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Syrian Arab Republic
Faculty of Pharmacy
Biomedical Science department, Syria ,2018.
Edited by: Qussai Abbas & Kinda Sharrouf
Supervised by: Dr. Sophie Barakel & Dr. Alia Omran
FOOD AND DRUG INTERACTIONS
Classification of drug-food interactions:.........................................................................................................................7
EFFECTS OF FOOD ON DRUG.......................................................................................................................................8
I. Pharmacokinetic interactions.............................................................................................................................8
II. Pharmacodynamics Interactions....................................................................................................................13
EFFECTS OF DRUGS ON NUTRITION STATUS.....................................................................................................14
Most common food drug interactions...........................................................................................................................18
St. John’s wort.....................................................................................................................................................................21
Alcohol and Medication Interactions......................................................................................................................36
Specific Alcohol-Medication Interactions.......................................................................................................38
Summary of some signifiant Food-Drug Interactions............................................................................................45
Medicinescan treat and curemany health problems. However, they must be
taken properly to ensure that they are safe and effective. Medicationsshould
be extremely specific in their effects, have the same predictable effect for all
patients, never be affected by concomitantfood or other medications, exhibit
linear potency, be totally non-toxic in any dosage and require only a single
dose to affect a permanent cure. However, this ideal drug is still to be
discovered. Many medicineshavepowerful ingredientsthat interact with the
human body in different ways. Diet and lifestyle can sometimes have a
significant impact on drugs.
A drug interaction is a situation in which a substance affects the activity of a
drug when both are administered together i.e. the effects are increased or
decreased, or they produce a new effect that neither produces on its own.
Typically, interactionsbetweendrugscome to mind (drug-drug interaction).
However, interactions may also exist between drugs and foods (drug-food
interactions), as well as drugs and medicinal plants or herbs (drug-plant
interactions). People taking antidepressant drugs such as monoamine
oxidase inhibitors should not take food containing tyramine as hypertensive
crisis may occur (an example of a drug-food interaction). These interactions
may occur out of accidental misuse or due to lack of knowledge about the
active ingredients involved in the relevant substances.
Drug interactionsmaybetheresult ofvariousprocesses. Theseprocessesmay
includealterationsinthepharmacokineticsofthedrug, such as alterationsin
the absorption, distribution, metabolism, and excretion (ADME) of a drug.
Alternatively, drug interactions may be the result of the pharmacodynamic
propertiesofthedrug, e.g., additive, synergistic, or antagonisticeffects(when
co-administration of a receptor antagonist and an agonist for the same
receptor) of a drug.
Drug interactions(DIs) represent an importantand widely under recognized
source of medication errors.
Interactions between food and drugs may inadvertently reduce or increase
the drug effect. Some commonly used herbs, fruits as well as alcohol may
causefailureof thetherapyup a point of to seriousalterationsofthepatient’s
health. The majority of clinically relevant food-drug interactions are caused
by food induced changesin the bioavailabilityof the drug. Major side-effects
of some diet (food) on drugs include alteration in absorption by fatty, high
protein and fiber diets.
Bioavailability is an important pharmacokinetic parameter which is
correlated with theclinicaleffect ofmost drugs. However, inorder toevaluate
the clinicalrelevance of a food-drug interactiontheimpact of food intake on
theclinicaleffect of the drug hasto bequantified aswell. The most important
interactionsare those associated with a high risk of treatment failurearising
from a significantly reduced bioavailability in the eating state. Such
interactions are frequently caused by chelation with components in food. In
addition, thephysiologicalresponse to food intake, in particular, gastricacid
secretion, may reduce or increase the bioavailability of certain drugs.
The gastrointestinal absorption of drugs may be affected by the concurrent
use of other agentsthat have a largesurfacearea upon which the drug canbe
absorbed, bind or chelate, alter gastric pH, alter gastrointestinal motility, or
affect transport proteins such as P-glycoprotein.
A reduction only in absorption rate of a drug is seldom clinically important,
whereasa reductioninthe extent of absorptionwill be clinicallyimportant if
it results in sub therapeutic serum levels.
Coenzyme Q-10 (CoQ10) is very widely consumed by humans as a food
supplement becauseof itsrecognitionby the public as an importantnutrient
in supporting humanhealth. It interfereswith intestinalefflux transporterP-
glycoprotein (P-gp) and as result food-drug interactions arise. The
interaction of natural products and drugs is a common hidden problem
encountered in clinical practice.
The interactions between natural products and drugs are based on the same
pharmacokinetic and pharmacodynamic principles as drug-drug
interactions. Several fruits and berries have recently been shown to contain
agents that affect drug-metabolizing enzymes.
Grapefruit isthemost well-knownexample, but alsosevillianorange, pomelo
and star fruit contain agents that inhibit cytochrome P450 3A4 (CYP3A4),
which is the most importantenzyme in drug metabolism. Thestudy of drug-
drug, food-drug, and herb-drug interactions and of genetic factors affecting
pharmacokineticsand pharmacodynamicsisexpected toimprovedrug safety
and will enable individualized drug therapy.
Drugs can show their efficacy only if administered in
drugs and foods and at appropriate time. In contrast
to the easy access to information on drug-drug
interactions, the information about food-drug
interactionisnot always availableconveniently. It isa
difficult and complex problem to accurately
determine the effects of food and nutrients on a
Foods can interfere with the stages of drug action in a number of ways. The
most common effect is for foods to interfere with drug absorption. This can
make a drug less effective because less gets into the blood and to the site of
action. Second, nutrients or other chemicalsinfoods canaffect how a drug is
used in the body. Third, excretionof drugs from the body may be affected by
foods, nutrients, or other substances. With somedrugs, it’simportant toavoid
taking food and medicationtogether becausethefood can makethedrug less
effective. For other drugs, it maybegood totakethedrug with food toprevent
It is also possible for drugs to interfere with a person’s nutritional status.
Somedrugsinterferewith theabsorptionofa nutrient. Other drugsaffect the
body’s use and/or excretionof nutrients, especiallyvitaminsand minerals. If
less of a nutrient is available to the body because of these effects, this may
lead to a nutrient deficiency. Sometimes drugs affect nutritional status by
increasing or decreasing appetite. This affects the amount of food (and
Synergy and antagonism
When the interaction causes an increase in the effects of the drug the
interaction is called a synergistic effect.
The oppositeeffect to synergy is termed antagonism: Whenthe interaction
causes a decrease in the effects of one or both of the drugs.
By studying the conditions that favour the appearance of interactions it
should be possible to prevent them or at least diagnose them in time. The
factorsor conditionsthat predisposeor favour theappearanceofinteractions
High-risk patients, such as the elderly patients taking
three or more medications for chronic conditions,
patients suffering from diabetes, hypertension,
depression, high cholesterol or congestive heart failure
should be especially monitored for such drug-food
Insufficient nutritional status can impair drug
metabolism. Some people at higher risk for drug-
nutrient interactions. They are who:
• have impaired hepatic, renal or gastro-intestinal
• are nutritionally compromised due to chronic disease.
• have recent weight loss or dehydration.
• are on multiple and prolonged drug therapy.
• areat the extremesofage with changesinlean bodymass, totalbodyfluids
and plasma protein concentration.
Classification of drug-food interactions:
Drug-nutrient interactions could be classified into one of five broad
categories. The many types of drug-nutrient interactions could thus be
categorized with each having an identified precipitating factor and an object
of the interaction. In some cases, the drug is the precipitating factor (i.e.,
causing changes to nutritional status), while in others the drug is the object
of the interaction (i.e., changes in drug disposition or effect result from a
nutrient, food, or nutritional status). In the event of the precipitating factor
produces significant change in the object of the interaction, drug-nutrient
interactionsareconsidered as important. Interactionsthat need to be totally
avoided are not common; instead close monitoring with modification to the
dosing schedules is usually all that is necessary.
EFFECTS OF FOOD ON DRUG
I. Pharmacokinetic interactions
Modifications in the effect of a drug are caused by differences in the
absorption, transport, distribution, metabolism or excretion of the drug.
These changesare basicallymodificationsinthe concentration of the drugs.
1- Absorption interactions:
Reduced or delayed drug absorption:
The presence of food may decrease or delay drug absorption and that could
be due to:
The formation of insoluble complexes
Delayed gastric emptying
Increased viscosity due to the presence of food
Some examples of drug-food interactions that delay and reduce the absorption of
Drug Mechanism Counseling
High pectin foods act as
adsorbant and protectant
Take on empty stomach if
foods bind drug
Take drug same time with
relation to food, Avoid
taking with high-fiber foods
Glipizide Mechanism unknown
Affects blood glucose; more
potent when taken half hour
Food raises gastric pH
Take on empty stomach if
Drug competes with
amino acids for
Avoid taking drug with
Methyldopa Competitive absorption
Avoid taking with high-
If anorally administereddrug harmsthestomach lining or decomposesinthe
acidic environment of the stomach, a tablet or capsule of the drug can be
coated with a substanceintended toprevent it from dissolving untilit reaches
thesmallintestine. Theseprotectivecoatingsaredescribed asenteric coating.
