvie’s syndrome) and paralytic ileus, also can cause diarrhea [4]. Irinotecan, a chemothera-peutic agent, can cause severe diarrhea from cholinergic-like syndrome through the inhibition of acetylcholinesterase [3]. ‘

Motilin, a peptide hormone found in the gastrointestinal M cells, and in some enterochromaffin cells of the upper small bowel, is a potent contractile agent of the upper GI tract. The effects of motilin can be mimicked by macrolide antibiotics, especially erythromycin, and can cause diarrhea. In addition to its motilin agonistic effect, erythromycin at lower doses (40–80 mg) may also entail cholin-ergic involvement, although the mechanisms are not well understood [4].

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