Drugs Affecting the. Gastrointestinal System

Transcription

1 Drugs Affecting the 9 Gastrointestinal System SECTION 1: AGENTS USED TO TREAT PEPTIC ULCER DISEASE ANTACIDS: Each of these agents is sold overthe-counter and therefore not covered in this book. ANTIMICROBIAL AGENTS: (See Chapter 10) AMOXICILLIN BISMUTH LARITHROMYCIN METRONIDAZOLE TETRACYCLINE ANTIMUSCARINIC AGENTS: DICYCLOMINE (See Chapter 4, Section 3) H 2 -HISTAMINE ANTAGONISTS: CIMETIDINE (sye MET i deen) (Tagamet ) FAMOTIDINE (fa MOE ti deen) (Fluxid, Pepcid ) NIZATIDINE (ni ZA ti deen) (Axid ) RANITIDINE (ra NI ti deen) (Zantac EFFERdose, Zantac ) PROTON-PUMP INHIBITORS: ESOMEPRAZOLE (es oh ME pray zol) (Nexium ) LANSOPRAZOLE (lan SOE pra zole) (Prevacid, Prevacid, NapraPAC, 1 Prevacid, SoluTab, Prevpac 2 ) OMEPRAZOLE (oh ME pray zol) (Prilosec, 3 Zegerid 3 ) PANTOPRAZOLE (pan TOE pra zole) (Protonix ) RABEPRAZOLE (ra BE pray zole) (AcipHex ) PROSTAGLANDINS: MISOPROSTOL (mye soe PROST ole) (Arthrotec, 4 Cytotec ) MISCELLANEOUS GASTROINTESTINAL AGENTS: CISAPRIDE (SIS a pride) (Propulsid ) SUCRALFATE (soo KRAL fate) (Carafate ) These agents are used to treat gastroesophageal reflux disease (GERD) and peptic ulcer disease. Peptic ulcer disease causes an erosion of the mucosal lining of the stomach (gastric) or the first part of the small intestine (duodenal). This erosion can cause pain, usually alleviated by food or antacids, but can become life-threatening if it causes a hemorrhage or perforation. While the complete pathogenesis of peptic ulcer disease is not completely understood, there are three factors that are commonly recognized. The first is an infection of helicobacter pylori (H. pylori), a small, difficult-toeradicate bacteria. The second factor is increased hydrochloric acid secretion in the stomach. And the final factor is inadequate mucos- 233

2 234 INTEGRATIVE PHARMACOLOGY Esophagitis: Inflammation of the esophagus Stricture: A narrowing or stenosis of a tube, duct, or hollow structure, usually consisting of a contracture or deposition of abnormal tissue Metaplastic: Pertaining to an abnormal transformation of adult, fully differentiated tissue of one kind into a differentiated tissue of another kind; often cancerous or precancerous Gastrins: Hormones secreted in the mucosa of the stomach that stimulate hydrochloric acid secretion Myenteric plexus: A plexus of unmyelinated nerve fibers and postganglionic autonomic cell bodies lying within the musculature of the esophagus, stomach and intestine; it communicates with the enteric plexus al protection against the acid in the stomach. This final factor may be caused by long-term or overuse of NSAIDs. Treatment is geared towards each of these factors. While GERD has a completely different pathophysiology, it is treated similarly to peptic ulcer disease with the exception of antibiotics. GERD is caused by reflux of acid from the stomach into the esophagus. This can cause changes in the esophagus including esophagitis, strictures, and Barrett s esophagus, a metaplastic condition that is precancerous. Drug treatment is geared towards reducing the acidity of the gastric secretions. Many of these agents are also useful in treating Zollinger-Ellison syndrome. This syndrome is caused by a tumor that excessively secretes gastrins, which causes hypersecretion of acid causing ulceration. FUNCTION The antimicrobials are used to eradicate the H. pylori infection in peptic ulcer disease. Antimuscarinic agents, histamine antagonists, proton-pump inhibitors, and prostaglandins all work to reduce the acidity of the gastric secretions. Antimuscarinic agents are used as an adjunct to other treatments and are generally used only in patients where other treatments have failed because they have extensive adverse effects. Prostaglandins are generally milder acting than the histamine antagonists and proton-pump inhibitors, but are especially useful in NSAID induced ulceration. Antacids directly, if mildly, reduce the acidity of the gastric secretions. They have been found to be more effective in treating duodenal ulcers than gastric ulcers. Calcium carbonate is also used as a calcium supplement. Sucralfate enhances the mucosal layer and adds protection to the stomach lining. Bismuth compounds, in addition to being antimicrobial, also help to form a protective mucosal lining. Cisapride is used in treating GERD and has been shown to increase the pressure of the lower esophageal sphincter and accelerate gastric emptying, both of which reduce reflux. MECHANISM OF ACTION Antacids act through a direct chemical reaction between a basic substance, the antacid, and the acidic gastric secretions. This raises the ph and reduces the acidity of the stomach contents. Antimuscarinic agents decrease GI motility and gastric secretion. H 2 -histamine antagonists, antimuscarinic agents, and prostaglandins all act to indirectly reduce the function of the H+/K+-ATPase or proton pump which pumps hydrogen ions, the ions that cause acidity, into the stomach lumen. Antimuscarinic agents do this by blocking the normal function of cholinergic s which release calcium ions which activate the proton pump. Cyclic AMP (camp) can also induce proton pump action. H 2 -histamine antagonists reversibly act on histamine s that activate adenylate cyclase, the enzyme that produces camp. Therefore, these antagonists prevent this normal activation and reduces the amount of camp and activation of the proton pump. Prostaglandins directly activate a that down-regulates adenylate cyclase and reduces the amount of camp. While these agents all indirectly reduce the action of the proton pump, proton-pump inhibitors directly and irreversibly block proper functioning of the proton pump. These effects are summarized in Figure 9.1. Cisapride acts by stimulating release of acetylcholine in the myenteric plexus which causes an increase in pressure of the lower esophageal sphincter and accelerates gastric emptying. Sucralfate protects the mucosal layer by bonding with proteins in the mucosal wall and forming a complex gel that prevents mucus degradation and inhibits acid secretion. In addition, it stimulates prostaglandin secretion, mucus production, and bicarbonate release.

