Is Natural Always Safe? Exploring the Lurking Dangers of Natural Products: Focus on Drug and Disease State Interactions with Dietary Supplements.

Transcription

1 Is Natural Always Safe? Exploring the Lurking Dangers of Natural Products: Focus on Drug and Disease State Interactions with Dietary Supplements. Lawrence R. Borgsdorf, Pharm.D., FCSHP Kaiser Permanente Kern County Service Area June 29, 2008

2 BACKGROUND INFORMATION ON DIETARY SUPPLEMENTS Unregulated Products Available Without Medical Oversight (per Dietary Supplement and Health Education Act of 1994) 1. Proof of efficacy and safety not required. 2. Content and purity not consistent unless USP Verified. 3. Truth in advertising does not pertain to supplemental materials. 4. Federal Trade Commission, not FDA, has oversight of label claims. 5. Warning statements (DUTY TO WARN) not required. 6 These statements have not been evaluated by the Food and Drug Administration. This product is not designed to diagnose, treat, cure or prevent any disease. 7. Interactions with RX and OTC medications and disease states not systematically studied: a. Case reports provide most of data base b. Small studies in some research laboratories

3 USP Verified The mark represents that USP has rigorously tested and verified the supplement to assure the following 1) What's on the label is in fact in the bottle all the listed ingredients in the declared amount. 2)The supplement does not contain harmful levels of contaminants. 3) The supplement will break down and release ingredients in the body 4) The supplement has been made under good manufacturing practices. USP is an independent, not-for-profit organization. No other organization in the U.S. that tests supplements is recognized in federal law as the nation's official standard-setting body for medicines and supplements. USP standards are enforceable by the FDA.

4 BACKGROUND INFORMATION ON DIETARY SUPPLEMENTS Cont d 31% of patients use dietary supplements concurrently with prescribed conventional therapy. 70% of patients who use dietary supplements concurrently with prescribed conventional therapy do not report use to their healthcare provider.

5 RATING THE SIGNIFICANCE OF DRUG-DRUG INTERACTIONS Significance Rating: 1 - is a severe and well-documented interaction 5 - is an interaction of no more than unlikely or possible documentation The formula for these number ratings is given in the following table: Significance Rating Severity Major Moderate Minor Major/Moderate Minor Any Documentation Suspected or > Suspected or > Suspected or > Suspected or > Possible Unlikely

6 Factors Which Limit Accuracy and Reproducibility of Drug-Dietary Supplement Interactions Purity? Is it the ingredient and/or a contaminant Content? variable content (Brand-to-Brand; batch-to-batch) Dosing? How much, how often, how consistent Combination products? Unknown effects of combined ingredients (remember Fen-Fen!!) Proprietary blends = secret ingredients. If you don t know what s in it how do you evaluate potential for benefit vs risk. 31% of patients use dietary supplements concurrently with prescribed conventional therapy 70% of patients who use dietary supplements concurrently with prescribed conventional therapy do not report use to health care provider.

7 RATING THE SIGNIFICANCE OF DRUG-DIETARY SUPPLEMENT INTERACTIONS Significance Rating: The interaction has potentially severe clinical consequences to the patient and concurrent use should be avoided. The interaction may have clinical consequences to the patient but can usually be avoided by appropriate monitoring and/or dosage adjustment Available data are insufficient to warrant a specific precaution; the interaction is unlikely to result in clinical consequences to the patient or there is no interaction

8 MECHANISMS OF DRUG-DIETARY SUPPLEMENT INTERACTIONS A. Pharmacokinetic Interactions (the BIG TICKET item) One drug or supplement alters one or more pharmacokinetic parameters (eg, maximum serum concentration, area under the serum concentrationtime curve, half-life, etc) of the object drug or supplement 1. Absorption 2. Distribution 3. Elimination (Metabolism or Excretion) B. Pharmacodynamic Interactions One drug or supplement induces a change in a patient s response to a drug or supplement without altering the object drug s (or supplement s) pharmacokinetics C. Pharmacologic Interactions Concurrent use of two or more drugs with similar or opposing pharmacologic actions a form of pharmacodynamic interactions

