This volume discusses
pharmacokinetics and pharmacodynamics. Chapters 1 through 4 discuss aspects of
pharmacokinetics. Chapters 5 through 8 discuss aspects of pharmacodynamics.
Pharmacokinetics is defined
as the study of the quantitative relationship between administered doses of a
drug and the observed plasma/blood or tissue concentrations. The field of
pharmacokinetics is concerned with drug absorption, distribution, biotransformation,
and excretion or elimination. These processes, in addition to the dose,
determine the concentration of drug at the effector or active site and,
therefore, the intensity and duration of drug effect.
The practice of
pharmacokinetics has been used in clinical medicine for many years in order to
optimize the efficacy of medications administered to treat disease. Through a
consideration of pharmacokinetics, physicians are able to determine the drug of
choice, dose, route, frequency of administration, and duration of therapy in
order to achieve a specific therapeutic objective. In the same manner, study of
the pharmacokinetics of abused drugs aids investigators in addiction medicine,
forensic toxicology, and clinical pharmacology in understanding why particular
drugs are abused, factors that affect their potential for abuse, how their use
can be detected and monitored over time, and also provides a rational,
scientific basis for treatment therapies.
Pharmacodynamics is the
study of the physiological and behavioral mechanisms by which a drug exerts its
effects in living organisms. An effect is initiated by the drug binding to
receptor sites in a cell’s membrane, setting in motion a series of molecular
and cellular reactions culminating in some physiological (e.g., opioid-induced
analgesia) or behavioral (e.g., alcohol-induced impairment) effect. Drugs
typically have multiple effects. For example, a benzodiazepine will produce its
primary anxiolytic effect, but may also cause side effects of sedation and
impaired performance.
The question of the
behavioral effects of abused drugs has been the focus of research by behavioral
pharmacologists for many decades. Because of the widespread use of psychoactive
drugs throughout society, employers have become increasingly concerned about
drugs in the workplace and the potential for impaired job performance and
onsite drug-related accidents. There are now computerized tests that employers
can use to aid in the detection of impaired employees. Some drugs of abuse also
produce characteristic effects on the visual system, and for this reason,
devices that detect eye movement and function are also being tested for their
ability to predict drug ingestion and potential impairment in the workplace.
Knowledge of both
pharmacokinetics and pharmacodynamics is central to an understanding of drug
abuse and its treatment.
INTRODUCTION
Pharmacokinetics is defined
as the study of the quantitative relationship between administered doses of a
drug and the observed plasma/blood or tissue concentrations.1 The
pharmacokinetic model is a mathematical description of this relationship.
Models provide estimates of certain parameters, such as elimination half-life,
which provide information about basic drug properties. The models may be used
to predict concentration vs. time profiles for different dosing patterns.
The field of pharmacokinetics
is concerned with drug absorption, distribution, biotransformation, and
excretion or elimination. These processes, in addition to the dose, determine
the concentration of drug at the effector or active site and, therefore, the
intensity and duration of drug effect. The practice of pharmacokinetics has
been used in clinical medicine for many years in order to optimize the efficacy
of medications administered to treat disease. Through a consideration of
pharmacokinetics, physicians are able to determine the drug of choice, dose,
route, frequency of administration, and duration of therapy in order to achieve
a specific therapeutic objective. In the same manner, study of the pharmacokinetics
of abused drugs aids investigators in addiction medicine, forensic toxicology,
and clinical pharmacology in understanding why particular drugs are abused,
factors that affect their potential for abuse, and how their use can be
detected and monitored over time, and also provides a rational, scientific basis
for treatment therapies.
TRANSFER ACROSS BIOLOGICAL
MEMBRANES
The processes of absorption,
distribution, biotransformation, and elimination of a particular substance
involve the transfer or movement of a drug across biological membranes.
Therefore, it is important to understand those properties of cell membranes and
the intrinsic properties of drugs that affect movement. Although drugs may gain
entry into the body by passage through a single layer of cells, such as the
intestinal epithelium, or through multiple layers of cells, such as the skin,
the blood cell membrane is a common barrier to all drug entry and therefore is
the most appropriate membrane for general discussion of cellular membrane structure.
