Medications for Irritable Bowel Syndrome and Other Gastrointestinal Problems

http://evolve.elsevier.com/Edmunds/NP/

Class	Subclass	Generic Name	Trade Name
Antispasmodics/anticholinergics		dicyclomine hydrochloride	Bentyl
		hyoscyamine sulfate	Levsin, NuLev
5-HT₃ Receptor antagonists		alosetron	Lotronex
GI stimulants/prokinetic agents		metoclopramide	Reglan
Prostaglandins		misoprostol	Cytotec
Ulcerative colitis treatment		mesalamine	Asacol
		sulfasalazine	Azulfidine
Locally acting agents		simethicone	Phazyme, Gas-X
		sucralfate	Carafate
Gallstone-solubilizing agents		ursodiol	Actigall

Key drug. Key drug chosen because dicyclomine has a lower incidence of side effects.

INDICATIONS

• See Table 31-1.

TABLE 31-1

Indications for Use of Miscellaneous GI Drugs

Drug Category	Individual Drugs	Indications
Antispasmodics/ anticholinergics	dicyclomine, hyoscyamine	IBS, PUD, hypermotility disorders, ulcerative colitis, diverticulitis
5-HT₃ receptor antagonists	alosetron	IBS with diarrhea
GI stimulants/prokinetic agents	metoclopramide	Diabetic gastroparesis, severe GERD
Prostaglandins	misoprostol	Reduce risk of NSAID PUD
Ulcerative colitis treatment	mesalamine sulfasalazine	Ulcerative colitis Ulcerative colitis, RA, JRA
Locally acting agents	simethicone	Flatulence
	sucralfate	Duodenal ulcer
Gallstone-solubilizing agents	ursodiol	Gallstones

• This chapter discusses many diverse classes of medications; the only thing they have in common is their effects on the GI tract. Each class is discussed separately. The disease that is discussed in this chapter is irritable bowel syndrome (IBS).

Irritable Bowel Syndrome

Antispasmodic agents (e.g., dicyclomine hydrochloride [Bentyl], hyoscyamine sulfate [Levsin]) are used primarily to treat patients with IBS and other functional GI disorders. A large number of antispasmodics are available on the market, but they are not used often. Only the two most common antispasmodic drugs are discussed in this chapter. Dicyclomine is used as the prototype.

Alosetron (Lotronex), a type 3 serotonin (5-HT₃) antagonist, is available only through the Prescribing Program for Lotronex because of risk for ischemic colitis; this is not discussed in detail.

Therapeutic Overview of Irritable Bowel Syndrome

Pathophysiology

The pathophysiology of IBS is not fully understood, but bowel motility is affected. In normal bowel motility, segmenting contractions assist transit through the bowel. When these contractions increase, diarrhea occurs. When they decrease, constipation occurs. External factors include stress, psychologic factors, laxative abuse, food intolerance, and menstruation. Some evidence of inflammation in this process has been obtained.

Disease Process

IBS is a common chronic functional bowel disorder. Other names for IBS include spastic colitis, mucous colitis, nervous colitis, spastic colon, nervous colon, irritated colon, and unstable colon. Functional bowel disorders consist of combinations of chronic or recurrent GI symptoms that cannot be explained by structural or biochemical abnormalities. Generally, the diagnosis is a clinical one that is based on a cluster of symptoms combined with exclusion of a specific organic cause. Diagnostic criteria have been developed to make the diagnosis of IBS more consistent. The history of the patient is critical for diagnosis of IBS. Common symptoms include abdominal pain, altered bowel frequency and stool consistency (often alternating diarrhea and constipation), abdominal distention or bloating, and varying degrees of anxiety or depression. The new Rome III guidelines maintain that IBS of any subtype is characterized by a strong relationship between abdominal pain and defecation. These individuals have visceral hypersensitivity, or increased perception of gut-related events. In IBS with constipation (IBS-C), the onset of constipation generally corresponds with onset of pain at defecation. Patients with IBS-C may report abdominal pain, even if they empty their bowels regularly. The pain is described as sharp, burning, or cramping. The location is usually diffuse. A careful history is necessary to determine what the patient means by such words as “diarrhea,” “constipation,” and “regular.” Nocturnal diarrhea may indicate a serious problem. Patients may be classified into categories based on their predominant symptom: pain, constipation, or diarrhea. Care should be taken to rule out organic causes of symptoms such as celiac disease, lactose or fructose intolerance, and infectious processes.

Mechanism of Action

• Antispasmodic/anticholinergic agents are also known as antimuscarinic drugs. The muscarinic nervous system is a subcategory of the anticholinergic nervous system. The other subcategory, the nicotinic nervous system, is seldom involved in drug actions. Anticholinergic agents decrease motility, relax smooth muscle tone in the GI tract, and decrease secretions.

