Gastroenterology

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Chapter 15 Gastroenterology

Antacids: Buffers

Description

These are agents that act as buffers in the stomach, neutralizing acid through a simple chemical reaction.

Prototypes

Calcium-Containing Agents

image Prototype: calcium carbonate (CaCO3)

Aluminum-Containing Agents

image Prototype: aluminum hydroxide (AlOH3)

Magnesium-Containing Agents

image Prototype: magnesium hydroxide (MgOH2)

Moa (Mechanism of Action)

image All buffers act locally in the stomach by reacting with H+ to increase pH. All buffers are bases; therefore they reduce acidity by reacting with acid in the stomach to form a neutral solution:

image

Pharmacokinetics

image Calcium, magnesium, and aluminum are typically poorly absorbed. However, patients with impaired renal function can have accumulation of these cations.
image Divalent and trivalent cations such as Ca2+, Mg2+, and Al3+ may chelate other drugs, interfering with their absorption. Where possible, administration of antacids should be separated from administration of other drugs that require systemic absorption, ideally by 2 hours.
image Antacids administered in suspension may have greater acid-neutralizing efficacy than those administered as tablets or powders.

Indications

image Hyperacidity, including reflux disease
image Indigestion

Contraindications

image None of major significance

Side Effects

Mg2+-Containing Buffers

image Diarrhea: Mg2+ salt exerts an osmotic effect on the gut.

Ca2+-Containing Buffers

image Hypercalcemia (at high doses): These agents may lead to formation of calculi (milk alkali syndrome). Calculi are solid formations, typically consisting of minerals, which precipitate in organs such as the kidney and obstruct ducts.
image Bloating, flatulence, belching, nausea: These effects are caused by the liberation of CO2 from carbonate-containing antacids.
image Constipation

Al3+-Containing Buffers

image Hypophosphatemia: Al3+ can bind phosphate in the gut, inhibiting its absorption.
image Constipation

Important Notes

image Although these agents act locally in the stomach, they are not devoid of systemic adverse effects, particularly at higher doses or with chronic use.
image As with other antacids, buffers may reduce pH enough to interfere with absorption of drugs that require a low pH for absorption.
image Al3+ and Mg2+ are often combined into one antacid formulation because of their complementary onset of action (Mg2+ is rapid, Al3+ is slow reacting) and side effects (Mg2+ causes diarrhea, Al3+ constipation).
image Simethicone is a surfactant added to antacids to decrease bloating. A surfactant is a substance that reduces surface tension, in this case reducing large bubbles into smaller ones. The foaming action of simethicone may also alleviate gastroesophageal reflux.
image Sodium bicarbonate, one of the first antacids, is still used in some regions. This formulation has fallen out of favor because of concerns over systemic alkalosis and the impact of sodium on cardiovascular health.
image Milk alkali syndrome is a rare disorder caused by ingestion of large amounts of calcium, resulting in hypercalcemia and alkalosis.

FYI

image Although the agents in this class have traditionally been referred to as antacids, the term antacid has much wider use and applies to each of the many classes of drugs that reduce acid secretion. The more appropriate term for the agents in this class is buffer, as this describes their mechanism and distinguishes them from other classes.

H2 Antagonists

Description

H2 antagonists comprise a group of agents that reduce acid secretion in the stomach.

Prototype and Common Drugs

image Prototype: ranitidine
image Others: cimetidine, famotidine, nizatidine

Moa (Mechanism of Action)

image The amount of gastric acid is largely determined by the secretion of protons (H+) by parietal cells in the stomach, as well as volume of stomach contents.
image In the parietal cell, the proton pump, H+/K+ ATPase, creates an ion gradient by pumping H+ into the lumen of the stomach. The pump is key to creating the acidic environment of the stomach (pH <1) while maintaining a relatively normal intracellular pH (approximately 7.3).
image The H2 receptor on parietal cells mediates both the basal and meal-stimulated release of acid. The binding of histamine to the H2 receptor stimulates the proton (H+/K+ ATPase) pump via the second messenger cyclic adenosine monophosphate (cAMP) (Figure 15-1).
image H2 antagonists competitively block the interaction of histamine with H2 receptors, thus reducing stimulation of the proton pump through this receptor.
image Nocturnal acid secretion depends largely on histamine; thus the H2 antagonists have a greater impact on nocturnal acid secretion than meal-stimulated acid secretion, which is stimulated by gastrin and acetylcholine (ACh), in addition to histamine.
image An additional mechanism, by which H2 antagonists are also able to attenuate the gastrin and ACh-stimulated release of gastric acid, has been proposed by some sources. ACh, by binding to muscarinic (M3) receptors, and gastrin, by binding to cholecystokinin (CCK2) receptors, also stimulate the proton pump.
image It is not clear how H2 antagonism attenuates the ability of gastrin and ACh to stimulate activity of the proton pump, but this would most likely be mediated through second messengers.
image

Figure 15-1

Pharmacokinetics

image All the H2 antagonists are available in oral formulations. Intravenous and intramuscular formulations of cimetidine, ranitidine, and famotidine are also available.
image Oral formulations are all rapidly absorbed, achieving peak plasma concentrations in 1 to 3 hours.
image All of the H2 antagonists are excreted by the kidneys, both by filtration and by renal tubular secretion; hence it may be necessary to adjust the dose of these agents in patients with impaired renal function.

Indications

image Gastroesophageal reflux disease (GERD)
image Peptic ulcer disease (with or without bleeding)
image Dyspepsia
image Gastritis
image Gastric protection in patients on life support

Contraindications

image None of major significance

Side Effects

image Generally well tolerated
image Common: Diarrhea, headache, drowsiness, fatigue, muscle pain, and constipation may occur.
image Rare central nervous system (CNS) side effects: Confusion, delirium, hallucinations, slurred speech, and headache can occur and are thought to be caused by antagonism of H2 receptors in the CNS. These CNS effects are more likely to occur with intravenous administration or in the elderly.
image Thrombocytopenia (rare): The mechanism has not been established, but theories include bone marrow suppression due to inhibition of DNA synthesis, and the development of platelet antibodies against H2 antagonists.

Cimetidine Only

image Gynecomastia (breast development in men) and galactorrhea (lactation not associated with childbirth): Cimetidine inhibits binding of testosterone to the androgen receptor, and as a CYP450 inhibitor, it inhibits the hydroxylation of estradiol.

