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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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  23. UC Irvine - Reynolds Grant

  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

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