Herb-Drug Interactions in Chronic Conditions
Herb-Drug Interactions in Chronic Conditions
By Dennis V.C. Awang, PhD, and Adriane Fugh-Berman, MD
Many reviews of herb-drug interactions in the medical literature include inadequately documented case reports, or theoretical extrapolations from in vitro activity. This review will focus on well-documented, potential drug interactions in those individuals with chronic diseases, particularly cardiovascular disease and diabetes. St. John’s wort interactions are covered in the companion article (see page 60).
Anticoagulant/Antiplatelet Interactions
Warfarin and other coumarin anticoagulants interact with many drugs, foods, and medicinal herbs. Both garlic (Allium sativum) and ginkgo (Ginkgo biloba) interfere with platelet function in vitro and may increase the risk of bleeding when combined with warfarin. Garlic inhibits platelet aggregation and fibrinolytic activity in both patients with coronary artery disease1 and healthy subjects,2 and has been associated with postoperative bleeding3,4 and spontaneous spinal epidural hematoma.5 In ginkgo, the constituent ginkgolides are potent antagonists of platelet activating factor. Ginkgo also has been associated with spontaneous bleeding, even in the absence of anticoagulant drugs.6
Many medicinal herbs contain anticoagulant coumarins (not all coumarins are anticoagulant), which can also have additive effects when combined with pharmaceutical anticoagulants.6 A Chinese herb, danshen (Salvia miltiorrhiza), has been associated with three cases of profound anticoagulation in patients on warfarin.6 Dong quai, or danggui (Angelica sinensis, syn A. polymorpha), another Chinese herb, doubled prothrombin time (PT) and International Normalized Ratio (INR) in a 46-year-old African-American woman, previously stabilized on warfarin, who had ingested dong quai for four weeks. Laboratory values normalized within one month of discontinuing the herb.7 In rabbits, dong quai extract affected neither baseline PT nor warfarin pharmacokinetics.8 Given the case reports, however, caution would dictate that patients avoid combining dong quai with warfarin.
In one poorly documented case report, the anticoagulant effect of warfarin was potentiated by consuming an extract of the green fruit of papaya (Carica papaya).9 Green papayas, high in papain, are commonly consumed in Southeast Asia.
Seven cases of decreased INR associated with concomitant use of St. John’s wort and warfarin have been reported.10 INR returned to target values after discontinuing St. John’s wort.
Although feverfew (Tanacetum parthenium) and ginger (Zingiber officinale) often are invoked as anticoagulant herbs in the literature, no cases of bleeding problems have been linked to these herbs. Although feverfew extracts and its sesquiterpene lactone constituents, notably parthenolide, inhibit platelet aggregation by inhibiting serotonin release,11 neither bleeding episodes nor abnormal coagulation tests have been reported. Although ginger inhibits platelet aggregation induced by arachidonic acid, epinephrine, adenosine diphosphate, and collagen,12 and a case report associated consumption of a marmalade containing 15% raw ginger with inhibited platelet aggregation,13 clinical studies are reassuring.
Three clinical trials designed to look at bleeding risk have been performed with ginger, more than with any other herb. A placebo-controlled crossover trial tested the effect of 2 g of dried ginger on eight men; ginger did not affect bleeding time, platelet count, or platelet function at three or 24 hours after ingestion.12 Another crossover trial in 18 healthy volunteers (including nine women) compared the effect of two weeks administration of placebo, 15 g raw ginger root, or 40 g cooked ginger stem.14 There was no significant effect of any dose on platelet cyclooxygenase activity. Very high doses of ginger, however, may affect platelets. A placebo-controlled trial found that a single 10 g, but not 4 g, dose of powdered ginger in patients with coronary artery disease significantly reduced platelet aggregation.15 Consumption of dried ginger should be limited to 4 g/d.
One case of decreased INR when Asian ginseng (Panax ginseng) was combined with warfarin has been reported.16 A subsequent in vivo study in rats found neither pharmacodynamic nor pharmacokinetic interactions of single-dose or steady-state ginseng upon warfarin.17 Until this situation is clarified, patients on coumarin anticoagulants should either refrain from consuming ginseng or have bleeding times regularly monitored.