3 DRUGS AFFECTING THE GASTROINTESTINAL SYSTEM 235 Figure 9.1: Summary of how various agents reduce stomach acidity. All act to slow or prevent the proton pump from secreting hydrogen ions into the lumen of the stomach. Antimuscarinic agents do this by blocking cholinergic s which normally release calcium ions and activate protein kinase and the proton pump. H 2 -histamine antagonists and prostaglandins both down-regulate adenylyl cyclase, lowering camp and protein kinase activity and ultimately decreasing proton pump action. Proton-pump inhibitors directly block the proton pump. DOSAGES CIMETIDINE, for children, mg/kg/day in divided doses every 6 hours. For children 12 years and adults, for heartburn, acid indigestion, sour stomach (OTC labeling), 200 mg up to twice daily, may take 30 minutes prior to eating foods or beverages expected to cause heartburn or indigestion. For adults, for short-term treatment of active ulcers, 300 mg qid or 800 mg nocte or 400 mg bid for up to 8 weeks, higher doses of 1600 mg nocte for 4 weeks may be beneficial for a subpopulation of patients with larger duodenal ulcers (>1 cm defined endoscopically) who are also heavy smokers ( 1 pack/day); for duodenal ulcer prophylaxis, 400 mg nocte; for gastric hypersecretory conditions, mg every 6 hours, dosage not to exceed 2.4 g/day; for gastroesophageal reflux disease, 400 mg qid or 800 mg bid for 12 weeks; for helicobacter pylori eradication (unlabeled use), 400 mg bid, requires combination therapy with antibiotics. CISAPRIDE, for children, mg/kg/dose 3-4 times/day up to a maximum of 10 mg/ dose. For adults, initiate at 10 mg qid at least 15 minutes before meals and at bedtime, in some patients the dosage will need to be increased to 20 mg to obtain a satisfactory result. DICYCLOMINE, for infants >6 months, 5 mg/

4 236 INTEGRATIVE PHARMACOLOGY dose 3-4 times/day. For children, 10 mg/dose 3-4 times/day. For adults, initiate with 80 mg/day in 4 equally divided doses, then increase up to 160 mg/day. ESOMEPRAZOLE, delayed-release capsules should be swallowed whole and taken at least 1 hour before eating. For adolescents years, for GERD, mg once daily for up to 8 weeks. For adults, for erosive esophagitis (healing), initiate at mg once daily for 4-8 weeks, if incomplete healing, may continue for an additional 4-8 weeks, maintenance dose is 20 mg once daily; for symptomatic GERD, 20 mg once daily for 4 weeks, may continue an additional 4 weeks if symptoms persist; for H. pylori eradication, 40 mg once daily for 10 days, requires combination therapy; for prevention of NSAID-induced gastric ulcers, mg once daily for up to 6 months. FAMOTIDINE, for children, for peptic ulcers, 1-16 years, 0.5 mg/kg/day nocte or divided twice daily up to a maximum dose of 40 mg/day; for GERD, <3 months, 0.5 mg/kg once daily, 3-12 months, 0.5 mg/kg bid, 1-16 years, 1 mg/kg/day divided twice daily up to a maximum dose of 40 mg bid. For children 12 years and adults, for heartburn, indigestion, sour stomach, mg every 12 hours, dose may be taken minutes before eating foods known to cause heartburn. For adults, for duodenal ulcer, acute therapy: 40 mg/day nocte for 4-8 weeks, maintenance therapy, 20 mg/day nocte; for H. pylori eradication (unlabeled use), 40 mg once daily; requires combination therapy with antibiotics; for gastric ulcer, acute therapy: 40 mg/day nocte; for hypersecretory conditions, initiate at 20 mg every 6 hours, may increase in increments up to 160 mg every 6 hours; for GERD, 20 mg bid for 6 weeks; for esophagitis and accompanying symptoms due to GERD, 20 mg or 40 mg bid for up to 12 weeks. HYOSCYAMINE, for children, for gastrointestinal disorders, using mg/ml drops, repeat dose every 4 hours as needed: children <2 years, 3.4 kg, 4 drops, up to a maximum of 24 drops/24 hours; 5 kg, 5 drops, up to a maximum of 30 drops/24 hours; 7 kg, 6 drops, up to a maximum of 36 drops/24 hours; 10 kg, 8 drops, up to a maximum of 48 drops/24 hours. For children 2-12 years, for gastrointestinal disorders, repeat dose every 4 hours as needed: 10 kg, mg, up to a maximum of 0.75 mg/24 hours; 20 kg, mg, up to a maximum of 0.75 mg/24 hours; 40 kg, mg, up to a maximum of 0.75 mg/24 hours; 50 kg, mg, up to a maximum of 0.75 mg/24 hours. For children >12 years and adults, for gastrointestinal disorders, mg every 4 hours or as needed (before meals or food) up to a maximum of 1.5 mg/24 hours; Cystospaz : mg up to 4 times/day. For timed release: for children >12 years and adults, for gastrointestinal disorders, mg every 12 hours up to a maximum of 1.5 mg/24 hours. LANSOPRAZOLE, for children 1-11 years, for GERD, erosive esophagitis, 30 kg, 15 mg once daily, >30 kg, 30 mg once