Outline Evidence for herb-drug interactions Pharmacokinetic (PK) versus pharmacodynamic (PD) interactions St. John’s wort Warfarin Miscellaneous Herb-drug interactions and surgical/dental procedures Use of computer databases for clinical questions
Learning objectives Distinguish between pharmacokinetic and pharmacodynamic interactions. Know the principal pharmacokinetic and pharmacodynamic interactions of St John’s Wort, i.e. induction of CYP450 3A4, and serotonin syndrome/photosensitivity Know the main reasons for herb-drug interactions with warfarin, i.e. vitamin K activity; decreased GI absorption or CYP450 2C9 metabolism; and herbs that decrease platelet aggregation or thromboxane synthesis or have coumarin content. Know the main reasons for caution with herbs and surgery or dental procedures, i.e., herbal anticoagulants (cause bleeding), sedative or stimulant herbs (modify anesthesia). Know principles for clinical coping with herb-drug interactions
Evidence for herb-drug interactions Case reports Underreported? 70% “don’t ask-don’t tell” Lab studies Define mechanisms Recent interest in CYP450 induction Not necessarily borne out in trials Human studies – interpret with caution Trials using probe drugs May be too short or expensive May be done on healthy population (not always) Genetic polymorphisms Multiple drug/herb users, elderly patients De Smet, Br J Clin Pharm 2006; 63:258-67
Drug Interaction Resolution Require dosage adjustments Temporary or complete elimination of one or the other agent to avoid serious consequences Close monitoring of the subject Total change of drug therapy
PK vs PD review PK: absorption, distribution, metabolism, elimination CYP450, PgP Absorption from GI tract (laxatives) PD: pharmacological function Anticoagulant drugs plus anticoagulant herbs Sedative herbs plus anesthesia Negative Most Positive or synergistic Possible PD or PK Decrease side effects
Prevalence: Canadian seniors Canadian seniors with osteoarthritis Survey, n = 191. Average 2.8 prescriptions, 1.9 self-care products Potential interactions detected using standard databases 214 instances, 14% possible clinical significance 7 herbs/supplements, associated with 5 clinically insignificant interactions 1 recommendation to stop medications (dilatiazem + atrorvastatin -> statin side effects intensified) Clinically significant interactions may be rare – but thus easier to forget about and harder to monitor! Putnam, Can Fam Physician 2006; 52:340-45
Prevalence: Mayo Clinic 6 specialty areas Survey of 1795 patients; 39.6% used supplements Potential interactions detected using Lexi-Interact (available on PDA) 107 interactions with potential clinical significance Garlic, valerian, kava, ginkgo and St. John’s wort accounted for most potential interactions – 68% Antithrombotics, sedatives, antidepressants, and antidiabetics most involved in interactions – 94% No patient was seriously harmed by herb-drug interaction Sood et al. 2008; 121(3):207-11
St. John’s wort (Hypericum perforatum) Mild-moderate depression; multiple clinical trials, fewer AEs than conventional drugs Case reports suggesting PK interactions (most important of SWJ interactions) Lab and clinical studies indicate PK interactions: CYP450 3A4 mechanism short-term inhibition Long-term induction; of most importance clinically Reduces various drugs to subtherapeutic levels Hyperforin, an active constituent, is a ligand for the xenobiotic pregnane X receptor -> CYP450 3A4
St John’s wort Other PK interactions P-glycoprotein (PgP): involved in multidrug resistance, acts as a pump to remove drugs from cells SJW induces; thus removes drugs from cells Also regulates MDR-1 (multidrug resistance gene) and other drug transporters Chavez, Life Sci 2006; 78:2146-57
St. John’s wort: PK interactions Human trial with irinotecan (cancer) Blood levels of active metabolite were reduced Other drugs affected Cyclosporin, tacrolimus, indinavir, nevirapine, imatinib, alprazolam, midazolam, amitriptyline, digoxin, fexofenadine, methadone, omeprazole, theophylline, verapamil, etoposide. Human study with oral contraceptives indicating reduced OC exposure and breakthrough bleeding (pregnancies resulted). Case of delayed emergence from general anesthesia observed. Multiple potential interactions with oncology drugs (but rare use by oncology patients?). Other CYP450s May inhibit CYP1A2, does not inhibit CYP2D6, hyperforin inhibits CYP2C9 Murphy Contraception 2005; 71:402-8
