Chapter 31: GI & Antiemetic Drugs

Question 1

ANTIMICROBIAL AGENTS

Answer 1

Amoxicillin AMOXIL, TRIMOX
Bismuth compounds PEPTO-BISMOL,
KAOPECTATE
Clarithromycin BIAXIN
Metronidazole FLAGYL
Tetracycline SUMYCIN

Question 2

H2 receptor blockers

Answer 2

Cimetidine TAGAMET
Famotidine PEPCID
Nizatidine AXID
Ranitidine ZANTAC

Question 3

PPI

Answer 3

Dexlansoprazole DEXILANT
Esomeprazole NEXIUM
Lansoprazole PREVACID
Omeprazole PRILOSEC
Pantoprazole PROTONIX
Rabeprazole ACIPHE

Question 4

Prostaglandin

Answer 4

Misoprostol

Question 5

ANTIMUSCARINIC AGENTS

Answer 5

Dicyclomine

Question 6

Antacids

Answer 6

Aluminum hydroxide ALTERNAGEL
Calcium carbonate TUMS
Magnesium hydroxide MILK OF MAGNESIA
Sodium bicarbonate NUMEROUS

Question 7

Mucosal protective agents

Answer 7

Bismuth subsalicylate PEPTO-BISMOL
Sucralfate CARAFATE

Question 8

Phenothiazine

Answer 8

Prochlorperazine COMPAZINE

Question 9

5-HT3 SEROTONIN RECEPTOR
BLOCKERS

Answer 9

5-HT3 SEROTONIN RECEPTOR
BLOCKERS
Dolasetron ANZEMET
Granisetron KYTRIL
Ondansetron ZOFRAN
Palonosetron ALOX

Question 10

SUBSTITUTED BENZAMIDES

Answer 10

Metoclopramide

Question 11

BUTYROPHENONES

Answer 11

BUTYROPHENONES
Droperidol
Haloperidol HALDOL

Question 12

BENZODIAZEPINES

Answer 12

BENZODIAZEPINES
Alprazolam XANAX
Lorazepam ATIVAN

Question 13

CORTICOSTEROIDS

Answer 13

CORTICOSTEROIDS
Dexamethasone DECADRON
Methylprednisolone MEDROL

Question 14

SUBSTANCE P/NEUROKININ-1
RECEPTOR BLOCKER

Answer 14

SUBSTANCE P/NEUROKININ-1
RECEPTOR BLOCKER
Aprepitant EMEND

Question 15

ANTIMOTILITY AGENTS

Answer 15

ANTIMOTILITY AGENTS
Diphenoxylate + atropine LOMOTIL
Loperamide IMODIUM A-D

Question 16

ADSORBENTS

Answer 16

ADSORBENTS
Aluminum hydroxide ALTERNAGEL
Methylcellulose CITRUCEL

Question 17

AGENTS THAT MODIFY FLUID AND
ELECTROLYTE TRANSPORT

Answer 17

AGENTS THAT MODIFY FLUID AND
ELECTROLYTE TRANSPORT
Bismuth subsalicylate PEPTO-BISMOL

Question 18

BULK LAXATIVES

Answer 18

BULK LAXATIVES
Methylcellulose CITRUCEL
Psyllium METAMUCIL, FIBERAL

Question 19

SALINE and OSMOTIC LAXATIVES

Answer 19

SALINE and OSMOTIC LAXATIVES
Magnesium citrate CITROMA
Magnesium hydroxide MILK OF MAGNESIA
Polyethylene glycol MIRALAX, GOLYTELY,
MOVIPREP, NULYTELY, TRILYTE
Lactulose CONSTULOSE, ENULOSE, GENER-
LAC, KRISTALOSE

