This article explores the pharmacology of drugs that affect gastric acid secretion and motility. It begins by exploring the physiological factors behind gastric acid secretion, before going on to look at classes of drugs that influence this secretion, as well as the motility of the gastrointestinal tract.

Factors Affecting Gastric Acid Secretion

As you can see in the diagram on the right, the gastric mucosa is divided into many different regions. These differing regions correspond to different secretary functions from the stomach itself. For simplicity sake, we can divide the stomach into three main areas of secretion:

Stomach

  • The Cardiac Area secretes mucus and pepsinogen. 
  • The Oxyntic (Parietal) Area which corresponds to the Fundus and body of the stomach, secretes hydrogen ions, pepsinogen, and bicarbonate.
  • The Pyloric Gland Area in the Antrum secretes gastrin and mucus.

The parietal cells secrete H+ in response to gastrin, cholinergic, and histamine stimulation. Both cholinergic- and gastrin-induced types of stimulation bring about a receptor-mediated rise in intracellular calcium, an activation of intracellular protein kinases, and eventually an increased activity of the H+–K+ pump leading to acid secretion into the gastric lumen. Following histamine stimulation, a guanine nucleotide–binding protein (Gs) activates adenylyl cyclase, leading to an increase in intracellular levels of the second messenger, cyclic adenosine monophosphate (cAMP). Activation of cAMP-dependent protein kinases initiates the stimulation of the H+–K+ pump.

The cephalic–vagal axis, gastric distention, and local mucosal chemical receptors can modulate acid secretion by the stomach.

  • The smell, taste, sight, or discussion of food may result in cephalic–vagal postganglionic cholinergic stimulation of target parietal cells and enhanced antral gastrin release.
  • After food is ingested, gastric distention initiates vagal stimulation and short intragastric neural reflexes, both of which increase acid secretion.
  • Proteins in ingested meals also stimulate acid secretion. Evidence from animal studies suggests that after protein amino acids are converted to amines, gastrin is released.

Gastric acid secretion is inhibited in the presence of acid itself. A negative feedback occurs when the pH approaches 2.5 such that further secretion of gastrin is inhibited until the pH rises. Ingested carbohydrates and fat also inhibit acid secretion after they reach the intestines; several hormonal mediators for this effect have been proposed. The secretion of pepsinogen appears to parallel the secretion of H+, while the patterns of secretion of mucus and bicarbonate have not been well characterized. The integrity of the mucosal lining of the stomach and proximal small bowel is in large part determined by the mucosal cytoprotection provided by mucus and bicarbonate secretion from the gastric and small bowel mucosa. Mucus retards diffusion of the H+ from the gastric lumen back into the gastric mucosal surface. In addition, the bicarbonate that is secreted into the layer between the mucus and epithelium permits a relatively high pH to be maintained in the region next to the mucosal surface. If any H+ does diffuse back to the level of the mucosal surface, both the local blood supply and the ability of the local cells to buffer this ion will ultimately determine whether peptic ulceration will occur. With duodenal and gastric peptic ulcer disease, a major causative cofactor is the presence of gastric Helicobacter pylori infection.

Medications that raise intragastric pH are used to treat peptic ulcer disease and gastroesophageal reflux disease. In addition, agents that enhance mucosal cytoprotection are used to decrease ulcer risk. Let’s take a brief look at some of these medications which include antacids, histamine receptor antagonists, and proton pump inhibitors (PPI’s). 

Antacids

  • The rationale for the use of antacids in peptic ulcer disease lies in the assumption that buffering of H+ in the stomach permits healing. The use of both low and high doses of antacids is effective in healing peptic ulcers as compared with placebo. Healing rates are comparable with those observed after the use of histamine (H2) blocking agents. The buffering agents in the various antacid preparations consist of combinations of ingredients that include sodium bicarbonate, calcium carbonate, magnesium hydroxide, and aluminum hydroxide. If diarrhea occurs or if there is renal failure, a magnesium based preparation should be discontinued. The agents are generally safe, but some patients resist because some of the formulations are unpalatable and expensive.
  • A variety of adverse effects have been reported following the use of antacids. If sodium bicarbonate is absorbed, it can cause systemic alkalization and sodium overload. Calcium carbonate may induce hypercalcemia and a rebound increase in gastric secretion secondary to the elevation in circulating calcium levels. Magnesium hydroxide may produce osmotic diarrhea, and the excessive absorption of Mg2+ in patients with renal failure may result in central nervous system toxicity.Aluminum hydroxide is associated with constipation; serum phosphate levels also may become depressed because of phosphate binding within the gut.The use of antacids in general may interfere with the absorption of a number of antibiotics and other medications.

