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Interactions in Clinical Practice:

Drug-Supplement, Drug-Nutrient
Leo Galland, M.D.
Applied Nutrition, Inc.
www.nutritionworkshop.com

Overview
Of almost 900 drugs and fixed-drug
combinations used in the U.S.:
Almost 400 may deplete specific nutrients.
Over 400 may interact with food or food
components.
Over 300 have been shown to interact with
dietary supplements, with adverse and
beneficial interactions equally common.

Types of Interactions
Pharmacodynamic: two substances exhibit
pharmacologic actions that reinforce or
interfere with each others actions.
Pharmacokinetic: the absorption,
distribution, excretion or enzymatic
transformation of one substance is altered
by another. Most adverse interactions are of
this type.

Pharmacokinetic Mechanisms
Alteration of gastrointestinal or urinary pH.
Stimulation, induction or inhibition of
enzymes involved in biotransformation or
transport of drugs or nutrients .
Displacement of a drug from binding to
plasma proteins.
Alteration of solubility.

Effects of Interactions
Nutrient depletion: Individual nutrients may have
their dietary requirement increased by specific
drugs (or supplements).
Adverse: A specific supplement may undesirably
decrease or increase the effect of a drug or
supplement being taken.
Beneficial: Drugs (or supplements) may have their
actions enhanced or side effects diminished by
specific supplements.

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


(contd)
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 statininduced 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.

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. Johns 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. Johns Wort


CYP3A4 stimulation by St. Johns 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. Johns wort.
Stimulated by continued St. Johns 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 SSRIs


Licorice and horsetail, diuretics or laxatives
Phenylalanine or kava and neuroleptics
Bee venom and ACE inhibitors
Brewers 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 ASAs increase
of LTB4 synthesis; no hemorrhage.
ASA increases synthesis of antiinflammatory 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.