daily. For children years, for nonerosive GERD, 15 mg once daily for up to 8 weeks; for erosive esophagitis, 30 mg once daily for up to 8 weeks. For adults, for duodenal ulcer, shortterm treatment: 15 mg once daily for 4 weeks, maintenance dose is 15 mg once daily; for gastric ulcer, short-term treatment: 30 mg once daily for up to 8 weeks; for NSAID-associated gastric ulcer (healing), 30 mg once daily for 8 weeks, controlled studies did not extend past 8 weeks of therapy; for NSAID-associated gastric ulcer (to reduce risk), 15 mg once daily for up to 12 weeks; for symptomatic GERD, short-term treatment, 15 mg once daily for up to 8 weeks; for erosive esophagitis, short-term treatment: 30 mg once daily for up to 8 weeks, continued treatment for an additional 8 weeks may be considered for recurrence or for patients that do not heal after the first 8 weeks of therapy,

5 DRUGS AFFECTING THE GASTROINTESTINAL SYSTEM 237 maintenance therapy dose is 15 mg once daily; for hypersecretory conditions, initiate at 60 mg once daily, adjust dose based upon patient response and to reduce acid secretion to <10 meq/hour (5 meq/hour in patients with prior gastric surgery), doses of 90 mg bid have been used, administer doses >120 mg/day in divided doses; for H. pylori eradication, dose varies with regimen, 30 mg once daily or 60 mg/day in 2 divided doses, requires combination therapy with antibiotics. METHSCOPOLAMINE, for adults, 2.5 mg 30 minutes before meals or food and mg nocte, may increase dose to 5 mg bid. MISOPROSTOL, for children 8-16 years, for fat absorption in cystic fibrosis (unlabeled use), 100 mcg qid. For adults, for prevention of NSAID-induced gastric ulcers, 200 mcg qid with food, if not tolerated, may decrease dose to 100 mcg qid with food or 200 mcg bid with food, last dose of the day should be taken at bedtime. NIZATIDINE, for children, <12 years, for GERD (unlabeled use), 10 mg/kg/day in divided doses given twice daily, may not be as effective in children <12 years; 12 years, for GERD, refer to adult dosing; for meal-induced heartburn, acid indigestion and sour stomach, refer to adult dosing. For adults, for duodenal ulcer, treatment of active ulcer, 300 mg nocte or 150 mg bid; maintenance of healed ulcer, 150 mg/day nocte; for gastric ulcer, 150 mg bid or 300 mg nocte; for GERD, 150 mg bid; for meal-induced heartburn, acid indigestion, and sour stomach, 75 mg tablet [OTC] bid, 30 to 60 minutes prior to consuming food or beverages; for H. pylori eradication (unlabeled use), 150 mg bid, requires combination therapy. OMEPRAZOLE, for children 2 years, for GERD or other acid-related disorders, <20 kg, 10 mg once daily, 20 kg, 20 mg once daily. For adults, for active duodenal ulcer, 20 mg/day for 4-8 weeks; for gastric ulcers, 40 mg/day for 4-8 weeks; for symptomatic GERD, 20 mg/day for up to 4 weeks; for erosive esophagitis, 20 mg/day for 4-8 weeks, maintenance dose is 20 mg/day for up to 12 months total therapy (including treatment period of 4-8 weeks); for H. pylori eradication, 20 mg once daily or 40 mg/day as single dose or in 2 divided doses, requires combination therapy with antibiotics; for pathological hypersecretory conditions, initiate at 60 mg once daily, doses up to 120 mg tid have been administered, administer daily doses >80 mg in divided doses; for frequent heartburn (OTC labeling), 20 mg/day for 14 days; treatment may be repeated after 4 months if needed. PANTOPRAZOLE, for adults, for erosive esophagitis associated with GERD, 40 mg once daily for up to 8 weeks, an additional 8 weeks may be used in patients who have not healed after an 8-week course, maintain at 40 mg once daily, lower doses (20 mg once daily) have been used successfully in mild GERD treatment and maintenance of healing; for hypersecretory disorders (including Zollinger-Ellison), initiate at 40 mg bid, adjust dose based on patient needs, doses up to 240 mg/day have been administered; for H. pylori eradication (unlabeled use), doses up to 40 mg bid have been used as part of combination therapy. RABEPRAZOLE, for adults >18 years and the elderly, for GERD, 20 mg once daily for 4-8 weeks, maintenance is 20 mg once daily; for duodenal ulcer, 20 mg/day before breakfast for 4 weeks; for H. pylori eradication, 20 mg bid for 7 days, to be administered with amoxicillin 1000 mg and clarithromycin 500 mg, also given twice daily for 7 days; for hypersecretory conditions, 60 mg once daily, dose may need to be adjusted as necessary, doses as high as 100 mg once daily and 60 mg bid have been used. RANITIDINE, for children 1 month to 16 years, for duodenal and gastric ulcer, 2-4 mg/kg/ day divided twice daily, maximum treatment dose is 300 mg/day, maintain at 2-4 mg/kg once daily, maximum maintenance dose is 150 mg/day; for GERD and erosive esophagitis, 5-10 mg/kg/day divided twice daily, max-

