Gastrointestinal tract

Heroin is commonly conceded to be a much more addicting drug than is morphine. Its importation and manufacture in the United States is forbidden. Successful enforcement of the Harrison Narcotic Act has restricted the use of heroin in recent years but a report by Hubbard in 1920 indicated that heroin was employed by 96.5 % of the addicts observed (75, 69). 

The medical addict usually confines himseK to morphine, but criminal addicts more frequently employ heroin and cocaine when available (Simon, 76). The danger of heroin lies in the ease ivith which addiction occurs, the intense euphoria which often supplants subjective depression, and the absence of unpleasant effects such as vomiting and constipation. The heroin addict is difficult to treat, usually relapses after apparent cure, and often represents a dangerous, asocial, and criminal type of personality. The morphine addict takes morphine in order to feel normal and prevent the appearances of withdrawal symptoms but the heroin addict continues his drug for the euphoric excitation it affords (69). 

Upon completion of this chapter, you will hove the ability to  

When drug molecules pass through the gastrointestinal tract, they encounter different environments with respect to the pH, enzymes, electrolytes, surface characteristics and viscosity of the gastrointestinal fluids. All these factors can influence drug absorption and interactions. Variations in the pH of various portions of the gastrointestinal tract are depicted in Fig. 5.3. 

The small intestine presents numerous folds and projections. 

Approximately 8-10 L per day of fluids are produced or secreted into the gastrointestinal tract and an additional 1-2 L of fluid is obtained via food and fluid intake. 

The gastrointestinal tract is highly perfused by a capillary network, which allows absorption and distribution of drugs to occur. This immediate circulation drains drug molecules into the portal circulation, where absorbed drugs are carried to the liver and may undergo first-pass effect. 

Bile salt deficiency as a result of a marked fecal loss of bile acids was 

It is partly owing to adaptation of the remaining small intestine to reabsorb bile acids that the length of ileal resection is not correlated with fecal bile acid excretion (64,101). In addition, accompanying malnutrition may limit the capacity of the liver to enhance its bile acid synthesis, so that in patients with extensive intestinal resections fecal bile acid excretion may be only moderately increased (64,101). In these cases, serum cholesterol is usually very low and depletion of body cholesterol in the presence of insufficiently enhanced cholesterol synthesis may be one factor for limited bile salt production. 

For diarrhea in ileopathy, see Section VD. Ineffectiveness of cholestyramine on diarrhea in patients with extensive ileal resection has been explained by the presence of hydroxy fatty acids and a low level of solubilized bile salts in feces (268). 

Studies with radioactive glycocholate or taurocholate demonstrated a virtual absence of the enterohepatic circulation of bile acids in patients with jejunotransversocolostomy (77). The small amount of absorbed bile acids contained some deconjugated cholate and deoxycholate (which had been reconjugated in the liver), indicating a rapid bacterial action during an apparently fast intestinal passage. Under these conditions, steatorrhea is apparently not solely due to bile salt deficiency induced impairment of micelle formation, but reduced absorptive area may play an important contributory role. No direct measurement of bile acid synthesis by fecal determination has been performed in this condition. 

Ileal bypass (see Section VB2) performed for hypercholesterolemic patients (269) increased cholesterol elimination in the study by Moore et al. (156) about fivefold as bile acids and threefold as neutral steroids according to the isotopic balance technique. Serum cholesterol reduction was about 40 %. In our own series, consisting of patients with familial hypercholesterolemia only, similar results have been obtained by the chemical balance technique except that elimination of cholesterol increased solely as bile acids (11,63,127). The fecal bile salt loss was associated with a 35 % fall in the serum cholesterol level, a severalfold increased cholesterol synthesis, impaired micellar solubilization of digested lipids, reduced intestinal bile salt concentrations, and decreased cholesterol level in the intestinal contents. The last suggests that biliary secretion of cholesterol was markedly decreased so that, despite impaired cholesterol reabsorption, fecal neutral steroid excretion remained quite unchanged. An increased fecal bile salt loss associated with stimulated cholesterol production has been reported also by Grundy et al. (94). 

