Delmar Nurse’s Drug Handbook / Drug Administration
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Section 3:
Drug Interactions: General and Nursing Considerations
DRUG-DRUG INTERACTIONS
Many clients now receive more than one pharmacologic agent; therefore, drug
interactions are potentially major clinical problems. In addition to having their intended,
specific therapeutic effect, drugs can also influence other physiologic systems. It is highly
possible that two concomitantly administered agents influence some of the same
pathways.
In many cases two interacting agents are concurrently administered, but are taken to
minimize interactions or side effects. Precautions, such as dosage adjustments, must be
taken in this event. Drug interactions are not always adverse, and they are sometimes
taken advantage of therapeutically. For example, probenecid can be administered with
penicillin to decrease the excretion rate of the penicillin and, therefore, result in higher
blood levels of penicillin.
The study of drug interactions is a complex subspecialty of pharmacology. An attempt
has been made throughout the Nurse’s Drug Handbook to reduce the complex
explanation of drug interactions to the simplest possible terms.
A brief review of the major mechanisms that give rise to drug interactions is included in
this section. Knowledge of these mechanisms should enable the provider to anticipate
similar situations with other drug combinations.
It is important to remember that interactions apply not only to the intended therapeutic
action of the drugs but also to their side effects. Also, the interactant does not have to be a
prescription drug. Salicylates (aspirin) sold over the counter (OTC) are an important
interactant, as are common laxatives and constipating agents. Beverages (e.g., alcohol)
and foods (e.g., tyraminerich cheese) can also play an important role.
Drug interactions often require an adjustment in dosage of one or both agents or a
discontinuation of one of the drugs. Common major drug interactions are described under
the drug or drug class.
Drugs with Opposing Pharmacologic Effects
The therapeutic effects of either or both agents may be cancelled, decreased, or abolished.
An example is the combination of pilocarpine (a cholinergic drug prescribed for
glaucoma) and an anticholinergic or atropine-like drug. The interaction is usually
described as “decreased effect” in the text. Correction could involve administration of
only one agent, adjustment in time of administration, or increase in the dosage of one or
both agents.
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Drugs with Similar Pharmacologic Effects
When two drugs have similar pharmacologic effects, their combined use can result in an
effect equal to, or even larger than, the sum of that obtained if either agent were used
separately. This interaction is described as “increased effects.” The terms additive or
potentiation might also be used to describe this interaction. An example of this
interaction is the concomitant use of agents with central nervous system (CNS)
depressant actions, such as alcohol, antianxiety agents, hypnotics, and antihistamines.
Another example is the use of two or more antihypertensive agents to reduce blood
pressure.
Changes in the Amount of Available Drug
Change in Absorption from the GI Tract. The absorption of most drugs from the
stomach or gastrointestinal (GI) tract is pH dependent. The concomitant use of an agent
that alters the pH can change the rate of absorption or the amount of drug absorbed, and
thus either increase (↑) or decrease (↓) the effect of the drug. For example, the use of
antacids, which increase the pH of the stomach, will result in a decrease in the absorption
of aspirin, which is more rapidly absorbed at a lower pH. The absorption of drugs is also
affected by how long drugs reside in the GI tract. Drugs that affect the motility of the GI
tract also affect drug absorption. The net effect of a laxative is usually decreased
absorption and effect because the drug to be absorbed in the GI tract stays there for a
shorter period of time. On the other hand, constipating agents often results
in increased absorption and effect. The presence of food can affect the rate of absorption
of drugs from the GI tract or the total amount of the drug absorbed. For example, the
absorption of tetracyclines is inhibited in the presence of dairy products (e.g., milk,
cheese), because the calcium present in such foods forms a complex with the drug.
Alteration of Urinary Excretion. Closely related to the rate at which drugs are absorbed
from the GI tract is the rate at which drugs are eliminated in the urine or reabsorbed from
the glomerular filtrate. Drugs that are eliminated more slowly because of another
concomitantly administered agent stay in the body longer; thus the effect of the drug is
increased. Drugs that are eliminated faster (less reabsorbed) because of another
concomitantly administered agent result in a decrease in the effect of the drug. As in the
case of absorption from the GI tract, elimination by the kidney is pH dependent. The pH
of the urine is sometimes altered purposely by the administration of an alkalizing agent
(sodium bicarbonate) or an acidifying agent (ammonium chloride). Whether a drug will
be excreted faster of slower with a change in pH depends on the drug. The alkalization of
the urine, for example, is sometimes undertaken for drugs such as sulfonamides. These
agents are more soluble at a higher pH, and thus the possibility of crystallization in the
kidney is reduced.