6 238 INTEGRATIVE PHARMACOLOGY Arrhythmia: An irregular heartbeat Gynecomastia: An abnormal enlargement of one or two breasts in men Galactorrhea: Abnormal production and secretion of milk from the beasts or any white discharge from the nipple Tachycardia: A rapid heart rate defined as over 100 bpm Fibrillation: Recurrent, abnormal muscle contraction that is not physiologically useful Torsade de Pointes: A specific type of ventricular tachycardia characterized by rapid irregular QRS complexes. It may end spontaneously or degenerate into ventricular fibrillation. It causes significant blood flow compromise and often causes death. imum for GERD is 300 mg/day and for erosive esophagitis, it is 600 mg/day. For children 12 years, for prevention of heartburn, 75 mg minutes before eating food or drinking beverages which cause heartburn, maximum dose is 150 mg/24 hours, do not use for more than 14 days. For adults, for duodenal ulcer, 150 mg bid, or 300 mg once daily after the evening meal or at bedtime, maintenance dose is 150 mg nocte; for H. pylori eradication, 150 mg bid, requires combination therapy; for pathological hypersecretory conditions, 150 mg bid, adjust dose or frequency as clinically indicated; doses of up to 6 g/day have been used; for gastric ulcer, benign, 150 mg bid, maintenance dose is 150 mg nocte; for erosive esophagitis, 150 mg qid, maintenance dose is 150 mg bid; for prevention of heartburn, 75 mg minutes before eating food or drinking beverages which cause heartburn, maximum dose is 150 mg in 24 hours, do not use for more than 14 days. SUCRALFATE, for children, dose not established, doses of mg/kg/day divided every 6 hours have been used; for stomatitis (unlabeled use), ml (1 g/10 ml suspension), swish and spit or swish and swallow qid. For adults, for stress ulcer prophylaxis, 1 g qid; for stress ulcer treatment, 1 g every 4 hours; for duodenal ulcer, 1 g qid on an empty stomach and at bedtime for 4-8 weeks, or alternatively 2 g bid, treatment is recommended for 4-8 weeks in adults, the elderly may require 12 weeks, maintenance for prophylaxis, 1 g bid; for stomatitis (unlabeled use), 1 g/10 ml suspension, swish and spit or swish and swallow qid. ADVERSE EFFECTS Antimuscarinic agents are used only in refractory cases given the amount of adverse effects that are reported at the doses necessary for gastric effects. Two serious side effects include arrhythmias and urinary retention. H 2 -histamine antagonists are generally well tolerated with a small number of users complaining of side effects. The most common of these effects include headache, diarrhea, dizziness, and muscular pain. Some nervous system effects, such as confusion or hallucinations, occur in elderly patients or with IV administration. Cimetidine has an antiandrogen effect and may cause gynecomastia, galactorrhea, and reduced sperm count when used long-term and/or in large quantities. Prostaglandins can produce uterine contractions and are contraindicated during pregnancy. The most common side effects are nausea and diarrhea and are dose-related. Proton-pump inhibitors have been shown to produce gastrin secreting tumors in animals, but no evidence exists of the same occurring in humans. There have been reports of viable bacteria colonies in the stomach with the use of these agents. RED FLAGS Patients taking cisapride have reported serious cardiac arrhythmias including ventricular tachycardias, ventricular fibrillations, Torsade de Pointes, and QT prolongations. INTERACTIONS DRUG Cimetidine inhibits cytochrome P450 and can slow metabolism of warfarin, diazepam, phenytoin, quinidine, carbamazepine, theophylline, and imipramine. Cisapride should not be used with clarithromycin among other drugs as they can increase the blood levels of cisapride. H 2 - antagonists should not be used with ketoconazole as the later needs an appropriately acidic environment for absorption. Theoretically, this interaction should be true of all the agents in this category that reduce acidity. Omeprazole interferes with the oxidation of

