Pharmacology - An Illustrated Review

27. Drugs Acting on the Gastrointestinal System

The gastrointestinal (GI) tract includes the mouth, stomach, small intestine (duodenum, jejunum, and ileum), large intestine (cecum and colon), rectum, anus, and its accompanying exocrine glands (the salivary glands, the pancreas, and the gallbladder).

Drugs affecting the GI system are used in the treatment of gastric acidity, peptic ulcers, and gastroesophageal reflux disease (GERD), bowel motility disorders (gastroparesis [delayed gastric emptying due to partial paralysis of the stomach muscles], constipation, and diarrhea), and for the treatment of nausea and vomiting.

27.1 Proton Pump Inhibitors

Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and Rabeprazole

Mechanism of action. Proton pump inhibitors inhibit the proton (H+-K+–ATPase) pump of the parietal cells in the stomach, thus inhibiting gastric acid (HCl) secretion into the lumen of the stomach (Fig. 27.1).

Fig. 27.1 image Drugs used to lower gastric acid production.

Proton pump inhibitors block the H+-K+-ATPase pump on gastric parietal cells. H2 receptor antagonists act to block histamine receptors on parietal cells. Both omeprazole and ranitidine ultimately lower gastric acid production. (ACh, acetylcholine; ECL, enterochromaffin-like cell.)

image

Uses

– Peptic ulcers

– GERD

Side effects. There are minimal side effects. GI pain and diarrhea are the most common.

H+-K+–ATPase (the proton pump)

H+-K+ ATPase is an integral transmembrane protein that is present in gastric parietal cells. It functions to actively transport H+ into the lumen of the stomach, against its electrochemical gradient, in exchange for K+ (one H+ is exchanged for one K+). The energy required to drive this exchange is derived from the hydrolysis of adenosine triphosphate (ATP). (See call-out box on page 345.)

 

Gastric acid production

Gastric acid is secreted from parietal cells when stimulated by the vagus nerve, histamine, and gastrin. CO2 and H2O react inside parietal cells, under the influence of carbonic anhydrase, to form bicarbonate (HCO3) and H+. H+ is then pumped into the lumen of the stomach by H+-K+ ATPase. Cl is also secreted from parietal cells into the lumen by simple diffusion. H+, Cl, and water combine in the lumen to form hydrochloric acid (HCl). The HCO3 produced is secreted into the bloodstream. (See call-out box on page 346.)

 

Gastroesophageal reflux disease (GERD)

Gastroesophageal reflux disease (GERD) occurs when stomach acid continuously refluxes into the esophagus causing pain, heartburn, and inflammation because the esophagus lacks the protective lining of the stomach. The pain of GERD radiates to the back and is worsened by stooping and ingesting hot drinks. GERD is exacerbated by increased intra-abdominal pressure (obesity, big meals, tight clothing), reduced lower esophageal sphincter (LES) tone (pregnancy, hiatus hernia, achalasia, fatty meals and smoking, and tricyclic and anticholinergic drugs). Treatment is with antacids (e.g., calcium carbonate), H2-receptor antagonists (e.g., cimetidine), or proton pump inhibitors (e.g., omeprazole). Medication to strengthen the LES, known as prokinetic drugs (e.g., metoclopromide), may also be used. If medications alone do not control symptoms, surgery to tighten the LES may be necessary.

 

27.2 Gastric Antacids

Mechanism of action. Gastric antacids (Fig. 27.2) partially neutralize gastric acid and inhibit pepsin (a proteolytic enzyme) activity both directly and by increasing pH, thus protecting the stomach mucosa. These agents must be taken frequently to maintain increased pH in the stomach.

– Nonsystemic antacids are compounds that are not absorbed into the systemic circulation. Their anionic group neutralizes the H+ ions in gastric acid. This releases their cationic group which combines with HCO3from the pancreas to form an insoluble basic compound that is excreted in feces. Thus these agents do not produce metabolic alkalosis.

– Systemic antacids are absorbed into the systemic circulation. They have a cationic group that does not form insoluble basic compounds with HCO3. Thus the HCO3can be absorbed producing a metabolic alkalosis.

Gastric pH and mucosal protection

Normal gastric pH is 2.0 to 3.0. Gastric mucosa is protected from this acidic environment by several mechanisms: the secretion of mucus provides a barrier between gastric acid and stomach mucosa; HCO3 ions secreted from the epithelium of the stomach neutralize H+ ions; the epithelium itself is largely impenetrable to H+ ions; and a rich mucosal blood supply ensures that if H+ ions do penetrate the epithelium, then they are rapidly removed.

 

Uses

– Peptic ulcers

– Acid indigestion

– Hyperchlorhydria (excess HCl in the stomach)

Peptic ulcers

An ulcer is a lesion extending through the mucosa and submucosa into deeper structures of the wall of the GI tract. Ulcers are the result of breakdown of the mucosal barrier (mucus and HCO3) that normally protects the lining of the GI tract and/or increased secretion of H+ or pepsin. There are two types of peptic ulcers: gastric ulcers and duodenal ulcers. Gastric ulcers are commonly found on the lesser curvature between the corpus and antrum of the stomach. They are often caused by Helicobacter pylori (H. pylori), a gram-negative spiral bacillus, which secretes cytotoxins that disrupt the mucosal barrier causing inflammation and destruction. H. pylori secretes high levels of membrane urease, which converts urea to NH3. NH3 neutralizes gastric acid around the bacterium, allowing it to survive in the acidic lumen of the stomach. Duodenal ulcers are the most common ulcers and are often associated with increased gastric H+ secretion (but not necessarily). Doudenal ulcers also frequently occur due to H. pylori that inhibits somatostatin secretion leading to increased gastric H+ secretion. There is also decreased HCO3 secretion in the duodenum, which impedes neutralization of the excess H+ delivered from the stomach.