Question 20

Stool softeners

Answer 20

Docusate COLACE, DOCU-SOFT

Question 21

Lubricant laxatives

Answer 21

Glycerin suppositories
Mineral oil

Question 22

CHLORIDE CHANNEL ACTIVATORS
Lubiprostone AMITIZA

Answer 22

Lubiprostone AMITIZA

Question 23

PPI

Answer 23

PPIs: Inhibitors of the H+/K+-ATPase proton pump
The PPIs bind to the H+/K+-ATPase enzyme system (proton pump)
and suppress the secretion of hydrogen ions into the gastric lumen.
The membrane-bound proton pump is the final step in the secretion
of gastric acid (Figure 31.4). The available PPIs include dexlanso-
prazole [DEX-lan-SO-pra-zole], esomeprazole [es-oh-MEH-pra-zole],
lansoprazole [lan-SO-pra-zole], omeprazole [oh-MEH-pra-zole], pan-
toprazole [pan-TOE-pra-zole], and rabeprazole [rah-BEH-pra-zole].
Omeprazole, esomeprazole, and lansoprazole are available over-the-
counter for short-term treatment of GERD.
1. Actions: These agents are prodrugs with an acid-resistant
enteric coating to protect them from premature degradation by
gastric acid. The coating is removed in the alkaline duodenum,
and the prodrug, a weak base, is absorbed and transported to the
parietal cell. There, it is converted to the active drug and forms a
stable covalent bond with the H+/K+-ATPase enzyme. It takes about
18 hours for the enzyme to be resynthesized, and acid secretion
is inhibited during this time. At standard doses, PPIs inhibit both
basal and stimulated gastric acid secretion by more than 90%. An
oral product containing omeprazole combined with sodium bicar-
bonate for faster absorption is also available over the counter and
by prescription.
2. Therapeutic uses: The PPIs are superior to the H2
antagonists in
suppressing acid production and healing ulcers. Thus, they are the
preferred drugs for stress ulcer treatment and prophylaxis and for
the treatment of GERD, erosive esophagitis, active duodenal ulcer,
and pathologic hypersecretory conditions (for example, Zollinger-
Ellison syndrome, in which a gastrin-producing tumor causes
hypersecretion of HCl). If a once-daily PPI is only partially effective
for GERD symptoms, increasing dosing to twice daily or adminis-
tering the PPI in the morning and adding an H2
antagonist in the
evening may improve symptom control. If an H2
-receptor antago-
nist is needed, it should be taken well after the PPI. H2
antagonists
reduce the activity of the proton pump, and PPIs require active
pumps to be effective. PPIs also reduce the risk of bleeding from
ulcers caused by aspirin and other NSAIDs and may be used for
prevention or treatment of NSAID-induced ulcers. Finally, they are
used with antimicrobial regimens to eradicate H. pylori.
3. Pharmacokinetics: All of these agents are effective orally. For
maximum effect, PPIs should be taken 30 to 60 minutes before
breakfast or the largest meal of the day. [Note: dexlansoprazole
has a dual delayed release formulation and can be taken with-
out regard to food.] Esomeprazole, lansoprazole, and pantopra-
zole are also available in intravenous formulations. Although the
plasma half-life of these agents is only a few hours, they have a
long duration of action due to covalent bonding with the H+/K+-
ATPase enzyme. Metabolites of these agents are excreted in urine
and feces.
4. Adverse effects: The PPIs are generally well tolerated.
Omeprazole and esomeprazole may decrease the effective-
ness of clopidogrel because they inhibit CYP2C19 and prevent the conversion of clopidogrel to its active metabolite. Although
the effect on clinical outcomes is questionable, concomitant use
of these PPIs with clopidogrel is not recommended because of
a possible increased risk of cardiovascular events. PPIs may
increase the risk of fractures, particularly if the duration of use is
1 year or greater (Figure 31.6). Prolonged acid suppression with
PPIs (and H2
antagonists) may result in low vitamin B12 because
acid is required for its absorption in a complex with intrinsic fac-
tor. Elevated gastric pH may also impair the absorption of calcium
carbonate. Calcium citrate is an effective option for calcium supple-
mentation in patients on acid suppressive therapy, since absorp-
tion of the citrate salt is not affected by gastric pH. Diarrhea and
Clostridium difficile colitis may occur in community patients receiv-
ing PPIs. Patients must be counseled to discontinue PPI therapy
and contact their physician if they have diarrhea for several days.
Additional adverse effects may include hypomagnesemia and an
increased incidence of pneumonia.

