Interactions in Clinical Practice DrugSupplement DrugNutrient Leo Galland

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 p. H. • 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 Q 10, folic acid, B 2, B 6, Mg, Zn are nutrients most likely to be depleted. • Mechanisms include impaired absorption or bioactivation; increased excretion.

Co-enzyme Q 10 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 Q 10 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 statininduced elevation of HDL 2 -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 Q 10. 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, B 1, B 6, C. Correcting B 1 deficit improves cardiac function of CHF patients. • Cephalosporins (parenteral) can deplete vitamin K 2, causing hemorrhage. • Steroids deplete Ca and Mg, causing bone loss. Reversible with calcium and vit D 3.

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 P 5 P, raising homocysteine; reversed with 400 mcg folate, 120 mg B 6 and 75 mg B 2. • 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, bisphonates, 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 P 450 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. • CYP 1 A 2, CYP 2 C 9, CYP 2 C 19, CYP 2 D 6, CYP 2 E 1 and CYP 3 A 4 most important for oxidation of drugs, xenobiotics.

CYP 1 A 2 • 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.

CYP 2: Drug-Drug Interactions • CYP 2 C 9 accounts for 30% of CYP activity in human liver. May be modified by Ginkgo biloba. • CYP 2 C 19 is primarily hepatic. Phenotype reflects the interaction of 8 gene alleles. • CYP 2 D 6 is extra-hepatic. Bioactivates codeine/codones. 55 alleles. • CYP 2 E 1 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.

CYP 3 A 4 • 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 CYP 3 A 4 is inhibited by grapefruit juice, Seville orange juice and Echinacea.

CYP 3 A 4 and St. John’s Wort • CYP 3 A 4 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 CYP 3 A 4 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 CYP 3 A 4 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 Q 10 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-CH 3 -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 10 days Ginkgo bilomba 100 mg/kg single dose Glutathione 5 gm i. v. Mg. SO 4 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 B 6 50 mg tid Glutamine 30 gm/day Melatonin 20 mg HS Coriolus versicolor 1 gm tid Theanine (in vitro) Inositol hexaphosphate (IP 6) (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 LTB 4 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.