 

Zollinger–Ellison syndrome

Zollinger–Ellison syndrome is a condition caused by gastrin-secreting pancreatic adenomas that lead to multiple ulcers in the stomach and duodenum. These ulcers are frequently drug resistant and are accompanied by diarrhea and steatorrhea (as well as all of the usual peptic ulcers symptoms, e.g., burning abdominal discomfort, heart-burn, nausea and vomiting, and weight loss). Tests for the condition will show raised serum gastrin and gastric acid levels. Treatment involves the use of proton pump inhibitors to heal the ulcers and surgical resection of the offending tumor if this is possible. If surgery is not an option, or if full resection is not possible, then chemo-therapy may be employed to slow tumor growth. The 5-year survival rate is low (20%) if the tumor metastasizes (usually to the liver).

 

Nonsystemic Antacids

Calcium Carbonate

Side effects

– Ca2+ salts have an unpleasant chalky taste, and they precipitate in the GI tract to cause constipation. Rapid neutralization of gastric acid can also cause belching (CO2 gas forms).

– Hypercalcemia can occur with chronic usage if large amounts of milk and dairy products are ingested (“milk–alkali syndrome”).

– May cause a rebound acid secretion

Fig. 27.2 image Drugs used to neutralize gastric acid.

Antacids have an anionic group that combines with H+in gastric acid, neutralizing it. The anion that is released in this reaction either remains in solution and is absorbed in the duodenum with HCO3 (from the pancreas) or it combines with HCO3to form an insoluble precipitate that is excreted in feces.

image

Magnesium Hydroxide (Milk of Magnesia)

Effects

– Mg2+ salts act as both antacids and laxative agents.

– The laxative effect is lessened by concomitant use with calcium carbonate or aluminum hydroxide; both tend to produce constipation.

Side effects. Some absorption and retention of Mg2+ (if renal function is impaired) could produce neurologic or cardiovascular toxicity.

Aluminum Hydroxide

Mechanism of action. Aluminum salts remain in the stomach for long periods and slowly react with stomach acid to form aluminum chloride. Aluminum hydroxide may inhibit the action of pepsin and stimulate stomach mucus secretion.

Side effects

– Constipation

– Osteomalacia (by interfering with PO43– absorption)

– Decreased absorption of some drugs (e.g., tetracyclines and other antibiotics)

Note: Because some antacids have constipating effects and others laxative effects, a mixture of these salts are combined in over-the-counter and prescription preparations to negate and thus avoid these unwanted effects.

Systemic Antacids

Sodium Bicarbonate

Side effects. Sodium bicarbonate (NaHCO3) is a highly soluble agent that rapidly neutralizes acid, producing lots of C02 and causing episodes of belching. Severe distention of the stomach by CO2 gas may be dangerous if a gastric ulcer that could perforate is present.

27.3 Histamine (H2) Receptor Antagonists

See Chapter 32 for a full discussion of histamine and antihistamines.

Cimetidine, Ranitidine, Famotidine, and Nizatidine

Mechanism of action. H2 receptor antagonists act specifically to competitively block the H2 histamine receptors of parietal cells (Fig. 27.1). They inhibit both basal and stimulated gastric acid secretion.

Pharmacokinetics. These drugs have a more rapid onset of action than the proton pump inhibitors and can be used for acute relief of symptoms.

– Ranitidine is several times more potent than cimetidine and thus requires less frequent dosing.

– Cimetidine inhibits cytochrome P-450 enzymes, possibly leading to drug interactions.

Uses

– Promotion of healing of peptic ulcers

– Prophylaxis of recurrent peptic ulcers

– GERD

Side effects. Headache, nausea, and skin rash

27.4 Mucosal Protective Agents

Sucralfate

Sucralfate is a complex of sulfated sucrose and polyaluminum hydroxide.

Mechanism of action. Sucralfate is thought to accelerate the healing of duodenal ulcers by forming a protective barrier over the ulcer base. It forms an ulcer-adherent complex with the proteinaceous exudate at the ulcer site. It is also thought to protect ulcers from pepsin (Fig. 27.3). Sucralfate is not absorbed and does not inhibit acid secretion or neutralize acid.

Exudates and transudates

Exudates are fluids that accumulate in tissues as a result of vascular leakiness in inflammatory states (e.g., in ulcers). They are composed of water, plasma proteins, and blood cells. Transudates are fluid a ccumulations caused by changes in colloid oncotic pressure, not by inflammation. They have a low protein content. It is important to distinguish between exudates and transudates in conditions such as pleural effusion (fluid accumulation in the pleural space). Exudate fluid suggests a local cause (e.g., cancer or pneumonia), whereas transudate fluid suggests the involvement of systemic factors (e.g., liver failure or renal failure).

 

Pharmacokinetics. It may bind digoxin or tetracyclines, decreasing their absorption.

Uses

– Peptic ulcers

Side effects. Constipation may occur.

Misoprostol

Mechanism of action. Misoprostol is a prostaglandin derivative that acts to promote protective mucus secretion from epithelial cells in the stomach and inhibit gastric acid secretion for gastric parietal cells (Fig. 27.4).

