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Drug – Herb Interactions

Drug – Herb Interactions. Does it Effect the Older Adult. Wadie Najm, MD, MEd. UC Irvine- Geriatric Division Supported by a Reynolds Grant. Retrieved September 29, 2011, from http:// opinion-forum.com/index/2009/07/overmedicating-children/. Objectives. Medication use by older adults

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Drug – Herb Interactions

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  1. Drug – Herb Interactions

    Does it Effect the Older Adult Wadie Najm, MD, MEd UC Irvine- Geriatric Division Supported by a Reynolds Grant Retrieved September 29, 2011, from http://opinion-forum.com/index/2009/07/overmedicating-children/
  2. Objectives Medication use by older adults Dietary Supplements – Regulations Quality Assurance How to Choose a Dietary Supplement Drug-herb interactions Resources UC Irvine - Reynolds Grant
  3. Percent of Prescriptions Medication Use in USA 1999 -2008 UC Irvine - Reynolds Grant
  4. UC Irvine - Reynolds Grant
  5. UC Irvine - Reynolds Grant
  6. UC Irvine- Reynolds Grant
  7. UC Irvine- Reynolds Grant
  8. Dietary Supplement Health and Education Act—(DSHEA) 1994 Passed by unanimous consent of House and Senate Signed into law by President Bill Clinton Amended the Food Drug & Cosmetic Act Recognized a new category of regulated products—”Dietary Supplements”(DS) Treats DS in many respect as food (i.e. does not require premarket approval) UC Irvine - Reynolds Grant
  9. Dietary Supplement Definition: A product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients Vitamins Minerals Herbs or other botanicals Amino acids Concentrate, metabolite, constituent, extract or combination of above listed ingredients UC Irvine - Reynolds Grant
  10. DSHEA Manufacturer responsible for safety evaluation FDA has burden of proving DS is unsafe once product is marketed Label must include: Name of each ingredient Quantity of each ingredient Total weight of all ingredient if a blend Identity of part of plant derived from Term “Dietary Supplement” Must contain nutritional labeling information UC Irvine - Reynolds Grant
  11. DSHEA DSHEA authorized use of FDA approved “Health claims” on label Describe the connection between a nutrient or food substance and a disease or health-related condition Statements may be included on the label that give the manufacturers description of the role of the D/S Must be accompanied by disclaimer “This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease” UC Irvine - Reynolds Grant
  12. FDA and cGMPJune, 2007 Requires proper controls to ensure that DS are processed in a consistent manner and meet quality standards. cGMP apply to all domestic and foreign companies involved in the US market Requires that DS are manufactured consistently as to identity, purity, strength and composition. Staggered 3 year phase for small business; effective June 2008 for large companies. UC Irvine - Reynolds Grant
  13. How to choose products U.S.P. notation! GMP or cGMP notation! Consumer Lab seal! Consider manufacturer / distributor Look at brand used in studies reporting positive outcome. UC Irvine - Reynolds Grant
  14. UC Irvine - Reynolds Grant FDA. (2010). TaintedDietarySupplements_1210. [pdf]. Retrieved September 29, 2011 from: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm236774.htm
  15. Tainted Products FDA has identified an emerging trend where several over-the-counter products, frequently represented as dietary supplements, contain hidden active ingredients that could be harmful List of Supplements: http://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=tainted_supplements_cder UC Irvine - Reynolds Grant
  16. Tainted Products Major delinquents: Weight loss supplements 70 + reports of contamination (2010) Sibutramine (Meredia®) Erectile function/Sexual enhancement 80 + reports of contamination (2010) Sildenafil (Viagra®), Tadalafil (Cialis®) Body building supplements 80 + reports of contamination (2010) Anabolic steroids or steroid analogs UC Irvine - Reynolds Grant
