**4.1 Drugs associated with diarrhea due to dysmotility and/or alterations in water absorption and/or secretion**

Several antibiotics, particularly the macrolides (e.g., azithromycin, clarithromycin, erythromycin), act as motilin analogues. Motilin is a hormone that induces MMC activity though four distinct phases: first one is a period of near quiescence, second is characterized by irregular small-amplitude waves, phase III induces highamplitude propulsive contractions all along the small intestine, and during phase IV, motor activity declines to basal values [20]. Although macrolides have a predominant gastroduodenal site-of-action, they may also induce diarrhea by similar MMC-related mechanisms in the small bowel, and are fully reversible after stopping the drug [21].

Laxatives are drugs used to treat different types of constipation, and may cause diarrhea through a number of mechanisms according to pharmacologic type. Osmotic agents extract through osmosis fluid into the intestinal lumen to soften stools an accelerate colon transit time, examples are non-absorbable carbohydrates (e.g., lactulose), polyethylene glycol, as well as citrate, sodium or phosphate-based products. Stimulant agents induce high-amplitude propagated contractions (HAPC) and alter intestinal and colonic absorption as well as secretion mechanisms, examples include the anthraquinones senna and cascara sagrada, bisacodyl and sodium picosulfate. Newer enterokinetic drugs such as tegaserod and prucalopride are agonists of serotonin 5-HT4 receptors throughout the GI tract, they also induce increased MMC and HAPC activity and accelerate enteric transit time. Secretagogue agents such as linaclotide, plecanatide, lubiprostone and tenapanor increase intestinal secretion by one of three different mechanisms: activation of intestinal guanylate cyclase C receptors, increasing intraluminal fluid secretion (e.g., linaclotide, plecanatide), type 2 chloride channel activation in the apical membrane of epithelial cells resulting in increased fluid and chloride secretion (e.g., lubiprostone), and inhibition of gastrointestinal sodium-hydrogen exchanger-3 (e.g., tenapanor). All these drugs are used for treating chronic constipation, and IBS with predominant constipation, and diarrhea is the most common side effect. Colchicine is a cytotoxin used to treat acute attacks of gout, and is frequently associated with diarrhea as enhances intestinal water secretion. Misoprostol, a prostaglandin analogue used in the past for drug-associated peptic ulcer disease or in the obstetric practice, is associated frequently with diarrhea induced by an increased smooth-muscle GI activity [22].