Uses

– Peptic ulcers

Side effects

– Diarrhea and abdominal cramping

Gastric ulcer formation with NSAIDs

Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX-1), an enzyme needed to produce prostaglandins which stimulate protective mucus formation in mucus neck cells in the epithelium of the stomach. They also decrease the formation of HCO3 in these cells. Diminished mucus and HCO3 production leaves the mucosa unprotected from the effects of gastric acid and more prone to gastric ulcer formation.

 

Bismuth Subsalicylate

Bismuth subsalicylate (C7H5BiO4) is found in over-the-counter preparations such as Pepto-Bismol™, which is a suspension of trivalent bismuth and salicylate in magnesium aluminum silicate clay.

Fig. 27.3 image Chemical structure and protective effect of sucralfate.

Sucralfate contains numerous aluminum hydroxide residues. When sucralfate is acted upon by gastric acid, it undergoes cross-linking and forms a paste that is able to adhere to the mucosal defect and exposed deeper layers. This coating of the ulcer protects it from acids and pepsin, allowing it to heal more rapidly.

image

Fig. 27.4 image Chemical structure and protective effect of misoprostol.

Locally released prostaglandins promote mucus production from surface epithelial cells and inhibit gastric acid secretion from parietal cells in the stomach. Misoprostol is a semisynthetic prostaglandin derivative and mimics these effects.

image

Mechanism of action. The mechanism of action is unclear.

Uses

– Heartburn

– Diarrhea

– It is included in combination drug regimens for Helicobacter pylori.

27.5 Drugs to Eradicate Helicobacter pylori

H. pylori is a gram-negative spiral bacillus that is found in the gastric epithelium of 70 to 90% of patients with peptic ulcers. It increases mucosal cell inflammation and destruction.

Diagnosis of H. pylori infection

H. pylori can be diagnosed by the carbon-13 -urea breath test. This involves fasting for about 6 hours and then drinking a solution of 13C-urea in water. Breath samples are then taken at intervals. If H. pylori is present, 13Curea is broken down to 13CO2 by urease and will be measurable in the expired breath.

 

Treatment of H. pylori

Combination drug regimens are recommended for patients who test positive for H. pylori.

– Triple therapy: Proton pump inhibitor plus clarithromycin or metronidazole or tetracycline plus amoxicillin for 2 weeks

– Quadruple therapy: Proton pump inhibitor plus metronidazole plus bismuth plus tetracycline for 2 weeks

27.6 Drugs to Dissolve Gallstones

Ursodiol

Ursodiol is a naturally occurring bile acid found in high amounts in bear bile and in small amounts in human bile.

Mechanism of action. Ursodiol decreases secretion of cholesterol into bile by reducing cholesterol absorption and suppressing liver cholesterol synthesis. This alters bile composition and allows reabsorption of cholesterol-containing gallstones. Because reabsorption is slow, therapy must continue for at least 9 months.

Note: Ursodiol will not dissolve pigment stones or stones containing Ca2+.

Pharmacokinetics

– Administered orally

– It is conjugated in the liver to glycine or taurine and excreted in the bile. Conjugated ursodiol undergoes extensive enterohepatic recirculation and has a long serum half-life. Thus, with long-term daily administration, ursodiol will eventually comprise 30 to 50% of the circulating bile acid pool.

Uses

– Treatment of gallstones

– It is also given prophylactically for the prevention of gallstones in obese patients undergoing rapid weight loss.

Side effects. Side effects associated with ursodiol are rare.

Contraindications

– Gallstones with a radiopaque component

Gallstones

The majority of gallstones (75%) are formed when the amount of cholesterol in bile exceeds the ability of bile salts and phospholipids to emulsify it, causing cholesterol to precipitate out of solution. Gallstones may also be caused by an increased amount of unconjugated bilirubin (often in the form of calcium bilirubinate) in the bile (“pigment stones”). Gallstones may be aymptomatic or they can cause obstruction of a duct causing severe pain, vomiting, and fever. Non-drug treatment includes lithotripsy (shock wave obliteration of gallstones that allow the stone fragments to be excreted) or surgical removal of the gallbladder (cholecystectomy).

 

27.7 Pancreatic Enzyme Replacements

Pancrelipase

Pancrelipase is the first pancreatic enzyme preparation approved by the U.S. Food and Drug Administration (FDA).

Mechanism of action. Pancrelipase is a combination of lipases, proteases, and amylases derived from porcine pancreas. It acts to replace the normal endogenous pancreatic enzymes.

Pharmacokinetics

– Enteric-coated microspheres in capsules withstand gastric acid and disintegrate at pH > 6.

– Administered with meals and snacks to treat malabsorption

Uses

– Chronic pancreatitis

– Cystic fibrosis (see page 258)

– Steatorrhea

Chronic pancreatitis

Chronic pancreatitis is ongoing inflammation of the pancreas. It is most commonly caused by alcohol abuse, but it may also occur with conditions such as gallstones, due to blockage of the pancreatic duct by the gallstone, or cystic fibrosis, due to blockage of the pancreatic duct by thick, viscous secretions. Typically, a patient with chronic pancreatitis has been ill for a prolonged period and has abdominal pain that radiates to the back, diabetes mellitus, steatorrhea (increased fat content of stools), and weight loss. Treatment involves pancreatic enzyme replacements, lifestyle changes, and surgery if necessary.