  17. Issues specific to Supplements Usually > 1 active ingredient per supplement Variation in potency by season, region, etc. Lack of clinical trials Lack of full understanding of pharmacology of herbs Presence of multiple ingredients not yet characterized. Formulations using concentrated plant extracts Use of multiple supplements at one time UC Irvine - Reynolds Grant
  18. HerbalGram. 2011 UC Irvine - Reynolds Grant
  19. HerbalGram. 2011 UC Irvine - Reynolds Grant
  20. UC Irvine - Reynolds Grant Ann Intern Med. 2002;136:596-603
  21. Ginkgo Evaluation of Memory (GEM) Study cohort 82.5% used at least 1 dietary supplement, with 54.5% using 3+. The overall mean number of prescription drugs was 3.5 ± 2.7 and dietary supplements were and 3.4 ± 3.0 83% of prescription drug users also used dietary supplements, and 90% of supplement users also used prescription drugs JAGS 57:1197–1205, 2009 UC Irvine-Reynolds Grant UC Irvine - Reynolds Grant
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  24. Take home How to choose a Supplement Look for available quality clinical research (Efficacy) Check for long tradition of use (Safety) Check that active ingredient(s) are identified Review mechanism of action determined Verify that Supplement is commercially available from a reliable source Ingredients and potency documented Quality assurance documented with seal of approval UC Irvine - Reynolds Grant
  25. Drug-Herb Interaction Mechanism Two types of interactions exist: Pharmacokinetic: herb–drug interactions are caused by one drug interfering with the elimination, metabolism, or absorption of another drug; Pharmacodynamic: Herb/supplement interaction due to pharmacological properties similar or opposite to conventional medications. UC Irvine - Reynolds Grant
  26. Drug-Herb Interactions: Mechanism Induction of hepatic and intestinal drug-metabolism enzyme (Cytochrome P450 {CYP450}): important for Phase I drug metabolism. Induction of drug transporters (intestines, liver, kidney) i.e. P-glycoprotein, plays important role: Absorption Distribution Excretion UC Irvine - Reynolds Grant
  27. Cytochrome P450 Over 80 dietary supplements have some effect on a Cytochrome (CYP) enzyme, The potential to interact with drugs metabolized by these enzymes is high. The majority of the research is based on laboratory work (in vitro or in animals). The clinical significance of these remains questionable. UC Irvine - Reynolds Grant
  28. Cytochrome P450 Role of CYP450 system is the metabolism and detoxification of endogenous compounds after they have been ingested. CYP 450 is found in high concentrations in the liver and small intestine. Comprehensive list of drug interaction: Indiana University http://medicine.iupui.edu/clinpharm/ddis/p450_Table_Oct_11_2009.pdf Prescriber’s letter: http://pharmacistsletter.therapeuticresearch.com/pl/DD_pu.aspx?cs=ce&pt=3&fpt=28&dd=-1&pb=PL&s=PL UC Irvine - Reynolds Grant
  29. Pharmacokinetic effect of CYP 450 and P-glycoprotein Drug Plasma Conc UC Irvine - Reynolds Grant
  30. St. John’s Wort (Hypericumperforatum) Used commonly alone or in combination withother supplements. Indications: Depression; anxiety; stress; insomnia Efficacy: good scientific evidence for mild to moderate depression. Standardized ingredient: Hyperforin; Hypericin Other phytochemicals are present. UC Irvine - Reynolds Grant
  31. St. John’s wort {SJW}(Hypericumperforatum) SJW is a complex mixture of over 24 constituents: flavonols, flavonol glycosides, biflavones, naphthodianthrones, acylphloroglucinols, and phenylpropanes Hyperforin is believed to be the major constituent responsible for its antidepressant activity, as it inhibits the reuptake of neurotransmitters in synapses Proposed action: inhibits 5-HT, NE, DA uptake; GABA receptor ligand; UC Irvine - Reynolds Grant
