Deja Review Pharmacology, 2nd Edition

CHAPTER 8. Gastrointestinal Agents

 

AGENTS FOR GASTROESOPHAGEAL REFLUX DISEASE

 

What is the main cause of gastroesophageal reflux disease (GERD)?

Decreased lower esophageal sphincter pressure

What complications may arise from GERD?

Strictures; esophagitis; Barrett esophagus (squamocolumnar metaplasia)

What are the drug therapy goals in treating GERD?

To eliminate symptoms; heal esophagitis; prevent the relapse of esophagitis; prevent the development of complications

What types of medications may be useful in the treatment of GERD?

Antacids; H2-receptor antagonists; proton pump inhibitors (PPIs); prokinetic agents (cisapride, metoclopramide, bethanechol); mucosal protectants (sucralfate)

Give the mechanism of action for each of the following drugs or drug classes:

Antacids

Weak bases that increase gastric pH through acid-neutralizing ability to form a salt and water

H2--receptor antagonists

Competitively antagonize H2 receptors on gastric parietal cells, thereby decreasing acid production

PPIs

Inhibit gastric acid secretion via inhibiting gastric parietal cell H+/K+-ATPase. Restoration of acid secretion requires resynthesis of the H+/K+-ATPase (proton pump).

Cisapride

Increases lower esophageal sphincter pressure; accelerate gastric emptying time; increases amplitude of esophageal contractions; 5-HT4 agonist; 5-HT3antagonist

Metoclopramide

Dopamine (D2) receptor antagonist; increases lower esophageal sphincter pressure; accelerates gastric emptying time

Sucralfate

When exposed to acid, complexes with positively charged proteins to form a viscous coat, thereby protecting gastric lining from gastric acid secretions

What are the adverse effects caused by metoclopramide?

Anxiety; insomnia; extrapyramidal symptoms; increased prolactin levels

What are the adverse effects caused by sucralfate?

Constipation; nausea; abdominal discomfort

What are the possible adverse effects of antacids?

Belching (sodium bicarbonate and calcium carbonate); diarrhea (magnesium salts); constipation (calcium or aluminum salts); acid-base disturbances; bone damage via binding phosphate in the gut (aluminum salts); worsening of hypertension and congestive heart failure (CHF) (sodium salts); decreased absorption of medications via pH alteration or formation of insoluble complexes (tetracycline, fluoroquinolones, isoniazid [INH], ferrous sulfate, ketoconazole, PPIs)

Which antacid(s) can produce a metabolic alkalosis?

Sodium bicarbonate; calcium carbonate

What causes the milk-alkali syndrome?

Ingestion of excessive amounts of calcium and absorbable alkali such as sodium bicarbonate or calcium carbonate

What is a potential complication after discontinuing chronic antacid use?

Acid rebound

List the names of the H2-receptor antagonists:

Cimetidine; famotidine; ranitidine; nizatidine

Which H2-receptor antagonist inhibits hepatic cytochrome P-450 metabolizing enzymes?

Cimetidine

Name at least five drugs showing potential drug interactions with cimetidine:

 

  1. Warfarin
  2. Diazepam
  3. Phenytoin
  4. Metronidazole
  5. Propranolol
  6. Lidocaine
  7. Calcium channel blockers (CCBs)
  8. Theophylline
  9. Certain tricyclic antidepressants (TCAs); chlordiazepoxide

 

Which H2-receptor antagonist can cause gynecomastia?

Cimetidine (prolactin-stimulating activity)

Which H2-receptor antagonist has antiandrogenic activity?

Cimetidine

List the names of the PPIs:

Omeprazole; esomeprazole; lansoprazole; rabeprazole; pantoprazole

What are the common side effects of PPIs?

Headache; dizziness; nausea; diarrhea; constipation. Prolonged use can lead to bacterial overgrowth in the GI tract. Note also that a recent analysis revealed that people (age > 50) taking high doses of PPIs for more than a year were 2.6 times as likely to break a hip as were people not taking PPIs. Histamine H2-receptor inhibitors also increased fracture risk, but not to the extent as did PPIs.

What is the most serious side effect of cisapride?

Prolongation of the QT interval

Cisapride should be avoided in which type of patients?

Patients with prolonged QT intervals; patients taking medications that inhibit cytochrome P-ISO 3A4 (fluconazole, ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir)

What arrhythmia can be caused by prolongation of the QT interval?

Torsades de pointes (a polymorphic ventricular tachycardia)

Which drugs increase cisapride blood levels by inhibiting the cytochrome P-450 3A4 enzymes that metabolize cisapride? (Please mention at least four drugs).