9 PHARMACOKINETIC INTERACTIONS - ABSORPTION - 1. Absorption a. Formation of non-absorbable complexes by chelation (eg, tetracycline/ciprofloxacin + di-trivalent cations); adsorption (eg, stains + pectin and oat bran). b. Efflux transporter protein (P-glycoprotein) excretes drugs back into GI lumen (concentration lowest in stomach and highest in colon) - induction of P-glycoprotein results in decrease in systemic bioavailability - inhibition of P-glycoprotein results in increase in systemic bioavailability c. Altered splanchnic blood flow, gut motility, gut ph, drug solubility, gut flora or gut mucosa (Khat delays or reduces GI absorption of amoxicillin)

10 PHARMACOKINETIC INTERACTIONS - DISTRIBUTION - Protein binding -Change free drug or supplement serum concentrations. Cyclosporine + Rosemary: Increased cyclosporine levels (Rosemary inhibits binding of CSA to p-glycoprotein)

11 PHARMACOKINETIC INTERACTIONS - ELIMINATION - Elimination (Metabolism or Excretion) a. Phase I: ( asynthetic phase ) b. Phase II ( synthetic phase ) c. Transporter proteins i. Glycoprotein P (efflux transporter protein) ii. Organic Anion Transporter Proteins (OATP - uptake transporter proteins)

12 PHARMACOKINETIC INTERACTIONS - ELIMINATION - Elimination (Metabolism or Excretion) a. Phase I: ( asynthetic phase ) - oxidize, demethylate, hydrolyze - hepatic (and gut) microsomal enzymes - mixed function oxidases (Cytochrome P450 enzymes) - - induction of these enzymes results in increased elimination of drugs which are substrates - inhibition of these enzymes results in decreased elimination of drugs which are substrates b. Phase II ( synthetic phase ) c. Transporter proteins

13 CYP450 Isoenzymes Induction and Inhibition

14 CYP3A4: Substrates/Inducers/Inhibitors Substrates: Amiodarone Amlodipine Atazanavir Atorvastatin Cerivastatin Citalopram Clopidogrel Cyclophosphamide Cyclosporine Delavirdine Digoxin Diltiazem Donepezil Efavirenz Ethinyl Estradiol Felodipine Fentanyl Glyburide Indinavir Itraconazole Ketoconazole Lansoprazole Losartan Lovastatin Methadone Nateglinide Nelfinavir Nevirapine Nifedipine Omeprazole Progesterone Propafenone Quetiapine Repaglinide Ritonavir Salmeterol Saquinavir Sertraline Simvastatin Sirolimus Tacrolimus Tamoxifen Troglitazone Venlafexine Verapamil R-Warfarin Inducers: Garlic supplements St. John s wort Inhibitors: Berberine Chamomile Echinacea Ginkgo Biloba Ginseng Grapefruit Juice Black Cherry Leaf Extract

15 CYP1A2: Substrates/Inducers/Inhibitors Substrates: Clomipramine Clozapine Cyclobenzaprine Desipramine Diazepam Imipramine Melatonin Methadone Mexiletine Mirtazapine Nortriptyline Olanzapine Propafenone Propranolol Ritonavir Tamoxifen Verapamin R-Warfarin Inducers: St. John s wort Inhibitors: Caffeine Daidzein Echinacea Grapefruit Juice

16 CYP2C8-10: Substrates/Inducers/Inhibitors Substrates: Amitriptyline (2C9) Carvedilol (2C9) Diazepam (2C8)Fluoxetine (2C9) Glimepiride (2C9) Imipramine (2C9) Losartan (2C9) Melatonin (2C9) Mirtazapine (2C9) Nateglinide (2C9) Omeprazole (2C8)Paclitaxol (2C8) Phenytoin (2C9) Ritonavir (2C9) Rosiglitazone (2C8) Sertraline (2C9)Torsemide (2C9) S- Warfarin (2C9) Inducers: Gingko Biloba (2C9) St. John s wort (2C9) Inhibitors: Echinacea (2C9) Ginseng (2C9)

17 CYP2C18-19: Substrates/Inducers/Inhibitors Substrates: Cilostazol (2C19) Citalopram (2C19) Clomipramine (2C19) Desmethyldiazepam(2C19) Diazepam (2C19) Divalproex (2C19) Imipramine (2C19) Lansoprazole (2C19) Melatonin (2C19) Omeprazole (2C19) Pantoprazole (2C19) Phenytoin (2C19) Propranolol (2C19) Rabeprazole (2C19) Ritonavir (2C19) Sertraline (2C19)Valproic Acid (2C19) S-Warfarin (2C18)Ziprasidone Inducers: St. John s wort (2C19) Inhibitors: Ginkgo biloba (2C19)

