Why do drugs that become charged in the acidic environment of the stomach absorb so well?
||It is a basic principle of pharmacology that acidic drugs tend to ionize in basic environments, and basic drugs tend to ionize in acidic environments. When a drug ionizes, it loses lipid solubility, hindering absorption considerably. If this is so, then why are Caffeine and Amphetamine bases absorbed so well when taken orally? Shouldn't they ionize in the the acidic environment of the digestive system like other alkaline drugs and produce no effect? What gives?|
||When an amine-bearing molecule enters the acidic environment of the stomach it does become protonated, and thus charged or ionized. The important thing to remember however, is that the protonation/deprotonation process is an equilibrium. This means that the protons are constantly hopping on and off the amine. In the acidic environment, there is a much greater chance to find the amine with an extra proton than without.|
The stomach has a pH of about 1-2. The ionization constant (pKa) of amphetamine is about 9.8. These are "log units", so each integer of difference corresponds to a ratio of 10. So 9.8 - 1 = 8.8, therefore there are 10^8:1 molecules of protonated:unprotonated (or charged:uncharged) amphetamine molecules in the stomach. Thus very few amphetamine molecules are going to absorb in the stomach. The intestines have a neutral or slightly basic pH (6.5-7). Thus when the amphetamine molecules reach the intestines (anywhere from 15-30 minutes after ingestion), they now reach a ratio of 9.8-7 = 2.8 => 10^2.8 or ~1000:1 charged:uncharged. While there are still not very many uncharged molecules around, any that are will be absorbed. This will drive the equilibrium to make more uncharged molecules, in order to restore the equilibrium. This will continue until all of the drug is absorbed. In combination with amphetamine's high potency, gives the apparent effect of high absorbtion/efficacy orally.
Caffeine is a slightly different story. While it is loaded with nitrogens, they are all involved in "aromatic" bonds. This makes it very difficult to protonate most of the nitrogens, as it would break the "aromaticity" (which makes the molecule less stable, and thus is unfavorable to do). In addition, this aromaticity actually leaves the molecule charged in places (though the net charge is 0). Yet even with these charges, caffeine has a pretty decent "partitioning coefficient" (logP, ratio of partitioning in octanol:water), which means it is actually somewhat lipophillic. Thus caffeine can be absorbed readily.
These are subtle points that aren't exactly obvious, but they are important to understanding how various drugs are absorbed.
[ Caffeine ]
[ Amphetamines ]
[ Pharmacology ]