Other gastrointestinal drugs

CHAPTER 80


Other gastrointestinal drugs


In this chapter we discuss an assortment of GI drugs with indications ranging from emesis to colitis to hemorrhoids. Four groups are emphasized: (1) antiemetics, (2) antidiarrheals, (3) drugs for irritable bowel syndrome, and (4) drugs for inflammatory bowel disease.




Antiemetics


Antiemetics are given to suppress nausea and vomiting. We begin our discussion by reviewing the emetic response. Next we discuss the major antiemetic classes. And then we finish by considering the most important application of these drugs: management of chemotherapy-induced nausea and vomiting (CINV).



The emetic response


Emesis is a complex reflex brought about by activating the vomiting center, a nucleus of neurons located in the medulla oblongata. Some stimuli activate the vomiting center directly; others act indirectly (Fig. 80–1). Direct-acting stimuli include signals from the cerebral cortex (anticipation or fear), signals from sensory organs (upsetting sights, noxious odors, or pain), and signals from the vestibular apparatus of the inner ear. Indirect-acting stimuli first activate the chemoreceptor trigger zone (CTZ), which in turn activates the vomiting center. Activation of the CTZ occurs in two ways: (1) by signals from the stomach and small intestine (traveling along vagal afferents); and (2) by the direct action of emetogenic compounds (eg, anticancer drugs, opioids, ipecac) that are carried to the CTZ in the blood. Once activated, the vomiting center signals the stomach, diaphragm, and abdominal muscles; the resulting coordinated response expels gastric contents.


image
Figure 80–1  The emetic response: stimuli, pathways, and receptors.
(CTZ = chemoreceptor trigger zone.)

Several types of receptors are involved in the emetic response. Important among these are receptors for serotonin, glucocorticoids, substance P, neurokinin1, dopamine, acetylcholine, and histamine. Many antiemetics, including ondansetron [Zofran], dexamethasone, aprepitant [Emend], prochlorperazine, and dimenhydrinate, act by blocking (or activating) one or more of these receptors.



Antiemetic drugs


Several types of antiemetics are available. Their classes, trade names, and dosages are summarized in Table 80–1. Uses and mechanisms are summarized in Table 80–2. Properties of the principal classes are discussed below.



TABLE 80–1 


Antiemetic Drugs: Classes, Trade Names, and Dosages









































































































































Class and Generic Name Trade Name Adult Dosage
Serotonin Antagonists
  Ondansetron Zofran, Zuplenz See text
  Granisetron Granisol, Kytril, Sancuso See text
  Dolasetron Anzemet See text
  Palonosetron Aloxi See text
Glucocorticoids
  Dexamethasone generic only 10–20 mg IV before chemotherapy, then 4–8 mg
  Methylprednisolone Solu-Medrol 2 doses of 125–500 mg IV 6 hr apart before chemotherapy
Substance P/Neurokinin1 Antagonists
  Aprepitant Emend 125 mg PO on day 1, then 80 mg PO on days 2 and 3
  Fosaprepitant Emend 115 mg IV, used in place of the first (125-mg) dose of aprepitant in the regimen above
Benzodiazepines
  Lorazepam Ativan 1–1.5 mg IV before chemotherapy
  Diazepam Valium 2–5 mg PO every 3 hr
Dopamine Antagonists
Phenothiazines
  Chlorpromazine generic only 10–25 mg (PO, IM, IV) every 4–6 hr PRN
  Perphenazine generic only 8–30 mg/day in divided doses (PO, IM, IV)
  Prochlorperazine generic only 5–10 mg (PO, IM, IV) 3–4 times a day PRN
  Promethazine* Phenergan 12.5–25 mg (PO, IM, IV) every 4–6 hr
Butyrophenones
  Haloperidol Haldol 1–5 mg (PO, IM, IV) every 12 hr PRN
  Droperidol generic only 2.5–5 mg (IM, IV) every 4–6 hr PRN
Others
  Metoclopramide† Reglan See Table 80–3
Cannabinoids
  Dronabinol Marinol 5 mg/m2 PO every 4–6 hr PRN
  Nabilone Cesamet 1–2 mg PO twice daily
Anticholinergics
Antihistamines
  Cyclizine Marezine 50 mg (PO, IM) every 4–6 hr PRN
  Dimenhydrinate generic only 50–100 mg (PO, IM, IV) every 4–6 hr PRN
  Diphenhydramine Benadryl 10–50 mg (PO, IM, IV) every 4–6 hr PRN
  Hydroxyzine Vistaril 25–100 mg (PO, IM) every 6 hr PRN
  Meclizine Bonine, Antivert 25–50 mg PO every 24 hr PRN
Others
  Scopolamine Transderm Scimagep 0.5 mg transdermal every 72 hr PRN
  Scopace 0.4–0.8 mg PO every 8 hr PRN