18 PHARMACOKINETIC INTERACTIONS - ELIMINATION - 3. Elimination (Metabolism or Excretion) a. Phase I: ( asynthetic phase ) - b. Phase II ( synthetic phase ) - glucuronidation, sulfation formation of usually inactive watersoluble metabolite(s) c. Transporter proteins

19 PHARMACOKINETIC INTERACTIONS - ELIMINATION - Elimination (Metabolism or Excretion) a. Phase I: ( asynthetic phase ) b. Phase II ( synthetic phase ) c. Transporter proteins i. Glycoprotein P (efflux transporter protein) - Glycoprotein P facilitates excretion of some drugs into the intestinal lumen, bile and urine, and out of the brain - induction of glycoprotein P would result in decreased serum levels and pharmacologic response of affected drug - inhibition of glycoprotein P would result in increased serum levels and pharmacologic response of affected drug ii. Organic Anion Transporter Proteins (OATP) (uptake transporter proteins) - OATPs facilitate uptake of some drugs - induction of OATP would result in increased serum levels and pharmacologic response of affected drug - inhibition of OATP would result in decreased serum levels and pharmacologic response of affected drug

20 P-glycoprotein Induction and Inhibition

21 Glycoprotein P: Substrates/Inducers/Inhibitors Substrates for P-Glycoprotein Amiodarone (eg, Cordarone) Bosentan (Tracleer) Cyclosporine (eg, Neoral) Digoxin (eg, Lanoxin) Diltiazem (eg, Cardizem) Doxorubicin (eg, Adriamycin) Estradiol (eg, Estrace) Felodipine (Plendil) Indinavir (Crixivan) Itraconazole (eg, Sporonox) Ketoconazole (eg, Nizoral) Lovastatin (eg, Mevacor) Nifedipine (eg, Procardia) Paclitaxel (eg, Taxol) Paroxetine (Paxil) Ritonavir (eg, Norvir) Saquinavir (eg, Fortovase) Sirolimus (Rapamune) Tacrolimus (Prograft) Tamoxifen (eg, Nolvadex) Inducers of P-Glycoprotein Garlic Supplements St. John s wort Inhibitors of P-Glycoprotein Goldenseal Grapefruit juice

22 Organic Anion Transporting Proteins (OATP) Induction and Inhibition

23 MECHANISMS OF DRUG- DIETARY SUPPLEMENT INTERACTIONS A. Pharmacokinetic Interactions (the BIG TICKET item) B. Pharmacodynamic Interactions One drug or supplement induces a change in a patient s response to a drug or supplement without altering the object drug s (or supplement s) pharmacokinetics (eg, warfarin + gingko biloba: increased risk of bleeding d/t gingko s effect on platelets; loop diuretics + Panax or Oriental Ginseng: reduced effect of loop diuretic) C. Pharmacologic Interactions Concurrent use of two or more drugs with similar or opposing pharmacologic actions a form of pharmacodynamic interactions (eg, benzodiazepines + kava: increased sedation leading to coma; alcohol + kava: enhanced impairment; NSAIDS, Aspirin, Plavix + gingko biloba: additive antiplatelet effects)

24 DRUG-DIETARY SUPPLEMENT INTERACTIONS - Gingko Biloba - 1. Antiplatelet Agents (eg, aspirin, NSAIDs; ticlopidine; cilostazol; clopidogrel): increased bleeding time; bruising and bleeding reported. Ginkgolide B may inhibit platelet-activating factor resulting in increased inhibition of platelet aggregation. 2. NASIDS (ibuprofen, rofecoxib): increased bruising and bleeding. CNS hemorrhage with death. Ginkgolide B may inhibit platelet-activating factor resulting in increased inhibition of platelet aggregation. 3. Warfarin (COUMADIN): increased risk of bleeding. Ginkgolide B may inhibit platelet-activating factor resulting in inhibition of platelet aggregation. 4. Trazodone (DESYREL): increased sedative effects. Mechanism unknown. 5. Haloperidol (HALDOL): may increase effectiveness and decrease extrapyramidal side effects of haloperidol. Gingko may scavenge free radicals produced by hyperdopaminergic activity. 6. Inhibition of hepatic cyctochrome P4502C9: may result in decreased hepatic metabolism of drugs which are substrates for this isoenzyme system.