Question 24

Prostaglandin

Answer 24

Prostaglandins
Prostaglandin E, produced by the gastric mucosa, inhibits secretion
of acid and stimulates secretion of mucus and bicarbonate (cytopro-
tective effect). A deficiency of prostaglandins is thought to be involved
in the pathogenesis of peptic ulcers. Misoprostol [mye-soe-PROST-
ole], an analog of prostaglandin E1
, is approved for the prevention
of NSAID-induced gastric ulcers (Figure 31.7). Prophylactic use of
misoprostol should be considered in patients who are taking NSAIDs
and are at moderate to high risk of NSAID-induced ulcers, such as
elderly patients and those with previous ulcers. Misoprostol is contra-
indicated in pregnancy, since it can stimulate uterine contractions and
cause miscarriage. Dose-related diarrhea and nausea are the most
common adverse effects and limit the use of this agent. Thus, PPIs
are preferred agents for the prevention of NSAID-induced ulcers.

Question 25

Antacids

Answer 25

Antacids Antacids are weak bases that react with gastric acid to form water and a salt to diminish gastric acidity. Because pepsin (a proteolytic enzyme) is inactive at a pH greater than 4, antacids also reduce pep- sin activity. 1. Chemistry: Antacid products vary widely in their chemical com- position, acid-neutralizing capacity, sodium content, palatability, and price. The efficacy of an antacid depends on its capacity to neutralize gastric HCl and on whether the stomach is full or empty (food delays stomach emptying allowing more time for the antacid to react). Commonly used antacids are combinations of salts of aluminum and magnesium, such as aluminum hydroxide and mag- nesium hydroxide [Mg(OH)2 ]. Calcium carbonate [CaCO3 ] reacts with HCl to form CO2 and CaCl2 and is also a commonly used preparation. Systemic absorption of sodium bicarbonate [NaHCO3 ] can produce transient metabolic alkalosis. Therefore, this antacid is not recommended for long-term use. 2. Therapeutic uses: Antacids are used for symptomatic relief of peptic ulcer disease and GERD, and healing of duodenal ulcers. They should be administered after meals for maximum effectiveness. [Note: Calcium carbonate prep- arations are also used as calcium supplements for the treatment of osteoporosis.] 3. Adverse effects: Aluminum hydroxide tends to cause constipa- tion, whereas magnesium hydroxide tends to produce diarrhea. Preparations that combine these agents aid in normalizing bowel function. Absorption of the cations from antacids (Mg2+, Al3+, Ca2+) is usually not a problem in patients with normal renal function; however, accumulation and adverse effects may occur in patients with renal impairment. Adverse effects: Aluminum hydroxide tends to cause constipa- tion, whereas magnesium hydroxide tends to produce diarrhea. Preparations that combine these agents aid in normalizing bowel function. Absorption of the cations from antacids (Mg2+, Al3+, Ca2+) is usually not a problem in patients with normal renal function; however, accumulation and adverse effects may occur in patients with renal impairment.

Question 26

Sucralfate

Answer 26

Sucralfate: This complex of aluminum hydroxide and sulfated sucrose binds to positively charged groups in proteins of both normal and necrotic mucosa. By forming complex gels with epi- thelial cells, sucralfate [soo-KRAL-fate] creates a physical barrier that protects the ulcer from pepsin and acid, allowing the ulcer to heal. Although sucralfate is effective for the treatment of duodenal ulcers and prevention of stress ulcers, its use is limited due to the need for multiple daily dosing and drug–drug interactions. Because it requires an acidic pH for activation, sucralfate should not be administered with PPIs, H2 antagonists, or antacids. Sucralfate is well tolerated, but it can interfere with the absorption of other drugs by binding to them. This agent does not prevent NSAID-induced ulcers, and it does not heal gastric ulcers.

Question 27

Bismuth subsalicylate

Answer 27

Bismuth subsalicylate: This agent is used as a component of quadruple therapy to heal peptic ulcers. In addition to its antimicro- bial actions, it inhibits the activity of pepsin, increases secretion of mucus, and interacts with glycoproteins in necrotic mucosal tissue to coat and protect the ulcer.

Question 28

Phenothiazine

Answer 28

. Phenothiazines: The first group of drugs shown to be effective antiemetic agents, phenothiazines, such as prochlorperazine [proe-klor-PER-ah-zeen], act by blocking dopamine receptors. Prochlorperazine is effective against low or moderately emeto- genic chemotherapeutic agents (for example, fluorouracil and doxorubicin). Although increasing the dose improves antiemetic activity, side effects are dose limiting.