image


*Promethazine is contraindicated for children under 2 years of age owing to a risk of fatal respiratory depression.


†Also blocks serotonin receptors.




Serotonin receptor antagonists

Serotonin receptor antagonists are the most effective drugs available for suppressing nausea and vomiting caused by cisplatin and other highly emetogenic anticancer drugs. These drugs are also highly effective against nausea and vomiting associated with radiation therapy, anesthesia, viral gastritis, and pregnancy. Four serotonin antagonists are available for treating emesis: ondansetron, granisetron, dolasetron, and palonosetron.



Ondansetron.

Ondansetron [Zofran, Zofran ODT, Zuplenz] was the first serotonin receptor antagonist approved for CINV. The drug is also used to prevent nausea and vomiting associated with radiotherapy and anesthesia. In addition, the drug is used off-label to treat nausea and vomiting from other causes, including childhood viral gastritis and morning sickness of pregnancy. In all cases, benefits derive from blocking type 3 serotonin receptors (5-HT3 receptors*) located in the CTZ and on afferent vagal neurons in the upper GI tract. The drug is very effective by itself, and even more effective when combined with dexamethasone. Administration may be oral or parenteral. The most common side effects are headache, diarrhea, and dizziness. Of much greater concern, ondansetron prolongs the QT interval and hence poses a risk of Torsades de Pointes, a potentially life-threatening dysrhythmia. Accordingly, the drug should not be given to patients with long QT syndrome, and should be used with caution in patients with electrolyte abnormalities, heart failure, or bradydysrhythmias, and in those taking other QT drugs. Since ondansetron does not block dopamine receptors, it does not cause the extrapyramidal effects (eg, akathisia, acute dystonia) seen with antiemetic phenothiazines. As discussed in Chapter 38, ondansetron is under investigation for treating early-onset alcoholism.



Administration is PO, IM, or IV. For oral dosing, ondansetron is available in solution (sold as Zofran), standard tablets (sold as Zofran), orally disintegrating tablets (sold as Zofran ODT), and a soluble film (sold as Zuplenz). To prevent CINV, the recommended IV dose is 0.15 mg/kg infused slowly (over 15 minutes) beginning 30 minutes before chemotherapy; this dose is repeated 4 and 8 hours later. Alternatively, ondansetron can be given as a single 32-mg IV dose. The dosage for patients undergoing radiation therapy is 8 mg PO (tablets, solution, or soluble film) 3 times a day. The dosage for postoperative nausea and vomiting is 16 mg PO (tablets, solution, or soluble film) 1 hour before induction of anesthesia.







Granisetron.