25 DRUG-DIETARY SUPPLEMENT INTERACTIONS - St. John s wort - 1. Induction of Cytochrome P4501A2, 2C9 and 3A4 results in increased hepatic metabolism of drugs which are substrates of these enzyme systems. 2. Cyclosporine (NEORAL): reduced serum levels and pharmacologic effects. Organ transplant rejection has been reported. 3. Tacrolimus (PROGRAF): reduced serum levels and pharmacologic effects. Organ transplant rejection has been reported. 4. Irinotecan (CAMPTOSAR): reduced plasma levels of active metabolite (SN-38) of irinotecan. Reduced chemotherapeutic response. 5. Digoxin (LANOXIN); reduced serum levels and pharmacologic effect. Mechanism appears to be induction of Glycoprotein P (transporter protein). 6. Serotonin Reuptake Inhibitors (eg, paroxetine, sertraline, nefazadone,etc): increased risk of serotonin syndrome (dizziness, nausea, vomiting, anxiety, restlessness) 7. Propofol (DIPRIVAN), Sevoflurane (ULTRANE): delayed emergence from general anesthesia. Mechanism unkown. 8. Methadone: reduced pharmacologic effects, resulting in opiate withdrawal symptoms. Mechanism appears to be increased hepatic CYP3A4 and/or altered P-glycoprotein transport activity.

26 DRUG-DIETARY SUPPLEMENT INTERACTIONS - St. John s wort continued - 9. Paroxetine: increased sedative-hypnotic effects. Mechanism unknown. 10. Estrogen-containing oral contraceptives: reduced pharmacologic effects, resulting in breakthrough bleeding and unwanted pregnancy. Increased hepatic CYP3A4 and/or P-glycoprotein transport activity. 11. Simvastatin (ZOCOR), lovastatin (MEVACOR): reduced serum levels and pharmacologic (lipid-lowering) effects. 12. Amiodarone (CORDARONE): reduced serum levels and pharmacologic (antiarrhythmic) effects. 13. Omeprazole (PRILOSEC): reduced AUC (50%) and Cmax (38%). Reduced pharmacologic (PPI) effects? 14. Imatinib Mesylate (GLEEVEC): increased imatinib clearance 43%; decreased AUC and t1/2 30% and Cmax 18%. Increased hepatic CYP3A4 activity. 15. Verapamil (CALAN): decreased verapamil AUC 80% and Cmax 78%. Increased gut CYP3A4 activity. 16. Rasagiline (AZILECT):risk of serotonin syndrome or hypertensive crisis may be increased. Hyperforin is potent inhibitor of serotonin reuptake. Hypericin may have MAO inhibitor activity (controversial).

27 DRUG-DIETARY SUPPLEMENT INTERACTIONS - Kava - 1. Benzodiazepines (eg, alprazolam-xanax): increased sedation leading to coma. Same CNS receptor resulting in additive or synergistic effects. 2. Levodopa (LARODOPA): decreased efficacy of levodopa. Mechanism unknown. 3. Alcohol: enhanced impairment

28 DRUG-DIETARY SUPPLEMENT INTERACTIONS - Panax or Oriental Ginseng - 1. Loop Diuretics (eg, furosemide): reduced effect of loop diuretic. Proposed mechanism is nephrotoxicity involving loop of Henle. 2. Phenelzine (NARDIL) and other MAO-inhibitors: insomnia, headache, tremor, induction of manic-like symptoms. Mechanism may be additional psychoactive central effects. 3. Warfarin (COUMADIN): decreased effect of warfarin (decreased INR); thrombosis of mechanical valve has been reported. Mechanism unknown. 4. Inhibition of hepatic cytochrome P4502C9: may result in decreased hepatic metabolism of drugs which are substrates for this isoenzyme system. 5. Digoxin: Serum digoxin concentrations may be falsely increased or decreased. Laboratory test interference of digoxin-like immunoreactive components of ginseng with polyclonal antibody-based digoxin immunoassays.

