Other weak electrolytes are bases, which ionize by accepting a proton. In the discussion of bond formation we pointed out that certain atoms like oxygen, sulfur and nitrogen can donate an electron pair to the naked proton of the hydrogen ion to form a coordinate covalent bond and retain the positive charge associated with the hydrogen ion. Since so many drugs are organic compounds containing nitrogen, this type of coordinate covalent bond formation plays an
Figure 4–6. Ionization of amines by coordinate covalent bond formation.
important role in the ionization of drugs. Figure 4–6 shows this ionization for three different drugs. Norepinephrine, which has a nitrogen attached to only one carbon, is an example of a primary amine; epinephrine, with its nitrogen attached to two carbon atoms, is an example of a secondary amine; and cocaine, with three carbons attached to the
nitrogen, is an example of a tertiary amine. All drugs which have one of these structures are weak bases and have the potential of becoming positively charged ions (cations) by the mechanism illustrated earlier for ammonia (see p. 41).
The degree to which a weak electrolyte will ionize is an inherent property of the molecule and is determined by the electron-attracting and electron-repelling properties of its constituent atoms. This tendency to ionize is a constant for a given weak electrolyte when measured in pure water at a given temperature and is expressed as the ionization constant. Moreover, the fraction that is ionized is always in equilibrium with the fraction that is unionized. Thus:
and
where HA symbolizes the undissociated acid and B, the unionized base.
Since such equilibria exist for the ionization of weak electrolytes, the law of mass action is applicable to them, and it is possible to change the fraction of ionized or unionized material present in solution by changing the hydrogen ion concentration. You will recall that the law of mass action states: when a chemical reaction reaches equilibrium at a constant temperature, the product of the active masses on one side of a chemical equation, when divided by the product of the active masses on the other side of the equation, is a constant regardless of the amount of each substance present at the beginning of the action. Thus, for an acid:
where [] stands for concentration. For a base:
If we add hydrogen ions to a solution of a weak acid, the concentration of the ionized portion, [A−], in the numerator must decrease and the concentration of the undissociated acid, [HA], in the denominator must increase in order to keep the relationship constant.
The converse would be true for the addition of hydrogen ions to a solution of a weak base. In both cases, an excess of hydrogen ions drives the ionization reaction of the weak electrolytes to the side of the equation which does not have free hydrogen ions.
Therefore, an excess of hydrogen ions in a solution of a weak acid tends to decrease the extent of ionization of the weak acid, and an excess of hydrogen ions in a solution of a weak base tends to increase the extent of ionization of the weak base.
It is much simpler to use the convention pH to express the hydrogen ion concentration of a solution. The term pH refers to the negative logarithm of the hydrogen ion concentration in molar units; i.e. the logarithm of the reciprocal of the hydrogen ion concentration. Therefore, the higher the pH of a solution, the lower the hydrogen ion concentration, and vice versa. From the relationships between the ionization of weak
electrolytes and pH, we can now draw the following generalizations: (1) the degree of ionization of a weak electrolyte is dependent on its ionization constant and on the pH of the aqueous medium in which it is dissolved; (2) the degree of ionization of a weak acid tends to be greater at higher pHs and lower at lower pHs; and (3) the degree of ionization of a weak base tends to be greater at lower pHs and lower at higher pHs.
The degree of ionization of weak acids and bases has a great deal of significance when we consider their diffusion across biologic barriers. At the pHs of biologic fluids, weak electrolytes are present partly in the ionized form and partly in the unionized form. The ionized groups of the weak electrolytes interact strongly with water, which makes them more water soluble and less fat soluble than the unionized molecule. If we consider diffusion only in terms of a solute’s ability to dissolve in the membrane lipid, then the ionized form of a weak electrolyte would diffuse across the membrane much more slowly than the more lipid-soluble, unionized form. However, in the case of ions, an additional barrier to passage through the membrane may arise from their interaction with negatively or positively charged groups at the protein surfaces. These two factors—the greater electrical resistance to passage and the much lower lipid solubility—combine to make the rate of penetration of the ionized form so slow that, for all practical purposes, the rate of diffusion of a weak acid or base may be entirely attributed to the concentration gradient of the unionized fraction itself. For weak electrolytes, then, we must now add another factor to the general principles governing their passive diffusion across cell membranes:
The rate of passive diffusion of weak electrolytes is dependent on their degree of ionization: the greater the fraction that is nonionized, the greater the rate of diffusion, since the rate of diffusion is mainly determined by that of the nonionized portion.
The stability of the pH of most fluids within the body is vigorously maintained at levels near neutrality by the body’s regulatory mechanisms. But the fluids within the stomach are characteristically at a low pH, whereas those within the intestines vary from a relatively acid pH near the stomach to more neutral values farther from it. The pH of the urine as it is formed in the kidney can be either lower or higher than 7 under various normal conditions. In certain abnormal states, even the pH of plasma or other body fluids may be above or below their normal range.
It can be readily appreciated, then, that the degree of ionization of a given compound may vary considerably at different biologic barriers or at a particular barrier under different conditions of pH. It follows from the relationship between rate of diffusion and degree of ionization that the rate of penetration of a weak electrolyte across a particular barrier also depends on the pH of its solution at the barrier site. This is well illustrated by the results obtained in studies of the effect of pH on the absorption of the weak base strychnine from the stomach of animals (Table 4–2). At pH 8, more than half of strychnine exists in solution in the more lipid-soluble, unionized form. Consequently, when strychnine was administered in alkaline medium, it rapidly crossed the stomach wall as measured by the fact that the animals died within a relatively short time. In contrast, when an equivalent amount of strychnine was administered in solution at pH 3, the concentration gradient of the unionized form was markedly