For these coatingsto dissolve, they must comein contact with theless acidic
environment of the small intestine or with the digestive enzymes there. One
example is aspirin, when food delays gastric emptying this delays aspirin
Increased drug absorption:
Increased drug absorption due to the presence of food has been frequently
reported. Accumulated evidencesuggest that morecompletedrugdissolution
due to the presence of food itself, or as a result of food induced
gastrointestinalsecretionsor delayed gastricemptying, oftenhasa significant
positive effect on absorption, particularly for fat soluble compounds.
In particular, poorly water soluble drugs (e.g. griseofulvin,
mebendazoleand halofantrine), whentaken asa solid formulationmay
not enter solution readilyin thestomach. Administrationofsuch drugs
with very fatty foods can increase bioavailability, possibly by such
mechanisms as the formation of solutions in the dietary oil.
Bioavailability of Axetil (Ceftin), an antibiotic, is 52% after a meal and
37% in the fasting state.
Absorptionoftheantiretroviraldrug saquinavir isincreasedtwofold by
Taking ketoconozoleand delavirdinewith orangeor cranberryjuicecan
reduce stomach pH and increase absorption, however in the case of
warfarin, patients who are taking warfarin should limit or avoid
completely drinking cranberry juice.
Some examples of drug-food interactions that accelerate the absorption of drugs
Drug Mechanism Counseling
Carbamazepine Increased bile production, enhanced
dissolution and absorption
Dicumerol Increased bile flow, delayed gastric
emptying permits dissolution and
Take with food
Griseofulvin Drug is lipid soluble, enhanced
absorption with high- fat foods.
Take with high- fat foods
Hydralazine, Labetalol and
Food may reduce first-pass extraction
Delayed gastric emptying improves
dissolution and absorption
Propranolol Food may reduce first-pass extraction
Take with food
Spironolactone Delayed gastric emptying permits
dissolution and absorption, bile may
solubilize the drug
2- Metabolism interactions:
Types of drug metabolism interaction:
Alteration in activities of enzymes that metabolize drugs can result in:
Increased blood concentration of drug (stronger physiological
effects)-ex. Grapefruit and statins
Decreased effectiveness of drug (ex. Warfarin and vitK)
Cytochrome P450 is a very large family of
hemoproteins that are characterized by
their enzymatic activityandtheir roleinthe
metabolism of a large number of drugs. Of
the various families that are present in
human beings the most interesting in this
respect are the 1, 2 and 3, and the most
important enzymes are CYP1A2, CYP2C9,
CYP2C19, CYP2D6, CYP2E1 and CYP3A4.
The majority of the enzymes are also involved in the metabolism of
endogenous substances, such as steroids or sex hormones, which is also
important should there be interference with these substances.
Fruit Molecular target Drug interactions
Grapefruit inhibits CYP3A4, CYP1A2, MRP2,
calcium channel antagonist, central nervous
system modulators, HMG-CoA reductase,
antihistamines, and antibiotics
Sevilla orange inhibits CYP3A4, P-glycoprotein,
vinblastine, fexofenadine, glibenclemida,
atenolol, ciprofloxacine, ciclosporine,
celiprolol, levofloxacin and pravastatin
Grapes inhibits CYP3A4 and CYP2E1 cyclosporine
Mango inhibits CYP1A1, CYP1A2,
CYP3A1, CYP2C6, CYP2E1, P-
midazolam, diclofenac, chlorzoxazone,
Apple inhibits CYP1A1,
Vegetable Molecular target Drug interactions
Broccoli inhibits CYP1A1, CYP2B1/2,
CYP3A4, CYP2E1, hGSTA1/2,
MRP1, MRP2, BCRP, UDP,
(SULTs) and quinone reductase
Spinach possible inhibition of CYP1A2 heterocyclic aromatic amines
Tomato inhibits CYP1A1, CYP1B1, UGP
increases UGT and CYP2E1
diethylnitrosamine, N-methyl- ,-N-
nitrosourea and 1,2 dimethylhydrazine
Carrot induces phenolsulfotransferases
and ethoxycoumarin O-
deethylase ECD inhibits CYP2E1
inhibits CYP1A2, CYP2A2,
CYP3A1, CYP2C11, CYP2B1,
in vitro and in vivo
3- Excretion interactions
Only the free fraction of a drug that is dissolved in the blood plasma can be
removed through the kidney. Therefore, drugs that are tightly bound to
proteins are not available for renal excretion, as long as they are not
metabolized when they may be eliminated as metabolites.
Theexcretionofdrugsfrom thekidney's nephronshasthe samepropertiesas
that of any other organic solute: passive filtration, reabsorption and active
secretion. In thelatter phasethe secretionofdrugsis an activeprocessthat is
subject to conditions relating to the saturability of the transported molecule
and competition between substrates. Therefore, these are key sites where
interactionsbetweendrug and nutritioncould occur. Filtrationdependson a
number of factors including the pH of the urine, it having been shown that
the drugs that act as weak bases are increasingly excreted as the pH of the
urine becomes more acidic, and the inverse is true for weak acids.
II. Pharmacodynamics Interactions
Foods may interact with medications by altering their
Diets high in vitamin K may cause
antagonism of warfarin and decreased
therapeutic efficacy of the anticoagulant.
Foods rich in vitamin K include green leafy
vegetables (kale, turnip greens, spinach
and broccoli), cauliflower, chick peas,
green tea, pork liver and beef liver. Garlic
can cause additive antiplatelet eﬀect in
combination with warfarin, heparin, and
low molecular weight heparin (LMWH),
and cause increased risk of bleeding.
Alcoholic beverages may increase the
central nervous system depressant effects
of medications such as benzodiazepines,
antipsychotic, muscle relaxants, narcotics
or any drug with sedative actions.
An example of a food potentiating the effect
of a medication is coffee, as caffeine has
additive effects on theophylline. It has been
reported that caffeine increased serum
theophylline levels by 20%–30% and
increased the half-life of theophylline by
decreasing clearance. Patients may
complain of nervousness, tremor or
insomnia. Caffeine has some
bronchodilator effects, which may enhance
the effects of theophylline. A lower dosage
of theophylline may be necessary for those
patients who consume excessive quantities
of coffee (more than 6 cups daily).
EFFECTS OF DRUGS ON NUTRITION STATUS
Some drugs can have an effect on a patient’s nutritional status. The
mechanisms for these effects are varied and are usually due to drug side
effects. A drug canenhance or inhibit nutrientbioavailability. Thus, it affects
the nutritional status of individuals. For instance, elderly people, who are
taking multiple medications for a long period of time are often found to be
deficient in one or more nutrients. Other age groups, such as young children
and adolescents, are also particularly at risk.
There is a potential problem with drug-nutrient interactions in adolescents
becausetheir nutrient needsare higher thanthoseofadults. Pregnant women
and infants are the other groups also at particular risk. The reason of these
deficiencies is not only based on the chemical reactions between drugs and
nutrients but also on the dose and duration of treatment or exposure to the
Drugs can interfere with nutrient at several sites starting from the ingestion
of the food to the final stage of excretion.
The influence of medicationonoverall nutritionalstatuscanbe due to many
• Appetite changes
• Oral taste and smell
• Dry mouth
• Gastrointestinal effects
• Organ system toxicity
• Glucose levels
Examples of drug categories that may affect appetite:
Some anorectic drugs are used for weight loss and to treat obesity by
reducing appetite. Examplesareadrenergic and serotoninergic agents,
which cause satiety, reduce appetite, and increase energy expenditure
leading to weight loss. A good example for adrenergic drugs are
amphetamines that stimulate secretion of norepinephrine and reduce
Hormones: Synthetic derivativeofprogesterone, medroxyprogesterone
acetate or megestrol acetate, used for the treatment of hormone-
sensitive breast and endometrial cancer, may increase appetite, food
intake, and weight gain.
Anticonvulsants (caramazepine and valproic acid)
Antihistamines (cyproheptadine hydrochloride – Periactin)
Psychotropic drugs (chlordiazepoxide hydrochloride – Librium,
diazepam – Valium, chloromazine hydrochloride – Thorazine,
meprobamate – Equanil)
Corticosteroids (cortisone, prednisone).
Dronabinol also known as THC (from tetrahydracannabinols), is also
used as an appetite stimulant.
1- Drugs affecting oral cavity, taste and smell
Taste changes: cisplatin, captopril (anti-hypertensive), amprenavir
(antiviral), clarithromycin (antibiotic), some hypoglycemic agents like
glipizide, the antimicrobials amphotericin B, ampicillin, and antiepileptic
Mucositis: antineoplastic drugs such as interleukin-2, paclitaxel,
Dry mouth: Anticholinergic drugs (tricyclic antidepressants such as
amytriptyline, antihistamines such as diphenhydramine, antispasmodics
such as oxybutynin).
