Unclassified Interactions

Effects of Nutritional Status on Drugs
The presence of nutritional abnormalities may have an effect on drugs. Drug
dosages may need adjustment based on actual body weight for some drugs. Other
drugs may need to be dosed differently in obese, normal, and underweight patients,
based on actual, ideal, or an adjusted body weight corrected for lean body mass.
Somatic protein status may affect the dosing of medications that bind to somatic
protein.
Effects of Drugs on Nutritional Status
The converse effect may also be observed. Some drugs will have an effect on a
patient’s nutritional status. The mechanisms for these effects are varied and are
usually due to drug side effects. Medications may have direct effects on the gastrointestinal
tract (GIT), which can affect food ingestion. Nonsteroidal antiinflammatory
agents, commonly used to treat arthritis, including aspirin, can cause irritation
of the upper gastrointestinal mucosa and even cause ulcers. This can depress appetite
and produce weight loss. Chemotherapeutic agents used to treat cancer can affect
rapidly growing tissues, particularly the lining of the GIT. Nausea is a common side
effect and will interfere with eating. Some patients develop oral and esophageal
lesions that cause pain upon chewing and swallowing (odynophagia), which limits
oral intake. Antibiotics can suppress commensal bacteria, and this may result in
overgrowth of other organisms such as Candida albicans. Overgrowth in the GIT
may produce malabsorption and, subsequently, diarrhea. Overgrowth in the mouth
may result in candidiasis or thrush, which can reduce oral intake. Drug-related
dysgeusia may result in alteration of taste perceptions and avoidance of certain foods.
Many drugs reduce salivation and cause dryness of the mucus membranes. This may
also inhibit oral intake. Nausea, vomiting, diarrhea, and constipation are ubiquitous
side effects associated with most medications and even with placebo medications.
Again, oral intake of food may be reduced due to these effects.
Some drugs have a direct effect on digestion. Orlistat (Xenical®) interferes with
the digestion and subsequent absorption of fat intentionally to enhance weight loss.
Pancreatic enzymes enhance digestion for patients with limited amounts of digestive
enzymes. Several types of drugs interfere with hydrochloric acid production, but
none have demonstrated a significant effect on macronutrient absorption. Increasing
the gastric pH may affect absorption of weakly acidic drugs, as well as iron and
vitamin B12. Intrinsic factor requires an acidic pH to bind with vitamin B12. Without
the acidic pH, B12 deficiency can have an irreversible effect on brain function if
prolonged without treatment.
Some drugs have a direct effect on appetite. The amphetamines and their derivatives
were long used for weight loss. Unfortunately, side effects and transient results
for most patients have limited their usefulness. Sibutramine (Meridia®) has both an
appetite suppressing effect and a mild antidepressant effect and is approved by the
Food and Drug Administration (FDA) for weight loss. These drugs are discussed in
more detail in the Chapter 11, Obesity and Appetite Drugs, and Chapter 7, Gastrointestinal
and Metabolic Disorders and Drugs.
Dronabinol (Marinol®), also known as THC (from tetrahydracannabinols), the
active principle in cannabis, is also used as an appetite stimulant. Oxandrolone
(Oxandrin®) is an anabolic steroid approved for weight gain. Megesterol (Megace®),
a progestin used to treat certain types of cancer, is also indicated to enhance appetite.
Cyproheptadine (Periactin®) has been used to enhance appetite, although this is an
off-label use and not an FDA-approved indication.
Besides drugs specifically indicated to effect changes in appetite, some drugs may
affect appetite as a side effect. Several antidepressants have been observed to consistently
increase or decrease appetite. When these drugs are prescribed, their relative
side-effect profiles in relation to weight change may make one or another a preferred
agent for an individual who would benefit from an increase or decrease in weight.