 

  1. Erythromycin
  2. Clarithromycin
  3. Itraconazole
  4. Fluconazole
  5. Ketoconazole
  6. Indinavir
  7. Ritonavir
  8. Class 1A antiarrhythmics
  9. Class III antiarrhythmics
  10. Certain TCAs
  11. Certain antipsychotics

 

AGENTS FOR PEPTIC ULCER DISEASE

 

What three mediators can stimulate acid secretion from parietal cells?

 

  1. Acetylcholine
  2. Histamine (via H2receptor)
  3. Gastrin

 

Name three causes of peptic ulcer disease (PUD):

 

  1. Helicobacter pyloriinfection (primary cause)
  2. Nonsteroidal anti-inflammatory drugs (NSAIDs)
  3. Extreme physiologic stress (ie, patients in the ICU setting being ventilated, burn patients)

 

What type of patients do acute peptic ulcers occur in?

Hospitalized patients who are critically ill (stress ulcers)

What is the name of the syndrome that is characterized by hypersecretion of gastric acid secondary to a gastrin-secreting tumor?

Zollinger-Ellison syndrome

Which are the drug therapy goals in treating PUD?

Control H. pylori infection; alleviate symptoms; promote healing; prevent recurrences; prevent complications (eg, hemorrhage)

What types of medications are useful for the treatment of PUD?

Antimicrobial agents; H2-receptor antagonists; PPIs; prostaglandins; antimuscarinic agents; antacids; mucosal protective agents; bismuth salts

How might H. pylori play a role in peptic ulcer development?

Direct mucosal damage; alterations in inflammatory response; induced hypergastrinemia

Meals worsen the pain associated with what type of ulcer?

Gastric ulcer

Meals relieve the pain associated with what type of ulcer?

Duodenal ulcer

What treatment options are available to eradicate H. pylori?

Triple therapy with a PPI added to two antimicrobial agents such as metronidazole, amoxicillin, tetracycline, or clarithromycin; four-drug regimens consisting of triple therapy plus bismuth subsalicylate; (must use triple or quadruple antibiotic therapy to eradicate H. pylori)

Why should you not give bismuth subsalicylate to children?

May be associated with Reye syndrome (contains salicylates)

What is Reye syndrome?

Acute onset encephalopathy and fatty liver formation. Symptoms begin with vomiting, lethargy, and confusion progressing to stupor, respiratory distress, coma, and seizures. Its cause is unknown, but has been found to be associated with aspirin use in young children. Therefore, aspirin administration is to be avoided in pediatric patients.

How do prostaglandins help treat PUD?

Prostaglandins such as PGE2 and PGI2inhibit gastric acid secretion and stimulate secretion of bicarbonate and mucus (cytoprotective activity); used to treat NSAID-induced peptic ulcers

Which prostaglandin analog is commonly used as a cytoprotective agent for the treatment of PUD?

Misoprostol (synthetic PGE1 analog)

Why should misoprostol not be given to a preterm pregnant woman?

Induction of premature uterine contractions (abortifacient properties)

AGENTS FOR INFLAMMATORY BOWEL DISEASE

 

What are the two forms of inflammatory bowel disease (IBD)?

 

  1. Crohn disease
  2. Ulcerative colitis (UC)

 

Does treatment of IBD cure or control the disease process?

Control

What types of medications are used to treat IBD?

Corticosteroids; aminosalicylates; immunosuppressives; monoclonal antibodies

Sulf asalazine is cleaved by gut bacteria in the colon to produce what two compounds?

 

  1. Sulfapyridine (sulfonamide antibiotic)
  2. Mesalamine (5-aminosalicylic acid, 5-ASA)

 

What is the active component of sulfasalazine for IBD?

Mesalamine or 5-ASA; 5-ASA is the metabolite active against IBD, while sulfapyridine is the metabolite active against rheumatoid arthritis. Formulation into sulfasalazine is necessary to prevent rapid proximal gut absorption so that sufficient 5-ASA is delivered to the distal gut to effectively treat IBD.

How does mesalamine work in the treatment of IBD?

Anti-inflammatory effects; immunomodulating effects

What type of vitamin supplementation should patients receive while on sulfasalazine?

Folic acid since sulfasalazine may interfere with absorption of folic acid in the gut, leading to megaloblastic anemia

What types of immunosuppressives are used to treat IBD?

Cyclosporine A; methotrexate; azathioprine; 6-mercaptopurine

What is the name of the monoclonal antibody indicated for the treatment of Crohn disease?

Infliximab

What is infliximab’s mechanism of action?

Monoclonal antibody that binds to soluble and bound forms of tumor necrosis factor-alpha (TNF-α)

True or False? Once remission has been achieved with ulcerative colitis, corticosteroids are used as maintenance therapy.

False. Corticosteroids should not be used to maintain disease remission due to their high systemic toxicity. Aminosalicylates or immunosuppressive agents are used for maintenance therapy for UC.

AGENTS FOR NAUSEA AND VOMITING

 

Name a major chemosensory area for emesis:

Chemoreceptor trigger zone (CTZ)

Where is the CTZ found?

