Herbal medicine and herb-drug interactions

1
Herbal medicine andherb-drug interactions

• Charlotte Gyllenhaal, Ph.D.
• Department of Medicinal Chemistry and
  Pharmacognosy
• and
• Block Center for Integrative Cancer Treatment
• 6-1870, gyllenha_at_uic.edu

2
Outline

• Evidence for herb-drug interactions
• Pharmacokinetic (PK) versus pharmacodynamic (PD)
  interactions
• St. Johns wort
• Warfarin
• Miscellaneous
• Herb-drug interactions and surgical/dental
  procedures
• Use of computer databases for clinical questions

3
Learning objectives

• Distinguish between pharmacokinetic and
  pharmacodynamic interactions.
• Know the principal pharmacokinetic and
  pharmacodynamic interactions of St Johns 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

4
Evidence for herb-drug interactions

• Case reports
• Underreported? 70 dont ask-dont 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 63258-67
5
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

6
PK vs PD review

• PK absorption, distribution, metabolism,
  elimination (ADME)
• 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

7
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 -gt 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 52340-45
8
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. Johns
  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
9
St. Johns 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 -gt CYP450
  3A4

10
St Johns wort (SJW)

• 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 782146-57
11
St. Johns 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 71402-8
12
St. Johns 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)
• Photosensitivity
• Active constituent hypericin is photosensitizing
  but generally not a problem with healthy persons.
  Potential interaction with other
  photosensitizing drugs?

13
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

14
International Normalized Ratio (INR) and Stroke
Warfarin (Coumadin) given as long-term therapy
after stroke dose is adjusted by periodic
monitoring of INR
15
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
101-5 Engelsen, Throm Hemost 2002 871075-6
16
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)

17
Warfarin and Chinese herbs

• Asian ginseng (Panax ginseng) ginsenosides may
  inhibit platelet aggregation (anticoagulant). 2
  case reports of lowered or unsteady INR
  (procoagulant)
• RCT in healthy volunteers showed no effect of
  Asian ginseng on INR, platelet aggregation.
  Vitamin K in extracts? Monitor closely.
• American ginseng (Panax quinquefolius) RCT in
  healthy volunteers indicated moderately reduced
  INR, warfarin levels, AUC.

Chavez, Life Sci 2006 782146-57 Jiang, Br J
Clin Pharm 2004 57592-9 Yuan, Ann Intern Med
2004 14123-7
18
Warfarin and G herbs

• Garlic (Allium sativum) 2 case reports.
  Continuing ingestion of high levels of garlic or
  garlic oil can decrease platelet aggregation
• Ginger (Zingiber officinalis) Inconclusive
  results in studies in healthy volunteers but case
  reports exist.
• Ginkgo (Ginkgo biloba) Preliminary human study
  indicates no effect on INR, but case reports
  suggest 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 782146-57
19
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 782146-57
20
Case Report

• Female, age 76, hx of hypertension,
  osteoarthritis, gastropathy due to NSAIDs, atrial
  fibrillation, stroke presents at ER with
  hematuria and bleeding gums.
• Meds hydrochlorothiazide, warfarin,
  acetaminophen. No recent illnesses, antibiotics,
  diet change reported.
• CBC normal, previous INR was 2.1 but now 7.0

21
Case Report

• Appropriate INR for stroke patients is 2.0-3.0.
• Elderly are at risk for bleeding d/t lower body
  weight, low vitamin K intake, drug interactions.
• Drug interactions include acetaminophen (not
  widely recognized) metabolized by 2C9, as is
  warfarin.
• Patient recently increased acetaminophen intake
  d/t osteoarthritis flare cautioned to reduce
  dose, use daily (not intermittently) and monitor
  INR more frequently.

22
Case Report

• INR at a therapeutic level for 6 m.
• Patient then returned with nosebleed and INR of
  10.
• Acetaminophen, aspirin, warfarin doses had
  remained the same, no illnesses.
• Closer questioning revealed use of ginger for
  upset stomach ginger tea and ginger root.