Like ondansetron, granisetron [Granisol, Kytril, Sancuso] suppresses emesis by blocking 5-HT3 receptors on afferent vagal neurons and in the CTZ. The drug is approved for preventing nausea and vomiting associated with cancer chemotherapy, radiation therapy, and surgery. Principal adverse effects are headache (responsive to acetaminophen), weakness, tiredness, and either diarrhea or constipation. Administration is PO, IV, or transdermal. The recommended dosage for CINV is either (1) 10 mcg/kg IV infused over 5 minutes, starting 30 minutes before chemotherapy, or (2) a single transdermal patch [Sancuso] applied 24 to 48 hours before chemotherapy, and removed 24 hours after chemotherapy is completed (but no more than 7 days after application). The dosage for patients undergoing radiation therapy is 2 mg (tablets or oral solution) once daily given within 1 hour of radiation treatment. The dosage for preventing postoperative nausea and vomiting is 1 mg IV injected slowly (over 30 seconds) either prior to induction of anesthesia or just before reversing anesthesia.




Palonosetron.


Palonosetron [Aloxi], indicated for CINV and postoperative nausea and vomiting, has the same mechanism, efficacy, and side effects as other serotonin antagonists, but differs from the others in two clinically significant ways. First, palonosetron has a much longer half-life (40 hours vs. about 8 hours). Second, because of its long half-life, palonosetron is effective against delayed emesis (as well as acute emesis), whereas the others are most effective against acute emesis. Palonosetron also has much greater affinity for 5-HT3 receptors than the other serotonin antagonists, but this difference does not appear to have clinical significance. Palonosetron is available only in an IV formulation. Capsules for oral dosing have been withdrawn. The recommended dosage for CINV in adults is 250 mcg IV delivered over 30 seconds starting 30 minutes before chemotherapy. To prevent postoperative nausea and vomiting, the dosage is 75 mcg IV delivered over 10 seconds immediately before induction of anesthesia.





Substance p/neurokinin1 antagonists

Two substance P/neurokinin1 antagonists are currently available: aprepitant and fosaprepitant, a prodrug that undergoes conversion to aprepitant in the body. Their principal application is prevention of CINV. A third drug—casopitant—–is in development.



Aprepitant. 





Drug interactions.


The potential for drug interactions is complex. Why? Because aprepitant is a substrate for, inhibitor of, and inducer of CYP3A4, a major drug-metabolizing enzyme. Inhibitors of CYP3A4 (eg, itraconazole, ritonavir) can raise levels of aprepitant. Conversely, inducers of CYP3A4 (eg, rifampin, phenytoin) can decrease levels of aprepitant. By inhibiting CYP3A4, aprepitant can raise levels of CYP3A4 substrates, including many drugs used for cancer chemotherapy. Among these are docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. Also, aprepitant can raise levels of glucocorticoids used to prevent CINV. Accordingly, doses of these drugs (dexamethasone and methylprednisolone) should be reduced.


In addition to affecting CYP3A4, aprepitant can induce CYP2D6, another drug-metabolizing enzyme. As a result, aprepitant can decrease levels of CYP2D6 substrates, including warfarin (an anticoagulant) and ethinyl estradiol (found in oral contraceptives). Patients receiving warfarin should be monitored closely. Patients using oral contraceptives may need an alternative form of birth control.













Dopamine antagonists


Phenothiazines.

The phenothiazines (eg, prochlorperazine) suppress emesis by blocking dopamine2 receptors in the CTZ. These drugs can reduce emesis associated with surgery, cancer chemotherapy, and toxins. Side effects include extrapyramidal reactions, anticholinergic effects, hypotension, and sedation. The basic pharmacology of the phenothiazines is discussed in Chapter 31 (Antipsychotic Agents and Their Use in Schizophrenia).


One phenothiazine—promethazine [Phenergan]—requires comment. Promethazine is the most widely used antiemetic in young children, despite its dangers (respiratory depression and local tissue injury), and despite the availability of safer alternatives (eg, ondansetron). Respiratory depression from promethazine can be severe. Deaths have occurred. Because of this risk, promethazine is contraindicated in children under the age of 2 years, and should be used with caution in children older than 2. Tissue injury can result in several ways. For example, extravasation of IV promethazine can cause abscess formation, tissue necrosis, and gangrene that requires amputation. Severe injury can also occur with inadvertent perivascular or intra-arterial administration, or with administration into or near a nerve. Risk of local injury is lower with IM dosing than with IV dosing. Accordingly, when parenteral administration is needed, the IM route is preferred. SubQ promethazine is contraindicated. If IV administration must be done, promethazine should be given through a large-bore, freely flowing line, in a concentration of 25 mg/mL or less at a rate of 25 mg/min or less. Patients should be advised to report local burning or pain immediately.