St. John’s wort PD interactions With other antidepressants Serotonin syndrome SJW has both SSRI and MAO inhibitor activity Restlessness, nausea, vomiting, tachycardia, hallucinations etc. Case reports with buspirone, loperamil, nefazodone, paroxetine, sertraline, venlafaxine Possible adrenergic crisis MAO inhibitor activity (not major activity)
Clinical strategy Avoid use with other medications unless checked out in an interaction database. Will have similar interaction profile to other CYP450 3A4 inducers. Major drug-drug interaction pathway
Warfarin-herb interactions Numerous drug-drug interactions: macrolides, NSAIDs, COX2s, SSRIs, omeprazole, 5FU etc (variable quality of evidence). Possible pathways: Vitamin K activity lowers INR Foods: leafy greens (healthy diet) “Green drinks”– clinical interactions with oncology patients. Case reports with cranberry juice also. Multivitamins (low vitamin K dose) CoQ10: similar structure to vitamin K, but RCT found no effect on INR. Case reports suggest monitoring. Rhode, Curr Opin Clin Nutr Metab 2007; 10:1-5 Engelsen, Throm Hemost 2002; 87:1075-6
Warfarin-herb interactions PK decreased absorption from GI tract due to mucilage (comfrey, Iceland moss) or laxative herbs (senna, rhubarb etc) CYP450 2C9 inhibition/induction, which metabolizes the active S-enantiomer of warfarin (saw palmetto, kava, bromelain possible but only lab data) PD Herbs that decrease platelet aggregation Decreased thromboxane synthesis Herbs with coumarin content (though coumarin is a relatively weak anticoagulant)
Warfarin and Chinese herbs Asian ginseng (Panax ginseng) –ginsenosides may inhibit platelet aggregation (anticoagulant). RCTs in in healthy volunteers & cardiac patients showed no effect of Asian ginseng on INR, platelet aggregation. Monitor closely. American ginseng (Panaxquinquefolius) – RCT in healthy volunteers indicated moderately reduced INR, warfarin levels, AUC. Avoid with warfarin. Many other Asian herbs with known platelet aggregation inhibition but no clinical study. Chavez, Life Sci 2006; 78:2146-57 Jiang, Br J Clin Pharm 2004; 57:592-9 Yuan, Ann Intern Med 2004; 141:23-7 Lee, Int J Cardiol 2010; 145: 275-6
Warfarin and “G” herbs Garlic (Alliumsativum) – 2 case reports. Continuing ingestion of high levels of garlic or garlic oil can decrease platelet aggregation Ginger (Zingiberofficinalis) – Inconclusive results in studies in healthy volunteers but case reports exist. Ginkgo (Ginkgo biloba) –Ginkgolide B decreases PAF, extract inhibits thromboxane and prostacyclin in diabetics. Preliminary human study indicates no effect on INR, but a case report suggests interaction Green tea (Camellia sinensis) – Inhibits platelet synthesis of thromboxane (lab). Case report of decreased INR in patient drinking 1 gal/day green tea – vitamin K. Chavez, Life Sci 2006; 78:2146-57
Warfarin and lipid-based agents Omega-3 fatty acids (fish oil, algal formulas) – case report of increased INR with fish oil in a stabilized warfarin patient, 67-y/o female. Strong antiinflammatory effects, but did not affect INR in an RCT. Saw palmetto – lipid extract. Case report of intraoperative hemorrhage (w/o warfarin) and increased INR in 2 warfarin patients. Chavez, Life Sci 2006; 78:2146-57
Garlic (Allium sativum) Drug Interactions: Alters pharmacokinetic variables of acetaminophen Clinical trial: Inhibits CYP2E1 No effect on warfarin PK or PD in 2 clinical trials but 2 cases reported in one paper, ↓ INR Produced hypoglycemia with chlorpropamide– case but bitter melon, another herbal hypoglycemic, also in curry that caused effect Izzo AA, Ernst E. Drugs, 2001, 61:2163-2175
Garlic (Allium sativum) Drug Interactions: Saquinavir (Fortovase) study-10 healthy volunteers AUC during the 8 hour dosing interval decreased by 51% 10 day wash out needed before Cmax, AUC levels returned to 60-70% of normal Ritonavir – possible interaction with garlic PK or PD, resulting in garlic toxicity to GI tract Garlic and Protease Inhibitors should be avoided Clin Infect Dis, 2002, 34:234-238.
