Gastric Antacids

Course Title: Pharmacognosy & Pharmacology G. C. Biswas Course Code: GEB 417 Lecturer Dept. of Genetic Eng. & Biotechnology, SUST.

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Topic: Gastric Antacids ** Gastric Secretion:

The stomach secretes about 2.5 litres of gastric juice daily. The principal exocrine secretions are proenzymes such as prorennin and pepsinogen elaborated by the chief or peptic cells and hydrochloric acid (HCl) and intrinsic factor secreted by the parietal or oxyntic cells. Mucus-secreting cells abound among the surface cells of the

gastric mucosa. Bicarbonate ions are also secreted and are trapped in the mucus, creating a gel-like protective barrier that maintains the mucosal surface at a pH of 6-7 in the face of a much more acidic environment (pH 1-2) in the lumen. Alcohol and bile can disrupt this layer. Locally produced 'cytoprotective' prostaglandins stimulate the secretion of both mucus and bicarbonate. Disturbances in these secretory and protective mechanisms are thought to be involved in the pathogenesis of peptic ulcer, and the therapy of this condition includes drugs that modify each of these factors. ** The Regulation of acid secretion by parietal cells:

The regulation of acid secretion by parietal cells is especially important in the pathogenesis of peptic ulcer, and constitutes a particular target for drug action. The secretion of the parietal cells is an isotonic solution of HCl (150 mmol/l) with a pH less than 1, the concentration of hydrogen ions being more than a million times higher than that of the plasma. The Cl- is actively transported into canaliculi in the cells that communicate with the lumen of the gastric glands and thus with the stomach itself. This Cl- secretion is accompanied by K+, which is then exchanged for H+ from within the cell by a K+/H+ ATPase (+ and bicarbonate ions. The latter exchanges across the basal membrane of the parietal cell for Cl-. The principal stimuli acting on the parietal cells are:

gastrin (a stimulatory hormone) acetylcholine (a stimulatory neurotransmitter) histamine (a stimulatory local hormone) prostaglandins E2 and I2 (local hormones that inhibit acid secretion).

Gastrin:

Gastrin is a peptide hormone synthesised in endocrine cells of the mucosa of the gastric antrum and duodenum, and secreted into the portal blood. Its main action is

stimulation of the secretion of acid by the parietal cells, but there is controversy about


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the precise mechanism of stimulatory action. Gastrin receptors on the parietal cells have been demonstrated using the radioactively labelled hormone. These receptors are blocked by the experimental drug proglumide, which inhibits gastrin action.

Gastrin also indirectly increases pepsinogen secretion, stimulates blood flow and increases gastric motility. Release of this hormone is controlled both by neuronal transmitters and blood- borne mediators, as well as the chemistry of the stomach contents. Amino acids and small peptides directly stimulate the gastrin-secreting cells, as do milk and solutions of calcium salts, explaining why it is

inappropriate to use calcium-containing salts as antacids. Acetylcholine:

Acetylcholine is released from (e.g. vagal) neurons and stimulates specific muscarinic receptors on the surface of the parietal cells and on the surface of histamine-containing cells.

Histamine:

Histamine is discussed in, and only those aspects of its pharmacology relevant to gastric secretion will be dealt with here. Within the stomach, mast cells (or histamine-containing cells similar to mast cells) lying close to the parietal cell release a steady basal release of histamine, which is further increased by gastrin and acetylcholine. The

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hormone acts on parietal cell H2 receptors, which are responsive to histamine concentrations that are below the threshold required for vascular H2 receptor activation. The coordinated role of acetylcholine, histamine and gastrin in regulating acid secretion:

Secretion of gastric acid, mucus and bicarbonate The control of the gastrointestinal tract is through nervous and

humoral mechanisms. o Acid is secreted from gastric parietal cells by a proton

pump (K+/H+ ATPase). o The three endogenous secretagogues for acid are

histamine, acetylcholine and gastrin. o Prostaglandins E2 and I2 inhibit acid, stimulate mucus

and bicarbonate secretion, and dilate mucosal blood vessels.

The genesis of peptic ulcers involves: o infection of the gastric mucosa with Helicobacter pylori. o an imbalance between the mucosal-damaging (acid,

pepsin) and the mucosal-protecting agents (mucus,

bicarbonate, prostaglandins E2 and I2, and nitric oxide ).

