**6.1 Drugs associated with diarrhea due to macroscopic enteral mucosal damage**

Non-steroidal anti-inflammatory drugs (NSAID) are prescribed for a variety of pain and inflammation-associated conditions such as rheumatologic and orthopedic disorders, migraine as well as post-surgical states, and exert their effects through cyclooxygenase (COX) inhibition with resultant decrease of prostaglandin synthesis. NSAID are associated both with upper and lower GI symptoms, as well as mucosal injury at any part of the GI tract, and symptoms vary widely from dyspepsia and heartburn to diarrhea, bloating and overt GI bleeding [7, 8, 11, 52–55]. Despite gastroduodenal damage is the most common clinical presentation in most NSAID long-term users, up to 70% may develop different degrees of mucosal breaks, including erosions, ulcerations, mucosal hemorrhage or even stenosis in distal portions of the small intestine such as jejunum or ileum, as determined by studies using video capsule endoscopy [56, 57]. Pathophysiology of NSAID-induced enteropathy is a complex one, and includes different mechanisms such as COX inhibition and topical effect, interactions with bacteria and bile acids, as well as overexpression of proinflammatory cytokines. Inhibition of COX-1 is associated with decreased mucosal blood flow, mucus production, and intestinal motility, which are predominant, but not critical factors for damage. Topical effect, a COX-independent action requiring mucosal contact of the drug from the luminal side, is considered the triggering event in most cases [53, 54]. Once NSAID is absorbed into the cell, induces mitochondrial injury by producing vacuolation and swelling, and alters oxidative phosphorylation and electron transport, considered one of the earliest intracellular changes after NSAID administration. As a result, intestinal permeability is increased, allowing luminal factors to disrupt the intestinal barrier function [54]. A second mechanism is associated with interactions between microbiota, bile acids and further activation of innate immunity after being exposed to NSAID. Animal models have shown that germ-free rats treated with NSAID do not develop intestinal ulcers unless bacteria are introduced. NSAID induce an increase in Gram-negative bacterial abundance, *Clostridium* spp. and *Enterobacterococci*. It is well known that Gram-negative bacterial lipopolysaccharides either activate or inhibit toll-like receptors (TLR), leading to inflammatory cascade activation. It has been suggested that antibiotics against Gram-negative bacteria may be effective in reducing NSAID-induced enteral damage [58]. Some bile acids have shown to induce a pro-inflammatory state associated with interleukin-8 (IL-8) and nuclear factor-kβ activation (NF-κβ) activation [54]. Degree of enteral damage varies according to NSAID type and their effect over COX isoforms: non-selective NSAID such as diclofenac, naproxen, meloxicam, or indomethacin inhibits both COX-1 (a constitutive enzyme involved in mucosal integrity), and COX-2 (an isoform primarily inducible related to inflammation), and therefore exert effects through several mechanisms, including topical and systemic effect, as well as dysbiosis. Naproxen have been associated with increased enteral permeability, while indomethacin induces overexpression of the pro-inflammatory tumor necrosis factor-α (TNF-α). NSAID enterohepatic circulation also plays a role in enteral damage, as many are carboxylic acids conjugated in the liver and excreted

to bile, cleaved by beta-glucoronidases in the small bowel lumen, and lately reabsorbed. Acetylsalicylic acid (e.g., aspirin), even at low doses, may induce small bowel mucosal breaks after 2 weeks of therapy, mainly due to direct contact damage. On the other part, selective COX-2 inhibitors (ICOX-2) such as celecoxib and etoricoxib have their effect only over the inflammatory isoform, sparing COX-2 and thus, reducing significantly the risk of mucosal damage, unless they are given for prolonged periods of time, after which may have similar risk to that seen with conventional NSAID [7, 11, 53, 54, 58, 59]. Several approaches may diminish the risk of NSAID-induced enteropathy, including withdrawal of drugs, use of selective ICOX-2, or NSAID at the lower therapeutic dose and for short periods of time, or combination with probiotics such as Lactobacillus casei, VSL#3, and S. boulardii, as well as misoprostol, a prostaglandin analog. PPI are not indicated for either prophylaxis nor therapy, and may indeed increase the risk of intestinal injury, apparently associated with changes in microbiota composition [60]. Novel intestinal-sparing NSAID known as co-drugs, consist of two portions: the "NSAID portion" and a gaseous mediator portion (based on nitric oxide or hydrogen sulfide) that exerts mucosal protective effect while sparing therapeutic effect [53]. Further studies are needed to prove their long-term safety in the GI tract.

