US Pharm. 2007;32(3)93-98.
Perhaps the most common question
patients ask about their medication, aside from "Why does this medication cost
so much?" is, "Should I take this with or without food?" In most cases, upon
looking in the package insert or drug information resource, the pharmacist
discovers that most drugs in question may be administered without regard to
meals. However, some food products are fortified with vitamins and/or minerals
that can interact with certain drugs. Therefore, the more appropriate question
to ask is, "Which foods should I avoid taking with my medications?"
Furthermore, many patients consume mega-vitamins and supplements with known
drug interactions, yet they are often unaware of these interactions. The
purpose of this article is to equip pharmacists with a better understanding of
drug–food interactions. This article differs from traditional reviews on this
topic because the food substance is categorized individually, with the
interacting drugs discussed under each heading. While there are hundreds of
drug–nutrient interactions reported in the literature, the aim here is to
focus on those that are more common and clinically significant.
Grapefruit Juice
One of the most well known food–drug
interactions is grapefruit juice and the HMG-CoA reductase inhibitors, more
commonly known as statins. Grapefruit juice, in large quantities (32 oz. or
more per day), can inhibit the cytochrome P450 3A4 (CYP3A4) enzyme and
increase blood levels of drugs metabolized by this pathway, such as certain
statin drugs.1,2 Note that this interaction applies to grapefruit
juice, not the whole fruit itself. Furthermore, not all statins exhibit this
interaction: Only atorvastatin (Lipitor), simvastatin (Zocor), and lovastatin
(Mevacor) are metabolized by the CYP3A4 isoform. Of these three statins,
atorvastatin is least affected by grapefruit juice. Thus, the other statins,
namely rosuvastatin (Crestor), pravastatin (Pravachol), and fluvastatin
(Lescol), may be acceptable alternatives for patients who regularly consume
large amounts of grapefruit juice.3
Underlying this interaction is
the ability of some constituents of grapefruit juice to inhibit CYP3A4 in the
intestine, thereby reducing the metabolism of the statins and increasing the
drug's bioavailability. Thus, when large amounts of grapefruit juice are
consumed in combination with these drugs, patients are at an increased risk of
statin-related side effects, most notably, muscle toxicity, which may manifest
as myalgia, myopathy, or rhabdomyolysis.
While the statins receive the
most public attention for their interaction with grapefruit juice, other drugs
exhibit this same interaction. Calcium channel blockers are popular drugs that
interact with grapefruit juice. All of the dihydropyridine calcium–blocking
drugs, such as amlodipine (Norvasc), nifedipine (Procardia), and nicardipine
(Cardene), as well as the non-dihydropyridine agent verapamil (Calan),
interact with grapefruit juice.2 The calcium antagonist that is the
most affected by the fruit juice is felodipine (Plendil), demonstrating as
high as a 200% increase in the area under the curve (AUC) with
coadministration. Diltiazem (Cardizem), although a substrate for CYP3A4
metabolism, does not show a substantial increase in serum concentrations due
to grapefruit juice consumption.3 Nonetheless, pharmacists should
warn patients to avoid drinking large volumes of grapefruit juice
simultaneously with any calcium antagonist. Otherwise, patients may be at an
increased risk of such side effects as orthostatic hypotension.
The phosphodiesterase
inhibitors, sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis),
used for erectile dysfunction, can also increase blood levels with concurrent
use of grapefruit juice, but this interaction is unpredictable. While the
clinical effects of the interaction are less pronounced than other classes of
drugs, patients may have a slightly higher risk of adverse reactions, such as
priapism, hypotension, and visual disturbances.1,3
Estrogen-containing oral
contraceptives are also affected by grapefruit juice; their serum levels
increase only modestly when grapefruit juice is used concomitantly.3
Tricyclic antidepressants are affected by grapefruit juice because they are
also substrates for CYP3A4; clomipramine (Anafranil) is considered to be the
most well-documented drug of this class to interact. Diazepam (Valium),
temazepam (Restoril), and midazolam (Versed) are interacting agents of the
benzodiazepine class that have increased concentrations and central nervous
system depressant effects with grapefruit juice.1,3 However,
other benzodiazepines (e.g., lorazepam, oxazepam) do not appear to be affected.
