|Pharmacology is concerned with drug effects (alterations in the normal
function of an existing biological process, such as changes in heart rate or blood
pressure and reduction of pain) and with drug actions (how and where a drug produces its
effects). Understanding drug actions and effects requires a strong background knowledge of
organic chemistry, physical chemistry, and biochemistry. Indeed, it might be argued that
pharmacology is one of the chemical sciences.
The chemistry of membrane structure and function is a fundamental aspect of pharmacology.
Membranes are the "skins" of the body cells; they hold the cell together,
maintaining shape and preventing loss of components of the cell to its environment. Some
of the important chemical and physiological functions of cells occur in or on the
membrane. Moreover, membranes control the absorption, distribution, and elimination
patterns of drugs. When administered orally, a drug molecule must pass through the
membrane lining of the gastrointestinal tract, cross the membranes that define the
circulatory system, pass through the capillary
membranes to the cells that make up an organ, and eventually reach the cell(s) where the
drug exerts its pharmacological action.
Phospholipids (Figure 1) are one chemical component of membranes. One end of these
remarkable molecules contains two highly lipophilic (fat-loving) alkyl chains, and the
other end contains a highly hydrophilic (water-loving) ionic group, typified (as shown) by
choline phosphate. The membrane consists of a highly ordered double layer of phospholipid
molecules, arranged as shown in Figure 2.
The spheres represent the ionic portion of the phospholipid molecule, and the
"tails" are the alkyl chains of the fatty acids. These alkyl chains hold the
membrane structure together by, inter alia, van der Waals interactions and hydrophobic
bonding phenomena. The central portion of the membrane also contains rigid, lipophilic
cholesterol molecules whose role is to give additional strength to the membrane matrix
through interactions with the alkyl chains. Thus, the inner and outer surfaces of the
membrane sandwich are covered with ions (positive and negative), rendering them extremely
hydrophilic; the center portion of the membrane is highly lipophilic. The membrane
structure also includes protein molecules (represented in Figure 2 by the irregularly
shaped masses); some of these proteins are enzymes. Other protein molecules extend
completely through the
membrane and can, by reversible changes in their conformation, open a channel through
which ions or small molecules can pass in and out of the cell.
A sodium ion-specific channel as a two-component structure is illustrated in Figure 3: a
"gating device" that opens and closes the channel because of conformational
changes of the protein and a "filter" portion that consists of carboxylate
anions, which attract the sodium cations and repel anions. There are other ion-specific
channels (for potassium, calcium, and chloride, among others) in the body's membranes.
The hydrophilic outer and inner surfaces of the membrane are coated with a stable crystal
lattice of water. Before a drug molecule can attach to some receptor area on the membrane,
or before a drug molecule can pass through the membrane for
transport in the body, it must disrupt and displace a portion of this coating of water.
Many endogenous substances in the body penetrate membrane barriers by some active
transport mechanism that involves a chemical reaction between the transported substance
and component(s) of the membrane, usually proteins. The sodium channel described
previously is an example of active transport.
Only a few drugs are structurally suitable for active transport; most of them are
absorbed, distributed, and excreted by passive diffusion across membranes, from a region
of high concentration to one of relatively lower concentration. Passive diffusion does not
involve the membrane channels. Instead, the drug molecule must "dissolve" in the
lipophilic membrane matrix, a process that requires the drug molecule to have some
lipophilic character. For optimum, efficient absorption and transport through the body, an
organic molecule must possess dual solubility-in lipid phases of the body and in water.
Solubility only in water or only in
nonpolar media (in the absence of an active transport mechanism) generally results in the
drug exhibiting few or no systemic effects because of poor membrane penetration.
Most drugs are either weak acids or weak bases; the development of a unit charge on the
molecule depends on its pKa and on the pH of its environment. Uncharged molecules, in
their maximally lipophilic states, diffuse across lipid membrane barriers much more
readily than the charged, hydrophilic form.
The fluids of the gastrointestinal tract have a wide pH range. From the strongly acidic
environment (pH 1-3) of the stomach, the pH rises to 5-7 in the upper small intestine and
thereafter slowly rises to a maximum of about 8 in the colon. The acidic environment of
the stomach favors absorption of weak acids such as aspirin (acetylsalicylic acid), whose
carboxyl group is maintained in the protonated, non-ionized form. As a part of the normal
digestive process, however, the stomach will empty its contents into the small intestine
before all of the aspirin can be absorbed.
Organic bases (e.g., alkaloids and amines) are in their protonated cationic forms in the
stomach, and absorption of the hydrophilic species across the stomach wall is negligible.