Types and Mechanisms of Drug–Drug and Drug–Nutrient Interactions

Now that basic information about pharmaceutics, pharmacokinetics, and pharmacodynamics
has been presented, drug interactions can be appreciated. The types
of interactions that can occur include potentiation, inhibition, alteration of absorption,
direct chemical interaction, alteration of metabolism, alteration of distribution,
competition at the site of action, and alteration of elimination.
Potentiation can be additive or synergistic and refers to an increase in the effect
of one drug as a result of a second drug or nutrient. The increased pain relief
experienced when acetaminophen is combined with a narcotic (Tylenol #3®, Vicodin
®, Lortabs®) illustrates a positive example of this effect. Adding bananas, potatoes,
and other foods rich in potassium to the diet at the same time a patient is taking a
prescribed potassium supplement (e.g., Kaon-Cl®) would cause an additive
food–nutrient effect with a therapeutic purpose.
Inhibition refers to the decrease of effect when two substances have opposite
effects on a process. The decreased anticoagulant effect of warfarin (Coumadin®)
seen when vitamin K intake is increased is a negative example of this type of
interaction. Warfarin therapy frequently requires adjustment because of such inhibition,
especially when patients suddenly increase their intake of green leafy vegetables
rich in vitamin K. This is a real hazard for patients who are avid gardeners and whose
vitamin K intake can vary drastically from season to season. Caffeine, a nonnutritive
food constituent, may oppose the pharmacological effect of tranquilizers.
Decreased absorption of nonheme iron from food is seen when antacids are
taken on a chronic basis with iron-containing foods. This may result in iron deficiency
anemia with its characteristic microcytic, hypochromic, red blood cells.
Grapefruit juice will increase the bioavailability of cyclosporine (Sandimmune®).
This will decrease the potential for organ rejection by recipients of organ transplants,
but may also increase the potential for cyclosporine toxicity. Deliberate ingestion
of grapefruit to decrease cytosporine doses is not advised due to the unpredictable
nature of this interaction.
An example of a direct chemical interaction is the reaction between dextrose
and amino acids in parenteral nutrition. This is the same reaction seen when meats
are cooked and is known as the Maillard reaction. The substrates involved tend to
reduce sugars and amino acids, and these factors limit the storage time for parenteral
nutrition solutions. The reaction results in a darkening of the solution.
Alterations of metabolism may also occur. This generally occurs in the liver but
may also be peripheral. Many enzymes responsible for drug metabolism are part of
the cytochrome P-450 family. St. John’s Wort induces an increase in the activity of
one P-450 isoform termed CYP 3A4. This can result in decreased levels of cyclosporine,
indinavir, and oral contraceptives. This drug interaction with St. John’s Wort
demonstrates the potential for herbal products to participate in significant herb-drug
interactions when used in combinations with conventional medications.
Alterations of distribution may occur when drugs are protein-bound. Binding to
protein will generally reduce the amount of free drug. Decreased amounts of free
drug may decrease the activity of the drug and also decrease the metabolism and
elimination of the drug. In this type of interaction, one substance that is bound
displaces another bound substance from a binding site. The effect, if any, may be
transient because the increased effect of the free drug may be countered by increased
metabolism and excretion of the free drug. Some significance is possible if the
second agent is taken on an intermittent basis. A nontransient example of this is the
need to adjust measured serum total calcium levels based on serum albumin levels.
Only ionized Ca++ is physiologically active. Most clinicians do not have rapid access
to ionized calcium levels; total serum calcium levels are commonly available.
Because each gram of albumin in the bloodstream will bind with approximately 0.8
mg of calcium, serum with a lower than normal albumin concentration will have a
lower amount of bound calcium. This will result in a lower total calcium level, even
if the ionized (unbound) calcium is normal. Many clinicians calculate the corrected
calcium level by subtracting the patient’s albumin level from either 4.0 g/dL (midpoint
of normal range) or 3.5 g/dL (low normal albumin), then multiplying this by
0.8 mg/g, and adding this factor to the total serum calcium.
An example of competition at the site of action is best illustrated by the effect
of naloxone (Narcan®) on narcotics. Naloxone reverses the effects of narcotics at a
receptor site. This can be useful after surgery to reverse the effects of intraoperative
narcotics. Naloxone is also useful in the treatment of narcotic overdoses. Caution is
needed if an individual is dependent on narcotic drugs because naloxone can cause
withdrawal symptoms. This interaction is further modified by drug metabolism.
Naloxone is eliminated faster than the narcotics that it affects. It is, therefore,
necessary to monitor a patient who has received a narcotic overdose even after he
appears to have recovered. The naloxone may wear off, and then the narcotic effect
will recur.
Renal excretion may also be involved in interactions between drugs and nutrients.
The classic example is the effect of most diuretics (e.g., loop diuretics and
thiazide diuretics) on potassium. These diuretics result in increased loss of potassium
in the urine. This may require pharmacological or nutritional supplementation of
potassium intake.
Drug Interaction Risk Factors and the Unknown
By now, the potential for unexpected effects as a result of interactions between
a drug and other drugs or foods has been well established. The risk of having drug
interactions will be increased as the number of medications taken by an individual
increases. This also implies a greater risk for the elderly and the chronically ill, as
they will be using more medications than the general population. Risks also increase
when a patient’s regimen originates from multiple prescribers. Filling all prescriptions
in a single pharmacy may decrease the risk of undetected interactions.
The method for getting new drugs approved has increased in efficiency in recent
years. Drug studies done to seek approval of a new agent are often done on “ideal”
populations, that is, individuals with a single ailment. This highlights the effect of
the drug being studied. As a result, few subjects are taking other medications. Once
the drug is approved, it is used by a less select group of patients. As a result, the
full extent of drug interaction potential may be only recognized after the drug is
widely available. In addition, medical practice is highly individualized and managed
based on specific patient response. This may delay or prevent recognition of interactions.
Taking a thorough medical, drug, and nutritional history from patients when
they seek medical attention may help identify drug–drug and drug–nutrient interactions.