Grapefruit juice doubles the oral systemic effects of budesonide
(Entocort), increasing the risk of the already prevalent glucocorticoid
effects.3 Buspirone levels and carbamazepine levels are increased
with concurrent administration of grapefruit juice.1 Although
ziprasidone levels can be elevated by concurrent consumption of grapefruit
juice, other atypical antipsychotics do not appear to be affected.3
It is important to note that
coadministration of grapefruit juice with the antiarrhythmic drug amiodarone
can be problematic. The AUC of amiodarone was increased by 50% in 11 subjects
when given with grapefruit juice (three 300-mL glasses on the day of
amiodarone administration).4 However, amiodarone has an active
metabolite that is also inhibited by grapefruit juice, making the net clinical
effect of the interaction difficult to predict.
Another potentially
significant grapefruit juice interaction is with the immunosuppressant
tacrolimus (Prograf). This drug is often used following organ transplantation.
Due to the ability of grapefruit juice to inhibit the metabolism of
tacrolimus, the manufacturer recommends avoiding the use of grapefruit juice
during therapy.
Caffeine
Not only do foods
affect the metabolism of drugs, but also in some cases, drugs interact with
and alter the metabolism of food additives, such as caffeine. While it is
appropriate to consider caffeine as a drug itself, rather than a food
additive, some patients may disregard the fact that a high content of caffeine
is found in coffee, tea, soft drinks, and other "energy" foods and beverages.
Many common drugs interfere with the metabolism of caffeine, resulting in an
increase in caffeine blood levels. Consumption of caffeinated beverages late
at night in combination with these medications may result in sleepless nights.
In addition, this may enhance caffeine's diuretic effect. Ciprofloxacin
inhibits the metabolism of caffeine, resulting in increased effects of
caffeine.3 The other fluoroquinolones do not appear to affect the
metabolism of caffeine and may therefore be seen as alternatives for patients
who consume large amounts of caffeine during the day. Cimetidine also
increases caffeine levels, thus a different H2 antagonist (e.g.,
ranitidine, famotidine) should be administered in caffeine users. Oral
contraceptives and prednisone also increase caffeine levels due to the
inhibition of caffeine metabolism.3 Conversely, caffeine inhibits
the metabolism of theophylline, which shares a similar chemical structure with
caffeine, and can increase the serum concentrations of theophylline.1
Pharmacists should warn patients taking theophylline that caffeine-containing
beverages may predispose patients to adverse theophylline-related effects,
such as jitteriness, insomnia, and cardiac arrhythmia.
Dairy Products/Calcium
In contrast to caffeine and
grapefruit juice, the use of dairy products containing calcium may cause a
chemical interaction, not a metabolic interaction. The calcium ion chelates
with the drug and may decrease its absorption. Most pharmacists are familiar
with the typical antacid and dairy product interactions. However, an
increasing number of foods is being fortified with calcium. Orange juice,
bread, and other foods enriched with calcium can result in the same type of
interactions seen with calcium-containing antacids and dairy products.5
The fluoroquinolones (e.g., ciprofloxacin, levofloxacin) may be rendered
ineffective when taken at the same time as dairy products or calcium
supplementation.2,5 Most manufacturers suggest minimizing this
interaction by administering an oral quinolone at least two hours before or
six hours after the dose of an oral calcium supplement or calcium-rich food.
Patients should be monitored for decreased therapeutic effects of oral
quinolones if administered with oral calcium supplements. Tetracyclines also
interact with concurrent administration of calcium and/or dairy products high
in calcium. Bisphosphonates (alendronate, risedronate, and ibandronate) have
low bioavailability, and little drug is absorbed when given with any type of
food or beverage other than water; this is especially problematic with dairy
products.
Levels of cefuroxime, a
cephalosporin antibiotic, are decreased when taken with dairy products.1
Other cephalosporins do not appear to be affected. In addition, methotrexate
levels are decreased with the consumption of milk-rich foods.3 As a
general rule, administration of dairy products and/or calcium supplements
should be separated from the interacting drug by at least two to four hours.
