The biochemical systems encountered by a drug molecule are extremely complex. Therefore, it should not be surprising that the factors affecting the drug's interactions and contributing to its final effect are also manyfold. The factors may be divided into three categories:
1. Physicochemical properties such as solubility, partition coefficients, and ionization.
2. Chemical structure parameters such as resonance, inductive effect, oxidation potentials, types of bonding, and isosterism.
3. Spatial considerations such as molecular dimensions, interatomic distances, and stereochemistry.
1.2.1. Physicochemical Properties
The physicochemical properties considered in this discussion are important because they all relate to the transport of the drug molecule to its site of action, more than likely a receptor with which the drug will interact in a given tissue or in an invading microorganism. Figure 1-1 represents a simplified distribution chart of a bioactive substance in the body.
A drug given orally or parenterally must traverse several semipermeable membranes before reaching its destination. The efficiency of the passage depends on the solubility characteristics of the drug, that is, its behavior in aqueous solution and toward lipids. Also, note that in each compartment the molecule is subject to various factors tending to decrease the concentration of the active form. Thus the drug may be constantly excreted either directly or following biochemical inactivation. In addition, if the drug is bound in a stored but inactive form, such as to plasma proteins, there tends to be a decrease in its effectiveness. Since it is only the unbound free drug that produces the desired pharmacologic actions, it may be possible to compensate for this phenomenon by increasing the dose.
We are concerned with solubility in polar solvents such as water and in nonpolar solvents such as lipids. More specifically we are interested in a drug's partition coefficient, which is the relative solubility between these two phases. Such a coefficient is determined by dissolving the substance in an aqueous solution and equilibrating it by agitation with an organic solvent.1 The ratio of the concentration of the drug in the two phases is the partition coefficient. Any ratio greater than 0.01 indicates appreciable lipid solubility.
Since most drugs are not structurally similar to normal cellular components, they are not likely to be transported across the membranes by "active transport" mechanisms. Rather, their rate of passage through the lipoprotein membranes is mainly a passive process determined by their degree of lipid solubility, or partition coefficient.
1 Chloroform, olive oil, or 1 -octanol to simulate the lipid phase of a biological system.
Solubility is important to bioactivity. Many groups of drugs, especially those with closely related structures, exhibit a direct relationship to solubility (i.e., increased lipid solubility exhibits higher bioactivity). This correlation is true in general anesthetics, local anesthetics, certain antibacterial agents, antiviral agents, and others. Of course, solubility factors are closely related to drug absorption. The degree of absorption is one important determinant of the intensity of the drug's action.
In addition to lipid solubility, another physicochemical property of molecules, which affects solubility directly, is the degree of the drug's electrolytic nature. All chemical compounds can be classified by their electrical conductivity behavior in aqueous solution. When dissolved, inorganic salts will completely dissociate into ions (charged particles). Positively charged ions, which are electron deficient with respect to the neutral atom, are called cations, whereas negatively charged ions (carrying excess electrons) are called anions. Thus sodium chloride will dissociate, or ionize, yielding sodium ions and chloride ions.
Substances that ionize completely in solution are considered to be strong electrolytes. Compounds that are completely undissociated, but that are still very water soluble, are termed nonelectrolytes. They do not ordinarily increase the electrical conductivity of the solution. Examples of nonelectrolytes are such polar organic compounds as sugars, low-molecular-weight alcohols, and urea. A majority of drugs are in a third category, weak electrolytes. These substances are only partially ionized in solution. They exist as a mixture of ionized and un-ionized molecular forms. The un-ionized molecular species is the more lipid-soluble form. The ionized portion of such a drug molecule usually has a much lower, often negligible, lipid solubility. Therefore, its passage through membranes frequently approaches insignificant levels. This fact has direct bearing on a drug's capacity for absorption, and therefore activity.
When a drug is a weak acid or a weak base, we find that its lipid solubility is greatly affected by the pH of its environment and by its degree of dissociation, expressed as pKa. The fraction of the total drug concentration that is in the molecular and ionic forms is indicated by the dissociation constant Ka. Equations 1.2 and 1.3 illustrate the interaction of weak acids and weak bases with water, which results in dissociation. A and B represent acids and bases, respectively.