7 DRUGS AFFECTING THE GASTROINTESTINAL SYSTEM 239 warfarin, phenytoin, diazepam, and cyclosporine. Sucralfate should not be combined with histamine antagonists or antacids as it needs an acidic environment to exert its effects. It can also affect the absorption of other drugs by binding with them. HERB Given that most of these drugs reduce the acidity of the stomach, herbs that are hard to digest may not be fully absorbed. ANTACIDS Ma Huang (Ephedra) (C) based on ephedrine content, antacids may cause ephedrine and pseudoephedrine toxicity from Ma Huang due to alkalinization of the urine (Brater, et al., 1980) Level 4 CIMETIDINE Lu Cha (Green tea) (D) the effect of caffeine in Lu Cha may be potentiated by cimetidine, CISAPRIDE Shan Zha (Hawthorn berry) (D) may inhibit potassium inflow causing an increased action potential in cardiac ventricular cells when used with cisapride, expert opinion (Gruenwald, Brendler, & Jaenicke, 2004) Level 5 FAMOTIDINE Aromatic and damp resolving herbs (D) may increase stomach acid and peristalsis possibly antagonizing histamine- 2 antagonists and proton-pump inhibitors, HISTAMINE- 2 RECEPTOR ANTAGONISTS Aromatic and damp resolving herbs (D) may increase stomach acid and peristalsis possibly antagonizing histamine- 2 antagonists and proton-pump inhibitors, LANSOPRAZOLE Aromatic and damp resolving herbs (D) may increase stomach acid and peristalsis possibly antagonizing histamine- 2 antagonists and proton-pump inhibitors, OMEPRAZOLE Aromatic and damp resolving herbs (D) may increase stomach acid and peristalsis possibly antagonizing histamine- 2 antagonists and proton-pump inhibitors, Bai Zhu (White atractylodes) (D) a component, hinesol, may potentiate omeprazole, bench research (Satoh, Nagaia, & Kano, 2000) Level 5 Cang Zhu (Atractylodes) (D) a component, hinesol, may potentiate omeprazole (Satoh, Nagaia, Kano, 2000) Level 5 PROTON-PUMP INHIBITORS Aromatic and damp resolving herbs (D) may increase stomach acid and peristalsis possibly antagonizing histamine- 2 antagonists and proton-pump inhibitors, RANITIDINE Aromatic and damp resolving herbs (D) may increase stomach acid and peristalsis possibly antagonizing histamine- 2 antagonists and proton-pump inhibitors, VITAMIN Prolonged inhibition of gastric acid can cause vitamin B 12 depletion as acid is required for absorption.

8 240 INTEGRATIVE PHARMACOLOGY SECTION 2: ANTIEMETIC AGENTS ANTICHOLINERGIC AGENTS: SCOPOLAMINE, TRIMETHOBENZAMIDE (See Chapter 4, Section 3) ANTIHISTAMINES: MECLIZINE, PROMETHAZINE (See Chapter 8, Section 2) ANTIPSYCHOTICS: HALOPERIDOL, PROCHLORPERAZINE (See Chapter 5, Section 6, Class 1) CANNABINOIDS: DRONABINOL (droe NAB i nol) (Marinol ) NABILONE (NA bi lone) (Cesamet ) CORTICOSTEROIDS: DEXAMETHASONE (See Chapter 7, Section 4) PROKINETIC GASTROINTESTINAL AGENTS: METOCLOPRAMIDE (met oh kloe PRA mide) (Reglan ) SELECTIVE 5-HT 3 (SEROTONIN) RECEPTOR ANTAGONISTS: DOLASETRON (dol A se tron) (Anzemet ) GRANISETRON (gra NI se tron) (Kytril ) ONDANSETRON (on DAN se tron) (Zofran ODT, Zofran ) PALONOSETRON (pal oh NOE se tron) (Aloxi ) SUBSTANCE P/NEUROKININ 1 RECEPTOR ANTAGONIST: APREPITANT (ap RE pi tant) (Emend ) These agents are used to treat nausea and vomiting especially in the case of chemotherapy. Nearly 70-80% of chemotherapy patients experience nausea and vomiting which depends on many factors including the specific chemotherapy agent, dose, route and times of administration, as well as patient factors such as age, sex, and personal tolerance. FUNCTION Emetogenic: Causes nausea and vomiting In addition to other functions, these agents all reduce nausea and vomiting. Scopolamine, and the antihistamines are useful for treating motion sickness. The other agents are useful for various types of chemotherapy-induced nausea and vomiting. Promethazine is useful for treating low to moderate emetogenic chemotherapy agents. Antipsychotics, based on their adverse effects are generally reserved for use when other agents fail. Cannaboids are useful in treating moderate emetogenic agents but are generally considered second-line agents due to their adverse effects. Corticosteroids can be useful in treating emesis from mild to moderate emetogenic agents. They are generally used in conjunction with other agents. The selective 5-HT 3 (serotonin) antagonists generally have a long duration of action and are useful for all types of emesisinducing chemotherapy agents. Prokinetic gastrointestinal agents are highly useful in treating emesis in patients who use cisplatin, which is highly emetogenic. Substance P/Neurokinin 1 antagonists are very useful in treating emesis in patients taking cisplatin. It is used in conjunction with a corticosteroid and an elective 5-HT 3 (serotonin) antagonist. MECHANISM OF ACTION There are two main areas where the impulse to nausea and vomiting are created. The first is the chemo trigger zone. This is an area of the fourth ventricle of the brain and part of the brain stem that is outside of the blood brain barrier and is therefore sensitive to the chemistry of the cerebrospinal fluid and the blood. Adverse chemistry in either of these two fluids can cause a nausea/vomiting response.