2- Drugs that affect the GI tract: Drugscandamagethe intestinalabsorptive
surfaces including villi, microvilli, brush border enzymes, and the
transport system. Also drugs can affect the absorption of nutrients by
changing the GI transit time or the overall GI chemical environment.
Absorption of micronutrients, vitamins and minerals, as well as
macronutrients, protein and fat, are affected by the type, dosage, and
strength of some drugs.
Alendronate (Fosamax) anti-osteoporosis drug, patients must sit upright
30 minutes after taking it to avoid esophagitis.
Orlistat – blocks fat absorption, cancauseoily spotting, fecalurgency and
Narcotic agents cause constipation.
Drug classes that cause diarrhea:
Laxatives Many laxatives, mineral oil, and cathartic agents reduce
transit time in the GI tract and may cause steatorrhea and loss of fat-
soluble vitamins, A and E, and possibly calcium and potassium. Also
drugs containing sorbitol, such as theophylline solutions, can induce
osmotic diarrhea and so shorten the transit time.
The using of chemotherapeutic agents to treat cancer can affect growing
tissues, particularlythelining ofthegastrointestinaltract (GIT). Nausea is
a commonsideeffect and caninterferewith eating. Somepatientscanhave
oral and esophageal lesions and it can cause pain upon chewing and
swallowing (odynophagia). Thus, these formations lead to limits oral
Non-steroidalanti-inflammatoryagents, commonlyused to treat
arthritis, including aspirin, cancauseirritationof theupper
gastrointestinalmucosa and even causeulcers which cancauseGI
bleeding and gastritis, thiscandepressappetiteand produceweight loss.
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 diarrhea. Overgrowth in the
mouth may result in candidiasisor thrush, which can reduce oral intake.
Antacids change the pH of the stomach and cause chelating with some
minerals, consequently reducing their absorption. Higher pH in the
stomach reduces the absorption of iron, calcium, zinc, and magnesium.
3- Drugs that may affect glucose levels:
Decrease glucose levels:
Antidiabetic drugs (acarbose, glimepiride, glipizide, glyburide, insulin,
metformin, miglitol, neteglinide, pioglitizone, repaglinide,
Drugs that can cause hypoglycemia: ethanol, quinine, disopyramide
(antiarrhythmic) and pentamidine isethionate (antiprotozoal).
Increase glucose levels:
Anti-retrovirals, protease inhibitors (amprenavir, nelfinavir, ritonavir,
Diuretics, antihypertensives (furosemide, hydrochlorothiazide,
Hormones (corticosteroids, danazol, estrogen or
estrogen/progesterone replacement therapy, megestrol acetate, oral
Niacin (antihyperlipidemic) baclofen, caffeine, olanzapine,
Some of the important functions of vitamins and several minerals are
being coenzymes/cofactorsinmetabolic processesinthehumanbody. As
a result, certain drugs are targeted to these coenzymes (antivitamins) in
order to reduce the activity of some enzymes in related metabolic
reactions. Good examples of these drugs are:
Vitamin folate (B6) is a cofactor for the enzyme dihydrofolate
reductase, it is necessary for nucleic acid biosynthesis and cell
replication. Thisvitaminwillbe excreted becausethedrugsdisplace
it from dihydrofolate reductase to reduce cell replication, like
methotrexate(MTX) for treating leukemiaand rheumatoidarthritis.
The anticoagulantdrug, warfarin(Coumadin) actsbypreventing the
conversion of vitamin K to a useful form, thus a balance or steady
state between dose of drug and consumption of vitamin K must be
Colchicine (gout) para-aminosalicylic acid (TB) sulfasalazine
(ulcerative colitis) trimethoprim (antibiotic) and pyrimethamine
(antiprotozoal) impair absorption of B12 or folate.
Antibioticscaneffect normalflora and causevitaminBdepletionand
antibiotics like cefamendole, cefoperazone, cefotetan can interfere
with vitamin K producing bacteria.
Nutrient excretion and altered reabsorption mechanisms can cause
drugs to induce nutrient excretion:
D-Penicillamine chelates with toxic metals, and with some other
metals like zinc, eliminating it via urine.
Ethylenediaminetetra-aceticacid (EDTA) hasbeenshowntocause
urinary excretion of zinc.
Some diuretics, such as furosemide, ethacrynic acid, and
triamterene, reduce the reabsorption of electrolytes and minerals
such as calcium, magnesium, zinc, and increaserenal excretionof
The using of thiazide and loop diuretics can often cause sodium
loss in the urine.
Phenothiazine antipsychotic drugs (chlorpromazine) increase
excretion of riboflavin which can lead to riboflavin deficiency in
those with poor intakes
Cisplatin causes nephrotoxicity and renal magnesium wasting
resulting in acute hypomagnesemia in 90% of patients (also
hypocalcemia, hypokalemia, hypophosphatemia), may require
intravenous magnesium supplementation or post-treatment
hydration and oral magnesium supplementation and that may
persist for months or years after therapy is finished.
Corticosteroids(prednisone) decreasesodium excretion, resulting
in sodium and water retention; increase excretion of potassium
and calcium (low sodium, high potassium diet is recommended,
calcium and vitamin D supplements are recommended with long
term steroid use to prevent osteoporosis.
Most common food drug interactions
Grapefruit juice can be part of a healthful diet—most of the time. It has
vitaminCand potassium—substancesyour bodyneedsto workproperly. But
it isn't good for you when it affects the way your medicines work.
Grapefruit juice and fresh grapefruit can interfere with the action of some
prescription drugs, as well as a few non-prescription drugs.
This interaction can be dangerous with most drugs that interact with
grapefruit juice, "the juice increases the absorption of the drug into the
bloodstream, whenthereisa higher concentrationofa drug, you tend tohave
more adverse events."
For example, if you drink a lot of grapefruit juice while taking certain statin
drugs to lower cholesterol, too much of the drug may stay in your body,
increasing your risk for liver damageand muscle breakdownthat canlead to
Drinking grapefruitjuiceseveralhours before or several hours after you take
your medicinemay stillbe dangerous, so it'sbest to avoid or limit consuming
grapefruit juice or fresh grapefruit when taking certain drugs.
Examples of some types of drugs that grapefruit juice can interact
some statin drugs to lower cholesterol, such as Zocor (simvastatin), Lipitor
(atorvastatin) and Pravachol (pravastatin)
some blood pressure-lowering drugs, such asNifediac and Afeditab (both
some organ transplant rejection
drugs, such as Sandimmune and
Neoral (both cyclosporine)
some anti-anxiety drugs, such as
some anti-arrhythmia drugs, such as
Cordarone and Nexterone (both
some antihistamines, such as Allegra
Drugs known to interact with grapefruit juice:
Too High or Too Low Drug Levels
Many drugs are broken down (metabolized) with the help of a vital enzyme
called CYP3A4 in the small intestine. Certain substances in grapefruit juice
blocktheactionofCYP3A4, soinstead ofbeing metabolized, moreofthedrug
enters the bloodstream and stays in the body longer. The result: potentially
dangerous levels of the drug in your body.
The amount ofthe CYP3A4 enzymein the intestinevariesfrom one personto
another. Some people have a lot, and others have just a little—so grapefruit
juice may affect people differently when they take the same drug.
While scientists have known for several decades that grapefruit juice can
causea potentiallytoxiclevelofcertaindrugsinthebody, morerecent studies
have found that the juice has the opposite effect on a few other drugs.
"Grapefruit juice reduces the absorption of fexofenadine," decreasing the
effectiveness of the drug. Fexofenadine (brand name Allegra) is available in
both prescription and non-prescription forms to relieve symptoms of
seasonalallergies. Fexofenadinemayalsobelesseffectiveiftakenwith orange
or apple juice, so the drug label states "do not take with fruit juices.
Why this opposite effect?
It involves the transportation of drugs within the body rather than their
metabolism. Proteins in the body known as drug transporters help move a
drug into cells for absorption. Substancesingrapefruit juiceblockthe action
of a specific group oftransporters. Asa result, lessof thedrug isabsorbed and
it may be ineffective.
Tips for Consumers:
Ask your pharmacist or other health care professional if you can have
fresh grapefruit or grapefruit juice while using your medication. If you
can’t, you maywant toask ifyou canhave other juiceswith themedicine.
Read theMedicationGuideor patient informationsheet that comeswith
your prescriptionmedicinetofind out if it could interact with grapefruit
juice. Some may advise not to take the drug with grapefruit juice. If it’s
OK to have grapefruitjuice, therewill be no mentionof it in the guideor
Read theDrug Factslabel on your non-prescription medicine, which will
let you know if you shouldn’t have grapefruitor other fruit juiceswith it.
If you must avoid grapefruitjuicewith your medicine, check the label of
bottles of fruit juiceor drinks flavored with fruit juice to make sure they
don’t contain grapefruit juice.
Seville oranges (often used to make orange marmalade) and tangelos (a
cross between tangerines and grapefruit) affect the same enzyme as
grapefruit juice, so avoid these fruits as well if your medicine interacts
with grapefruit juice.
