Drug-induced gastrointestinal lesions

Introduction

Approximately 75% of all marketed medicinal products are manufactured for oral administration as the most convenient and inexpensive route of therapy. However, prolonged contact of poorly absorbed drugs with the gastrointestinal mucosa, especially when gastrointestinal motility is impaired or when drugs with delayed release are used, does not always pass without adverse consequences for the digestive tract. This is further facilitated by the high biological activity and sensitivity of the cells that constitute the gastrointestinal tissues to xenobiotics (particularly in children). As a result, in terms of frequency and diversity of clinical forms and manifestations, drug‑induced lesions of the digestive system occupy one of the leading positions in human drug‑related pathology.

Lesions of the upper gastrointestinal tract

Oral cavity. When using a number of drugs, both locally and systemically, various adverse changes in the initial part of the gastrointestinal tract may occur [1].

Contact stomatitis. The irritant effect leading to catarrhal stomatitis is known for topical antiseptics such as Lugol's solution.

Ulceration of the oral mucosa is mainly associated with drugs such as tacrolimus, alendronate, and hydroxyurea; this possibility is also admitted for calcium channel blockers. Furthermore, among the adverse drug reactions of the copper chelator penicillamine, used in hepatolenticular degeneration (Wilson–Konovalov disease), lesions of the oral mucosa — glossitis and aphthous‑ulcerative stomatitis — are noted [2].

Xerostomia (dry mouth) — decreased salivation occurs due to the atropine‑like action of drugs such as antidepressants (amitriptyline), antipsychotics (chlorpromazine), and antihistamines (loratadine, chloropyramine, clemastine).

Infectious, most often fungal stomatitis. Fungi, especially of the genus Candida, being opportunistic flora of the oral mucosa, can become activated when the protective properties of the macroorganism (natural antifungal resistance) are reduced, for example under the influence of broad‑spectrum antibiotics, glucocorticoids, cytostatics, or irradiation of the head and neck.

The most vulnerable groups are newborns, especially premature infants with very low birth weight (acute candidiasis – “thrush”), and elderly patients with diabetes mellitus, particularly those who are debilitated [3, 4].

Gingival hyperplasia. This adverse reaction was first noted more than 60 years ago in nearly 50% of patients on long‑term therapy with the anticonvulsant phenytoin. Later, such gingival changes were observed with the use of calcium channel blockers (amlodipine, nifedipine, verapamil) with a reported frequency of 80–83%. The risk and incidence of hyperplasia may vary depending on oral hygiene status. The immunosuppressant cyclosporine is also characterized by this adverse reaction (frequency up to 70%), with the main risk factors being higher doses and serum concentrations of the drug. The gingival changes regress after drug discontinuation or under a 2‑week course of oral metronidazole if cyclosporine therapy is continued [5].

Esophagus. On the one hand, the esophagus is a transit organ, and the residence time of drugs there is short, so therapy‑related complications might be expected to be less frequent than lesions of other gastrointestinal segments. However, drug retention in the esophagus can be prolonged for a number of reasons (discussed below); moreover, adverse effects may occur not only during the passage of the drug through the esophagus (antegrade type) but also during retrograde reflux of the food bolus or acidic refluxate together with the drug (retrograde type). The latter is possible in patients with underlying gastroesophageal reflux disease or upon taking drugs that relax the lower esophageal sphincter: natural and synthetic xanthines (coffee, aminophylline), cholinolytics (atropine, platyphylline), drugs with pronounced cholinolytic (antidepressants) or atropine‑like (first‑generation antihistamines) action. In addition, the duration of contact of gastric contents and drugs with the esophageal mucosa is determined by the efficiency of esophageal clearance. Esophageal clearance, as the ability for self‑cleansing, depends on the activity of esophageal peristalsis and the processing of the food bolus by the alkaline environment of saliva and the coating effect of esophageal mucous secretion [6]. Prolongation of esophageal emptying time due to slowed peristalsis (reduced clearance) may result from drug intervention, e.g., with opioids, or from pre‑existing neuropathy (myasthenia), as well as from strictures in the terminal esophagus as a consequence of GERD.