Ethanol, a neutral molecule, has excellent dual solubility characteristics
and is readily absorbed across the stomach and intestinal walls. In the higher pH
environment of the small intestine, a greater proportion of organic base molecules is
present in nonprotonated forms, and absorption of these lipophilic neutral species is
It might be concluded that absorption of weakly acidic molecules (which is facilitated by
the acidic environment of the stomach) does not occur from the relatively alkaline
intestine because of proton loss from the acidic moieties and formation of a hydrophilic
anion. However, most weakly acidic drugs (including aspirin) are efficiently absorbed
across the intestinal wall, even though the molecules are in the anionic state.
An explanation for this unexpected behavior is that the entire inner surface of the small
intestine is covered with villi: microscopic, hairlike, thin-walled structures that
contain many small blood vessels. There are large numbers of villi per square
inch of intestine and, as a result, the total surface area of the inner wall of the small
intestine is increased approximately 600-fold. The physiological function of villi is to
facilitate absorption of dietary components that have hydrophilic and lipophilic
properties that do not favor passive diffusion processes. Villi serve the same purpose in
the case of negatively charged drug molecules: The large surface area created by the villi
permits a large total absorption of hydrophilic molecules that have only an extremely poor
A drug receptor is a macromolecular component of the body whose chemical interaction with
a drug molecule results in a physiological change. Receptors are normal participants in
the body's biochemistry and physiology, and drug action represents an externally derived
alteration of this normal activity. It has long been recognized that some proteins are
drug receptors; other biopolymers (such as nucleic acids and even carbohydrates), which
are essential to the physiology of the cell, may also be drug receptors.
Drug molecules may squeeze in between adjacent base pairs of a DNA strand and bind there
(intercalation). The net result may be that the geometry of the helical structure is
slightly altered, and thereby the normal biochemical activity of the DNA is altered to
produce an observable pharmacological effect. Some receptors (e.g., for steroids) are
soluble proteins located in the cytoplasm of the cells. Lipophilic steroid molecules
diffuse through the cell membrane and interact with these receptors. Subsequently, this
steroid-protein complex will migrate into the nucleus of the cell and interact with yet
another receptor macromolecule, and the resulting complex may then participate in the
biochemistry of protein synthesis.
There are two kinds of membrane-bound protein-derived receptors: ion channels and
G-protein-linked receptors. One kind of receptor for the neurotransmitter substance
acetylcholine (and for some acetylcholine-like drugs) is a sodium channel.
Acetylcholine binds reversibly to this channel protein and induces a conformational change
such that the channel opens and ions flow across the membrane, leading to the observed
pharmacological response, in this instance, activation of nerve fibers. Certain other
drugs interact with these sodium channels and prevent their opening, thus blocking the
activity of the nerve.
G-protein-linked receptors are a part of a communication system by which a drug-receptor
interaction on the outer surface of a membrane can affect the catalytic activity of an
enzyme on the inner surface. As illustrated in Figure 4, a drug molecule (represented by
the triangle) interacts with the receptor on the membrane outer surface, and a resulting
change in conformation of the receptor protein induces a change in the conformation of a
transducer ("G") protein inside the membrane.
This altered G protein migrates in the plane of the membrane to the catalytic area of the
enzyme, which is in an inactive, noncatalytic state. Interaction of the altered G protein
with the enzyme causes the enzyme catalytic surface to become activated.
The enzyme now will accept substrate molecules and will generate products essential to the
cell's biochemistry. Certain receptors for the neurotransmitters norepinephrine, dopamine,
and acetylcholine are of this type.
The nature of the interaction between a drug molecule and its receptor adds several more
degrees of complexity to understanding the chemical mechanisms of drug action. Drug
molecules attach (frequently in a reversible manner) to their
receptors, not at a single site or by a single type of interaction, but rather at several
sites on the drug molecule interacting in a variety of chemical modes with a number of
complementary sites on the receptor molecule. Interactions that can be involved
include relatively strong forces such as covalent bonding (comparatively rare), ion-ion
interactions, and hydrogen bonding, and/or much weaker forces such as ion-dipole
interactions, dipole-dipole interactions, charge-transfer complexation, van der Waals
interactions, and hydrophobic bonding. The weaker attractive forces are frequently of
prime importance in drug receptor interactions; although individually weak, in the
aggregate they provide a suitably strong attachment of the drug to the receptor.
As a corollary to considerations of interactive forces between drug and receptor, the
three-dimensional geometry (stereochemistry) of drug-receptor interactions is also
important. Nature is asymmetric. Most (possibly all) of the receptor sites
in the body recognize and discriminate between stereo- and geometric isomers of drug
The chemist's rational design of new drug molecules and the pharmacologist's pursuit of
understanding of the actions and effects of these molecules in a living system must
consider the preceding chemical concepts and parameters. All of them act in concert
ultimately to determine whether an organic molecule will produce a pharmacological effect,
what that effect will be, where in the body the effect will occur, and how long it will