29 DRUG-DIETARY SUPPLEMENT INTERACTIONS - Garlic - 1. Warfarin (COUMADIN): increased risk of bleeding and possible increase in INR. In addition, garlic components inhibit platelet aggregation. 2. Protease Inhibitors (eg, saquinavir) 50% reduction in AUC and Cmax of protease inhibitor with 600 mg garlic caplets BID. Proposed MOA induction of CYP4503A4 and possibly P-glycoprotein. Garlic from food sources is unlikely to induce this interaction.

30 DRUG-DIETARY SUPPLEMENT INTERACTIONS - Miscellaneous Dietary Supplements - Melatonin 1. Nifedipine (PROCARDIA): reduced effectiveness of nifedipine. Mechanism unknown. 2. Fluvoxamine (LUVOX): increased plasma concentrations of melatonin. Inhibition of melatonin metabolism is suspected. Green Tea 1. Warfarin (COUMADIN): decreased anticoagulant effect. Green tea contains substantial amounts of vitamin K (brewed tea contains less but still problematic with large amounts).

31 DRUG-DIETARY SUPPLEMENT INTERACTIONS - Miscellaneous Dietary Supplements CONT D Karela 1. Sulfonylureas (eg, glipizide): hypoglycemia. Additive or synergistic effect. Coenzyme Q10 (Ubiquinone) 1. Warfarin (COUMADIN): reduced anticoagulant effects. Mechanism not known but ubiquinone is closely related to vitamin K2. Dong Quai 1. Warfarin (COUMADIN): increased effect of warfarin (increased INR). Mechanism unknown. Milk Thistle: 1. Indinavir (CRIXIVAN): reduction of indinavir trough plasma concentrations. Mechanism unknown.

32 DRUG-DIETARY SUPPLEMENT INTERACTIONS - Miscellaneous Dietary Supplements CONT D Daidzein (isoflavone in soybeans, celery, puerarin and trefoil) 1. Theophylline (THEODUR): elevated theophylline blood levels and risk of toxicity. Inhibition of theophylline metabolism (CYP1A2) suspected. Rosemary 1. Cyclosporine: increased cyclosporine levels. Inhibits binding of CSA to P- glycoprotein. Pectin 1. HMG-CoA reductase Inhibitors (STATINS): may decrease absorption resulting in elevation of LDL-C. Glucosamine-chondroitin 1. Warfarin (COUMADIN): increased anticoagulant effect of warfarin. Increased INR and risk of bleeding. Mechanism unknown. Most likely a contaminant.

33 CLASS-SPECIFIC AND DISEASE SPECIFIC CONSIDERATIONS Antiplatelet Agents, Anticoagulants and Bleeding Disorders 1. Bilberry leaf: increased potential for bleeding. Decreases platelet aggregation 2. Black cohosh: increased potential for bleeding. Contains coumarin constituents 3. Chamomile: increased potential for bleeding. Contains coumarin constituents 4. Ginger: increased potential for bleeding. Mechanism unknown. 5. Goldenseal: increased potential for bleeding. Mechanism unknown. 6. Feverfew: increased potential for bleeding. Mechanism unknown. 7. Ginkgo: increased potential for bleeding. Decreased platelet aggregation. 8. Panax Ginseng: increased potential for bleeding. Decreased platelet aggregation. 9. Angelica root: increased potential for bleeding. Contains coumarin constituents. 10. Arnica flower: increased potential for bleeding. Contains coumarin constituents. 11. Fenugreek: increased warfarin anticoagulany activity; increased risk of bleeding. Coumarin constituents. 12. Horse chestnut: increased potential for bleeding. Contains coumarin constituents. 13. Passionflower herb: increased potential for bleeding. Contains coumarin constituents. 14. Meadowsweet: increased potential for bleeding. Contains salicylate constituents. 15. Willow bark: increased potential for bleeding. Contains salicylate constituents.

