Learning objectives

• Define the term drug–nutrient interaction in its broadest sense

• Describe the classification of drug–nutrient interactions with
examples of each
• List possible approaches for identifying, preventing, and
managing drug-nutrient interactions
• Highlight potential pharmacokinetic and pharmacodynamic sites
of drug-nutrientinteractions
 Definition
• Drug-nutrient interaction is defined as an interaction resulting from a
physical, chemical, physiologic, or pathophysiologic relationship between
a drug and a nutrient, multiple nutrients, food in general, or nutritional
status
• An interaction is considered to be clinically significant if it alters
pharmacotherapeutic response or compromises nutritional status. The
clinical consequences of an interaction are related to alterations in the
disposition and effect of the drug or nutrient. The term disposition refers
to the absorption, distribution, and elimination of a drug or nutrient
which can involve physiologic transporters and metabolizing enzymes.
And the term effect refers to the physiologic action of a drug or nutrient
at the level of cellular or subcellular targets. Drug–nutrient interactions
can influence health outcomes particularly in vulnerable populations
 Key Terms
• Bioavailability: degree to which a drug or other substance
reaches the circulation and becomes available to the target
organ or tissue
• Half-life: amount of time it takes for the blood
concentration of a drug to decrease by one half of its
steady state level
• Side effect: adverse effect/reaction or any undesirable
effect of a drug
 Other Terms
• Bioavailability: % free to function
• Absorption rate: % absorbed and time for absorption
• Transported: amount in blood (free or bound)
• Metabolized: altered by enzymes in tissues
• Mixed-function oxidase system (MFOS): enzyme system that
metabolizes drugs, carcinogens, compounds in foods, etc.
 Physiologic Conditions and Functions at Sites within the GI Tract
Site Major Secretions Activity Related to Drugs Activity Related to Foods
Mouth Saliva Disintegration of solid forms started Maceration; Carbohydrate digestion started
Salivary amylase
Esophagus None Transport to stomach; Disintegration Transport to stomach; Continue
continues carbohydrate digestion
Stomach Gastrin Disintegration; dissolution of acid Mixing; chime formation; carbohydrate
Gastric acid (HCl) soluble drugs; some absorption of digestion; begin protein digestion; release
Pepsinogen (pepsin) small, lipophilic molecules and non- nutrients from food; reduction of iron (Fe
Gastric lipase polar weak acids that are soluble in +3) few nutrients absorbed
Intrinsic factor low pH
Duodenum Gut hormones Disintegration of enteric coated Osmolality and pH of chyme control gastric
Pancreatic enzymes drugs; dissolution of drugs soluble at emptying; carbohydrate, protein, and fat
Bile pH 5-7; Passive absorption of drugs digestion; absorption of protein, fats, and
in solution many micronutrients
Jejunum VIP Dissolution of drugs soluble at pH 5- Absorption of carbohydrate, protein, fat,
Aminopeptidases 7; passive absorption of most drugs and many micronutrients
Dipeptidases occurs to some extent
Disaccharidases
Ileum Aminopeptidases Continued dissolution of drugs Absorption of carbohydrate, protein, fat,
Dipeptidases soluble at pH5-7; passive absorption and many micronutrients; site of active
Disaccharidases of most drugs occurs to some extent absorption for vitamin B12; reabsorption
of bile acids
Absorbtion
• Swallowing
• Disintegration
– tablet swells
– breaks up
• Dissolution
– reactions with acid
– faster when ionized
• Absorption
– most post pyloric
– in basic environment
– require non-ionized state
 Pharmacokinetics
Movement of drugs through the body by
• Absorption
• Distribution
• Metabolism
• Excretion
 Absorption

• Movement of the drug from the site of administration to the

bloodstream; depends on
– The route of administration
– The chemistry of the drug and its ability to cross membranes
– The rate of gastric emptying (for oral drugs) and GI movement
– The quality of the product formulation

• Food, food components and nutritional supplements can

interfere with absorption, especially if the drug is taken orally
 Distribution

When the drug leaves the systemic circulation and

moves to various parts of the body
• Drugs in the bloodstream are often bound to
plasma proteins; only unbound drugs can leave the
blood and affect target organs
• Low serum albumin can increase availability of
drugs and potentiate their effects
 Metabolism (biotransformation)

• Primarily in the liver; cytochrome P-450 enzyme

system facilitates drug metabolism; metabolism
generally changes fat soluble compounds to water
soluble compounds that can be excreted
• Foods or dietary supplements that increase or inhibit
these enzyme systems can change the rate or extent
of drug metabolism
 FIRST-PASS EFFECT
• The venous drainage system of the stomach and intestines differs from that
of most other organs in a way that has implications for drug-nutrient
interactions. The venous drainage of most organs goes directly to the heart,
but venous drainage of the GI tract sends blood into the portal circulation,
which delivers blood to the liver. Hepatic venous drainage then goes to the
heart. This is of clinical significance because the liver is a site of active
biotransformation (drug metabolism) and a potential site for interactions
• Biotransformation in the liver can be extensive (>99% for some commonly
used drugs). In some cases, this biotransformation results in the conversion
of an inactive parent substance (a pro-drug ) to its active metabolite(s). More
often, the metabolites are less active than the parent substance. Once
through the liver, the drug and its metabolites follow the venous drainage to
the heart and into the systemic circulation. All subsequent pharmacokinetic
features are the same as for any other systemically administered substance
 BLOOD-BRAIN BARRIER
• Many drugs have only limited ability to enter the brain because of their
physico-chemical properties. The morphologic basis for the blood-brain
barrier includes tight junctions between the epithelial cells lining the
brain capillaries and transport mechanisms that pump substances out of
the brain. In general, the blood-brain barrier restricts the passage of
substances that are either too hydrophilic (water soluble) or too lipophilic
(fat soluble). Nutritionally required substances can be actively
transported across the blood-brain barrier
• The permeability of the blood-brain barrier depends on such factors as
age, disease, and other influences, including nutritional state. Plasma
protein binding is also a factor, since drug molecules highly bound to
plasma proteins are less able to traverse the blood-brain barrier. Hence,
drug interaction at the level of plasma protein binding can affect blood-
brain barrier passage
 Excretion
• Drugs are eliminated from the body as an unchanged
drug or metabolite
– Renal excretion the major route of elimination; affected by
renal function and urinary pH
– Some drugs eliminated in bile and other body fluids
 Pharmacodynamics
• Physiologic and biochemical effects of a drug or
combination of drugs
• The mechanism of action, e.g. how a drug works
• Often the drug molecule binds to a receptor, enzyme, or
ion channel, producing a physiological response
 Pharmacogenomics

• Genetically determined variations that are revealed solely

by the effects of drugs
• Affect only a subset of people
• Examples include G6PD (glucose-6-phosphate
dehydrogenase) enzyme deficiency, warfarin resistance,
and slow inactivation of isoniazid (IHN) or phenelzine
 G6PD (glucose-6-phosphate dehydrogenase) enzyme
deficiency
• X-chromosome-linked
• Can lead to neonatal jaundice, hemolytic anemia or acute
hemolysis
• Most common in African, Middle Eastern, and Southeast Asians
• Also called favism
• Fava beans or pollen, Vitamin K or Vitamin C can cause
hemolysis
 Classification of Drug-Nutrient Interactions

Precipitating factor Object of the interaction Potential consequence

Nutritional status
Food or food component
Specific nutrient or other
dietary supplement ingredient
Drug
Drug
Drug Treatment failure or drug
toxicity
Drug Treatment failure or drug
toxicity
Drug Treatment failure or drug
toxicity
Nutritional status Altered nutritional status
Specific nutrient Altered nutrient status

Pharmacotherapy 2005;25:1789–1800
 Location and Mechanisms of Drug-Nutrient Interactions

Site of interaction Consequence Mechanism of interaction

In drug (or nutrient) delivery
device or gastrointestinal
lumen
Gastrointestinal mucosa
Systemic circulation or tissues
Organs of excretion
Reduced bioavailability
Altered bioavailability
Altered distribution/effect
Altered clearance
Physicochemical reaction and
inactivation
Altered transporter and/or
enzyme function
Altered transporter, enzyme,
or other physiologic function
Antagonism, impairment, or
modulation of elimination

Curr Opin Clin Nutr Metab Care 2002;5:327–332

 Examples of drug-nutrient interactions
Drug Indication Possible Effects
Coumadin Anticoagulant (blood thinner) Vitamin K is a nutrient in the body that helps
blood to clot. Vitamin K is present in foods such
as green, leafy vegetables and fish. It will
interfere with a blood thinner like coumadin
Dilantin Anticonvulsant (anti-seizure) Vitamin D and folic acid levels in the body are
decreased by the taking of these types of drugs
Norvasc Antihypertensive (for high blood Consuming foods high in sodium (i.e., licorice,
pressure) processed meats, canned foods) will decrease
the effectiveness of the drug.
Aspirin Anti-inflammatory/pain reliever Taking large amounts of these drugs will cause
a loss of Vitamin C in the body
 Examples of drug-nutrient interactions
Drug Indication Possible Effects
Birth control pills Oral contraceptives Women who take these drugs often have low levels
of folic acid and Vitamin B6 in the blood.
Dyazide/Thiazide Diuretics (water- Taking diuretics often leads to a loss of potassium
eliminating) in the body
Tetracycline Antibiotic Calcium may interact with the effectiveness of the
antibiotic. Avoid dairy products for two to three
hours before and after taking the medicine
Lipitor/Zocor Statins (cholesterol- Antioxidants (Vitamin A, C, E, B, folic acid) may
lowering drugs) interact with the drug by reversing its effect
Prednisone Corticosteroid The drug may increase appetite thus increasing
nutrient intake
Lasix Diuretic (water- The drug may decrease appetite thus decreasing
eliminating) nutrient intake
 Nutrient depletion drugs
Drug Nutrient Depletions Potential Depletion Problems
Non–Steroidal Anti–inflammatory Drugs (NSAIDs)
Ibuprofen, Naproxen, Sulindac, Piroxicam, Folic acid, folates, iron* Anemia, brittle nails, fatigue, hair
Diclofenac, Diflunisal, Etodolac, Fenoprofen, loss, weakness, birth defects,
Ketoprofen, Ketorolac, Meclofenamate, cardiovascular disease, cervical
Nabumetone, Tolmetin, Mefenamic Acid, dysplasia
Indomethacin*
Salicylates
Aspirin, choline magnesium trisalicylate, Folates, Fe, K, Na, Edema, fatigue, irregular heartbeat,
choline salicylate vitamin C muscle weakness; Dehydration, loss
of appetite, poor concentration,
muscle weakness; easy bruising, poor
wound healing, weakened immune
system
Salsalate Folates Anemia, birth defects, cardiovascular
disease, cervical dysplasia
 APAP alternate MFO pathways
• 2 different pathways for APAP Phase I metabolism in liver
• CYP 2A6 pathway
– produces non-toxic metabolites
– major metabolite is 3-hydroxyl-APAP
– ring hydroxyls are typically non- toxic (not electrophilic)
• CYP 2E1 pathway
– produces toxic metabolites
– major metabolite is N-acetylbenzoquinoneimine (NABQI, NAPQI)
– NABQI is highly electrophilic at C-4 position on benzene ring
– NABQI reacts with target and non-target nucleophiles
• alcohol is a good inducer of the CYP 2E1 isoform in liver cells
– Heavy drinking can create hypersusceptibility to APAP hepatotoxicity
– ‘Social drinking’ may also be risky
 APAP protection by GSH
or NAC
1. Conjugation is the normal nontoxic
pathway for APAP 2A6 2E1
non-toxic toxic
2. High-dose APAP is toxic
MFO oxidation by CYP 2E1 NAC