Important Notes

image The H2 antagonists are considered to be less effective than the more expensive proton pump inhibitors (PPIs). However, it is important to note that the H2 antagonists are able to reduce daily acid secretion by about 60% to 70%.
image Tolerance can develop to the acid-suppressant effects of the H2 antagonists, occurring as early as 3 days after initiation of therapy. One theory is that secondary hypergastrinemia may stimulate histamine release from enterochromaffin-like cells. Hypergastrinemia is an elevation in gastrin levels in the blood in response to low pH in the stomach. Gastrin stimulates the proton pump to release acid into the stomach.
image Cimetidine may also enhance cell-mediated immunity when administered in high doses. This has lead to its use in treating infections such as candidiasis and herpesvirus in immunocompromised patients, as well as warts.

Advanced

Drug Interactions

image Cimetidine inhibits a variety of CYP450 enzymes; thus drug interactions are common with this agent.

Evidence

Versus Other Agents for Treatment of GERD

image A 2006 Cochrane review (31 studies, N = 9457 patients) found that PPIs were more efficacious for achieving heartburn remission than H2-receptor antagonists (seven trials, relative risk [RR] 0.66) and prokinetics (two trials, RR 0.53).

Versus Other Agents for Endoscopy Negative Reflux Disease

image The same 2006 Cochrane review found that PPIs were more efficacious at achieving heartburn remission compared with H2 antagonists (three trials, RR 0.78) and compared with prokinetics (one trial, RR 0.72). Endoscopy-negative reflux disease is simply GERD without any evidence of histologic changes on endoscopic examination.

Versus Proton Pump Inhibitors for Acute Bleeding from Peptic Ulcer

image A 2006 Cochrane review (24 studies, N = 4373 patients) found no statistically significant difference between PPIs and H2 antagonists with regard to the incidence of surgery required to treat peptic ulcer bleeding.

Versus Other Agents for Nonulcer Dyspepsia

image A 2006 Cochrane review (73 trials) examined the efficacy of various agents in nonulcer dyspepsia. H2-receptor antagonists (12 trials, N = 2183 participants) improved dyspepsia in more patients than placebo (54% versus 40%), and PPIs also demonstrated improvement versus placebo (34% versus 25%).

FYI

image Because of their relatively innocuous side effect profile, the H2 antagonists, particularly ranitidine and famotidine, are available over the counter in most jurisdictions. Because of its propensity for drug interactions, cimetidine is not available over the counter in some jurisdictions.

Proton Pump Inhibitors (PPIs)

Description

PPIs comprise a class of agents that reduce acid secretion by inhibiting the acid (proton)–secreting pump in the stomach. Accordingly, they are also often referred to as antisecretory agents.

Prototype and Common Drugs

image Prototype: omeprazole
image Others: pantoprazole, lansoprazole, esomeprazole, rabeprazole

Moa (Mechanism of Action)

image The amount of gastric acid is largely determined by the secretion of protons (H+) by parietal cells in the stomach, as well as the volume of stomach contents.
image In the parietal cell, the proton pump, H+/K+ ATPase, creates an ion gradient by pumping H+ into the lumen of the stomach. The pump is key to creating the acidic environment of the stomach (pH <1) while maintaining a relatively normal intracellular pH (approximately 7.3) (Figure 15-2).
image PPIs enter the parietal cell and bind to the proton pump, resulting in an irreversible inactivation of the pump. This dramatically reduces the amount of H+ that is pumped into the lumen of the stomach, and because the binding is irreversible, the effects of PPIs persist until new pumps are synthesized. The reduction in gastric acid secretion can thus persist up to 48 hours after a single dose.
image The PPIs tend to be particularly adept at reducing acid secretion because the proton pump is the final and key step in secreting acid (H+) into the lumen of the stomach. All other agents that suppress acid secretion work by reducing gastric H+ concentration act upstream of the proton pump, rather than directly at the proton pump.
image The release of gastrin is modulated by intragastric acid levels, such that higher acidity suppresses gastrin release. Gastrin stimulates ECL cell hyperplasia, which may predispose patients to developing malignancies.
image

Figure 15-2

Pharmacokinetics

image Although they act on cells in the stomach, PPIs must be absorbed into the systemic circulation from the small intestine. It is from the systemic circulation that they reach the parietal cells of the stomach.
image This is important because the PPIs (ironically) tend to be unstable in an acidic environment. Hence all PPIs have some form of enteric coating, to protect them until they reach the small intestine and can be absorbed. Disruption of this enteric coating (e.g., by splitting the tablet) will likely reduce the bioavailability of the PPI.
image All PPIs are prodrugs that are activated in the acidic environment of the parietal cell acid canaliculi. Food intake stimulates acid secretion. Oral PPIs should be taken approximately 30 to 60 minutes before meals. This allows enough time for the PPI to be absorbed into the systemic circulation and to be distributed to the parietal cells. This will also ensure that the PPIs are active at the same time as maximal activation of the proton pumps.
image All PPIs are cleared primarily by hepatic metabolism.

Indications

image Gastric and duodenal ulcers

image Nonsteroidal antiinflammatory drug (NSAID)-induced ulcers
image Non–NSAID-induced ulcers
image Helicobacter pylori eradication

image GERD
image Upper gastrointestinal (GI) bleeding
image Pathologic hypersecretory conditions:

image Zollinger-Ellison syndrome—a rare syndrome characterized by gastric hypersecretion and hyperacidity as well as persistent peptic ulcers

Contraindications

image None of major significance

Side Effects

image Generally well tolerated

Common

image GI: nausea, abdominal pain, constipation, diarrhea, flatulence

Less Common

image Hypergastrinemia: Gastrin levels become elevated because of the body’s response to chronic gastric acid suppression. This may lead to rebound hypersecretion of gastric acid if the PPI is stopped. There is also concern over the chronic effects of hypergastrinemia, including development of gastric tumors.

Important Notes

image Of all agents used to treat hyperacidity, PPIs are the most effective at reducing daily acid secretion, capable of reducing acid (basal and stimulated) by 80% to 95%. H2 antagonists are able to achieve a 60% to 70% reduction in acid.
image PPIs inhibit only active proton pumps. Not all proton pumps are active at the same time; therefore, although pumps are irreversibly inhibited once bound by the PPI, it takes a few days to achieve the inhibition of proton pumps seen at steady state.
image PPIs are often prescribed in combination with other GI drugs and antibiotics for eradication of H. pylori. By increasing intragastric pH, PPIs appear to enhance the antimicrobial activity of these agents. PPIs may also have a minor antimicrobial effect. Some of the more common combinations are listed in Table 15-1.