• Antispasmodics decrease GI motility by relaxing smooth muscle tone. These medications have anticholinergic properties; thus, they compete with acetylcholine for receptors at postganglionic fibers of the parasympathetic nervous system.

• Dicyclomine has indirect and direct effects on the smooth muscle of the GI tract. It indirectly blocks acetylcholine receptor sites and directly antagonizes bradykinin and histamine in GI tract smooth muscle. Both of these actions help to relieve smooth muscle spasm.

• Hyoscyamine, a belladonna alkaloid, inhibits the muscarinic actions of acetylcholine at postganglionic parasympathetic neuroeffector sites, including smooth muscle, secretory glands, and CNS sites. Thus, this drug has an effect on peripheral cholinergic receptors present in the smooth muscle of the GI tract. Specific anticholinergic responses are dose related. Low doses inhibit salivary and bronchial secretions and sweating. Next, pupil dilation and accommodation are affected, and heart rate is increased. Higher doses decrease motility in GI and urinary tracts, and then inhibit gastric acid.

• Antidepressants (particularly the TCAs), 5-HT₃ (alosetron), and misoprostol have been found to be helpful in some patients. Please see Chapter 47 on antidepressants for a discussion of these products.

Treatment Principles

Standardized Guidelines for IBS

• The American Gastroenterological Association developed guidelines for the treatment of patients with IBS; these were revised in 2002. World Gastroenterology Organization Practice Guideline—Irritable Bowel Syndrome. See www.worldgastroenterology.org/irritable-bowel-syndrome.html.

• American College of Gastroenterology Task Force on Irritable Bowel Syndrome: An evidence-based position statement on the management of irritable bowel syndrome, Am J Gastroenterol 104(Suppl 1):S1-S34, 2009.

Evidence-Based Recommendations for IBS

Likely to be beneficial are the following:

• Antidepressants: Tricyclics and SSRIs have been shown to reduce symptoms; it is not clear whether this is a separate effect from the antidepressant effect.

• Smooth muscle relaxants have been noted to improve symptoms.

• Psyllium fiber, certain antispasmodics, and peppermint oil are effective. See Table 31-2 for more on complementary and alternative therapies.

TABLE 31-2

Complementary and Alternative Products That May Have Interactions with Other Drugs

Condition	Product	Comments
Irritable bowel	Cat’s claw	Potential interaction with anticoagulants, aspirin, antiplatelet agents. May stimulate immune system. May protect against GI damage from NSAIDs.
	Flaxseed	May slow down absorption of oral medications or other nutrients if taken at the same time.
	Grapefruit seed extract	Avoid concurrent administration of terfenadine, astemizole, cisapride; use other medications metabolized by the CYP 3A4 subsystem with caution.
	Evening primrose	Potential interaction with anticoagulants, aspirin, NSAIDs, antiplatelet agents; phenothiazines used to treat schizophrenia
	Peppermint	No known interactions
Gallbladder/gallstones	Milk thistle Artichoke Goldenseal	No reported toxicities with any of these products
Gallbladder disease	Milk thistle Artichoke	No reported toxicities with either of these products

• A trade-off occurs between benefits and harms of all medications.

• 5-HT₃ receptor antagonist alosetron (Lotronex): This agent has improved symptoms in women with diarrhea-predominant IBS and has increased constipation. It may be associated with ischemic colitis.

Cardinal Points of Treatment

• Pharmacotherapy is based on severity and is targeted at specific symptoms.

• All patients with alternating constipation/diarrhea:

• Increased dietary fiber (25 g/day)

• Pain

• Antispasmodic (anticholinergic) medication—short term

• TCAs—long term

• Diarrhea

• Loperamide—short term; often used for breakthrough diarrhea

• Antidepressants (TCAs)—long term

• Alosetron (ordered by GI specialists) if resistant to all other interventions

• Constipation

• Fiber

• Laxatives

Nonpharmacologic Treatment

Treatment of patients with IBS begins with patient education. The patient must be reassured that there is no organic cause for the symptoms. Teach that this is a chronic condition and that it will not lead to an organic problem.

Diet with adequate fiber is the cornerstone of treatment. Amounts of fiber and fluid usually have to be increased. Fiber should be increased gradually to avoid bloating. (See Chapter 28 for a list of high-fiber foods.) The patient should drink 6 to 8 glasses of water a day. The patient should identify and eliminate foods that cause symptoms. Foods that commonly cause problems include raw fruits and vegetables, high-fat foods, beverages such as carbonated beverages, coffee and other forms of caffeine, red wine and beer, and artificial sweeteners such as fructose and sorbitol. Exclude lactose intolerance.

Other important lifestyle changes include good bowel habits and exercise. See Chapter 28 for a discussion of bowel training. The best exercise is usually regular walking.