St. John’s wort
St John's wort (also known as Hypericum
perforatum) is a flowering plant in the family
Hypericaceae. The common name "St John's
wort" maybe used to refer to any speciesof the
genus Hypericum. Therefore, Hypericum
perforatum is sometimes called "common St
John's wort" or "perforate St John's wort" in
order to differentiateit. Historically, St. John’s
wort has been used for a variety of conditions,
including kidney and lung ailments, insomnia
and to aid wound healing. Now it isa medicinal
herb with antidepressant activityand potent anti-inflammatorypropertiesas
an arachidonate 5-lipoxygenase inhibitor and COX-1 inhibitor.
1- St John’s wort isknown toaffect several cytochromeP450 isoenzymes and
this accounts for the wide range of drugs with which St John’s wort has
been reported to interact. The following is a list of cytochrome P450
isoenzymes that have been assessed with St John’s wort in a clinical
CYP3A4: the main clinically relevant effect of St John’s wort on
cytochrome P450 is the induction of CYP3A4. This has been shown to be
related to the constituent, hyperforin. Products vary in their hyperforin
content; preparations with a high-hyperforin content, given for a long
period of time, will induce CYP3A4 activity, and therefore decrease the
levels of drugs metabolised by CYP3A4, by a greater extent than
preparationscontaininglow-hyperforinlevelstakenfor a shorter period of
Conventionaldrugsareoftenused asprobesubstratesinorder toestablish
the activity of another drug on specific isoenzyme systems.
CYP2C19: there are some clinical reports suggesting that St John’s wort
CYP2C8: St John’s wort may induce CYP2C8.
CYP2C9: St John’swort mayinduce CYP2C9, but themechanism for these
interactionsisnot conclusivebecausenot allCYP2C9 substrateshavebeen
found to interact.
CYP2E1: St John’s wort may induce CYP2E1 but the general clinical
importance of this is unclear.
CYP1A2: St John’swort isalsothoughttobeaninducer ofCYP1A2aslevels
of caffeine and theophylline, both of which are CYP1A2 substrates, have
been reduced by St John’s wort. However, the generalclinicalimportance
of thisis unclear as other studieshave found no clinicallysignificanteffect
on these drugs. This may be because St John’s wort only has a minor
inducing effect on CYP1A2, which maydepend on the level of exposureto
CYP2D6: St John’s wort does not appear to affect the activity of CYP2D6
to a clinically relevant extent.
St John’s wort is known to affect P-glycoproteinactivity, especiallyintestinal
P-glycoprotein, and it isgenerallythought that inhibitiontakesplaceinitially,
and briefly, but is followed by a more potent and longer-acting induction. It
is the induction that leads to the clinically relevant drug interactions of St
John’s wort that occur asa result ofthismechanism. Hyperforinisimplicated
as the main constituent responsible for the effect.
3- Serotonin syndrome: St John’s wort inhibits the reuptake of 5-
hydroxytryptamine (5-HT, serotonin) and this has resulted in a
pharmacodynamic interaction, namely the development of serotonin
syndrome with conventionaldrugsthat also have serotonergic properties.
St John’s wort is known to interact with manyconventional drugsbecauseof
its ability to induce the activity of CYP3A4 and P-glycoprotein, which are
involved in the metabolism and distribution of the majority of drugs.
Hyperforin is the active constituent believed to be central to the inducing
effects of St John’s wort. As St John’s wort preparations and dose regimens
are varied, the amount of hyperforin exposure will also vary a great deal,
which makespredictingwhether aninteractionwilloccur, and towhat extent,
St John’s wort interaction with Antidiabetics:
St John’swort modestlydecreasestheAUCofgliclazideand
rosiglitazone. Pioglitazone and repaglinide are similarly
metabolised and may therefore be expected to interact
similarly. St John’s wort does not affect the metabolism of
Gliclazide is a substrate of the cytochrome P450
isoenzyme CYP2C9 and St. John’s wort induces this isoenzyme, thereby
increasing the metabolism of gliclazide and reducing its levels.
Tolbutamide, anotherCYP2C9 substrate, wasunaffected bySt John’swort
suggests that other factors may be involved.
Rosiglitazone is known to be metabolised principally by the cytochrome
P450 isoenzyme CYP2C8, and it was therefore concluded that St John’s
wort induces this isoenzyme.
St John’s wort interaction with Antiepileptics:
St John’s wort modestly increased the clearance of single-dose
carbamazepine, but had no effect on multiple-dose carbamazepine
pharmacokinetics. St John’s wort increased the clearanceof mephenytoinby
about 3-fold and is predicted to reduce the blood levels of phenytoin and
St John’s wort is a known inducer of CYP3A4, and the results with single-
dose carbamazepine are as predicted. However, carbamazepine is also an
inducer of CYP3A4, and inducesitsown metabolism (autoinduction). It is
suggested that St John’s wort is not sufficiently potent an inducer to
further induce carbamazepine metabolism when autoinduction has
occurred, and thereforea smallinteractionisseenwith singledosesbut no
interaction is seen with multiple doses.
Mephenytoin is a substrate of CYP2C19 and St John’s wort appears to
induce this isoenzyme.
St John’s wort interaction with Benzodiazepines:
Long-term use of St John’s wort decreases the plasma levels of alprazolam,
midazolam and quazepam. StJohn’swort preparationstakenasa singledose,
or containing low-hyperforin levels, appear to have less of an effect.
Alprazolam, midazolam and quazepam are substrates of the cytochrome
P450 isoenzyme CYP3A4. St John’s wort appearsto induce CYP3A4, thus
increasing themetabolism oforalmidazolam, alprazolam1and quazepam,
and reducing the bioavailability of these benzodiazepines.
St John’s wort interaction with Calcium-channel blockers:
St John’s wort significantly reduces the bioavailability of nifedipine and
verapamil. Other calcium-channel blockers would be expected to interact
It appears that St John’s wort decreased the bioavailability of both
nifedipineand verapamilby inducing their metabolism bythe cytochrome
P450 isoenzyme CYP3A4 in the gut.
St John’s wort interaction with Chlorzoxazone:
St John’s wort increases the clearance of chlorzoxazone.
It appears that St John’s wort increases the clearance of chlorzoxazone by
inducing its metabolism by the cytochrome P450 isoenzyme CYP2E1.
St John’s wort interaction with Cyclosporine:
Marked reductions in ciclosporin blood levels and transplant rejection can
occur within a few weeks of starting St John’s wort.
St John’s wort is induces the cytochrome P450 isoenzyme CYP3A4 by
which cyclosporine is metabolized. Concurrent use therefore reduces
cyclosporine levels. It has also been suggested that St John’s wort affects
cyclosporine reabsorption by inducing the drug transporter protein, P-
glycoprotein, in the intestine.
St John’s wort interaction with Cimetidine:
Cimetidine does not significantly alter the metabolism of the constituents of
St John’s wort.
Cimetidine is an inhibitor of the cytochrome P450 isoenzymes CYP3A4,
CYP1A2 and CYP2D6. This study suggests that St John’s wort is not
significantly metabolised by these isoenzymes.
St John’s wort interaction with Digoxin:
There is good evidence that some preparations of St John’s
wort canreducethelevels of digoxinbyabout one-quarter to
St John’s wort, and specificallyhyperforin hasbeenshown
to increase the activity of the P-glycoprotein drug
transporter protein in the intestines, which reduces the
absorption of digoxin
St John’s wort interaction with Imatinib:
St John’s wort lowers serum imatinib levels.
St John’s wort induces intestinal CYP3A4 and it therefore also reduces
St John’s wort interaction with NNRTIs:
Thereis some evidenceto suggest that St John’swort may decreasethelevels
of nevirapine. Delavirdine and efavirenz would be expected to be similarly
This finding supports predictions based on the known metabolism of the
NNRTIs delavirdine, efavirenz and nevirapine by the cytochrome P450
isoenzyme CYP3A4, of which St John’s wort is a known inducer
St John’s wort interaction with Opioids:
St John’s wort reduces the plasma concentrations of methadone and
withdrawal symptoms may occur.
St John’s wort is metabolised intheliver and inducesthecytochromeP450
enzyme CYP3A4, and so could affect plasma levels of drugsmetabolised in
this way, such as methadone.
St John’s wort interaction with Protease inhibitors:
St John’s wort causes a marked reduction in the serum levels of indinavir,
which mayresult inHIV treatment failure. Otherproteaseinhibitors, whether
used alone or boosted by ritonavir, are predicted to interact similarly
Not fully understood, but it seems highlylikely that St John’s wort induces
theactivityofthecytochromeP450 isoenzymeCYP3A4, therebyincreasing
the metabolism of indinavir and therefore reducing its levels.
St John’s wort interaction with Proton pump inhibitors:
St John’s wort induces the metabolism of omeprazole, and this might result
in reduced efficacy. Other proton pump inhibitors are likely to be similarly
St John’s wort increases the metabolism of omeprazole by inducing both
CYP2C19 and CYP3A4.
St John’s wort interaction with SSRIs:
Cases of severe sedation, mania and serotonin syndrome have been reported
in patients taking St John’s wort with SSRIs.