H2-Receptor Antagonists

Mechanism of Histamine Antagonists

  • The histamine receptor antagonists (H2 blockers) marketed in the United States are cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid) and nizatidine (Axid). These agents bind to the H2-receptors on the cell membranes of parietal cells and prevent histamine induced stimulation of gastric acid secretion. After prolonged use, down-regulation of receptor production occurs, resulting in tolerance to these agents. H2-blockers are approved for the treatment of gastroesophageal reflux disease, acute ulcer healing, and post–ulcer healing maintenance therapy. Although there are substantial differences in their relative potency, 70 to 85% of duodenal ulcers are healed during 4 to 6 weeks of therapy with any of these agents. The incidence of healing of gastric ulceration after 6 to 8 weeks of therapy approaches 60 to 80% with the use of cimetidine or ranitidine.
  • Since nocturnal suppression of acid secretion is particularly important in healing, nighttime-only dosing can be used. Most are available in low-dose over-thecounter formulations.
  • Cimetidine, the first released H2-blocker, like histamine, contains an imidazole ring structure. It is well absorbed following oral administration, with peak blood levels 45 to 90 minutes after drug ingestion. Blood levels remain within therapeutic concentrations for approximately 4 hours after a 300-mg dose. Following oral administration, 50 to 75% of the parent compound is excreted unchanged in the urine; the rest appears primarily as the sulfoxide metabolite.
  • Cimetidine may infrequently cause diarrhea, nausea, vomiting, or mental confusion. A rare association with granulocytopenia, thrombocytopenia, and pancytopenia has been reported. Gynecomastia has been demonstrated in patients receiving either high-dose or long-term therapy. This occurs because cimetidine has a weak antiestrogen effect. Since cimetidine is partly metabolised by the cytochrome P450 system, co-administered drugs such as the benzodiazepines, theophylline, and warfarin, which are also metabolised by this system, may accumulate if their dosage is not adjusted.
  • Ranitidine is well absorbed after oral administration, with a peak plasma level achieved 1 to 3 hours after ingestion. Elimination is by renal (25%) and hepatic (50%) routes. The half-life of elimination is 2.5 to 3.0 hours. Nizatidine is the newest H2-receptor antagonist. Similar to ranitidine, it has a relative potency twice that of cimetidine. About 90% of an oral dose is absorbed, with a peak plasma concentration occurring after 0.5 to 3 hours; inhibition of gastric secretion is present for up to 10 hours. The elimination half-life is 1 to 2 hours, and more than 90% of an oral dose is excreted in the urine.
  • Famotidine has an onset of effect within 1 hour after oral administration, and inhibition of gastric secretion is present for the next 10 to 12 hours. It is the most potent H2-blocker. Elimination is by renal (65–70%) and hepatic (30–35%) routes. Ranitidine, famotidine, and nizatidine do not alter the microsomal cytochrome P450 metabolism of other drugs, nor do they cause gynecomastia. A reduction in dosage of any of the H2-blockers is recommended in the presence of renal insufficiency.

Proton Pump Inhibitors

Proton Pump Inhibitors

  • The proton pump inhibitors available in the United States are omeprazole (Prilosec), lansoprazole (Prevacid), pantoprazole (Protonix), rabeprazole (Aciphex), and esomeprazole (Nexium). These are substituted benzimidazole prodrugs, which accumulate on the luminal side of parietal cells’ secretory canaliculi. They become activated by acid transport and then bind covalently to the actual H+–K+ ATPase enzymes (proton pumps) irreversibly blocking them. These drugs markedly inhibit gastric acid secretion. New proton pumps are continuously formed, and thus no tolerance develops. Peptic ulcers and erosive esophagitis that are resistant to other therapies will frequently heal when these agents are used. The proton pump inhibitors are also used to treat patients with Zollinger-Ellison syndrome, which is the result of a gastrin-hypersecreting neuroendocrine tumor.
  • The prodrugs are unstable in the presence of acid and therefore must be administered as an enteric-coated preparation or as a buffered suspension. Pantoprazole is also available in an intravenous formulation. The most commonly reported side effects are diarrhea and headache. Hypergastrinemia has been noted as a reaction to the marked reduction in acid secretion. Gastric carcinoid tumors have developed in rats but not in mice or in human volunteers, even after long-term use.