Delayed transit, and consequently prolonged exposure time to the esophageal mucosa, may also be related to the drug formulation and administration conditions, for example, when swallowing large tablets or gelatin capsules (with their “stickiness” and tendency to lodge in one place) without drinking sufficient water, especially with reduced salivary secretion. In more than 50% of cases, dragees or gelatin capsules can be retained for more than 5 minutes upon swallowing.

Among other predisposing factors are the use of drugs that cause dry mouth (xerostomia) and deprive saliva of its coating properties, making it difficult for the food bolus, dragees, pills, or tablets to pass, thus prolonging the contact time of the drug with the esophageal mucosa — “pill” esophagitis [7].

The esophageal damage (inflammation, ulceration) arising under these conditions is most often localized in the transitional zone of the esophagus — between the upper and middle thirds — where the esophagus is subject to mild compression by the aortic arch.

Delayed esophageal transit is associated with the direct toxic effect of many (>70%) drugs; however, the leading agents are NSAIDs regardless of the route of administration (oral, intramuscular, intravenous): 8–40% for non‑selective (indomethacin, ketoprofen, ketorolac) and 5–8% for selective (piroxicam) with an ulceration rate of 10–25%. The combination of NSAIDs and aspirin increased the risk of ulcer bleeding by 10–12 times. Next are tetracyclines (especially doxycycline) — 22% and bisphosphonates (mainly alendronate) — 9–15%, while the slow‑release anticonvulsant Depakine® Chrono and ferrous sulfate in gelatin capsules are suspected of causing esophagitis with perforation [3, 5, 8].

Infectious lesions of the esophagus. The most common is candidal esophagitis. It develops in debilitated patients of all ages, but especially in elderly patients with diabetes mellitus treated with antibiotics, cytostatics, or glucocorticoids (particularly inhaled steroids when the inhalant is swallowed). Under conditions of immunosuppression, Candida fungi, saprophytic on the oral and pharyngeal mucosa, become pathogenic and spread to the esophageal mucosa.

Stomach and duodenum. Although concomitant esophageal damage is possible during oral drug intake, the main burden falls on the stomach, with superficial or erosive‑ulcerative changes in the gastric mucosa and the threat of perforation or ulcer bleeding. Unfortunately, oral administration of gastrotoxic drugs is not the only route of gastric mucosal injury. After parenteral administration (intravenous and even intra‑articular), drugs are transported hematogenously and lymphogenously to the gastric vessels and are subsequently excreted through the mucosa. The very possibility of gastric mucosal damage upon intra‑articular injection of gastrotoxic agents is of interest and supports our earlier hypothesis of the existence of joint clearance [9]. Furthermore, in the case of duodenogastric reflux, retrograde damage to the antral parts of the stomach by drugs that have passed into the jejunum may occur.

In terms of frequency of gastric mucosal lesions, glucocorticoids and NSAIDs occupy the first places. According to the risk of ulceration in the stomach and duodenum, glucocorticoids rank in the following order: prednisolone → hydrocortisone → triamcinolone → dexamethasone. Acute steroid ulcers are complicated by perforation in 27.7% of cases and by bleeding in 33.8% [10]. According to some authors [1], the frequency of ulceration depends not so much on the dose of the drugs but on the underlying disease (mainly diffuse connective tissue diseases) and the duration of use.

In the pathogenesis of steroid ulcers, it is believed [1] that increased HCl production and damage to the mucous‑bicarbonate layer lining the gastric mucosa are important. A gender dependence is also observed: males (as in peptic ulcer disease) are affected more often.

Features of steroid ulcers include their more frequent location along the greater curvature of the stomach, suggesting a contact genesis of ulcer formation, frequent multiplicity, oligosymptomatic or even latent course, shallow flat nature of the lesion, and relatively rapid (within 2–3 weeks) disappearance after withdrawal of the “culprit” drug. In addition, combined involvement of the stomach and duodenum is often noted in a 2:1 ratio.

Due to the breadth of indications, NSAIDs are frequently prescribed drugs: more than 300 million patients worldwide take them annually. Acute NSAID‑induced gastroduodenopathies, ranging from dyspeptic symptoms to erosive‑ulcerative lesions often with bleeding or perforation, are detected in approximately 70% of patients regularly taking NSAIDs for 6 weeks or more, with a mortality rate of almost 10% [10].