A pharmacodynamic interaction may occur between St John’s wort and
venlafaxine because they can both inhibit the reuptake of 5-
St John’s wort interaction with Statins:
St John’s wort modestly decreases the plasma levels of atorvastatin and
simvastatin, but not pravastatin.
The reason for this interactionisunknown, but St John’s wort may reduce
the levels of simvastatin and its metabolite, and atorvastatin, by inducing
the cytochrome P450 isoenzyme CYP3A4 or by having some effect on P-
St John’s wort interaction with Tricyclic antidepressants:
The plasma levels of amitriptylineand itsactivemetabolite, nortriptyline, are
modestly reduced by St John’s wort.
Not fully understood. St John’s wort is known to induce the activity of the
cytochrome P450 isoenzyme CYP3A4, which is a minor route of
metabolism of the tricyclic antidepressants. However, the tricyclics are
predominantlymetabolised byCYP2D6, soan effect on CYP3A4 is unlikely
to lead to a clinically relevant reduction in their levels.
St John’s wort interaction with Warfarin and related drugs:
St John’s wort can causea moderatereductioninthe anticoagulanteffectsof
phenprocoumon and warfarin.
Uncertain, but itissuggested thattheStJohn’swort increasesthemetabolism
and clearanceoftheanticoagulantspossiblyby inductionof cytochromeP450
isoenzyme CYP3A4, and possibly also CYP2C9, as both R- and S-warfarin
The impact ofcarbohydrateson drug metabolism isconflicting. It is known
that high-carbohydratedietsmayinducetheexpressionof several glycolytic
and lipogenic hepatic enzymes, but some suggest that carbohydrateshave
little impact ondrug metabolism. However, noted that antipyrineand
theophylline metabolism decreased incarbohydrate-supplemented dietsbut
increased inthe protein-enriched diet, suggesting that carbohydratesand
proteinhave oppositeeffects on oxidativedrug metabolism. Although many
medicationsareoften given to childrenin a sugar syrup, littleresearch has
been done on its effect on dispositionand action. Somestudiessuggested
that dietarycarb ohydratesand fat may significantlyinfluencethe hepatic
Several investigators have reported that medications that undergo extensive
first-pass effect, such as propranolol, metoprolol and lidocaine, can have
enhanced bioavailabilityafter a high-proteinmealowing toenhanced hepatic
blood flow. High-extraction drugs can then rapidly pass through the liver,
allowing higher drug concentrationsinthesystemic circulation. A decreasein
dietaryproteindepressescreatinineclearanceand renalplasma flow. Specific
dietaryproteinscanalsoimpacta responsetoa medication. Oneoftheclassic
examples is that of the monoamine oxidase inhibitor (MAOI) drug class and
the amino acid tyramine that is contained in aged cheeses, pickled/smoked
meats, fermented foods, and red wines. Tyramine is an indirect
sympathomimetic amine that releases norepinephrine from the adrenergic
neurons, causing a significant pressor response. Typically, tyramine is
metabolized by the enzyme monoamine oxidase before any significant
increases in blood pressure are seen. If the enzyme is blocked, however,
severe and potentiallyfatalrises in blood pressure canoccur when tyramine-
rich foods are ingested.
Other medications, such as the oxazolidinone antibiotic, linezolid, also have
MAOI properties and patients should avoid ingesting large amounts of
tyramine while being treated with this antibiotic.
Dietaryproteinalsoaffectstherenaltubular transport ofcertaincompounds,
although the mechanism by which this occurs is still not understood. The
binding of dietary proteins to a drug may underscore changes in
bioavailability after a protein meal. For example, increases in both the
maximum concentration and area under the curve are seen in patients
receiving gabapentin. This enhanced absorption was attributed to trans-
simulation, a carrier-mediated processin which increased intestinalluminal
amino acid concentrations result in an up-regulation and/or increased
activity of the L-amino acid transporter.
Lipids are an essential part of cell membrane structure and are involved in
many of the normal enzymatic activities located within the cell membrane.
Diets that are deficient in fat or essential fatty acids decrease the activity of
the enzyme systems responsible for the metabolism ofnutrients. Plasma free
fatty acid levels become elevated after consumption of a high-fat meal,
increasing the potential to become bound to plasma albumin, and
subsequently displace albumin bound drugs, increasing the risk of drug
Dietary fats along with food-stimulated secretions (eg, bile salts) may
facilitate the solubility of lipophilic compounds. This may contribute to a
reduction in the extent of first past metabolism due to enhanced splanchnic
blood flow. Ingestion of diets high in fat has been associated with the
induction of CYP2E1. The extent to which this enzyme is up-regulated is
dependent upon the type of fat. Polyunsaturated fats such as corn and
menhadenoils appear to have thegreatest influencein comparisontolard or
olive oils. This can result in enhanced peroxidation of the polyunsaturated
fatty acid substrates and contribute to free radical production. The rate of
gastric emptying is also influenced by the fat content of a meal. Fat retards
gastric emptying to a greater degree than does protein or carbohydrate.
The antiviral agent zidovudine is also impacted by dietary fat. When
administered orally, its absorption is reduced when the drug is taken with a
high-fat meal in comparison with when taken in the fasted state. It is
recommended that zidovudinebetakenonanemptystomach toachievepeak
High-fat, high-cholesterol meals can sharply reduce the effect of ACE
inhibitors such as enalapril, as well as statins and other cholesterol
Some medications, notablybeta blockers such as metoprololthat are used to
treat high blood pressure, are greatly inhibited by high levels of calcium or
sodium at a meal. Thosenutrients, whilenecessaryin their ownright, bind to
the medication and decrease its availability to the body. Others like
tetracycline and ciprofloxacin are markedly reduced by milk and other dairy
products, because the calcium in the milk binds the antibiotic due to their
chelation property that lead to insoluble complex that prevents gut
absorption as well as supplemental magnesium, iron, or zinc will decrease
these drugs absorption
Diets rich in vegetables and fruit may also impact the response to
medications. Both serve as sources of trace minerals that are contained in
metalloenzymes, including several antioxidants. Many plants contain
flavonoids, isothiocyanates, and allyl sulfides that are potent modulators of
the cytochrome monoxygenase system.
Phyotochemicals are linked with the modulation of a variety of metabolic
pathways. The most frequently sources includecruciferousvegetables, citrus
juices, and spices. Dietary supplements and herbs are also associated with
There are five major families of phytochemicals: carotinoids (eg, beta
carotene, lycopene), alkaloids, phenolics (include flavonoids, coumarins,
tannins), nitrogen compounds, and sulfur compounds (eg, isothiocyanates,
Recent research has focused on how vegetables and fruits can influence a
variety of enzymatic pathways. Typically induction of these enzyme systems
is rapid and plateaus within days of continued daily ingestions of the food
with theenzymeinducing capacity. Cruciferousvegetables, including brussels
sprouts, cabbage, turnips, broccoli, cauliflower, and spinach, contain indols
that induce arylhydrocarbon hydroxylase enzyme activity as well as the
conjugation of phenacetin and acetaminophen.
Potatoes, tomatoes, and eggplant contain natural insecticide compounds
called solanaceous glycoalkaloids that even in small amounts may greatly
slow the metabolism of muscle relaxants and anesthetic agents such as
suxamethonium, mivacurium, and cocaine. Cooking does not reduce them
and theymayremaininthebodyfor several daysafter ingestion. Solanaceous
glycoalkaloids inhibit butyryl cholinesterase, which breaks down many
anesthetic agentsand cetylcholinesterase, which breaks down acetylcholine.
High-fiber foods can have unpredictable effects on the absorption of
medications. For example, insoluble dietary fiber, the kind found in bran or
brown rice, can seriously inhibit body's absorption of the heart medication
digoxin. Whole grains can also take a long time to move through digestive
tract and that means medicationswhich isbeen takenwith or just before the
meal can spend longer than they should in the high-acid environment of the
stomach, and their effectiveness can be impaired by the time they reach the
Soluble fibers and gelling agents:
Soluble fiber is the kind found in oatmeal and in fiber supplements such as
psyllium. It forms a stickygel inthe presenceof moisture, which immobilizes
nutrientsand medicationsinthedigestivesystem and slowstheir absorption,
it can seriously reduce the absorption of many antibiotics and other drugs
such as warfarin. Solublefiber and closely related gelling agentssuch as guar
gum and xanthan gum, often found in gluten-free foods, can also slow
absorption of many common medications.
Very low calorie diets:
In diets involving severe protein-energy restriction, such as extreme
slimming diets, the metabolism of drugsmay be affected in one of two ways.
First, tissueproteiniscatabolized and used asanenergysource, thusreducing
theavailabilityofaminoacidsfor proteinsynthesis, which inturnreducesthe
amount of enzymes available for drug metabolism.
Second, endogenous substrates derived from carbohydrate and protein such
as glucuronide, sulfate, and glycine could also compete for the tissue needs
for these nutrients and that of the drug metabolism.