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With respect to acute toxicity, based on lethaHty in rats or rabbits, acryhc monomers are slightly to moderately toxic. Mucous membranes of the eyes, nose, throat, and gastrointestinal tract are particularly sensitive to irritation. Acrylates can produce a range of eye and skin irritations from slight to corrosive depending on the monomer. 

Toxicity. Fluoroborates are excreted mostly in the urine (22). Sodium fluoroborate is absorbed almost completely into the human bloodstream and over a 14-d experiment all of the NaBF ingested was found in the urine. Although the fluoride ion is covalently bound to boron, the rate of absorption of the physiologically inert BF from the gastrointestinal tract of rats exceeds that of the physiologically active simple fluorides (23). 

Health and Safety Factors. Fluorocarbons containing bromine or iodine are more toxic than the corresponding chloro compounds. When the ratio of the fluorine to other halogens is high, the toxicity can be quite low, especially for bromofluorocarbons. Perfluoro-l-bromooctane [423-55-2] has an LD q of greater than 64 mL/kg when adininistered into the gastrointestinal tract, and has Htde effect when instilled into the lungs (49). Other examples are included in Table 7. 

The carcinogenicity of nitrosamines has created widespread concern over the safety of food products that are significant sources of nitrates and nitrites. Nitrosamines are readily formed by reaction of secondary amines with nitrites at acid pH, conditions which may occur in the gastrointestinal tract. 

Lactic Acid B cteri. The lactic acid bacteria are ubiquitous in nature from plant surfaces to gastrointestinal tracts of many animals. These gram-positive facultative anaerobes convert carbohydrates (qv) to lactic acid and are used extensively in the food industry, for example, for the production of yogurt, cheese, sour dough bread, etc. The sour aromatic flavor imparted upon fermentation appears to be a desirable food trait. In addition, certain species produce a variety of antibiotics. 

Synthesis. Histamine [51-45-6] 2-(4-imidazolyl)ethylarnine (1) is formed by decarboxylation of histidine by the enzyme L-histidine decarboxylase (Fig. 1). Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils. In humans mast cells are found in the loose connective tissue of all organs, especially around blood and lymphatic vessels and nerves. These cells are most abundant in the organs expressing allergic diseases the skin, respiratory tract, and gastrointestinal tract. 

The absorption of sulfonylureas from the upper gastrointestinal tract is faidy rapid and complete. The agents are transported in the blood as protein-bound complexes. As they are released from protein-binding sites, the free (unbound) form becomes available for diffusion into tissues and to sites of action. Specific receptors are present on pancreatic islet P-ceU surfaces which bind sulfonylureas with high affinity. Binding of sulfonylureas to these receptors appears to be coupled to an ATP-sensitive channel to stimulate insulin secretion. These agents may also potentiate insulin-stimulated glucose transport in adipose tissue and skeletal muscle. 

Only a small (ca 3%) fraction of ingested or inhaled manganese is absorbed, which occurs primarily by the intestines (209). Once absorbed, manganese is regulated by the Hver, where it is excreted into the bile and passes back into the intestine, where some reabsorption may occur (210). Manganese is elirninated almost exclusively (>95%) by the bile in the gastrointestinal tract. 

The largest use of endoscopic techniques is in the examination of the gastrointestinal tract. Upper intestinal endoscopy is the examination of the esophagus, stomach, and proximal duodenum. Colonoscopy is the examination of the colon, large intestine, and in some cases the distal parts of the small intestine. Cholangiopancreatography is the examination of the biUary tree and pancreas. 

M. O. Blackstone, Endoscopic Interpretation—Mormal and Pathologic Appearances of the Gastrointestinal Tract, Raven Press, New York, 1984. 

Two CCK receptor subtypes, CCK and CCKg are known. A related receptor, the gastrin receptor, has also been described. CCK receptors predominate in the gastrointestinal tract and pancreas and are also localized in discrete brain regions. CCKg receptors predominate in the brain. A 71623... 

