Herbal Medicines

Outline

▶ Evidence for herb-drug interactions

▶ Pharmacokinetic (PK) versus pharmacodynamic

(PD) interactions

Herb-drug interactions ▶ St. John’s wort

▶ Warfarin

Charlotte Gyllenhaal, Ph.D.1,3

Gail Mahady, Ph.D.2 ▶ Miscellaneous

Departments of Medicinal Chemistry and Pharmacognosy,1

Pharmacy Practice2

▶ Herb-drug interactions and surgical/dental

Block Center for Integrative Cancer Treatment3

6-1870, gyllenha@uic.edu procedures

▶ Use of computer databases for clinical questions









Learning objectives Evidence for herb-drug interactions

▶ Distinguish between pharmacokinetic and ▶ Case reports

pharmacodynamic interactions.  Underreported? 70% “don’t ask-don’t tell”

▶ Know the principal pharmacokinetic and pharmacodynamic

interactions of St John’s Wort, i.e. induction of CYP450 ▶ Lab studies

3A4, and serotonin syndrome/photosensitivity  Define mechanisms

▶ Know the main reasons for herb-drug interactions with ▶ Recent interest in CYP450 induction

warfarin, i.e. vitamin K activity; decreased GI absorption or ▶ Not necessarily borne out in trials

CYP450 2C9 metabolism and herbs that decrease platelet ▶ Human studies

aggregation or thromboxane synthesis or have coumadin  Trials using probe drugs

content.

 May be too short or expensive

▶ Know the main reasons for caution with herbs and surgery

or dental procedures, i.e., herbal anticoagulants (cause  May be done on healthy population (not always)

bleeding), sedative or stimulant herbs (modify anesthesia).  Genetic polymorphisms

 Multiple drug/herb users, elderly patients

De Smet, Br J Clin Pharm 2006; 63:258-67









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Drug Interaction Resolution PK vs PD

▶ Require dosage adjustments ▶ PK: absorption, distribution, metabolism, elimination

 CYP450, PgP

▶ Temporary or complete elimination of one  Absorption from GI tract (laxatives)



or the other agent to avoid serious ▶ PD: pharmacological function

 Anticoagulant drugs plus anticoagulant herbs

consequences  Sedative herbs plus anesthesia



▶ Close monitoring of the subject ▶ Negative

 Most

▶ Total change of drug therapy ▶ Positive or synergistic

 Possible PD or PK

 Decrease side effects









Prevalence: unknown but under St. John’s wort (Hypericum

investigation perforatum)

▶ Canadian seniors with osteoarthritis ▶ Mild-moderate depression -> long-term treatment;

 Survey, n = 191. Average 2.8 prescriptions, 1.9 self- multiple clinical trials, fewer AEs than conventional

care products drugs

▶ Potential interactions detected using standard ▶ Case reports suggesting PK interactions (most

databases important of SWJ interactions)

 214 instances, 14% possible clinical significance ▶ Lab studies indicate PK interactions:

 7 herbs/supplements, associated with 5 clinically ▶ CYP450 3A4 mechanism

insignificant interactions

▶ short-term inhibition

 1 recommendation to stop medications (dilatiazem + ▶ Long-term induction; of most importance clinically

atrorvastatin -> statin side effects intensified) ▶ Reduces various drugs to subtherapeutic levels

 Clinically significant interactions may be rare – but thus ▶ Hyperforin, an active constituent, is a ligand for the xenobiotic

easier to forget about and harder to monitor! pregnane X receptor -> CYP450 3A4



Putnam, Can Fam Physician 2006; 52:340-45









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St John’s wort St. John’s wort: PK interactions

▶ Human trial with irinotecan (cancer)

▶ Other PK interactions  Blood levels of active metabolite were reduced

▶ Other drugs affected

▶ P-glycoprotein (PgP): involved in multidrug  Cyclosporin, tacrolimus, indinavir, nevirapine, imatinib,

resistance, acts as a pump to remove drugs alprazolam, midazolam, amitriptyline, digoxin, fexofenadine,

methadone, omeprazole, theophylline, verapamil, etoposide.

from cells  Human study with oral contraceptives indicating reduce OC

exposure and breakthrough bleeding.

 SJW induces this orphan nuclear receptor  Case of delayed emergence from general anesthesia observed.

 Also regulates MDR-1 (multidrug resistance  Multiple potential interactions with oncology drugs (but rare use

by oncology patients?).

gene) and other drug transporters

▶ Other CYP450s

 May inhibit CYP1A2, does not inhibit CYP2D6





Chavez, Life Sci 2006; 78:2146-57 Murphy Contraception 2005; 71:402-8









St. John’s wort Clinical strategy

▶ PD interactions

 With other antidepressants ▶ Avoiduse with other medications unless

▶ Serotonin syndrome checked out in an interaction database. Will

 SJW has both SSRI and MAO inhibitor activity

have similar interaction profile to other

 Restlessness, nausea, vomiting, tachycardia,

hallucinations etc. CYP450 3A4 inducers.