The exact mechanism of action of the three secretagogues on the parietal cell is not entirely clear. A general scheme is given in Figure 25.2, which summarises the two main theories: the 'single-cell' or 'permission' hypothesis, and the 'two-cell' or 'transmission' hypothesis. According to the former concept, the parietal cell itself has H2

receptors for histamine and muscarinic M2 receptors for acetylcholine, as well as receptors for gastrin itself. Acid secretion follows after the synergistic stimulation of H2 receptors (which increases cAMP), and M2 and gastrin receptors (which increase cytosolic Ca2+). Arguing against this is the observation that cimetidine (an H2 receptor antagonist) can block the action of all stimuli under some circumstances. This was accounted for in terms of potentiating interactions at the postreceptor level. According to the alternative, two-cell hypothesis, which has more explanatory power, gastrin and acetylcholine act on parietal cells but also on a second cell type that then releases histamine that further stimulates the parietal cells. Some inter- and even intraspecies specificity was observed in the histamine dependence of the gastrin response. Their overall conclusion is that both models can operate side by side; that histamine released by muscarinic stimulation or gastrin may integrate the local secretory and circulatory responses to these hormones; and that interactions between histamine, acetycholine and gastrin regulate H+ secretion by the parietal cell itself.




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Fig.: Schematic diagram showing the one-cell and two-cell hypotheses of the action of secretagogues on the acid-secreting gastric parietal cell, illustrating the site of action of drugs influencing acid secretion. ** Drugs used for Gastric acidity, peptic ulcers and gastroesophageal reflux diseases:

The acid-peptic diseases are those disorders in which gastric acid and pepsin are necessary, but usually not sufficient, pathogenic factors. Barriers to the reflux of gastric contents into the esophagus comprise the primary esophageal defense. If these protective barriers fail and reflux occurs, dyspepsia and/or erosive esophagitis may result. The treatment and prevention of these acid-related disorders are accomplished either by decreasing the level of gastric acidity or by enhancing mucosal protection. The


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appreciation that an infectious agent, Helicobacter pylori, plays a key role in the pathogenesis of acid-peptic diseases has stimulated new approaches to prevention and therapy. >> H2-receptor antagonists:

Although antagonists of the histamine H2-receptor (H2 antagonists) block the actions of histamine at all H2 receptors, their chief clinical use is as inhibitors of gastric acid secretion. By com-petitively blocking the binding of histamine to H 2 receptors, these agents reduce intracellular concentrations of cyclic AMP and thereby, secretion of gastric acid. The four drugs used cimetidine, ranitidine, famotidine [fa MOE ti deen] and nizatidine, potently inhibit (>90%) basal, food-stimulated, and nocturnal secretion of gastric acid after a single dose. Cimetidine is the prototype histamine H2-receptor antagonist.

Actions:

The histamine H2-receptor antagonists--cimetidine, rantidine, famotidine, and nizatidine- act on H2-receptors in the stomach, blood vessels, and other sites. They are competitive antagonists of histamine and are fully reversible. These agents completely inhibit gastric acid secretion induced by histamine, or gastrin. However, they only

partially inhibit gastric acid secretion induced by acetylcholine or bethanechol. These drugs are less potent than proton pump inhibitors but still suppress 24-hour gastric acid secretion by ~70%. The H2 receptor antagonists predominantly inhibit basal acid secretion, which accounts for their efficacy in suppressing nocturnal acid secretion. Because the most important determinant of duodenal ulcer healing is the level of nocturnal acidity, evening dosing of H2 receptor antagonists is adequate therapy in most instances.

Histamine

Pharmacokinetics:

Cimetidine: Cimetidine and the other H2-antagonists are given orally, distribute widely throughout the body (including in breast milk and across the placenta) and are excreted mainly in the urine. Cimetidine normally has a short serum half-life, which is increased in renal failure. Approximately 30% of a dose of cimetidine is slowly inactivated by the liver's microsomal mixed function oxygenase system; the other 70% is excreted unchanged in the urine.


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Ranitidine: Compared to cimetidine, ranitidine is longer acting and is five to ten times more potent. Ranitidine has minimal side effects, and does not produce the antiandrogenic or prolactin-stimulating effects of cimetidine. Unlike cimetidine, it does not inhibit the mixed function oxygenase system in the liver, and thus does not affect the concentrations of other drugs. Famotidine: Famotidine is similar to ranitidine in its pharmacologic action, but it is 20 to 160 times more potent than cimetidine and 3 to 20 times more potent than ranitidine. Nizatidine: Nizatidine is similar to ranitidine in its pharmacologic action and potency. In contrast to cimetidine, ranitidine, and famotidine (which are metabolized by the liver), nizatidine is eliminated principally by the kidney. Since little first-pass metabolism occurs with nizatidine, its bioavailability is nearly 100%.