Herbs and diabetes Numerous herbs used for diabetes have shown laboratory effects on hypoglycemia; case reports suggesting interaction beginning to appear in literature. Examples: bitter melon, nopal or prickly pear cactus, gymnema, fenugreek, ginseng (Asian, American), cinnamon, glucomannan, guar gum, chia and others. Need to be discussed with patients.
Herbs and Statins Pharmacodynamic interactions: the “herbal statins” (frequently in cholesterol-lowering supplements). Effect on statin side effects (liver, myalgia, rhabomyolysis)? Usually due to polypharmacy. Red yeast rice (monacolin = lovastatin); case report of rhabdomyolysis with lovastatin and cyclosporine after initiating red yeast ricepantethine (a stabilized form of vit B5 included in some cholesterol lowering supplments)artichokereishi mushroom tocotrienolspolicosanolguggulgarlicfish oil (also raises LDL cholesterol) possibly goldenseal resveratrol plant stanols chlorogenic acid (coffee, though not absorbed easily)luteolin (parsley, peppers)luteolin 7-0-glucoside (dandelion flower) Armitage 2007; Lancet 370; 1781-90; NAPRALERT; naturalstandard.org
Herbs and Statins Pharmacokinetic interactions: CYP450 3A4: lovatstatin, simvastatin, atrorvastatin. CYP 2C9: fluvastatin, rouvastatin, pitavastatin Herb/supplement 3A4 and 2C9 inhibitors/inducers: berberine Oregon grape (contains berberine) bromelain resveratrol cranberry St. John’s wort DHEA schizandra uncaria feverfew Also grapefruit juice
Ginkgo Cases/trials on interactions: Aspirin – hyphema Acetaminophen - bilateral subdural hematomas Warfarin - intracerebral hemorrhage but no effect in 2 clinical trials Ibuprofen -- cerebral hemorrhage Rofecoxib – bleeding, case report Valproate: 2 cases of seizures Risperidone – priapism; vasodilating effect of both substances? Induction of CYP2C19 – clinical trial, case report. Possible/weak effects on CYPs 3A4 and 2C9
Ginkgo and psychotropics Female with Alzheimer disease was switched from bromazepam and vitamin E to trazodone and ginkgo. Lapsed into a coma, but was reversed by giving flumazenil. Ginkgo increases GABA, causing coma, by binding to benzodiazepine receptor and inducing activation of trazodone through CYP3A4. Flumazenil antagonizes benzodiazepine receptor, decreasing GABA enough to break the coma. Antioxidant effect may result in enhanced activity of haloperidol. Galluzzi, J Neurol Neurosurg Psych 68:679-80 Zhang, J Clin Psychopharm 21:85-88
Kava (Piper methysticum) One case report of coma induced by a combination of kava and alprazolam-a benzodiazepine Extrapyramidal side effects-4 cases of dopamine antagonism-oral, lingual and trunk dyskinesia Inhibition of CYP2E1 – clinical trial Do not combine with alcohol, sedatives, tranquilizers or CYP2E1 substrates
Licorice (Glycyrrhiza glabra) Sore throat, dyspepsia, peptic ulcer disease Triterpene saponins-glycyrrhizin Prolonged use > 6weeks of >50 g/day-pseudaldosteronism Potassium depletion, sodium retention, edema, hypertension and weight gain Drug Interactions Thiazide and loop diuretics, cardiac glycosides Antihypertensives Spironolactone or amiloride Verapamil (animal study) Only clinically significant in cases of excessive use, however… appears with excessive licorice candy Possible with multiple use of herbal formulas containing licorice (ie in Chinese formulas)
Licorice: positive interaction Small trial of women being treated for polycystic ovary syndrome with spironolactone, which has side effects of diuresis, low blood pressure, volume depletion. 20% of drug-alone, none of drug + licorice had symptoms, also metrorrhagia improved. Also useful due to estrogenic effect of licorice. Armanini Eur J Obst Gynecol Reprod Biol. 2007; 131:61-7