large amounts of toxic NABQI

3. GSH conjugates to NABQI
GSH
GSH depletion begins to occur
4. NABQI makes electrophilic attack on
cellular nucleophiles
GSH depletion becomes severe
5. NABQI covalent binding to many
target proteins (adducts) GSH

protein inactivation, cell damage

6. Cell death (hepatic necrosis)
 Nutrient depletion drugs
Drug Nutrient Depletions Potential Health Problems
ACE Inhibitors
Captopril (Capoten, Duraclon) Zinc Loss of sense of smell and taste, lower
immunity, slow wound healing
Beta Blockers
Propranolol, Metoprolol, Atenolol, Co-Q10 Congestive heart failure, high blood
Pindolol, Acetutulol Betaxolol, pressure, low energy
Bisoprolol, Carteolol, Carvedilol,
Esmolol, Labetalol, Nadolol, Sotalol,
Timolol
Brand names available include Betachron E-R, Betapace, Betimol, Betoptic, Blocadren, Brevibloc, Cartrol, Coreg, Corgard,
Inderal, Kerlone, Lopressor, Normodyne, Ocupress, Sectral, Tenormin, Timoptic, Toprol XL, Trandate, Visken, Zebeta.
Cardiac Glycosides
Digoxin (Lanoxin) Magnesium Asthma, cardiovascular problems,
cramps, osteoporosis, PMS
Vitamin B depression, edema, irritability, memory
loss, muscle weakness
 Nutrient depletion drugs
Drug Nutrient Depletions Potential Health Problems
Centrally Acting Antihypertensives
Chlorthalidone (Hygroton, Zinc Loss of sense of smell and taste,
Thalitone) lower immunity, slow wound
healing
Chlorthalidone (Hygroton, Co-Q10 Congestive heart failure, high
Thalitone) blood pressure, low energy

Methyldopa (Aldomet) CoQ10 Congestive heart failure, high

blood pressure, low energy
 Nutrient depletion drugs
Drug Nutrient Depletions Potential Health Problems
Loop Diuretics
Furosemide (Lasix) Calcium Heart/blood pressure irregularities, osteoporosis
Bumetanide (Bumex)
Ethacrynic Acid (Edecrin)
Magnesium Asthma, cardiovascular problems, cramps
Potassium Edema, fatigue, irregular heartbeat, muscle weakness
Vitamin B1 Depression, edema, irritability, memory loss, muscle weakenss
Vitamin B6 Depression, increased cardiovascular disease risk, sleep disturbance
Zinc Loss of sense of smell and taste, lower immunity, slow wound healing
Potassium-Sparing Diuretics
Triamterene (Dyrenium) Calcium Osteoporosis, heart/blood pressure irregularities, tooth decay
Folic Acid Birth Defects, cervical dysplasia, anemia, cardiovascular disease
Zinc Slow wound healing, loss of sense of smell and taste, lower immunity
Hydrochlorothiazide and Calcium Osteoporosis, heart/blood pressure irregularities, tooth decay
Triamterene (Dyazide, Maxzide)
Folic acid Birth defects, cervical dysplasia, anemia, cardiovascular disease
Vitamin B6 Depression, sleep disturbances, increased cardiovascular disease risk
 Nutrient depletion drugs
Drug Nutrient Potential Health Problems
Depletions

Thiazide Diuretics
Thiazide Diuretics* blood Co-Q10 congestive heart failure, high blood pressure, low energy

Magnesium asthma, cardiovascular problems, cramps, osteoporosis,

PMS
Potassium edema, fatigue, irregular heartbeat, muscle weakness

Zinc lower immunity, slow wound healing

*Drugs in this category include hydrochlorothiazide, methyclothiazide, indapamide and metolazone and are available
under the following brand names: Aqatensen, Enduron Esidrix, Ezide, HydroDIURIL, Hydro-Par, Microzide, Oretic, Lozol,
Mykrox and Zaroxolyn.
Vasodilators
Hydralazine Vitamin B6 Anemia, increased cardiovascular disease risk, tiredness,
weakness
CoQ10 Congestive heart failure, high blood pressure, low energy
 Nutrient depletion drugs
Drug Nutrient depletions Potential Depletion
Gout medications
Colchicine Beta-Carotene Lower immunity, reduced antioxidant
protection
Potassium Edema, fatique, irregular heartbeat,
muscle weakness
Sodium Dehydration, muscle weakness, loss of
appetite, poor concentration
Vitamin B12 Anemia, increased cardiovascular
disease risk, tiredness, weakness
Drug Nutrient Depletions Potential Health Problems
"Bile Acid Sequestrant" Drugs

Atorvastatin, Cerivastatin, Lovastatin, Coenzyme Q10 Congestive heart failure, high blood pressure, low energy
Fluvastatin, Pravastatin, Simvastatin
Cholestyramine Beta-carotene Vision problems, weakened immunity
Calcium Blood clotting, cell wall permeability, enzyme dysfunction, high blood
pressure, osteoporosis, rickets
Folates Anemia, birth defects, cervical dyslasia, elevated homocysteine
Iron hair loss
Magnesium Increased incidence of artheroderosis, heart attacks, hypertension,
stroke
Vitamin A Vision problems
Vitamin B12 Anemia, appetite loss, depression, dermatitis, fatigue, nausea, poor
blood clotting
Vitamin D Hearing loss, muscle weakness, phosphorous retention in kidneys,
rheumatic pains
Vitamin E Cataracts, dry skin, dry hair, easy bruising, eczema, poor wound
healing, PMS
Vitamin K Easy bleeding, rickets and other skeletal disorders
Zinc Acne, anorexia, decreased immunity, depression, delayed wound
healing, frequent infections, impaired sense of smell and taste
Colestipol Beta-carotene, Folates, See above
Iron, Vitamin A, Vitamin
B12, Vitamin D, Vitamin
 ACE inhibitors
Drug Nutrient Depletions Potential Health Problems

Lotensin® (captopril), Zinc
Capoten®, Vasotec®,
Prinovil®, Zestril®
Sodium
Slow wound healing, loss of sense of smell and taste, lower
immunity
Dehydration, loss of appetite, muscle weakness, poor
concentration. Note: Replacement not recommended (depletion due
to therapeutic effect)
Potential Interactions
Potassium: May increase potassium levels, especially in combination
with potassium-sparing diuretics (spironolactone) or salt-substitutes or
potassium supplements
Cayenne (Capsicum frutescens): Coughing reported when cayenne
(Capsicum frutescens) cream was applied in conjunction with the use of
ACE inhibitors
Iron: Iron supplementation inhibits cough associated with ACE
 Anticonvulsants
Drug Nutrient Depletions Potential Depletion Problems
Barbituates Calcium Heart/blood pressure irregularities,
(Amytal, Tuinal, Butalan, osteoporosis, tooth decay
Buticaps, Butisol Sodium,
Mebaral, Brevital, Barbita,
Nembutal, Luminal, Solfoton,
Seconal, Pentothal)
Folates Anemia, birth defects, cardiovascular
disease, cervical dysplasia
Vitamin D Hearing loss, muscle weakness,
osteoporosis
Vitamin K Blood clotting and skeletal problems
 Anticonvulsants
Drug Nutrient Depletions Potential Depletion Problems

Phenytoin Biotin Cardiac irregularities, depression,

(Dilantin) dermatitis, hair loss
Calcium Heart/blood pressure irregularities,
osteoporosis, tooth decay
Folates Anemia, birth defects, cardiovascular
disease, cervical dysplasia
Vitamin B1 Depression, edema, irritability, memory loss,
muscle weakness
Vitamin B12 Anemia, increased cardiovascular risk,
tiredness, weakness
Vitamin D Blood coagulation and skeletal problems
 Anticonvulsants