In addition to NSAID, several drugs may induce small intestine mucosal disease secondary to vasoconstriction and ischemia, including potassium supplements, oral contraceptive pills, and a number of cytotoxic drugs such as methotrexate and chemotherapeutic agents that are associated with different degrees of mucositis [11], and are discussed below.

Among patients receiving oncologic therapy, those treated with cytotoxic drugs, radiotherapy, targeted therapy, and immunotherapy, particularly with the so-called check-point inhibitors have increased risk of developing various degrees of enteropathy and diarrhea. Between 40 and 100% of cancer patients treated with chemotherapeutic agents develop gut toxicity at some point during their treatment, a term called "chemotherapy-induced intestinal mucositis" (CIM). Prevalence and severity depend on drug and dosing regimen, intensity, route of delivery, and patient predisposing conditions. CIM pathophysiology involves mainly mechanisms related to cell growth inhibition, immunological reactions, and dysbiosis [61]. Cytotoxic agents such as methotrexate, doxorubicin, 5-fluorouracil, capecitabin and irinotecan target enteral tissue by interrupting DNA synthesis by direct injury or by generation of reactive oxygen species, leading to release of active signaling factors (i.e., caspases, β-catenin, and NF-κβ), and eventually to mucosal damage and apoptosis, most of which wipe out the intestinal crypt stem cell pool [61, 62]. A five-stage model for CIM has been proposed, that includes: 1) initiation, 2) signal activation and primary damage response, 3) pathway amplification, 4) tissue inflammation (e.g., erosions, ulcerations, apoptosis), and 5) healing. Clinical picture varies widely, and ranges from short periods of diarrhea and abdominal pain, to severe degrees of enterocolitis. When bone marrow-targeted chemotherapeutic agents are also given, increased risk of neutropenic enterocolitis, abdominal sepsis, and even death may occur. Treatment options, beside adjusting dose or even withdrawal of the drug may include antibiotics and probiotics in order to restore normal gut microbiota and reduce pathogenic intestinal bacteria, octreotide to decrease peptide-associated intestinal secretions, antioxidants such as amifostine, a drug that detoxifies reactive metabolites and scavenges free radicals, steroid anti-inflammatory agents to reduce inflammatory response, and possibly incretins and anti-apoptotic agents, most of which are under investigation [11, 61, 62].

### *Drug-Related Enteropathy DOI: http://dx.doi.org/10.5772/intechopen.103734*

Radiation therapy plays an important role as sole curative therapy for 25% of all cancers, and as adjuvant with chemotherapy in many other cases. During radiotherapy of abdominal and/or pelvic tumors, either the small intestine, colon or both are included in the treatment field and may be prone to toxicity. Risk factors for gut damage include those related to therapy itself such as radiation dose, time-dose-fractionation parameters, volume, and concomitant chemotherapy, and patient-related factors such as advanced age, previous abdominal surgeries, as well as vascular and metabolic comorbidities. Radiation enteropathy is classified as early or delayed when occurs prior or after 3 months after treatment. Early symptoms are nausea and abdominal pain, while diarrhea occurs usually after 2 or 3 weeks of treatment onset, and may persist for longer periods of time. Mechanisms of damage are multifactorial and include increased production of reactive oxygen species, mitotic cell death, mucosal atrophy, endothelitis, microvascular sclerosis, as well as fibrosis of the entire bowel wall. As radiation affects predominantly rapidly proliferating intestinal cells, villus epithelium turnover is insufficient to keep normal absorptive mechanisms. Long-term side-effects may include nutrient malabsorption, anemia, stenosis, and in most severe cases, intestinal obstruction. Management is largely symptomatic, with anti-diarrheal agents. As one of the early mechanisms of damage is production of reactive oxygen species, free radical scavengers such as amifostine can be used for reduction of radiotherapy side effects, but it has a narrow therapeutic time window and potential life-threathening side effects. Several candidate mitigator drugs are under investigation [63].

