**8. Drugs reactions affecting gastrointestinal tract**

ADR that cause damage in gastrointestinal tract usually produce GI bleeding/peptic ulcerations, diarrhea (mainly associated to antibiotics), pancreatitis and liver toxicity. About 40% of ADR affect gastrointestinal and liver in hospitalized patients. As said before, gastrointestinal bleeding is the most frequent ADRs causing hospitalization or produced during hospitalization. In this issue, we try to review the ADRs affecting gastrointestinal tract.

#### **8.1 GI bleeding**

514 New Advances in the Basic and Clinical Gastroenterology

Drug classes most frequently associated with ADRs in both inpatients and outpatient populations are non steroidal anti-inflamatory drugs (NSAIDs), diuretic, anticoagulants,

In adults and elderly people, there a great variety of drugs causing adverse drug reactions. However, it depends the type of hospitalization, the deparment, etc, the type of adverse reactions and drugs implicated are quite different. Pimohamed et al. (2004) found that aspirin was the casual agent in 18% of cases of all admission for ADRs, while other NSAIDs and diuretics were implicates in 12% and 27% respectively. The most common ADRs of NSAIDs were GI bleeding, peptic ulcerations, haemorrhagic cerebrovascular accident, renal impairment, wheezing and rash. Grenouillet-Delacre et al. (2007) found that psychotropic drugs, immunosuppressive drugs, anticoagulants and antibiotics were more than 50% of life-threatening adverse drug reactions at admission to medical intensive care. In Spain, antibiotic and anticoagulants are the drugs more frequently implicated in ADRs appeared during hospitalization but in another epidemiologic study (Carrasco Garrido, 2010) found that main drugs implicated in admission into the hospital were antineoplastics and immunosuppressive therapy. However there are very few studies that show antineoplastics and immunosuppressive therapies as the cause of adverse drug reactions although they are being increasingly used and promote the appearance of infections, medullar aplasia, etc. Also cardiovascular drugs, mainly diuretics and hypotensors drugs account for some

ADR that cause damage in gastrointestinal tract usually produce GI bleeding/peptic ulcerations, diarrhea (mainly associated to antibiotics), pancreatitis and liver toxicity. About 40% of ADR affect gastrointestinal and liver in hospitalized patients. As said before, gastrointestinal bleeding is the most frequent ADRs causing hospitalization or produced

Antibiotic and vaccination reactions are more frequent in the 0 –to-9 year age group.

Variable OR (95% CI) Points 4 Comorbid conditions 1.31 (1.04-1.64) 1 Heart failure 1.79 (1.39-2.30) 1 Liver disease 1.36 (10.6-1.74) 1

 5 1 [Reference] 0 5-7 1.90 (1.35-2.68) 1 8 4.07 (2.93-5.65) 4 Previous ADR 2.41 (1.79-3.23) 2 Renal failure 1.21 (0.96-1.51= 1

Abbreviations: ADR, adverse drug reactions; CI, confidence interval; OR, odd ratio.

Table 1. Variables included in the Score (adapted from Onder *et al*)

**8. Drugs reactions affecting gastrointestinal tract** 

**7. Main drugs implicated in reactions** 

antiobiotics and antineoplastic agents.

No. of drugs

common ADRs.

Mainly non steroidal anti-inflammatory drugs and antiplatelet/anticoagulants are implicated in gastrointestinal bleeding. The most frequent lesion is gastric erosions (about 40.2%), combination of gastric ulcer and gastric erosions (16.1%), gastric ulcer (15.0%), duodenal ulcer (13.8%), normal (13.8%) and duodenal erosions (1.1%). In a recent study 26% of patients admitted because of gastrointestinal bleeding had antiplatelet or anticoagulants as the cause of bleeding. The distribution of lesions was quite similar to the study from Devy, being gastric ulcer the most common lesion involved in the bleeding. Inhibition of cyclooxygenase, leading to inhibition of gastric prostaglandin synthesis, and impaired GI defense mechanisms represent additional mechanisms of drug-induced GI bleeding. In the particular setting of Intensive Care Units (ICUs) the most frequent lesion found in patients is the stress-related mucosal bleeding, in which another causes apart from drugs are implicated. In the study from Wikman-Jorgensen (2011) mortality of upper gastrointestinal bleeding was 3,5%, all in patients with great comorbidity which limited treatment of bleeding.

Drugs most frequently causing bleeding were aspirin in 36%, acenocumarol in 27%, clopidogrel in 18%. Combination of aspirin and clopidogrel are responsible of 6% of upper gastrointestinal bleeding. Aspirin is the drug more frequently implicated but it may chance in the future because of the increasing use of doble antiplatelet treatments and new anticoagulants (Rivaroxaban, Apixaban and Dabigatran). It is possible than in the near future we begin to see hemorrhages with dabigatran because of the recent approval in USA for the use of treatment in atrial fibrillation, including patients with low risk of thromboembolism. The risk of bleeding is bigger with Rivaroxaban as shown in the prophylaxis studies, but the approval for AF is pending.

Also lower gastrointestinal bleeding is increasing because of use of AINES mainly. New techniques for diagnosing lesions in small and large intestine are proving this increase in lower gastrointestinal bleeding. AINES can cause diverticulum perforation, mucosal inflammation, ulceration, causing bleeding in the intestine. Use of aspirin, clopidogrel or anticoagulants and the lower intestinal bleeding is an issue that has to be studied because of its frequency, use and potential harmful in small and large intestine. There´s little information about its presentation and management.