Drug Nutrient Depletions Potential Depletion Problems

Carbamazepine Biotin Cardiac irregularities, depression, dermatitis,
(Carbatrol, Epitol, Tegretol) hair loss
Folic acid Hearing loss, musle weakness, osteoporosis
Vitamin D Anemia, birth defects, cardiovascular disease
risk, cervical dysplasia
Folates Biotin Anemia, birth defects, cardiovascular disease
risk, cervical dysplasia
Folates Cardiac irregularities, depression, dermatitis,
hair loss
Valproic Acid Carnitine Cramps, fatigue, muscle weakness
(Depacon, Depakene, Depakote) Folic acid Anemia, birth defects, cardiovascular disease
risk, cervical dysplasia
 Ulcer/Antacid Medications
Drug Depletions Potential Depletion Problems
H-2 receptor heart/blood pressure irregularities,
calcium
antagonists osteoporosis, tooth decay
anemia, birth defects, cardiovascular
folic acid
disease, cervical dysplasia
anemia, brittle nails, fatigue, hair loss,
iron
weakness
anemia, increased cardiovascular disease
vitamin B12
risk, tiredness, weakness
vitamin D hearing loss, muscle weakness, osteoporosis
loss of sense of smell and taste, lowered
zinc
immunity, slow wound healing
 Antidiabetics
Drug Nutrient Potential Depletion Problems
Depletions
Sulfonylureas (Acetohexamide, Coenzyme Q10 high blood pressure, congestive heart failure, low
Glyburide, Tolazamide) energy
Biguanides Vitamin B12 anemia, tiredness, weakness, increased cardiovascular
disease risk
Glucophage® (metformin) Vitamin B12 anemia, tiredness, weakness, increased cardiovascular
Actos® disease risk
Avandia® (pioglitazone)
Folic Acid Anemia, birth defects, cardiovascular disease, cervical
dysplasia

Coenzyme Q10 high blood pressure, congestive heart failure, low

energy
Potential Interactions
DHEA Dehydroepiandrosterone. Metformin has been
shown to increase blood levels of DHEA
 Corticosteroids
Nutrient
Drug Potential Depletion Problems
Depletions
Anemia, birth defects, cardiovascular disease, cervical
Sulfasalazine Folates
dysplasia
Heart/blood pressure irregularities, tooth decay,
Betamethasone, Budesonide Calcium
osteoporosis
Anemia, birth defects, cardiovascular disease, cervical
Cortisone, Dexamethasone Folates
dysplasia
Flunisolide, Fluticasone,
Magnesium Asthma, cardiovascular problems, cramps, PMS
Hydrocortisone
Mometasone,
Patassium Edema, fatigue, irregular hearbeat, muscle weakness
Methylprednisolone
Prednison, Prednisolone Selenium Lower immunity, reduced antioxidant protection
Triamcinolone Vitamin C Easy bruising, lower immunity, poor wound healing
Vitamin D Hearing loss, muscle weakness, osteoporosis
Zinc Loss of sense of taste and small, slow wound healing
 Antibiotics
Drug Nutrient Depletions Potential Health Problems
General Antibiotics
penicillins, cephalosporins, Lactobacillus acidophilus; Bifidobacteria short-term depletion effects are
fluoroquinolones, macrolides, bifidum (bifidus); vitamins B1, B2, B3, minimal
aminoglycosides, sulfonamides B6, B12, K; biotin, inositol
calcium heart/blood pressure irregularities,
osteoporosis, tooth decay
magnesium asthma, cardiovascular problems,
cramps, osteoporosis, PMS
iron anemia, brittle nails, fatigue, hair loss,
weakness
tetracyclines, sulfonamides Lactobacillus acidophilus; Bifidobacteria short-term depletion effects are
bifidum (bifidus); vitamins B1, B2, B3, minimal
B6, B12, K; biotin, inositol
neomycin beta-carotene; vitamin A, B12 minimal problems with short-term use
co-trimoxazole Lactobacillus acidophilus, Bifidobacteria minimal problems with short-term use
bifidum (bifidus), folic acid
 Tuberculosis antibiotics
Drug Nutrient Potential Health Problems
Depletions
Isoniazid Vitamin B6 Anemia, tiredness, weakness, increased
(Laniazid, Nydrazid) cardiovascular disease risk
Vitamin B3 Skin, gastrointestinal and nervous system
problems
Vitamin D Osteoporosis, muscle weakness, hearing loss
Rifampin Vitamin D Osteoporosis, muscle weakness, hearing loss
(Rifadin, Rimactane)
Ethambutol Zinc Slow wound healing, loss of sense of smell and
(Myambutol) taste, lower immunity
Copper Anemia, fatigue, cardiovascular and connective
tissue problems
 SPECIFIC FOODS OR FOOD COMPONENTS

• Di- and trivalent cation-containing dietary products including

dairy foods are known to chelate with the fluoroquinolone
antibiotics and reduce their bioavailability. This remains true for
the newer drugs in this class
• Cow’s milk may also reduce drug bioavailability by its xanthine
oxidase content as in the case of mercaptopurine and its
transformation to the inactive 6-thiouric acid by the enzyme. It is
suggested that a 6 h gap should be sufficient to prevent the
interaction
 SPECIFIC FOODS OR FOOD COMPONENTS

• Cruciferous vegetables are a dietary source of glucosinolates that are

metabolized to isothiocyanates and indoles. The isothiocyanates are
not only substrates for but also inducers of glutathione-S-transferase
(GST) enzymes
• Soy protein isolates reduce the expression and activity of the
cytochrome P450(CYP)-metabolizing isoenzyme CYP1A1, most likely
by a posttranslational reduction of the transcription factor AhR (aryl
hydrocarbon receptor)
• Based on a gene array screening method, soy isoflavones can
significantly upregulate two drug transporters and three phase I and
two phase II enzymes
 Effect of Specific Nutrients or Other Dietary Supplement
Ingredients on Drug Disposition
• Vitamin D, particularly in its most biologically active form,
increases the expression of several phase I and II metabolizing
enzymes
• This is not unexpected given that the vitamin D receptor is a
nuclear receptor in the same subfamily as others involved in
enzyme induction
• The influence of a nutrient on drug disposition may be a positive
interaction. One example would be the use of pyridoxine in the
prevention or treatment of isoniazid toxicity
 Influence of Drugs on Global Nutritional Status

• The influence of medication on overall nutritional status can be

multifactorial. Drugs can influence food intake, digestion, and absorption.
A drug may alter food intake by direct effects on the gastrointestinal tract
or the gut-brain axis.
• When significant, disturbance in gastrointestinal function (e.g., taste
disorder, stomatitis, nausea, vomiting, diarrhea) can impair individuals’
ability to maintain or improve their nutritional status. Alternatively
indirect effects on food intake may occur as a result of drug-induced
cognitive disturbances, visual changes, movement disorders, and gait
abnormalities when severe. Impaired ability to gather, prepare, or ingest
food may play a role
 Influence of Medication on the Status of Specific Nutrients
• Carnitine deficiency can occur with valproic acid treatment, resulting in reductions of
both plasma-free carnitine and plasma total carnitine concentrations, as well as a
reduction in urinary total and free carnitine with chronic valproic acid treatment
• Tissue carnitine depletion during treatment with valproic acid may in part be due to
an inhibition of tissue uptake. Valproic acid treatment is also associated with altered
acylcarnitine subspecies that reflect impaired intermediary metabolism likely
responsible for drug-induced hepatotoxicity
• Valproic acid seems to inhibit the hepatic synthesis of carnitine thereby contributing
to a deficiency state. This appears to occur at the level of butyrobetaine hydroxylase
but without direct inhibition, likely a result of reduced α-ketoglutarate levels
required as a cofactor
• This deficit may contribute to the drug’s adverse effects including hyperammonemia.
Management of clinical deficiency has required a significant dose of carnitine in
children, in which case symptoms resolved within 1 week of the intervention

Epilepsia 2007;48:72-76
 Influence of Medication on the Status of
Specific Nutrients
• It has been suggested that oral L-carnitine supplementation be considered for
patients with symptomatic valproic acid-associated hyperammonemia, or
those with multiple risk factors for valproic acid hepatotoxicity, and infants
and children using valproic acid. The recommended oral dose of L-carnitine is
100 mg/kg daily to a maximum of 2 g daily. Intravenous administration of L-
carnitine is also an option for patients with valproic acid-induced
hepatotoxicity or other acute metabolic crises associated with carnitine deficits
• Supplementation may not be needed in all patients receiving valproic acid
who are otherwise healthy and ingest a regular diet. An appropriate
prophylactic dose has not been described.

Pediatrics 1998;101:E9
 Influence of Medication on the Status of
Specific Nutrients
• There are some medication regimens that are associated with improvements
in nutrient status. For example, the use of highly active antiretroviral therapy
in management of HIV infection is associated with improved concentrations
of α-carotene, β-carotene, α-tocopherol, vitamin B12, and folate, although
these findings were not adjusted for inflammatory state
• The 3-OH-3-CH3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors may
improve vitamin D status, which may play a role in the drug’s therapeutic
benefit beyond cholesterol concentration modification
• The role played by the increased availability of 7-dehydrocholesterol as the
vitamin D precursor in the skin following HMG-CoA reductase inhibition is
unclear

Am J Clin Nutr 2007;85:333–345; Am J Cardiol 2007;99:903-905

 HMG-CoA reductase inhibitors and rhabdomyolysis

• HMG-CoA reductase inhibitors belong to an important class of

cholesterol-lowering medications. However, they can cause
significant toxicity. Unwanted effects range from diffuse myalgia
and elevated creatine phosphokinase to severe skeletal muscle
degeneration (rhabdomyolysis) and associated acute renal failure
• These effects can occur when the plasma concentration of HMG-CoA
reductase inhibitor is markedly elevated. Atorvastatin, lovastatin
and simvastatin are extensively metabolized by CYP3A4 and have
low oral systemic availability
 Plant Stanols and Statins
• The management of dyslipidemia combines drug therapy with lifestyle
modifications. HMG-CoA reductase inhibitors (statins) are the most widely
prescribed agents to lower serum LDL concentration
• Besides reducing saturated fat, trans fat,and cholesterol intake, an
alternate or adjunct approach in managing hypercholesterolemia is
inhibiting cholesterol absorption with dietary inclusion of plant sterols
and stanols. Plant sterols and stanols block dietary and biliary cholesterol
absorption in the small intestines with subsequent reduction of serum
cholesterol and LDL concentrations
 Plant Stanols and Statins
• Plant sterols (phytosterols) are naturally occurring plant constituents. They are
28-carbon (campesterol) and 29-carbon (sitosterol and stigmasterol) sterols
found in edible oils, nuts, and seeds. Plant stanols are saturated derivatives of
plant sterols, with sitostanol being the most common. Sitostanol is found
mainly in wood pulp, tall oil, and to a lesser extent, in soybean oil
• The Western diet provides about 100-300 mg/day of plant sterols and 20-50
mg/day of plant stanols. Plant stanols and sterols have been incorporated into
various food products, including margarine and salad dressing. They are more
commonly used in Europe than in the United States.
 Plant Stanols and Statins
• Although plant stanols and sterols have been shown to be equally effective in
reducing serum cholesterol concentrations, the compounds have inherent
differences. For instance, plant stanols are preferable over plant sterols because
they are relatively unabsorbed from the gastrointestinal tract. Although plant
sterols are poorly absorbed, daily sterol intake of 3.24 g increases serum
sitosterol and campesterol by 40 and 70%, respectively. Because of concerns
that plant sterols and their byproducts may initiate the development of
atherosclerosis, plant stanols appear safer substances, especially during long-
term consumption
• Plant stanols have been used as adjunctive therapy with statins to manage
hypercholesterolemia. Because statins inhibit cholesterol synthesis and stanols
block cholesterol absorption, an additive effect of combining the two agents
would be anticipated to further lower serum cholesterol concentrations. The
combined effects of statins and plant stanols are equivalent to a one-to two fold
increase in statin dose
 Slow CYP2D6 Metabolizers

