The efficacy of certain drugs is affected by pH. Many drugs are absorbed into the blood through cells lining the stomach or the small intestine by direct diffusion across the plasma membrane. Since the interior of the plasma membrane is hydrophobic, uncharged molecules cross the membrane faster than charged (ionized) molecules. If a drug contains an ionizable group, its absorption will be dependent on the pH. Let us now apply your understanding of acid/base chemistry and solubility to explain the pH dependence of codeine absorption. Codeine, shown below in its uncharged form, is an opiate drug used for pain and cough relief. The pKa of codeine is 8.2.

Question

The efficacy of certain drugs is affected by pH. Many drugs are absorbed into the blood through cells lining the stomach or the small intestine by direct diffusion across the plasma membrane. Since the interior of the plasma membrane is hydrophobic, uncharged molecules cross the membrane faster than charged (ionized) molecules. If a drug contains an ionizable group, its absorption will be dependent on the pH. Let us now apply your understanding of acid/base chemistry and solubility to explain the pH dependence of codeine absorption. Codeine, shown below in its uncharged form, is an opiate drug used for pain and cough relief. The pKa of codeine is 8.2.

a. In the structure above, is codeine depicted in the HA or A- form?

b. On the diagram above, draw the charged form of codeine.

c. The pH in the stomach is approximately 2.0 and in the intestine approximately 8. Calculate what proportion of codeine will be in its neutral form in the stomach and in the intestine (as ratio of neutral to charged species). Fill in the table below with your answers, and show your work.

neutral/charged codeine

stomach

intestine

d. Is codeine absorbed more efficiently in the stomach or in the intestine?

Answer 1

a. In the structure above, codeine is depicted in the HA form, which represents its uncharged form.

b. To draw the charged form of codeine, we need to consider its ionization at a specific pH. At low pH (acidic conditions), codeine will be protonated, resulting in the A- form. So, we can draw the charged form of codeine by adding a positive charge to the nitrogen atom in the ring structure. The structure will look like this:

```
H
|
H - C - O - C - CH3
| \
CH3 N(+) - CH3
|
H
```

c. To calculate the proportion of codeine in its neutral form in the stomach and intestine, we need to compare the pH of each compartment to the pKa of codeine.

For the stomach (pH = 2):

pH - pKa = 2 - 8.2 = -6.2

Since the difference (pH - pKa) is negative, we can use the Henderson-Hasselbalch equation to calculate the proportion of codeine in its neutral form:

proportion of neutral codeine in stomach = 10^(pH - pKa) = 10^(-6.2) = 0.000001 (or 1 x 10^(-6))

So, in the stomach, the proportion of neutral codeine is very low compared to the charged form.

For the intestine (pH = 8):

pH - pKa = 8 - 8.2 = -0.2

Since the difference (pH - pKa) is still negative but very close to zero, the proportion of codeine in its neutral form in the intestine will be higher than in the stomach but still quite low.

d. Since codeine is absorbed more efficiently in its uncharged (neutral) form, it will be absorbed more efficiently in the stomach where the proportion of neutral codeine is lower than in the intestine.