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 other’s 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 (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-Qsynthesis 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.

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/daySarcosine (N-CH3-glycine) 2 gm/dayEicosapentaenoate (EPA) 2 gm/dayGlycine 0.4-0.8 mg/kg/day

Cisplatin Toxicity

• Protective supplements:Bismuth 150 mg/kg/day X 10daysGinkgo bilomba 100 mg/kg single doseGlutathione 5 gm i.v.MgSO4 3 gm i.v./ Mg 160 mg tidSilibinin 200 mg/kg i.v. single doseN-acetyl cysteine 8 gm/daySelenium 4000 mcg/day X 8 daysVitamin C 50-200 mg/kg i.v. single doseVitamin 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.