There are several useful routes of drug administration, but almost all require that the drug cross a biological membrane to reach its site of action.
Drugs cross membranes by passive diffusion or active transport.
This statement is somewhat simplified, but it provides a useful starting point. Passive diffusion requires a concentration gradient across the membrane. The vast majority of drugs gain access to their site of action by this method.
A drug tends to pass through membranes if it is uncharged.
Uncharged drugs are more lipid soluble than charged drugs. In addition, most drugs are weak acids or weak bases.
For a weak acid, when the pH is less than the pK, the protonated form (nonionized) predominates. When the pH is greater than the pK, the unprotonated (ionized) form predominates.
Weak acids are hydrogen ion donors; they are happy to give up a hydrogen ion and become charged. If you have trouble remembering whether they become charged or uncharged after donating their hydrogen ion, think of a strong acid, such as HCl. As you know, when you put HCl into water, it immediately turns into H+ and Cl–. Use this example to remember that weak acids donate a hydrogen ion and become charged.
Remember the pK? That is the equilibrium constant (of course, the p means we’ve taken the negative log of the equilibrium constant). When the pH is equal to the pK, there are equal amounts of weak acid in the ionized and nonionized forms. If we decrease the pH by adding more H+, we will drive the equilibrium for the weak acid more to the left, which is the nonionized (uncharged) form.
If we take away H+, making the pH higher, we will drive the equilibrium toward the right. This increases the concentration of the ionized form of the weak acid (Figure 3–1).
The relationship between the pH and the degree of ionization of a weak acid is presented. When the pH is higher than the pK for the acid, the charged form of the acid predominates.
For a weak base, when the pH is less than the pK, the ionized form (protonated) predominates. When the pH is greater than the pK, the unprotonated (nonionized) form predominates.
Weak bases are the opposite of weak acids. A weak base is a hydrogen ion acceptor. If a loose hydrogen ion seeks to join it, the base may accept it. If it accepts the hydrogen ion, then it becomes charged.
Adding H+ to lower the pH will drive the equilibrium to the right toward the protonated (charged) form. Removing H+ to raise the pH will drive the equilibrium to the left toward the uncharged form (unprotonated) of the base (Figure 3–2).
In this graph the effects of pH on the degree of ionization of both a weak acid and a weak base are presented.
To test your understanding of this, try out these questions. Answers appear at the bottom of the page.*
*Answers: (1) a weak base; (2) higher, because more weak acid will be ionized the more the pH exceeds the pK.
In the intestine (pH 8.0), which will be better absorbed, a weak acid (pK 6.8) or a weak base (pK 7.1)?
If we alkalinize the urine to a pH of 7.8, will a lower or higher percentage of a weak acid (pK 7.1) be ionized, compared with when the urine pH was 7.2?