|MadSci Network: Medicine|
1. In the stomach, which generally has a pH of 1-1.5, the drug must dissolve to be absorbed. This is generally not a problem (whether it dissolves or not), because little drug absorption usually occurs in the stomach - the total surface area of the stomach is much less than that of the small intestine (where most drug absorption occurs). Sometimes however, in people taking a lot of antacid or in the elderly, the pH is higher than normal (pH4-5) which can cause problems. A few drugs need to be activated by acid exposure. If the pH of the stomach is high, then the drug is not activated. If it's later absorbed in the small intestine, it will be absorbed an inactive form. This happens relatively rarely, however.
2. Drug absorption is by "passive non-ionic diffusion" in the small intestine. Passive means no energy is involved. The higher concentration of drug in the intestine drives absorption across the intestinal membrane. Non-ionic means only the un-ionized or neutral form of the drug can pass through the membrane. The membrane is primarily lipid, so charged molecules do not readily pass through it. Thus, the only form that can be absorbed is the neutral or non-ionized form. If the pKa of the drug is such that the pH of the intestine makes it ionized, then it will be poorly absorbed. If the pKa of the drug is such that some portion of it is in the neutral form, then it will diffuse through the membrane leaving behind any ionized form in the intestine. There is always (ALWAYS) an ongoing rapid equilibrium between the dissolved forms of the drug, between the ionized and nonionized forms. Once the non-ionized form of the drug leaves the compartment it is in (the intestine) then the two forms are no longer in equilibrium. Immediately some of the ionized form with become non-ionized to re-establish the equilibrium. Then more non-ionized form is present and can be absorbed, thus putting the two forms out of equilibrium, so some more will become non-ionized and so on in a continual cycle. The trick is that the pKa and pH must be sufficiently close so that some fraction is non-ionized to start with. Usually 0.1% is sufficient.
3. All that said, pH is not a major determinant of drug absorption. Because even 0.01-0.1% of the non-ionized form is sufficient to allow absorption of some drug, thus causing more to become non-ionized and subsequently be absorbed, the passage of the drug through the intestine is usually slow enough to allow complete absorption.
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