Cannabinoids

Two cannabinoids—dronabinol [Marinol] and nabilone [Cesamet]*—are approved for medical use in the United States. Both drugs are related to marijuana (Cannabis sativa). Dronabinol (delta-9-tetrahydrocannabinol; THC) is the principal psychoactive agent in C. sativa. Nabilone is a synthetic derivative of dronabinol. A third cannabinoid preparation, sold as Sativex (a combination of THC and cannabidiol), is available in Canada (for treating neuropathic pain) but is illegal in the United States. The basic pharmacology of THC and other cannabinoids is discussed in Chapter 40 (Drug Abuse: Major Drugs of Abuse Other Than Alcohol and Nicotine).





Abuse potential.

Because they can mimic the subjective effects of marijuana, cannabinoids have some potential for abuse. When first approved for medical use, both drugs were classified under Schedule II of the Controlled Substances Act—a classification reserved for drugs with a high abuse potential. However, in 1998, the manufacturer of dronabinol petitioned the Drug Enforcement Agency (DEA) to reclassify the drug under Schedule III. Two arguments for the reduced classification were offered: (1) because of its slow onset, dronabinol does not produce the same “high” produced by smoking marijuana, and (2) there is little or no interest in dronabinol on the street. Apparently, the DEA agreed: Dronabinol is now classified under Schedule III. Nabilone remains under Schedule II, although its abuse potential seems no greater than that of dronabinol.






Chemotherapy-induced nausea and vomiting


Many anticancer drugs cause severe nausea and vomiting, leading to dehydration, electrolyte imbalances, nutrient depletion, and esophageal tears. Worse yet, these reactions can be so intense that patients may discontinue chemotherapy rather than endure further discomfort. Fortunately, CINV can be minimized with the antiemetics.


Chemotherapy is associated with three types of emesis: (1) anticipatory, (2) acute, and (3) delayed. Anticipatory emesis occurs before anticancer drugs are actually given; it is triggered by the memory of severe nausea and vomiting from a previous round of chemotherapy. Acute emesis begins within minutes to a few hours after receiving chemotherapy, and often resolves within 24 hours. In contrast, delayed emesis develops a day or more after drug administration. For example, with cisplatin, emesis is maximal 48 to 72 hours after dosing, and can persist for 6 to 7 days.


Antiemetics are more effective at preventing CINV than at suppressing CINV that has already begun. Accordingly, antiemetics should be administered prior to chemotherapy. For prevention, antiemetics may be given orally or parenterally. Both routes are equally effective (although dosage may differ). In general, oral therapy is preferred. However, if emesis is ongoing, oral therapy won’t work, and hence parenteral therapy is required.


The antiemetic regimen for a particular patient is based on the emetogenic potential of the chemotherapy drugs being used. For drugs with a low risk of causing emesis, a single antiemetic (dexamethasone) may be adequate. For drugs with a moderate or high risk of causing emesis, a combination of antiemetics is needed. The current regimen of choice for patients taking highly emetogenic drugs consists of three agents: aprepitant plus dexamethasone plus a 5-HT3 antagonist (eg, ondansetron, palonosetron). Lorazepam may be added to reduce anxiety and anticipatory emesis, and to provide amnesia as well. The superior efficacy of combination therapy suggests that anticancer drugs may induce emesis by multiple mechanisms. Table 80–3 shows representative regimens for preventing CINV in patients receiving anticancer drugs with low, moderate, and high emetogenic risk.