Risk factors. From the patient side: elderly age, smoking, low physical activity, self‑medication, history of ulcers. An important place is occupied by individual genetic characteristics related to the rate of NSAID biotransformation involving CYP450 enzymes, among which CYP2C9 plays a leading role. At least 85 allelic variants of this enzyme are known, with normal function (2C9*1), reduced function (2C9*2,5,8,11), or complete absence of function (2C9*3,6,13). In patients carrying the latter two variants, a marked slowing of NSAID biotransformation, pronounced prolongation of elimination half‑life, and increased plasma concentrations can be expected, which creates conditions for the development of adverse reactions [3, 11]. From the drug side: among NSAIDs, indomethacin, ketorolac, ketoprofen, and piroxicam have the highest ulcerogenic risk, while diclofenac, ibuprofen, sulindac (an indoleacetic acid derivative), and aspirin (a salicylic acid derivative) have the lowest. However, the concomitant use of drugs that slow gastrointestinal motility — narcotic analgesics, anticholinergic agents, phenothiazine antipsychotics — promotes longer contact of aspirin with the gastric mucosa, increasing the risk of ulceration [11]. This risk is further increased by the combination of NSAIDs with glucocorticoids and by the duration of NSAID treatment. Unfortunately, the development of enteric‑coated or rapidly soluble aspirin formulations has not substantially reduced the complication rate [1].

The para‑aminophenol derivative paracetamol is a weak non‑selective inhibitor of both cyclooxygenase enzymes (COX‑1 and COX‑2). However, one study showed that the risk of gastric mucosal ulceration and bleeding with paracetamol is comparable to other NSAIDs when the dose of this simple analgesic is increased to 2 g or more per day — a dose‑dependent effect [5, 12].

Damage to the gastroduodenal zone is also possible with another simple analgesic, the pyrazolone derivative metamizole sodium (analgin), and the nature of the damage has much in common with the effect of aspirin [13].

The pathogenesis of NSAID‑induced gastropathy is primarily associated with the suppression by NSAIDs of the protective COX‑1, reduction of the bicarbonate layer, and stimulation of cytokine production that promotes neutrophil adhesion, forming “white” thrombi in gastric mucosal vessels and reducing blood flow. In addition, NSAIDs are weak acids and can exert a direct damaging effect, while indomethacin does so also indirectly — being an antagonist of carbonic anhydrase inhibitors, it activates carbonic anhydrase, leading to increased HCl secretion. Moreover, indomethacin can induce apoptosis of gastric epithelial cells [1].

Features of NSAID‑induced ulcerative lesions include their oligosymptomatic course, and therefore they are often (in 40–50% of patients) discovered upon sudden gastric bleeding. Unlike steroid ulcers, NSAID ulcers are predominantly localized in the antral and prepyloric regions. Furthermore, the pathological changes caused by non‑steroidal drugs are not characteristic of any particular class (group) of drugs, i.e., they have a similar clinical and endoscopic picture for all NSAIDs.

Damage to the stomach and duodenum due to drug‑induced hypercalcemia deserves attention. It most often occurs in adults as a result of excessive vitamin D intake in the treatment of hypoparathyroidism, and in children due to accidental poisoning or treatment of rickets‑like diseases. The development of gastroduodenal ulcers in these cases is associated with hyperplasia of the glandular epithelium, increased acidity, and pepsin formation. These ulcers usually resolve fairly quickly after discontinuation of vitamin D [10].

Damage to the lower gastrointestinal tract

Small intestine. Drug‑induced intestinal lesions may be due to direct toxic effects on the mucosa, effects on mesenteric vessels, or neuromuscular plexuses of the intestinal wall. The adverse effects of NSAIDs are not limited to the stomach and duodenum; according to [3], the small intestine is even a more frequent target for non‑steroidal agents, and the direct toxic mucosal damage usually runs a subclinical (latent) course and is detected many months later by capsule endoscopy.