Protein-Rich Foods
Protein-rich foods can interfere
with or potentiate the absorption of various medications. Consuming a meal
high in protein and taking propranolol concurrently can increase the
beta-blocker's bioavailability. When propanolol was given with protein-rich
foods, a mean increase in bioavailability of 53% was reported.6
Coadministration of protein and propranolol may increase such adverse events
as bradycardia, hypotension, and, due to nonselectivity for beta-1 receptors,
bronchoconstriction.3 High-protein diets can decrease concentration
and efficacy of carbidopa/levodopa and theophylline, resulting in
subtherapeutic conditions and exacerbation of conditions.1
High-Fat Meals
Many drugs have their
pharmacokinetics altered by fatty foods. Most drug monographs will list that
maximum concentration is decreased, but total absorption remains the same.
3 Due to the multitude of these medications and the variability
observed, they are not discussed in this article. Some drugs have altered
pharmacokinetics based on the fatty content of meals. For example,
griseofulvin has a significantly increased absorption when taken with food,
especially a high-fat meal. Thus, griseofulvin is recommended to be taken with
a fatty meal to benefit from this interaction.7 However, this
should be done on a consistent basis, and certain extended-release
formulations may show increased "dose- dumping" with fatty meals, whereas
others do not.8
Fiber
Fiber, much like calcium, works to
bind drugs, resulting in decreased concentrations. For example, patients with
diabetes who try to decrease their cholesterol levels by eating oatmeal after
taking metformin might be worsening their diabetic control. Metformin blood
levels are decreased when taken with large amounts of fiber.1
Levothyroxine is another drug that is altered when taken with fiber. Digoxin
and penicillin are also affected by this food–drug interaction. However, other
antibiotics in the penicillin class do not appear to be altered by the use of
dietary fiber.1,3
Vitamin C and Fruit Juices
Increasingly more fruit juices are
fortified with vitamin C and other vitamins, if they do not contain them
already. The absorption of amphet amine-containing drugs (e.g., Adderall) is
altered, increased, or decreased if taken with acidic food or juices or
vitamin C.3 Maximal absorption of amphetamines occurs in the
intestinal alkaline environment. Acidic fruits or juices consumed concurrently
with these drugs may impair gastrointestinal absorption. Foods that acidify
the urine may increase renal clearance of amphetamines, leading to lower drug
levels. In addition, fexofenadine levels are decreased when taken with fruit
juices. Other second-generation antihistamines, such as cetirizine and
loratadine, may be affected but not to the same extent as fexofenadine.1,2
One of the largest populations that take these medications--children (for
attention-deficit hyperactivity disorder)--should avoid taking these drugs with
apple or orange juice in the morning.
Tyramine-Containing Foods
Tyramine is a
chemical found in foods and beverages such as cheese and red wine. It has a
significant interaction with monoamine oxidase inhibitors (MAOIs). These drugs
are used infrequently but are occasionally used to treat depression and are
becoming increasingly popular for the treatment of Parkinson's disease.
Linezolid, a newer oxazolidinone antibiotic, has some MAOI properties, thus
showing characteristics and potential for this interaction.1
Therefore, linezolid should be used cautiously in patients taking serotonin
selective reuptake inhibitors (SSRIs).3 Lastly, isoniazid, a
mainstay in the treatment of tuberculosis, also exhibits MAOI effects and
should not be taken with tyramine-containing foods.1,9
Warfarin
Consistency is the
key with warfarin in all circumstances. The most notorious food–drug
interaction regarding warfarin occurs with "green, leafy vegetables" due to
their rich vitamin K content. Warfarin, by its mechanism of action, interferes
with the synthesis of vitamin K–derived clotting factors.3
Increasing vitamin K intake will result in more clotting factors, reducing the
efficacy of warfarin. Some people erroneously believe that warfarin recipients
cannot eat any green, leafy vegetables. However, if patients remain consistent
with vitamin K intake, taking their medication as directed, the interaction is
not substantial. Yet, when patients become vegetarians or avoid these foods
completely after regular consumption, adverse events or changes in INR
(international normalized ratio) occur. Soy milk, char grilled foods, and
sushi containing seaweed may also decrease the effect of warfarin.10
Cranberry juice, in contrast, can significantly increase INR and potentiate
the anticoagulant effects of warfarin.2
Alcohol
While not a food per se, drug
interactions with alcohol are numerous and important. The list of drugs that
have sedating properties when used with alcohol is nearly endless. Some
examples are benzodiazepines, antidepressants, barbiturates, antihistamines,
opiates, muscle relaxants, antipsychotics, and anticonvulsants. When these
drugs are taken concurrently with alcohol, patients are at an increased risk
of ataxia, somnolence, respiratory depression, and motor impairment, which can
lead to falls, accidents, and injury. Excessive use of acetaminophen with
regular alcohol intake increases the risk of hepatotoxicity. Patients should
be advised not to exceed 4 g of acetaminophen in 24 hours and consult their
physician if they regularly drink three or more alcoholic drinks per day. A
disulfiram reaction (facial flushing, vomiting, tachycardia) can occur if
alcohol is ingested with drugs such as metronidazole, sulfonylureas, or
isoniazid.
