Pharmacology
Summary
For a drug to permeate a membrane, it must first be in solution. This doesn't necessitate the administration of the drug in a solution form but indicates the need for solubilization to facilitate absorption. The body's systemic circulation acts as a sink to maintain concentration gradient, effectively pumping the absorbed drug away from the absorption site. This mechanism maintains a low concentration at the absorption site, thereby encouraging further drug absorption down the concentration gradient. After oral administration, the stomach serves as the initial site for absorption. Due to the stomach's acidic pH, acids are better absorbed here than bases. Acids remain primarily in their unionized form in this environment, enabling easier permeation through cell membranes. However, all drug types, whether acidic, basic, or neutral, are most effectively absorbed in the small intestine to be a more effective absorption site than the stomach. This is attributed to the small intestine's larger surface area and greater perfusion, which together facilitate a higher rate of drug absorption. Moreover, the permeability of intestinal membranes surpasses that of the stomach's, aiding both acidic and basic drugs.
Several factors can impact drug absorption in the GI system. Consuming certain foods, especially those high in fat, as well as specific drugs like some antidepressants, opioids, and antihypertensives, can decelerate gastric emptying, leading to a reduced drug absorption rate. Factors such as the decreasing surface area from the duodenum to the rectum and tighter epithelial spaces in the colon further diminish drug absorption. The molecular weight of a drug also plays a role--drugs weighing over 350 g/mol have diminished permeability. Yet, certain transport mechanisms, like facilitated transport using uptake transporters (PEPT1, OATP3), can enhance absorption for drugs like amoxicillin and gabapentin which might otherwise face poor oral absorption. Conversely, efflux transporters, like Pgp, can reduce systemic absorption by transporting drug molecules back into the intestinal lumen. A significant factor in drug absorption is the transit time through the intestines, which at ~4 hours, may be insufficient for some drugs. The oral bioavailability (F) equation, FA x FG x FH, is useful in understanding the fraction of drug that successfully navigates each absorption step. Some drugs face the first-pass effect following oral absorption, being metabolized as they pass through intestinal tissues and into the liver. Drugs with poor oral absorption or those subjected to extensive metabolism might be more suitably administered parenterally (e.g IV).
Lesson Outline
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FAQs
Oral drug absorption relies on several key factors including the drug's solubility, the presence of acids or bases, the composition of the stomach and intestines, the presence of certain foods or other drugs, and the overall rate of gastric emptying. Furthermore, the permeability of intestinal membranes, the release of drugs into systemic circulation and the surface area of the absorption site all play significant roles in oral drug absorption.
While the stomach is the first potential site for drug absorption, the small intestine is typically more effective at absorbing drugs. This is due to the small intestine's larger surface area and greater perfusion, allowing for more ample space and blood flow for drug absorption. Additionally, the permeability of intestinal membranes is greater than the stomach, which assists both acidic and basic drugs in absorption.
Food, especially high-fat food, can significantly impact oral drug absorption by slowing down the rate of gastric emptying. As a result, the rate of drug absorption decreases. Some drugs, such as certain antidepressants, opioids, and antihypertensives, can also slow gastric emptying and thereby affect oral drug absorption.
The molecular weight of a drug is a major determinant of its intestinal absorption. Molecules with a molecular weight greater than 350 g/mol tend to have decreased permeability, and subsequently, reduced intestinal absorption. In addition, specific transporters can assist or hinder absorption, playing a significant role in the ultimate bioavailability of an orally administered drug.
Oral bioavailability (F) is the fraction of a drug dose that reaches systemic circulation following oral administration. It can be determined by factors such as the absorption of the drug (FA), the fraction that reaches the liver (FG), and the fraction that goes through first-pass metabolism (FH). Drugs with poor oral absorption or extensive first-pass metabolism may have poor oral bioavailability, in which case parenteral administration could be more suitable.
