CHAPTER 6 DRUG INTERACTIONS

I. DRUG-DRUG INTERACTIONS
- can occur whenever a patient takes two or more drugs (MORE DRUGS,
MORE CHANCES OF
INTERACTIONS)
- may take multiple drugs to treat a single disorder or multiple
disorders
- may take OTC drug in addition to prescription medications
- may take caffeine, nicotine, alcohol, and other drugs that have
nothing to do with their illness
- some interactions are both intended and desired
- some interactions are both unintended and undesired
- some adverse interactions are well known and generally unavoidable,
other are yet to be documented

A. CONSEQUENCES OF DRUG-DRUG INTERACTIONS

1. Intensification of Effects
potentiative – when a patient is taking two medications, one drug
may intensify the
effects of the other
- interaction that enhances therapeutic effects is clearly
beneficial
- interaction that intensifies adverse effects is clearly
detrimental

2. Reduction of Effects
inhibitory – interactions that result in reduced drug effects
- interactions that reduce toxicity are beneficial
- interactions that reduce therapeutic effects are detrimental
- ex. asthmatic meds and beta blockers

3. Creation of a Unique Response – rarely, the combination of two drugs

produces a new response not
seen with either agent alone

B. BASIC MECHANISMS OF DRUG-DRUG INTERACTIONS

1. Direct Chemical or Physical Interaction – because of their physical or

chemical properties, some
drugs can undergo direct interaction with other drugs
- direct physical and chemical interactions usually render both drug
inactive
- occur most commonly when drugs are combined in IV solutions
which frequently, but not
always, produces a precipitate
- if precipitate appears, solution should be discarded
- direct drug interactions may not always leave visible evidence, so
you cannot rely on simple
 inspection to reveal all direct interactions
- because drugs can interact in solution, never combine two or
more drugs in the same
container unless it has been established that a direct
interaction will not occur
- same kinds of interactions that can take place when drugs are
mixed together in a bottle can
also occur when drugs are mixed together in a patient

2. Pharmacokinetic Interactions
a. Altered Absorption
- by elevating gastric pH, antacids can decrease the ionization
of basic drugs in the
stomach, thereby increasing the ability of basic drugs to
cross membranes and
be absorbed
- laxatives can reduce absorption by accelerating their
passage through the intestine
- drugs that depress peristalsis (morphine, atrophine) prolong
drug transit time in the
intestine, increasing the time of absorption
- drugs that induce vomiting can decrease absorption of oral
drugs
- cholestryramine and certain other absorbent drugs (which
are administered orally but
do not undergo absorption) can absorb other drugs onto
themselves,
preventing absorption of the other drug into the blood
- drugs that reduce regional blood flow can reduce absorption

b. Altered Distribution
i. Competition for Protein Binding – when two drugs bind to
the same site on plasma
albumin, coadminstration of these drugs produces
competition for binding
- binding of both agents is reduced, causing plasma
levels of free drug to rise
- increase in free drug can intensify effects
- increase in plasma levels of free drug is rarely
sustained or significant due to
rapid elimination
ii. Alteration of Extracellular pH – a drug with the ability to
change extracellular pH can
alter the distribution of other drugs
- ability of drugs to alter pH and thereby alter the
distribution of other drugs can
be put to practical use in the management of
poisoning
 c. Altered Metabolism – one of the most important and complex
mechanisms by which drugs
interact
- some drugs increase the metabolism of other drugs by
inducing synthesis of hepatic
drug metabolizing enzymes
- some drugs decrease the metabolism of other drugs by
inhibiting hepatic drug
metabolizing enzymes
- majority of drug metabolism is catalyzed by the cytochrome
P450 (CYP) group of
enzymes; 5 of which are responsible for the metabolism
of most drugs,
designated as CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP3A4

i. Induction of CYP Isozymes

inducing agents – drugs that stimulate the synthesis of
CYP isozymes
- ex. is Phenobarbital
- can stimulate their own metabolism as well as
that of other drugs
- can increase the rate of drug metabolism by as
much as two- or
three-fold
- when taken concurrently with another medicine,
dosage of the other
medicine may need adjustment
- when discontinuing, dosages of other drugs may
need to be lowered
to prevent drug levels from climbing
dangerously high as rates
of hepatic metabolism decline to their
baseline values
ii. Inhibition of CYP Isozymes – although inhibition of drug
metabolism can be
beneficial, as a rule, inhibition has undesirable
results
- when an inhibitor increases the level of another drug,
the outcome is toxicity
- when an inhibitor is taken with other medicines, be
alert for possible adverse
effects

d. Altered Renal Excretion

- renal excretion includes filtration, reabsorption, and active
secretion
- glomerular filtration can be decreased by drugs that reduce
cardiac output which
 decreased renal blood flow, decreases glomerular
filtration at the glomerulus,
which in decreases the rate of drug excretion
- by altering urinary pH, one drug can alter the ionization of
another, increasing or
decreasing the extent to which that drug undergoes
passive tubular
reabsorption
- competition between two drugs for active tubular secretion
can decrease renal
excretion of both agents