Question 29

5HT3 receptor blockers

Answer 29

5-HT3 receptor blockers: The 5-HT3 receptor antagonists include ondansetron [on-DAN-seh-tron], granisetron [gra-NI-seh- tron], palonosetron [pa-low-NO-seh-tron], and dolasetron [dol-A- seh-tron]. These agents selectively block 5-HT3 receptors in the periphery (visceral vagal afferent fibers) and in the brain (CTZ).This class of agents is important in treating emesis linked with chemotherapy, largely because of their longer duration of action and superior efficacy. These drugs can be administered as a sin- gle dose prior to chemotherapy (intravenously or orally) and are efficacious against all grades of emetogenic therapy. Ondansetron and granisetron prevent emesis in 50% to 60% of cisplatin-treated patients. These agents are also useful in the management of post- operative nausea and vomiting. 5-HT3 antagonists are extensively metabolized by the liver; however, only ondansetron requires dos- age adjustments in hepatic insufficiency. Elimination is through the urine. Electrocardiographic changes, such as a prolonged QTc interval, can occur with dolasetron and high doses of ondanse- tron. For this reason, dolasetron is no longer approved for CINV prophylaxis.

Question 30

Substituted benzamides

Answer 30

Substituted benzamides: One of several substituted benzamides with antiemetic activity, metoclopramide [met-oh-kloe-PRAH-mide] is effective at high doses against the emetogenic cisplatin, prevent- ing emesis in 30% to 40% of patients and reducing emesis in the majority of patients. Metoclopramide accomplishes this through inhibition of dopamine in the CTZ. Antidopaminergic side effects, including extrapyramidal symptoms, limit long-term high-dose use. Metoclopramide was previously used as a prokinetic drug for the treatment of GERD. However, due to the adverse effect profile and the availability of more effective drugs, such as PPIs, it should be reserved for patients with documented gastroparesis

Question 31

Butyrophenones

Answer 31

Butyrophenones: Droperidol [droe-PER-i-doll] and haloperidol [hal-oh-PER-i-doll] act by blocking dopamine receptors. The butyr- ophenones are moderately effective antiemetics. Droperidol had been used most often for sedation in endoscopy and surgery, usu- ally in combination with opioids or benzodiazepines. However, it may prolong the QTc interval and should be reserved for patients with inadequate response to other agents. High-dose haloperidol was found to be nearly as effective as high-dose metoclopramide in preventing cisplatin-induced emesis.

Question 32

Benzodiazepines

Answer 32

Benzodiazepines: The antiemetic potency of lorazepam [lor-A- ze-pam] and alprazolam [al-PRAH-zoe-lam] is low. Their beneficial effects may be due to their sedative, anxiolytic, and amnesic prop- erties. These same properties make benzodiazepines useful in treating anticipatory vomiting. Concomitant use of alcohol should be avoided due to additive CNS depressant effects.

Question 33

Corticosteroid

Answer 33

Corticosteroids: Dexamethasone [dex-a-MEH-tha-sone] and methylprednisolone [meth-ill-pred-NIH-so-lone], used alone, are effective against mildly to moderately emetogenic chemotherapy. Most frequently, however, they are used in combination with other agents. Their antiemetic mechanism is not known, but it may involve blockade of prostaglandins.

Question 34

Substance P/neurokinin-1 receptor blocker:

Answer 34

Substance P/neurokinin-1 receptor blocker: Aprepitant [ah- PRE-pih-tant] targets the neurokinin receptor in the brain and blocks the actions of the natural substance. Aprepitant is indicated only for highly or moderately emetogenic chemotherapy regi- mens. It is usually administered orally with dexamethasone and a 5-HT3 antagonist. It undergoes extensive metabolism, primar- ily by CYP3A4, and it may affect the metabolism of other drugs that are metabolized by this enzyme, such as warfarin and oral contraceptives.

Question 35

Antimotility

Answer 35

Antimotility agents Two drugs that are widely used to control diarrhea are diphenoxylate [dye-fen-OX-see-late] and loperamide [loe-PER-ah-mide]. Both are analogs of meperidine and have opioid-like actions on the gut. They activate presynaptic opioid receptors in the enteric nervous system to inhibit acetylcholine release and decrease peristalsis. At the usual doses, they lack analgesic effects. Because these drugs can contrib- ute to toxic megacolon, they should not be used in young children or in patients with severe colitis.