The scale of the problem can be judged from data [14], according to which NSAID‑induced enteropathies, including severe manifestations such as perforations, ulcers, and strictures, are observed in about 71% of patients who have taken these drugs long‑term, with diclofenac and indomethacin being particularly prominent [5, 7]. By penetrating the intestinal mucosal barrier through inhibition of prostaglandins E, F, J produced in the intestinal wall, indomethacin promotes the formation of ulcers, necrosis, and perforations in the jejunum of patients with rheumatoid arthritis and other systemic connective tissue diseases. Mucosal damage is accompanied by invasion of Gram‑negative flora and the formation of inflammatory changes. Moreover, some authors suggest that the basis of indomethacin‑induced ulcers may be intestinal vascular thrombosis [1]. Perforation of the small intestine has also been described after intravenous indomethacin for persistent ductus arteriosus in a premature newborn [15].

Toxic mucosal damage with the development of acute drug‑induced enteritis occurs in methotrexate overdose in rheumatology patients and is also associated with tetracyclines — natural (tetracycline) or semi‑synthetic (doxycycline) — with possible mucosal atrophy (partial or subtotal) and the development of gluten enteropathy (celiac syndrome) [16].

The use of IFN‑α in patients with hepatitis C, due to its immunomodulatory properties, particularly the activation of CD4 T‑cells that play a central role in controlling the immune response to gluten, may also be accompanied by the development of celiac syndrome or exacerbation of pre‑existing primary celiac disease [17].

Hemorrhagic enteritis (0.1%) is observed mainly in elderly men treated with heparin preparations, manifesting as inflammatory changes in the mucosa and numerous ulcerations. The observed changes could be exacerbated by the concomitant use of antibiotics that suppress vitamin K synthesis by the intestinal microflora [10]. In isolated cases, mechanical obstruction due to submucosal hematomas may develop against the background of dicoumarin derivatives. Mechanical obstruction in the form of small‑bowel intussusception was recorded (in 12%) during vaccination of children with a tetravalent vaccine [18], while dynamic (paralytic) obstruction was observed by the authors when using vincristine in a 5‑year‑old oncology child [19]. The toxic effect of vincristine with damage to intramural ganglia in this case is explained by its low biotransformation rate due to age‑related decrease in CYP3A4 activity and almost complete absence of CYP3A5 in 80% of Caucasians (the girl was from Dagestan). Secondary changes in the small intestine related to tablet and capsule excipients may also occur: the presence of unrefined starch containing gluten or lactose is unacceptable for patients suffering from celiac disease or disaccharide intolerance, respectively [7].

Large intestine. As a result of intensive antibiotic use, one of the most common complications is antibiotic‑associated diarrhea caused by Clostridium difficile, with its most severe manifestation being pseudomembranous colitis. However, the suppression of protective anaerobic flora (lacto‑ and bifidobacteria) resulting from antibiotic therapy may also be accompanied by excessive growth of fungal flora (Candida, Aspergillus, Mucor) involving not only the large intestine but also the rectosigmoid region — fungal colitis, proctosigmoiditis [10].

In terms of effect on intestinal flora, it is difficult to single out any particular group of antibiotics, but one of the most prescribed are β‑lactams, particularly cephalosporins (78.6%), among which cefixime and drugs with dual (renal and hepatic) elimination — ceftriaxone and cefoperazone — and their combination with macrolides (which also act as prokinetics) are notable [7, 20, 21, 22].

Neutropenic colitis (typhlitis) with necrotizing mucosal changes occurs during deep neutropenia after polychemotherapy in cancer patients due to cytotoxic drug damage and the overgrowth of opportunistic flora [5].

Furthermore, during immunosuppression, the intestine becomes susceptible not only to bacterial but also to opportunistic infections such as cytomegalovirus infection with typical inclusion bodies detectable on biopsy.

A link has also been suggested between repeated, long‑term (e.g., in cystic fibrosis patients) antibiotic use and the development of ulcerative colitis. A similar association has been noted with the use of oral contraceptives in women [18].

In addition to infectious colitis associated with immunosuppression, ischemic colitis may develop during treatment with certain chemotherapeutic agents (cisplatin, 5‑fluorouracil). A similar effect can be caused by drugs from other groups — vasopressors, atypical antipsychotics, oral contraceptives, ergot derivatives [3, 6].

