Monday, 30 May 2011

Parietal cell : Production and inhibition

The key player in acid secretion is a H+/K+ ATPase or "proton pump" located in the cannalicular membrane. The current model for explaining acid secretion is as follows:
  • Hydrogen ions are generated within the parietal cell from dissociation of water. The hydroxyl ions formed in this process rapidly combine with carbon dioxide to form bicarbonate ion, a reaction cataylzed by carboni anhydrase.
  • Bicarbonate is transported out of the basolateral membrane in exchange for chloride. The outflow of bicarbonate into blood results in a slight elevation of blood pH known as the "alkaline tide". This process serves to maintain intracellular pH in the parietal cell.
  • Chloride and potassium ions are transported into the lumen of the cannaliculus by conductance channels, and such is necessary for secretion of acid.
  • Hydrogen ion is pumped out of the cell, into the lumen, in exchange for potassium through the action of the proton pump; potassium is thus effectively recycled.
  • Accumulation of osmotically-active hydrogen ion in the cannaliculus generates an osmotic gradient across the membrane that results in outward diffusion of water - the resulting gastric juice is 155 mM HCl and 15 mM KCl with a small amount of NaCl.
Drug therapy for suppressing gastric acid production

The most effective inhibitors fall into two classes.
  1. H2 Receptor Antagonists Histamine is clearly one of the primary regulators of acid secretion, and the parietal cell receptor for histamine is of the H2 type. Evidence of histamine's role in acid secretion is strongly supported by finding that H2 receptor antagonists are quite effective in inhibiting acid secretion. Examples of H2 antagonists commonly used to suppress gastric acid secretion include cimetidine (Tagamet HB), ranitidine (Zantac 75), famotidine (Pepcid AC) and nizatidine (Axid AR). These drugs, particularly cimetidine, are among the most widely prescribed drugs in man. They are also useful for management of certain gastric diseases in dogs and horses. Antihistamines that engage H1 receptors (e.g. those used to treat colds) have no effect on acid secretion.

  2. Proton Pump Inhibitors Acid secretion is absolutely dependent on function of the H+/K+ ATPase or proton pump located in the cannilicular membrane of the parietal cell. Several drugs have been developed that non-competively bind and inactivate the ATPase, resulting in strong inhibition of acid secretion. Omeprazole (Prilosec) is an acid-activated prodrug that binds covalently to two cysteines on the ATPase, resulting in its irreversible inactivation. Other inhibitors, including lansoprazole (Prevacid), esomeprazole (Nexium), rabeprazole (Aciphex) and pantoprazole (Protonix) have similar modes of action.

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