Cimetidine

Ranitidine

Famotidine

Nizatidine

Adverse effects:

The adverse effects of cimetidine are usually minor and are associated mainly with the major pharmacologic activity of the drug, namely reduced gastric acid production. Side effects occur only in a small number of patients and generally do not require discontinuation of the drug. The most common side effects are headache, dizziness, diarrhea, and muscular pain. Other central nervous system (CNS) effects (confusion, hallucinations) occur primarily in elderly patients or after prolonged administration. Cimetidine can also have endocrine effects, since it acts as a

nonsteroidal antiandrogen. These effects include gynecomastia, galactorrhea


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(continuous release/discharge of milk), and reduced sperm count. Cimetidine inhibits cytochrome and can slow metabolism (and thus potentiate the action) of several drugs (for example, warfarin, diazepam, phenytoin, quinidine, carbamazepine, theophylline, imipramine), sometimes resulting in serious adverse clinical effects. Therapeutic uses:

a. Peptic ulcers: All four agents are equally effective in promoting healing of duodenal and gastric ulcers. However, recurrence is common after treatment with H2 antagonists is stopped (60 to 100% per year). This can be effectively prevented by eradication of H. pylori and H2 antagonists continue to be widely used in peptic ulcer therapy in combination with antimicrobial drugs. b. Zollinger-Ellison syndrome: Zollinger-Ellison syndrome is a rare condition in which a gastrin-producing tumor causes hypersecretion of HCI. With H2 antagonists,

the hypersecretion of gastric acid can be kept at safe levels in patients with Zollinger-Ellison syndrome. c. Acute stress ulcers: These drugs are useful in managing acute stress ulcers associated with major physical trauma in high-risk patients in intensive care units. d. Gastroesophageal reflux disease (heartburn): Low doses of H2 antagonists, recently released for over-the-counter sale, appear to be effective for prevention and treatment of heartburn (gastroesophageal reflux). Because they act by stopping acid secretion, they may not relieve symptoms for at least 45 minutes. Antacids more efficiently neutralize secreted acid already in the stomach. >> Prostaglandin:

Prostaglandins E2 and I2, produced by the gastric mucosa, inhibit secretion of HCI and stimulate secretion of mucus and bicarbonate (cytoprotective effect). A deficiency of prostaglandins is thought to be involved in the pathogenesis of peptic ulcers. Misoprostol [miz 0 PROS tol], a stable analog of prostaglandin E1, is currently the only agent approved for prevention of gastric ulcers induced by non-steroidal anti-inflammatory agents (NSAIDs). It is less effective than H2 antagonists for acute treatment of peptic ulcers. Although misoprostol has cytoprotective actions, it is clinically effective only at higher doses that diminish gastric acid secretion. Routine prophylactic use of misoprostol may not be justified except in patients taking NSAIDs who are at high risk of NSAID-induced ulcers, such as the elderly or patients with ulcer complications. Like other prostaglandins, misoprostol produces uterine contractions and is contraindicated during pregnancy. Dose-related diarrhea and nausea are the most common adverse effects. >>Inhibitors of the H+/K+-ATPase proton pump:

Omeprazole [om ME pary zol] is the first of a new class of drugs that binds to the H+/K+-ATPase enzyme system (proton pump) of the parietal cell,


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suppressing secretion of hydrogen ions into the gastric lumen. The membrane-bound proton pump is the final step in the secretion of gastric acid (see Figure 24.3). A second proton pump inhibitor, lansoprazole, is also available. Actions:

At standard doses, both omeprazole and lansoprazole inhibit basal and stimulated gastric acid secretion more than 90%. Acid suppression begins within 1 to 2 hr after the first dose of lansoprazole, and slightly earlier with omeprazole.

Fig.: Proton pump inhibitors. A. Inhibitors of gastric H+,K+-ATPase (proton pump). B. Conversion of omeprazole to a sulfenamide in the acidic secretory canaliculi of the parietal cell. The sulfenamide interacts covalently with sulfhydryl groups in the proton pump, thereby irreversibly inhibiting its activity. The other three proton pump inhibitors undergo analogous conversions.