The next section covers the basic physiology of the GI tract which is a prerequisite to understanding how drugs affect this system. It also covers drugs that both increase and decrease the level of motility in the GI tract.

Normal Physiology of the GI Tract

The gastrointestinal (GI) tract consists of the esophagus, stomach, small intestine, and colon. It processes ingested boluses of food and drink and expels waste material. Intervention by disease or pharmacological therapy may alter function of the GI tract.

Gastrointestinal Motility

From the mid-esophagus to the anus, smooth muscle surrounds the alimentary canal and is responsible for active movement and segmentation of intestinal contents. This smooth muscle, which lies in the muscularis propria, consists of a circular and a longitudinal layer of muscle.

From the gastric body to the colon, repetitive spontaneous depolarizations originate in the interstitial cells of Cajal, from which they spread to the circular muscle layer and then to the longitudinal muscle layer. The rate of slow-wave contraction varies in different regions of the gastrointestinal tract, occurring approximately 3 per minute in the stomach, 12 per minute in the proximal intestine, and 8 per minute in the distal intestine. The increased frequency of contraction in the proximal intestine forms a gradient of contraction, and intestinal contents are therefore propelled distally. Though the stomach has fewer spontaneous contractions than does the small intestine, there is normally no retrograde spread of a depolarization wave from duodenum to stomach.

The underlying intrinsic smooth muscle motility is modulated by neurohormonal influences. Afferent sensory neurons, extrinsic motor neurons, and intramural neurons innervate the gut. It also has mucosal sensory receptors for monitoring chemical, osmotic, or painful stimuli and muscle receptors to monitor degrees of stretch.

Both the parasympathetic and sympathetic nervous systems provide extrinsic gastrointestinal innervation. Parasympathetic stimulation increases muscle contraction of the gut, while sympathetic stimulation inhibits contractions. Stimulation of either α- or β- adrenoceptors will result in inhibition of contractions.

Nerve Complexes

The intramural nervous system consists of a myenteric (Auerbach’s) plexus between the circular and longitudinal muscle areas and a submucosal (Meissner’s) plexus between the muscularis mucosa and the circular muscle layers. These two plexuses contain stimulatory cholinergic neurons.

Ingested liquids are rapidly emptied from the stomach into the intestine, while digestible solids are first mechanically broken down in the stomach by peristaltic contractions. Stimulation of osmotic, carbohydrate, and fat receptors in the small bowel inhibits gastric peristaltic contractions and retards gastric emptying.

The small intestinal motility in the fed state consists of random slow-wave contractions that result in slow transit and long contact of food with enzymes and absorptive surfaces. With fasting, an organized peristaltic wave, termed the interdigestive migrating motor complex, begins to cycle every 84 to 112 minutes. During the migrating motor complex, a peristaltic contraction ring travels from the stomach to the cecum at 6 to 8 cm per minute. In the stomach the contractions sweep against a widely patent pylorus, permitting the passage of undigestible solids. In the small intestine this is to clear the intestine of undigested material: it functions as an intestinal housekeeper. The migrating motor complex appears to correlate with motilin hormonal levels and is modulated by vagal innervation. Motilin is a 22–amino acid polypeptide released from the duodenal mucosa as a regulator of normal GI motor activity. Exogenous motilin is a potent inducer of gastric motor activity.

Colonic motor function also has cyclic slow waves in the proximal colon. These contractions are primarily retrograde in the proximal colon, allowing segmentation and liquid reabsorption. In the distal colon a propulsive mass movement occurs intermittently. This may be stimulated by food ingestion and is termed the gastrocolonic reflex.