34 CLASS-SPECIFIC AND DISEASE SPECIFIC CONSIDERATIONS Antiplatelet Agents, Anticoagulants and Bleeding Disorders 16. Bromelain: increased potential for bleeding. Antiplatelet activity. 17. Cayenne: increased potential for bleeding. Mechanism unknown. 18. Dong quai: increased anticoagulant effect of wararin. Mechanism unknown. 19. Devil s Claw: increased potential for bleeding. Mechanism unknown. 20. Aloe Vera: may inhibit secondary platelet aggregation 21. Boldo: enhances anticoagulant effect of warfarin. Mechanism unknown. 23. Danshen: increased warfarin anticoagulant activity. Mechanism unknown. 22. Fiddleheads: reduced warfarin anticoagulant activity. Fiddleheads contain vitamin K. 23. Fish Oil: doses greater than 2 Gm/day may interfere with vitamin K-dependent clotting factors and platelet aggregation. Bleeding has been reported. 24. Menthol (eg. Hall s Menthol Cough Drops): Reduced warfarin anticoagulant activity. Mechanism unknown. 25. Royal Jelly: increased warfarin anticoagulant activity; risk of bleeding increased. Mechanism unknown. 26. Soy: reduced warfarin anticoagulant activity. Mechanism unknown.

35 CLASS-SPECIFIC AND DISEASE SPECIFIC CONSIDERATIONS Sedatives (eg, alcohol, benzodiazepines, barbiturates, nonbenzodiazepine sedatives) 1. Valerian: increased sedative effects. Increased GABA concentrations. 2. Ginger: increased sedative effects. Mechanism unknown. 3. Goldenseal: increased sedative effects. Mechanism unknown. 4. Chamomile: increased sedative effects. Mechanism unknown. 5. Kava: increased sedative effects. Mechanism unknown. MAO-Inhibitors 1. Ephedra (MaHuang): hypertensive crisis. Inhibition of breakdown of catecholamines released by Ephedra (and other indirect-acting sympathomimetics)

36 CLASS-SPECIFIC AND DISEASE SPECIFIC CONSIDERATIONS Hepatotoxic Agents (eg, thiazolidenes) and Hepatitis 1. Borage 2. Kava 3. Gotu Kola 4. Black Cherry Leaf Extract 5. Sassafras 6. Coltsfood 7. Chaparrel 8. Senna 9. Comfrey 10. Germander 11. Skull cap 12. Rue 13. Mistletoe 14. Echinacea 15. Tansy 16. Pennyroyal 17. Jin Bu Huan (germander/ma-huang)

37 CLASS-SPECIFIC AND DISEASE SPECIFIC CONSIDERATIONS Potassium Wasting Medications (eg, diuretics, adrenocorticosteroids) 1. Herbal Diuretics 2. Aloe: may increase potassium loss via the GI tract Potassium Supplements or Potassium Conserving Therapy (eg, spironolactone, ACE-I) 1. Noni Juice: May increase serum potassium. Contains large amounts of potassium. Immunosuppresssants (eg, cyclosporine, azathioprine, tacrolimus) 1. Echinacea: decreased immunosuppressant effect. Mechanism unknown. 2. Astragalus: decreased immunosuppressant effect. Mechanism unknown. 3. Rosemary: increased cyclosporine levels. Inhibits binding of CSA to p-glycoprotein. Theophyllines and Xanthine Dervivatives 1. Ephedra (MaHuang) : excessive stimulation 2. Green Tea: excessive stimulation. Additional effect of caffeine in tea. 3. Guarana: excessive stimulation. Additional effect of caffeine in guarana.

38 CLASS-SPECIFIC AND DISEASE SPECIFIC CONSIDERATIONS Hypoglycemic Agents and Diabetes 1. Panax ginseng: hypoglycemia. Panaxosides may reduce blood sugar 2. Garlic: hypoglycemia. Additive effect on blood sugar 3. Fenugreek: hypoglycemia. Additive effect on blood sugar 4. Bitter melon: hypoglycemia. Additive effect on blood sugar. 5. Rosemary: hyperglycemia. Increases blood sugar. 6. Stinging nettle: hyperglycemia. Increased blood sugar 7. Goat s Rue: hypoglycemia. Additive effect on blood sugar Nephrotoxic Medications (eg, aminoglycosides, amphotericin) and CKD 1. Calamas: potential nephrotoxin. 2. Birch bark: potential nephrotoxin. 3. Birch leaf: potential nephrotoxin. 4. Rue: potential nephrotoxin. 5. Birthwart: potential nephrotoxin. 6. Aristolochic acid (Chinese herb): known nephrotoxin. 7. Stephania (Chinese herb): known nephrotoxin. 8. Magnolia (Chinese herb): known nephrotoxin