Displacement of Drugs from Protein-Binding Site
Drugs that bind to plasma protein may not be fully available to exert a pharmacologic
effect.
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1. Protein binding is considered when dosage is established so that a given amount of
drug will have the desired pharmacologic effect, even though that drug may be
significantly bound to plasma protein. However, this relationship can be altered when
another agent, which also binds to protein, is added to the therapy. If the attraction of
drug B for the protein is greater than that of drug A, drug A will be displaced (or
released) from the protein-binding site. This displacement, then, will result in a
greater amount of drug A being available, and thus the effect of drug A will be
increased. One such example is the Coumadin-type anticoagulants, which are bound
to protein but can be displaced by a variety of agents. A greater than expected amount
of anticoagulant can have severe side effects, including fatal hemorrhages.
2. Any condition or disease state such as hepatic disease, nephrotic syndrome, the aging
process, and malnutrition will cause an increase in plasma proteins. Protein-bound
drugs will have increased availability because there are fewer serum proteins.
Therefore, dose adjustment must be considered to avoid an increased concentration of
free drug, which can cause toxicity or adverse effects.
Changes in Drug Metabolism
Most drugs are degraded in the liver by specific enzymes (drug-metabolizing enzymes).
A change in the activity of an enzyme results in a change in the availability of the drug.
Often such an interaction results in inhibition of the enzyme, and an increased effect of
the drug is observed. However, certain drugs can stimulate the activity of enzymes
involved in the breakdown of another pharmacologic agent. For example, the long-acting
barbiturates stimulate certain drugmetabolizing enzymes in the liver. This results in a
more rapid breakdown of the drugs normally degraded by such enzymes (e.g., steroid
hormones including estrogen and progesterone, and Coumadin-type anticoagulants). The
rate of metabolism of any drug that undergoes hepatic biotransformation will be reduced
when there is loss of liver function because of aging or disease. The pharmacologic mode
of action of certain drugs, such as the monoamine oxidase (MAO) inhibitors or
disulfiram, consists of inhibiting a particular enzyme. An interaction can occur when this
inhibited enzyme system is called on to degrade another drug or food product. For
example, the above mechanism plays a role in the much publicized interaction of the
MAO inhibitors and tyramine-rich foods, such as cheese. The tyramine cannot be
degraded (as usual) by MAO because the enzyme is inhibited. Tyramine thus
accumulates and can cause severe hypertension. Such an interaction is also considered in
the treatment of alcoholics with disulfiram (Antabuse). The latter interferes with the
metabolism of alcohol, leading to the accumulation of acetaldehyde, which has such
unpleasant physiologic effects that the client will refrain from alcohol ingestion while on
this therapy.
Alteration of Electrolyte Levels. Drugs that promote the loss (e.g., potassium) or
retention (e.g., calcium) of electrolytes can cause the heart to become particularly
sensitive to the toxic effects of digitalis. Such an interaction has been noted in the
concomitant use of thiazide diuretics (which cause potassium loss) and digitalis.
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Alteration of GI Flora. Antibiotics and other antimicrobial agents often kill the intestinal
flora that synthesize vitamin K. A decrease in the concentration of vitamin K, which is
involved in blood coagulation, increases the effects of anticoagulants and can result in
hemorrhage.
A number of drug interactions are significant enough to warrant a special listing. These
are as follows:
• Toxic levels of carbamazepine (Tegretol) can results from the inhibition of
microsomal metabolism in the liver by cimetidine, danazol, diltiazem,
erythromycin, fluoxetine, isoniazid, propoxyphene, and verapamil.
• Fluoxetine (Prozac) given with MAO inhibitors can result in shivering, anxiety,
nausea, confusion, and death.