TABLE 15-1 Combination Therapy for H. pylori Eradication

Proton Pump Inhibitors Other Agents
Lansoprazole Clarithromycin Amoxicillin
Omeprazole Clarithromycin Metronidazole
Pantoprazole   Metronidazole
Rabeprazole Bismuth subsalicylate Tetracycline

Advanced

Drug Interactions

image All PPIs are metabolized by CYP450 enzymes (particularly CYP2C19 and CYP3A4). However, only omeprazole is able to act as both an inhibitor (2C19—phenytoin) and inducer (1A2—antipsychotics) of CYP450 enzymes.
image Some drugs require an acidic environment for their proper dissolution and absorption. By increasing gastric pH, the PPIs may therefore interfere with the absorption of vitamin B12, ampicillin, and ketoconazole, among others.

Pharmacogenomics

image Asians are more likely to have the CYP2C19 genotype that correlates with slow metabolism of the PPIs, and this may lead to increased efficacy and/or toxicity in this population.

Evidence

Versus Other Agents for Treatment of Gastroesophageal Reflux Disease

image A 2006 Cochrane review (31 studies, N = 9457 patients) found that PPIs were more efficacious for achieving heartburn remission than H2-receptor antagonists (seven trials, RR 0.66) and prokinetics (two trials, RR 0.53).

Versus Other Agents for Endoscopy Negative Reflux Disease

image The same 2006 Cochrane review found that PPIs were more efficacious at achieving heartburn remission compared with H2 antagonists (three trials, RR 0.78) and compared with prokinetics (one trial, RR 0.72). Endoscopy-negative reflux disease is simply GERD without any evidence of histologic changes on endoscopic examination.

Versus H2 Antagonists for Acute Bleeding from Peptic Ulcer

image A 2006 Cochrane review (24 studies, N = 4373 patients) found no difference in mortality between PPIs and controls but did find that PPIs reduced rebleeding (incidence of 10.6% for PPI versus 17.3% control) and surgery (6.1% versus 9.3%, respectively) versus control. No benefit was seen for PPIs versus H2 antagonists with regard to surgery.

FYI

image Omeprazole is a racemic mixture of R- and S- isomers, and esomeprazole is the S- isomer of omeprazole (S-omeprazole). Because the S- isomer is eliminated more slowly than the R-isomer, esomeprazole has a longer half-life than omeprazole.

Gastrointestinal Cytoprotectants

Description

Gastrointestinal cytoprotectants are a heterogeneous group of agents that protect cells in the lining of the stomach.

Prototypes and common drugs

image Prostaglandin analogue: misoprostol (prostaglandin E1 [PGE1])
image Coating agents: sucralfate, bismuth

Moa (Mechanism of Action)

Prostaglandin Analogue

image Protection of the mucosal lining of the stomach can be achieved in two ways: by increasing gastric pH or by enhancing the mucosal barrier that protects the stomach.
image The prostaglandin E receptor 3 (EP3) receptors are found on parietal cells of the stomach and, when stimulated, have an inhibitory effect on the proton pump. The proton pump stimulates the release of hydrogen ions (acid) into the lumen of the stomach.
image Endogenous PGE2 acts as an agonist at EP3 receptors on parietal cells and reduces activity of the proton pump, thereby reducing secretion of gastric acid (Figure 15-3).
image PGE2 also contributes to maintenance of the mucosal barrier, stimulating secretion of mucin and bicarbonate and enhancing mucosal blood flow. Mucin is a thick substance that has a protective effect on the lining of the stomach. Bicarbonate helps to raise the pH of the stomach, particularly in the area close to the mucosal lining.
image PGE2 is synthesized through the cyclooxygenase (COX) pathway, largely through the COX-1 enzyme.
image NSAIDs work by inhibiting COX enzymes, thus reducing the amount of PGE2 and subsequently reducing the amount of protective mucus in the stomach. Nonselective (i.e., COX-1 and COX-2) inhibitors are thus implicated in damage to the gastric mucosa.
image Therefore a PGE1 analogue such as misoprostol is typically given as an adjunct in patients undergoing NSAID therapy, for the purpose of substituting for the PGE lost with NSAID use (Figure 15-4).
image

Figure 15-3

image

Figure 15-4

Sucralfate

image Sucralfate is a complex of sucrose and aluminum hydroxide that forms a viscous paste in aqueous acidic media. This negatively charged paste binds to positively charged proteins in the ulcer, forming a direct protective barrier for up to 6 hours.
image Sucralfate works by multiple mechanisms, both direct and indirect, to enhance the amount of mucus to protect cells lining the stomach.
image Indirectly, sucralfate exerts a mucoprotective effect by stimulating PG synthesis of mucus and secretion of bicarbonate. In addition, sucralfate may stimulate growth factors that promote mucosal repair, although this mechanism has not been confirmed.

Bismuth Salts

image Bismuth salts work by forming a protective barrier on the ulcer and enhancing secretion of PGs, mucus, and bicarbonate.
image They also inhibit the growth of H. pylori and prevent adherence of H. pylori to gastric mucosa.

Pharmacokinetics

image Misoprostol has a short half-life and thus must be administered frequently (3 or 4 times daily).
image Sucralfate primarily acts locally in the GI tract, is only minimally absorbed, and is excreted mainly in the feces. It also must be administered 4 times daily. Sucralfate should be administered 1 hour before meals, as it is activated by acid.
image Every tablet of sucralfate contains aluminum. Although only a very small proportion of aluminum is absorbed, because elimination relies on urinary excretion, caution should be exercised in those with chronic renal failure, as an accumulation of aluminum may occur. This is particularly important if these patients are also receiving aluminum in another form, such as an antacid.

Indications

Prostaglandins

(See also ophthalmic prostaglandins and vasodilator prostaglandins in Chapters 22 and 24, respectively, for non-GI indications.)

image Prevention of NSAID-induced ulcers

Sucralfate

image Treatment of duodenal and gastric ulcers
image Prevention of ulcer recurrence

Bismuth

image Adjunctive therapy in H. pylori eradication
image Acute diarrhea
image Heartburn

Contraindications

Misoprostol

image Pregnancy: Misoprostol stimulates uterine contractions and could induce premature labor.

Bismuth Subsalicylate

image Similar to acetylsalicylic acid (ASA), bismuth subsalicylate may be associated with a higher risk of Reye’s syndrome in children; therefore it should be avoided in children or teenagers with viral infections such as influenza or chickenpox. Reye’s syndrome is an often fatal encephalopathy in children that has been associated with the use of ASA during viral infection.