  32. St. John’s wort (SJW)(Hypericumperforatum) In vitro studies have demonstrated that SJW extract is a potent inducer of CYP3A4 and 2B6, and the responsible component was hyperforin. Based on in vitro, in vivo animal and human studies, SJW interacted with CYPs in two ways: induction of CYP and modulation (inhibition or stimulation) of enzyme activity, which may be the underlying mechanism for the observed SJW–drug interactions. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7500-2. UC Irvine - Reynolds Grant
  33. Effect of SJW on CP3A4 Phenotype among older adults Comparison of pre-supplementation and post-supplementation phenotypic ratios for CYP3A4. (A= St John’s wort (SJW); B = garlic oil); Clin Pharmacol Ther 2002;72:276-87 UC Irvine - Reynolds Grant
  34. Apparent sex-related difference in St John’s wort (SJW)–mediated CYP3A4 induction. Differences in pre-supplementation and post-supplementation) were significantly greater for female subjects. Clin Pharmacol Ther 2002;72:276-87 UC Irvine - Reynolds Grant
  35. Transplantation. 2001 Jan 27;71(2):239-41. Drug interaction between St. John's wort and cyclosporine. Barone GW, et al. Ann Pharmacother. 2000 Sep;34(9):1013-6. herb-drug interactions in renal transplant patients.. Nowack R, Nephrology 2008 Jun;13(4):337-47. Interaction of Hypericumperforatum (St. John's wort) with cyclosporin A metabolism in a patient after liver transplantation. Karliova M, et al. J Hepatol. 2000 Nov;33(5):853-5. UC Irvine - Reynolds Grant
  36. Grapefruit Juice Grapefruit has the potential to interact with numerous drugs. A number of organic compounds, identified as furanocoumarin derivatives, interfere with the hepatic and intestinal CYP3A4. Other bioactive compounds interfere with P-glycoprotein and organic anion transporting polypeptides (OATPs) either increasing or decreasing bioavailability of a number of drugs. Clin Pharmacol Ther. 2007 May;81(5):631-3 UC Irvine - Reynolds Grant
  37. Grapefruit Juice Concomitant ingestion of grapefruit juice and fexofenadine reduced fexofenadine area under curve (AUC)0–8 h by 52%; Grapefruit juice ingested 4 h before drug had no effect. UC Irvine - Reynolds Grant
  38. NYTimes, March 20, 2006 UC Irvine - Reynolds Grant
  39. Effect of Juices on Drug Plasma Concentrations Br J Clin Pharmacol 2010;70(5);645–655 UC Irvine - Reynolds Grant
  40. Thyroid Approximately 60 -80% of levothyroxine is absorbed after oral administration. This absorption occurs within the first 3 h of ingestion and is localized mainly in the jejunum and ileum. Absorption of levothyroxine is maximal when the stomach is empty UC Irvine - Reynolds Grant
  41. ThyroidLevothyroxine Levothyroxine plus chromium picolinate 1000 mcg; decreases levothyroxine levels by 17% Calcium binds levothyroxine in the GI tract; variably reduces absorption Levothyroxine taken with coffee decreases levothyroxine levels by 27% to 36%. John-Kalarickal J, et al. Thyroid 2007;17:763-5. Benvega S, et al. Thyroid 2008;18:293-301. UC Irvine - Reynolds Grant
  42. Conditions and medications that may affect absorption of levothyroxine Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 781–792 UC Irvine - Reynolds Grant
  43. Warfarin Warfarin exerts its effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K1 epoxide). Treatment with warfarin results in the hepatic production of partially carboxylated & decarboxylated proteins with reduced anticoagulant activity. The anticoagulant effect of warfarin can be reversed by the intake of vitamin K1 (phytonadione) Expert Opin. Drug Saf. (2006) 5(3):433-451 UC Irvine - Reynolds Grant
  44. Warfarin Factors that can contribute to variability: age, gender, ethnicity, vitamin K intake, Body weight, albumin level Other medication(s) Expert Opin. Drug Saf. (2006) UC Irvine - Reynolds Grant
  45. Older adults are more likely to eat vegetables, therefore, have higher vitamin K intake. Vitamin K intake among adults > 55 years is estimated to range from 80 to 210 μg/day. Expert Opin. Drug Saf. (2006) 5(3) UC Irvine - Reynolds Grant