Herbal laxatives Decrease blood levels of drugs by shortening gastrointestinal transit time Increase potassium loss Common herbal laxatives: aloe, cascara sagrada, rhubarb, senna Abebe W, 2003. J Dental Hygiene 77(1):37-46
Other potential interactions Ephedra (diet pills) – illegal in US but possibly obtained internationally/Internet. Increase in blood pressure, thus contraindicated with antihypertensives and stimulants (e.g. caffeine). Black Cohosh (menopausal symptoms but UIC trial negative) – some hepatotoxicity due to adulteration recently; use cautiously. Ginkgo – 2 case reports of interaction with phenelzine; insomnia, headache, irritability Hawthorn – interference with digoxin blood level tests; possible pharmacodynamic interaction
Other possible interactions Tamoxifen – inhibitors of CYP2D6 should not be taken because of metabolism of prodrug to its active form. Genetic polymorphism in population. Several antidepressants are strong inhibitors but SJW is weak if at all. Valerian in vitro activity. Goldenseal– strong inhibition in clinical trial. Chinese herbs –Scutellaria species – induction of CYP2E1, 2C9. Angelica dahurica– inhibited CYP1A2 (but no effect of Angelica tenuissima). Hundreds of other Asian herbs with no info.
Surgery and Dental Procedures Drug interactions and physiological reactions: CNS herbs: potential PD interactions with anesthesia: Valerian, kava, St. John’s wort (PK interaction also), lavender, passionflower, lemon balm, ashwaganda, ginseng, ephedra). Midazolam – SJW, goldenseal and possibly ginkgo PK effects but ginkgo studies are contradictory Blood sugar – ginseng, bitter melon, chromium, fenugreek, cinnamon Ang-Lee, JAMA 2001; 286:208-16
Surgery and Dental Procedures Anticoagulant herbs: post-op bleeding and interaction with aspirin or other NSAIDs that may cause bleeding. Garlic, ginger, ginkgo, ginseng, feverfew. Angelica, asafoetida, anise, astragalus, arnica, bogbean, bromelain, borage seed, capsicum, clove, curcumin, dong quai, fenugreek, fish oil, green tea, horsechestnut, juniper, licorice, meadowsweet, onion, pau d’arco, parsley, passionflower, quassia, red clover, reishi, salvia, turmeric, willow.
Surgery and Dental Procedures Stop herb and supplement use 7-14 days prior to surgery. All pre-surgical patients should be questioned about herb/supplement use to determine recent consumption of anticoagulant or drug-interacting herbs.
Dental procedures: herb side effects Feverfew (Tanacetum parthenium): mouth sores and irritation if leaves are chewed Feverfew, ginkgo: gingival bleeding due to anticoagulant effect Echinacea (Echinacea purpurea) and kava (Piper methysticum): tongue numbness St John’s wort: xerostomia Yohimbine (Pausinystalia yohimbe): salivation
Clinical coping Counteract “don’t ask-don’t tell” Open and nonjudgmental discussion Follow up herb use found in case histories Explain importance of potential interactions Avoid SJW and warfarin interactions Patients on complicated medical regimens should avoid herbs and supplements unless carefully screened/supervised, but prioritize drugs with narrow therapeutic index, ie: carbamazepine, cyclosporine, digoxin, ethosuximide, levothyroxine, phenytoin, procainamide, theophylline and warfarin
Checking for herb-drug interactions Natural Standard (www.naturalstandard.com). Subscription service. Partial database at MedlinePlus.gov Natural Medicines Comprehensive Database (www.naturaldatabase.com). Subscription service. Lexi-Interact. Subscription service (www.lexi-comp.com) MicroMedex – Altmedex. Subscription service (www.micromedex.com) Some misleading information but generally err on the side of pointing out interactions for which there is little to no evidence base.