• CYP2D6 and CYP2C19 metabolize 25% of drugs including

many antidepressants, antipsychotics, and narcotics
• Slow metabolizers are at risk for toxicity and adverse drug
effects
• Fast metabolizers have unpredictable response
• Drug genotyping in future will help determine most
effective meds for individuals
 Benefits of Minimizing Food Drug
Interactions
• Medications achieve their intended effects
• Improved compliance with medications
• Less need for additional medication or higher dosages
• Fewer caloric or nutrient supplements are required
• Adverse side effects are avoided
Benefits of Minimizing Food Drug Interactions

• Optimal nutritional status is preserved

• Accidents and injuries are avoided
• Disease complications are minimized
• The cost of health care services is reduced
• There is less professional liability
• Licensing agency requirements are met
 Therapeutic Importance
Therapeutically important interactions are those that:
• Alter the intended response to the medication
• Cause drug toxicity
• Alter normal nutritional status
Patients at Risk for Food-Nutrient Interactions

• Patient with chronic disease

• Elderly
• Fetus
• Infant
• Pregnant woman
• Malnourished patient
• Allergies or intolerances
Food and Drug-Related Risk Factors

• Special diets
• Nutritional supplements
• Tube feeding
• Herbal or phytonutrient products
• Alcohol intake
• Polypharmacy
• Drugs of abuse
• Non-nutrients in foods
• Excipients in drugs or food
 Malnutrition Effect on Drugs
• Low albumin levels can make drugs more potent by increasing
availability to tissues
– Lower doses often recommended for persons with low albumin
– Warfarin and phenytoin are highly protein bound in blood; ↓ albumin
can result in poor seizure control (phenytoin) or hemorrhage (warfarin)
• Body composition: obese or elderly persons have a higher ratio
of adipose tissue; fat soluble drugs may accumulate in the body
↑ risk of toxicity
 Impact of protein-calorie malnutrition on Medication (PCM)

• With malnutrition, drug absorption, distribution, and

clearance are negatively impacted. Changes in drug
disposition may vary with the degree of altered body
composition and function associated with PCM. In severe
PCM, drug absorption maybe reduced, protein carriers
limited, and metabolism slowed, resulting in higher drug
concentrations and a potential for toxicity especially with
drugs that have a narrow safety margin
• In mild to moderate malnutrition, changes in metabolism
may be minimal or of limited clinical significance
 Food/Nutrient Effects on Drugs

Absorption
– Presence of food and nutrients in intestinal tract may affect
absorption of drug
– Antiosteoporosis drugs Fosamax or Actonel: absorption
negligible if given with food; ↓ 60% with coffee or orange
juice
 Food/Nutrient Effects on Drugs

Absorption
• Absorption of iron from supplements ↓↓ 50% when taken
with food
• Best absorbed when taken with 8 oz of water on empty
stomach
• Food may ↓↓ GI upset
• If take with food, avoid bran, eggs, fiber supplements, tea,
coffee, dairy products, calcium supplements
 Food/Nutrient Effects on Drugs
Absorption
– Ciprofloxacin and Tetracycline form insoluble complexes with
calcium in dairy products or fortified foods; also zinc,
calcium, magnesium, zinc or iron supplements; aluminum in
antacids
– Stop unnecessary supplements during drug therapy or give
drug 2 hours before or 6 hours after the mineral
 Food/Nutrient Effects on Drugs
• Absorption
– Presence of food enhances the absorption of some
medications
– Bioavailability of Axetil (Ceftin), an antibiotic, is 52% after a
meal vs 37% in the fasting state
– Absorption of the antiretroviral drug saquinavir is increased
twofold by food
 Food/Nutrient Effects on Drugs
• Adsorption: adhesion to a food or food component
– High fiber diet may decrease the absorption of tricyclic
antidepressants such as amitriptyline (Elavil)
– Digoxin (Lanoxin) should not be taken with high phytate
foods such as wheat bran or oatmeal
 Food/Nutrient Effects on Drugs

• GI pH can affect drug absorption

• Achlorhydria or hypochlorhydria can reduce absorption of
ketoconozole and delavirdine
• Antacid medications can result in reduced acidity in the
stomach
• Taking these meds with orange or cranberry juice can
reduce stomach pH and increase absorption
 Food/Nutrient Effects on Drugs

Metabolism
Changes in diet may alter drug action
• Theophylline: a high protein, low CHO diet can enhance clearance
of this and other drugs
• Grapefruit/juice: inhibits the intestinal metabolism (cytochrome
P-450 3A4 enzyme) of numerous drugs (calcium channel
blockers, HMG CoA inhibitors, anti-anxiety agents) enhancing
their effects and increasing risk of toxicity; may interfere with
the absorption of other drugs
 Grapefruit Inhibits Metabolism of Many Drugs

• Inactivates metabolizing intestinal enzyme resulting in

enhanced activity and possible toxicity
• Effect persists for 72 hours so it is not helpful to separate
the drug and the grapefruit
• Many hospitals and health care centers have taken
grapefruit products off the menu entirely
Drugs known to interact with grapefruit juice
• Anti-hypertensives (filodipine, • Lipid-Lowering Drugs
nifedipine, nimodipine, (atorvastatin, lovastatin,
nicardipine, isradipine) simvastatin)
• Immunosuppressants • Anti-anxiety, anti-depressants
(cyclosporine, tacrolimus) (buspirone, diazepam, midazolam,
• Antihistamines (astemizole) triazolam, zaleplon,
• Protease inhibitors (saquinavir) carbamazepine, clomipramine,
trazodone
 Food/Nutrient Effects on Drugs

• Excretion
—Patients on low sodium diets will reabsorb more lithium along
with sodium; patients on high sodium diets will excrete more
lithium and need higher doses
—Urinary pH: some diets, particularly extreme diets, may affect
urinary pH, which affects resorption of acidic and basic
medications
 Food/Nutrient Effects on Drug Action:
MAOIs
• Monoamine oxidase inhibitors (MAOI) interact with pressor
agents in foods (tyramine, dopamine, histamine)
• Pressors are generally deaminated rapidly by MAO; MAOIs
prevent the breakdown of tyramine and other pressors
• Significant intake of high-tyramine foods (aged cheeses, cured
meats) by pts on MAOIs can precipitate hypertensive crisis
 MAO Inhibitors
• These drugs decrease the body's use of compounds called monoamines. MAO inhibitors
can also react with tyramine (a monoamine) found in foods. This reaction can cause a
dangerous rise in blood pressure. If not treated, this can cause death. Some aged and
fermented foods are high in tyramine. They should be avoided by people taking MAO
inhibitors. A few of these foods are:

• aged cheese

• Brewer's yeast, yeast extracts

• Chianti wine

• pickled herring

• fava beans
 Food/Nutrient Effects on Drug Action:
Caffeine
• Increases adverse effects of stimulants such as
amphetamines, methylphenidate, theophylline, causing
nervousness, tremor, insomnia
• Counters the antianxiety effect of tranquilizers
Food/Nutrient Effects on Drug Action: Warfarin

• Warfarin (anticoagulant) acts by preventing the conversion of

vitamin K to a usable form
• Ingestion of vitamin K in usable form will allow production of
more clotting factors, making the drug less effective
• Pts must achieve a balance or steady state between dose of drug
and consumption of vitamin K; recommend steady intake of K
• Other foods with anticlotting qualities may also have an effect
(garlic, onions, vitamin E in large amounts, and ginseng)
 Food/Nutrient Effects on Drug Action:
Alcohol
• In combination with some drugs will produce additive
toxicity
• With CNS-suppressant drugs may produce excessive
drowsiness, incoordination
• Acts as gastric irritant; in combination with other
irritants such as NSAIDs may increase chance of GI
bleed
 Food/Nutrient Effects on Drug Action:
Alcohol
• Should not be combined with other hepatotoxic drugs
such as acetominophen, amiodarone, methotrexate
• Can inhibit gluconeogenesis when consumed in a fasting
state; can prolong hypoglycemic episode caused by
insulin or other diabetes meds
Food/Nutrient Effects on Drug Action: Alcohol
• Can produce life-threatening reaction when combined
with disulfiram (Antabuse) which prevents the
catabolism of ethanol by the liver
– Causes nausea, headache, flushing, increased blood pressure
• Metronidazole, Cefoperazone, chlorpropamide
(Diabenese) and procarbacine cause similar symptoms
 Drug Effects on Nutrition: Metabolism
• Phenobarbital and phenytoin increase metabolism of
vitamin D, vitamin K, and folic acid
– Patients on chronic tx may need supplements

• Carbamazepine may affect metabolism of biotin,

vitamin D, and folic acid, leading to possible depletion
Drug Effects on Nutrition: Metabolism