Side Effects

Misoprostol

image Diarrhea, abdominal cramping: Diarrhea is the most common side effect and can be very severe. PGs stimulate contractions of smooth muscle in the GI tract. Patients with inflammatory bowel disease may be at increased risk for developing severe diarrhea.
image Uterine contractions: PGs stimulate uterine contractions.

Sucralfate

image Sucralfate has minimal systemic effects because it is not absorbed to an appreciable extent.
image Constipation occurs rarely, because of the aluminum. It is not clear why aluminum causes constipation.

Bismuth

image Black tarry stools: Bismuth causes discoloration of the stool, which may mask the appearance of or be mistaken for blood in stool. Bismuth salts react with hydrogen sulfide to form bismuth sulfide, which turns stool black.
image Discoloration of tongue: Bismuth can cause a harmless blackening of tongue.
image Constipation may occur.
image Tinnitus: Ringing of the ears may occur at high doses because of the salicylate content.

Important Notes

image The acid-suppressant effects of misoprostol are dose related. An oral dose of 100 to 200 mcg inhibits basal acid secretion by up to 95% and meal-stimulated acid secretion by up to 85%.
image Misoprostol is marketed in a fixed-dose combination with diclofenac.
image Because of the high risk of diarrhea, it is recommended that misoprostol be administered with food to mitigate this side effect.
image Bismuth subsalicylate contains salicylic acid, with a dose of 30 mL having approximately the same salicylate content as a 325-mg ASA tablet. Thus people who have an allergy or intolerance to ASA must avoid bismuth subsalicylate.

Advanced

image Sucralfate may reduce absorption of other drugs, binding them in the GI tract. Because of these and other unexplained interactions, it is recommended that the administration of sucralfate be separated from that of other orally administered agents.
image Sucralfate requires an acidic environment to be active; therefore agents that reduce gastric acidity will reduce its efficacy. Antacids should not be taken within 30 minutes of sucralfate.

Evidence

Prevention of NSAID-Induced Upper GI Toxicity

image A 2002 Cochrane review (40 studies) compared interventions (PG analogues, H2-antagonists, PPIs) for prevention of NSAID-induced upper GI toxicity. The review found that although all classes prevented NSAID-related gastric and duodenal ulcers, only misoprostol reduced the risk of ulcer complications such as perforation, hemorrhage, and obstruction.
image The authors also concluded that misoprostol is associated with significant adverse effects, particularly at higher doses.

FYI

image Misoprostol is used off-label in many jurisdictions for induction of uterine contractions in abortion and has therefore become a controversial drug.
image Colloidal bismuth subcitrate is a commonly used bismuth compound in the rest of the world, but not in North America.

Prokinetics: Dopamine Antagonists

Description

These are dopamine antagonists that are used to enhance gastric motility.

Prototype and Common Drugs

image Prototype: metoclopramide
image Others: domperidone

Moa (Mechanism of Action)

image Dopamine has an inhibitory effect on GI motility, mediated by the inhibitory effect of D2 receptors on ACh release. These natural inhibitory effects of dopamine include reduction of lower esophageal sphincter tone.
image Therefore D2 antagonists increase lower esophageal sphincter tone, and stimulate contractions of the stomach and small intestine. The effects of metoclopramide and domperidone are largely confined to the upper GI tract, with minimal effect on the colon (Figure 15-5).
image The increase in lower esophageal sphincter tone is useful in reflux disorders such as GERD because it reduces the volume of gastric acid that enters the esophagus.
image The D2 antagonists also act as antinauseants through central inhibition of the vomiting center (chemoreceptor trigger zone).
image Although they share D2 antagonism as a mechanism, the prokinetic actions of metoclopramide are very complex compared with those of domperidone. Metoclopramide also has the following actions:

image It acts as an agonist at serotonin-4 (5-HT4) receptors.
image It acts as an antagonist at muscarinic receptors and central 5-HT3 receptors.
image It may also sensitize muscarinic receptors on smooth muscle.

image It is not clear what the relative contributions of these other receptors are to the actions of metoclopramide.
image Conversely, domperidone is almost exclusively a D2 antagonist.
image

Figure 15-5

Pharmacokinetics

image Metoclopramide is rapidly absorbed, undergoes hepatic metabolism, and is excreted mainly in the urine.
image Domperidone is also rapidly absorbed (peak plasma levels in <30 minutes) but has low oral bioavailability because of an extensive first-pass effect.
image Although the bioavailability of domperidone is increased with food, food also increases the time to peak plasma concentration. It is recommended that domperidone be taken 15 to 30 minutes before eating.

Indications

image Disorders of GI motility:

image Gastroparesis
image Nausea, vomiting

image GERD
image Diagnostic procedures (adjunct)
image Facilitation of intubation of the small bowel
image Contrast radiography of GI Tract
image Critically ill patients who do not tolerate enteral feeding

Contraindications

image Avoid using these prokinetics in situations in which stimulation of GI motility may be harmful, such as in patients with obstruction or perforation.

Side Effects

All

image Hyperprolactinemia: DA inhibits prolactin release, so DA antagonism can lead to increased prolactin and the following:

image Galactorrhea: spontaneous flow of milk from the nipple not associated with nursing a baby
image Gynecomastia: development of breasts in males
image Dysmenorrhea: painful menstruation

Metoclopramide

image Extrapyramidal: Extrapyramidal effects are analogous to the side effects seen with the antipsychotics that are DA antagonists:

image Abnormal muscle tone (acute) and Parkinson-like symptoms (after a few weeks): Both are reversible and can also be managed with anticholinergics. DA plays an important role in normal movement, so blocking its effects will lead to disordered movement.
image Tardive dyskinesia: These are abnormal, uncontrolled movements, particularly of the face (lips, tongue). They are seen with chronic therapy (months to years) and may not be reversible. Again, these are believed to be caused by inhibiting the effects of DA on normal movement. In this case, blockade of DA receptors may lead to enhanced sensitivity of these receptors, causing uncontrolled movement.

image Other CNS effects: Drowsiness, restlessness, insomnia, anxiety, and agitation may be more common in the elderly. The mechanism has not been established.
image Rare: Methemoglobinemia may occur in premature and full-term neonates. Methemoglobinemia is a condition in which the hemoglobin in blood is not able to carry oxygen.