GASTROINTESTINAL PHYSIOLOGICAL RESPONSE TO INGESTED FOOD AND LIQUIDS

The anatomy of the GIT has been well characterized by numerous texts and will
not be covered in this chapter. The effects of food, however, on GIT secretions,
motility, and dynamics are integral to understanding how food will affect the pharmacokinetic
parameters mentioned in the previous section. The primary focus of
this section will be to discuss the physiological processes mentioned in the rate of
absorption section.
Gastric Emptying Rate
Arguably, the gastric (stomach) emptying rate (GER) is the most important
parameter that influences the rate of drug absorption from the GIT. Since most of
a drug dose is absorbed in the small intestine, the rate at which the drug is presented
to the small intestine is often the rate-limiting process of drug absorption. Many
factors can influence the GER, including the type and volume of meal ingested, the
emotional state of the patient, the body position of the patient, and coadministered
drugs.1 Table 2.1 eloquently describes how various factors influence gastric emptying
rate. The GER is slower for solids, which need more processing than do liquids
prior to presentation to the small intestine.1,2
Solids
Owing to the primary function of the stomach, the ingestion of food delays the
gastric emptying rate.3 In addition, the magnitude of this decrease in GER is dependent
on the volume and the type of meal ingested (see Table 2.1). High-fat meals
tend to slow the rate of gastric emptying to a greater degree than one rich in
carbohydrates or amino acids. The ingestion of food elevates gastric pH and slows
the longitudinal motility of the stomach to allow food sequestration in the stomach
for processing. Changes in stomach pH that result from food ingestion can produce
significant effects on drug absorption for those drugs whose dissolution is dependent
on low pH. This topic will be covered in the section on Drug Dissolution.
In some instances, food can alter the rate order of drug absorption. The amount
of the vitamin riboflavin absorbed has been studied in fasted and fed subjects.3 In
fasted subjects, riboflavin is absorbed in a zero order fashion. In other words, the
amount of drug absorbed as a function of time will not change regardless of the
magnitude of the dose. In the presence of food, the presentation of riboflavin to
Table 2.1 Circumstances That Influence Gastric Emptying