 

Steatorrhea

Steatorrhea is the production of feces that have a high content of fat. They are often oily and foul-smelling, and they tend to float. Steatorrhea occurs when fat digestion or absorption is impaired. This can occur due to pancreatic disease (e.g., cystic fibrosis, chronic pancreatitis) where there is a deficiency of pancreatic lipase that would normally digest fats. It may also occur in conditions that cause hypersecretion of gastrin (e.g., Zollinger-Ellison syndrome) where gastrin increases H+secretion which lowers duodenal pH, inactiviating pancreatic lipase. It may also occur due to liver disease which causes a deficiency of bile acids. Ileal resection will impair fat absorption due to impairment of bile recirculation to the liver. Treatment for steatorrhea due to pancreatic disease is pancreatic enzyme replacement (e.g., pancrelipase).

 

27.8 Antiemetic Drugs

Nausea and vomiting (emesis) are mechanisms to remove toxic or noxious substances after ingestion. However, they also may occur in response to motion, pregnancy, or disease. Vomiting is controlled by the vomiting center in the medulla, which receives inputs from the nearby chemoreceptor trigger zone (CTZ), the vestibular apparatus of the inner ear, the cerebral cortex, and the GI tract. Table 27.1 summarizes the drugs that are most effective in treating different causes of nausea and vomiting and indicates their sites of action. Each class of drug includes a page reference to where these drugs are discussed in detail. The drugs that are not discussed in other sections are included below.

The vomiting reflex

The vomiting reflex begins with a single retrograde peristaltic contraction beginning in the middle of the small intestine that propels intestinal contents through a relaxed gastroduodenal junction into the stomach. Inspiration occurs against a closed glottis, lowering intraesophageal pressure. The duodenum and antrum contract to prevent movement of chyme back into the small intestine. The abdominal muscles then forcibly contract (Valsalva maneuver), increasing intra-abdominal pressure which creates more pressure in the stomach than in the esophagus. This forces gastric contents into the esophagus. The larynx and hyoid bone are drawn forward, decreasing the tone of the upper esophageal sphincter (UES) leading to the gastric and esophageal contents being expelled via the oral cavity.

 

NK1 Antagonists

Aprepitant

Mechanism of action. Aprepitant is a neurokinin-1-receptor (substance P) antagonist that blocks that action of neurokinin-1 in the brain.

Pharmacokinetics

– Given orally

– Extensively metabolized in the liver (via cytochrome P-450 3A4 [CYP3A4])

Uses

– Chemotherapy-induced nausea and vomiting

Side effects

– Constipation, diarrhea, and loss of appetite

– Headache, hiccups, and fatigue

Drug interactions. Interactions may occur due to induction of cytochrome P-450 enzymes in the liver.

Cannabinoid Agonists

Dronabinol

This agent is a derivative of marijuana.

Mechanism of action. Dronabinol acts on the vomiting center of the brain to prevent emesis, but the mechanism is unknown.

Pharmacokinetics

– Given orally

Uses

– Chemotherapy-induced emesis, which is unresponsive to other drugs

Side effects

– Sympathomimetic activity that leads to heart palpitations and tachycardia

– Marijuana-like central nervous system (CNS) effects, such as euphoria, somnolence, dizziness, and disturbances in thinking

– Abdominal pain, nausea, and vomiting

– Xerostomia (dry mouth) is very common.

Anticholinergic Drugs

Scopolamine

Mechanism of action. Scopolamine is a competitive antagonist at muscarinic receptors.

Pharmacokinetics. Scopolamine can be given via transdermal patch to reduce the side effects.

Uses

– Motion sickness

– Inner ear disease (vertigo)

Side effects. Side effects include dry mouth, blurred vision, urinary retention, palpitations, and headache.

Vertigo

Vertigo is the illusion of movement (e.g., that the room is spinning). It is most commonly caused by disorders of the inner ear, such as Meniere disease (a syndrome characterized by vertigo, tinnitus, and deafness), vestibular neuronitis, lesions involving cranial nerve VIII, head injury causing vestibular damage, benign postural vertigo (vertigo occurs when certain positions are adopted or movements made), and by drugs (e.g., gentamicin, barbiturates, and alcohol). Other causes of vertigo are migraine, epilepsy, multiple sclerosis, and tumors. Treatment depends on the cause, but anticholinergic drugs and antihistamines are often used to prevent nausea and vomiting. Note that dizziness is a distinct entity from vertigo and is used to describe a feeling of lightheadedness or weakness.

 

Antihistamines

These agents are also discussed in Chapter 32.

Diphenhydramine and Dimenhydrinate

Mechanism of action. These agents act in the vestibular apparatus of the inner ear and the GI tract to prevent emesis, probably via their anticholinergic actions.

Uses

– Motion sickness

– Inner ear disease (vertigo)

Side effects

– Sedation and the usual anticholinergic side effects (listed above for scopolamine)

Dopamine Antagonists

Prochlorperazine and Thiethylperazine

Mechanism of action. These agents prevent vomiting by blocking D2 dopamine receptors in the medullary chemoreceptor trigger zone.

Uses

– Medication-, toxin-, or metabolic-induced emesis

Side effects

– Anticholinergic: orthostatic (postural) hypotension, dry mouth, constipation, and blurred vision

Contraindications

– Parkinson disease

5-Hydroxytryptamine type 3 (5-HT3) Antagonists

Ondansetron, Granisetron, Dolasetron, and Palonosetron

Mechanism of action. These agents block 5-HT3 receptors in the CNS and GI tract. Activation of these receptors normally triggers vomiting.