Important Notes

image Domperidone does not cross the blood-brain barrier as readily as metoclopramide; therefore it lacks the extrapyramidal side effects associated with metoclopramide. Domperidone still does exert effects on areas that lie outside the blood-brain barrier, including the chemoreceptor trigger zone (nausea, vomiting). Hence domperidone maintains antinauseant effects.
image The prokinetic activity of domperidone is considered to be relatively weak compared with that of metoclopramide.
image Children and young adults may be more susceptible to extrapyramidal side effects associated with metoclopramide.

Advanced

Drug Interactions

image Domperidone is extensively metabolized, primarily by CYP3A4 enzymes.
image Animal studies suggest that P-glycoprotein transporters may be responsible for the low penetration of domperidone into the CNS.
image Because of its prokinetic effect and site of action, metoclopramide may decrease the extent of absorption of drugs from the stomach while accelerating absorption from the small intestine. The clinical implications of these interactions are unknown.

Toxicology

image Metoclopramide is toxic in overdose, oxidizing hemoglobin to methemoglobin. Signs and symptoms of toxicity include cyanosis, nausea, vomiting, vertigo, tachycardia, tachypnea, convulsions, coma, and death. The antidote is methylene blue.

Evidence

Nasoenteral Tube Migration

image A 2002 Cochrane review (four studies, N = 204 patients), updated in 2008, examined the use of intravenous metoclopramide on transpyloric passage of a nasoenteral tube compared with placebo or no intervention. The four included studies were small and did not find a statistically significant improvement in the enhancement of migration of nasoenteral tubes with metoclopramide.

FYI

image Structurally, domperidone is classified as a butyrophenone. This is the same chemical class as haloperidol, a DA antagonist with CNS effects, primarily used in the treatment of schizophrenia.
image Nasoenteral tubes are also known as small bowel feeding tubes. Similar tubes that go into the stomach (instead of the small bowel) are commonly referred to as nasogastric tubes, or NG tubes. If the same tube is inserted via the mouth, it is called an orogastric or OG tube.

Antidiarrheals

Description

Antidiarrheal agents are used to treat diarrhea, either by reducing GI motility or by providing bulk to stool.

Prototypes and Common Drugs

Opiates

image Prototype: loperamide
image Others: diphenoxylate, difenoxin

Bulk or Hygroscopic (“Water-Attracting”) Agents

image Prototype: kaolin/pectin
image Others: attapulgite, bismuth

Moa (Mechanism of Action)

Opiates

image The bowel contains both µ and δ opioid receptors. The δ receptors mediate intestinal secretion, the µ receptors mediate peristalsis, and both types of receptors play a role in intestinal absorption (Figure 15-6).
image Loperamide and diphenoxylate are piperidines, structurally related to opiates such as meperidine. They are µ agonists, although they have less propensity for eliciting the euphoric effect typically seen with opiate analgesics because of limited CNS penetration.
image µ Agonists reduce or completely abolish peristalsis in the colon, significantly delaying passage of feces through the bowel. The delayed transit through the bowel also increases the opportunity for increased absorption of fluid from the feces, producing a drying effect on the stool that further slows its progress through the bowel.
image In addition, anal sphincter tone is also enhanced, as is the reflex relaxation that normally occurs in response to rectal distension.
image

Figure 15-6

Bulk-Forming Agents

image Although bulk-forming agents are used to treat constipation, they have also been successfully used to treat mild cases of diarrhea. The mechanism is not well understood, but colloids that are insoluble and do not ferment may provide some additional structural integrity to the stool, reducing its viscosity.
image Some of the bulk agents may also work by binding enterotoxins, the bacteria that cause diarrhea in the first place. Kaolin may be one example of a bulk agent that binds enterotoxins.

Pharmacokinetics

image Loperamide does not penetrate the blood-brain barrier very readily, in large part because of the actions of the P-glycoprotein (Pgp) transporter. This limits the euphoria experienced with loperamide use. It is not clear whether concomitant administration of Pgp inhibitors is able to increase the euphoria experienced with loperamide.
image Loperamide and diphenoxylate have low solubility; thus they are unlikely to be abused parenterally.
image The bulk-forming or hydroscopic agents are generally clays that are able to absorb a significant amount of water. This absorptive ability is not selective, however, and agents such as kaolin may bind other substances, including drugs and nutrients. It is therefore advised that administration of these agents be separated from the administration of other agents by about 2 to 3 hours.

Indication

image Diarrhea

Contraindications

image The use of opiates in some forms of severe, infectious diarrhea in some cases is contraindicated or warrants extreme caution, as it will interfere with the clearance of these microorganisms from the GI tract and prolong these serious illnesses:

image Acute dysentery
image Bacterial enterocolitis caused by invasive organisms (Salmonella, Shigella, Campylobacter)
image Pseudomembranous colitis secondary to broad-spectrum antibiotics

image Severe inflammatory bowel disease in which a reduction in GI motility could lead to serious sequelae such as ileus, megacolon, and toxic megacolon

Side Effects

All

image Constipation

Opiates

image CNS effects, abuse potential: These effects are possible with higher doses of diphenoxylate or difenoxin. They are likely to occur with only very high (toxic) doses of loperamide.

Important Notes

image Diarrhea is generally considered to be a self-limiting condition that is best treated with oral rehydration and maintenance of electrolytes. In many cases, particularly with infectious diarrhea, treatment with constipating agents may actually prolong the disease, unless accompanied by antibiotic therapy (see evidence section).
image Diphenoxylate and difenoxin are marketed as combination products with atropine. Atropine is an anticholinergic and will therefore also reduce GI motility. This reduces the need for higher doses of these agents, which in turn reduces the potential for abuse.
image Although studies have shown that loperamide elicits very little euphoria, even at high doses, diphenoxylate does induce an opiate-like euphoric effect at higher doses (40 to 60 mg). Hence diphenoxylate remains a controlled drug, while loperamide is readily available without a prescription.
image Difenoxin is a metabolite of diphenoxylate and has actions similar to those of the parent drug.
image Bismuth compounds are also widely used in the treatment of diarrhea (see the discussion of GI cytoprotectants in this chapter for other actions and details about bismuth compounds). Their mechanism in the treatment of diarrhea is not well defined, although they do contain clays and this might contribute as a bulk-forming agent, as described earlier. The bismuth compounds may also have antisecretory and antimicrobial effects.
image Somatostatin analogues (octreotide, somatostatin) are also used to treat certain forms of diarrhea. See the discussion of somatostatin analogues in Chapter 14.

Advanced

image Racecadotril is a novel antidiarrheal that targets δ opiate receptors indirectly, by inhibiting an enzyme (enkephalinase) that breaks down endogenous enkephalins, hence enhancing their stimulation of this opiate receptor. Thus this agent specifically targets the secretory component of diarrhea. It has been investigated in types of diarrhea characterized by large secretion of fluid.