• INH (anti-tuberculosis) blocks conversion of

pyridoxine to active form
– Patients with low intake at higher risk
– May cause deficiency and peripheral neuropathy
– Pts on long term tx may need supplements
• Hydralazine, penacillamine, levodopa and
cycloserine are also pyridoxine antagonists
 Drug Effects on Nutrition: Metabolism
• Methotrexate (cancer and rheumatoid arthritis) and
pyrimethamine (malaria, toxoplasmosis) are folic acid
antagonists
– May treat with folinic acid (reduced form of folic acid, does
not need conversion to active form) or folic acid supplements
 Drug Effects on Nutrition: Excretion
• Loop diuretics (furosemide, bumetanice) increase
excretion of potassium, magnesium, sodium, chloride,
calcium
– Patients may need supplements with long term use, high
dosages, poor diets
– Electrolytes should be monitored
 Drug Effects on Nutrition: Excretion
• Thiazide diuretics (hydrochlorthiazide) increase the excretion of
potassium and magnesium, but reduce excretion of calcium
– High doses plus calcium supplementation may result in hypercalcemia
• Potassium-sparing diuretics (spironolactone) increase excretion
of sodium, chloride, calcium
– Potassium levels can rise to dangerous levels if pt takes K+
supplements or has renal insufficiency
 Drug Effects on Nutrition: Excretion
• Corticosteroids (prednisone) decrease sodium 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 (lupus, RA) to prevent osteoporosis
 Drug Effects on Nutrition: Excretion

• Phenothiazine antipsychotic drugs (chlorpromazine) increase excretion of

riboflavin
– 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 mg supplementation or post-treatment hydration and oral mg
supplementation
– May persist for months or years after therapy is finished
 Drug Effects on Nutrition: Absorption

• Drug-nutrient complexes: example, ciprofloxacin and

tetracycline will complex with calcium, supplemental
magnesium, iron, or zinc
– Take minerals 2 to 6 hours apart from the drug
• Decreased transit time: cathartic agents, laxatives, drugs
containing sorbitol, drugs that increase peristalsis
 Drug Effects on Nutrition; Absorption

• Change GI environment
– Proton pump inhibitors, H2 receptor antagonists inhibit gastric
acid secretion, raise gastric pH; cimetidine reduces intrinsic
factor secretion; this impairs B12 absorption; ↑ pH may impair
absorption of calcium, iron, zinc, folic acid, and B-carotene
 Drug Effects on Nutrition: Absorption
Damage GI Mucosa
• Chemotherapeutic agents, NSAIDs, antibiotic therapy
• Alters ability to absorb minerals, especially iron and calcium
Affect Intestinal Transport
• Cochicine (gout) paraaminosalicylic acid (TB) sulfasalazine
(ulcerative colitis) trimethoprim (antibiotic) and pyrimethamine
(antiprotozoal)
– Impair absorption of B12 or folate
 Drug Effects on Nutrition: Adsorption

• Cholestyramine (antihyperlipidemic bile acid sequestrant)

also adsorbs fat-soluble vitamins A, D, E, K, possibly folic
acid; may need supplements for long term therapy,
especially if dosed several times a day
• Mineral oil: (>2 tbsp/day) ↓ absorption of fat soluble
vitamins
– take vitamins at least 2 hours after mineral oil
Drug Side Effects that Affect Nutritional Status
• Appetite changes
• Oral taste and smell
• Nausea
• Dry mouth
• Gastrointestinal effects
• Organ system toxicity
• Glucose levels
Examples of Drug Categories That May Decrease Appetite

• Antiinfectives
• Antineoplastics
• Bronchodilators
• Cardiovascular drugs
• Stimulants
 Drugs That May Increase Appetite

• Anticonvulsants
• Hormones
• Psychotropic drugs
—Antipsychotics
—Antidepressants, tricyclics, MAOIs
Drugs Affecting Oral Cavity, Taste and Smell
• Taste changes: cisplatin, captopril (anti-hypertensive)
amprenavir (antiviral) phenytoin (anti-convulsive),
clarithromycin (antibiotic)
• Mucositis: antineoplastic drugs such as interleukin-2, paclitaxel,
carboplatin
• Dry mouth: Anticholinergic drugs (tricyclic antidepressants such
as amytriptyline, antihistamines such as diphenhydramine,
antispasmodics such as oxybutynin
 Drugs that Affect the GI Tract

• Alendronate (Fosamax) anti-osteoporosis drug-patients must sit

upright 30 minutes after taking it to avoid esophagitis
• Aspirin or other NASAIDs –can cause GI bleeding, gastritis
• Orlistat – blocks fat absorption, can cause oily spotting, fecal
urgency, incontinence
• Narcotic agents cause constipation
Examples of Drug Classes That Cause Diarrhea

• Laxatives
• Antiretrovirals
• Antibiotics
• Antineoplastics
• + liquid medications in elixirs containing sugar
alcohols
 Drugs That May Lower Glucose Levels

• Antidiabetic drugs (acarbose, glimepiride, glipizide,

glyburide, insulin, metformin, miglitol, neteglinide,
pioglitizone, repaglinide, roiglitizone
• Drugs that can cause hypoglycemia: ethanol, quinine,
disopyramide (antiarrhythmic) and pentamidine
isethionate (antiprotozoal)
 Drugs That Raise Blood Glucose

• Antiretrovirals, protease inhibitors (amprenavir, nelfinavir,

ritonavir, saquinavir)
• Diuretics, antihypertensives (furosemide, hydrochlorothiazide,
indapamide)
• Hormones (corticosteroids, danazol, estrogen or
estrogen/progesterone replacement therapy, megestrol acetate, oral
contraceptives)
• Niacin (antihyperlipidemic) baclofen, caffeine, olanzapine,
cyclosporine, interferon alfa-2a
 Nutrition Implications of Excipients in Drugs

• Excipients: are inactive ingredients added to drugs as fillers,

buffers, binders, disintegrant, flavoring, dye, preservative,
suspending agent, coating
• Approved by FDA for use in pharmaceuticals
• Vary widely from brand to brand and formulation strengths of
the same drug
 Nutrition Implications of Excipients in Drugs

• Excipients may cause allergic or health reactions in persons with

celiac disease, dye sensitivity, other allergies, inborn errors of
metabolism
• Examples of excipients that might cause reactions are albumin,
wheat products, alcohol, aspartame, lactose, sugar alcohols,
starch, sulfites, tartrazine, vegetable oil
• Some meds may contain sufficient CHO or protein to put a patient
on a ketogenic diet out of ketosis
 Nutrition Implications of Excipients in Drugs
• Some drugs at usual dosages may contain enough
excipients to be nutritionally significant
– Agenerase: 1744 IU vitamin E
– Accupril: 50-200 mg magnesium
– Fibercon/Fiberlax: 600 mg Ca+ in 6 tabs
– Propofol (Diprivan) contains 10% soybean emulsion; may
provide 1663 kcals/day for 70 kg person
 Food/Nutrient Effects on Drugs-Enteral Feedings

• Most medications should not be mixed with enteral

feedings; physical incompatibilities can occur including
granulation, gel formation, separation of the feeding
leading to clogged tubes
• Enteral feedings interfere with phenytoin absorption;
window the feeding around drug dose (2 hours before and
after)
 Enteral Nutrition and Drugs

• Drugs put in feeding tubes may cause:

—Diarrhea
—Drug-nutrient binding
—Blocked tube
• If patient does not receive total volume of enteral
feeding, he/she will not receive the full dose of the
drug
 Enteral Nutrition and Drugs
• Avoid adding drug to formula
• When drugs must be given through tube:
– Stop feeding, flush tube, give drug, flush
– Use liquid form of drug (but be aware of effects of elixirs on
bowel function)
– Avoid crushing tablets
 Enteral Nutrition and Drugs
• Be aware of potential interactions between enteral
feedings and drugs
– Phenytoin
– Ciprofloxacin
 MNT for Food-Drug Interactions

• Prospective: MNT offered when the patient first

starts a drug
• Retrospective: evaluation of symptoms to
determine if medical problems might be the result
of food-drug interactions
 Avoiding Food-Drug Interactions:
Prospective
• When medications are initiated, patients should be
provided with complete written and verbal drug education
at an appropriate reading level including food-drug
interaction information
• Patients should be encouraged to ask specific questions
about their medications and whether they might interact
with each other or with foods
• Patients should read the drug label and accompanying
materials provided by the pharmacist
 Avoiding Food-Drug Interactions:
Prospective
• In acute-care settings, patients receiving high risk medications
should be identified and evaluated
• Nurses should have information regarding drug-food
interactions and drug administration guidelines available at the
bedside
• Med pass times should be evaluated in light of potential food-
drug interactions
 Avoiding Food-Drug Interactions:
Prospective
• Systems should be established so that pharmacists can
communicate with food and nutrition staff regarding
high risk patients
Avoiding Food-Drug Interactions: Retrospective
• Clinicians including dietitians should obtain a full drug and diet
history including the use of OTC and dietary supplements and
review potential drug-food interactions
• A plan should be developed for dealing with potential drug-food
interactions for short and long term drug therapy
• When therapeutic goals are not met, clinicians should ask
questions about how and when drugs are being taken in relation
to foods and nutritional supplements
Avoiding Food-Drug Interactions: Retrospective
• Clinicians should evaluate whether medical problems
could be the result of drug-food interactions
• Often it may be the dietitian who is most aware of these
issues
Avoiding Food-Drug Interactions: Example
• A 20-year-old disabled patient who was a long term resident of
a nursing home was admitted to an acute care hospital for a
workup to determine the cause of chronic diarrhea
• The enteral feeding had been changed numerous times in an
effort to normalize the patient’s bowel function
• The patient was currently receiving a defined formula feeding at
a slow rate
Avoiding Food-Drug Interactions: Example
• The workup revealed no apparent medical reason for the
impaired bowel function
• After reviewing the pts medications, the dietitian suggested that
the patient’s medications (given in liquid elixir forms containing
sugar alcohols) might be causing the diarrhea
• The patient’s medications were changed, and the diarrhea
resolved
• The patient returned to the nursing home on a standard enteral
feeding formula
 Summary
• Most drugs have nutritional status side effects.
• Always look for therapeutically significant
interactions between food and drugs
• Identify and monitor high risk patients, those on
multiple medications and marginal diets
 Examples of drug classes and their uses
Class Used to treat...
Analgesic Pain
Antacid, Acid Blocker Stomach upset, ulcers
Antibiotic Infection
Anticoagulant Blood clots
Anticonvulsant Seizures, epilepsy
Antihistamine Allergies
Antihyperlipemic High blood cholesterol, hypertriglyceridemia
Antihypertensive High blood pressure
Anti-inflammatory Fever, inflammation
Antineoplastic Cancer
Diuretic Water retention
Laxative Constipation
Psychotherapeutic Depression, anxiety
 Examples of Drug-Nutrient Interactions
Drug Class Food that Interacts Effect of the Food What to Do
Acid Blocker