Eating habits, especially among dieters that omits or severely restrict whole
categoriesoffoods, havea negativeimpactonmicronutrient status. Dietsthat
eliminate all animal foods have been associated with other vitamin
deficiencies including vitamin C. Moreover, skipping meals and fad diets to
lose weight frequently compromise micronutrient intake. It should be
routinelyassumed that it isextremelydifficult tomeet alltherequirementsat
intakes of less than 1,200 calories per day.
Patientswithverylow caloriediet weightlosshaveimproved hyperinsulinism
as a result of a reduction in basal insulin production as well as enhanced
hepatic insulin extraction. Moreover, it is thought the weight loss through
very low calorie diet lowers the hepatic glucuronidation of drugs leading to
higher plasma concentrations of the affected drugs.
Other dietary restrictions:
In additiontocaloric restriction, restrictionof other dietarycomponentscan
also impact drug response.
In patients who have sodium restricted diets, there is an increased risk of
acuterenal failure if these samepatientsare given concomitantangiotensin-
converting enzyme inhibitors (ACE inhibitors) or non-steroidal anti-
inflammatoryagents (NSAIDS). Thereisenhanced nephrotoxicityinpatients
who are sodium depleted and are given cyclosporine or tacrolimus. Sodium
restriction can also increase the renal tubular absorption of lithium, leading
to toxicity. Patients receiving aminoglycosides, amphotericin, cisplatin, or
radiocontrast mediainconjunctionwith a low-sodium diet haveanincreased
risk for hemodynamic nephrotoxic and ischemic acute renal failure. For
reasonsstill not known, theefficacyof calcium channelblockersisreduced in
patients on a sodium-restricted diet.
Drug metabolism among vegetarianswillvarydramaticallydepending onthe
protein intake. Most research has focused on Asian vegetarians in which the
half-livesof drugsthat underwentsignificanthepaticmetabolism (antipyrine,
acetaminophen and phenacetin) were significantly longer than in
Vegetarian diets are also associated with lower circulating concentrations of
sex steroids hormones, increased fecal excretion of estrogens and different
hormonal profiles in comparison to individuals consuming an omnivorous
diet. Vegetable intake may influence total body estrogen load via the
modulationofCYP enzymesinvolved inestrogenmetabolism. CYP13C, found
in cruciferous vegetables, can increase estrogen hydroxylation.
Impact of beverage type on drug bioavailability:
The term beveragereferstoany drinkableliquid other thanplainwater. They
are typically classified as caffeinated, alcoholic, milk-based, mineral waters,
or fruit/vegetables juices. Depending upon the type of fluid taken with a
medication, drug absorption may be affected.
Mixing drugs with fruit juices or other beverages to mask their taste may
impact absorption due to changes in gastric pH.
Dairy products decrease the absorption of tetracyclines and reduce their
bioavailability due to the formation of insoluble chelates between the drug
and the calcium present in the beverage. Similar decreases in bioavailability
were noted when fluoride tablets are taken with milk.
Tannins present in teas may impair iron absorption.
Alcoholic beveragesreducethe absorptionoffolic acid, cyanocobalamin, and
Soft drinks, such as colas, may decrease drug absorption for a variety of
reasons. The phosphoric acid and sugar present in these drinks can slow
gastric emptying and the tendencyto serve them chilled may also reducethe
rate of blood flow within the intestines. Moreover, the carbonation may
increase mixing and possibly motility. Interestingly, the acidic pH of cola
beveragescanbeused tooptimizeclinicalresponses ofboth ketoconazoleand
itraconazole in patients with gastric hypochlorhydria, such those patients
with AIDS gastropathy. The effects of grapefruit juice on drug disposition
have been discussed separately.
Liquorice contain glycyrrhizin (glycyrrhizinic or glycyrrhizic acid) which is
hydrolyzed in the intestine to pharmacologically active compound
glycyrrhetic acid which inhibit 11 betahydroxysteroid dehydrogenase. This
increase cortisol in kidney and act as aldosterone (fluid retention,
hypokalemia, hypertension), so Liqourice should not be administrated with
Aspirin and protease inhibitors are some of the medicines that may cause a
negative interaction with garlic. Drug interactions such as these may cause
complications, such asdecreasing themedications' effectivenessor increasing
the risk of bleeding.
Garlic may exaggerate the activity of medications that inhibit the action of
platelets in the body. Examples of such medications include indomethacin,
dipyridamole, Plavix, and aspirin, as well as there have been reports of a
possible interaction between garlic and warfarin that could increase the risk
of bleeding in people taking this blood thinning medication.
Garlic may reduce blood levels of protease inhibitors, a medication used to
treat people with the human immunodeficiency virus (HIV) which include
indinavir, ritinavir, and saquinavir.
Anti-thyroid drugs are compounds that interfere with the body’s production
of thyroid hormones, thereby reducing the symptoms of hyperthyroidism.
Anti-thyroid drugs work by preventing iodine absorption in the stomach. A
high-iodine diet requires higher doses of anti-thyroid drugs. The higher the
dose of anti-thyroid drugs, the greater the incidence of side effects that
include rashes, hives, and liver disease.
The richest dietary sources of iodine are seafood and seaweed, such as kelp
and nori. Iodine is also found in iodized salt and to a lesser extent in eggs,
meat, and dairy products.
.Alcohol and Medication Interactions
Most people who consume alcohol, whether in moderate or large quantities,
also take medications, at least occasionally. As a result, many people ingest
alcohol while a medication is present in their body or vice versa. A large
number of medications—both those available only by prescription and those
availableover the counter (OTC)—havethe potentialtointeract with alcohol.
Those interactions can alter the metabolism or activity of the medication
and/or alcohol metabolism, resulting in potentially serious medical
For example, thesedativeeffectsofboth alcoholand sedativemedicationscan
enhanceeach other (i.e., the effectsareadditive), therebyseriouslyimpairing
a person’s ability to drive or operate other types of machinery. Most studies
assessing alcohol medication interactions focus on the effects of chronic
Relatively limited information is available, however, on medication
interactions resulting from moderate alcohol consumption (i.e., one or two
standard drinks 1 per day). Researchers, physicians, and pharmacists must
therefore infer potentialmedicationinteractionsat moderatedrinking levels
based on observations made with heavy drinkers. In addition, moderate
alcohol consumption may directly influence some of the disease states for
which medications are.
Common Alcohol-Medication Interactions:
Mechanisms of Alcohol-Medication Interactions
Interactions between alcohol and a
medication can occur in a variety of
situationsthatdiffer based onthetiming
of alcohol and medicationconsumption.
For example, such interactions can
occur in people who consume alcohol
with a mealshortlybeforeor after taking
a medication or who take pain
medications after drinking to prevent a hangover. Alcohol-medication
interactions fall into two general categories: pharmacokinetic and
- Pharmacokinetic interactions are those in which the presence of alcohol
directly interferes with the normal metabolism of the medication. This
interference can take two forms, as follows:
The breakdown and excretion of the affected medications are delayed,
because the medications must compete with alcohol for breakdown by
cytochromeP450. Thistypeof interactionhasbeen described mostlyfor
metabolic reactions involving CYP2E1, but it also may involve CYP3A4
The metabolism of the affected medications is accelerated, because
alcohol enhances the activity of medication-metabolizing cytochromes.
When alcohol is not present simultaneously to compete for the
cytochromes, increased cytochrome activity results in an increased
elimination rate for medications that these enzymes metabolize.
- Pharmacodynamic alcohol-medication interactions do not involve enzyme
inhibitionor activation, but rather refer totheadditiveeffectsofalcoholand
certain medications. In this type of interaction, which occurs most
commonly in the centralnervous system (CNS), alcohol alters the effects of
the medication without changing the medication’s concentration in the
blood. With some medications (e.g., barbiturates and sedative medications
called benzodiazepines), alcoholactsonthesamemoleculesinsideor onthe
surface of the cell as does the medication. These interactions may be
synergistic—that is, theeffectsofthe combined medicationsexceed thesum
of the effects of the individual medications. With other medications (e.g.,
antihistamines and antidepressants) alcohol enhances the sedative effects
of those medications but acts through different mechanisms from those
Specific Alcohol-Medication Interactions
This section describes different classes of medications and their interactions
with alcohol. The potential for the occurrence and relevance of alcohol-
medication interactions in moderate drinkers may differ, however, between
pharmacokinetic and pharmacodynamic interactions. The number of
potential pharmacokinetic interactions with alcohol is great, because the
various cytochrome P450 enzymes metabolize many medications. However,
many of the pharmacokinetic interactions discussed here were first
discovered in heavy drinkers or alcoholics or were studied in animals given
large alcohol doses in their diet. Although the potential for such effects
certainlyexistseven after low alcohol consumption, researchershavenot yet
demonstrated the occurrence and relevance of those effects in moderate
drinkers. Conversely, pharmacodynamic interactions can occur with
intermittent alcoholconsumptionand evenafter a single episodeof drinking.
Accordingly, those interactions clearly pertain to moderate drinkers.