• Plasma levels of lithium, resulting in toxicity, can be increased by concomitant
administration of most nonsteroidal anti-inflammatory drugs (NSAIDs).
•
•
•
•
•
•
•
Severe methotrexate toxicity has been associated with concomitant use of
NSAIDs and antineoplastic doses of methotrexate. The risk is considerably
lower if low doses of methotrexate are used with NSAIDs (e.g., in the treatment
of psoriasis and arthritis).
Drugs that induce microsomal enzymes (e.g., barbiturates, carbamazepine,
phenytoin, primidone, rifampin) reduce the effectiveness of oral contraceptives.
Antacids containing aluminum, calcium, and/or magnesium significantly reduce
the absorption of quinolone antibiotics (e.g., ciprofloxacin, norfloxacin,
ofloxacin).
Sympathomimetics (e.g., amphetamines, ephedrine, metaraminol,
phenylephrine, pseudoephedrine) given with MAO inhibitors can cause a
hypertensive crisis. Symptoms include severe hypertension, hyperpyrexia,
arrhythmias, seizures, and death.
Theophylline levels can increase to the point of toxicity if the drug is given with
microsomal enzyme inhibitors such as cimetidine, ciprofloxacin,
clarithromycin, enoxacin, erythromycin, troleandomycin, and verapamil.
The hypoprothrombinemic response to warfarin can be slowly reduced (i.e.,
over 1–2 weeks) if the drug is given with inducers of microsomal enzymes
including barbiturates, carbamazepine, phenytoin, primidone, and rifampin.
The hypoprothrombinemic response to warfarin can be increased if the drug is
given with inhibitors of microsomal enzymes, including allopurinol,
amiodarone, cimetidine, ciprofloxacin, disulfiram, erythromycin, fluconazole,
ketoconazole, metronidazole, sulfinpyrazone, and
trimethoprimsulfamethoxazole (bactrim, septra).
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FOOD-DRUG INTERACTIONS
General Considerations
Certain physiologic changes are induced by food in the GI tract. These may diminish,
increase, interrupt, or stop the absorption of drugs, or delay the time a drug takes to reach
peak blood levels after administration. Although there is increasing knowledge and
concern about drug interactions, the effects of food-drug interactions are not as well
known. Yet, these interactions can produce dramatic effects, for example, when a food
containing tyramine is ingested by a client on MAO inhibitor therapy, a hypertensive
crisis is precipitated. MAO inhibitors increase levels of serotonin and norepinephrine in
the CNS and potentiate the cardiovascular effects of substances such as tyramine.
Symptoms include palpitations, severe occipital headaches, nausea, vomiting, and neck
stiffness. Caffeine and MSG (monosodium glutamate) can also enhance the effects of
MAO inhibitors. Grapefruit, pomelos and Seville oranges may interfere with enzymes
that break down certain drugs including some calcium channel blockers and cholesterollowering drugs. This may result in excessively high drug levels with potentially serious
adverse drug effects (e.g., Felodopine, Amiodarone, Zocor, Mevacor, Lipitor, Tegretol,
Zoloft).
DRUGS AND NUTRIENT UTILIZATION
Drugs can affect the way the body uses food by hastening the excretion of certain
nutrients, hindering the absorption of nutrients, or interfering with the body’s ability to
convert nutrients into usable forms. Foods can affect the action of drugs by altering
absorption, distribution, metabolism, and excretion and drugs can alter nutrient
absorption, metabolism, utilization, and excretion. These interactions can lead to vitamin
and mineral deficiencies, particularly in children, older adults, the chronically ill, and
those on marginal diets. Therefore, the diets of such clients should be modified to include
more foods rich in vitamins and iron. Some factors found to increase the potential for
interactions include long-term drug administration, poor dietary intake, pre-existing
disease states (especially gastrointestinal disease), increased nutritional needs resulting
from recent surgery or infection, and the patient's age (very young or very old). Druginduced nutritional deficiencies have been found and are usually slow to develop. They
occur most frequently with long-term drug treatment of chronic disease. Some
identified nutrition-related side effects of drugs include altered taste sensation, gastric
irritation, appetite suppression, altered GI motility, and altered nutrient metabolism and
function, including enzyme inhibition, vitamin antagonism, and increased urinary loss.