Uses

– Chemotherapy- and radiation-induced emesis

– Postoperative emesis

– Pregnancy

  Table 27.1 image Summary of Drugs Used to Treat Different Causes of Nausea and Vomiting

Etiology of Nausea or Vomiting

Drug Class

Examples

Site of Action

Motion sickness Inner ear disease

Antihistamine (pp. 343 and 344)

Diphenhydramine, Dimenhydrinate

Vestibular, GI

 

Anticholinergic (p. 52)

Scopolamine

CTZ, Vestibular, GI

Medication-, toxin-, or metabolic-induced vomiting

D2 dopamine antagonist

Prochlorperazine, thiethylperazine

CTZ, GI

Chemotherapy- and radiationinduced vomiting

Postoperative vomiting

Pregnancy

5-HT3 antagonist (p. 70)

Ondansetron, granisetron

CTZ, GI

Chemotherapy-induced nausea and vomiting

NK1 antagonist

Aprepitant

GI

Chronic idiopathic nausea

Functional vomiting

Cyclic vomiting syndrome

Tricyclic antidepressant (p. 86)

Amitriptyline, nortriptyline

Cortex

Chemotherapy-induced vomiting unresponsive to other drugs

Cannabinoid agonist

Dronabinol

Vomiting center

Abbreviations: CTZ, chemoreceptor trigger zone; GI, gastrointestinal.

Side effects

– Constipation, diarrhea, headache, and fatigue

Tricyclic Antidepressants

Amitriptyline and Nortriptyline

Mechanism of action. These agents act in the cortex of the brain to inhibit the reuptake of norepinephrine and serotonin (see Chapter 10).

Uses

– Chronic idiopathic nausea

– Functional vomiting

– Cyclic vomiting syndrome

27.9 Prokinetic (Gastric Motility Promoting) Drugs

Gastroparesis, also known as delayed gastric emptying, is a disorder in which the stomach takes too long to empty its contents. The most frequent cause is diabetes mellitus, but it can also be caused by smooth muscle or nervous system disorders and, in many cases, is idiopathic.

Metoclopramide

Mechanism of action. Metoclopramide is a D2 dopamine receptor antagonist that increases release of acetylcholine from nerve endings in the GI tract, leading to increased GI motility and rate of gastric emptying. It also increases lower esophageal tone.

Uses

– Gastroparesis

– Reflux esophagitis

– Antiemetic

Side effects

– Extrapyramidal side effects similar to those seen with typical antipsychotics, including parkinsonism, dystonia, and, with longer term use, tardive dyskinesia (see page 99)

– Sedation

– Prolactin secretion is increased.

Erythromycin

See pages 296 and 297 for a full discussion of this agent.

Mechanism of action. Erythromycin stimulates motilin receptors and increases GI motility. Motilin is an endogenous peptide that produces contraction of the upper GI tract via motilin receptors on smooth muscle cells and enteric neurons.

Side effects. Nausea, vomiting, and abdominal cramps

27.10 Laxative and Cathartic Drugs

Laxatives and cathartics are drugs that promote defecation. Laxatives promote the excretion of a soft, formed stool, and cathartics promote fluid evacuation. The uses and contraindications for these laxatives and cathartics are included in Table 27.2.

  Table 27.2 image Uses and Contraindications of Laxatives and Cathartics

Uses

Contraindications

 

Radiologic exams of gastrointestinal tract

Bowel surgery

Proctologic exam

Useful in patients with a hernia or cardiovascular disease (to avoid straining at stool)

Anorectal disorders (e.g., hemorrhoids)

Useful after anti-helmintic therapy or poisoning by drugs or foods

Colic (attacks of severe abdominal pain), nausea, and cramps

Undiagnosed abdominal pain

Patients with symptoms of appendicitis

 

Contact (Stimulant–Irritant) Cathartics

Mechanism of action. Contact cathartics increase intestinal motor activity (peristalsis) and stimulate water and electrolyte accumulation in the colon (Fig. 27.5).

Peristaltic reflex

Stretching of the intestinal wall during the passage of a bolus triggers a reflex that simultaneously contracts the circular muscles behind the bolus and relaxes the circular muscles in front of it. At the same time, longitudinal muscles behind the bolus are relaxed and in front of it are contracted. This propels the bolus in an aboral direction.

 

Castor Oil

Castor oil is derived from the seeds of Ricinus communis.

Pharmacokinetics. Pancreatic lipases hydrolyze castor oil to the active irritant agent ricinoleic acid, which acts on the small intestine in 1 to 3 hours.

Side effects. Castor oil has a disagreeable taste and should not be used just prior to bedtime.

Diphenylmethanes

Bisacodyl

Pharmacokinetics. Bisacodyl given orally acts in 6 to 8 hours; thus, it is often given at bedtime to produce effects by morning. Rectal suppositories are effective within 1 hour.

Anthraquinones

Cascara, Aloe, and Senna

Pharmacokinetics. They act on the large intestine in 6 to 8 hours.

Side effects

– Electrolyte imbalance from excessive catharsis

Fig. 27.5 image Stimulation of peristalsis by mucosal irritation.

Irritant laxatives exert an irritant action on the intestinal mucosa. This causes less fluid to be absorbed than is secreted. This filling of the intestinal lumen stimulates reflex peristalsis. Peristalsis is also directly simulated by the irritant action.

image

Electrolytes

Electrolytes are ions that can conduct electricity when in solution (as acids or bases). The main body electrolytes are Na+, K+, Ca2+, Mg2+, Cl, HPO42−, and HCO3. Osmotic gradients exist across cell membranes in the body such that the movement of ions can regulate water balance, acid-base balance (blood pH), nerve conductance, and muscle contractility. Pharmacological causes of electrolyte disturbances include cathartics, thiazide diuretics, spironolactone, and alcohol abuse. Pathophysiological causes include renal disease and malignancy of endocrine glands.