Area postrema of the fourth ventricle of the brain

Give examples of drug classes that are effective in the treatment of nausea and vomiting:

Antihistamine-anticholinergics; benzodiazepines; butyrophenones; cannabinoids; corticosteroids; phenothiazines; substituted benzamides; 5-HT3-receptor antagonists; neurokinin receptor antagonists

Give examples of specific drugs in each of the following drug classes used in the treatment of nausea and vomiting:

Antihistamine-anticholinergics

Diphenhydramine; hydroxyzine; meclizine; cyclizine; promethazine; pyrilamine; scopolamine; trimethobenzamide

Benzodiazepines

Alprazolam; diazepam; lorazepam

Butyrophenones

Haloperidol; droperidol; domperidone

Cannabinoids

Dronabinol; nabilone

Corticosteroids

Dexamethasone; methylprednisolone

Phenothiazines

Prochlorperazine; chlorpromazine; perphenazine

Substituted benzamides

Metoclopramide

5-HT3--receptor antagonists

Ondansetron; dolasetron; granisetron

Neurokinin receptor antagonists

Aprepitant (oral); fosaprepitant (IV formulation converted to aprepitant)

Do synthetic cannabinoids have psychotropic activity?

No

How does metoclopramide work as an antiemetic?

Blocks dopamine receptors centrally in the CTZ

What is intractable emesis leading to dehydration and hypotension during pregnancy called?

Hyperemesis gravidarum

What are the drugs of choice for treating emesis during pregnancy?

Meclizine; cyclizine; promethazine

What antihistamine is often used to treat motion sickness?

Meclizine

What anticholinergic is often used to treat motion sickness?

Scopolamine

How is scopolamine normally administered?

As a transdermal patch to prevent systemic anticholinergic effects

What medication is often used in combination regimens to enhance antiemetic activity?

Dexamethasone

What are the side effects of cannabinoids?

Anxiety; memory loss; confusion; motor incoordination; hallucinations; euphoria; relaxation; hunger; gynecomastia

What are the side effects of the phenothiazine antiemetics?

Extrapyramidal symptoms; sedation; hypotension

Why doesn’t ondansetron cause extrapyramidal side effects?

Blocks 5-HT3 instead of dopamine receptors in the CTZ

What chemotherapy agent has one of the highest emetogenic potentials?

Cisplatin

What over-the-counter (OTC) medication can be given in combination with metoclopramide to reduce its extrapyramidal side effects?

Diphenhydramine can be used for its anticholinergic properties. EPS symptoms with metoclopramide use are due to central dopamine receptor blockade, and tardive dyskinesia, if it develops, may be irreversible. Therefore, metoclopramide should only be used for short-term therapy if possible.

What macrolide antibiotic also has prokinetic properties for the GI tract?

Erythromycin, though tolerance to this effect develops rapidly, limiting its usefulness

AGENTS FOR DIARRHEA AND CONSTIPATION

 

Name three classes of drugs that are effective in the treatment of diarrhea:

 

  1. Adsorbents
  2. Antimotility agents
  3. Antisecretory agents

 

Define adsorbent:

A substance offering a suitable active surface, upon which other substances may adhere to

Give examples of specific drugs in each of the following drug classes used in the treatment of diarrhea:

Adsorbents

Kaolin; pectin; polycarbophil; attapulgite

Antimotility agents

Diphenoxylate; loperamide; morphine

Antisecretory agents

Bismuth subsalicylate

Give the antidiarrheal mechanism of action for each of the following drug classes:

Adsorbents

Adsorbs (adheres to) drugs, nutrients, toxins, and digestive juices

Antimotility agents

Decrease peristalsis by activating presynaptic opioid receptors in the enteric nervous system

Antisecretory agents

Decrease fluid secretion in the bowel

What adsorbent can absorb 60 times its weight in water and treat both diarrhea and constipation?

Polycarbophil

What are the potential side effects of bismuth subsalicylate?

Salicylism (tinnitus, nausea, vomiting); darkening of tongue; darkening of stools; induce gout attacks in susceptible patients

What antidiarrheal can decrease tetracycline absorption if given concomitantly?

Bismuth subsalicylate

What antidiarrheal is often formulated in combination with atropine?

Diphenoxylate

Which class of antidiarrheals can cause paralytic ileus?

Antimotility agents

What medication is often used to treat flushing and diarrhea seen in carcinoid syndrome and vasoactive intestinal peptide secreting tumors (VIPomas)?

Octreotide

What is octreotide’s mechanism of action?

Synthetic analog of somatostatin which blocks release of serotonin and other vasoactive peptides; direct inhibitory effects on intestinal secretion; direct stimulatory effects on intestinal absorption

What are the non-antidiarrheal uses of octreotide?

