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Gastrointestinal Drugs

Gastrointestinal Drugs

A 21-year-old woman arrives with her parents to discuss Crohn’s disease treatment options. Her Crohn’s disease was diagnosed two years ago, affecting her terminal ileum and proximal colon, as confirmed by colonoscopy and small bowel radiography. She was initially treated with mesalamine and budesonide with good results, but she has relapsed her symptoms in the last two months. She is suffering from fatigue, cramping, abdominal pains, and non-bloody diarrhea up to ten times per day, and she has lost 15 pounds.
She has no previous medical or surgical history. Her current medications are 2.4 g/d mesalamine and nine mg/d budesonide. She appears thin and exhausted. An abdominal examination reveals tenderness in the right lower quadrant without guarding; no masses are palpable. There is no tenderness, fissure, or fistula on the perianal test. Her laboratory results show anemia and elevated C-reactive protein. What are her immediate treatment options for her symptoms and disease? What are long-term management options available?

Many of the drug classes discussed in this book have important applications in treating gastrointestinal and other organ diseases. Other groups are almost entirely used for their effects on the gut; these are discussed in the following text regarding their therapeutic applications.


Nausea and vomiting can occur due to various conditions, including medication side effects, systemic disorders or infections, pregnancy, vestibular dysfunction, central nervous system infection or increased pressure, peritonitis, hepatobiliary disorders, radiation or chemotherapy, and gastrointestinal obstruction, dysmotility, or conditions.

The “vomiting center” in the brainstem is a loosely organized neuronal region within the lateral medullary reticular formation that coordinates the complex act of vomiting via interactions with cranial nerves VIII and X and neural networks in the nucleus tractus solitarius that control respiratory, salivatory, and vasomotor centers. The vomiting center contains high muscarinic M1, histamine H1, neurokinin 1 (NK1), and serotonin 5-HT3 receptors
Gastrointestinal Drugs
Neurologic pathways involved in nausea and vomiting pathogenesis (see text). (With permission, adapted from Krakauer EL et al.: Case records of the Massachusetts General Hospital. The New England Journal of Medicine, 2005;352:817. Copyright; Massachusetts Medical Society, 2005. Massachusetts Medical Society (reprinted with permission.)

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The vomiting center receives afferent input from four major sources:

The “chemoreceptor trigger zone,” or area postrema, is located at the fourth ventricle’s caudal end. This is accessible to emetogenic stimuli in the blood or cerebrospinal fluid because it is outside the blood-brain barrier. Dopamine D2 receptors, opioid receptors, and possibly serotonin 5-HT3 receptors and NK1 receptors are abundant in the chemoreceptor trigger zone.

Through cranial nerve VIII, the vestibular system plays an important role in motion sickness. It has a high concentration of muscarinic M1 and histamine H1 receptors.

5-HT3 receptors are abundant in vagal and spinal afferent nerves from the gastrointestinal tract. Chemotherapy, radiation therapy, distention, or acute infectious gastroenteritis cause mucosal serotonin release and activation of these receptors, stimulating vagal afferent input to the vomiting center and chemoreceptor trigger zone.

Vomiting caused by psychiatric disorders, stress, and anticipatory vomiting before cancer chemotherapy involves the central nervous system.

Identifying the various neurotransmitters involved in emesis has allowed for the developing of a diverse group of antiemetic agents with an affinity for different receptors. Combinations of antiemetic agents with varying mechanisms of action are frequently used, particularly in patients suffering from vomiting caused by chemotherapeutic agents.

Pharmacokinetics and Pharmacodynamics of SEROTONIN 5-HT3 ANTAGONISTS
Selective 5-HT3 receptor antagonists have potent antiemetic properties, partly mediated by blocking central 5-HT3 receptors in the vomiting center and chemoreceptor trigger zone but primarily by blocking peripheral 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves. These agents’ antiemetic action is limited to emesis caused by vagal stimulation (e.g., postoperative) and chemotherapy; other emetic stimuli, such as motion sickness, are poorly controlled.

In the United States, four agents are available: ondansetron, granisetron, dolasetron, and palonosetron. (Tropisetron is available outside of the United States.) The first three agents (ondansetron, granisetron, and dolasetron, Figure 62-5) have a serum half-life of 4-9 hours and can be given orally or intravenously once daily. All three drugs have comparable efficacy and tolerability when administered at equal doses. Palonosetron is a newer intravenous agent with greater affinity for the 5-HT3 receptor and a long serum half-life of 40 hours. All four drugs are extensively metabolized in the liver and eliminated via renal and hepatic excretion. Dose reduction is not necessary for geriatric patients or those with renal insufficiency. Ondansetron dose reduction may be required in patients with hepatic insufficiency.

5-HT3 receptor antagonists do not inhibit dopamine or muscarinic receptors. They do not affect esophageal or gastric motility, but they can slow colonic transit.