 

Saline (Osmotic) Cathartics

Mechanism of action. Saline cathartics act by causing water to be retained through an osmotic effect. Stretching of the bowel lumen by this increase in water stimulates peristalsis.

Magnesium Hydroxide, Sodium Phosphate, and Polyethylene Glycol

Pharmacokinetics

– Poorly and slowly absorbed from the GI tract

– Water retention indirectly increases peristalsis, with watery evacuation occurring in < 3 hours.

– Approximately 20% of magnesium is absorbed, but it is rapidly excreted if renal function is normal. Mg2+ intoxication can occur if renal function is impaired, resulting in weakness, nausea, vomiting, and respiratory depression.

Side effects

– Electrolyte imbalance

– Cerebral failure can occur with sodium phosphate.

Lactulose

Mechanism of action. Intestinal bacteria hydrolyze the drug, which leads to a more acid pH of the colon. This reduces the ability of bacteria to form ammonia.

Pharmacokinetics

– Given orally, but not absorbed

Uses. Lactulose is a specialized laxative for chronic liver disease or hepatic coma to decrease plasma levels of ammonia.

Stool Softeners

Mechanism of action. Stool softeners act by keeping feces soft so tenesmus (straining at stool) is avoided. There is no direct or reflex stimulation of peristalsis with these agents.

Docusate

Mechanism of action. Docusate produces stool softening by lowering surface tension to promote water penetration into feces.

Pharmacokinetics. Effects are seen within 1 to 2 days.

Uses. The main use of this agent is to limit straining, as it has minimal laxative effects.

Lubricant Laxatives

Mechanism of action. Lubricant laxatives act by retarding reabsorption of water.

Mineral Oil

Mineral oil is a mixture of liquid hydrocarbons obtained from petroleum.

Side effects

– Lipid pneumonia in elderly or debilitated patients if oil is aspirated

– Foreign-body reactions in mesenteric lymph nodes, liver, spleen, and intestinal mucosa may occur.

– Absorption of essential fat-soluble substances (vitamins A, D, and K, and carotene) may be blocked.

Bulk-forming Laxatives

Mechanism of action. Bulk-forming laxatives act by absorbing and retaining water, causing fecal material to become hydrated and soft. They may also act to reflexively stimulate peristalsis (Figs. 27.6 and 27.7).

Bran (and Other Dietary Fiber), Methylcellulose, Sodium Carboxymethylcellulose, and Psyllium Preparations

These are naturally occurring or synthetic polysaccharides.

Pharmacokinetics

– Action is within 1 to 3 days.

– Some drug absorption may be reduced because of binding to these agents.

Side effects. Intestinal obstruction has been reported.

Fig. 27.6 image Bulk laxatives.

Bulk laxatives are insoluble and nonabsorbable from the intestine. They absorb water and expand within the intestinal lumen; this stimulates peristalsis.

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Fig. 27.7 image Stimulation of peristalsis by an intraluminal bolus.

Distention of the intestinal wall by fecal matter activates mechanoreceptors that induce a neuronally mediated ascending reflex contraction of intestinal smooth muscle (red) and a descending relaxation (blue). This propulsive movement of the intestinal musculature (peristalsis) allows fecal matter to move in the direction of the anus for evacuation.

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Effects of fiber

In the stomach, fiber binds water which enlarges the particle size so that fiber passes the pyloric sphincter later, delaying gastric emptying. In the ileum and colon, in particular, the water-binding (swelling) capacity of fiber lowers transit time. Fiber may bind mineral and trace elements as well as fat-soluble vitamins, which may not allow them to be absorbed. The binding of steroids leads to an increased excretion of bile acids and cholesterol, which may be helpful in people with fat metabolism disorders. Glucose absorption is also delayed by high fiber intake, improving glucose control in diabetics. Stool volume is increased and the consistency of stool is softer with fiber in-take. However, intestinal bacteria ferment the polysaccharides in fiber producing methane and CO2. During fermenetation, short-chain fatty acids are produced that positively affect the composition of the intestinal flora and the intestinal pH. Finally, the binding of ammonia by fiber increases fecal nitrogen excretion thereby unburdening the liver and kidneys.

 

27.11 Antidiarrheal Agents

Antidiarrheal therapy aims to prevent the dehydration and electrolyte imbalance that can quickly occur in severe diarrhea, as well as preventing excessive bowel movements.

Note: Antibacterial agents are useful only if bacteria are the cause of the diarrhea (which is uncommon). They cause depletion of the normal intestinal bacterial flora, which, in turn, may cause proliferation of pathogenic bacteria, leading to diarrhea.

Adsorbents

Bismuth Subsalicylate, Kaolin, and Pectin

– Bismuth subsalicylate

– Kaolin (hydrated aluminum silicate)

– Pectin (a purified carbohydrate from acid extracts of apples or the rinds of citrus fruits)

Mechanism of action. These agents absorb bacterial toxins and fluid in the gut.

Pharmacokinetics

– Bismuth subsalicylate is given as chewable tablets or in an aqueous suspension.

– Kaolin is often given in a mixture with pectin.

Uses

– Diarrhea and dysentery

Side effects. These drugs are not absorbed, so they do not have systemic side effects. Constipation may occur.

Opioids

See Chapter 13 for a full discussion of these drugs.

Mechanism of action. These agents decrease propulsion and peristalsis. GI contents are delayed in passage, allowing time for feces to become desiccated. This further retards passage through the colon.

– Opioids are effective in acute diarrheal states, but they should not be used for enteric infections.

