ADRs Affecting the Gastrointestinal System

Nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, and anorexia were among the 30 most common potential ADRs associated with therapeutic dosages of the top 200 drugs dispensed by U.S. community pharmacies in 2008.¹⁵ CIOMS does not list nausea and vomiting and considers abdominal pain an undesirable term to describe ADRs. When a patient complains of abdominal pain CIOMS recommends considering drug-induced colitis, pancreatitis, and peptic ulcer disease in the differential diagnosis.¹⁴

The physiologic purpose of nausea (ADR #2) is to prevent food intake and the purpose of vomiting is to expel food or other toxic substances present in the upper part of the gastrointestinal tract.²⁶ Nausea and vomiting occur in response to activation of the vomiting center either directly or through the chemoreceptor trigger zone (CRTZ). The CRTZ is outside the blood-brain barrier and is accessible to drugs circulating in the vascular compartment. NSAIDs, antibiotics, opioids, digitalis, and antineoplastic agents are examples of emetic drugs.²⁶

Diarrhea (ADR # 5) and associated fecal urgency and incontinence may be defined as passage of loose, unformed stool with increased frequency.^14,27 Chronic diarrhea may be due to lactose intolerance, inflammatory bowel disease, malabsorption syndromes, endocrine disorders, irritable bowel syndrome, and the abuse of laxatives.²⁷ Common causes of acute diarrhea include viral and bacterial infections; and drugs such as antibacterial agents, Mg-containing antacids, antineoplastic agents, and colchicine.²⁷

Constipation (ADR # 7) may be defined as the passage of excessively dry stool, infrequent stool, or stool of insufficient size.^14,28 It involves the subjective sensations of incomplete emptying of the rectum, bloating, flatus, lower abdominal discomfort, anorexia, malaise, headache, weakness, and giddiness. Common causes of acute constipation include antihistamines, opioid analgesics, neuroleptics, antidepressants, anticonvulsants, aluminum- and Ca-based antacids, Ca-channel blocking agents, and anti-parkinsonian drugs.²⁸

Abdominal pain (ADR #12) is any pain in the topographical area of the abdomen. When describing an ADR, its relation to anatomical site and other symptoms should be specified.²⁹ For example, drug-induced pancreatitis is usually an acute condition characterized by upper abdominal pain accompanied by severe nausea and vomiting.^14,29 Some medications implicated in causing acute pancreatitis include corticosteroids, diuretics, oral hypoglycemic agents, estrogens, anticonvulsants, and antineoplastic agents.²⁹

The principal symptom of peptic ulcer disease is also abdominal pain. Vomiting may also occur and the patient is predisposed to hemorrhage and perforation.^14,30 Hemorrhage may vary from slight bleeding to massive hemorrhage and the patient may vomit variable quantities of blood. If the blood goes down into the intestines, a large amount of altered blood makes the stools black and tarry (melena). The ulcerogenic effect of NSAIDs is well established and is attributable to inhibition of prostaglandin synthesis.³⁰

Of particular concern to oral healthcare providers should be the patient complaining of lower abdominal pain, acute diarrhea with blood in the stool that is currently taking or has been prescribed in the recent past clindamycin or a broader spectrum penicillin or cephalosporin. The signs and symptoms are likely due to bacterial superinfection, e.g., an overgrowth of C. difficile in the gastrointestinal tract, a serious presentation of which is termed pseudomembranous colitis.³¹

Dyspepsia (ADR # 17) is a sensation of discomfort or pain in the upper abdomen below the sternum. Patients may describe it as heartburn or indigestion and complain of feeling nauseous and bloated after eating and relate regurgitating (burping) food or liquid.³² Drugs associated with acute dyspepsia include NSAIDs, opioids, antibacterial agents, oral hypoglycemic agents, ACE-inhibitors, angiotensin II-receptor antagonist, corticosteroids, estrogens, anti-parkinsonian drugs, digoxin, niacin, fenofibrate, and SSRIs.³²

Anorexia (ADR #25) is defined as lack or loss of appetite for food.^14,15 It is to be differentiated from lack of appetite related to nausea, vomiting, or diarrhea; or hyporexia, decreased appetite; or anorexia nervosa, which is characterized by refusal to maintain normal body weight. With anorexia, limitation of food-intake and weight loss is not deliberate. Drugs that may have inhibitory effects on appetite and food intake include certain antibacterial agents, antineoplastic agents, fluoxetine, digoxin, quinidine, hydralazine, and vitamin A.