Herb-drug interactions

Subehan, M.Pharm.Sc., PhD., Apt.

Pharmacognosy-Phytochemistry Lab.
Faculty of Pharmacy, Hasanuddin University

Drug interactions in Medline in 1995.

Items for drug interactions in PubMed in 2007

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 Evaluation of Herbal/Drug Interactions

Speculative or Theoretical

e.g. St. John’
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
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’
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?

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 Top 20 Selling Herbals for 2007-
2007- Mass Market
HerbalGram 2008;78:61-
2008;78:61-62

Product M $ % change rank in 2006

1. soy 25 -17 1

2. cranberry 24 +24 3

3. garlic 20 -13 2

4. ginkgo 18 +12 5

5. saw palmetto 17 - 6 4

6. echinacea 16 - 9 6

7. black cohosh 09 -0.5 8

8. milk thistle 09 -0.4 7

9. ginseng 08 +3 10

10. St. John’
John’s wort 08 -6 9

11. Green tea 05 -7 11

12. Evening primrose oil 04 -9 12

13. valerian 03 -9 13

14. Horny goat weed 02 -2 14
Red indicates risk for drug interactions

Top 20 Selling Herbals for 2007-

2007- Mass Market
HerbalGram 2008;78:61-
2008;78:61-62

Product M $ % change rank in 2004

15. bilberry 02 -9 15

16. grape seed 02 -9 16

17. Yohimbe 01 -15 17

18. red clover 01 -13 18

19. Horse chestnut seed 01 -21 19

20. ginger 0.7 -20 20

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,
stores, and mass
market retailers but with Wal-
Wal-Mart figures not included. It does not include
warehouse buying clubs (Costco), convenience stores, natural foods foods stores,
multilevel marketers, health professional sales, mail order or internet
internet sales.

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 Herbals affecting drug management (i.e.,
herbal/drug interactions)

literature analysis (Fugh-Berman and Ernst, Herbal Drug

“Interactions and Assessment of Reliability” Br J Clin
Pharmacol 2001;52:587-595)
• 108 reported cases of suspected interactions
• 69% “unable to be evaluated”
• 19% possible interactions
• 13% (14) well documented
• 11/14 involved warfarin
• 7/14 involved St. John’s wort

Types of Drug Interactions

– Decreased bioavailability of drug
↓ Absorption (fibers, mucilage herbs, ↑ p-glycoprotein)
↑ Metabolism (↑ CYP 450)
↑ Elimination (laxative or diuretic herbs)
– Increased bioavailability of drug
↑ Absorption (Ginger, Cayenne, Black Pepper)
↓ Metabolism (↓ CYP 450, eg. Grapefruit Juice)
↓ Elimination (Licorice- anti-diuretic)
– Potentiation of drug via similar activity
Eg. Drug diuretic and herb diuretic
– Potentiation of drug via complementary activity
↓ P-glycoprotein system (eg. Eluthero and antibiotics)
Eg. Bitter melon, gymnema, fenugreek,etc. and insulin or oral
hyoglycemics
– Decreased effectiveness of drug via antagonistic activity
Eg. CNS stimulant with CNS depressant
– Reduced side effects of drug
Eg. Milk Thistle and hepatotoxic drugs, Licorice and corticosteroids,
Astragalus and chemotherapeutics

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 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
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

St. John’s Wort

Just Say No To
– Cyclosporine
– Digoxin
– Protease inhibitors
– Warfarin
– Oral contraceptives
No reports of unwanted pregnancies
Possible breakthrough bleeding
– Theophylline – not valid
– Irinotecan
– Imarinib (Gleevec) - ↓ AUC 30%

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 St. John’s Wort (Hypericum perforatum)

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
breakthrough bleeding.
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

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KEY: * theoretically possible ‡ experimental † isolated case report/s ∆ clinical study/ies

Astragalus
– ↑ immune effects of interleukin-2 and acyclovir
– May be incompatible with immunosuppressive
drugs
Cyclosporine
Azathioprine
Methotrexate

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 Bromelain

– May ↑ bleeding with

anticoagulants
Monitor
– May ↑ effects of antibiotics
– ↑ efficacy of 5-fluoroiuracil
and vincristine