9 DRUGS AFFECTING THE GASTROINTESTINAL SYSTEM 241 The second area is the vomiting center located in the medulla oblongata (also just called the medulla) of the brain stem. This area oversees the physical aspects and mechanisms of vomiting. It receives input from many areas including the vestibular system (the main progenitor of motion sickness), the periphery, especially the pharynx and the GI tract, and higher brainstem and cortical areas of the brain. Chemotherapy causes nausea and vomiting by directly stimulating these areas as well as potentially triggering the peripheral s activated through cell damage. Higher areas of the brain can also stimulate these areas and cause nausea and vomiting even before the use of chemotherapy agents in a phenomenon called anticipatory vomiting. The cannaboids mechanism of action is unknown but is thought not to be central given that synthetic cannaboids that are not psychotropic are still antiemetic. The corticosteroids mechanism of treating emesis is unknown but is thought to involve blocking prostaglandins. Promethazine acts by blocking dopamine s in the vomiting center. Prokinetic gastrointestinal agents also work by blocking dopamine s as well as serotonin s in the chemo trigger zone. The selective 5-HT 3 (serotonin) antagonists selectively block serotonin s in the periphery and in the chemo trigger zone. Substance P/Neurokinin 1 antagonists act by blocking neurokinin in the brain. These agents are new and their full activities are not completely understood. DOSAGES APREPITANT, for adults, 125 mg on day 1, followed by 80 mg on days 2 and 3 in combination with a corticosteroid and 5-HT 3 antagonist. DOLASETRON, for children 2-16 years, for nausea and vomiting prophylaxis, chemotherapy-induced (including initial and repeat courses), 1.8 mg/kg within 1 hour before chemotherapy up to a maximum of 100 mg/dose; for prevention of postoperative nausea and vomiting, 1.2 mg/kg within 2 hours before surgery up to a maximum of 100 mg/dose. For adults, for nausea and vomiting prophylaxis, chemotherapy-induced (including initial and repeat courses), 100 mg single dose 1 hour prior to chemotherapy; for prevention of postoperative nausea and vomiting, 100 mg within 2 hours before surgery. DRONABINOL, for children and adults, as an antiemetic, 5 mg/m2 1-3 hours before chemotherapy, then 5 mg/m2/dose every 2-4 hours after chemotherapy for a total of 4-6 doses/day, increase doses in increments of 2.5 mg/m2 up to a maximum of 15 mg/ m2/ dose. For adults, as an appetite stimulant, initiate at 2.5 mg bid (before lunch and dinner), increase up to a maximum of 20 mg/day. GRANISETRON, for adults, for prophylaxis of chemotherapy-related emesis, 2 mg once daily up to 1 hour before chemotherapy or 1 mg bid, the first 1 mg dose should be given up to 1 hour before chemotherapy; prophylaxis of radiation therapy-associated emesis, 2 mg once daily given 1 hour before radiation therapy. METOCLOPRAMIDE, for children, for gastroesophageal reflux (unlabeled use), mg/kg/dose qid. For adults, for gastroesophageal reflux, mg/dose up to qid 30 minutes before meals or food and at bedtime, single doses of 20 mg are occasionally needed for provoking situations, treatment >12 weeks has not been evaluated; for diabetic gastric stasis, 10 mg 30 minutes before each meal and at bedtime; for chemotherapy-induced emesis, alternate dosing: moderate emetic risk chemotherapy: 0.5 mg/kg every 6 hours on days 2-4, low and minimal risk chemotherapy: 1-2 mg/kg every 3-4 hours, breakthrough treatment: 1-2 mg/kg Vestibular: Pertaining to the inner ear apparati in control of body balance Psychotropic: Can affect the mind, emotions, and behavior; pertaining to drugs used in the treatment of mental illness

10 242 INTEGRATIVE PHARMACOLOGY Dysphonia: Any disorder affecting voice quality or the ability to produce voice Extrapyramidal symptoms: Exhibiting movement disorders, especially postural and locomotor, resembling Parkinson s disease every 3-4 hours or moderate emetic risk chemotherapy: 0.5 mg/kg every 6 hours or 20 mg qid on days 2-4, low and minimal risk chemotherapy: mg every 4-6 hours, breakthrough treatment: mg every 4-6 hours. NABILONE, for children >4 years (unlabeled use), <18 kg: 0.5 mg bid, kg: 1 mg bid, >30 kg: 1 mg tid. For adults, 1-2 mg bid up to a maximum of 6 mg divided in 3 doses daily. ONDANSETRON, for children, prevention of chemotherapy-induced emesis, 4-11 years, 4 mg 30 minutes before chemotherapy, repeat 4 and 8 hours after initial dose, then 4 mg every 8 hours for 1-2 days after chemotherapy completed. For children 12 years: refer to adult dosing. For adults, for chemotherapy-induced