Question 36

Adsorbents

Answer 36

Adsorbents Adsorbent agents, such as aluminum hydroxide and methylcellulose [meth-ill-CELL-you-lowse], are used to control diarrhea. Presumably, these agents act by adsorbing intestinal toxins or microorganisms and/or by coating or protecting the intestinal mucosa. They are much less effective than antimotility agents, and they can interfere with the absorption of other drugs.

Question 37

Agents that modify fluid and electrolyte transport

Answer 37

Agents that modify fluid and electrolyte transport Bismuth subsalicylate, used for traveler’s diarrhea, decreases fluid secretion in the bowel. Its action may be due to its salicylate compo- nent as well as its coating action. Adverse effects may include black tongue and black stools.

Question 38

Senna

Answer 38

Senna: This agent is a widely used stimulant laxative. Its active ingredient is a group of sennosides, a natural complex of anthra- quinone glycosides. Taken orally, senna causes evacuation of the bowels within 8 to 10 hours. It also causes water and electrolyte secretion into the bowel. In combination products with a docusate- containing stool softener, it is useful in treating opioid-induced constipation.

Question 39

Bisacodyl

Answer 39

Bisacodyl: Available as suppositories and enteric-coated tablets, bisacodyl is a potent stimulant of the colon. It acts directly on nerve fibers in the mucosa of the colon.

Question 40

Castor oil

Answer 40

Castor oil: This agent is broken down in the small intestine to ricinoleic acid, which is very irritating to the stomach and promptly increases peristalsis. Pregnant patients should avoid castor oil because it may stimulate uterine contractions.

Question 41

Bulk laxatives

Answer 41

Bulk laxatives The bulk laxatives include hydrophilic colloids (from indigestible parts of fruits and vegetables). They form gels in the large intestine, causing water retention and intestinal distension, thereby increasing peristaltic activity. Similar actions are produced by methylcellulose, psyllium seeds, and bran. They should be used cautiously in patients who are immobile because of their potential for causing intestinal obstruction

Question 42

Saline & osmotic laxatives

Answer 42

Saline and osmotic laxatives Saline cathartics, such as magnesium citrate and magnesium hydroxide, are nonabsorbable salts (anions and cations) that hold water in the intestine by osmosis. This distends the bowel, increasing intestinal activity and producing defecation in a few hours. Electrolyte solutions containing polyethylene glycol (PEG) are used as colonic lavage solutions to prepare the gut for radiologic or endoscopic pro- cedures. PEG powder for solution is available as a prescription and also as an over-the-counter laxative and has been shown to cause less cramping and gas than other laxatives. Lactulose is a semisyn- thetic disaccharide sugar that acts as an osmotic laxative. It can- not be hydrolyzed by GI enzymes. Oral doses reach the colon and are degraded by colonic bacteria into lactic, formic, and acetic acids. This increases osmotic pressure, causing fluid accumulation, colon distension, soft stools, and defecation. Lactulose is also used for the treatment of hepatic encephalopathy, due to its ability to reduce ammonia levels.

Question 43

Stool softeners

Answer 43

Stool softeners (emollient laxatives or surfactants) Surface-active agents that become emulsified with the stool produce softer feces and ease passage. These include docusate sodium and docusate calcium. They may take days to become effective and are often used for prophylaxis rather than acute treatment. Stool soften- ers should not be taken concomitantly with mineral oil because of the potential for absorption of the mineral oil.

Question 44

Lubricant laxatives

Answer 44

Lubricant laxatives Mineral oil and glycerin suppositories are lubricants and act by facili- tating the passage of hard stools. Mineral oil should be taken orally in an upright position to avoid its aspiration and potential for lipid or lipoid pneumonia.

Question 45

Chloride channel activators

Answer 45

Chloride channel activators Lubiprostone [loo-bee-PROS-tone], currently the only agent in this class, works by activating chloride channels to increase fluid secre- tion in the intestinal lumen. This eases the passage of stools and causes little change in electrolyte balance. Lubiprostone is used in the treatment of chronic constipation, particularly because tolerance or dependency has not been associated with this drug. Also, drug– drug interactions appear minimal because metabolism occurs quickly in the stomach and jejunum.