Physiology of Gastric Acid Secretion

FIGURE 64.1 Omeprazole inhibits proton pump. H2 = histamine2. 

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The discovery and increasing understanding of the importance of the H, K -ATPase in the late 1970s revolutionized our knowledge of the physiology of gastric acid secretion [25]. It is well accepted that the activation of H, K -ATPase is the final step in the stimulation of acid secretion and the specific PPIs, the substituted benzimidazoles, completely inhibit gastric acid secretion stimulated by cAMP and histamine [2]. 

Histamine is a biogenic amine that is widely distributed in the body and functions as a major mediator of inflammation and allergic reactions, as a physiological regulator of gastric acid secretion in the stomach, as a neurotransmitter in the central nervous system (CNS) and may also have a role in tissue growth and repair. 

Apart from its role as a major mediator of inflammation and allergic reactions and as physiological regulator of gastric acid secretion, histamine is also a neurotransmitter in the CNS. Central histaminergic cell bodies are located in the posterior hypothalamus and project diffusely to almost all brain regions and to the spinal cord. There are four types of histamine receptors, all G-protein-coupled, Hi, H2, H3 and H4. Hi receptors couple to Gq/11 proteins. H2 receptors couple to Gs. H3 and H4 receptors couple to Gi/o. 

Glucose-dependent insulinotropic polypeptide is originally known as gastric inhibitory polypeptide (GIP), which is a 42-residue peptide first isolated by Brown and Dryburgh (14). It is secreted from the duodenum and proximal jejunum in response to food. Two major physiological effects of GIP are inhibition of gastric acid secretion and stimulation of insulin release. 

It was soon recognized that gastric HVK -ATPase is the site of action for omeprazole [27,43] and that enzyme inhibition parallels inhibition of gastric acid secretion in laboratory animals [38]. Physico-chemically, omeprazole represents a lipid-permeable weak base with a pK of 4 [42]. At physiological pH, it is predominantly unionized and this neutral form passes freely across biological membranes. However, in an acidic environment with a pH below 4, it is predominantly protonated. This results in a limited permeability of the drug [28]. Due to the unique structure of the gastric... 

Histamine released from mast cells plays an important physiological role in immediate hypersensitivity and allergic responses. In addition, histamine functions as a neurotransmitter in the CNS and it is a potent stimulus for gastric acid secretion. These actions depend on the interaction of histamine with two types of receptors, Hi and H2. Hi and H2 receptors are coupled via G proteins to phospholipase C and adenylyl cyclase, respectively. The principal H3 receptor response is stimulation of gastric acid secretion, whereas other actions of histamine (e.g., smooth muscle contraction, vasodilation, increased capillary permeability, pain, and itching) are prunarily mediated by Hi receptors. 

The aim of this review is to outline the drugs that are currently available and the medicinal chemistry that led to their discovery. The physiological processes associated with acid secretion and the mechanism of action of inhibitors of this process are described. Current research into inhibitors of gastric acid secretion is aimed at producing a reversible PPI or antagonist of receptor-mediated acid secretion. The medicinal chemistry and pharmacology of such approaches are considered. 

Debas HT, Lloyd KCK. Peripheral regulation of gastric acid secretion. In Johnson LR, ed. Physiology of the gastrointestinal tract, 3rd ed., vol 2. New York Raven Press, 1994 1185. 

Histamine was synthesized in 1907 and later isolated from mammalian tissues. Early hypotheses concerning the possible physiologic roles of tissue histamine were based on similarities between the effects of intravenously administered histamine and the symptoms of anaphylactic shock and tissue injury. Marked species variation is observed, but in humans histamine is an important mediator of immediate allergic (such as urticaria) and inflammatory reactions, although it plays only a modest role in anaphylaxis. Histamine plays an important role in gastric acid secretion (see Chapter 62) and functions as a neurotransmitter and neuromodulator (see Chapters 6 and 21). Newer evidence indicates that histamine also plays a role in chemotaxis of white blood cells. 

Histamine A chemical produced by various cells in the body that is involved in the modulation of certain physiologic responses (e.g., secretion of gastric acid), as well as in the mediation of hypersensitivity (allergic) responses. 

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