Other Significant
Interactions
Levothyroxine
should not be taken with foods that may be goitrogenic.3 High
sodium intake can decrease drug levels of lithium, and low sodium intake can
increase levels of lithium; thus, consistency and moderation is important.
1 In addition, patients with hypertension and those with heart failure
should avoid sodium as much as possible, since it can exacerbate symptoms of
both conditions.1 Colchicine and metformin decrease the absorption
of vitamin B12, which may have an impact in patients with certain
types of anemia. Phenobarbital and corticosteroids decrease calcium
absorption. As a result, patients on long-term corticosteroid treatment should
have high levels of calcium supplementation, as well as a bisphosphonate for
osteoporosis prevention.1,3 Lastly, patients taking an
angiotensin-converting enzyme inhibitor or potassium-sparing diuretic (e.g.,
spironolactone or triamterene) should avoid excessive potassium intake, as
these drugs already increase potassium levels in the body.3
Conclusion
As evidenced by all
of the interactions discussed, it appears that the safest thing to take
medications with, unless clearly known otherwise, is a large glass of water.
Fad diets may bring new interactions that are unknown. For example,
pomegranate juice is becoming increasingly popular and has shown implications
of inhibiting CYP3A4, similar to grapefruit juice. Thus far, no drug
interactions have been directly linked to it, but the juice should be
considered as a potential offender.11 Whenever possible,
pharmacists should discuss drug administration instructions with each patient.
In cases where certain foods or beverages are known to impact therapy, the
pharmacist should determine the clinical relevance, if any, and advise
patients appropriately. Many drugs also interact with alcohol, herbal therapy,
and dietary supplements. Thus, it is important for the pharmacist to take a
thorough dietary history to determine if patients need additional counsel
about medication administration.
References
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2. Huang SM, Lesko LJ. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned? J Clin Pharmacol. 2004;44:559-569.
3. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Lexi-Drugs – Comprehensive and specialty fields. Hudson, OH: Lexi-Comp, Inc; 2006.
4. Libersa CC, Brique SA, Motte KB, et al. Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. Br J Clin Pharmacol. 2000;49:373-378.
5. Wallace AW, Amsden GW. Is it really ok to take this with food? Old interactions with a new twist. J Clin Pharmacol. 2202;42:437-443.
6. Liedholm H, Wahlin-Boll E, Melander A. Mechanisms and variations in the food effect on propranolol bioavailability. Eur J Clin Pharmacol. 1990;38:469-475.
7. Hardman JG, Limbird LE, Gilman AG. Goodman and Gilman's the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001.
8. Wonnemann M, Schug B, Schmucker K, Brendel E, et al. Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union. Int J Clin Pharmacol Ther. 2006;44:38-48.
9. Kaneko T, Ishigatsubo Y. Isoniazid and food interactions: fish, cheese, and wine. Intern Med. 2005;44:1120-1121.
10. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095-1106.
11. Summers KM. Potential drug-food
interactions with pomegranate juice. Ann Pharmacotherapy.
2006;40:1472-1473.
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