Gastric acid synthesis

Multiple stimuli for the release of gastric acid exist, so blockade of the histamine receptor only decreases secretion to the extent that other stimuli are present or absent. Proton-pump inhibitors act at the last step of gastric acid synthesis and thus are not subject to the effects of other mediators. 

CCK is found in the digestive tract and the central and peripheral nervous systems. In the brain, CCK coexists with DA. In the peripheral nervous system, the two principal physiological actions of CCK are stimulation of gaU. bladder contraction and pancreatic enzyme secretion. CCK also stimulates glucose and amino acid transport, protein and DNA synthesis, and pancreatic hormone secretion. In the CNS, CCK induces hypothermia, analgesia, hyperglycemia, stimulation of pituitary hormone release, and a decrease in exploratory behavior. The CCK family of neuropeptides has been impHcated in anxiety and panic disorders, psychoses, satiety, and gastric acid and pancreatic enzyme secretions. 

Uracil is used more effectively, in nucleic acid synthesis within a rat hepatoma than in normal liver. This observation appears to have stimulated the synthesis of 5-fluorouracil (1027) as an antimetabolite mainly because the introduction of a fluorine atom involves a minimal increase in size. In the event, 5-fluorouracil did prove to have antineoplastic activity and it is now a valuable drug for treatment of tumors of the breast, colon or rectum, and to a lesser extent, gastric, hepatic, pancreatic, uterine, ovarian and bladder carcinomas. As with other drugs which interfere with DNA synthesis, the therapeutic index is quite low and great care is required during treatment (69MI21301). 

Heparin inhibits the formation of fibrin clots, inhibits the conversion of fibrinogen to fibrin, and inactivates several of the factors necessary for the clotting of blood. Heparin cannot be taken orally because it is inactivated by gastric acid in the stomach therefore, it must be given by injection. Heparin has no effect on clots that have already formed and aids only in preventing the formation of new blood clots (thrombi). The LMWHs act to inhibit clotting reactions by binding to antithrombin HI, which inhibits the synthesis of factor Xa and the formation of thrombin. 

Theory Cortisol (or hydrocortisone) was introduced in the year 1951, for the treatment of rheumatoid arthritis. It has a significant effect on protein metabolism. It also exerts widespread effects on carbohydrates, lipid and protein synthesis (or anabolism). The cardinal side effects such as excessive potassium excretion and sodium retention, enhanced gastric acidity, oedema, psychosis and negative nitogen balance are some of the exaggerated manifestations of the normal metabolite functions of cortisol. 

Inhibits protein synthesis by inhibiting DNA and RNA polymerase Blocks H2 receptor and reduces secretion of gastric acid and pepsin output... 

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

Ethionamide is an analog of isoniazid and also inhibits mycolic acid synthesis. Its usefulness is limited by the rapid development of resistance. It can cause intense gastric pain and, like isoniazid, may also be neurotoxic. 

TEicosanoids are paracrine hormones, substances that act only on cells near the point of hormone synthesis instead of being transported in the blood to act on cells in other tissues or organs. These fatty acid derivatives have a variety of dramatic effects on vertebrate tissues. They are known to be involved in reproductive function in the inflammation, fever, and pain associated with injury or disease in the formation of blood clots and the regulation of blood pressure in gastric acid secretion and in a variety of other processes important in human health or disease. 

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 hL pvlori colonization and stimulation of prostaglandin synthesis. 

Fig. 2.4 Substituted benzimidazoles tested in the search for the optimal inhibition of gastric acid secretion. Substituents added to the pyridine ring resulted in the synthesis of H 168/88 (omeprazole).

There are at least two different types of COX, COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 (which is constitntive) this leads to an inhibition of prostanoid synthesis, and reduced levels of PGE2 in particular lead to an increase in gastric acid production (Chapter 4), as weU as a reduction in mucous secretion. Aspirin also modifies the enzymatic activity of COX-2 (which is inducible) normally COX-2 produces prostanoids, most of which are pro-inflammatory, but aspirin-modified COX-2 produces lipoxins, which are anti-inflammatory. 

The structures of all currently approved gastric acid secretion inhibitors that act as inhibitors of the sodium-potassium pump consists of variously substituted pyiidylsulfonyl-benzimidazoles. A structurally very distinct compound based on a pyrimidine moiety has much the same activity as the benzimidazole-based drugs. In yet another convergent synthesis, reaction of (3-phenethylamine (53) with acetic anhydride affords amide 54. Treatment with polyphosphoric acid (PPA) then leads to ring closure to form the dihydroisoquinoline (55). Sodium borohydride then reduces the enamine function to afford fragment 56. 

Histamine is an endogenous substance that activates histamine H2, and H3 receptors, and its principal pharmacologic effects involve exocrine glands, extravascular smooth muscles, and the cardiovascular system. H, receptor stimulation increases inositol-1,4,5-triphosphate, which increases intracellular calcium, resulting in vasoconstriction. Activation of H2 receptors increases intracellular cAMP, which mediates gastric acid secretions and cardiovascular effects. H3 receptor stimulation may be involved in feedback inhibition of histamine synthesis and release. 

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