– Opium alkaloids are effective for controlling severe diarrhea or dysentery, but with chronic therapy, there is a risk of dependence.

Paregoric

Paregoric is a camphorated tincture of opium.

Uses

– Infantile diarrhea

Codeine and/or Morphine

These are purified opium alkaloids.

Pharmacokinetics. They exert a local action in the GI tract.

Diphenoxylate

Diphenoxylate is a congener of meperidine. It is often given in combination with atropine.

Side effects. High or chronic doses lead to euphoria and physical dependence.

Loperamide

Loperamide is a derivative of haloperidol that resembles meperidine.

This agent appears to be as effective as diphenoxylate, with few side effects reported.

Uses

– Prophylaxis and treatment of travelers’ diarrhea

– Irritable bowel syndrome (IBS)

Irritable Bowel Syndrome (IBS)

IBS is a chronic idiopathic condition. Symptoms include abdominal pain, bloating, and cramps, which are associated with bowel habit alteration in the form of constipation or diarrhea. Treatment is guided by the symptoms and their severity. Mild IBS may respond to dietary changes. Drugs may be called for in patients with moderate to severe symptoms. Antispasmodics, such as hyoscyamine and dicyclomine, laxatives (docusate, bisacodyl, senna, or osmotic agents) and loperamide are standard. In severe cases with diarrhea, alosetron, a potent and selective antagonist of the 5-HT3receptor that decreases intestinal motility and pain may be used with caution, as it can lead to severe constipation. Note: IBS is not associated with pathophysiological changes in gut structure and is diagnosed only when all else has been excluded.

 

Antidiarrheal agents and their site of action are summarized in Fig. 27.8.

Fig. 27.8 image Antidiarrheals and their site of action.

Bacteria can secrete toxins that inhibit the ability of enterocytes to absorb sodium chloride (NaCl) and water. They also stimulate fluid secretion into the intestinal lumen. Bacteria and viruses also cause mucosal inflammation, which further causes luminal fluid loss. This increase in luminal fluid stimulates peristalsis. Adsorbents bind to toxins and promote their evacuation. As a consequence, more salt and water are able to be reabsorbed. Opioids activate enteric nerves, resulting in inhibition of propulsion and peristalsis. Loperamide is pumped back into the body by the endothelial cells of the blood–brain barrier, so it does not produce the unwanted central nervous system (CNS) effects of morphine and diphenoxylate. Oral rehydration solutions contain glucose, which is absorbed into intestinal cells, drawing water along with it.

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27.12 Drugs Used in Inflammatory Bowel Disease

There are two types of inflammatory bowel disease: Crohn disease and ulcerative colitis (Fig. 27.9). Crohn disease is a chronic inflammatory disease that can affect the entire GI tract but most commonly affects the terminal ileum and colon. It causes ulcers, fistulas (abnormal communications), and granulomata, producing symptoms such as fever, diarrhea, weight loss, and abdominal pain. Ulcerative colitis is a recurrent inflammatory disease of the colon and rectum that produces bloody diarrhea, weight loss, fever, and abdominal pain. The goal of therapy for inflammatory bowel diseases is to reduce the inflammatory response by using drugs such as steroids and sulfasalazine.

Fig. 27.9 image Crohn disease and ulcerative colitis.

The typical pattern of Crohn disease is segmental inflammation that affects all layers of the intestinal wall, producing fistulae, abscesses, and perforation. Inflammatory conglomerate tumors develop in adjacent structures due to fistulae and abscess formation. Crohn disease is associated with human leukocyte antigens (HLA) DR1 and DQw5. Patients were often not breastfed for a long period as infants, and have a history of smoking and high intake of refined carbohydrates. In ulcerative colitis, there is relapsing and remitting inflammation of the colon, as well as superficial ulcerations that spread proximally. This leads to flattening of the intestinal mucosa and destruction of goblet cells. Hyperregeneration causes pseudopolyp production. Ulcerative colitis is thought to be autoimmune and is associated with immunoglobulin A (IgA) nephritis and autoimmune hepatitis, among other conditions.

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Aminosalicylates

Mesalamine, Balsalazide, Olsalazine, and Sulfasalazine

– Mesalamine is 5-aminosalicylic acid (5-ASA), the active moiety of all the aminosalicylates used to treat inflammatory bowel disease.

– Balsalazide, olsalazine, and sulfasalazine are prodrugs that are metabolized to 5-ASA.

Mechanism of action. Five-aminosalicylate (5-ASA) acts within the intestinal tract (mainly the terminal ileum and colon) to inhibit prostaglandin and leukotriene synthesis thus reducing the inflammatory reaction (Figs. 27.10 and 27.11).

Uses

—Mild to moderate ulcerative colitis

Side effects

– Nausea, vomiting, diarrhea, headache, and abdominal pain

– Bone marrow suppression

Fig. 27.10 image Drug treatment of Crohn disease and ulcerative colitis.

Acute attacks of Crohn disease and ulcerative colitis are treated with sulfasalazine and 5-aminosalicylic acid (5-ASA) (see also Fig. 27.11). Crohn disease also may involve treatment with steroids. These drugs inhibit prostaglandin and leukotriene synthesis and intervene late in the inflammatory cascade.

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Fig. 27.11 image Sulfasalazine.

Sulfasalazine is converted to its active forms sulfapyridine and 5-ASA by intestinal bacteria. These active forms inhibit the inflammatory reaction in intestinal mucosa.

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Tumor Necrosis Factor-α Inhibitors

Adalimumab, Certolizumab Pegol, and Infliximab

Mechanism of action. These agents are monoclonal antibodies or antibody fragments that bind and neutralize tumor necrosis factor-α (TNF-α), a principal cytokine that mediates IBD.