39 CLASS-SPECIFIC AND DISEASE SPECIFIC CONSIDERATIONS Antihypertensive Agents and Hypertension 1. Ephedra (MaHuang): increased blood pressure. Increased alpha and beta receptor activation. 2. Goldenseal: increase or decrease in blood pressure. Mechanism unknown - beberine and hydrastinine components may have cardiac effects. 3. Black Cohosh: decreased blood pressure. Mechanism unknown aceteina may have hypotensive effects. Cardiac Glycoside (eg, digoxin) 1. Aloe: increased risk of digoxin toxicity. Increased potassium loss. 2. Hawthorn: decreased or increased effect. Mechanism unknown. 3. Goldenseal: decreased or increased effect. Mechanism unknown.

40 CLASS-SPECIFIC AND DISEASE SPECIFIC CONSIDERATIONS Methotrexate 1. Camp bark: increased toxicity. Salicylate-induced increased in blood levels. 2. Willow: increased toxicity. Salicylate-induced increase in blood levels. 3. Wintergreen. Increased toxicity. Salicylate-induced increase in blood levels. 4. Birch bark: increased toxicity. Contains methylsalicylate. 5. Birch leaf: increased toxicity. Contains methylsalicylate. 6. Caffeine: may interfere with effects of methotrexate (adenosine receptor antagonist) Lithium 1. Herbal diuretics: increased blood levels and side effects secondary to decreased sodium Angiotensin Converting Enzyme Inhibitors 1. Capsaicin topical/inhalational: exacerbation of ACE I cough

41 RECOMMENDATIONS FOR MANAGING DRUG- & DISEASE STATE-DIETARY SUPPLEMENT INTERACTIONS A. Identify Use of Dietary Supplements 1. Have patients list, and give to you, trade name and ingredients of dietary supplements ( supplements, herbs, vitamins ) they are taking or considering taking. 2. Add ingredients to KP Health Connect Medication Profile. If not listed no way for active screening for potential interactions. Drug interaction data base is periodically updated so new interaction data should screen for previously entered dietary supplements. B. Special Counseling of Patients Using High-Risk Medications 1. Specific instructions to avoid use of dietary supplements due to known or unknown risk.

42 RECOMMENDATIONS FOR MANAGING DRUG- & DISEASE STATE- DIETARY SUPPLEMENT INTERACTIONS Cont d C. Limiting Availability of High-Risk Dietary Supplements 1. Available only after consultation with pharmacist (eg, St John s wort) D. Closer Monitoring of Patients On High-Risk Medications Who Choose to Use a Dietary Supplement 1. If patients taking RX or OTC medications and dietary supplements appear to experience loss of therapeutic control (eg, reduction of pharmacologic benefit) or evidence of possible drug toxicity (increase in pharmacologic activity) or unusual or unexpected effects (eg, elevated liver enzymes) consider the possibility of a drug-dietary supplement interaction and discontinue the dietary supplement immediately. 2. If a dietary supplement-drug interaction is suspected report the event via the FDA s MedWatch program.

43 Interesting Case #1 70 y.o. male referred by PCP for review of prescription medications and dietary supplements Problem List Hyperlipidemia (elevated LDL, TGs) Hypertension MI, old Diverticulosis

44 Interesting Case #1 cont d History Diagnosed with gouty arthritis (8/1/07) and given RX for indomethacin 50 mg TID for 7 days. Read the PPI and became very frightened by the warnings and cautions. Spouse advised visiting a health food store to see if there was anything natural and safe that could treat gout. Health food store owner suggested: Black Cherry Leaf Extract for his gout advised him that it was particularly effective in patients with his blood type. Omega 3, 6 & 9 oils for his cholesterol and to protect his heart Coenzyme Q 10 for lowering his blood pressure and to protect his heart Gotu Kola to treat his solar keratosis The health food store owner assured the patient that her products were natural, of proven benefit and were perfectly safe with his current medical conditions and prescription medications.

