needs to have a basic knowledge of pharmacokinetics. Pharmacokinetics is a science
that deals with the progressive movement and alteration of chemical substances
within the body. Bioavailability is important when reviewing the effects or pharmacology
of a drug. In order for a drug to have an effect, it needs to be physically
present at the site where it exerts its pharmacological action. First, the drug needs
to be absorbed, and then it needs to be distributed or transported to a receptor—the
site of action. The drug may then exert its pharmacological effect. Subsequently, the
drug may be metabolized and then excreted. The acronym ADME is used to help
people remember the pharmacokinetic arenas of absorption, distribution, metabolism,
and elimination.
Keep in mind that drugs are usually substances not commonly ingested. All the
pharmacokinetic mechanisms for each of the four ADME processes probably did
not evolve to handle drugs. Drugs can be likened to a “Trojan Horse.” Most frequently,
drugs enter the body via the gastrointestinal tract, a route that clearly serves
the purpose of absorbing food. Drugs have to be chemically similar to food substances
in order to be absorbed, but dissimilar enough to avoid digestion. For
example, the reason that insulin must be injected is that it is a polypeptide. If ingested,
insulin would be digested into smaller peptides and amino acids and lack the
pharmacological action expected from insulin.
In order to understand drug dosing, one needs to appreciate how the amount of
drug in the bloodstream changes after administration of the drug. Pharmacologists
will frequently employ a graph of serum concentrations of a drug vs. time in order
to describe the drug’s bioavailability. The serum concentration is affected by each
ADME component. The relative amount of absorbed drug compared with administered
drug is referred to as the drug’s bioavailability. Total bioavailability and the
time course of absorption affect drug action. Even while the drug is being absorbed,
the processes of distribution, metabolism, and elimination are already at work affecting
serum levels. When a drug leaves the bloodstream and accumulates in another
tissue, this lowers the serum level. Sometimes, this will increase the activity of the
drug, particularly for drugs that exert their effects in tissues other than the bloodstream.
General anesthetics and antidepressants have their effects in the CNS. Other
drugs may accumulate in adipose tissue, only to be released slowly over an extended
time. A graph of the serum concentration of a typically orally administered drug
plotted against time is depicted in Figure 1.1.
Absorption
Many factors affect absorption. The principal factors are the route of administration,
the dosage form, the chemical nature of the drug, and the local environment
One general principle to remember is that drugs are generally absorbed in an
unionized form. Weakly acidic drugs are, therefore, generally absorbed in the stomach,
while weakly basic drugs are absorbed in the small intestine. Most drugs are
weakly basic. Binding to other chemicals in the gastrointestinal tract may interfere
with absorption.
Distribution
Once the drug enters the body, it travels within the bloodstream. Depending on
its chemical nature, the drug may preferentially concentrate in a particular tissue.
Many water-soluble drugs remain in the fluid compartment. Other drugs may preferentially
accumulate in adipose tissue or muscle. This affects the serum levels of
the drug. Theoretically, the concentration of a drug put in a solvent should be equal
to the amount of the drug divided by the volume of the solvent. If you think of the
organism as the solvent for a drug, then the amount of the drug absorbed divided
by the volume of the organism should equal the measured drug concentration. Since
the organism is not a single solvent, this does not work. A theoretical construct
called volume of distribution (Vd) is used to reconcile the measured serum level
and the amount of drug absorbed. A volume of distribution of 0.6 L/kg indicates
that the drug is distributed principally in the fluid compartment that accounts for
about 60% of our body weight. A lower Vd would indicate that the drug is preferentially
found in the bloodstream. Higher Vds indicate that the drug is sequestered
in tissues other than the bloodstream (i.e., muscle, bone, CNS, etc.).
Metabolism
When a drug enters the body, it will encounter metabolic processes that may
alter its chemistry. As a general rule, the metabolic processes in the body tend to
decrease toxicity and enhance the elimination of foreign chemicals. These paired
processes are achieved by three principal mechanisms: (1) increasing the water
solubility of these chemicals, (2) decreasing the size of the foreign molecules, and (3) binding the drugs to larger molecules (conjugation). The end products of these
processes are referred to as metabolites. Metabolism can happen in the peripheral
tissue of the body or in a specific organ. The liver is frequently the organ involved
in this process. Many enzymes participate in drug metabolism; one group of liver
enzymes responsible for much of this activity is the cytochrome P450 enzymes.
Furthermore, many subgroups of enzymes exist in this class. One drug or nutrient
may alter the action of these enzymes on a second drug or nutrient by binding to
or having a greater affinity for the enzymes than the other substance. This may result
in drug–drug or drug–nutrient interactions. Changes in liver function may also affect
drug metabolism. Age alone, in the absence of liver pathology, will affect drug
metabolism. This will be elaborated in later chapters of the text.
Elimination
Several organs are involved in eliminating drugs from the body. The kidneys are
the most important organs in this regard. These organs of homeostasis remove drugs
and drug by-products from circulation by both passive action (filtration) and by active
processes involving secretion and resorption of substances from the plasma. The
lungs, the liver, the skin, and various glands may also help in the elimination of
chemicals from the body.
Once again, age will be a factor because renal function declines as a function
of normal aging. Substances processed by the kidney may be actively or passively
secreted into the urine as it traverses the nephron, which is the functional unit of
the kidney. Substances can also be actively or passively reabsorbed into the bloodstream
before leaving the nephron. This process can be affected by the pH of the
urine and can be enhanced or inhibited by the presence of other substances in the
urine or the blood. Drugs that alter urine production, such as diuretics, may also
affect the urinary excretion of drug and drug metabolites, and this may result in
interactions.
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