The cellular blood membrane consists of a phospholipid bilayer of 7- to 9-nm
thickness with hydrocarbon chains oriented inward and polar head groups
oriented outward. Interspersed between the lipid bilayer are proteins, which
may span the entire width of the membrane permitting the formation of aqueous
pores.2 These proteins act as receptors in chemical and electrical signaling
pathways and also as specific targets for drug actions.3 The lipids in the cell
membrane may move laterally, conferring fluidity at physiological temperatures
and relative impermeability to highly polar molecules. The fluidity of plasma
membranes is largely determined by the relative abundance of unsaturated fatty
acids. Between cell membranes are pores that may permit bulk flow of
sub-stances. This is considered to be the main mechanism by which drugs cross
the capillary endo-thelial membranes, except in the central nervous system
(CNS), which possesses tight junctions that limit intercellular diffusion.3
Physicochemical properties
of a drug also affect its movement across cell membranes. These include its
molecular size and shape, solubility, degree of ionization, and relative lipid
solubility of its ionized and non-ionized forms. Another factor to consider is
the extent of protein binding to plasma and tissue components. Although such
binding is reversible and usually rapid, only the free unbound form is
considered capable of passing through biological membranes.
Drugs cross cell membranes
through passive and active or specialized processes. Passive movement across
biological membranes is the dominant process in the absorption and distribution
of drugs. In passive transfer, hydrophobic molecules cross the cell membrane by
simple diffusion along a concentration gradient. In this process there is no
expenditure of cellular energy. The magnitude of drug transfer in this manner
is dependent on the magnitude of the concentration gradient across the membrane
and the lipid water partition coefficient. Once steady state has been reached,
the concentration of free (unbound) drug will be the same on both sides of the
membrane. The exception to this situation is if the drug is capable of
ionization under physiological conditions. In this case, concentrations on
either side of the cell membrane will be influenced by pH differences across the
membrane. Small hydrophilic molecules are thought to cross cell membranes
through the aqueous pores.4 Generally, only unionized forms of a drug cross
biological membranes due to their relatively high lipid solubility. The
movement of ionized forms is dependent on the pKa of the drug and the pH
gradient. The partitioning of weak acids and bases across pH gradients may be
predicted by the Henderson Hasselbalch equation. For example, an orally
ingested weakly acidic drug may be largely unionized in the acidic environs of
the stomach but ionized to some degree at the neutral pH of the plasma. The pH
gradient and difference in the proportions of ionized/non-ionized forms of the
drug promote the diffusion of the weak acid through the lipid barrier of the
stomach into the plasma.
Water moves across cell
membranes either by the simple diffusion described above or as the result of
osmotic differences across membranes. In the latter case, when water moves in
bulk through aqueous pores in cellular membranes due to osmotic forces, any
molecule that is small enough to pass through the pores will also be
transferred. This movement of solutes is called filtration. Cell membranes
throughout the body possess pores of different sizes; for example, the pores in
the kidney glomerulus are typically 70 nm, but the channels in most cells are
<4 nm.2
The movement of some
compounds across membranes cannot be explained by simple diffusion or
filtration. These are usually high-molecular-weight or very lipid soluble
substances. Therefore, specialized processes have been postulated to account
for the movement. Active processes typically involve the expenditure of
cellular energy to move molecules across biological membranes. Characteristics
of active transport include selectivity, competitive inhibition, storability,
and movement across an electrochemical or concentration gradient. The drug
complexes with a macromolecular carrier on one side of the membrane, traverses
the membrane, and is released on the other side. The carrier then returns to
the original surface. Active transport processes are important in the
elimination of xenobiotic. They are involved in the movement of drugs in
hepatocytes, renal tubular cells, and neuronal membranes. For example, the
liver has four known active transport systems, two for organic acids, one for
organic bases, and one for neutral organic compounds.2 A different specialized
transport process is termed “facilitated diffusion.” This transport is similar
to the carrier-mediated transport described above except that no active
processes are involved. The drug is not moved against an electrochemical or
concentration gradient and there is no expenditure of energy. A biochemical
example of such transport is the movement of glucose from the gastrointestinal
tract through the intestinal epithelium.
Absorption
In order for a drug to exert
its pharmacological effect, it must first gain entry into the body, be absorbed
into the bloodstream, and transported or distributed to its site of action.
This is true except in the case of drugs that exert their effect locally or at
the absorption site. The absorption site, or port of entry, is determined by
the route of drug administration.
Routes of administration are
either enteral or parenteral. The former term denotes all routes pertaining to
the alimentary canal. Therefore, sublingual, oral, and rectal are enteral
routes of administration. All other routes, such as intravenous, intramuscular,
subcutaneous, dermal, vaginal, and intraperitoneal, are parenteral routes.
Absorption describes the
rate and extent to which a drug leaves its site of administration and enters
the general circulation. Factors that, therefore, affect absorption include the
physicochemical properties of the drug that determine transfer across cell
membranes as described earlier; formulation or physical state of the drug; site
of absorption; concentration of drug; circulation at absorption site; and area
of absorbing surface.