the absorption site is slowed to the point that absorption occurs at a first order rate.
The presentation of riboflavin was sufficiently slow that the transport carriers were
not saturated. Thus, the amount of drug absorbed increased as the dose increased
(Table 2.2).
Liquids
The ingestion of liquids does not significantly reduce the GER, primarily because
liquids need minimal physiological processing before their presentation into the small
intestine. Recent studies suggest, however, that liquids can indeed slow the GER as
a function of their caloric content.2–3 This theory is supported by data obtained in
various laboratories that investigated whether the use of an acidic beverage, such as
Coca-Cola® or grapefruit juice, may lower the pH of the stomach and thus promote
the dissolution of the weakly basic drugs (e.g., itraconazole and ketoconazole). In
addition, this longer residence time in the stomach may aid in the solvation of poorly
Table 2.2 First Order and Zero Order Absorption as a Function of Food
Presence

soluble, lipophilic drugs such as itraconazole.5–8 Figure 2.4 depicts the benefit of a
delay in gastric emptying as the CMAX and AUC of itraconazole were dramatically
improved by the reduction in gastric emptying rate following ingestion of Coca-
Cola®. At pH values that should have promoted prompt drug dissolution and absorption
(e.g., pH 1–3), the rates of absorption of these drugs, as reflected in TMAX values,
was not enhanced by the acidic beverage.8 To further emphasize the point, Carver
and colleagues lowered the gastric pH using glutamic acid and demonstrated that
the TMAX of itraconazole was unchanged.5 Therefore, the caloric content of the liquid
may be the determining factor in the magnitude of GER reductions.
The volume of fluid also plays a role in the rate of absorption. This was demonstrated
in studies with several antibiotics taken with a small volume of water (e.g.,
20–25 mL) or a large volume of water (e.g., 250–500 mL). Dramatic differences
were observed in the drug concentration vs. time profiles for these drugs simply as
a function of the volume of fluid ingested (Figure 2.5). Thus, patients who take
medications with a large volume of water as opposed to a small volume of water
may exhibit considerably different onset, duration, and intensity of drug action. Not
all drugs will show these substantial changes in their disposition as a function of
the type and volume of fluid ingested, but it is wise to instruct patients to be consistent
in their chosen method of ingesting medications.
As previously mentioned, the pH of the stomach may play a role in the rate of
absorption of drugs. In general, weakly basic drugs, such as antihistamines and nasal

decongestants, dissolve rapidly into the low pH environment of the stomach due to
the favorable ionization profile. Conversely, weakly acidic drugs, such as most
nonsteroidal antiinflammatory drugs (NSAIDs), are poorly soluble in the stomach
because acid molecules tend to remain unionized in strongly acidic environments.
One of the fundamental steps in the absorption process is the dissolution (or solvation)
of the drug molecules into stomach fluids from the administered dosage form.
If a drug is poorly soluble in the stomach and, as a result, the dissolution of the
drug molecules is slow, then the rate of absorption of the drug will decrease.
Paradoxically, a solubilized drug in an ionized state is considered to be poorly
absorbed. Drugs must be deionized to cross a lipophilic biological membrane, unless
a specific active transport mechanism exists to facilitate its movement across membranes.
Ideally, a drug molecule must be ionized to facilitate its dissolution and then
unionized to be absorbed. In reality, even ionized drug molecules are absorbed well
in the small intestine due to its tremendous surface area and lengthy residence time.
Table 2.3 displays the pH values and residence times of various portions of the GIT
during a fasted condition.