The immune system has an important role in recognizing and eliminating some tumors. Activation of T cells require a signal between T-cell receptors and the major histocompatibility complex along with a stimulatory checkpoint expressed on T cells called CD-28, and the antigen-presenting cells [64]. Tumors may use immunecheckpoint pathways as a mechanism of immune resistance. Two well-known immune-checkpoint receptors are CTLA-4 (CD152), a negative regulator of T-cellmediated anti-tumor response, and the programmed cell death protein 1 (PD-1 or CD279), expressed on the surface of activated T cells that interacts with programmed death ligand (PD-L1 and L2), leading to T-cell inactivation [64, 65]. The immune check-point inhibitors (ICI) are monoclonal antibodies that block these pathways, including inhibitors of PD-1, PD-L1, and CTLA-4. Immunomodulating therapy, or immunotherapy act to enhance anti-tumor immune responses by blocking negative regulators of immunity, and has revolutionized cancer therapy by improving survival outcomes and is now the standard treatment of different types of cancer, including several metastatic tumors. Currently approved ICI are the anti-PD-1 pembrolizumab and nivolumab, used for treating melanoma and metastatic non-small-cell lung cancer, the anti-CTLA-4 ipilimumab, a fully humanized monoclonal antibody approved for metastatic melanoma, as well as the anti-PDL-L1 atezolizumab and durvalumab, also for non-small cell lung cancer. Ipilimumab, for instance, competitively binds to CTLA-4, blocking tolerance to self-antigens, without blocking CD28 (a stimulatory checkpoint), increasing T-cell proliferation and activation leading to autoimmune damage to a number of organs, including the entire GI tract. In a similar way, anti-PD1/PDL-1 agents such as nivolumab and pembrolizumab increase T-cell response while reducing self-tolerance, and the result is similar to that seen with ipiliumumab [64–67]. This kind of damage behaves similarly to that seen on inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis, as well as their clinical presentation, with various degrees of enteral and/or colonic damage ranging from erosions and ulcerations to obstruction, and wall necrosis, and presenting as chronic

diarrhea, abdominal pain, GI bleeding and progressive anemia [68]. Histologic findings range from combined acute (e.g., neutrophils) and chronic (i.e., lymphocytes and plasma cells) inflammatory infiltrates, eosinophilia, atrophy, granulomatous reaction, crypt abscesses, and bullous pemphigoid, and in most severe cases an increased apoptotic activity within the crypt epithelium may be seen, affecting small intestine, colon or both [69, 70]. Treatment is similar to that given for IBD and may include mesalazine, systemic corticosteroids, and in refractory cases, biologic therapy with infliximab [71, 72].

Another category of oncologic treatment is the called targeted therapy, which acts by identifying and attacking certain types of cancer cells, and by inhibiting oncogenes driving aberrant growth, and may include monoclonal antibodies and small molecule inhibitors. A number of targeted therapies are approved for different types of cancer. Many of them may be associated with different degrees of oral and GI mucositis, particularly cetuximab, erlotinib, gefitinib, lapatinib, sorafenib, and sunitinib, with odds ratio for diarrhea and enteritis ranging from 1.5 to 4.5 [73]. More recently, the HER-2-targeted monoclonal antibody trastuzumab, used for HER-2 overexpressing breast cancer, has been associated with a number of GI manifestations associated to toxicity, including diarrhea, abdominal pain, and ulcerative enterocolitis similar to that seen with ICI. Mechanism underlying GI toxicity remains under investigation, but it seems to be associated with HER-2 receptors in gut epithelial cells [74]. Treatment is empiric, following the same principles as for ICI.