  46. Effect on Warfarin Absorption of warfarin may be inhibited by drugs that affect the bioavailability of warfarin, such as colestyramine or sucralfate. Warfarin also interacts with medications that are highly protein-bound (salsalate, sulfasalazine). Warfarin is inhibited by medications that induce cytochrome P450 liver enzymes (rifampin, carbamazepine) Warfarin is enhanced by medications that inhibit CYP liver enzymes (metronidazole, cimetidine). Pharmacodynamic interactions may occur with drugs that affect platelet function and aggregation, causing increased risk of bleeding (aspirin, clopidogrel, NSAIDs) Expert Opin. Drug Saf. (2006) 5(3):433-451 UC Irvine - Reynolds Grant
  47. Warfarin Glucosamine Over 40 reports of interactions with warfarin (Coumadin) Glucosamine alone or in combination with chondroitin Most reports involved typical doses, Glucosamine 1500 mg/day and chondroitin 1200 mg/day Effect: bruising, bleeding {increased INR) Knudsen J et al., Pharmacotherapy 2008;28:540-8. UC Irvine - Reynolds Grant
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  49. Clinically significant drug interactions can occur when an interacting drug, food or herbal supplement is added during warfarin therapy, discontinued during warfarin treatment, or used intermittently during warfarin treatment. J ThrombThrombolysis (2011) 31:326–343 UC Irvine - Reynolds Grant
  50. Expert Opin. Drug Saf. (2006) 5(3) UC Irvine - Reynolds Grant
  51. Expert Opin. Drug Saf. (2006) 5(3) UC Irvine - Reynolds Grant
  52. UC Irvine - Reynolds Grant
  53. Bitter orange Bitter orange contains the stimulant “synephrine” QT-interval prolongation in case reports Combining with other QT-interval prolonging drugs increases risk of arrhythmia: Amiodarone Quinidine Sotalol Stimulants Several others Nasir JM, et al. Mayo Clin Proc 2004;79:1059-62. UC Irvine - Reynolds Grant
  54. Other Ephedra Alternatives found in supplements Caffeine Ephedra Guaraná Kola nut Yerba maté Green tea Bitter orange Combinations Guaraná Kola nut Yerba maté Green tea Black tea Cocoa UC Irvine - Reynolds Grant
  55. Take Home Medical history should include information about Herbal/Dietary supplements Consider Herbal – Drug interactions Physicians and patient must become better educated about the potential for interactions. Elderly people are subject to higher risk for Drug-Herb interactions UC Irvine - Reynolds Grant
  56. Resources UC Irvine - Reynolds Grant
  57. Natural MedicineComprehensive Database UC Irvine - Reynolds Grant
  58. UC Irvine - Reynolds Grant
  59. UC Irvine - Reynolds Grant
  60. Natural Standard UC Irvine - Reynolds Grant
  61. UC Irvine - Reynolds Grant
  62. Nutrient Depletion UC Irvine - Reynolds Grant
  63. Facts & Comparison UC Irvine - Reynolds Grant
  64. UC Irvine - Reynolds Grant
  65. UC Irvine - Reynolds Grant
  66. Resources Books Herbal Supplements-Drug Interactions: Scientific and Regulatory Perspectives Y.W. Francis Lam, Shiew-Mei Huang, Stephen D. Hall (2006) Herbal Supplements: Efficacy, Toxicity, Interactions with Western Drugs, and Effects on Clinical Laboratory Tests. AmitavaDasgupta (2011) A-Z Guide to Drug-Herb-Vitamin Interactions Revised and Expanded 2nd Edition: Alan R. Gaby (2006) UC Irvine - Reynolds Grant
  67. How to report adverse reactions tonatural supplements Mandatory reporting for manufacturers Voluntary reporting for health professionals Report it to MedWatchhttp://www.fda.gov/medwatch/ Report using Natural Medicines Comprehensive Database: Natural Medicines Watch UC Irvine - Reynolds Grant
  68. Tips for Older Dietary Supplement Users http://www.fda.gov/Food/DietarySupplements/ConsumerInformation/ucm110493.htm My Dietary Supplements (MyDS) Mobile App (ODS) http://ods.od.nih.gov/About/mobile/AboutMyDS.aspx Zhou SF, et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007 Dec;29(6):687-710. UC Irvine - Reynolds Grant
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