Intestinal Transit
Whereas the GER is sensitive to ingested solids and liquids, the intestinal emptying
rate is virtually independent of food or liquid ingestion.9 Numerous drugs,
however, can affect intestinal tone and motility. Stimulant laxatives increase the
movement of material from the small intestine distally, and this disruption in homeostasis
can easily affect the extent of drug absorption. Alternatively, antidiarrheals,
such as loperamide as well as narcotic analgesics, significantly slow intestinal
motility, and this may alter the extent of drug absorption. Concomitantly administered
medications that affect intestinal tone also affect intestinal transit to a greater
degree than food ingestion.
Drug Dissolution
The physical and chemical microphenomena that characterize drug dissolution
are covered in great detail in several biopharmaceutics textbooks. It is important to
mention in this forum a few basic concepts of drug dissolution. The measurement
of the rate of drug dissolution is a prime aspect in the Food and Drug Administration
(FDA) review of new drug applications. As previously mentioned, weakly basic
drugs dissolve well in acidic environments and weakly acidic drugs dissolve well
in basic environments. If food (solid or liquid) alters the pH of the stomach fluid,
then the dissolution rate of weak acids and bases will be affected.
The dissolution rate of many drugs is slower than the overall rate of drug
absorption. For such drugs, the dissolution rate limits their absorption. Tablets,
capsules, and other compressed, oral dosage forms typically belong to this category.
Circumstances that influence the dissolution rate for these drugs will have a substantial
impact on drug absorption. Whereas food and calorie-laden liquids reduce
the gastric emptying rate and thereby reduce the rate of absorption of drugs, the
effect of food on the dissolution rate of drug molecules is not as clear. The dissolution
rate of numerous drugs is unaffected by the ingestion of food; however, this is not
the case for all drugs.
In general, the dissolution rate of highly lipophilic drugs is enhanced when the
drug is taken with food, especially foods rich in fat. A great example is the original
formulation of the antifungal drug, griseofulvin. The dissolution rate and, thus, the
rate of absorption of griseofulvin is substantially increased when taken with food.
The dissolution rate of highly lipophilic drugs, therefore, may be enhanced when
taken with a fatty meal. In the case of griseofulvin, its absorption has been remarkably
enhanced by reducing the particle size of the drug aggregates and thus improving
its dissolution characteristics.
Complexation and Degradation
In addition to the influence on the GER and dissolution rate, the ingestion of
food may endanger the drug molecule. These dangers are manifested in the forms
of acidic degradation, food–drug adsorption, and complexation. Any of these may
significantly reduce or prevent drug absorption.
Acidic degradation of acid-sensitive drugs is a primary concern when drugs and
food are taken together. Classic examples of acid-sensitive drugs include aspirin and
the various first-generation penicillins. If the residence time of these drugs in the
stomach is increased by the presence of food, then the degradation of these drugs
increases. As a result, the extent of drug absorption may be substantially reduced
because the active degradation reduces the amount of drug available to be transported
across the mucosa and distributed in the circulation.
Drug molecules may adsorb onto food components and, thus, may lead to a
reduction in the rate and extent of absorption. Conversely, food particles may interact
with drug molecules in the stomach and small intestine. Numerous instances of
multivalent cation complexation with the older tetracyclines exist. When these medications
are taken with food (or other drug preparations) containing iron, calcium,
aluminum, magnesium, and other multivalent cations, insoluble complexes may be
formed that render the drug unabsorbable.
The effect of food on the rate and extent of absorption, by any of the above
mechanisms, is generally considered to be less critical when drugs are taken 30 min
or more before feeding or 2 h postprandial. Although the preceding sections contained
several examples of prescription drugs, these types of interactions may easily
occur with OTC medications. Indeed, with the recent increasing trend of prescription
to OTC movement, these interactions may become more prevalent.

PHARMACOKINETIC PARAMETERS of Biopharmaceutics of Orally Ingested Products

This discussion limits its consideration to the movement of orally ingested drugs
through the gastrointestinal tract (GIT). The movement is active rather than passive.
During the sequence from ingestion to elimination, a variety of active processes
common to both foods and drugs play important roles. Several pharmacokinetic
parameters are used to judge the clinical importance of food/drug interactions.
Pharmacy: Basic Concepts demonstrated that the appearance and disappearance of drug concentrations
in whole blood or blood components (principally plasma or serum) are the
primary measures of drug movement into target tissues. Pharmacologic effects occur
when the drug reaches these sites in appropriate amounts. The plasma or serum drug
concentration vs. time profile of a typical, immediate-release tablet is given in Figure
2.1. From this profile, several meaningful parameters can be obtained that relate the
rate and extent of drug absorption from the dosage form. The rate refers to how fast
the drug reaches the systemic circulation, which is generally considered to translate
into the onset and intensity of the intended drug effect. The extent refers to the total
exposure of the drug in the bloodstream. The extent of drug absorption is integral
in determining the duration, termination, intensity, and therapeutic index of the drug.
Drugs may be absorbed by various routes and processes. For most drugs, the
rate of absorption can be classified as a zero-order or first-order rate process.
Although an in-depth discussion of rate orders of reactions is beyond the mission
of this chapter, a general understanding of these rate orders facilitates a deeper
understanding of how food may alter overall rates of drug absorption. The zeroorder
rate process proceeds in a constant fashion and without regard to any other
factor. In terms of drug absorption, a certain amount of the drug will be absorbed
in a given time period and will not change. Usually, zero-order absorption is the

