Prokinetic Drugs A gastroprokinetic agent, gastrokinetic, or prokinetic, is a type of drug which enhances gastrointestinal motility by increasing the frequency of contractions in the small intestine or making them stronger, but without disrupting their rhythm. They are used to treat irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.

1. Cholinomimetic agents Not commonly used Cholinomimetic agonists; Bethanechol stimulate muscarinic M3 receptors on smooth muscle cells and at myenteric plexus synapses. Due to multiple cholinergic effects and the advent of less toxic agents, it is now seldom used. The acetylcholinesterase inhibitor: Intravenous neostigmine can be used in the treatment of acute large bowel distention . Cholinergic effects include excessive salivation, nausea, vomiting, diarrhea, and bradycardia.

2. D2 receptor antagonists. Mechanism of action Metoclopramide and domperidone are dopamine D2 receptor antagonists. Within the gastrointestinal tract activation of D2 receptors block cholinergic smooth muscle stimulation. Blocking D2 will unblock the cholinergic smooth muscle stimulation.

Pharmacological action Increase esophageal peristaltic amplitude Increase lower esophageal sphincter pressure Enhance gastric emptying Have no effect on small intestine or colonic motility. Antinausea and antiemetic action.

Therapeutic Uses Impaired Gastric Emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis. Prevention and treatment of emesis. Gastroesophageal Reflux Disease (GERD): Metoclopramide is used mainly in combination with acid suppressors in patients with regurgitation or refractory heartburn. Nonulcer Dyspepsia Adverse Effects Metoclopramide causes CNS side effects. Restlessness, drowsiness, insomnia, anxiety, and agitation, especially the elderly.

Metoclopramide cause extrapyramidal effects (dystonias, akathisia, parkinsonian features) due to central dopamine receptor blockade. Irreversible tardive dyskinesia, can occur in patients treated for a prolonged period with metoclopramide. Elevated prolactin levels (caused by both metoclopramide and domperidone) can cause galactorrhea, gynecomastia, impotence, and menstrual disorders. Domperidone does not cross the blood-brain barrier to a significant degree, neuropsychiatric and extrapyramidal effects are rare.

3. Macrolides Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle and promote gastric peristalsis, however, tolerance rapidly develops. It may be used in patients with acute upper gastrointestinal hemorrhage to promote gastric emptying of blood prior to endoscopy.

Inflammatory bowel disease (IBD) IBD refers to the bowel disorders, ulcerative colitis and Crohn's disease. The etiology is unknown. It is most commonly seen in young patients. Ulcerative colitis; It is an inflammatory disorder of the mucosa of the rectum and colon. Crohn's disease; affects all layers of the bowel wall and may do so usually in a patchy distribution throughout the entire gastrointestinal (GI) tract.

DRUGS USED IN TREATMENT OF IBD Immunosupressive drugs Steroids Cytotoxic drugs (Azathioprine, Mercaptopurine, Methotrexate ) Infliximab 5-aminosalicylates Mesalamine Sulfasalazine Olsalazine

1. Immunosuppressive drugs Glucocorticoids: They are used both systemically and topically (given by enema). They are often able to induce clinical remission, but are less valuable in maintaining remission. Infliximab: It is a monoclonal antibody to TNF-alpha. TNF-alpha is believed to play a role in the pathogenesis of Crohn’s disease. A single IV infusion is effective in inducing clinical remission of the disease.

Cytotoxic agents (azathioprine, mercaptopurine, methotrexate): They can be beneficial in patients who do not respond to glucocorticoids. They are superior to glucocorticoids in maintaining remission but they have a slow onset of action (sometimes 1-2 months). Methotrexate has a more rapid onset of action and is effective in Crohn’s disease but not in ulcerative colitis.

2. 5-aminosalicylates Unabsorbed 5-aminosalicylic acid (5-ASA) is an active anti-inflammatory drug in IBS. Mechanism of action 5-ASA likely acts by multiple mechanisms including: Inhibition of PGs and leukotriene biosynthesis (likely the main mechanism) Scavenging of reactive oxygen metabolites Reduction of macrophage chemotaxis and phagocytosis Inhibition of cytokine production by intestinal cells

A. Mesalamine (5-ASA) It is administered rectally or as a delayed-release oral tablet. Readily absorbed from the small intestine whereas absorption from the colon is poor. Systemic effects are rare.

B. Sulfasalazine Sulfasalazine combines sulfapyridine with 5-ASA. Taken orally, it is poorly absorbed and is broken down in the colon by bacteria to release 5-ASA and sulfapyridine. It has a higher incidence of adverse effects due to systemic absorption of sulfapyridine moiety. Its use has declined because sulfapyridine may cause agranulocytosis.

Adverse effects of 5-aminosalicylates Sulfasalazine has a high incidence of adverse effects, mainly related to hypersensitivity reactions to the sulfa moiety. They include, hepatitis, pancreatitis, exfoliative dermatitis, hemolytic anemia, bone marrow suppression. 5-ASA is well tolerated. It can cause nausea and vomiting, abdominal discomfort and (rarely) nephrotoxicity.

Clinical uses 5-aminosalicylates are effective in mild or moderate ulcerative colitis, but less so in severe colitis and in Crohn’s disease. They are more effective in maintaining than in achieving clinical remission.

Irritable bowel syndrome (IBS, or spastic colon) It is a symptom-based diagnosis characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits. Diarrhea or constipation may predominate A diagnosis of exclusion

Treatment of IBS Although there is no cure for IBS, there are treatments that attempt to relieve symptoms It include dietary adjustments, medication and psychological interventions.  Pharmacological management include; antidiarrheal, laxatives (for diarrhea or constipation) and small dose of TCA for abdominal pain The anticholinergic drugs dicyclomine and hyoscyamine are used as antispasmodics

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