Pharmacokinetics. These drugs must be given by injection.

Uses

– Moderate to severe Crohn disease unresponsive to other therapies (adalimumab, certolizumab pegol, and infliximab)

– Moderate to severe ulcerative colitis not responsive to other drugs (infliximab)

Fig. 27.12 image Corticosteroids: effects and side effects.

Corticosteroids act to decrease inflammation, and reduce connective tissue proliferation by the mechanisms shown. Short-term side effects are edema and weight gain. Gastric ulceration, hypertension, steroid-induced diabetes mellitus, and increased susceptibility to infections may also occur. Longer-term use may lead to more serious side effects, such as Cushing syndrome, skin atrophy, osteoporosis, and seizures. (IL-1, interleukin-1; IL-2, interleukin-2; MHC, major histocompatibility complex; TNF, tumor necrosis factor.)

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Side effects

– Reactivation of tuberculosis

– Increased respiratory infections

Corticosteroids

These agents are also discussed in Chapters 162632, and 34.

Prednisone and Budesonide

Uses. Corticosteroids are effective in both ulcerative colitis and Crohn disease in inducing a remission in acute persistent disease. They are used systemically until adequate control of inflammation is achieved, then the dose is tapered and discontinued to avoid the side effects seen with long-term systemic steroid use (see page 154).

Figure 27.12 provides a summary of the effects and side effects of corticosteroids.

Immunosuppressants

These agents are also discussed in Chapter 34.

Cyclosporine

Mechanisms of action. Cyclosporine decreases interleukin-2 (IL-2) synthesis in T-helper cells.

Uses. These agents are sometimes used in patients unresponsive to steroids or in chronic cases of moderate to severe IBD, although they are not approved by the FDA for this purpose.

Antimetabolites

These agents are discussed further in Chapters 33 and 34.

Methotrexate, Azathioprine, and Mercaptopurine

Mechanisms of action

– Methotrexate inhibits dihydrofolate reductase, which reduces purine and pyrimidine synthesis in lymphocytes and so dampens the immune response (Fig. 27.13).

Fig. 27.13 image Antimetabolites.

Methotrexate inhibits purine and thymidine synthesis. It does this by inhibiting the formation of tetrahydrofolate by binding to dihydrofolate reductase, the enzyme that catalyzes its formation from folate. Methotrexate also inhibits cell growth in rapidly proliferating tissues (e.g., bone marrow). Azathioprine is converted to 6-mercaptopurine, which is a false substrate for purine biosynthesis. It is also incorporated in DNA and RNA, where it acts as a “wrong” base and damages the cell.

image

— Azathioprine is converted to 6-mercaptopurine. Mercaptopurine is a purine analogue that causes pseudofeedback inhibition of the first step in purine biosynthesis and inhibition of purine intraconversions.

Pharmacokinetics. The onset of action of these drugs takes several weeks.

Uses

– Moderate to severe inflammatory bowel disease (mainly Crohn disease)

Side effects

– Bone marrow depression

27.13 Appetite-suppressing and Appetite-enhancing Drugs

CNS-acting Appetite Suppressants

Amphetamine and Its Derivatives: Methylphenidate, Ephedrine, Phenylpropanolamine, and Phentermine

Mechanism of action. These sympathomimetic agents are effective in suppressing appetite; however, any weight lost while on the drug is rapidly regained upon cessation.

Uses. These agents are unsuitable for the treatment of obesity due to their CNS-stimulating and other side effects (see page 123).

Fenfluramine and Dexfenfluramine

Dexfenfluramine is the D-isomer of fenfluramine.

These agents were previously used as appetite suppressants, but they were shown to cause pulmonary hypertension and valvular heart disease, which led to their withdrawal from the market.

Sibutramine

Mechanism of action. Sibutramine is a serotonin and norepinephrine reuptake inhibitor.

Uses. Sibutramine is the only anorexiant currently approved for long-term use in patients with body mass index (BMI) > 30 or with diabetes and BMI > 27. It produces a weight loss of ~5 to 9% at 12 months.

Side effects. Headache, dry mouth, insomnia, and constipation. It also increases heart rate and blood pressure. Body weight increases when the medication is discontinued.

Peripherally Acting Weight-loss Medication

Orlistat

This agent is available over-the-counter.

Mechanism of action. Orlistat is an inhibitor of the pancreatic and gastric lipases that hydrolyze dietary fat into fatty acids and monoacylglycerols. This prevents ~30% of dietary fat from being absorbed. Orlistat produces a weight loss of ~9 to 10% in 12 months.

Pharmacokinetics. Not absorbed from the GI tract.

Side effects. No systemic side effects are seen; however, adverse GI effects are common and include flatulence, fecal urgency, fatty/oily stools, and increased frequency of defecation. These side effects can be minimized by decreasing dietary fat intake.

Appetite Enhancers

Megestrol

Megestrol is a synthetic form of progesterone.

Mechanism of action. The mechanism to affect the appetite is unknown.

Uses. Megestrol is used to enhance appetite in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and cancer.

Dronabinol

Dronabinol is synthetic δ-9-tetrahydrocannabinol, the main active ingredient in marijuana.

Mechanism of action. Dronabinol stimulates the appetite by acting on cannabinoid receptors in the CNS (see page 265).

Uses. In states where it is available, medicinal marijuana is used by patients with AIDS and cancer as an appetite enhancer and to prevent chemotherapy-induced nausea and vomiting.