Approximately 1 to 1.5 L of fluid is ingested per day, and coupled with secretions from the stomach, pancreas, and proximal duodenum, approximately 8 L of chyme enters the jejunum per day. Reabsorption of 6 to 7 L occurs within the small bowel, leaving a residual of 1.5 L fluid, 90% of which is reabsorbed in the colon. This pattern of liquid reabsorption permits the elimination of fecal waste containing an average of 0.1 to 0.2 L fluid per day. Diarrhoea occurs if there is an altered rate of intestinal motility, if mucosal function or permeability is altered, or if the fluid load entering the colon overwhelms colonic reabsorption. Constipation may occur if intestinal movement is inhibited or if there is a fixed obstruction.

Drugs that Increase Drug Motility

  • Decreased GI motility can affect one or more parts of the GI tract and can be the result of a systemic disease, intrinsic GI disorder, or medication. Gastroparesis is the term for delayed gastric emptying. Symptoms may range from postprandial bloating and fullness to nausea and vomiting. Half of ingested liquid should be emptied within 30 minutes, and half of a digestible solid should be emptied within 2 hours. Emptying time can be prolonged as a result of autonomic neuropathy seen with long-standing diabetes mellitus.
  • Pseudoobstruction due to an idiopathic intestinal muscle disease or intestinal neuropathy may also cause delays in gastric emptying and intestinal transit. Rarer causes of delayed GI motility include Chagas’ disease, muscular dystrophy, scleroderma, and infiltrative diseases, such as amyloidosis. Decreased GI transit can occur acutely following electrolyte disorders and gastroenteritis. In addition, many medications, including anticholinergic medications, tricyclic antidepressants, levodopa, and β-adrenergic agonists, inhibit GI motility.
  • Drugs that enhance GI motility are often called prokinetics. Their goal is to increase contractile force and accelerate intraluminal transit. Most of these drugs act either by enhancing the effect of acetylcholine or by blocking the effect of an inhibitory neurotransmitter such as dopamine. The prokinetics discussed in this article are metoclopramide, cisapride and tegaserod, and erythromycin.

Metoclopramide Hydrochloride

  • Metoclopramide (Reglan) stimulates upper GI tract motility and has both central and peripheral actions. Centrally, it is a dopamine antagonist, an action that is important both for its often desirable antiemetic effect and other less desirable effects. Peripherally, it stimulates the release of intrinsic postganglionic stores of acetylcholine and sensitizes the gastric smooth muscle to muscarinic stimulation. The ability of metoclopramide to antagonize the inhibitory neurotransmitter effect of dopamine on the GI tract results in increased gastric contraction and enhanced gastric emptying and small bowel transit.
  • Metoclopramide is rapidly absorbed following an oral dose in a patient with intact gastric emptying. Peak plasma concentration is achieved within 40 to 120 minutes. With normal renal function, plasma half-life is about 4 hours.About 20% of an oral dose is eliminated unchanged in the urine, while 60% is eliminated as sulphate or glucuronide conjugates.
  • Improved gastric emptying will frequently alleviate symptoms in patients with diabetic, postoperative, or idiopathic gastroparesis. Since metoclopramide also can decrease the acid reflux into the esophagus that results from slowed gastric emptying or lower esophageal sphincter pressure, the drug can be used as an adjunct in the treatment of reflux esophagitis.
  • Side effects include fatigue, insomnia, and altered motor coordination. Parkinsonian side effects and acute dystonic reactions also have been reported. Metoclopramide stimulates prolactin secretion, which can cause galactorrhea and menstrual disorders. Extrapyramidal side effects seen following administration of the phenothiazines, thioxanthenes, and butyrophenones may be accentuated by metoclopramide.

Cisapride & Tegaserod

  • Cisapride (Propulsid) and tegaserod (Zelnorm) are both serotonin-4 (5-HT4) receptor agonists that stimulate GI motility. Cisapride appears to act by facilitating the release of acetylcholine from the myenteric plexus. It has no antiadrenergic, antidopaminergic, or cholinergic side effects. Following oral administration, peak plasma levels occur in 1.5 to 2 hours; the drug’s half-life is 10 hours. Cisapride has been successfully used to treat gastroparesis and mild gastroesophageal reflux disease.
  • The most frequent side effect has been diarrhea. A few patients had seizure activity that was reversible after medication was discontinued. Cisapride was pulled from the U. S. market after deaths from drug-associated cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. Tegaserod is being developed as a treatment for constipation- predominant irritable bowel syndrome (IBS).
  • Within the first week, patients treated with tegaserod had significant improvements in abdominal pain and discomfort, constipation, and overall well-being. Efficacy was maintained throughout the treatment period. Tegaserod also demonstrated significant improvements in the three bowel-related assessments (stool frequency, stool consistency, and straining) within the first week, and these improvements were sustained throughout the treatment period. The most common adverse events reported thus far are headache and diarrhea.

