ADH, a nonapeptide, released from the posterior pituitary gland promotes reabsorption of water in the kidney. This response is mediated by vasopressin receptors of the V2 subtype. ADH enhances the permeability of collecting duct epithelium for water (but not for electrolytes). As a result, water is drawn from urine into the hyperosmolar inter-stitium of the medulla. Nicotine augments (p. 110) and ethanol decreases ADH release. At concentrations above those required for antidiuresis, ADH stimulates smooth musculature, including that of blood vessels ("vasopressin"). The latter response is mediated by receptors of the V1 subtype. Blood pressure rises; coronary vasoconstriction can precipitate angina pectoris. Lypres-sin (8-L-lysine vasopressin) acts like ADH. Other derivatives may display only one of the two actions.
Desmopressin is used for the therapy of diabetes insipidus (ADH deficiency), nocturnal enuresis, thrombasthe-mia (p. 148), and chronic hypotension (p. 314); it is given by injection or via the nasal mucosa (as "snuff").
Felypressin and ornipressin serve as adjunctive vasoconstrictors in infiltration local anesthesia (p. 206).
Drugs for Gastric and Duodenal Ulcers
In the area of a gastric or duodenal peptic ulcer, the mucosa has been attacked by digestive juices to such an extent as to expose the subjacent connective tissue layer (submucosa). This self-digestion occurs when the equilibrium between the corrosive hydrochloric acid and acid-neutralizing mucus, which forms a protective cover on the mucosal surface, is shifted in favor of hydrochloric acid. Mucosal damage can be promoted by Helicobacter pylori bacteria that colonize the gastric mucus.
Drugs are employed with the following therapeutic aims: (1) to relieve pain; (2) to accelerate healing; and (3) to prevent ulcer recurrence. Therapeutic approaches are threefold: (a) to reduce aggressive forces by lowering H+ output; (b) to increase protective forces by means of mucoprotectants; and (c) to eradicate Helicobacter pylori.
Ia. Acid neutralization. H+-binding groups such as CO32-, HCO3- or OH-, together with their counter ions, are contained in antacid drugs. Neutralization reactions occurring after intake of CaCO3 and NaHCO3, respectively, are shown in (A) at left. With nonabsorb-able antacids, the counter ion is dissolved in the acidic gastric juice in the process of neutralization. Upon mixture with the alkaline pancreatic secretion in the duodenum, it is largely precipitated again by basic groups, e.g., as CaCO3 or AlPO4, and excreted in feces. Therefore, systemic absorption of counter ions or basic residues is minor. In the presence of renal insufficiency, however, absorption of even small amounts may cause an increase in plasma levels of counter ions (e.g., magnesium intoxication with paralysis and cardiac disturbances). Precipitation in the gut lumen is responsible for other side effects, such as reduced absorption of other drugs due to cipitated antacid or, phosphate depletion of the body with excessive intake of Al(OH)3.
Na+ ions remain in solution even in the presence of HCO3--rich pancreatic secretions and are subject to absorption, like HCO3-. Because of the uptake of Na+, use of NaHCO3 must be avoided in conditions requiring restriction of NaCl intake, such as hypertension, cardiac failure, and edema.
Since food has a buffering effect, antacids are taken between meals (e.g., 1 and 3 h after meals and at bedtime). Nonabsorbable antacids are preferred. Because Mg(OH)2 produces a laxative effect (cause: osmotic action, p. 170, release of cholecystokinin by Mg2+, or both) and Al(OH)3 produces constipation (cause: astringent action of Al3+, p. 178), these two antacids are frequently used in combination.
Acting on their respective receptors, the transmitter acetylcholine, the hormone gastrin, and histamine released intra-mucosally stimulate the parietal cells of the gastric mucosa to increase output of HCl. Histamine comes from entero-chromaffin-like (ECL) cells; its release is stimulated by the vagus nerve (via M1 receptors) and hormonally by gastrin. The effects of acetylcholine and hista-mine can be abolished by orally applied antagonists that reach parietal cells via the blood.
The cholinoceptor antagonist pi-renzepine, unlike atropine, prefers cho-linoceptors of the M1 type, does not penetrate into the CNS, and thus produces fewer atropine-like side effects (p. 104). The cholinoceptors on parietal cells probably belong to the M3 subtype. Hence, pirenzepine may act by blocking Mi receptors on ECL cells or submucosal neurons.
Histamine receptors on parietal cells belong to the H2 type (p. 114) and are blocked by H2-antihistamines. Because histamine plays a pivotal role in the activation of parietal cells, H2-anti-histamines also diminish responsivity to other stimulants, e.g., gastrin (in gas-
trin-producing pancreatic tumors, Zollinger-Ellison syndrome). Cimetidine, the first ^-antihistamine used thera-peutically, only rarely produces side effects (CNS disturbances such as confusion; endocrine effects in the male, such as gynecomastia, decreased libido, impotence). Unlike cimetidine, its newer and more potent congeners, ranitidine, nizatidine, and famotidine, do not interfere with the hepatic biotransformation of other drugs.
Omeprazole (p. 167) can cause maximal inhibition of HCl secretion. Given orally in gastric juice-resistant capsules, it reaches parietal cells via the blood. In the acidic milieu of the mucosa, an active metabolite is formed and binds co-valently to the ATP-driven proton pump (H+/K+ ATPase) that transports H+ in exchange for K+ into the gastric juice. Lansoprazole and pantoprazole produce analogous effects. The proton pump inhibitors are first-line drugs for the treatment of gastroesophageal reflux disease.
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