Hypertension
Consuming yohimbe (Pausinystalia yohimbe) bark or extracts increases the risk of hypertension. The constituent alkaloid, yohimbine (used conventionally to treat erectile dysfunction), increases blood pressure more in hypertensive than in normotensive subjects.18 Hypertensive effects are potentiated when yohimbine is combined with tricyclic antidepressants.19
Ephedra or ma huang (Ephedra sinica, E. equisetina, E. intermedia) has been associated with numerous reports of adverse cardiovascular effects including hypertension, palpitations, tachycardia, seizure, and stroke.20 Coadministration of ephedra preparations with monoamine oxidase (MAO) inhibitors can lead to life-threatening hypertension.21
Digoxin Interactions
Foxglove (Digitalis purpurea) and other herbs contain cardiac glycosides that could have an additive effect with digitaloid cardiac glycosides,22 but these are not commonly used medicinal herbs. The only reported case of an herb-drug interaction associated with digitalis proved to be interference between a preparation purported to contain Siberian ginseng (eleuthero) (Eleutherococcus senticosus) and the digoxin assay, causing spuriously elevated digoxin levels.23
Diabetes
Glucose control in both insulin-dependent (Type 1) and non-insulin dependent (Type 2) diabetics can be affected by consumption of hypoglycemic herbs.
Ginseng clearly has a hypoglycemic effect (see Alternative Therapies in Women’s Health, March 2002). More than 400 plants have been traditionally used for their hypoglycemic action;24 of these, Aloe vera, syn. A. barbadensis, leaf juice;25 the fruit of bitter melon/karela (Momordica charantia) (found to improve glucose tolerance without increasing insulin levels);26,27 and the seeds of fenugreek (Trigonella foenum-graecum),28 are commonly used herbs with documented hypoglycemic effects. Also, two clinical studies with a water-soluble acidic fraction of an ethanol extract of gurmar (Gymnema sylvestre) leaves have reportedly reduced insulin requirements in both insulin-dependent and non-insulin-dependent diabetics,29,30 effects comparable to those observed with Aloe vera juice and glibenclamide.31 The anti-diabetic effect of fenugreek is attributed to intestinal effects of the gum fiber (galactomannans), which also displays hypocholesterolemic activity.28
There have been no reported cases of adverse events attributed to combining hypoglycemic herbs and drugs. While additive effects are certainly possible, appropriate self-monitoring by the patient and clear lines of communication between the patient and health care practitioner should avert problems.
Laxative Herbs and Drugs
Bulk-forming laxative herbs, such as the hydrocolloidal-fiber-containing guar (Cyamopsis tetragonolobus) gum, psyllium (Plantago spp.), konjac (Amorphophallus rivieri), and others, taken in sufficient quantity can delay gastric emptying and reduce the rate of absorption of carbohydrates and drugs, including lithium,32 glibenclamide,33 lovastatin,34 tricyclics,35 and digoxin.36
Laxative herbs that contain stimulant anthranoids, including senna species (Cassia senna, C. acutifolia, and C. angustifolia), Chinese rhubarb (Rheum officinale), cascara sagrada (Rhamnus purshiana), frangula or alder buckthorn (Rhamnus frangula), yellow dock (Rumex crispus), and drug aloe, the leaf exudate of Aloe vera, can decrease the absorption of intestinally absorbed drugs due to an increased rate of intestinal transit.37
Summary and Recommendations
Although it would be prudent to be aware of the potential for adverse health effects resulting from combining herbal medicines with orthodox drugs, there are relatively few conditions for which a clear danger has been established.
Patients on anticoagulants should avoid the use of ginkgo, ginseng, dong quai, and danshen; those who consume other herbs whose pharmacology suggests anticoagulant potential, should have their bleeding times monitored.29 Anyone on critical chronic medication should not take St. John’s wort, because it reduces the bioavailability of many drugs. The effect of herbal laxatives in decreasing absorption also should be borne in mind.
References
1. Bordia A, et al. Effect of garlic (Allium sativum) on blood lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids 1998;58:257-263.
2. Legnani C, et al. Effects of a dried garlic preparation on fibrinolysis and platelet aggregation in healthy subjects. Arzneimittelforschung 1993:43:119-122.
3. German K, et al. Garlic and the risk of TURP bleeding. Br J Urol 1995;76:518.
4. Burnham BE. Garlic as a possible risk for postoperative bleeding. Plast Reconstr Surg 1995;95:213.
5. Rose KD, et al. Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic consumption: A case report. Neurosurgery 1990; 26:880-882.
6. Fugh-Berman A, Ernst E. Herb-drug interactions: Review and assessment of report reliability. Br J Clin Pharmacol 2001;52:587-595.