Note that the initial reaction for both substances is shown as a protolytic reaction (pro-tonation) between an acid species and water. The water is present in such large excess that the proton transfer has only a negligible effect on its total concentration. Thus water can be eliminated from the equation without significant error. Our simplified equation for a weak acid now becomes
Applying the law of mass action we obtain the general relationship:
The equation can be rearranged into the more useful Henderson-Hasselbach equation:
where Cu and Q represent the concentrations of un-ionized and ionized forms of the drug, respectively. The corresponding relationships for weak bases are:
Weak acids have a higher pKa than stronger ones. Thus, an acid with a pKa of 5 is 100 times weaker than an acid whose pKa is 3; conversely weaker bases have lower pKa values.
It is not surprising that the bioactivity of many weak acids and bases is directly related to their degree of ionization, which in turn is greatly affected by the pH of the medium in which the drug finds itself.
Since many of the drugs we encounter are weak acids or bases, an understanding of their solubility characteristics is important. Because the ionic form is the more water-soluble chemical species and the pH of the solvent environment determines the degree of ionization achieved, it becomes possible, for example, to formulate liquid pharmaceutical products such as injectables, syrups, and elixirs of drugs that would ordinarily be poorly soluble.
Low-molecular-weight carboxylic acids such as acetic acid and propionic are totally water soluble. However, as they go beyond a five-carbon content their solubility decreases rapidly. An interesting example of how advantage can be taken of these factors to form a water-soluble parenteral dosage form of a drug that is highly insoluble is the steroid methylprednisolone (structure I).
C—CH -O-R Methylprednisolone chu o a
Methylprednisolone Sodium Succinate
Reacting the drug with succinic anhydride results in the hemisuccinate derivative, obviously now a large 25-carbon carboxylic acid. Its solubility is less than 1 mg/ml. However, by the simple expedient of neutralizing the acidic function and forming the ionic sodium salt the solubility is increased to over 200 mg/ml. This is more than adequate to formulate injectable products of considerable concentrations.
Let us apply these concepts and attempt to make some predictions. The very useful, widely used drug aspirin is a weak acid with a pKa of 3.5. It is usually taken orally. The pH of gastric juice in the stomach is about 1; in the small intestine it is about 6. From which area would the majority of this drug be absorbed into the bloodstream? By applying Equation 1.6 we find that the drug is almost completely un-ionized in the gastric juice.
Since we have already seen that the molecular form of a drug is the lipid-soluble species, we would expect it to be readily absorbed in the stomach, which has lipoprotein membranes in its lining. This is actually the case for many weakly acidic drugs. The converse argument, of course, would apply to weakly basic drugs. We would expect their absorption from the stomach to be poor.
Consider the three barbituric acid derivatives thiopental, secobarbital, and barbital with respective pKa of 7.6, 7.9, and 7.8. These drugs are very weak acids. On the basis of their ionization constants we would expect very little difference in their absorption rates from the stomach, yet the drugs are absorbed at very different rates. The reason becomes apparent when the partition coefficients between chloroform and water are considered. Thiopental's value is over 100, whereas the values of secobarbital and barbital are 23 and 0.7, respectively. Now which would one predict to be the least rapidly absorbed and which the most? By considering only one physicochemical parameter and excluding others, erroneous conclusions can result. Figure 1-2 illustrates a hypothetical relationship of biological activity as a function of pH only.
Studies on the distribution of drugs between the intestine and plasma, between kidney tubules and urine, and between plasma and other body compartments suggests that the important general conclusion that only lipid-soluble, undissociated forms of a drug passes through membranes readily. Ionized species usually cannot pass unless a mediated transport system is present for a specific compound (or a close congener) in a given membrane, which is a rare occurrence.
The previous discussion may be an oversimplification since there are some anomalies that are more difficult to explain. For example, almost two thirds of a dose of salicylic acid (pKa 3) is absorbed from the rat stomach in 1 hour at pH 1, as might be expected. However, if the pH is raised to 8, at which point the acid is completely ionized, over one-tenth of the dose is still absorbed. Another possibility that should be kept in mind is that the un-ionized form of some weak electrolyte drugs may have intrinsically poor lipid solubility because of
Bask Consideration of Drug Activity
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