Evidence

Antimotility Agents in Combination with Antibiotics for Traveler’s Diarrhea

image A 2008 systematic review (nine trials, N = 1435 participants) examined the effect of using antimotility agents such as loperamide in conjunction with antibiotics for traveler’s diarrhea. The authors found that combinations of loperamide and antibiotics were more likely to produce a cure than antibiotics alone, both after 24 hours (odds ratio [OR] 2.6) and after 48 hours (OR 2.2).

Antimotility Agents for Chronic Diarrhea in Patients with HIV/AIDS

image A 2008 Cochrane review (one trial, N = 91 participants) assessed the effectiveness of antimotility agents in treating chronic diarrhea in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). The authors did not find any trials involving antimotility agents. They found no evidence that the adsorbent attapulgite was superior to placebo in controlling diarrhea.

Laxatives

Description

Laxatives are agents that promote defecation.

Prototypes and Common Drugs

Stimulants

image Prototype: sennosides
image Others: castor oil, bisacodyl

Bulk

image Prototype: psyllium

Osmotics

image Sugars: Prototype—lactulose
image Salts: Prototype—magnesium sulfate
image Others: magnesium hydroxide, magnesium citrate, sodium phosphate
image Polyethylene glycol

Softeners

image Prototype: docusate

Peripheral Opioid Antagonists

image Prototype: methylnaltrexone

Moa (Mechanism of Action)

Stimulant

image Stimulant laxatives are also known as irritant laxatives, and, as the name suggests, they work by irritating the intestinal wall, which leads to an accumulation of fluid and electrolytes and increased motility.
image The method by which stimulant laxatives irritate the intestinal wall has not been clearly defined, although likely mediators include the activation of cAMP and cyclic guanosine monophosphate (cGMP) pathways, inhibition of Na/K-ATPase, and increased platelet activating factor production (Figure 15-7).
image

Figure 15-7

Bulk

image Water is the largest determinant of stool volume, making up 70% to 85% of stool. A large amount of fluid is also extracted from stool as it makes its way through the intestines. Interruptions in this extraction of water, either excess extraction (constipation) or reduced extraction (diarrhea) can lead to GI problems.
image Fiber is the component of food that cannot be broken down by digestive enzymes.
image Fiber promotes intestinal motility by increasing the bulk of the stool. This is accomplished by increasing the bacterial content of stool by fermentation of fiber (fermentable fiber) or simply by drawing water into the stool (nonfermentable fiber). Many substances in the diet perform a combination of the two. Fiber, and specifically the short-chain fatty acids produced by fiber, may also have a direct stimulatory effect on the gut.
image For a list of fermentable versus nonfermentable fibers, see Important Notes, later.

Osmotics

image There are two types of osmotic laxatives: those made of sugars and alcohols and those that are salts of electrolytes.
image A shared mechanism of both types is that they create an osmotic force, pulling water into the stool and creating additional bulk, in a manner analogous to that seen with the bulk agents. The sugars are typically nonabsorbable, such as mannitol, sorbitol, and lactulose.
image Additional mechanisms may contribute to the efficacy of the electrolyte salts, and these agents are generally considered to be more potent than the sugars. For example, magnesium-containing laxatives may stimulate CCK release, which in turn leads to increased fluid and electrolytes within the gut lumen and increased motility.

Softeners

image As the name suggests, softeners are emollients that soften the stool, making defecation easier. They accomplish this in a variety of ways.
image Docusate salts are surfactants that allow mixing of aqueous and fatty substances in the stool. The docusate salts also increase intestinal fluid secretion.
image Mineral oil is not digested to an appreciable extent, so it stays in the gut and is absorbed into the stool, having a direct softening effect.

Opiate Antagonists

image Constipation caused by opiate analgesics such as morphine is a result of agonist effects on µ opiate receptors in the gut.
image Peripheral opiate µ antagonists are charged molecules that have limited ability to cross into the brain; therefore they selectively block the receptors that cause constipation without antagonizing the central analgesic effects of the opiates.

Pharmacokinetics

image Laxatives work best when poorly absorbed, as they all act locally within the gut.
image Because they work by a local irritant effect, bisacodyl tablets are designed to be released in the intestine but not before. Crushing or chewing of tablets will lead to irritation of the stomach.
image A number of the osmotic and stimulant laxatives can also be given as enemas or suppositories (bisacodyl).

Indications

image Constipation
image As cathartics, in preparation for radiologic or surgical procedures

Contraindications

Fiber

image Patients with obstructive symptoms or megacolon. Increasing the bulk of the stool will worsen these conditions.

Side Effects

image Laxatives are generally well tolerated when used in moderation, with mild side effects that are typically an extension of their pharmacologic effect
image Diarrhea: The osmotic and stimulant agents, in particular, have the potential to cause diarrhea.

Bulk

image Abdominal distension: The fermentation process by bacteria contributes to the production of gas, which leads to bloating. This side effect usually improves with time.

Osmotics, Sugars

image Abdominal distension, flatulence: These effects are likely caused by increased fermentation of the sugars by bacteria in the large intestine and tend to improve with continued use.

Osmotic Salts

image Electrolyte abnormalities are usually seen only at higher doses or in patients with preexisting electrolyte disturbances or renal dysfunction. The osmotic salts should be used with extreme caution (or not at all) in these patients or in patients on diuretic therapy.

Mineral Oil

image Interferes with vitamin absorption: Mineral oil interferes with the absorption of fat-soluble substances, including vitamins.
image Foreign body reactions: Mineral oil can elicit foreign body reactions in the gut.
image Lipid pneumonitis is a rare side effect that occurs when mineral oil has been aspirated.

Important Notes

image Osmotic sugar laxatives are useful in the treatment of constipation caused by opiates, as well as constipation in the elderly.
image Lactulose is used as a treatment for hepatic encephalopathy (confusion or decreased level of consciousness caused by liver failure). Patients with severe liver disease have difficulty detoxifying ammonia, which is produced by bacterial metabolism of feces. The actions of lactulose decrease intestinal pH, which traps ammonia within the lumen of the gut, facilitating its exit from the body.
image There are two types of mineral oil, and it is important that their use not be confused. Light mineral oil is for topical use as an emollient, whereas heavy mineral oil is used as a laxative.
image Composition of various forms of dietary fiber are shown in Table 15-2.