Clinical Applications
1. Nausea and vomiting caused by chemotherapy—
The primary agents for preventing acute chemotherapy-induced nausea and emesis are 5-HT3-receptor antagonists. When used alone, these medications have little or no efficacy in preventing delayed nausea and vomiting (occurring more than 24 hours after chemotherapy). The drugs work best when given as a single intravenous injection 30 minutes before chemotherapy in the following doses: ondansetron (8 mg), granisetron (1 mg), dolasetron (100 mg), or palonosetron (0.25 mg). In the following regimens, a single oral dose given 1 hour before chemotherapy may be equally effective: ondansetron, 8 mg twice daily or 24 mg once; granisetron, 2 mg; dolasetron, 100 mg. Although 5-HT3-receptor antagonists are effective as single agents for the prevention of chemotherapy-induced nausea and vomiting, combination therapy with a corticosteroid (dexamethasone), an NK1-receptor antagonist, and a dopamine D2 antagonist improves their efficacy (antipsychotics; see below).

2. Nausea and vomiting after surgery and radiation—5-HT3-receptor antagonists are used to prevent or treating postoperative nausea and vomiting. Because of the side effects and restrictions on other antiemetic agents, 5-HT3-receptor antagonists are becoming more popular for this indication. They are also effective in preventing and treating nausea and vomiting in patients undergoing whole-body or abdominal radiation therapy.

Negative Effects
5-HT3-receptor antagonists are well-tolerated drugs with high safety profiles. Headache, dizziness, and constipation are the most commonly reported side effects. All four agents cause a small but statistically significant prolongation of the QT interval, but dolasetron is the most pronounced. Although dolasetron has not been linked to cardiac arrhythmias, it should not be used in patients with prolonged QT intervals or in conjunction with other medications that may prolong the QT interval (see Chapter 14). Patients taking 5-HT3-receptor antagonists in combination with other serotonergic drugs have developed serotonin syndrome (selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]; see Chapter 30).

Drug Reactions
There have been no reports of significant drug interactions with 5-HT3-receptor antagonists. The hepatic cytochrome P450 system metabolizes all four agents, but they do not appear to affect other drugs’ metabolism. On the other hand, other medicines may reduce the hepatic clearance of 5-HT3-receptor antagonists, altering their half-life.

Corticosteroids (dexamethasone, methylprednisolone) have antiemetic effects, but the mechanism is unknown. This class of drug pharmacology is covered in Chapter 39. These agents appear to improve the efficacy of 5-HT3-receptor antagonists in patients receiving moderately to highly emetogenic chemotherapy regimens to prevent acute and delayed nausea and vomiting. Although a variety of corticosteroids have been used, the most commonly used is dexamethasone, 8-20 mg intravenously before chemotherapy, followed by eight mg/d orally for 2-4 days.

Antiemetic properties of neurokinin 1 (NK1)-receptor antagonists are mediated by central blockade in the area posttrauma. Aprepitant, netupitant, and rolapitant (all oral formulations) are NK1-receptor antagonists that cross the blood-brain barrier and bind to brain NK1 receptors. They don’t like serotonin, dopamine, or corticosteroid receptors. Netupitant (300 mg) is only available in combination with palonosetron (0.5 mg). Fosaprepitant is an intravenous formulation converted to aprepitant within 30 minutes of infusion.

Aprepitant has a 65% oral bioavailability and a serum half-life of 12 hours. Because netupitant and rolapitant have longer half-lives (90 and 180 hours, respectively), they can be administered in a single dose. The liver metabolizes all three agents, primarily through the CYP3A4 pathway.

Clinical Applications NK1-receptor antagonists are used with 5-HT3-receptor antagonists and corticosteroids to prevent acute and delayed nausea and vomiting caused by highly emetogenic chemotherapeutic regimens. A combination of an NK1 antagonist, a 5-HT3 antagonist, and dexamethasone prevents acute emesis in 80-90% of patients, compared to less than 70% of patients treated without an NK1 antagonist. Delayed emesis is contained in more than 70% of patients receiving combined therapy, compared to 30-50% of patients treated without an NK1 antagonist. Prepitant 125 mg given 1 hour before chemotherapy, followed by oral aprepitant 80 mg/d for two days after chemotherapy; rolapitant 180 mg; or netupitant 300 mg/palonosetron 0.5 mg given as a single dose 1-2 hours before chemotherapy. Intravenous fosaprepitant 115 mg may be given as a single intravenous dose 1 hour before chemotherapy to patients who cannot tolerate oral therapy. With highly emetogenic chemotherapeutic regimens, adding the antipsychotic agent olanzapine 10 mg on days, 1-4 reduces the incidence of acute and delayed nausea and vomiting by 15-30%.