ranitidine (Zantac),
Consult your physician regarding B12
cimetidine (Tagamet), Vitamin B12 Decrease vitamin absorption
supplementation
famotidine (Pepcid),

nizatidine (Axid)
Antihyperlipemic
Fat soluble vitamins Include rich sources of these vitamins in
cholestyramine (Questran), Decreases vitamin absorption
(A, D, E, K) the diet
colestipol (Colestid)
Antineoplastic Consult your physician regarding
Folic acid, vitamin B12 Decreases vitamin absorption
methotrexate supplementation
Diuretic
Include fresh fruits and vegetables in the
furosemide (Lasix), Many minerals Increases mineral loss in urine
diet
hydrochlorothiazide (HCTZ)
Laxative Consult your physician regarding
Vitamins and minerals Decreases nutrient absorption
fibercon, Mitrolan supplementation
 Examples of Food/Drug Interactions
Drug Class Food that Interacts Effect of the Food What to Do
Analgesic
Increases risk for
acetaminophen Alcohol Avoid alcohol
liver toxicity
(Tylenol)
Antibiotic →Do not take with
→Decreases drug milk. Take 1 hour
→tetracyclines absorption before or 2 hours
→Dairy products;
→amoxicillin, →Decreases drug after food/milk.
iron supplements
penicillin, absorption →Take 1 hour
zithromax, →Food
→Decreases GI before or 2 hours
erythromycin →Food
distress, slows drug after meals.
→nitrofurantoin absorption →Take with food or
(Macrobid) milk.
 Examples of Food/Drug Interactions
Drug Class Food that Interacts Effect of the Food What to Do
Anticonvulsant Causes increased
Alcohol Avoid alcohol
drowsiness
phenobarbital, Decrease in drug
primidone Vitamin C Avoid excess vitamin C
effectiveness
Antifungal Increases drug Take with high-fat
High-fat meal
griseofulvin (Fulvicin) absorption meal

Antihistamine
diphenhydramine
(Benadryl), Alcohol Increased drowsiness Avoid alcohol
chlorpheniramine
(Chlor-Trimeton)
 Examples of Food/Drug Interactions

Drug Class Food that Interacts Effect of the Food What to Do

Antihyperlipemic Enhances drug
Food Take with food
lovastatin (Mevacor) absorption
Consult your
Antihypertensive
Increases drug physician or
felodipine (Plendil), Grapefruit juice absorption Pharmacist before
nifedipine
changing diet.
→Decreases GI →Take with food or
Anti-inflammatory →Food or milk
irritation milk
naproxen →Increases risk for
(Naprosyn), liver
→Alcohol →Avoid alcohol
ibuprofen (Motrin) →Damage or
stomach bleeding
 Examples of Food/Drug Interactions

Drug Class Food that Interacts Effect of the Food What to Do

Diuretic
Decreases GI
spironolactone Food Take with food
irritation
(Aldactone)
Psychotherapeutic
MAO inhibitors: Foods high in
tyramine: aged
isocarboxazid
cheeses, Chianti Risk for Avoid foods high in
(Marplan),
wine, pickled hypertensive crisis tyramine
tranylcypromine herring, Brewer's
(Parnate), yeast, fava beans
phenelzine (Nardil)
 Examples of Food/Drug Interactions
Drug Class Food that Interacts Effect of the Food What to Do
Acid Blocker

ranitidine (Zantac),
Consult your physician
cimetidine (Tagamet), Vitamin B12 Decrease vitamin absorption
regarding B12 supplementation
famotidine (Pepcid),

nizatidine (Axid)
Antihyperlipemic
Fat soluble vitamins Include rich sources of these
cholestyramine (Questran), Decreases vitamin absorption
(A, D, E, K) vitamins in the diet
colestipol (Colestid)
Antineoplastic Consult your physician
Folic acid, vitamin B12 Decreases vitamin absorption
methotrexate regarding supplementation
Diuretic
Include fresh fruits and
furosemide (Lasix), Many minerals Increases mineral loss in urine
vegetables in the diet
hydrochlorothiazide (HCTZ)
Laxative Consult your physician
Vitamins and minerals Decreases nutrient absorption
fibercon, Mitrolan regarding supplementation
 Medications to be Administered on an Empty Stomach

Generic Name Brand Name Clinical Effect/Reason

Azithromycin capsules Zithromax Food decreases absorption of capsules by
50%; taken on an empty stomach. Tablets
and suspension can be taken without regard
to meals
Bisphosphonates Dairy products/food can impair absorption;
•Alendronate Fosamax administer 2 h prior to meal
•Etidronate Didronel
•Ibandronate Boniva
•Risedronate Actonel
Dextroamphetamine Adderall Acidic foods/juices will impair absorption
Digoxin Lanoxin Food delays absorption and may decrease
peak concentrations; take consistently with
respect to meals
Diltiazem Tiazac, Cardizem Absorption is increased in the fasting state;
administer before meals
Furosemide Lasix Absorption is increased in the fasting state
 Medications to be Administered on an Empty Stomach

Generic Name Brand Name Clinical Effect/Reason

Glipizide Glucotrol XL Increased absorption and improved clinical
effect when administered 30 min prior to
meal
Levothyroxine Levoxyl, Synthroid Absorption is increased in the fasting state;
take at same time daily and consistently with
respect to meals
Metronidazole Flagyl Food decreases the peak concentration and
time to peak
Phenytoin Dilantin Food alters absorption; taken consistently
with respect to meals
Proton pump inhibitors Administer before meals to improve
•Esomeprazole Nexium absorption and maximize clinical effect
•Lansoprazole Prevacid
•Omeprazole Prilosec
•Pantoprazole Protonix
•Rabeprazole Aciphex
 Medications to be Administered on an Empty Stomach

Generic Name Brand Name Clinical Effect/Reason

Tetracyclines Absorption is significantly impaired by
• Doxycycline Vibramycin iron/milk/food
• Minocycline Minocin
• Tetracycline Sumycin
Theophylline TheoDur, TheoBid, Food may decrease absorption; taken
SloBid consistently with respect to meals
Warfarin Coumadin Food alters absorption; taken
consistently with respect to meals
Zafirlukast Accolate Food decreases absorption by up to 40%
Zolpidem Ambien Food may delay the onset of action
 Medications to be Administered with food

Generic Name Brand Name Clinical Effect/Reason

Amoxicillin/clavulanate Augmentin Food increases absorption and decreases
GI upset
Carbamazepine Tegretol Food increases absorption
Carvedilol Coreg Food decreases risk for orthostatic
hypotension
Divalproex Depakote Food will decrease GI upset
Fenofibrate Tricor Food increases bioavailability
Glucocorticoids Food will decrease GI upset
• Methylprednisolone Medrol
• Prednisone
Glyburide/metformin Glucovance Food will decrease GI upset from
metformin
Labetalol Normodyne Food increases absorption; taken
consistently with respect to meals
 Medications to be Administered with food
Generic Name Brand Name Clinical Effect/Reason
Metformin Glucophage(regular Food will decrease GI upset
and XR)
Metoprolol Toprol, Toprol XL Food increases absorption; taken
consistently with respect to meals
Niacin Niaspan Food decreases GI upset
Nitrofurantoin MacroBid Food improves tolerance and increases
bioavailability
Nonsteroidal Agents Food will decrease GI upset
• Celecoxib Celebrex
• Diclofenac Voltaren
• Etodolac Lodine
• Ibuprofen Motrin
• Meloxicam Mobic
• Nabumetone Relafen
• Naproxen Naprosyn
• Various others
 Medications to be Administered with food

Generic Name Brand Name Clinical Effect/Reason

Potassium chloride K-Dur, Klor-Con Food will decrease GI upset
Tamsulosin Flomax Food alters bioavailability; take
consistently 30 min after same meal
daily
Trazodone Desyrel Food increases absorption by 20%
Venlafaxine Effexor Food will decrease GI upset
 Type of meal and drug-nutrient interaction

• Although different meal types provide a similar rate of fluid delivery from
the stomach to the small intestine based on caloric density, intestinal fluid
volumes and resultant drug concentrations depend strongly on meal type.
Simple carbohydrate meals may result in substantial water absorption in
the small intestine that may, in theory, result in more concentrated drug
solutions in the intestinal lumen
• Protein meals promote higher intestinal fluid volumes as the result of
significant pancreatic secretions which may, in theory, result in more dilute
drug solutions. Even greater intestinal volumes should result from intake
of high-fat meals since pancreatic and biliary secretions will be stimulated
to a greater extent than with other meal types
 Folate
• Folic acid is involved in DNA synthesis
• Deficiency causes:
– Megaloblastic anaemia
– Diarrhoea

• Folate metabolism

Dihydrofolate reductase (DHFR)