TABLE 15-2 Dietary Sources of Fiber

Highly Fermentable Poorly Fermentable or Nonfermentable
Hemicellulose Lignin
Mucilages and gums Cellulose
Pectins  

Evidence

Laxatives for Hemorrhoid Symptoms

image A 2005 Cochrane review (seven trials, N = 378 participants) evaluated the ability of laxatives to treat hemorrhoid symptoms. The authors found that the risk of persisting symptoms was significantly reduced with fiber (RR 0.47), as was the risk of bleeding (RR 0.50).

Laxatives for Constipation in Palliative Care Patients

image A 2006 Cochrane review (four trials, N = 280 participants) compared laxatives used for constipation in palliative care patients. All laxatives demonstrated a limited degree of efficacy, although these results were confounded by significant use of rescue laxatives during the studies. The only significantly different treatments were in a comparison of lactulose + senna versus danthron + poloxamer. The authors concluded that there was a paucity of data for this indication in this population.

FYI

image Several of the most commonly used laxatives are plant-derived, including many of the stimulant laxatives such as cascara (bark of the Buckthorn tree), senna (leaflets on pods of Cassia angustifolia), and castor oil (bean of the castor plant).
image Castor oil contains ricin, a very toxic protein that has been used in the past as a poison. Although castor oil was one of the original laxatives, the development of safer alternatives has lead to a reduction in its use.
image The stimulant laxatives have a checkered past with respect to safety. Phenolphthalein, the original Ex-Lax and once the most popular stimulant laxative, was withdrawn from the market in the late 1990s because of concerns over potential carcinogenicity.

Cannabinoids

Description

image The cannabinoids are the major active component of Cannabis sativa, also known as marijuana.

Prototype and Common Drugs

Agonists

image Prototype: dronabinol, also known as Δ9-tetrahydrocannabinol (THC)
image Others: nabilone, cannabidiol

Antagonists

image Prototype: rimonabant

Moa (Mechanism of Action)

image The cannabinoid (CB) receptors are G-protein–coupled receptors that are widely distributed throughout the body, most notably in the CNS.
image CB1 receptors are found in the hypothalamus, amygdala, basal ganglia, and cerebellum (Figure 15-8).
image In the periphery, CB1 receptors are found in adipocytes, the adrenal gland, the ovaries, the testes, and the GI tract.
image The location of CB1 receptors in areas of the brain (i.e., the hypothalamus) associated with feeding, coupled with the longstanding observation of the appetite-stimulating effects of cannabis, led to the conclusion that CB1 receptors may play an important role in the treatment of obesity.
image These regions of the brain are also interrelated with the mesolimbic DA pathway, also known as the reward pathway. This explains another, perhaps more well known effect of cannabis, that of euphoria and reward. The link between the reward pathways in the brain and the hypothalamus might also explain why eating is also associated with reward.
image Evidence of a link between smoking and the endocannabinoid pathway comes from the observation that THC triggers release of DA in the reward pathway via CB1 receptors, in the same way that nicotine stimulates DA release via nicotinic receptors. Chronic nicotine administration increases levels of endogenous cannabinoids, which then bind to CB1 receptors and elicit a feeling of reward.
image The potential of CB1 antagonists as antiobesity drugs is supported by the actions of CB1 in adipose tissue. CB1 antagonism may decrease lipogenesis and increase adiponectin levels. Adiponectin is a hormone secreted by adipocytes. It plays a role in lipid and glucose metabolism and also influences response to insulin. Low levels of adiponectin are found in obesity, and high levels are associated with reduced risk of heart attack.
image

Figure 15-8

Pharmacokinetics

Agonists

image Δ9-THC is well absorbed but undergoes extensive first-pass metabolism and significant distribution into tissues, thus limiting the amount (10% to 20%) of oral dose that reaches the systemic circulation.
image It has an active metabolite, 11-OH-Δ9-THC. Both the parent and active metabolite are eliminated by hepatic metabolism.
image The combination of Δ9-THC and cannabidiol is available as a buccal spray.

Antagonists

image Rimonabant is a lipophilic drug with an exceptionally long elimination half-life (t1/2) of 6 to 9 days. This prolonged t1/2 is doubled in obese patients (16 days), as drug deposits in fatty tissue.
image Rimonabant undergoes hepatic metabolism, primarily by CYP3A4.

Indications

Agonists

image Emesis (typically secondary to cancer chemotherapy)
image Anorexia (typically associated with AIDS)
image Neuropathic pain in multiple sclerosis (MS)

Antagonists

image Smoking cessation
image Obesity

Contraindications

Agonists

image Serious cardiovascular disease: Cannabinoids are not recommended for patients with a history of ischemic heart disease, arrhythmia, poorly controlled hypertension, or severe heart failure. See details under Side Effects, later.
image Significant hepatic or renal impairment
image History of psychosis
image Pregnancy: Animal studies suggest that cannabinoids may impair fetal development.

Side Effects

Agonists

image CNS effects consistent with marijuana use: euphoria, drowsiness, impaired sensory perception
image Cardiovascular effects: tachycardia, hypotension

Antagonists

Rimonabant

image Nausea: CB agonists have an antinauseant effect, so it is not surprising that antagonizing these receptors will lead to a pronauseant effect.

Serious

image Depression and suicidality: The mechanisms is unclear, but at present the simple explanation is that if CB1 agonists can generate euphoria, blocking this receptor may lead to severe dysphoria in some patients.

Important Notes

image The combination of Δ9-THC and cannabidiol, a nonpsychoactive plant cannabinoid, is being used for neuropathic pain in MS and as an adjunctive analgesic in advanced cancer.
image Concerns over side effects of severe depression and suicidal ideation led to the withdrawal of rimonabant in Europe and lack of approval in the United States. There are other CB1 antagonists in development, and these agents will need to address this safety issue.
image The location of function of CB2 receptors is not as well understood. It is believed that CB2 receptors might mediate antinociception, and thus CB2 agonists may have potential as analgesics.

FYI

image Endocannabinoids such as anandamide are eicosanoids and are therefore derived from arachidonic acid. The name anandamide is derived from Sanskrit for bliss.
image There are approximately 70 naturally occurring cannabinoids, and THC is the most important psychoactive compound of the group. There are many isomers of THC, but the Δ9-THC isomer is considered to be the most active.
image The cannabinoids have been investigated in a variety of disorders, including neurologic disorders such as MS and Parkinson’s disease. In MS, cannabis is often used to treat spasticity. Cannabis has also been used since the 1970s for glaucoma.
image Legal issues around the use of medicinal marijuana have created problems with the study of cannabinoid agonists. Specific agonists such as dronabinol have been developed to further “medicinalize” the use of THC. However, the problem with using these specific compounds is that they may lose some of the pharmacologic contributions from the variety of other cannabinoids found in marijuana.