Adverse Reactions and Drug Interactions
The NK1-receptor antagonists are well tolerated, with little fatigue or dizziness. The drugs are metabolized by CYP3A4 and may inhibit the metabolism of CYP3A4-metabolized other medicines. CYP3A4 is involved in the metabolism of several chemotherapeutic agents, including docetaxel, paclitaxel, etoposide, irinotecan, imatinib, vinblastine, and vincristine. Aprepitant plasma levels may be significantly increased by drugs that inhibit CYP3A4 metabolism (e.g., ketoconazole, ciprofloxacin, clarithromycin, nefazodone, ritonavir, nelfinavir, verapamil, and quinidine). Aprepitant lowers the international normalized ratio (INR) in warfarin patients.

Several antipsychotic agents have antiemetic and sedative properties (see Chapter 29). Phenothiazines’ antiemetic properties are mediated by inhibiting dopamine and muscarinic receptors. The antihistamine activity gives them soothing properties. Prochlorperazine, promethazine, and thiethylperazine are the most commonly used antiemetics. Olanzapine (a thienobenzodiazepine) may have antiemetic properties due to the inhibition of dopamine D2 and serotonin 5-HT1c and 5-HT3 receptors.

Because of their central dopaminergic blockade, antipsychotic butyrophenones also have antiemetic properties (see Chapter 29). Droperidol is the main agent used and can be administered intramuscularly or intravenously. Droperidol is extremely sedating in antiemetic doses. Previously, it was widely used for postoperative nausea and vomiting, as well as sedation for surgical and endoscopic procedures, neuroleptanalgesia, and the induction and maintenance of general anesthesia. Extrapyramidal symptoms and hypotension are possible. Droperidol can cause QT interval prolongation, leading to fatal ventricular tachycardia episodes, including torsades de pointes. Droperidol should therefore be avoided in patients with QT prolongation and used only in patients who have not responded adequately to alternative agents.

Metoclopramide (discussed previously) and trimethobenzamide are examples of substituted benzamides. Their primary antiemetic mechanism is thought to be a dopamine-receptor blockade. Trimethobenzamide also has minor antihistaminic properties. Metoclopramide can be given in relatively high doses of 10-20 mg orally or intravenously every 6 hours to prevent and treat nausea and vomiting. Trimethobenzamide is usually taken in 300 mg orally or 200 mg intramuscularly. The principal adverse effects of these central dopamine antagonists are extrapyramidal: restlessness, dystonias, and parkinsonian symptoms.

The pharmacology of anticholinergic agents is discussed in Chapter 8, and that of H1 antihistaminic agents in Chapter 16. As single agents, these drugs have weak antiemetic activity, although they are particularly useful for preventing or treating motion sickness. Their use may be limited by dizziness, sedation, confusion, dry mouth, cycloplegia, and urinary retention. Diphenhydramine and one of its salts, dimenhydrinate, are first-generation histamine H1 antagonists with significant anticholinergic properties. Because of its sedating properties, diphenhydramine is commonly used in conjunction with other antiemetics for treating emesis due to chemotherapy. Meclizine is an H1 antihistaminic agent with minimal anticholinergic properties that also causes less sedation. It is used for the prevention of motion sickness and the treatment of vertigo due to labyrinth dysfunction.

Hyoscine (scopolamine), a prototypic muscarinic receptor antagonist, is one of the best agents for preventing motion sickness. However, it has a very high incidence of anticholinergic effects when given orally or parenterally. It is better tolerated as a transdermal patch. The superiority of dimenhydrinate has not been proved.

Benzodiazepines such as lorazepam or diazepam are used before the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety. The pharmacology of these agents is presented in Chapter 22.

Dronabinol is Δ9-tetrahydrocannabinol (THC), the major psychoactive chemical in marijuana (see Chapter 32). (see Chapter 32). After oral ingestion, the drug is almost completely absorbed but undergoes significant first-pass hepatic metabolism. Its metabolites are excreted slowly in the feces and urine over days to weeks. Like crude marijuana, dronabinol is a psychoactive agent used medically as an appetite stimulant and antiemetic, but the mechanisms for these effects are not understood. Because of the availability of more effective agents, dronabinol is now uncommonly used to prevent chemotherapy-induced nausea and vomiting. Combination therapy with phenothiazines provides synergistic antiemetic action and appears to attenuate the adverse effects of both agents. Dronabinol is usually administered at 5 mg/m2 just before chemotherapy and every 2–4 hours as needed. Adverse effects include euphoria, dysphoria, sedation, hallucinations, dry mouth, and increased appetite. It has some autonomic impacts that may result in tachycardia, conjunctival injection, and orthostatic hypotension. Dronabinol has no significant drug-drug interactions but may potentiate the clinical effects of other psychoactive agents.

Summary of the Unit/Classification
Minimum of three types of drugs or supplements
Typical routes of administration
Common side effects and adverse effects
Special considerations
Common Nursing interventions

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