Folic Acid Dihydrofolate Tetrahydrofolate

 Folate Deficiency

DHFR Inhibitors Impaired Absorption or

Utilisation
• Methotrexate • Alcohol
• Trimetrexate • Metformin
• Pentamidine • Nitrofurantoin
• Proguanil • O.C.P
• Pyrimethamine • Phenobarbitone
• Trimethoprim • Phenytoin (Carl, 1992)
• Triamterene • Primidone
• Sulphasalazine (Pironi, 1988)
 Types of Interactions
• Drug-Nutrient Interactions
– Effect of a medication on food or a nutrient in food
– Both prescription and over-the-counter medications can affect
the way your body uses nutrients in food
• Nutrient-Drug Interactions
– Effect of food or a nutrient in food on a medication
 Nutrition Implications
• Little chance taking a medication for a short time will
affect your nutritional status
• However, using some medications for months or years
may affect your nutritional health
– Changing diet to include more foods rich in vitamins and
minerals is preferred to taking vitamin or mineral
supplements
 Drug-Nutrient Interactions
• Medications, can affect nutrients by:
– Decreasing food intake
– Decreasing nutrient absorption
– Slowing down nutrient production
– Interfering with nutrient metabolism
– Increasing nutrient excretion
 Drug-Nutrient Interactions: Food Intake

• Some medications can affect nutritional health by

causing poor food intake due to:
– Decreased appetite
– Nausea or vomiting
– Unpleasant taste or dry mouth
– Gastrointestinal sores or inflammation
 Drug-Nutrient Interactions:
Food Intake
• Many medications may cause loss of appetite or
nausea in some people, but it usually subsides after
the first few doses
• However, nutritional health can be affected if
decreased food intake persists
 Drug-Nutrient Interactions:
Food Intake
• Examples:
– Appetite suppressants are medications which affect food
intake by depressing appetite
– Several cancer medications and treatments may dramatically
reduce food intake by causing:
• Loss of appetite
• Changes in taste perception
• Nausea, vomiting
• Dry mouth
• Mouth and intestinal sores or inflammation
Drug-Nutrient Interactions: Nutrient Absorption
• Some medications can affect nutritional health by
decreasing nutrient absorption due to:
– Decreasing time in intestine
– Altering stomach acidity
– Damaging intestinal lining
– Competing for absorption
– Binding nutrients
 Drug-Nutrient Interactions: Nutrient Absorption

• Examples:
– Laxatives can cause food to move rapidly through the
intestinal track which can decrease nutrient absorption
– Antacids can lower stomach acidity which can may interfere
with iron, folate and vitamin B12 absorption
– Many cancer medications and treatments can damage the
intestinal lining which can decrease nutrient absorption
 Drug-Nutrient Interactions:
Nutrient Absorption (cont.)
• Examples:
– Some anticonvulsants can compete for absorption with
folate resulting in decreased folate absorption
– Some cholesterol lowering medications reduce
cholesterol by removing bile acids
• Bile acids are needed to absorb essential fatty acids and fat-
soluble vitamins
• As a result some cholesterol lowering medications can reduce
absorption of fat-soluble nutrients
 Drug-Nutrient Interactions:
Nutrient Production
• Some medications can affect nutritional health by
slowing down nutrient production
 Drug-Nutrient Interactions:
Nutrient Production
• Vitamin K produced by bacteria in the intestine
• Antibiotics kill harmful bacteria, but they can also kill
helpful bacteria
– Killing helpful vitamin K producing bacteria can result in
decreased vitamin K production
 Drug-Nutrient Interactions:
Nutrient Metabolism
• Some medications can affect nutritional health by
interfering with body’s ability to metabolize nutrients
due to:
– Affecting enzyme systems
– Competing with enzyme systems
 Drug-Nutrient Interactions:
Nutrient Metabolism
• Examples:
– Some anticonvulsants alter liver enzyme activity causing
increased metabolism of folate, vitamin D, and vitamin K
– Methotrexate resembles folate in structure and competes
with enzymes that converts folate to its active form, this
can result in folate deficiency
 Drug-Nutrient Interactions:
Nutrient Excretion
• Some medications can affect nutritional health by
increasing nutrient excretion due to:
– Decreased kidney reabsorption
– Increased urinary excretion
 Drug-Nutrient Interactions:
Nutrient Excretion
• Diuretics remove excess fluid from the body
– Some diuretics may also increase loss of potassium along
with fluids
– Potassium is very important in proper functioning of the
heart and other muscles
• Large amounts of aspirin can cause increased loss of
folate
 Drug-Nutrient Interactions:
Nutrient Excretion
• Examples:
– Some anticonvulsant medications can cause the liver to
increase removal of vitamin D from the body
– Isoniazid, an antituberculosis medication, is similar in
structure to vitamin B6 and induces vitamin B6 excretion
• Since treatment is for 6 months, B6 supplements are routinely
given to prevent deficiency
 Food-Drug Interactions
• Some foods or nutrients in food can also alter a
medication’s effectiveness by:
– Decreasing medication absorption
– Interfering with medication metabolism
– Interfering with medication removal
• Some foods or nutrients in food can increase or
decrease Nutrient
medication absorption by:
Interactions:
– Decreasing stomach emptying
Medication
– Binding to medications
Absorption
– Competing for absorption
– Altering acidity
 Nutrient Interactions:
Medication Absorption
• Absorbing less than the intended dose lowers the
chance a medication will work properly
• Absorbing more than the intended dose increases
the chance of an overdose effect
 Nutrient Interactions:
Medication Absorption
• Medications are typically absorbed more quickly
when the stomach is empty
• Having food in the stomach typically will slow down a
medications absorption
 Nutrient Interactions:
Medication Absorption
• Some medication should be taken with food
• Some medication should be taken on an empty
stomach (1 hour before or 2 hours after eating)
• Read the directions to see if a medication should or
should not be taken with food
 Nutrient Interactions:
Medication Absorption
• Examples:
– Dietary calcium can bind to the antibiotic tetracycline
making it unavailable for absorption
– Amino acids compete for absorption with levodopa
 Nutrient Interactions:
Medication Absorption
• Examples:
– Acidity of food or beverage consumed with a medication
can affect absorption
• Some medications are better absorbed in an acidic environment
• Other medications can be damaged by an acid environment,
these types of medications are often available in coated forms to
resist stomach acidity
 Food-Drug Interactions:
Medication Metabolism
• Some foods or nutrients in foods may interfere with
a medication’s metabolism or action in the body by:
– Affecting enzyme systems
– Interacting with medications
– Having a similar chemical structure resulting in
competition
 Food-Drug Interactions:
Medication Metabolism
• Examples:
– Components in grapefruit juice
• Inactivate enzymes that metabolize many medications which can
result in increased medication levels
– Aged and fermented foods
• Contain a chemical called tyramine that interacts with a
medication, monoamine oxidase inhibitor, which can result in
dangerously high blood pressure
– Vitamin K
• Structurally similar to the anticoagulant warfarin which can
decrease the effectiveness of warfarin
 Food-Drug Interactions:
Medication Removal
• Some food or nutrients in foods may interfere with
removal of a medication from the body by:
– Affecting enzymes involved in preparing medications for
removal
– Altering urine pH
 Food-Drug Interactions:
Medication Removal
• Examples
– Liver enzymes prepare medications for removal from
the body
• These enzymes require nutrients to work properly
• If nutrients are not present the medication may stay active in
the body longer than intended
– Quinidine is excreted more readily in an acidic urine
• Foods that cause the urine to be more basic, such as sodium
bicarbonate, may reduce quinidine excretion
 Many Medications
• These are just a few examples to understand how
medications and nutrients can interact, this is not
indented to be a complete list of possible
interactions
• There are thousands of medications on the market
and numerous new medications that come out ever
year
 Alcohol Interacts With Medications
• Alcohol and medications do not mix
• Alcohol can adversely affect medications
– Alcohol can slow down or speed up how the body
metabolizes a medication
• Medication action can be either intensified or reduced
– In some cases, mixing alcohol and medications can be
fatal
 Alcohol Interacts With Medications
• A rule of thumb is to avoid alcoholic beverages when
taking prescription and over-the-counter
medications
 Nutrient Supplements
• Nutrient supplements themselves can result in drug-
nutrient interactions
• In excessive amounts, vitamin and mineral
supplements can act like drugs instead of nutrients
• Nutrients in excessive amounts may:
– Compete with other nutrients for absorption, transport or
metabolism
– Have a direct overdose effect
 Follow Directions
• It is very important to follow the directions on how
to take a medication
• Many people do not take prescription or over-the-
counter medications properly
• Following directions on how to take a medication
can affect how or if a medication will work properly
 Who Is At Greater Risk
• Persons who are poorly nourished
• Persons with serious health problems
• Growing children
• Pregnant women
• Older adults
 Who Is At Greater Risk (cont.)
• Persons taking two or more medications at the same
time
• Persons using prescription and over-the-counter
medications together
• Persons not following medication directions
• Persons taking medications for long periods of time
• Persons who drink alcohol excessively
 Lower The Risk of
Drug-Nutrient Interactions
• Eat a healthy diet
• Follow directions on how to take medications
– Both prescription and over-the-counter
• Read warning labels
• Do not share medications
 Lower The Risk of
Drug-Nutrient Interactions (cont.)
• Tell your physician all the medications you are
taking both prescription and over-the-counter
• Tell your physician and pharmacist about any new
symptoms that develop when taking a medication
• Keep a list of all medications
• Ask if you have any questions
 Drug-Induced Nutrient Depletion
• About half the drugs used in clinical practice have
documented nutrient depleting effects.
• Co-enzyme Q10, folic acid, B2, B6, Mg, Zn
are nutrients most likely to be depleted.
• Mechanisms include impaired absorption or
bioactivation; increased excretion.
 Co-enzyme Q10 Depletion
• Statin-induced co-Q depletion impairs mitochondrial
function, raising the serum lactate/pyruvate ratio.
Simvastatin but not atorvastatin depletes myofibrillar co-Q.
• Supplemental co-Q, 100 mg/day, prevents the decline in
serum co-Q levels without impairment of the lipid-lowering
effect of statins and may reverse symptoms of statin
myopathy.
 Co-enzyme Q10 Depletion (cont’d)
• Statin-induced Co-Q depletion is increased by vitamin E (700
IU/day).
• Co-Q is consumed in recycling tocopheryl quinones back to
tocopherols.
• Thiazides, some beta-blockers and many older psychotropic
drugs have been shown to interfere with co-Q dependent
enzymes, creating a possible need for co-Q supplementation
in patients receiving them.
 Are reported adverse cardiovascular
effects of vitamin E supplements
related to co-Q depletion in patients
taking drugs that interfere with co-Q
synthesis or co-Q dependent
enzymes?
 Vitamin E and Statins
• a-Tocopherol prevents statin benefits in people with
low HDL-C and normal TC.
• Related to tocopherol inhibition of statin-induced
elevation of HDL2-C.
• Selenium (100 mcg/day) and fish oil have the
opposite effect.
• a-Tocopherol depletes gamma-tocopherol by
competitive binding to transport protein.
 Clinically Significant Depletions-1
• Adriamycin depletes co-enzyme Q10.
Cardiotoxicity is reduced by co-Q and proprionyl-L-
carnitine.
• Cisplatin depletes Mg. Nephtrotoxicity is reduced by
i.v. and oral Mg (160 mg tid).
• Thiazides and 5-ASA derivatives deplete folate,
raising homocysteine concentration.
 Clinically Significant Depletions-2
• Loop diuretics increase excretion of K, Ca, Mg, Zn,
B1, B6, C. Correcting B1 deficit improves cardiac
function of CHF patients.
• Cephalosporins (parenteral) can deplete vitamin K2,
causing hemorrhage.
• Steroids deplete Ca and Mg, causing bone loss.
Reversible with calcium and vit D3.
 Antiretroviral Nutrient Depletion
• AZT depletes muscle carnitine and increases
lymphocyte apoptosis. Reversed with carnitine
supplementation.
• AZT is associated with decreased serum zinc and
copper; zinc 200 mg/day reduced Candida and
Pneumocystis infections in patients taking AZT.
 Phenytoin-induced Depletions
• Phenytoin may deplete biotin, folate, thiamine,
vitamin D (causing hypocalcemia and osteomalacia
and vitamin K.
• Memory impairment is associated with reduced RBC
folate. Folic acid, 1 mg/day, prevents deficiency
without adversely affecting phenytoin metabolism.
 Valproic Acid Depletions
• Valproate depletes carnitine, raising ammonia;
reversed with carnitine 2 g/day.
• Valproate acid lowers serum folate and P5P, raising
homocysteine; reversed with 400 mcg folate, 120 mg
B6 and 75 mg B2.
• Valproate inhibits biotinidase. Biotin 10 mg/day
reverses valproate-associated hair loss and
dermatitis in children.
 Chelation and Drug Absorption
• Chelation by minerals impairs absorption of
quinolone or tetracycline antibiotics, thyroid,
bisphosphonates, L-DOPA, some ACE inhibitors.
• Even some herbs like dandelion and fennel, can be
so rich in minerals that they inhibit absorption of
these same drugs.
.
 The Cytochrome P450 System and Drug-
Supplement Interactions
• Expressed chiefly in liver, intestines, lungs and
kidneys (“Phase 1 detoxication”).
• 20 different human CYPs, grouped by amino acid
homology, not by function.
• CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and
CYP3A4 most important for oxidation of drugs,
xenobiotics.
 Major CYP Enzymes in Human Drug Metabolism