45 Interesting Case #1 cont d Medications/Supplements ASA EC tablet: 1 daily Diltia XT 180 mg: 1 daily Niacin 500 mg: BID with food Simvastatin 40 mg: 1 ½ tablets Q evening Cyclobenzaprine 10 mg: Q 12 hr PRN spasm Maxzide 75-50: ½ tablet daily Fluticasone Nasal Spray: 1 spray daily in each nostril Gotu Kola:1 capsule TID for solar keratosis Black Cherry Leaf Extract:1 capsule BID for gout Omega 3,6 & 9 oils:1200 mg BID for cholesterol Coenzyme Q 10: 50 mg BID for blood pressure control

46 Interesting Case #1 cont d ANY CONCERNS OR ISSUES WITH THESE DIETARY SUPPLEMENTS OR IS THE NATURAL FOOD STORE OWNER CORRECT? Let s review available information from Natural Medicines Database in the Permanente Knowledge Connection AND / OR Facts and Comparison s Clin-eguide Drug-Dietary Supplement interaction tool (linked to Facts and Comparison s Herbal Interaction Facts) available in the Permanente Knowledge Connection Permanente Knowledge Connection: pkc.kp.org

47 Interesting Case #1 cont d BLACK CHERRY LEAF EXTRACT No evidence of effectiveness in treating or preventing hyperuricemia and gouty arthritis. Black Cherry Leaf constituents can be heptotoxic. Black Cherry Leaf constituents contain CYP3A4 inhibitors making use of CYP3A4 substrates (eg, simvastatin) dangerous due to increase in serum concentrations, clinical effects, including toxic effects. Benefit does not exceed risk

48 Interesting Case #1 cont d OMEGA 3, 6 & 9 OILS Omega 6 fatty acids Insufficient reliable evidence for safety or any of it s proposed uses Can increase triglyceride levels and is contraindicated in hypertriglyceridemia Omega 3 fatty acids (alpha-linoleic; docosahexanoic; Cod Liver Oil; Fish Oil) Fish oil from supplements or from dietary sources can reduce triglyceride levels by 20% to 50% but even 4 gm/day not as effective as gemfibrozil. In people with existing heart disease (secondary prevention), consuming fish oil from dietary sources or taking fish oil supplements seems to reduce the risk of cardiovascular and all-cause mortality. Omega 9 fatty acids (Olive Oil) Olive oil evidence based on consumption of olive oil as part of daily diet and not supplements

49 Interesting Case #1 cont d Gotu Kola No evidence of benefit in treatment of solar keratosis May cause hepatitis if taken in excessive doses or if taken with other hepatotoxic herbs (eg, Black Cherry Leaf Extract) and/or medications (eg, simvastatin). Benefit does not outweigh risk

50 Interesting Case #1 cont d COENZYME Q 10 Taking coenzyme Q-10 orally with other antihypertensives seems to provide an additional blood pressure lowering effect and might allow dosage reduction or discontinuation of some antihypertensive medications. Patient self-discontinued his Maxzide and noted that his blood elevated above goal shortly thereafter. He restarted his Maxzide and blood pressure returned to goal.

51 Interesting Case #2 68 year old male with chronic A.Fib on stable warfarin dose (30 mg/wk: 5 mg Mon Wed Fri; 3.75 mg all other days). Routine INR reported back as 15.2 (Target 2 to 3). Repeat INR 15.4 No bleeding, unusual bruising, tiredness, weakness or dizziness. Uses pill box, no extra doses, no change in diet, activity or RX medications. Only change identified was patient switching brands of Saw Palmetto (160 mg BID) to reduce out of pocket expenses. Elevated INR managed by withholding warfarin and administering 2.5 mg vitamin K by mouth.

52 Interesting case #2 - cont d: Outcome: No obvious bleeding or loss of blood, some additional bruising, INR eventually returned to target INR range and patient maintained on warfarin 30 mg/week. Three months later patient asked to restart saw palmetto works better than any prescription drug I have tried. Advised to restart Saw Palmetto but to use same brand he had been using for years. INR remained in target range on 30 mg warfarin/week What s going on? Noncompliance (warfarin regimen or diet). Interaction with Saw Palmetto. Contaminant in newly acquired brand of Saw Palmetto (not USP Verified ). Just another example of those unexplainable situations that develops in patients on chronic warfarin therapy.