However, the effect of some groups of drugs (NSAIDs) on the large intestine may be not only harmful but also beneficial. Epidemiological studies have shown a consistent reduction in the risk of colorectal cancer in patients regularly taking aspirin. Moreover, several randomized trials with sulindac and celecoxib have demonstrated a reduction in the number and size of adenomas in patients with familial adenomatous polyposis — a precursor of cancer. The underlying mechanism is inhibition of COX‑2, which is expressed in 90% of sporadic colorectal cancer cells and in 40% of adenoma cells, restoring apoptosis and inhibiting angiogenesis. However, sulindac and aspirin at a prophylactic dose of 100 mg lack COX‑2 inhibition, yet the protective effect remains. Thus, another protective mechanism is suggested — induction of expression of the regulatory protein p21, associated with apoptosis of cancer cells and intestinal adenoma cells [14, 23].

Pancreas. The frequency of drug‑induced pancreatitis, the diagnosis of which is based mainly on case series and individual reports, is 0.1–5.3% in the general population, whereas in paediatric practice it is 15–30% [8].

Drugs that cause pancreatitis are divided into 6 groups:

1. Drugs for HIV infection (didanosine, pentamidine);

2. Antibacterial agents (tetracycline, metronidazole, sulfonamides);

3. Diuretics (thiazides, furosemide);

4. Immunosuppressants (L‑asparaginase, azathioprine, 6‑mercaptopurine);

5. Anticonvulsants (valproates);

6. Anti‑inflammatory drugs.

A miscellaneous group includes oestrogens, calcium preparations, tamoxifen, and ACE inhibitors.

Drugs associated with drug‑induced pancreatitis are subdivided into definitely causing pancreatic damage — 24 drugs, but with known frequency only 5 of them (ACE inhibitors, amiodarone, cytarabine, azathioprine, L‑asparaginase, valproic acid) and probably associated with drug‑induced pancreatitis (26 drugs) [8].

The proposed criteria for drug‑induced pancreatic injury are common to all drug‑induced lesions:

1. The complication developed during the use of a particular drug;

2. Other possible causes were absent;

3. Reversal of changes after withdrawal of the suspected drug;

4. Recurrence of pancreatitis after re‑administration of the suspected drug.

The last condition, although rarely fulfilled for ethical reasons, was exactly what allowed the Danish Committee on Adverse Drug Reactions to establish a reliable association (retrospective study) between the use of mesalazine, azathioprine, and simvastatin and the development of acute pancreatitis.

The pathogenesis of drug‑induced pancreatitis may be related to an allergic reaction (sulfonamides, azathioprine and 6‑mercaptopurine), explained by direct toxic action (diuretics, steroids), or induction of hypertriglyceridemia (oestrogens, tamoxifen), which itself provokes pancreatitis [24]. When treating with high doses of vitamin D, the resulting hypercalcaemia with deposition of calcium salts in the parenchyma and ducts of the pancreas with duct obstruction is important. The authors observed duct obstruction with the development of acute reactive pancreatitis in several children after endoscopic retrograde cholangiopancreatography (experience not published). Tetracycline antibiotics, excreted in unchanged form in bile in fairly high concentrations, may exert an inhibitory effect on the activity of some pancreatic enzymes, mainly lipase.

One proposed mechanism of drug‑induced pancreatitis — increased viscosity of pancreatic juice with impaired secretion and enzyme activity — may occur, for example, during prolonged treatment with saluretics (“chlorothiazide pancreatitis”). It is known that secretion by the ductal epithelium of the pancreas is largely dependent on carbonic anhydrase activity, with which the cells of this epithelium are particularly rich. Inhibition of this enzyme even by therapeutic doses of acetazolamide can reduce exocrine pancreatic function by up to 50% [10].

Diabetogenic effects with a tendency to increase blood glucose levels during treatment with diuretic drugs are related to direct or secondary (due to hypokalaemia) inhibition of insulin release from pancreatic β‑cells and blockade of its peripheral action [10].

There are no defined average time frames for the development of drug‑induced pancreatitis, as it may be detected after the first dose or even years after the start of therapy [8].

The course of drug‑induced pancreatitis may be acute (most often) with reversibility of function after withdrawal of the suspected drug, or chronic if pancreatic function is not restored for a long time or at all, for example, in chronic pancreatitis that develops during long‑term glucocorticoid treatment of diffuse connective tissue diseases.