23
Case Report

• Patient advised to stop ginger consumption
  monitor INR more frequently excessive
  anticoagulation stopped with iv vitamin K.
• Problem ginger did not cause CYP450 interaction
  in pharmacodynamic/pharmacokinetic study and
  trials in healthy patients indicated only
  questionable clinical effect on coagulation
• Combined effect of ginger anticoagulant effect
  and acetaminophen 2C9 effect? Patient age?
• Very similar story for chamomile (very weak
  antiinflammatory effects).

Lesho EP et al. Cleve Clinic J Med 2004
71651-655 Segal R et al CMAJ 2006 1741281-2
24
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, 612163-2175

25
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, 34234-238.

26
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 rice
• pantethine (a stabilized form of vit B5 included
  in some cholesterol lowering supplments)artichoke
  reishi 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
27
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. Johns wort
• DHEA schizandra
• uncaria
• feverfew
• Also grapefruit juice

28
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

29
Ginkgo and psychotropics

• Female with Alzheimer disease was switched from
  bromazepam and vitamin E to trazodone and ginkgo.
  Lapsed into a coma (later reversed).
• Antioxidant effect may result in enhanced
  activity of haloperidol (antipsychotic).
• Ginkgo 2 case reports of interaction with
  phenelzine (MAO inhibitor) insomnia, headache,
  irritability

Galluzzi, J Neurol Neurosurg Psych
68679-80 Zhang, J Clin Psychopharm 2185-88
30
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
  (spasmodic movements)
• Inhibition of CYP2E1 clinical trial
• Do not combine with alcohol, sedatives,
  tranquilizers or CYP2E1 substrates

31
Licorice (Glycyrrhiza glabra)

• Drug Interactions
• Thiazide and loop diuretics, cardiac glycosides
• Antihypertensives
• Spironolactone or amiloride
• 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)

• Sore throat, dyspepsia, peptic ulcer disease
• Triterpene saponins-glycyrrhizin
• Prolonged use gt 6weeks of gt50 g/day-pseudaldostero
  nism
• Potassium depletion, sodium retention, edema,
  hypertension and weight gain

32
Licorice positive interaction

• Small trial of women being treated for polycystic
  ovary syndrome with spironolactone (antiandrogen
  and diuretic PCOS due to high androgen levels),
  which has side effects of diuresis, low blood
  pressure, volume depletion. 20 of drug-alone,
  none of drug licorice had symptoms, also
  metrorrhagia due to spironolactone improved.
  Also useful due to estrogenic effect of
  licorice.

Armanini Eur J Obst Gynecol Reprod Biol. 2007
13161-7
33
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

34
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) although
  debated, some expert analyses suggest rare
  hepatoxicity, thus should not be used with
  hepatoxic drugs.

35
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.

36
Surgery and Dental Procedures

• Drug interactions and physiological reactions
• CNS herbs potential PD interactions with
  anesthesia
• Valerian, kava, St. Johns 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 286208-16
37
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 darco, parsley,
  passionflower, quassia, red clover, reishi,
  salvia, turmeric, willow.

38
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.

39
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 Johns wort xerostomia
• Yohimbine (Pausinystalia yohimbe) salivation

40
Apthous ulcers and licorice

• Clinical trial, disssolving oral patch with
  glycyrrhizin (compound from licorice) in aphthous
  ulcer

Control and patch groups were similar in levels
of stimulated pain at baseline. By visit 3 (3
days) the treatment group had less pain. larger
reduction in ulcer size.
Martin M. IADR/AADR/CADR 85th General Session and
Exhibition (March 21-24, 2007)
41
Clinical coping

• Counteract dont ask-dont 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

42
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 subscription services give indications of
  interactions according to class of drugs and may
  thus be excessively broad in definitions of
  interactions.