The psychological and physical status of the client influences drug action as well. For
example, malnutrition reduces the effectiveness of drugs by affecting the rates of
absorption and elimination of drugs, as well as tissue uptake and response. Depression
reduces salivary output, causing changes in nutritional uptake and possibly altering drug
action.
Table 3-1 lists drugs that affect utilization of nutrients. Table 3-2 presents a compilation
of foods that are acid, alkaline, or neutral.
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posted to a publicly accessible website, in whole or in part.
Delmar Nurse’s Drug Handbook / Drug Administration
Although the list of drugs and food interactions is continuously being revised and
updated, it is by no means current. The health care provider must carefully assess all
client complaints or altered responses (such as changes in physical condition or
behaviors) that could be related to an adverse drug effect. By completing a thorough
nursing and medication history, the provider can identify whether the client has disease
states, previous reactions, or nutritional, genetic, age, or other related factors that can
alter pharmacokinetic or pharmacodynamic parameters.
Table 3-1. Drugs That Affect Utilization of Nutrients
Drug
Alcohol
Aminopterin
Antacids
Anti-infectives
Anticoagulants
Antidiabetic agents
(oral)
Aspirin
Atropine,cortisone,
digitoxin, epinephrine,
and ethacrynic acid
Cathartics
Clofibrate
Colchicine
Contraceptives (oral)
Cycloserine
Diuretics and
ganglionic blockers
H2 blockers
Hydralazine and
isoniazid
Methotrexate
Mineral oil
Neomycin
Phenobarbital
Phenothiazine,
tricyclic
antidepressants
Surface-acting
agents
Thorazine
Effect
Malabsorption of folic acid and vitamin B12
Antagonizes folic acid; interferes with absorption of vitamin B12
Cause phosphate depletion, muscle weakness, and vitamin D
deficiency
Decrease utilization of folic acid and malabsorption of vitamin B12,
Ca, and Mg; decrease bacterial synthesis of vitamin K; inactivate B6;
impair amino acid transfer
Cause deficiencies of vitamin D, folic acid, and vitamin B12 by
increasing vitamin turnover rate in the body
Impair absorption of vitamin B12
Causes folate deficiency
Alter pancreatic or intestinal digestive function
Diminish nutrient absorption
Alters taste sensation; may suppress appetite and reduce nutrient
intake; malabsorption of folic acid and vitamin B12, electrolytes, and
sugar
Impairs absorption of vitamin B12, fat, lactose, and electrolytes
Deplete folic acid and vitamin B6
Causes folate deficiency
Cause potassium depletion
Interfere with vitamin D absorption; → osteopenia
Deplete vitamin B6 by inhibiting production of enzymes needed to
convert it into a form the body can use, or by combining to form a
compound which is excreted
Antagonizes folic acid
Hinders absorption of vitamins D, E, K, and carotene
Impairs absorption of vitamin B12; alters pancreatic absorption or
digestive function; interferes with bile activity
Causes folate deficiency
Stimulate appetite, result in increased food intake and weight gain
Alter absorption of nutrients by affecting fat dispersion
Induces hypercholesterolemia
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Delmar Nurse’s Drug Handbook / Drug Administration
Table 3-2. Acid, Alkaline, and Neutral Foods
Acidifiers: Acid Ash Food—Urinary Acidifiers
Dairy foods: cheeses (all types)
Eggs
Fish (including shellfish)
Fruits: cranberries, plums, and prunes
Gelatin
Macaroni: noodles, spaghetti
Mayonnaise
Meats
Nuts: Brazil nuts, peanuts, walnuts, filberts
Poultry
Vegetables: corn, lentils
Alkalizers: Alkaline Ash Foods—Urinary Alkalinizers
Dairy foods: milk, cream, buttermilk
Fruits (except cranberries, plums, prunes)
Jams, jellies, honey
Molasses
Nuts: almonds, chestnuts, coconuts
Olives
Vegetables (except corn, lentils)
Neutral Foods
Butter or margarine
Beverages: coffee, tea
Cooking oils and fats
Starches: corn, arrowroot
Sugars
Syrup
Tapioca
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