TABLE 80–3 




























High-Emetogenic-Risk Chemotherapy
  Aprepitant 125 mg PO on day 1, 80 mg PO on days 2 and 3 plus
  Dexamethasone 12 mg PO or IV on day 1, 8 mg PO or IV on days 2–4 plus
  Ondansetron 8 mg PO twice on day 1 or 8 mg or 1.5 mg/kg IV on day 1
Moderate-Emetogenic-Risk Chemotherapy
  Dexamethasone 8 mg PO or IV plus
  Palonosetron 0.25 mg IV or 0.5 mg PO
Low-Emetogenic-Risk Chemotherapy
  Dexamethasone 8 mg PO or IV


image


Representative Regimens for Preventing Chemotherapy-Induced Nausea and VomitingData from Basch E, Prestrud AA, et al. Antiemetics: American Society of Clinical Oncology. Clinical Practice Guideline Update J. Clin Oncol 29:4189-4198, 2011.



Nausea and vomiting of pregnancy


Nausea and vomiting of pregnancy (NVP) is extremely common, especially during the first trimester. About 50% of women experience nausea plus vomiting, and another 25% experience nausea alone. A few women experience hyperemesis gravidarum, a severe form of NVP characterized by dehydration, ketonuria, hypokalemia, and loss of 5% or more of body weight. Fortunately, most cases of NVP abate early in pregnancy: about 60% resolve within 13 weeks, and 90% resolve by the end of 20 weeks. Although NVP is commonly called morning sickness, it shouldn’t be. Why? Because NVP can occur any time of the day, not just in the morning.


NVP can be managed with drugs and with nondrug measures. Nondrug measures include (1) eating small portions of food throughout the day, (2) avoiding odors, foods, and supplements that can trigger NVP (eg, fatty foods, spicy foods, iron tablets), and (3) use of alternative treatments, such as acupuncture and ginger. Despite use of these nondrug measures, about 10% of women require drug therapy.


First-line therapy consists of a two-drug combination: doxylamine plus vitamin B6. In randomized, controlled trials, the combination reduced NVP by 70%, and showed no evidence of adverse fetal outcomes. In Canada, doxylamine and vitamin B6 are available in a fixed-dose combination sold as Diclectinimage. In the United States, no fixed-dose combination is available. However, doxylamine is available alone as Unisom Sleep Tabs, and vitamin B6 is readily available as a supplement. When the drugs are taken separately, the dosage of doxylamine is 25 mg at bedtime plus 12.5 mg in the morning and afternoon, and the dosage of vitamin B6 is 10 to 25 mg every 8 hours.


If doxylamine and vitamin B6 fail to suppress NVP, alternatives include prochlorperazine, metoclopramide, and ondansetron. Methylprednisolone may be tried as a last resort, but only after 10 weeks of gestation (earlier use greatly increases the risk of cleft lip, with or without cleft palate).



Drugs for motion sickness


Motion sickness can be caused by sea, air, automobile, and space travel. Symptoms are nausea, vomiting, pallor, and cold sweats. Drug therapy is most effective when given prophylactically, rather than after symptoms begin.





Antihistamines

The antihistamines used most often for motion sickness are dimenhydrinate, meclizine [Antivert, others], and cyclizine [Marezine]. Because these drugs block receptors for acetylcholine in addition to receptors for histamine, they appear in Table 80–1 as a subclass under Anticholinergics. Suppression of motion sickness appears to result from blocking histaminergic (H1) and muscarinic cholinergic receptors in the neuronal pathway that connects the inner ear to the vomiting center (see Fig. 80–1). The most prominent side effect—sedation—results from blocking H1 receptors. Other side effects—dry mouth, blurred vision, urinary retention, and constipation—result from blocking muscarinic receptors. Antihistamines are less effective than scopolamine for treating motion sickness, and sedation further limits their utility.

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Jul 24, 2016 | Posted by in NURSING | Comments Off on Other gastrointestinal drugs

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