Erythromycin

  • Erythromycin is an antibiotic in the macrolide famil that also has promotility effects because it is a motilin agonist. Erythromycin is used (offlabel indication) to accelerate gastric emptying in diabetic gastroparesis and postoperative gastroparesis. Tachyphylaxis will occur, so it cannot be used uninterruptedly for long periods.

Drugs that Decrease Drug Motility

Diarrhea is the frequent passage of watery, unformed stools. Its many causes include IBS, infectious disorders, thyrotoxicosis, malabsorption, medication side effect, and laxative abuse. Attempts to treat diarrhea should first focus on the patient’s list of medications followed by a search for an underlying systemic disorder. Opioids and 5-HT3 receptor antagonists, such as alosetron, slow motility and can therefore decrease or eliminate diarrhea.

Opioids

  • Most of the opioids have a constipating action; morphine was used in the treatment of diarrhea before it was used as an analgesic. Unfortunately, many of the opium preparations, while relieving diarrhea and dysentery, also produce such objectionable side effects as respiratory depression and habituation. The opioids are capable of altering the motility pattern in all parts of the GI tract. These compounds usually produce an increase in segmentation and a decrease in the rate of propulsive movement. The feces become dehydrated as a result of their longer stay in the GI tract. The tone of the internal anal sphincter is increased, and the subjective response to the stimulus of a full rectum is reduced by the central action of the opioids. All of these actions produce constipation. Opioids should not be used indiscriminately in bloody diarrhea, since their use in inflammatory bowel disease involving the colon may increase the risk of megacolon and their use in infectious enterocolitis may promote intestinal perforation.
  • The dangers of dependency and addiction clearly preclude the use of such compounds as morphine, meperidine, and methadone as treatment for diarrhea. Antidiarrheal specificity therefore is of paramount importance in choosing among the synthetic opioids and their analogues (e.g., diphenoxylate and loperamide). Diphenoxylate (marketed in combination with atropine as Lomotil in the United States) is chemically related to both analgesic and anticholinergic compounds.
  • It is as effective in the treatment of diarrhea as the opium derivatives, and at the doses usually employed, it has a low incidence of central opioid actions.
  • Diphenoxylate is rapidly metabolized by ester hydrolysis to the biologically active metabolite difenoxylic acid. Lomotil is recommended as adjunctive therapy in the management of diarrhea. It is contraindicated in children under 2 years old and in patients with obstructive jaundice.
  • Adverse reactions often caused by the atropine in the preparation include anorexia, nausea, pruritus, dizziness, and numbness of the extremities.
  • Loperamide hydrochloride (Imodium) structurally resembles both haloperidol and meperidine. In equal doses, loperamide protects against diarrhea longer than does diphenoxylate. It reduces the daily fecal volume and decreases intestinal fluid and electrolyte loss.
  • Loperamide produces rapid and sustained inhibition of the peristaltic reflex through depression of longitudinal and circular muscle activity.The drug also possesses antisecretory activity, presumably through an effect on intestinal opioid receptors. Loperamide is effective against a wide range of secretory stimuli and can be used in the control and symptomatic relief of acute diarrhea that is not secondary to bacterial infection.
  • Adverse effects associated with its use include abdominal pain and distention, constipation, dry mouth, hypersensitivity, and nausea and vomiting. Tincture of opium (10% opium) is a rapidly acting preparation for the symptomatic treatment of diarrhea. The more widely used paregoric (camphorated opium tincture) is equally effective and is frequently used in combination with other antidiarrheal agents. Codeine also has been used for short-term symptomatic treatment.

Alosetron

  • Alosetron (Lotronex) is a 5-HT3 receptor antagonist. Blocking this receptor results in decreased GI motility. Alosetron received FDA approval in February 2000 for the treatment of women with diarrhea-predominant IBS. In November 2000, at the request of the FDA, the drug was voluntarily withdrawn due to reported cases of ischemic colitis, including some fatalities.
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