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.