Download Herb-drug interactions

Herbal medicine and
herb-drug interactions
Charlotte Gyllenhaal, Ph.D.
Department of Medicinal Chemistry and Pharmacognosy
and
Block Center for Integrative Cancer Treatment
6-1870, [email protected]
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
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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

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
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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
(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
Prevalence: Canadian seniors
► Canadian
seniors with osteoarthritis
 Survey, n = 191. Average 2.8 prescriptions, 1.9 selfcare 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 (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; 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)
► Photosensitivity
 Active constituent hypericin is photosensitizing but
generally not a problem with healthy persons.
Potential interaction with other photosensitizing
drugs?
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
International Normalized Ratio (INR) and Stroke
Warfarin (Coumadin) given as long-term therapy after stroke;
dose is adjusted by periodic monitoring of INR
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
ginseng (Panax ginseng) – ginsenosides may
inhibit platelet aggregation (anticoagulant). 2
case reports of lowered or unsteady INR
(procoagulant)
► Asian
 RCT in healthy volunteers showed no effect of Asian
ginseng on INR, platelet aggregation. Vitamin K in
extracts? Monitor closely.
ginseng (Panax quinquefolius) – RCT in
healthy volunteers indicated moderately reduced
INR, warfarin levels, AUC.
► American
Chavez, Life Sci 2006; 78:2146-57
Jiang, Br J Clin Pharm 2004; 57:592-9
Yuan, Ann Intern Med 2004; 141:23-7
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; 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
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
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.
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.
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; 71:651-655
Segal R et al CMAJ 2006; 174:1281-2
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 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
tocotrienols
policosanol
guggul
garlic
fish 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
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3A4 and 2C9 inhibitors/inducers:
berberine
bromelain
cranberry
DHEA
uncaria
feverfew
Also grapefruit juice
Oregon grape (contains berberine)
resveratrol
St. John’s wort
schizandra
Ginkgo
Cases/trials on interactions:
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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
(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 68:679-80
Zhang, J Clin Psychopharm 21:85-88
Kava (Piper methysticum)
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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
Licorice (Glycyrrhiza glabra)
throat, dyspepsia, ► Drug Interactions
 Thiazide and loop diuretics,
peptic ulcer disease
cardiac glycosides
► Triterpene saponins Antihypertensives
glycyrrhizin
 Spironolactone or amiloride
► Prolonged use >
 Only clinically significant in
6weeks of >50 g/daycases of excessive use,
pseudaldosteronism
however… appears with
► Sore
 Potassium depletion,
sodium retention,
edema, hypertension
and weight gain
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 (antiandrogen and diuretic –
PCOS due to high androgen levels), which
has side effects of diuresis, low blood
pressure, volume depletion. 20% of drugalone, 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; 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) –
although debated, some expert analyses
suggest rare hepatoxicity, thus should not
be used with hepatoxic drugs.
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
(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
► Feverfew
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)
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
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.lexicomp.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.