Therapeutic uses:

Omeprazole and lansoprazole are used for short-term treatment of erosive esophagitis and active duodenal ulcer, and for long-term treatment of pathologic hypersecretory conditions (for example, Zollinger-Ellison syndrome). Only omeprazole is approved for refractory gastroesophageal reflux disease and maintenance therapy of erosive esophagitis. Clinical studies to date have shown lansoprazole, like omeprazole, is more effective in the short term than the H2 antagonist, ranitidine. Omeprazole is successfully used with antimicrobial regimens to eradicate H. pylori.


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Pharmacokinetics:

Omeprazole and lansoprazole are enteric-coated to protect them from premature activation by gastric acid. After absorption in the duodenum, they are transported to the acid parietal cell canaliculus, where they are converted to active species. Metabolites of these agents are excreted in urine and feces. Adverse effects:

Omeprazole and lansoprazole are generally well tolerated, but concerns about long-term safety have been raised. In animal studies, both drugs increase the incidence of gastric carcinoid tumors, possibly related to the effects of prolonged hypochlorhydria and secondary hypergastrinemia. Increased concentration of viable bacteria in the stomach have been reported with continued use of these drugs. Omeprazole interferes in the oxidation of warfarin, phenytoin, diazepam and cyclosporine; lansoprazole does not. >> Antacids:

Antacids are weak bases that react with gastric acid to form water and a salt, thereby diminishing gastric acidity. Since pepsin is inactive at pH>4.0, antacids also reduce peptic activity. They may have other actions as well, such as reduction of H. pylori colonization and stimulation of prostaglandin synthesis. There are differences in the types of antacids, in terms of their contents, neutralizing capacity, duration of action, side effects, and cost. These must be considered when choosing an antacid for therapeutic use. Antacids are OTC drugs. The most widely used antacids are sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide. General Consideration for antacid:

Antacids are the simplest of all the therapies for treating the symptoms of excessive gastric acid secretion. They directly neutralise acid, thus raising the gastric pH; this also has the effect of inhibiting the activity of peptic enzymes, which practically ceases at pH 5. Given in sufficient quantity for long enough, they can produce healing of duodenal ulcers but are less effective for gastric ulcers. Most antacids in common use are salts of magnesium and aluminium. Magnesium salts cause diarrhoea and aluminium salts constipation, so mixtures of these two can, happily, be used to preserve normal bowel function. Some preparations of these substances (e.g. magnesium trisilicate mixture and some proprietary aluminium preparations) contain high concentrations of sodium and should not be given to patients on a sodium-restricted diet. Numerous antacid preparations are available; a few of the more significant are given below.

Magnesium hydroxide is an insoluble powder that forms magnesium chloride in the stomach. It does not produce systemic alkalosis, because Mg2+ is poorly absorbed from the gut. Another salt, magnesium trisilicate, is an insoluble powder that reacts slowly with the gastric juice, forming magnesium chloride and colloidal silica.



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This agent has a prolonged antacid effect, and it also adsorbs pepsin. Aluminium hydroxide gel forms aluminium chloride in the stomach;

when this reaches the intestine, the chloride is released and is reabsorbed. Aluminium hydroxide raises the pH of the gastric juice to about 4, and also adsorbs pepsin. Its action is gradual, and its effect continues for several hours.2 Colloidal aluminium hydroxide combines with phosphates in the gastrointestinal tract, and the increased excretion of phosphate in the faeces that occurs results in decreased excretion of phosphate via the kidney. This effect has been used in treating patients with chronic renal failure. Sodium bicarbonate acts rapidly and is said to raise the pH of gastric juice to about 7.4. Carbon dioxide is liberated, and this causes eructation (belching). The carbon dioxide stimulates gastrin secretion and can result in a secondary rise in acid secretion. Because some sodium bicarbonate is absorbed in the intestine, large doses or frequent administration of this antacid can cause alkalosis, the onset of which can be insidious. To avoid this possibility, sodium bicarbonate should not be prescribed for long-term treatment, nor should it be given to patients who are on a sodium-restricted diet. Alginates or simeticone are sometimes combined with antacids. The former are believed to increase the viscosity and adherence of mucus to the oesophageal mucosa, forming a protective barrier, whereas the latter is a surface active compound that, by preventing 'foaming', can relieve bloating and flatulence. Chemistry of antacids:

Antacid products vary widely in their chemical composition, acid-neutralizing capacity, sodium content, palatability and price. The acid-neutralizing ability of an antacid depends on its capacity to neutralize gastric HCI and on whether the stomach is full or empty (food delays stomach emptying, allowing more time for the antacid to react). Commonly used antacids are salts of aluminum and magnesium, such as aluminum hydroxide (usually a mixture of AI(OH)3 and aluminum oxide hydrates) or magnesium hydroxide [Mg(OH)2] ("milk of magnesia"), either alone or in combination. Since calcium salts stimulate gastrin release, use of calcium-containing antacids, such as calcium carbonate [CaCO3] (Tums, Rolaids) may be counterproductive. Systemic absorption of sodium bicarbonate [NaHCO3] can produce transient metabolic alkalosis; this antacid is not recommended for long-term use. Mechanism of Action

Antacids neutralize hydrochloric acid and raise gastric pH, thus inhibiting pepsin (a gastric enzyme). Antacids reduce the concentration and total load of acid in the gastric contents. By increasing gastric pH, antacids also inhibit pepsin activity. In addition, they strengthen the gastric mucosal barrier.




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Therapeutic uses:

Aluminum- and magnesium-containing antacids can promote healing of duodenal ulcers; evidence for efficacy in treatment of acute gastric ulcer is less compelling. Adverse effects:

Aluminum hydroxide may be constipating; magnesium hydroxide may produce diarrhea. Preparations that combine these agents aid in normalizing bowel function. In addition to the potential for systemic alkalosis, NaHCO3 liberates CO2, causing belching and flatulence. Absorption of cations from antacids (Mg++, AI+++, Ca++) is usually not a problem in patients with normal renal function, but the sodium content of antacids can be an important consideration in patients with hypertension or congestive heart failure. Drug interactions:

It is usually advisable to avoid concurrent administration of antacids and other drugs. By altering gastric and urinary pH or delaying gastric emptying, antacids can affect rates of dissolution and absorption, bioavailability, and renal elimination of many drugs. By binding to drugs (for example, tetracycline), AI+++ compounds can form insoluble complexes that are not absorbed. On the other hand, antacids can increase the rate of absorption of some drugs, for example, levodopa.


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Factors Considered When an Antacid is prescribed:

Before a patient is prescribed a particular antacid preparation, the prescriber must consider the patient’s condition as well as group of other factors. Some of these factors are listed below:

1. Gastric acid neutralization:

The chief reason for prescribing an antacid preparation is the neutralization of the hydrochloric acid in the stomach. Antacid preparations contain one or more drugs which chemically neutralize this hydrochloric acid. Not all chemicals neutralize the same amount of stomach acid on a weight by weight basis. Therefore, the prescriber must be aware of the active ingredient(s) present in an antacid preparation and how effectively that preparation is able to neutralize stomach acid in relation to other antacid preparations.

2. Effect on stomach pH:

Most antacid agents remain in the gastrointestinal system when they are taken to neutralize stomach acid. However, some agents (e.g., Sodium Bicarbonate NaHCO3), because of their ability to ionize, are capable of going into systemic circulation in the bloodstream once they are ingested, the bicarbonate ion (HCO3

-) can be systemically absorbed and affect the pH of the blood. This effect is highly undesirable. ** Peptic Ulcer:

Peptic ulcer refers to a lesion located in either the stomach (gastric ulcer) or in the duodenum (small intestine) (Figure 15-3). In general, ulcers occur whenever there is an increase in acid secretion or a decrease in mucosal resistance. Mucosal injury in the acid peptic diseases includes gastric ulcer, duodenal ulcer, and gastroesophageal reflux disease, which are mediated by gastric acid. Hydrochloric acid is secreted by parietal cells in the body of the stomach. It is regulated by adjacent endocrines, such as gastrin, or by histamine, somatostatin, and prostaglandin E2. Gastrin is a relatively weak stimulant of the parietal cells. It acts primarily to cause the release of histamine, which is the most potent stimulus of acid secretion, and acts as the common mediator. Histamine antagonists inhibit acid secretion that is stimulated by gastrin and acetylcholine, as well as histamine. There are a number of causes of peptic ulcer, including: Family history Smoking tobacco Alcohol Coff ee Stress Infection with Helicobacter pylori (H. pylori) Blood group O


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Anti-infl ammatory drugs (aspirin, NSAIDs, and glucocorticoids) A wide variety of prescription and OTC medications are available for the treatment of peptic ulcer. These drugs include: antacids, H2-receptor antagonists, proton pump inhibitors, and antibiotics. Antibiotics treat peptic ulcers caused by Helicobacter pylori.

Fig.: Sites of peptic ulcers

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