emesis, for highly-emetogenic agents/singleday therapy, 24 mg given 30 minutes prior to the start of therapy; moderately-emetogenic agents, 8 mg every 12 hours beginning 30 minutes before chemotherapy, continuously for 1-2 days after chemotherapy completed; for total body irradiation, 8 mg 1-2 hours before each daily fraction of radiotherapy; for single high-dose fraction radiotherapy to abdomen, 8 mg 1-2 hours before irradiation, then 8 mg every 8 hours after first dose for 1-2 days after completion of radiotherapy; for daily fractionated radiotherapy to abdomen, 8 mg 1-2 hours before irradiation, then 8 mg 8 hours after first dose for each day of radiotherapy; for postoperative nausea and vomiting: 16 mg given 1 hour prior to induction of anesthesia; for treatment of hyperemesis gravidum (unlabeled use), 8 mg every 12 hours. ADVERSE EFFECTS Cannaboids have many adverse effects that limit their clinical usefulness. These include dysphonia, hallucinations, sedation, vertigo, and disorientation. Prokinetic gastrointestinal agents have a variety of adverse effects of blocking dopamine including sedation, diarrhea, and extrapyramidal symptoms. These effects are most common in younger patients. Promethazine causes hypotension and restlessness and even though its antiemetic properties are increased with higher doses, so are these adverse effects. Extrapyramidal symptoms and sedation may also occur. Selective 5-HT 3 (serotonin) antagonists commonly cause headaches. Dolasetron has been reported to cause prolongation of the QT interval on ECGs and should be used with caution in patients who may be at risk. Substance P/Neurokinin 1 antagonists can cause constipation and fatigue. RED FLAGS INTERACTIONS DRUG Substance P/Neurokinin 1 antagonists are metabolized by CYP3A4 and drugs needing this enzyme may have their metabolism altered. Use with warfarin may shorten its half-life.

11 DRUGS AFFECTING THE GASTROINTESTINAL SYSTEM 243 SECTION 3: ANTIDIARRHEALS The majority of these agents are sold over-the-counter and are not covered here. ASPIRIN (See Chapter 11, Section 1) DIFENOXIN (dye fen OKS in) (Motofen, 5 ) DIPHENOXYLATE (dye fen OKS i late) (Lomotil, 6 Lonox 6 ) INDOMETHACIN (See Chapter 11, Section 1) OPIUM TINCTURE (See Chapter 5, Section 7) PSYLLIUM (SIL i yum) (Fiberall ) FUNCTION There are three main types of antidiarrheals: antimotility agents, adsorbents, and agents that modify fluid and electrolyte transport. Anti motiliy agents decrease peristalsis and slow the action of the intestines. These include difenoxin, diphenoxylate, and opium tincture. Psyllium is an adsorbent. These agents can also be used as laxatives. Agents that modify fluid and electrolyte transport include aspirin and indomethacin. MECHANISM OF ACTION Antimotiliy agents decrease peristalsis and slow the action of the intestines by activating presynaptic opioid s in the enteric nervous system which inhibits acetylcholine release. Adsorbents act by absorbing intestinal toxins or microorganisms and/or by protecting or coating the mucosa. When used as a laxative, this is a bulkifying agent. Agents that modify fluid and electrolyte transport, in all probability, act by inhibition of prostaglandin synthesis. DOSAGES PSYLLIUM, for children 6-11 years, approximately 1/2 adult dosage, for children 12 years and adults, take 1 dose up to 3 times/day; all doses should be followed with 8 oz of water or liquid. For capsules, a dose is 4 capsules. For powder, a dose is 1 rounded tablespoonful. For tablets, a dose is 1 tablet. For wafers, a dose is equal to 2 wafers. ADVERSE EFFECTS Antimotiliy agents can cause fatigue, abdominal cramping, and dizziness. Adsorbents can cause constipation especially when taken without enough fluids. RED FLAGS Antimotiliy agents may cause toxic megacolon and should not be used in young children or in patients with severe colitis. INTERACTIONS DRUG Adsorbents can interfere with the absorption of other drugs and should be administered at least 2 hours before or after other drugs. HERB These agents are designed to alter the functioning of the small and large intestines and could therefore affect the absorption of herbs. These agents should be administered either 4 hours before or 2 hours after to minimize interactions. Enteric nervous system: A semiautonomous system of nerves located within the digestive system; while a separate system from the CNS and ANS, it can still receive modifying input from these systems. Two plexuses primarily constitute this system: the submucosal nerve plexus and the myenteric nerve plexus. Toxic megacolon: A severe complication of several conditions that involves a large dilation of the colon with possible local bacterial overgrowth. Rupture of the colon is a possibility and has a 50% mortality. Emergency treatment for this condition is necessary and can prevent sepsis, shock, and possibly death. Colitis: An inflammatory condition of the large intestine