The package inserts for most antibiotics include a warning for patients to
avoid using alcohol with those medications. Therationalefor these warnings
isnot entirelyclear, however, becauseonlya few antibioticsappear tointeract
with alcohol. For example, although some antibiotics induce flushing, most
antibiotics do not. The antibiotic erythromycin may increase alcohol
absorptionintheintestine(and, consequently, increaseBALs) byaccelerating
gastric emptying. Furthermore, people taking the antituberculosis drug
isoniazid should abstain from alcohol, because isoniazid can cause liver
damage, which maybeexacerbatedbydailyalcoholconsumption. Asidefrom
these effects, however, moderate alcohol consumption probably does not
interfere with antibiotic effectiveness. Possibly, concerns regarding the
concurrent use of alcohol and antibiotics grew from research findings
indicating that heavy alcohol use can impair the function of certain immune
cells and that alcoholics are predisposed to certain infections. These effects,
however, are unlikely to occur in moderate drinkers.
Several classes of antidepressant medications exist, including tricyclic
antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs),
monoamine oxidase (MAO) inhibitors, and atypical antidepressants. These
classes differ in their mechanism of action in that they affect different brain
chemicals. All types of antidepressants, however, have some sedative as well
assome stimulating activity. TCAswith a higherratioofsedativeto-stimulant
activity (i.e., amitriptyline, doxepin, maprotiline, and trimipramine) will
causethemost sedation. AlcoholincreasestheTCAs’ sedativeeffectsthrough
pharmacodynamic interactions. In addition, alcohol consumption can cause
pharmacokinetic interactions with TCAs. For example, alcohol appears to
interferewith thefirst-passmetabolism ofamitriptylineintheliver, resulting
in increased amitriptyline levels in the blood. In addition, alcohol-induced
liver disease further impairs amitriptyline breakdown and causes
significantlyincreased levels of activemedicationin the body (i.e., increased
bioavailability). High TCA levels, in turn, can lead to convulsions and
disturbances in heart rhythm. SSRIs (i.e., fluvoxamine, fluoxetine,
paroxetine, and sertraline), which are currently the most widely used
antidepressants, are much less sedating than are TCAs. In addition, no
serious interactions appear to occur when these agents are consumed with
moderate alcohol doses. In fact, SSRIs have the best safety profile of all
antidepressants, even when combined in large quantities with alcohol (e.g.,
insuicideand overdosesituations). Conversely, peopletaking MAOinhibitors
or atypical antidepressants can experience adverse consequences when
simultaneously consuming alcohol. Thus, MAO inhibitors (e.g. phenelzine
and tranylcypromine) can induce severe high blood pressure if they are
consumed together with a substancecalled tyramine, which is present in red
wine. Accordingly, people taking MAO inhibitors should be warned against
drinking red wine. The atypical antidepressants (i.e., nefazodone and
trazodone) may cause enhanced sedation when used with alcohol.
These medications, which are available both by prescription and OTC, are
used in the management of allergies and colds. Antihistamines may cause
drowsiness, sedation, and low blood pressure(i.e., hypotension), especiallyin
elderly patients. Through pharmacodynamic interactions, alcohol can
substantially enhance the sedating effects of these agents and may thereby
increase, for example, a person’s risk of falling or impair his or her ability to
drive or operate other types of machinery. As a result of these potential
interactions, warning labels on OTC antihistamines caution patients about
the possibilityof increased drowsinesswhen consuming themedicationwith
alcohol. Newer antihistamines (i.e., certrizine and loratidine) have been
developed tominimizedrowsinessand sedationwhilestillproviding effective
allergy relief. However, these newer medicationsmaystill be associated with
an increased risk of hypotension and falls among the elderly, particularly
when combined with alcohol. Consequently, patients taking nonsedating
antihistamines still should be warned against using alcohol.
These medications are sedative or sleep-inducing (i.e., hypnotic) agents that
arefrequentlyused for anesthesia. Phenobarbital, which isprobablythemost
commonly prescribed barbiturate in modern practice, also is used in the
treatment of seizure disorders. Phenobarbital activates some of the same
molecules in the CNS as does alcohol, resulting in pharmacodynamic
interactionsbetweenthetwosubstances. Consequently, alcoholconsumption
side effects. Patients taking barbiturates therefore should be warned not to
perform tasks that require alertness, such as driving or operating heavy
machinery, particularlyafter simultaneousalcoholconsumption. In addition
to thepharmacodynamic interactions, pharmacokineticinteractionsbetween
alcohol and phenobarbital exist, because alcohol inhibits the medication’s
breakdown in the liver. This inhibition results in a slower metabolism and,
possibly, higher blood levels of phenobarbital. Conversely, barbiturates
increase total cytochrome P450 activity in the liver and accelerate alcohol
eliminationfrom theblood. Thisaccelerationofalcoholeliminationprobably
does not have any adverse effect.
Like barbiturates, benzodiazepines(BZDs) areclassified assedative-hypnotic
agents and act through the same brain molecules as do barbiturates.
Accordingly, as with barbiturates, concurrent consumption of BZDs and
moderateamountsofalcoholcancausesynergistic sedativeeffects, leadingto
substantial CNS impairment. It is worth noting that both barbiturates and
benzodiazepines can impair memory, as can alcohol. Consequently, the
combination of these medications with alcohol would exacerbate this
memory-impairing effect. Infact, thiseffect sometimesisexploited bymixing
alcoholic beverages with BZDs, such as the rapid-acting flunitrazepam, an
agent implicated in date rape. In addition, the metabolism of certain BZDs
involves cytochrome P450, leading to the alcohol-induced changes in
metabolism described earlier in this article.
Histamine H 2 Receptor Antagonists (H2RAs)
As mentioned earlier in this article, H2RAs (e.g., cimetidine, ranitidine,
nizatidine, and famotidine), which reduce gastric acid secretion, are used in
the treatment of ulcers and heartburn. These agents reduce ADH activity in
the stomach mucosa, and cimetidine also may increase the rate of gastric
emptying. Asa result, alcohol consumed with cimetidineundergoeslessfirst-
pass metabolism, resulting in increased BALs. For example, in a study of
people who consumed three or four standard drinks over 135 minutes while
taking cimetidine, BALs rose higher and remained elevated for a longer
period of timethaninpeople not taking cimetidine. Not allH2RAs, however,
exert the sameeffect on BALs when takenwith alcohol. Thus, cimetidineand
ranitidine have the most pronounced effect, nizatidine has an intermediate
effect, and famotidine appears to have no effect (i.e., appears not to interact
with alcohol). In addition, because women generally appear to have lower
first-pass metabolism of alcohol, they may be at less risk for adverse
interactions with H2RAs.
Several muscle relaxants (e.g., carisoprodol, cyclobenzaprine, and baclofen),
when taken with alcohol, may produce a certain narcotic-like reaction that
includesextremeweakness, dizziness, agitation, euphoria, and confusion. For
example, carisoprodol is a commonly abused and readily available
prescription medication that is sold as a street drug. Its metabolism in the
liver generates an anxiety-reducing agent that was previously marketed as a
controlled substance (meprobamate). The mixture of carisoprodol with beer
is popular among street abusers for creating a quick state of euphoria.
Nonnarcotic Pain Medications and Anti-Inflammatory Agents
Many people frequently use nonnarcotic pain medications and anti-
inflammatory agents (e.g., aspirin, acetaminophen, or ibuprofen) for
headaches and other minor aches and pains. In addition, arthritis and other
disorders of the muscles and bones are among the most common problems
for which older people consult physicians. Nonsteroidal anti-inflammatory
drugs (NSAIDs) (e.g., ibuprofen, naproxen, indomethacin, and diclofenac)
and aspirin are commonly prescribed or recommended for the treatment of
these disorders and are purchased OTC in huge amounts. Several potential
interactions exist between alcohol and these agents, as follows:
• NSAIDs have been implicated in an increased risk of ulcers and
gastrointestinal bleeding in elderly people. Alcohol may exacerbate that
risk by enhancing the ability of these medications to damage the stomach
• Aspirin, indomethacin, and ibuprofen cause prolonged bleeding by
inhibiting the function of certain blood cells involved in blood clot
formation. This effect also appears to be enhanced by concurrent alcohol
• Aspirin has been shown to increase BALs after small alcohol doses,
possibly by inhibiting first-pass metabolism.
An important pharmacokinetic interaction between alcohol and
acetaminophen can increase the risk of acetaminophen-related toxic effects
on the liver. Acetaminophen breakdown by CYP2E1 (and possibly CYP3A)
results in the formation of a toxic product that can cause potentially life-
threatening liver damage. As mentioned earlier, heavy alcohol use enhances
CYP2E1 activity. In turn, enhanced CYP2E1 activity increases the formation
of the toxic acetaminophen product. To prevent liver damage, patients
generally should not exceed the maximum doses recommended by the
manufacturers (i.e., 4 grams, or up to eight extra-strength tablets of
acetaminophen per day). In people who drink heavily or who are fasting
(which also increases CYP2E1 activity), however, liver injury may occur at
doses as low as 2 to 4 grams per day. The specific drinking levels at which
acetaminophen toxicity is enhanced are still unknown. Because
acetaminopheniseasilyavailableOTC, however, labels on thepackageswarn
people about thepotentiallydangerousalcohol-acetaminophencombination.