Enzyme Percentage of prescription drugs

metabolized
CYP3A4 45–50
CYP2D6 25–30
CYP2C9 10
CYP2C19 5
CYP2B6 2–4
CYP2E1 2–4
CYP1A2 2

Toxicol Appl Pharmacol 2005;207:S52–S56

 CYP1A2
• Liver only. Inactivates caffeine and bioactivates
aromatic and heterocyclic amines; large inter-
individual differences (up to 100-fold). Induced by
char-broiled meat, cigarettes, pollutants, dioxins and
cruciferous vegetables.
 CYP2: Drug-Drug Interactions
• CYP2C9 accounts for 30% of CYP activity in human liver. May
be modified by Ginkgo biloba.
• CYP2C19 is primarily hepatic. Phenotype reflects the
interaction of 8 gene alleles.
• CYP2D6 is extra-hepatic. Bioactivates codeine/codones. 55
alleles.
• CYP2E1 in liver, lung, brain metabolizes organic solvents like
ethanol. Induced with chronic ethanol use, fasting, obesity.
Inhibited by acute alcohol intake, tea, broccoli, garlic, onion,
watercress.
 CYP3A4
• Liver and small intestine.
• Transforms about 50% of common drugs.
• Induced by St. John’s wort (liver, intestine) and
Echinacea (liver only).
• Inhibited by peppermint oil and piperine.
• Intestinal but not liver CYP3A4 is inhibited by
grapefruit juice, Seville orange juice and Echinacea.
 CYP3A4 and St. John’s Wort
• CYP3A4 stimulation by St. John’s wort reduces blood
levels of benzodiazepines, calcium channel blockers,
anti-retrovirals, estrogens (including OCPs),
amitriptyline, cyclosporine, methadone, tacrolimus
and possibly warfarin.
 Intestinal CYP3A4 Inhibition
• Increases blood levels of amiodarone, artemisinin,
atorvastatin, buspirone, carbemazepine,
cyclosporine, diazepam, diltiazem, erythromycin,
estradiol, felodipine, fentanyl, fluoxetine, lovastatin,
methyl-prednisolone, nifedipine, nimodipine,
praziquantel, saquinavir, sertraline, sildenafil,
simvastatin, verapamil
 P-glycoprotein Transporter (P-gp)
• Ejects xenobiotics from cells and causes backflow of
some drugs from intestinal mucosa into the lumen.
• Produces multi-drug resistance to cancer
chemotherapy.
• Inhibited by piperine, milk thistle and acutely by St.
John’s wort.
• Stimulated by continued St. John’s wort.
 Alteration of Intestinal CYP3A4 and/or P-
glycoprotein
• Often involves the same substrates.
• Primarily effects drugs that pass slowly through
intestinal mucosa.
• Interactions in vivo may not be predicted by
interactions in vitro.
 Adverse Pharmacodynamic Interactions
• 5-HTP and SSRI’s
• Licorice and horsetail, diuretics or laxatives
• Phenylalanine or kava and neuroleptics
• Bee venom and ACE inhibitors
• Brewer’s yeast and MAO inhibitors
• Interferon-alpha and bupleurum
 Antithrombotic Interactions
• 35 natural products inhibit platelet function in vivo
following oral use. They may reinforce each other or
interact with antithrombotic medication.
• Aspirin-vitamin E interaction: aspirin inhibits platelet
aggregation; vitamin E inhibits platelet adhesion to
endothelium.
 Aspirin-Vitamin E Interactions
• a-Tocopherol (50 IU/day) raised risk of gingival bleeding 25%
among ASA users.
• 400 IU/day a-tocopherol added to 325 mg ASA/day reduced
incidence of TIAs compared to aspirin alone.
• Vit E 50 IU/day, decreased ischemic stroke by 30% but
increased hemorrhagic stroke by 145% in hypertensive, non-
diabetic male smokers. In diabetics, there was no increase in
hemorrhagic stroke and ischemic stroke decreased by 70%.
 Warfarin Interactions
• 49 natural products may interfere with warfarin; 21
confirmed, 28 possible.
• Herbal coumarins might compete for binding to
plasma protein, increasing plasma free warfarin
concentration.
• Controlled studies found no effect on vitamin E or
coenzyme Q10 on INR of patients taking warfarin.
 Beneficial Drug-Supplement Interactions
• Reflect additive/complementary effects of
supplements and drugs, or amelioration of toxic
drug effects by supplements.
• Fish oils enhance anti-inflammatory, antiarrhythmic,
anti-lipemic, antidepressant, and neuroleptic drugs,
beta-blockers, lithium and insulin. EPA and DHA may
have differential effects.
 Acetaminophen Toxicity
• Protective supplements:
N-acetyl cysteine (clinical use)
L-methionine and SAMe
Milk thistle
Andrographis
Schisandra
 ASA/NSAID Gastropathy
• Protective supplements (human trials):
Vit C (500-1000 mg bid)
SAMe 500 mg/day
Cayenne 20 grams
Deglycyrrhizinated licorice 350 mg tid
Colostrum 125 mg tid
 Neuroleptic Side Effects
• Protective supplements:
Vitamin E 1200-1600 IU/day (T.D.)
Branched chain amino acids (T.D.)
Ginkgo biloba 350 mg/day
Sarcosine (N-CH3-glycine) 2 gm/day
Eicosapentaenoate (EPA) 2 gm/day
Glycine 0.4-0.8 mg/kg/day
 Cisplatin Toxicity
• Protective supplements:
Bismuth 150 mg/kg/day X 10days
Ginkgo bilomba 100 mg/kg single dose
Glutathione 5 gm i.v.
MgSO4 3 gm i.v./ Mg 160 mg tid
Silibinin 200 mg/kg i.v. single dose
N-acetyl cysteine 8 gm/day
Selenium 4000 mcg/day X 8 days
Vitamin C 50-200 mg/kg i.v. single dose
Vitamin E 300 IU/day till 3 months post-chemotherapy
 More Antineoplastic Toxicity
• Protective supplements
Vitamin B6 50 mg tid
Glutamine 30 gm/day
Melatonin 20 mg HS
Coriolus versicolor 1 gm tid
Theanine (in vitro)
Inositol hexaphosphate (IP6) (in vitro)
Calcium D-glucarate (in vitro)
 Fish oils, NSAIDs, ASA
• 2600 mg of EPA + DHA for 3 months allow NSAID
reduction in rheumatoid arthritis. Plasma
phospholipid EPA must reach 5%.
• Fish oil 30 ml/day reversed ASA’s increase of LTB4
synthesis; no hemorrhage.
• ASA increases synthesis of anti-inflammatory
resolvins and protectins from DHA in vitro by
acetylating COX-2.
 Conclusion
• Almost half the drugs commonly used in the US may
deplete specific nutrients, creating a need for
nutritional supplementation.
• Adverse interactions have received extensive press
coverage.
• Beneficial drug-supplement interactions are at least
as important and permit creative nutritional
therapies.