Three tachykinin GPCRs, NK, NK, and NK, have been identified and cloned. AH are coupled to phosphatidjhnositol hydrolysis. The NK receptor is selective for substance P (SP) and is relatively abundant in the brain, spinal cord, and peripheral tissues. The NK receptor is selective for NKA and is present in the gastrointestinal tract, urinary bladder, and adrenal gland but is low or absent in the CNS. The NIC receptor is selective for NKB and is present in low amounts in the gastrointestinal tract and urinary bladder, but is abundant in some areas of the CNS, ie, the spinal dorsal bom, soUtary nucleus, and laminae IV and V of the cortex with moderate amounts in the interpeduncular nucleus. Mismatches in the distribution of the tachykinins and tachykinin receptors suggest the possibility of additional tachykinin receptor subtypes. 

Tannate Complexation. Certain dmgs, those that contain amine groups, complex readily with tannic acid. Such complexes release the dmg gradually and uniformly. The rate seems to be affected by the pH and the electrolytes present in the gastrointestinal tract. At lower pH, the dmg is released more quickly. Other complexing compounds have also been used. 

Poly(ethylene oxide) resins are safely used in numerous pharmaceutical and personal-care appHcations. Poly(ethylene oxide) resins show a low order toxicity in animal studies by all routes of exposure. Because of their high molecular weight, they are poorly adsorbed from the gastrointestinal tract and completely... 

Mesitylene. One of the principal derivatives of mesitylene is the stericaHy hindered phenol of the stmcture shown in Eigure 4. Its trade name is Ethanox 330 and it is produced by Albemarle Corporation (formerly Ethyl Corporation) (31). Ethanox 330 is an important noncoloring antioxidant and thermal stabiHzer for plastics, adhesives, mbber, and waxes (qv) (32,33) (see Antioxidants). The oral toxicity of Antioxidant 330 is extremely low (oral LD q in rats >15 g/kg) since its large size, C H gO, effectively eliminates absorption from the gastrointestinal tract. 

Normally, dietary tyramine is broken down in the gastrointestinal tract by MAO and is not absorbed. In the presence of MAOI, however, all of its potent sympathomimetic actions are seen. Other side effects of MAOI include excessive CNS stimulation, orthostatic hypotension, weight gain, and in rare cases hepatotoxicity. Because the monoamine oxidase inhibitors exhibit greater toxicity, yet no greater therapeutic response than other, newer agents, clinical use has been markedly curtailed. The primary use for MAOIs is in the treatment of atypical depressions, eg, those associated with increased appetite, phobic anxiety, hypersomnolence, and fatigues, but not melancholia (2). 

Sucralfate [54182-58-0] an aluminum salt of sucrose octasulfate, is used as an antacid and antiulcer medication (59). Bis- and tris-platinum complexes of sucrose show promise as antitumor agents (60). Sucrose monoesters are used in some pharmaceutical preparations (21). A sucrose polyester is under evaluation as a contrast agent for magnetic resonance imaging (mri) (61). Oral adrninistration of this substance opacifies the gastrointestinal tract and eliminates the need for purging prior to mri. 

The relative toxicities of thallium compounds depend on their solubHities and valence states. Soluble univalent thallium compounds, eg, thaHous sulfate, acetate, and carbonate, are especiaHy toxic. They are rapidly and completely absorbed from the gastrointestinal tract, skin peritoneal cavity, and sites of subcutaneous and intramuscular injection. Tb allium is also rapidly absorbed from the mucous membranes of the respiratory tract, mouth, and lungs foHowing inhalation of soluble thallium salts. Insoluble compounds, eg, thaHous sulfide and iodide, are poorly absorbed by any route and are less toxic. 

Swallowing. If it is sufficiently irritant or caustic, a swallowed material may cause local effects on the mouth, pharynx, esophagus, and stomach. Additionally, carcinogenic materials may induce tumor formation in the alimentary tract. Also, the gastrointestinal tract is an important route by which toxic materials are absorbed. The sites of absorption and factors regulating absorption have been reviewed (42,43). 

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