3. Pharmacodynamic Interactions – may be potentiative or inhibitory and

are of great clinical
significance

a. Interactions at the Same Receptor – almost always inhibitory

- inhibition occurs when an antagonist drug blocks access of
an agonist drug to its
receptor
- some reduce therapeutic effects and are undesirable
- some reduce toxicity and are beneficial
- ex. morphine and narcan

b. Interactions Resulting from Actions at Separate Sites

- even though two drugs have different mechanisms of action
and act at separate sites,
if both drugs influence the same physiologic process,
then one drug can alter
responses produced by the other

4. Combined Toxicity
- common sense tells us that if drug A and drug B are both toxic to
the same organ, then taking
them together will cause more injury than if they were not
combined
- unfortunately, when treating certain illness (tuberculosis,
HIV/AIDS), the combination is
essential, and hence can’t be avoided

C. CLINICAL SIGNIFICANCE OF DRUG-DRUG INTERACTIONS

- it should be clear that drug interactions have the potential to affect the
outcome of therapy
- interactions that increase therapeutic effects or reduce toxicity are
desirable
- interactions that reduce therapeutic effects or increase toxicity are
detrimental
- risk of serious drug interaction is proportional to the number of drugs
that a patient is taking, SO
 ALWAYS BE ALERT
- interactions are especially important for drugs that have a low
therapeutic index
- interactions that produce a modest increase in drug levels can
cause toxicity
- interactions that produce a modest decrease in drug levels can
cause therapeutic failure
- if a patient develops unusual symptoms, it is wise to suspect that dug
interaction may be the cause

Ways to Minimize Adverse Interactions:

- minimize the number of drugs a patient receives
- take a thorough drug history that identifies all drugs the patient is
taking to allow the prescriber
to adjust the regimen accordingly
***NOTE: illicit drugs or OTC preparations may fail to be
reported***
- adjust the dosage when an inducer of metabolism is added to or
deleted from the regimen
- adjust the timing of administration to minimize interference with
absorption
- monitor for early signs of toxicity when combinations of toxic
agents cannot be avoided

II. DRUG –FOOD INTERACTIONS

- drug-food interactions are both important and poorly understood
- important because they can result in toxicity or therapeutic failure
- poorly understood because research has been sorely lacking

A. IMPACT OF FOOD ON DRUG ABSORPTION

1. Decreased Absorption
- frequently decreases the rate of drug absorption which merely
delays the onset of effects
- peak effects are not lowered
- occasionally decreases the extent of absorption which reduces the
intensity of peak responses
- high fiber foods can reduce absorption of some drugs
- interaction between calcium-containing foods and tetracycline
antibiotics is the classic
example of food reducing drug absorption
- tetracyclines bind with calcium to form an insoluble and
nonabsorbable complex
causing absorption to be reduced and antibacterial
effects may be lost

2. Increased Absorption
- with some drugs, food increases the extent of drug absorption
- when this occurs, peak effects are heightened
B. IMPACT FOOD ON DRUG TOXICITY
OF
- drug-food interactions sometimes increase toxicity
- most dramatic example is the interaction between monoamine axidase
(MAO) inhibitors (family of
antidepressants) and food rich in tyramine (e.g., aged cheese, yeast
extracts, Chianti wine)
- combining an MAO inhibitor with these foods can raise blood
pressure to a life-threatening
level
- other examples include:
Theophylline (an asthma medicine) plus caffeine, can result in
excessive CNS excitation
Potassium-sparing diurectics (e.g., spironolactone) plus salt
substitutes, can result in
dangerously high potassium levels
Aluminum-containing antacids (e.g., Maalox) plus citrus beverages
(e.g., orange juice), can
result in excessive absorption of aluminum

C. IMPACT
OF FOOD ON DRUG ACTION
- although most drug food interactions concern drug absorption or drug
metabolism, food may also
(rarely) have a direct impact on drug action

D. TIMING DRUG ADMINISTRATION WITH RESPECT TO MEALS

OF
- administration of drugs at the appropriate time with respect to meals is
an important facet of drug
therapy
- absorption of some drugs can be significantly decreased by food; these
drugs should be
administered on an empty stomach
- absorption of other drugs can be increased with food; these drugs should
be administered with meals
- drugs may cause stomach upset when taken without food – if food does
not reduce their absorption,
administer with meals; however, if it does reduce absorption:
administer with food and reduce stomach upset (good news)
but reduce absorption
(bad news)
OR
administer without food and improve absorption (good news)
but increase stomach
upset (bad news)
no obvious choice
- to administer with meals means shortly after a meal
- to administer on an empty stomach means either 1 hour before or 2
hours after a meal
 - medication orders frequently fail to indicate when a drug should be
administered with respect to meals
- if you are uncertain, ASK the prescriber

III. DRUG-HERB INTERACTIONS

- herbal supplements are used widely in the U.S. creating the potential for
frequent and significant
interactions with conventional drugs
- of greatest concern are the interactions that reduce beneficial responses
to conventional drugs and
interactions that increase toxicity
- reliable information about herbal supplements is largely lacking –
including information on interactions
with conventional agents