12 244 INTEGRATIVE PHARMACOLOGY SECTION 4: LAXATIVES The majority of these agents are sold overthe-counter and are not covered here. LACTULOSE (LAK tyoo lose) (Constulose, Enulose, Generlac, Kristalose ) POLYETHYLENE GLYCOL (pol i ETH i leen GLY kol) (Colyte, GoLYTELY, GlycoLax MiraLax, NuLYTELY, TriLyte ) PSYLLIUM (See Previous Section) Emulsify: To disperse a liquid into another liquid FUNCTION Laxatives cause the movement of stool, usually in order to treat constipation. They fall into three categories: irritants and stimulants, bulking agents, and stool softeners. Each of the prescribed agents listed above are in the category of bulking agents. MECHANISM OF ACTION Irritants and stimulants act by either irritating the GI tract and increasing peristalsis or by directly stimulating colonic activity. Bulking agents, such as psyllium, are fiber and other indigestible foods that form a gel in the intestines by absorbing water and causing intestinal distension. This stimulates peristalsis. Agents, such as polyethylene glycol and lactulose, are actually osmotic agents that cause water to stay in the intestines causing similar effects as bulking agents. Stool softeners are what the name implies: they soften the stool by emulsifying with the stool. This allows for easier passage of the stool. DOSAGES LACTULOSE, for infants, for prevention of portal systemic encephalopathy (PSE), ml/ day divided 3-4 times/day, adjust dosage to produce 2-3 stools/day. For older children, for prevention of portal systemic encephalopathy (PSE), daily dose of ml divided 3-4 times/day, if initial dose causes diarrhea, then reduce it immediately, adjust dosage to produce 2-3 stools/day. For children, for constipation, 5 g/day (7.5 ml) after breakfast. For adults, for constipation, ml/day increased to 60 ml/day in 1-2 divided doses if necessary; for acute PSE, g (30-45 ml) every 1-2 hours to induce rapid laxation, adjust dosage daily to produce 2-3 soft stools, doses of ml may be given hourly to cause rapid laxation, then reduce to recommended dose, usual daily dose is g ( ml) daily. POLYETHYLENE GLYCOL, for children 6 months, for bowel cleansing prior to GI exam, ml/kg/hour for 4-10 hours (until rectal effluent is clear), ideally, patients should fast for 3-4 hours prior to administration, absolutely no solid food for at least 2 hours before the solution is given, patients <2 years should be monitored closely. For adults, for bowel cleansing prior to GI exam, 240 ml (8 oz) every 10 minutes, until 4 L are consumed or the rectal effluent is clear, rapid drinking of each portion is preferred to drinking small amounts continuously, ideally, patients should fast for 3-4 hours prior to administration, absolutely no solid food for at least 2 hours before the solution is given. ADVERSE EFFECTS No adverse effects observed. RED FLAGS No major red flags noted. INTERACTIONS DRUG Laxatives can alter the regular kinetics of drug absorption by altering the transit time of substances in the intestines. This can affect almost any other drug. Whether or not this effect is significant depends on individual drugs.

13 DRUGS AFFECTING THE GASTROINTESTINAL SYSTEM 245 HERB These agents are designed to alter the functioning of the small and large intestines and could therefore affect the absorption of herbs. These agents should be administered either 4 hours before or 2 hours after to minimize interactions. LAXATIVES Downward draining herbs (D) such as Da Huang (Rhubarb root), Mang Xiao (Sodium sulfate, mirabilite), Fan Xie Ye (Senna leaves), etc.; should be used with caution with laxatives as they can act synergistically and cause excessive diarrhea, dehydration, and electrolyte imbalance, expert opinon (Chen & Chen, 2004) Level 5 Gan Cao (Licorice) (D) theoretically may lead to increased potassium loss when used with laxatives, expert opinion (Gruenwald, Brendler, & Jaenicke, 2004) Level 5 ENDNOTES 1 Combination of Naproxen and Lansoprazole. 2 Combination of Amoxicillin, Lansoprazole, and Clarithromycin. 3 Combination of Omeprazole and Sodium Bicarbonate. 4 Combination of Diclofenac and Misoprostol. 5 Motofen contains difenoxin in addition to atropine and is used in treating diarrhea. 6 Combination of Atropine and Diphenoxylate. CHINESE MEDICAL DESCRIPTIONS The Chinese medical explanation of the drug categories in this chapter may be found in Chapter 13 on pages