The course of drug‑induced pancreatitis is influenced by underlying patient conditions: prolonged parenteral nutrition, HIV infection (when treated with didanosine), kidney transplantation, inflammatory bowel disease, as well as female sex and latent carbohydrate metabolism disorders.

The manifestations of drug‑induced pancreatitis are usually moderate and often resolve spontaneously. However, according to 30‑year data from the Danish Committee on Adverse Drug Reactions, 68% of all suspected drug‑induced pancreatitis cases required hospitalisation, and the mortality rate was 9% due to fulminant course, with the highest mortality from drug‑induced pancreatitis associated with azathioprine, didanosine, furosemide, and hydrochlorothiazide [7, 24].

Liver. The authors have repeatedly addressed the topic of drug‑induced liver injury in oral presentations and in print, both in review articles and in case reports [25–28].

However, more than two years have passed since our last publication, and new data have emerged that refine previous concepts, for example, regarding idiosyncratic liver reactions. Previously (2006), it was defined as a genetically determined heightened hepatic response to drugs, caused by defects in the enzyme systems involved in drug biotransformation — oxidation and conjugation [29]. According to updated data, the pharmacogenetic marker in newly occurring liver damage in children, for example associated with the use of meropenem and tigecycline, is the carriage of the homozygous CYP3A5*3/*3 genotype [30], while the immunophenotype of the immune response involves cytotoxic CD8 cells (T‑killers) and B‑cells producing antibodies to the drug, and the regulation of adaptive immunity involves CD4 cells (T‑helpers) [31].

Additional mechanisms of idiosyncratic liver reactions are the formation of reactive oxygen species, drug‑induced inhibition of canalicular bile acid export pumps, and mitochondrial damage.

Hepatocellular or hepatocholestatic changes in the liver resulting from an idiosyncratic reaction, for example to amoxicillin + clavulanic acid, bentazepam, atorvastatin, captopril, do not always resolve after withdrawal of the “culprit” drug. In some cases (according to some data, in almost a third of patients), the process becomes chronic, progressing to cirrhosis or chronic hepatitis (biopsy‑proven), with initial mixed (hepatocholestatic) changes being more prone to chronicity [32].

The most severe manifestation of drug‑induced liver injury is acute liver failure, which ends either in death (unpublished personal experience of death of a young child from valproate‑induced hepatitis) or, under favourable conditions, in liver transplantation. According to data [27], acute liver failure requiring subsequent transplantation was most frequently associated with the use of the following four drug groups: acetaminophen (40%), antituberculous drugs (8%), anticonvulsants (7%), and antibiotics (6%). One‑year survival was only 52% for anticonvulsants, but 76% for acetaminophen and 82% for antituberculous drugs.

Conclusion

The multi‑level structure of the gastrointestinal tract, its length of several metres, and the vast surface area of the mucosa create conditions for prolonged contact with drugs (chemically active substances) and the possibility of damage to any part of the gastrointestinal tract. It is therefore no coincidence that gastrointestinal adverse effects rank first among all adverse reactions to drugs, with NSAIDs occupying the leading position.

In addition to direct damaging effects on the mucosa, often with ulcer formation and subsequent complications, some drugs, e.g., antibiotics, exert indirect effects by suppressing physiological flora and thereby promoting the growth of pathological flora — bacterial or fungal — leading to inflammatory bowel changes.

Recognising and identifying a drug‑induced gastrointestinal lesion is not an easy task. The Naranjo scale (1981), which consists of 10 criteria, is not always helpful, as two of them — withdrawal of the suspected drug and placebo challenge — are difficult to implement, for example, in the setting of polychemotherapy. Moreover, one of the main criteria — the time interval between drug initiation and the appearance of changes (clinical and laboratory) — may be too extended to serve as a diagnostic support. Furthermore, there are no strictly specific morphological changes characteristic of drug‑induced pathology.

Nevertheless, all these difficulties should not weaken the efforts of clinicians and clinical pharmacologists to identify and publish various cases of drug‑induced gastrointestinal lesions for subsequent interpretation and discussion.