result of specific drug carriers working at their maximal capacity. The first-order
rate process differs considerably from that of a zero-order process. The first-order
rate process will increase as the concentration of drug at the absorption site increases.
In terms of drug absorption, the rate of drug absorption increases as the drug
concentration at the absorption site increases. Figure 2.2 displays the zero- and firstorder
rate processes as a function of drug concentration at the absorption site.
Rate of Absorption (KA)
The overall rate of drug absorption, KA, represents the sum of many individual
rates of processes that eventually lead to the appearance of drug in the bloodstream.
These individual rates include: (1) the rate of disintegration of the dosage form, (2)
the rate of dissolution (or solvation) of the drug from the disintegrated dosage form,
(3) the rate of gastric emptying, (4) the rate of drug degradation in the GIT, and (5)
the rate of intestinal emptying (transit). If food interferes with any of these processes,
then the overall rate of absorption will be affected. Several different methods of
determining the rate of absorption exist, and these methods are covered in detail in
clinical pharmacokinetics textbooks. In this chapter, we will focus on the use of the
KA term, rather than its discovery from experimental data.
As explained previously, one cannot inspect a plasma-drug concentration vs.
time profile and identify the component of the curve that represents KA. KA is
determined, however, by mathematical treatment of the plasma-drug concentration
vs. time data. KA is used to calculate a tangible parameter called the time to maximal
drug concentration (TMAX). This parameter also corresponds to the time to peak
absorption. Figure 2.3 relates TMAX to other clinical pharmacokinetic parameters
important in the assessment of drug absorption. When considering the implications
of the magnitude of KA, one sees that a small TMAX value leads to a rapid onset of
action. Thus, a rapid onset of action correlates to a small TMAX value, which in turn
is proportional to a rapid KA. For certain drugs, food may enhance the rate of
absorption, while the same food may substantially reduce the rate of absorption of
other drugs.

Maximal Drug Concentration (CMAX)
The maximal concentration or peak concentration of drug in plasma after a single
dose occurs at TMAX. Stated differently, CMAX is a function of and is inversely related
to TMAX. CMAX directly impacts the intensity of the pharmacological and/or toxicological
drug action. Therefore, circumstances that may slow the rate of absorption
(and thus increase TMAX) may result in a decrease in CMAX. This in turn may reduce
the intensity of drug action. Figure 2.3 visually demonstrates the relationship
between TMAX and CMAX.
Area under the Plasma Concentration vs. Time Curve (AUC)
AUC is the fundamental pharmacokinetic parameter that denotes the extent of
drug absorption. Many dosing regimens are based on the total systemic exposure of
a drug after a given dose as measured by the plasma-drug AUC. The unusual
dimension of the AUC term (mass × time/volume) is due to the formula used to
derive AUC. Two (x, y) coordinates on the plasma-drug concentration vs. time curve
create a trapezoid, and, as such, the area contained in that trapezoid can be calculated
with elementary geometry. Thus, the “AUC” term is the sum of all the individual
trapezoids formed by the drug plasma concentration vs. time data. The magnitude
of the AUC value influences the intensity, duration and termination of activity (see
Figure 2.1). AUC is also governed by metabolic and elimination pathways; therefore,
the prediction of how food may directly alter the magnitude of AUC is confounding.
One of the main elimination routes of any drug absorbed in the GIT occurs
during its first pass through the liver. As a result of this pathway that is designed to
protect the body from toxins, it is quite likely that not all of the drug that is absorbed
will reach the systemic circulation. The AUC value is thus used to calculate the
bioavailability (F) of the drug or the percentage of the dose that reaches the systemic
circulation. The following expressions describe the relationships among the parameters
discussed in this section.
AUC ∝ F
TMAX ∝ 1/KA
CMAX ∝ KA
CMAX ∝ F