Furthermore, people should be aware that combination cough, cold, and flu
medications may contain aspirin, acetaminophen, or ibuprofen, all of which
might contribute to serious health consequences when combined with
Opioids are agents with opium-like effects (e.g., sedation, pain relief, and
euphoria) that areused aspainmedications. Alcoholaccentuatestheopioids’
sedating effects. Accordingly, all patients receiving narcotic prescriptions
should be warned about the drowsiness caused by these agents and the
additive effects of alcohol. Overdoses of alcohol and opioids are potentially
lethal becausethey can reducethe cough reflex and breathing functions; asa
result, the patientsareat riskofgetting foods, fluids, or other objectsstuckin
their airways or of being unable to breathe. Certain opioid pain medications
(e.g., codeine, propoxyphene, and oxycodone) are manufactured as
combinationproductscontaining acetaminophen. Thesecombinationscanbe
particularly harmful when combined with alcohol because they provide
“hidden” doses of acetaminophen. As described in the previous section,
alcohol consumption may result in the accumulation of toxic breakdown
productsofacetaminophen. Therefore, patientsusing opioid-acetaminophen
combinationproductsshould becautioned aboutrestricting thetotalamount
of acetaminophen they ingest daily (i.e., they should not take regular
acetaminophen in addition to the combination product).
The anticoagulant warfarin is used for the prevention of blood clots in
patientswith irregular heart rhythmsor artificialheart valves; it is also used
to treat clots that form in extremities such as legs, arms, or sometimes the
lungs. Its anticoagulant effect is acutely altered by even small amounts of
alcohol. In people taking warfarin and ingesting a few drinks in one sitting,
anticlotting effects may be stronger than necessary for medical purposes,
placing these people at risk for increased bleeding. This excessive warfarin
activity results from alcohol related inhibition of warfarin metabolism by
cytochrome P450 in the liver. Conversely, in people who chronically drink
alcohol, long term alcohol consumption activates cytochrome P450 and,
consequently, warfarin metabolism. As a result, warfarin is broken down
faster than normal, and higher warfarin doses are required to achieve the
desired anticoagulant effect. Thus, alcohol consumption can result in
dangerouslyhigh or insufficient warfarinactivity, depending onthe patient’s
drinking pattern. Therefore, patients taking warfarin generally should avoid
Counseling and Guidance about Drug-Food Interactions:
The following information can be given to the patients while dispensing the
1. Read the prescription label on the container. If you do not understand
something or think you need more information, ask your physician or
2. Read directions, warnings and interaction precautions printed on all
medication labels and package inserts. Even over-the-counter medications
can cause problems.
3. Take medication with a full glass of water.
4. Do not stir medicationintoyour food or takecapsules apart (unlessdirected
by your physician). This may affect the efficacy of medication.
5. Do not takevitaminpillsat thesametimeyou takemedication. Vitaminsand
minerals can interact with some drugs.
6. Do not mix medicationintohot drinksbecausethe heat from the drink may
destroy the effectiveness of the drug.
7. Never take medication with alcoholic drinks.
8. Be sure to tell your physician and pharmacist about all medications you are
taking, both prescription and nonprescription.
9. Checkwith thepharmacist onhow food canaffect specific medications taken
with the food.
Summary of some signifiant Food-Drug Interactions
Condition Drug Use Interactions/Guidelines Examples
Allergies Antihistamine To relieve or
Food: Take with water, if
GI distress occurs
if taken with apple,
orange, or grapefruit
To treat mild
Food: For rapid relief,
take on empty stomach
Caffeine: May increase
the rate of absorption of
Food: Take with food,
water, or milk to
decrease stomach upset.
With a high dose of this
drug, one may need to
increase consumption of
vitamin C, vitamin K, and
Caffeine: Limit intake
Supplements: Limit or
avoid products that
affect blood coagulation
(garlic, ginger, gingko,
ginseng, or horse
areas of the
Food: Take with food or
milk to decrease
stomach upset. Limit
citrus fruits. While
taking this drug, one
may need to decrease
sodium, and supplement
the diet with calcium,
vitamin D, K, A, C, or
Caffeine: Limit intake
Food: Take with food or
milk to decrease
To treat the
Food: Take with food if
stomach upset occurs.
increase the amount of
theophylline in the
body, while high-
decrease it. Different
foods may have
decrease it. Different
foods may have varying
effects depending on
Caffeine: Avoid eating or
drinking large amounts
of foods and beverages
that contain caffeine
Diuretics To help
Food: Take on an empty
stomach since food
reduces drug availability.
Take with food or milk if
stomach upset occurs.
Since some diuretics
causeloss of potasium,
these minerals may be
known as a “potassium
sparing” diuretic. When
taking triamterene avoid
eating large amounts of
such as bananas,
oranges and green leafy
vegetables or salt
Food: Take with food.
Do not take with
grapefruitor other citrus
fruits. Follow a diet low
in cholesterol and
Beta Blockers To decrease
Food: Take with food to
Take separately from
orangejuice, and avoid
natural licorice. Itmay
be necessary to
decrease dietary calcium
and sodium, which may
Nitrates To relax
for oxygen by
Food: Take on an empty
stomach with water to
increase absorption, 1
hour before meals or 2
Food: High fat meals
decrease absorption of
adequate fluid intake.
Avoid salt, calcium, and
Avoid salt, calcium, and
should be taken with the
evening meal to
rate of LDL
Decreasedietary fat and
cholesterol while taking
Supplements: Avoid St.
Food: Limit foods with
vitamin K, since it
the effectiveness of
anticoagulants. Do not
exceed the upper limit
for vitamin E and A
garlic, ginger, ginko saw
palmetto, and horse
Food: Take on an empty
stomach, or 1 hour
before or 2 hours after
food. If upsetstomach
occurs, takewith food.
Avoid guar gum
caution when taking
Quinolones To treat
Food: Take on an empty
stomach, or 1 hour
before or 2 hours after
food. If upsetstomach
occurs, takewith food
but not with dairy or
Caffeine: Taking these
products may increase
caffeine levels, leading
products may increase
to excitability and
Food: Take on an empty
stomach, or 1 hour
before or 2 hours after
food. If upsetstomach
occurs, takewith food
Macrolides To treat
Food: May take with
food if stomach upset
occurs Exceptions: Zmax
should be taken on an
empty stomach one
hour before or 2 hours
after food. Avoid taking
with citrus foods, citrus
juices, and carbonated
Sulfonamides To treat
Food: Take with food
and at least 8 ounces of
Tetracyclines To treat
Food: Take with food
and at least 8 ounces of
water. Avoid taking
tetracycline with dairy
tetracycline with dairy
products, antacids, and
containing iron because
they can interfere with
Nitromidazole To treat
Food: May take with
food to decrease
stomach upset, but food
Antifungals To treat
Food: Take with food to
increase absorption. Do
not take itraconazole
related citrus with
medications have many
dietary restrictions and
those taking them
should follow the
dietary guidelines and
very carefully. A rapid,
potentially fatal increase
in blood pressurecan
occur if foods or
containing tyramine are
consumed while taking
MAO inhibitors. Avoid
foods high in tyramine
and other pressor
amines during drug use
and for 2 weeks after
include aged cheeses,
aged meats, soy sauce,
tofu, fava beans,
chocolate, and caffeine
Food: May take with
food if upsetstomach
occurs. Limit grapefruit
and citrus consumption
Caffeine: May cause
hyperactivity and lessen
the anti-anxiety effects
of the drugs
caution with sedative
herbal products such as
chamomile, kava, or
stimulants such as
caffeine or, Sedative-
medications can be with
Stimulant Food: Take with or
without meals. Limit
caffeine, and ensure
Food: Do not take with
food, or immediately
after a meal
medications can be
taken with or without
food, with 8 ounces of
water. A bland diet is
drug 2 hours beforean
iron or antacid
decrease iron and
vitamin B12 absorption
products may irritate
Food: Take with food or
milk to decrease
stomach upset Avoid
citrus fruits, star fruits,
calcium and vitamin D
1- Stockley’s Drug Interactions; Eighth edition; Edited by Karen Baxter, 2008.
2- Handbook of Food-Drug interactions; Edited by Beverly J. McCabe, Eric H. Frankel
and Jonathan J. Wolfe, 2003.
3- Chan LN: Drug-Nutrient Interactions; in Shils ME, Shike M, Ross AC, Caballero B,
Cousins RJ (eds): Modern Nutrition in Health and Disease. Baltimore, Lippincott
Williams & Wilkins, 2006, pp 1540–1553.
4- Food and drug interactions: general review, Department of Food Engineering, Ege
University of Izmir, 35100 Bornova Izmir, Turkey.
5- Pharmacological Sciences: Perspectives for Research and Therapy in the Late 1990s