Esophageal varices; acromegaly

What medication can be used in conjunction with antibiotics to bulk stools and absorb Clostridium difficile toxins A and B in C. difficile colitis?

Cholestyramine, a nonabsorbable binding agent

What types of medications cause constipation?

Opioid analgesics; anticholinergics; calcium-containing antacids; aluminum-containing antacids; calcium channel blockers; clonidine; iron; sodium polystyrene sulfonate

Give examples of drug classes that are effective in the treatment of constipation:

Bulk forming agents; irritants and stimulants; stool softeners

Give examples of specific drugs in each of the following drug classes used in the treatment of constipation:

Bulk forming agents

Methylcellulose; psyllium; bran; magnesium-containing salts; polyethylene glycol

Osmotic laxatives

Lactulose; magnesium hydroxide (milk of magnesia); sorbitol; magnesium citrate; sodium phosphate; polyethylene glycol

Irritants and stimulants

Cascara; senna; aloe; bisacodyl

Stool softeners

Mineral oil; docusate (oral or enema, trade name: Colace); glycerin suppository

Cl channel activators

Lubiprostone (Amitiza)

Give the mechanism of action for each of the following drug classes:

Bulk-forming agents

Form gels in large intestine which causes water retention and intestinal distention, thereby increasing peristaltic activity

Osmotic laxatives

Nonabsorbable compounds which draw fluid into the colon to maintain osmotic neutrality

Irritants and stimulants

Irritate gut lining which subsequently increases peristalsis

Stool softeners

Surfactants that become emulsified with stool, thereby softening feces

Cl channel activators

Activate CIC-2 Cl channels in the apical membrane of intestinal cells increasing fluid and intestinal motility without altering serum Na+ or K+ levels. The effects are localized to the GI tract, increase fluid secretion into the intestinal lumen, and accelerate fecal transit.

What are the potential side effects of bisacodyl?

Abdominal cramping; atonic colon

CLINICAL VIGNETTES

 

A 50-year-old woman is in the surgical intensive care unit (ICU) status post right middle cerebral artery hemorrhagic stroke. She is being mechanically ventilated. Her morning laboratories come back with a platelet count of 50,000 (normal 150,000-450,000). Given her history, she is not on deep venous thrombosis (DVT) prophylaxis with heparin. What other prophylactic medication, commonly employed in a critical care setting, may be responsible for her drop in platelet count?

Patients in ICUs are routinely put on DVT and GI prophylaxis given the prolonged immobility and high physiologic stress of intensive care. Pharmacologic DVT prophylaxis is not appropriate in this patient, and mechanical methods such as sequential compression stockings should be used instead. However, this patient was most likely started on omeprazole for prevention of stress-induced gastric ulcers. Omeprazole can cause thrombocytopenia. This patient should be switched to a different GI prophylactic medication. Esomeprazole, the S-enantiomer of omeprazole, while controversial as to whether or not it is more effective to inhibit stomach acid secretion, does not carry the same risk of lowering platelets.

A 60-year-old woman with a past medical history of rheumatoid arthritis (RA) and chronic iron deficiency anemia is found to have blood in her stool. Colonoscopy is negative, but a gastric ulceration is discovered upon upper endoscopy. After successful treatment of the ulcer, what medication could be added to the patient’s regimen to prevent a repeat ulcer or gastric perforation?

Patients with a chronic inflammatory disease such as RA are often successful in relieving their pain symptoms with long-term treatment with NSAIDs. However, this therapy can lead to gastric ulceration and chronic gastrointestinal bleeding that can lead to iron deficiency anemia. This anemia is often overlooked in patients with chronic autoimmune disorders as anemia of chronic disease. All GI bleeding must be considered colon cancer until proven otherwise, especially in patients older than 50 years, but once ruled out the next most likely location in this patient is a gastric ulcer due to disruption of the gastric mucosa by long-term NSAID administration. Because of the patient’s RA, NSAID cessation is difficult. In patients such as this, addition of misoprostol, a prostaglandin analog, may be appropriate.

An 86-year-old woman with a history of chronic constipation is treated with lactulose with good relief of her constipation. However, she complains of painful abdominal cramps and embarrassing flatus and wishes to try another medication. What laxative has a similar mechanism of action to lactulose and will not cause large electrolyte imbalances, making it safe to use in this elderly patient?

Polyethylene glycol (PEG) is an osmotic laxative used in high concentration formulas as a bowel cleanser prior to endoscopic procedures. It is effective in lower concentrations for treatment of chronic constipation. Unlike lactulose and sorbitol, it is not metabolized by colonic bacteria, decreasing colonic gas formation. It does not cause large fluid or electrolyte shifts. Therefore, unlike magnesium citrate, sodium phosphate, or magnesium hydroxide, PEG does not carry a risk for electrolyte disturbances, making it an ideal choice for elderly patients and/or patients with renal insufficiency.