Pancreatic Enzymes

Description

Pancreatic enzymes are agents that act as enzyme supplements. They are used in patients with pancreatic enzyme deficiency.

Prototype and Common Drugs

image Prototype: pancrelipase
image Others: pancreatin

Moa (Mechanism of Action)

image Deficiencies of pancreatic enzymes occur in disorders such as cystic fibrosis and chronic pancreatitis or in people in whom the pancreas has been surgically resected.
image Pancreatic enzyme secretion below 10% of normal interferes with proper digestion of fats and proteins, leading in turn to steatorrhea, azotorrhea, malabsorption of vitamins, and weight loss.
image Pancreatic enzyme supplements contain a mix of amylase, lipase, and proteases.

Pharmacokinetics

image As proteins, the pancreatic enzymes are quickly destroyed by gastric acids. For this reason, some formulations are encapsulated with acid-resistant microspheres or microtablets. The non–enteric-coated formulations must be coadministered with acid suppressants such as PPIs or H2 antagonists.
image Doses are titrated based on patient age and weight, extent of pancreatic insufficiency, and dietary fat intake. Inadequate response to enteric-coated formulations may be caused by insufficient mixing of granules with food and/or slow dissolution and release of enzymes.

Indications

image Pancreatic enzyme deficiency secondary to the following:

image Cystic fibrosis
image Chronic pancreatitis
image After pancreatectomy
image After GI bypass surgery
image Duct obstruction from pancreatic tumor

Contraindications

image None of major significance

Side Effects

image Diarrhea, abdominal pain: typically only seen with higher doses
image Hyperuricosuria or renal stones: caused by the high purine content of the enzyme supplements

Important Notes

image Most cystic fibrosis patients will experience pancreatic insufficiency. Cystic fibrosis is characterized by disruption of chloride transport as well as other transporters for sodium and bicarbonate. Patients have excessive intestinal mucoprotein, increasing the viscosity of the intestinal lumen. The increased viscosity leads to blockade of ducts, which damages acinar cells and causes fibrosis as well as exocrine pancreatic insufficiency.

Serotonin Antagonists

Description

Serotonin antagonists act as antinauseants by blocking serotonin-3 (5-HT3) receptors.

Prototype and Common Drugs

image Prototype: ondansetron
image Others: granisetron, alosetron, tropisetron, ramosetron, dolasetron, palonosetron

Moa (Mechanism of Action)

image 5-HT3 receptors in the gut mediate contraction of various segments of the GI tract, including the fundus, corpus, and antrum. These receptors also sensitize spinal sensory neurons and participate in vagal signaling of nausea. 5-HT3 receptors in the brain also mediate nausea.
image Chemotherapeutic agents used in cancer stimulate the release of 5-HT from enterochromaffin cells in the GI tract. This 5-HT activates 5-HT3 receptors on vagal sensory afferent neurons, and these neurons project to the emetic center in the brainstem (Figure 15-9).
image 5-HT3 receptor antagonists were thus first developed for, and continue to be first-line agents in the treatment of chemotherapy-induced nausea and vomiting.
image Antagonism of 5-HT3 receptors also appears to slow intestinal transit and secretions of the small bowel and decreases colonic compliance. This accounts for the efficacy of some 5-HT3 antagonists in treating conditions such as irritable bowel syndrome (IBS).
image The first 5-HT3 antagonist to be approved for treatment of IBS (alosetron) is a much more potent antagonist at 5-HT3 than ondansetron, suggesting that efficacy in IBS may be determined by potency.
image

Figure 15-9

Pharmacokinetics

image The 5-HT3 antagonists all appear to have a prolonged biologic half-life, with actions persisting well past elimination from the systemic circulation.
image All are well absorbed from the GI tract. All appear to undergo hepatic metabolism, typically via the CYP450 enzymes.
image The 5-HT3 antagonists are also available in parenteral preparations, both intravenous and intramuscular.

Indications

image Nausea, vomiting
image IBS

Contraindications

image None of major significance

Side Effects

image Generally well tolerated
image Constipation or diarrhea: Constipation is more common, and likely occurs because of 5-HT3 antagonism in the gut, which slows intestinal transit. The mechanism for the diarrhea is not clear.
image Headache
image Light-headedness

Rare but Serious

image Ischemic colitis has been associated with alosetron. This may be related to the ability of alosetron to induce contractions in the GI tract, in this case resulting in severe spasms in certain individuals.
image Electrocardiographic (ECG) changes: QT prolongation and other ECG changes have been reported. These changes are typically harmless but rarely may lead to clinically significant arrhythmias. Caution is advised when administering other drugs that may prolong the QT interval or in patients with QT prolongation.

Important Notes

image Alosetron was withdrawn from the U.S. market in 2000 because of concerns over ischemic colitis but was reintroduced in 2002 with a revised indication for women with severe IBS.
image Of all antiemetic agents, the 5-HT3 antagonists are among the most specific, having little if any affinity for any receptors other than serotonin receptors. This specificity may account for their paucity of side effects.
image The 5-HT3 antagonists were considered to be breakthrough drugs in the treatment of chemotherapy-induced nausea and vomiting. However, they do not appear to be efficacious in management of nausea caused by motion sickness.
image Neurokinin (NK1) receptor antagonists are a newer class of antiemetics that are used in combination with 5-HT3 antagonists for chemotherapy-induced nausea and vomiting. These agents work centrally, in the area postrema. The first two NK1 antagonists were aprepitant and fosaprepitant.

Evidence

Prevention of Postoperative Nausea and Vomiting

image A large (>100,000 subjects) 2006 Cochrane review compared a wide variety of agents with placebo and found that ondansetron, granisetron, tropisetron, and dolasetron were among eight drugs that prevented postoperative nausea and vomiting. Others were droperidol, dexamethasone, cyclizine, and metoclopramide.

Relief of Emesis in Pediatric Gastroenteritis

image A 2006 Cochrane review examined the effectiveness of antiemetics in children and adolescents with vomiting induced by gastroenteritis. The conclusions were limited by the small studies (total of 396 subjects over three studies). The results suggested that ondansetron performed better than placebo in reducing the number of vomiting episodes in this population. This was at the expense of an increased incidence of diarrhea, thought to be a result of the retention of toxins that would normally have been eliminated by vomiting.

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