#### **8.2 Diarrhea**

Diarrhoea may be defined by frequency or grams of loose grames per day: 3–5 times per day and/or loose stools 200– 300 grams/day (250 mL/day).

It´s estimated that diarrhoea accounts for the 7% of ADRs. There are lot of drugs producing diarrhea as a secondary effect: metformin, some chemotherapies, antibiotics, mainly clavulanic, clindamicin, immunosuppressant… Most of them cause diarrhea only while taking, or only at the beginning of prescription, but some are associated with chronic diarrhoea as metformin. However, the possibility of a drug causing a severe diarrhea is less common except in the case of antibiotics, hipomotility drugs, steroids, proton pump inhibitors because of the possibility of Clostridium difficile diarrhea.

Adverse Reactions and Gastrointestinal Tract 517

interesant review from Balani (2008) showed a table with drugs commonly implicated in pancreatitis: ACE inhibitors, ARA-2, loop diuretics and thiazides, statins, bezafibrate, some antibiotics, pentamidine, azathioprine, mercaptopurine, aminosalicylates, anticonvulsivants

and antipsychotics, estrogens, carbimazole, some antineoplastics, codeine, sulindac.

sulfamethoxazole/trimethoprim, sulindac, tetracycline, valproic acid.

**8.4.2 Drugs with a potential or questionable association** 

**8.4.1 Drugs with a likely association** 

**8.5 Drug-Induced Liver Injury (DILI)** 

DILI from drugs that are unlikely to do so.

In critically ill patients there's also a review of drugs implicated in pancreatitis (Lat, 2010):

**Drugs with a likely association**: Asparaginase, azathioprine, cimetidine, corticosteriopids, corticotrophin, cytarabin, dapsone, didanosine, enalapril, estrogens, furosemide, isonizid, mercaptopurine, mesalamine, methyldope, metronidazole, omeprazol, opiates, pentamidine, pravastatin, salycilates, simvastatin, sulfasalizine,

**Drugs with a potential or questionable association**: acetaminophen, amiodarone, ampicilin, benzapril, carbamazepine, captopril, ceftriaxone, clarithromycin, cyclosporine, diphenoxylate, cisplatinerythromycin, fluvastatin, gemfibrozil, interferon, ribavirin, ketoprofen, lisinopril, ketoprofen, lisinopril, lovastatin, metformin, naproxen, thiazides, octerotide, penicillin, procainamide, propofol, propoxyphene, ramipril, ranitidine, rifampin.

Hepatotoxicity and drug-induced liver injury (DILI) are terms used interchangeably. DILI can be defined as a liver injury induced by a drug or herbal medicines leading to liver test abnormalities or liver dysfunction with reasonable exclusion of other competing etiologies. Most cases of DILI are due to idiosyncratic or unexpected reactions. In contrast to paracetamol-induced hepatotoxicity, which occurs with dose-dependent overdose of the drug. Idiosyncratic drug reactions have been traditionally considered dose independent. However, drugs with well-documented idiosyncratic DILI have been shown to have a dosedependent component. Idiosyncratic DILI, excluding injury caused by acetaminophen overdose, accounts for 7–15% of the cases of acute liver failure in Europe and the United States and is the most frequent reason for the withdrawal of an approved drug from the market. Estimates of the rate of incidence of DILI leading to hospital referral vary from 2.4 per 100,000 person-years (in a retrospective population-based study of 1.64 million UK subjects) to 13.9 per 100,000 inhabitants (in a prospective analysis in France). Complementary or alternative medicines are used by at least 20% of individuals in Western, Eastern, and African cultures, and reports of DILI have increased. Given its rarity, DILI may not be identified during clinical trials and may come to light only after the culprit drug has obtained market approval and large numbers of patients have been exposed. In addition, in preregistration clinical trials, mild asymptomatic liver injuries, often characterized by asymptomatic elevations in liver enzymes, are commonly seen. However, drugs capable of inducing severe DILI as well as drugs that have a low potential for causing severe injury (e.g., aspirin and heparin) can generate similar patterns of liver injury. It is therefore necessary to develop an approach that can distinguish drugs that are likely to cause severe

Mechanisms of drugs producing diarrhoea are multiple: osmotic, secretory, motor, exudative, malabsorptive, infectious/inflammatory, and others. Examples of osmotic diarrhoea are enteral nutrition feeding, magnesium salts, etc. Examples of secretory diarrhoea (increase in intestinal ion secretion or diminution in intestinal ion absorption) are digoxin, quinidine, propafenone and theophiline. Examples or rapid intestinal transit are procinetic and macrolids. Exudative diarrhoea (changes in permeability and integrity of intestinal mucosa) are NSAIDs and antineoplastic. Drug-related malabsorption of fats, carbohydrates, and/or bile can also lead to diarrhea. Examples include octreotide (at high doses), highly active antiretroviral therapy, tetracycline, NSAIDs, and antineoplastic agents. Drug-induced infectious/inflammatory diarrhea includes microbial proliferation, pseudomembranous colitis, and histologic colitis. The risk of antibiotic associated diarrhea is higher with broad-spectrum agents (particularly those with antianaerobic activity and activity against Enterobacteriaceae), agents with high luminal concentrations (although oral/enteral administration is not necessarily a risk), longer duration of therapy, and use of multiple antibiotics.