 Case reports with buspirone, loperamil, nefazodone,  Major drug-drug interaction pathway

paroxetine, sertraline, venlafaxine

▶ Possible adrenergic crisis

 MAO inhibitor activity

▶ Photosensitivity

 Active constituent hypericin is photosensitizing but

generally not a problem with healthy persons.

Potential interaction with other photosensitizing drugs









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Warfarin-herb interactions Warfarin-herb interactions

▶ Numerous drug-drug interactions: macrolides,

▶ PK

NSAIDs, COX2s, SSRIs, omeprazole, 5FU etc

 decreased absorption from GI tract due to mucilage

(variable quality of evidence). (comfrey, Iceland moss) or laxative herbs (senna,

▶ Possible pathways: Vitamin K activity lowers INR rhubarb etc)

 CYP450 2C9 inhibition/induction, which metabolizes the

 Foods: leafy greens (healthy diet)

active S-enantiomer of warfarin

 “Green drinks” – clinical interactions with oncology

patients. Case reports with cranberry juice also.

▶ PD

 herbs that decrease platelet aggregation

 Multivitamins

 Decreased thromboxane synthesis

 CoQ10: similar structure to vitamin K, but RCT found

 Herbs with coumarin content (though this is a relatively

no effect on INR. Case reports suggest monitoring. weak anticoagulant)

Rhode, Curr Opin Clin Nutr Metab 2007; 10:1-5

Engelsen, Throm Hemost 2002; 87:1075-6









Warfarin and Chinese herbs Warfarin and “G” herbs

▶ Dan-shen (Salvia miltiorrhiza) – animal studies, case ▶ Garlic (Allium sativum) – 2 case reports. Continuing

reports ingestion of high levels of garlic or garlic oil can decrease

▶ Dong quai (Angelica sinensis) – animal studies, case platelet aggregation

reports ▶ Ginger (Zingiber officinalis) – Inconclusive results in studies

▶ Asian ginseng (Panax ginseng) – ginsenosides may inhibit in healthy volunteers but case reports exist.

platelet aggregation (anticoagulant). 2 case reports of ▶ Ginkgo (Ginkgo biloba) – Ginkgolide B decreases PAF,

lowered or unsteady INR (procoagulant) extract inhibits thromboxane and prostacyclin in diabetics.

 RCT in healthy volunteers showed no effect of Asian ginseng on Preliminary human study indicates no effect on INR, but a

INR, platelet aggregation. Vitamin K in extracts? Monitor closely. case report suggests interaction

▶ American ginseng (Panax quinquefolius) – RCT in healthy ▶ Green tea (Camellia sinensis) – Inhibits platelet synthesis

volunteers indicated moderately reduced INR, warfarin of thromboxane. Case report of decreased INR in patient

levels, AUC. Avoid with warfarin. drinking 1 gal/day green tea.

Chavez, Life Sci 2006; 78:2146-57

Jiang, Br J Clin Pharm 2004; 57:592-9

Yuan, Ann Intern Med 2004; 141:23-7 Chavez, Life Sci 2006; 78:2146-57









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Warfarin and lipid-based agents Case Report

▶ Omega-3 fatty acids (fish oil, algal formulas) – Female, age 76, hx of hypertension,

case report of increased INR with fish oil in a osteoarthritis, gastropathy due to NSAIDs,

stabilized warfarin patient, 67-y/o female. atrial fibrillation, stroke: presents at ER

 Strong antiinflammatory effects, but did not affect INR with hematuria and bleeding gums.

in an RCT.

Meds: hydrochlorothiazide, warfarin,

▶ Saw palmetto – lipid extract. Case report of acetaminophen. No recent illnesses,

intraoperative hemorrhage (w/o warfarin) and antibiotics, diet change reported.

increased INR in 2 warfarin patients.

CBC normal, previous INR was 2.1 but now

7.0



Chavez, Life Sci 2006; 78:2146-57









Case Report Case Report

Appropriate INR for stroke patients is 2.0-3.0. INR at a therapeutic level for 6 m.

Elderly are at risk for bleeding d/t lower body

weight, low vitamin K intake, drug

Patient then returned with nosebleed and INR

interactions. of 10.

Drug interactions include acetaminophen (not Acetaminophen, aspirin, warfarin doses had

widely recognized): metabolized by 2C9, as is remained the same, no illnesses.

warfarin.

Patient recently increased acetaminophen Closer questioning revealed use of ginger for

intake d/t osteoarthritis flare; cautioned to upset stomach – ginger tea and ginger root.

reduce dose, use daily (not intermittently)

and monitor INR more frequently.