Cayenne

– May ↑ metabolism of
drugs by enhancing
absorption
– ↓ gastric mucosal damage
when taken 30 min
– Topical use ↑ ACE
inhibitor cough

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 Garlic
(Allium sativum)
– May ↑ bleeding times with anticoagulants
– ↓ blood levels of protease inhibitor (Saquinavir®)
– ↑ Indomethacin, insulin, statins
Monitor
– Some garlic preparations containing allicin may increase
the activity of 3A4

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 Ginger
(Zingiber officinalis)
– May ↑ absorption of drugs
– May ↑ bleeding with anticoagulants (?)
– May ↑ cholesterol lowering effects of drugs
– Case reports of ↓ effect of antacids (heartburn)

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 Ginkgo
(Ginkgo biloba)
– May ↑ bleeding with anticoagulants
– May ↑ activity and side effects of MAO inhibitors
– May ↑ efficacy (potency) of haloperidol in schizophrenia (study)
– ↑ nifedipine plasma levels (study)

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 American Ginseng
(Panax quinquefolius)
– Hypoglycemic
- Journal of the American
College of Nutrition, Vol.23,
No. 3,248-258 (2004)
- American and Vietnamese
lowered 90 min. plasma
glucose

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 Green Tea (Camellia sinensis)
– High in tannin, do not take with codeine or theophylline
(inhib absorption)
Large amounts may ↑ effects and side effects
of theophylline??????????
– May ↓ effect of coronary vasodilator drugs such as
dipyridamle if taken simultaneously
– Synergistic with sulindac and/or tomaxifen and may ↓
adverse effects
– Little or no effect on 3A4 or 2D6. Drug
Metab Disposition. 2004
– May ↓ effects of warfarin (Case report)
– Green tea should not be taken with warfarin, a
bloodthinning medication, because the herb contains
vitamin K and, thus, can render warfarin ineffective.
– Similarly, green tea and aspirin should not be mixed
because they both prevent platelets from clotting.
Using the two together, therefore, may increase your
risk of bleeding.

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 Kava (Piper methysticum)
– ↑ actions of depressant drugs,
alcohol
– Contraindicated with
hepatotoxic drugs and alcohol
– ↓ efficacy of Parkinson drugs
(L-Dopa)
– ↓ 3A4, isolated kavalactones
No systematic studies on
pharmacokinetic interactions
No unequivocal clinical
evidence; In vitro studies
based on theoretical
considerations

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 Licorice

– ↓ efficacy ↑ toxicity of
diuretics
Large doses ↓ K
– ↓ efficacy and ↑ side
effects of digoxin
Large doses ↓ K, Low K
↑ risk or dig toxicity
– Potentiates corticosteroids
– ↑ blood pressure
(pseudoaldosteronism)

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 Milk Thistle
– ↓ hepatotoxicity of drugs
haloperidol, halothane,
dilantin, butyrophenones, and
phenothiazines, phenytoin
– ↓ kidney toxicity (without
reducing actions) cisplatin and
doxorubicin
– ↓ kidney toxicity of anesthetics
– Contrary to previous reports little
or no effect on 3A4 or 2D6
[Clin Pharmacol Ther,
2004;75(2):35]

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 Schizandra

– ↓ cardiotoxicity of
adriamycin
– ↓ CNS stimulation of
caffeine and amphetamines
– ↓ hepatotoxicity of drugs
(including APAP)
– May ↑ action of
pentobarbital

Valerian

– ↑ effects of CNS depressants

Phamracodynamic
– Drug Metab Dispos. 2004;32::1333-1336
Minimal effect of 3A4 and no effect on
2D6
– Alprazolam (3A4) not significantly altered
after Valerian dosing

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 What can we do?

dialog with MD and other prescribers

recommend the best products

ask patients about herbals they may be taking

herbals should not usually be recommended for

acute or serious illnesses

stay informed

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 References with Good Herbal/Drug
Interactions Discussion

“Top 100 Drug Interactions” Hansten PD and
Horn JD. H&H Publications 2008

Natural
Medicines Comprehensive
Database.
Online version updated “daily”
daily”. UW Healthlinks
http://www.naturaldatabase.com/;
http://www.naturaldatabase.com/; $92

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