PHARMACODYNAMICS IN DRUG INTERACTIONS

The study of the actions of drugs is called pharmacodynamics. Drugs can be
categorized as exerting an action in a general or a specific manner. Drugs with
general, nonspecific effects may affect all body tissues and cells. Drugs with specific
effects will have a target substrate that they act on, in one or more organ systems.
The fewer systems affected by the drug, the more specific its action. Specifically
acting drugs are generally considered better to work with from a pharmacodynamic
perspective. In contrast to the serendipitous manner in which drugs were developed
in the past, drug development now focuses on chemical specificity based on drug
and receptor structure. Drugs or foods that interfere directly with another drug’s
action would cause a drug–drug or drug–nutrient interaction. Drugs with an effect
similar to another drug may cause a greater than additive pharmacological effect.
This type of interaction is called synergism. Drugs with opposing pharmacological
effects may negate the benefits of one of the agents.

PHARMACOKINETICS IN DRUG INTERACTIONS

In order to understand drug interactions and drug interactions with nutrients, one
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

at the site of absorption (i.e., pH, blood flow, physiological changes of tissue, etc.).
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.

DOSAGE FORMS

In order to take advantage of this multitude of medication administration routes,
a similarly diverse number of dosage forms have been devised. Some, such as urethral bougies, are no longer in common use, while others, such as the transcutaneous
patch and metered dose inhalers (MDI), are becoming increasingly popular.

Pills and Powders
When the general public thinks of an oral dosage form, the word pill is commonly
used. The pill is actually an archaic dosage form. Pills consist of medication combined
with inactive ingredients to form a gelatinous (doughy) mass. This mass is
then divided, rolled into cylinders on a pill tile, and then cut into individual pills.
The pills are then dried prior to use. Currently, few medications are truly pills.
Carter’s Little Liver Pills® and Lydia Pinkham’s Pills® are among the last of a once
popular dosage form for both manufactured and extemporaneously prepared medications.
Powder papers (a small, precisely measured quantity of medication and
diluent inside a folded piece of paper) were once a popular method of drug delivery.
Two over-the-counter (OTC) popular medications are available in this form: BC
Powders® and Goody’s Powders®.

Tablets, Capsules, and High Tech

The most common dosage form is the tablet. It is prepared from a dry mixture
of active and inactive ingredients (excipients). The excipients include binders, lubricants,
diluents, and coloring agents. This mixture is mechanically compressed into
solid tablets in various shapes. The excipients are considered inert ingredients, but
can occasionally cause difficulty in individual patients. Lactose is commonly used
as a diluent. The quantity is usually too small to cause adverse effects, even in a
lactose intolerant individual. Tartrazine, commonly called FD&C yellow dye No. 5,
is a coloring agent. Serious allergic reactions are possible to this agent and to
medications colored with it. Capsules are the other most common oral dosing form.
Active ingredients, diluents, and lubricants (to improve the flow of the powder
through the equipment) are put into preformed, hard gelatin shells that are then
mated with a second gelatin shell. Liquid medication can also be sealed into a
capsular shell. Several variations on the manufacturing of tablets and capsules can
result in delayed or extended medication release into the gastrointestinal tract. The
absorption of the drug into the bloodstream and the pharmacological effect of the
drug will be affected by this alteration in the release of the medicine. The most
advanced oral dosage forms use semipermeable membranes or laser technology to
produce dosage forms that release medication into the gastrointestinal tract at a
controlled rate.
Some drugs may be absorbed from the capillary beds in the mouth. Nitroglycerin
tablets are designed to dissolve under the tongue and will be absorbed sublingually.
Recently, rapid dissolving tablets have been developed to deliver medications into
the gastrointestinal tract. The medication is released in the oral cavity but is absorbed
at numerous locations in the gastrointestinal tract. This results in a quicker onset of
action. Rapid disintegration (RD) is frequently associated with this type of dosage
form. Other medications may be designed for absorption from the inner aspect of
the cheek. These are referred to as buccal dosage forms. Lozenges may be used to
deliver medication into the oral cavity for both local and systemic action. Local
anesthetics for treating a sore throat can be put into a lozenge. A powerful pain
medication, fentanyl, is available in a lozenge on a stick form for transmucosal
absorption. Cough suppressants are also available as lozenges.