7. Page RL 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy 1999;19:870-876.
8. Lo ACT, et al. Danggui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits. Eur J Drug Metab Pharmacokinet 1995;20:55-60.
9. Shulman A. Toxicological problems of traditional remedies and food supplements. Int J Altern Complement Med 1997; Jan:9-10.
10. Yue QY, et al. Safety of St. John’s wort (Hypericum perforatum). Lancet 2000;355:576-577.
11. Groenewegen WA, Heptinstall S. A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew on human platelet activity in-vitro. J Pharm Pharmacol 1990;42:553-557.
12. Lumb AB. Effect of dried ginger on human platelet function. Thromb Haemost 1994;71:110-111.
13. Dorso CR, et al. Chinese food and platelets [letter]. N Engl J Med 1980;303:756-757.
14. Janssen PL, et al. Consumption of ginger (Zingiber officinale Roscoe) does not affect ex vivo platelet thromboxane production in humans. Eur J Clin Nutr 1996;50:772-774.
15. Bordia A, et al. Effect of ginger (Zingiber officinale Rosc.) and fenugreek (Trigonella foenumgraecum L.) on blood lipids, blood sugar and platelet aggregation in patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids 1997;56:379-384.
16. Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health Syst Pharm 1997;54: 692-693.
17. Zhu M, et al. Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats. J Pharm Pharmacol 1999;51:175-180.
18. De Smet PAGM. Yohimbe alkaloids—general discussion. In: De Smet PAGM, et al, eds. Adverse Effects of Herbal Drugs. Vol. 3. Berlin: Springer; 1997:181-206.
19. Lacomblez L, et al. Effect of yohimbine on blood pressure in patients with depression and orthostatic hypertension induced by clomipramine. Clin Pharmacol Ther 1989;45: 241-251.
20. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000; 343:1833-1838.
21. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 8th ed. New York: MacMillan; 1993:213-214.
22. Brinker F. Interactions of pharmaceutical and botanical medicines. J Naturopath Med 1997;7:14-20.
23. McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. CMAJ 1996;155:293-295.
24. Bever VO, Zahnd GR. Plants with oral hypoglycaemic action. Q J Crude Drug Res 1979;17:139-196.
25. Yongchaiyudha S, et al. Antidiabetic activity of Aloe vera L. juice. 1. Clinical trial in new cases of diabetes mellitus. Phytomedicine 1996;3:241-243.
26. Welihinda J, et al. Effect of Momordica charantia on the glucose tolerance in maturity onset diabetes. J Ethnopharmacol 1986;17:277-282.
27. Leatherdale BA, G et al. Improvement in glucose tolerance due to Momordica charantia (karela). BMJ 1981;282: 1823-1824.
28. Al-Habori M, Raman A. Antidiabetic and hypocholestrolaemic effects of fenugreek. Phytother Res 1998;12:233-242.
29. Shanmugasundaram ERB, et al. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus. J Ethnopharmacol 1990;30:281-294.
30. Baskaran K, et al. Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin-dependent diabetes mellitus patients. J Ethnopharmacol 1990;30:295-300.
31. Bunyapraphatsara N, et al. Antidiabetic activity of Aloe vera L. juice. II. Clinical trial in diabetes mellitus patients in combination with glibenclamide. Phytomedicine 1996;3: 245-248.
32. Perlman BB. Interaction between lithium salts and isphagula husk. Lancet 1990;335:416.
33. De Smet PAGM, D’Arcy PF. Drug interactions with herbal and other non-orthodox remedies. In: D’Arcy PF, et al, eds. Mechanisms of Drug Interactions. Berlin: Springer-Verlag; 1996.
34. Richter WO, et al. Interaction between fiber and lovastatin. Lancet 1990;335:416.
35. Stewart DE. High-fiber diet and serum tricylic anti-depressant levels. J Clin Psychopharmacol 1992;12:438-440.
36. Brown DD, et al. Decreased bioavailability of digoxin due to hypocholesterolemic interventions. Circulation 1978;58: 164-172.
37. Westendorf J. Anthranoid derivatives—general discussion. In: DeSmet PAGM, et al, eds. Adverse Effects of Herbal Drugs. Vol.2. Berlin: Springer; 1993:105-118.
Awang DVC, Fugh-Berman A. Herb-drug interactions in chronic conditions. Altern Ther Women's Health 2002;4:57-60.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.