The issue • 50% of people who reported that they used complementary and alternative therapies also used conventional medicines on the same day • 57% did not report the use of complementary therapies to their doctor. MacLennan AH, Myers SP, Taylor AW.The continuing use of complementary and alternative medicine in South Australia: costs and beliefs in 2004. Med J Aust. 2006;184:27-31.
Steps for Detecting and Advising on Herbal/Drug Interactions • Is the patient taking any herbal supplements? • Does the herbal have efficacy for the intended use? • Is the product reliable? (i.e.,what are they REALLY taking?) • Is the Rx drug one with a narrow therapeutic margin?
Evaluation of Herbal/Drug Interactions • Speculative or Theoretical • e.g. St. John’s Wort and tyramine containing foods due to MAOI effects or evening primrose oil and risk for bleeds with warfarin • In vitro effects • e.g. ginkgo and microsomal studies showing inhibition of CYP2C9 • In vivo - animal studies • e.g. kava and alcohol • In vivo - human case reports • e.g. ginkgo and warfarin bleeds • In vivo - healthy human volunteer studies • e.g. indinivir and St. John’s Wort • In vivo - clinical studies in patients
Important Criteria for Evaluation of a Human Herbal/Drug Interaction Report • Reputable standardized product used and carefully described? • Product used analyzed for marker compounds? • Same batch used throughout study? • Doses appropriate? • Steady state study to discern CYP induction? • Is observation consistent with known mechanisms of action? • Is observation consistent with literature observations? • Randomized, placebo controlled human volunteer study with appropriate n?
Top 20 Selling Herbals for 2007- Mass Market HerbalGram 2008;78:61-62 • Product M $ % change rank in 2006 • 1. soy 25-17 1 • 2. cranberry24 +24 3 • 3. garlic 20-132 • 4.ginkgo18+125 • 5. saw palmetto 17- 64 • 6. echinacea 16 - 96 • 7. black cohosh 09 -0.5 8 • 8. milk thistle09-0.47 • 9. ginseng 08 + 310 • 10. St. John’s wort 08- 69 • 11. Green tea 05 - 7 11 • 12.Evening primrose oil 04 - 912 • 13. valerian 03 - 9 13 • 14. Horny goat weed 02 - 2 14 Red indicates risk for drug interactions
Top 20 Selling Herbals for 2007- Mass Market HerbalGram 2008;78:61-62 • Product M $ % change rank in 2004 • 15. bilberry02- 9 15 • 16.grape seed 02 - 9 16 • 17. Yohimbe01-1517 • 18. red clover 01-1318 • 19. Horse chestnut seed 01-2119 • 20. ginger 0.7-2020 Total (all herbs) 268 +7.6 Red indicates potential risk for drug interactions Note: total herbal sales are estimated at $4.7 billion The above figures include only sales from food stores, drug stores, and mass market retailers but with Wal-Mart figures not included. It does not include warehouse buying clubs (Costco), convenience stores, natural foods stores, multilevel marketers, health professional sales, mail order or internet sales.
Herb-drug interactions: potentially important but woefully under researchedE. ErnstEur J Clin Pharmacol 2000: 56: 523-524 • Why have only so few cases of suspected herb-drug interactions been reported in the medical literature? • Truly rare events? • Significant unreporting?
Clinical risk management of herb-drug interactions • Risk identification and assessment • Development and implementation of risk reduction strategies • Evaluation of risk reduction strategies De Smet, PAGM. Br J Clin Pharmacol 2006
Clinical significance of herb-drug Interactions • Patient characteristics • Nature of pharmacodynamic response • Mechanism of interaction • Safety margin of the interacting herb and drug • Quality of the product • Size of the dose • Duration of therapy • Time course of drug interaction • Order and timing of administration PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions: an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25
Understanding the mechanism of a herb-drug interaction allows the • prediction of other interactions • assessment of clinical significance • guide risk minimisation strategies
Study designs used to assess herb-drug interactions • Controlled trials in patients • Controlled trials in healthy subjects • Case reports or series • Animal studies • In vitro studies • Adverse event data • Theoretical PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions: an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25
Investigating drug interactions Type of study Mechanism Clinical Relevance Ethical Issues Cost Enzyme, Cells or microsomes Animals Healthy subjects Patients