Liquids
Of course, oral liquids remain a popular dosage form. This category includes
solutions such as teas (infusions and decoctions), fluid extracts, syrups, drops, and
tinctures, as well as emulsions and powders ready for reconstitution with water. With
the popularity of “natural remedies,” the use of teas and homemade preparations has
increased. All oral liquids are relatively simple in comparison to oral liquid nutritional
supplements. The supplements are generally oil-based solutions emulsified within
water-based solutions with some of their ingredients suspended in a colloidal form.
Recently, the introduction of foods having desirable pharmacological properties
has further blurred the distinction among drugs, nutritional supplements, and foods.
Benecol® (contains plant stanol esters) and Take Control® (plant sterol-enriched
spread) are the best examples of this, but even the marketing of oatmeal and oat
bran ventures into this newly grayed area separating drugs and foods.

Rectal Dosage Forms
Other enteral dosage forms are designed for absorption in the sigmoid colon and
may be solid dosage forms (suppositories), liquids (enemas), or aerosols (foams).
Again, both local and systemically acting medications may be given via this route.
Hemorrhoid treatments, antiemetics, laxatives, and antipyretics (medications used
to treat fever) are all commonly given in these forms.

Topical Agents
Topical dosage forms are similarly diverse. Ointments (oil base) may deliver
topical medications. Creams (water-soluble base), gels, and mustards (pasty substance
spread on a cloth and wrapped around a body part) also do so. Shampoos,
soaps, solutions, and topical patches may also deliver medication in a useful manner.
Nasal, ophthalmic, and otic (for the ear) solutions and suspensions are available.
Aerosols, sprays, nebulized medications, metered dose inhalers, and powders for
inhalation are used to deliver medication to the respiratory tract. Intravaginal suppositories
(also called vaginal tablets), creams, douches, and sponges are used to
deliver medications.

Injections
Parenteral dosage forms are mainly water-based solutions, but a few novel
approaches are used. These include solutions in solvents other than water, oil-in- water emulsions, and even drug-impregnated solids used as subdermal implants.
Recently, drugs have even been delivered inside liposomes in a parenteral liquid.

Pharmaceutical Elegance: Coats to Disguise, Protect, and
Increase Duration
Coatings have been used on tablets to hide bad tastes (e.g., E-Mycin—erythromycin).
One liquid suspension (Biaxin®—clarithromycin) consists of film-coated
granules. The coating again hides the taste of the medicine. Interestingly, this is a
liquid medication that should not be given via a small-bore feeding tube. The
granules can “logjam” at the curves in the tube and occlude it. Other coatings,
referred to as enteric coatings, are used to prevent dissolution and inactivation of
the drug in the stomach by gastric secretions. Extensive efforts have been made to
engineer dosage forms that change the absorption of medications. The goal is usually
to extend the duration of action for a drug with a relatively short half-life. Repetabs®
provide an example of tablets designed to provide a quantity of quickly released
medication followed by a quantity of drug released slowly over time. Capsules can
contain pellets coated with varying thickness of slowly dissolving excipients to
achieve a timed-release bioavailability. Since medications are sometimes crushed
before administration, one needs to know why the coating was on the tablet, where
the drug will enter the gastrointestinal tract, and how removing the coating will
affect the bioavailability of the dosage form.