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Case Report Garlic (Allium sativum)

▶ Drug Interactions:

Patient advised to stop ginger consumption &

monitor INR more frequently; excessive  Alters pharmacokinetic

anticoagulation stopped with iv vitamin K. variables of

Problem: ginger did not cause CYP450 interaction acetaminophen

in pharmacodynamic/pharmacokinetic study  Decreases blood

and trials in healthy patients indicated only concentrations of warfarin

questionable clinical effect on coagulation

 Produces hypoglycemia

Combined effect of ginger anticoagulant effect when taken with

and acetaminophen 2C9 effect? Patient age?

chlorpropamide (oral

Very similar story for chamomile. antidiabetic)

Izzo AA, Ernst E. Drugs, 2001, 61:2163-2175

Lesho EP et al. Cleve Clinic J Med 2004; 71:651-655

Segal R et al CMAJ 2006; 174:1281-2









Garlic (Allium sativum) Ginkgo

▶ Drug Interactions: Case reports of interactions:

 Saquinavir (Fortovase) study-10 healthy volunteers  Aspirin – hyphema (blood in eye)

 Dose of 1200 mg 3 times daily for 4 days  Acetaminophen - bilateral subdural hematomas

 AUC during the 8 hour dosing interval decreased by  Warfarin - intracerebral hemorrhage

51%

 Ibuprofen added to ginkgo supplementation

 10 day wash out needed before Cmax, AUC levels was followed by cerebral hemorrhage

returned to 60-70% of normal

 Valproate: 2 cases of siezures

 Garlic and Protease Inhibitors

 Possible induction of CYP2C19 and CYP450 3A4,

Clin Infect Dis, 2002, 34:234-238. but studies have conflicting results









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Kava (Piper methysticum) Licorice (Glycyrrhiza glabra)

▶ One case report of coma induced by a ▶ Sore throat, dyspepsia, ▶ Drug Interactions

combination of kava and alprazolam-a peptic ulcer disease  Thiazide and loop diuretics,

benzodiazepine cardiac glycosides

▶ Triterpene saponins-

 Antihypertensives

▶ Extrapyramidal side effects-4 cases of glycyrrhizin

 Spironolactone or amiloride

dopamine antagonism-oral, lingual and trunk ▶ Prolonged use >

 Only clinically significant in

dyskinesia 6weeks of >50 g/day- cases of excessive use,

pseudaldosteronism however… commonly

▶ Do not combine with alcohol, sedatives,

 Potassium depletion, licorice candy

tranquilizers sodium retention,  Possible with multiple use

edema, hypertension of herbal formulas

and weight gain containing licorice (ie in

Chinese formulas)









Herbal laxatives Oral herb use side effects

▶ Decrease blood levels of drugs by ▶ Feverfew (Tanacetum parthenium): mouth

shortening gastrointestinal transit time sores and irritation if leaves are chewed

▶ Increase potassium loss ▶ Feverfew, ginkgo: gingival bleeding due to

▶ Common herbal laxatives: aloe, cascara anticoagulant effect

sagrada, rhubarb, senna ▶ Echinacea (Echinacea purpurea) and kava

(Piper methysticum): tongue numbness

▶ St John’s wort: xerostomia

▶ Yohimbine (Pausinystalia yohimbe):

Abebe W, 2003. J Dental Hygiene 77(1):37-46 salivation









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Surgery and Dental Procedures Surgery and Dental Procedures

Drug interactions and physiological reactions: Anticoagulant herbs: post-op bleeding and

CNS herbs: potential PD interactions with interaction with aspirin or other NSAIDs that

anesthesia: may cause bleeding.

Valerian, kava, St. John’s wort (PK interaction Garlic, ginger, ginkgo, ginseng, feverfew.

also), lavender, passionflower, lemon balm, Angelica, asafoetida, anise, astragalus, arnica,

ashwaganda, ginseng, ephedra (now illegal but bogbean, bromelain, borage seed, capsicum,

may be available elsewhere). clove, curcumin, dong quai, fenugreek, fish oil,

green tea, horsechestnut, juniper, licorice,

Blood sugar – ginseng, bitter melon, chromium, meadowsweet, onion, pau d’arco, parsley,

fenugreek, cinnamon passionflower, quassia, red clover, reishi, salvia,

turmeric, willow.



Ang-Lee, JAMA 2001; 286:208-16









Surgery and Dental Procedures Clinical coping

Stop herb and supplement use 7-14 days prior ▶ Counteract “don’t ask-don’t tell”

to surgery.  Open and nonjudgmental discussion

All pre-surgical patients should be questioned  Follow up herb use found in case histories

 Explain importance of potential interactions

about herb/supplement use to determine

recent consumption of anticoagulant or ▶ Avoid SJW and warfarin interactions

drug-interacting herbs. ▶ Patients on complicated medical regimens

should avoid herbs and supplements unless

carefully screened/supervised

▶ Package inserts









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Checking for herb-drug interactions



Standard

▶ Natural

(www.naturalstandard.com). Subscriptions

for PDA/desktop available.

 Partial database at MedlinePlus.gov

▶ Natural Medicines Comprehensive Database

(www.naturaldatabase.com). Subscription

service.









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