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Gastric Juice

pH = 1.4

HA ^-7 A"+ H+

nonionized ionized

FIGURE 1-2 Influence of pH on the partitioning of a weak acid (pKa = 4.4) between plasma (pH = 7.4) and gastric juice (pH = 1.4) separated by a lipid barrier. The gastric mucosal membrane behaves as a lipid barrier permeable only to the lipid-soluble, nonionized form of the acid. The ratio of nonionized to ionized drug at each pH is readily calculated from the Henderson-Hasselbalch equation that relates the pH of the medium and the drug's dissociation constant (p^Q) to the ratio of the protonated (HA) and unprotonated (A-) forms. The same principles apply to drugs that are weak bases (BH+ ^ B + H+).

drugs given in solid form, the rate of dissolution may be the limiting factor in their absorption. Since most drug absorption from the GI tract occurs by passive diffusion, absorption is favored when the drug is in the nonionized and more lipophilic form. The epithelium of the stomach is lined with a thick mucous layer, and its surface area is small; by contrast, the villi of the upper intestine provide an extremely large surface area (~200 m2). Accordingly, the rate of absorption of a drug from the intestine will be greater than that from the stomach even if the drug is predominantly ionized in the intestine and largely nonionized in the stomach. Thus, any factor that accelerates gastric emptying will be likely to increase the rate of drug absorption, whereas any factor that delays gastric emptying is expected to have the opposite effect. Gastric emptying is highly variable and influenced by numerous factors.

Drugs that are destroyed by gastric secretions or that cause gastric irritation sometimes are administered in dosage forms with an enteric coating that prevents dissolution in the acidic gastric contents. The use of enteric coatings is helpful for drugs such as aspirin that can cause significant gastric irritation.

Controlled-Release Preparations

A slow rate of dissolution of a drug in GI fluids is the basis for controlled-release, extended-release, sustained-release, and prolonged-action preparations that are designed to produce slow, uniform absorption of the drug for 8 hours or longer. Such preparations are offered for medications in all major drug categories. Potential advantages are reduction in the frequency of administration of the drug as compared with conventional dosage forms (possibly with improved compliance by the patient), maintenance of a therapeutic effect overnight, and decreased incidence and/or intensity of both undesired effects (by elimination of the peaks in drug concentration) and nontherapeutic blood levels of the drug (by elimination of troughs in concentration) that occur after administration of immediate-release dosage forms. Controlled-release dosage forms, while more expensive, are most appropriate for drugs with short t/2 (<4 hours) where patient non-compliance becomes a determinant of therapeutic failure.

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