THE
EFFECTS OF COMPLEMENTARY MEDICINES ON
ANTICOAGULANT THERAPY
By Dr. Daniel T. Wagner
Anticoagulants or “blood thinners” are drugs
that work in various ways to inhibit blood clotting factors like fibrinogen.
Warfarin effectively prevents recurrent thromboembolic events, and though there have been
scientists searching for a suitable alternative strategy for managing patients
with long-term anticoagulation, an acceptable one has not been found.
The Mechanism of Anticoagulants, Antifibrinolytic Agents, and Antiplatelet
Agents
A basic understanding into the mechanics
of how a clot forms, and why anticoagulant, antifibrinolytic
and antiplatlet agents are used, is essential to the
health care practitioner. When an insult
or injury occurs to the blood vessel wall (due to high-risk surgery, hip
surgery, atrial fibrillation, an MI, a mechanical
valve replacement, and/or certain types of heart diseases) there are three ways
in which the body reacts to “form” a clot or plug so that the patient does no
bleed excessively. One is via vessel
contraction, another is by collagen release, and a third by tissue thromboplastin release (see chart). The vessel contraction that occurs after a
vessel injury produces a temporary hemostatic plug
when the body releases fibrinogen. The fibrinoytic system is part of localized repair of damaged endothelium
cells as a regulatory mechanism in clot formation. Thrombin is the catalyst for converting
fibrinogen to fibrin, which induces a clot formation. When collagen is released after a injury to a vessel wall, platelet reaction is stimulated
in the body. Platelets (erythocytes found in the blood that play a role in blood
coagulation) aggregate at the site of damage, thus also produces a clot or
plug. The main channel in which a clot
is formed is via tissue thromboplastin release after
a blood vessel wall is injured. In this
cascade thromboplastin release causes coagulation
activation. However, coagulation cannot
take place without the release of vitamin K. Vitamin K aids in blood coagulation and is
necessary for the formation of prothrombin. When vitamin K is released, an enzyme prothrombin is formed, which causes the
formation of thrombin, which catalyzes the conversion of fibrinogen to fibrin
that causes coagulation. 3
Warfarin
and heparin are drugs that block the release of vitamin K in the body, thus
inhibiting coagulation activation, and suppressing the release of prothrombin to thrombin.
This is the most potent mechanism for blocking clot formation and
keeping the blood “thin.” Vitamin K
reverses the effects of warfarin. Warfarin decreases
morbidity, has a good onset and a long duration of action and has predictable
clinical effects. It is extensively
plasma-protein bound (97-99%) to albumin, has low intrinsic clearing, low
unbound fraction plasma clearance, and is increased by renal insufficiency. 14
Antiplatelet
drugs like aspirin, dipyridamole and Plavix inhibit the body’s production of platelets that will
aggregate at the site of damage, thus further blocking clot formation and
“thinning” the blood. Aspirin and warfarin increase the anticoagulant effect to the point of
bleeding. Aspirin therapy is used in
patients who have had strokes, the risk of stroke, post-MI, and TIA’s.
Thrombocytopenia occurs when severe reduction in platelet counts (due to
acute infection or shock) occurs and is a serious health complication. Thrombocytosis
occurs when there is an extraordinarily large increase in the number of
platelets, which may occur after surgery, tissue injury, or violent exhaustion.
14
The
mechanism of action of antifibrinolytic agents (Amicar, Cyklokapron, Trasylol) is to block plasmin and plasminogen binding
sites and completely inhibit fibrinogen’s conversion to fibrin. These are very potent drugs with a myriad of
risk factors including renal failure, thrombosis, and anaphylaxis shock. These drugs are used in cases of excessive
bleeding, post-surgery and in bypass surgery. 14
PT and INRs
There are two methods to effectively measure
the therapeutic range regarding warfarin levels. Although there is considerable controversy
regarding reagents and technique, the PT (Prothrombin)
test appears to be useful in monitoring treatment with oral
anticoagulants. Previous recommendation
for therapeutic anticoagulation in the United States has been 1.5 to 2.5 times
the laboratory control value of PT. This
suggested PT ratio (patient: laboratory control value) has been shown to be
clinically successful but is associated with a high risk of bleeding. 2
The
World Health Organization (WHO) has prepared a thromboplastin
standard to promote standardization of oral anticoagulant therapy. The international normalized ratio (INR) has
been introduced, which takes into account the sensitivity of thromboplastin used in determining the PT for each specific
laboratory. The current recommendation
for anticoagulant intensity is based on the circulation of INR. For the treatment of pulmonary embolism and
deep vein thrombosis, an INR of 2.0 to 3.0 (PT 1.3 to 1.6) is suggested. For recurrent systemic embolism, an INR of 3.0
to 4.5 (PT 1.6 to 1.8) is recommended. 3
With either heparin or warfarin,
the major toxic effect is hemorrhage.
Bleeding complications are proportional to the intensity of
anticoagulation and duration of therapy and are increased by the presence of
risk factors.3
There
is obvious concern that other drugs, vitamins, herbs, or supplements taken
concomitantly with warfarin could cause false INR or
PT readings. This is the main objective
of this paper.
According
to research conducted by Dupont Pharma, the
manufacturers of Coumadin, caution should be
exercised when botanical medicines (botanicals) are taken concomitantly with Coumadin. Few
adequate, well-controlled studies exist evaluating the potential for metabolic
and/or pharmacologic interactions between botanicals and Coumadin.1 Another
problem is the lack of uniform standardization of most alternative medicines in
the United States. This fact could
possibly further confound the ability to assess potential interactions and
effects on anticoagulant therapy. It is
advisable for health professionals, especially pharmacists, to monitor the
patient’s response with additional PT/INR determinations when initiating or
discontinuing botanicals.
Herbal and Botanical Considerations
Herbal
and botanical products have seen a recent boom in sales in the United
States. Most botanical medicines contain
herbal preparations, and the possibility of interactions is always increased by
using multiple herbal products or combinations of herbals together in one product. Many herbs and botanicals have coumarin constituents, fibrinolytic/coagulant
properties, and/or antiplatelet properties and may have
anticoagulant activity and thus are blood serum platelet aggregation
inhibitors. The effects may vary and be
mild, moderate or severe. Some herbals
cause increases in human blood coagulation, some are warfarin
and heparin antagonists, others reduce the absorption of the drug, some have
hemolytic activity, and many simply render false INR and PT readings. The latter can be dangerous from the
standpoint that warfarin, which has a narrow
therapeutic index, may be increased or decreased in dosage by a physician from
assessing the laboratory results. If
these are falsely positive or negative and the dosage is adjusted accordingly,
the patient may experience a life-threatening situation.
Potential
adverse reactions to warfarin that may be precipitated
by alternative medicines include fatal or nonfatal hemorrhage from any tissue
or organ, bleeding that occurs when the PT/INR are falsely affected, necrosis
of the skin and other tissues, and miscellaneous adverse reactions including
hypersensitivity/allergic reactions, purple toe syndrome, hepatitis, jaundice,
elevated liver enzymes, vaculitis, edema, fever,
rash, dermititis, urticaria,
malaise, nausea, vomiting, diarrhea, pain, headache, dizziness, pruritus, alopecia, cold and chills.6
Figure 1: Botanicals with Anticoagulant
Properties1
Admittedly,
there are relatively few reported adverse reactions associated with herbal
products when compared to prescription drugs.
There may be many reasons for this including the lack of a mechanism for
consumers to report adverse events when consuming alternative medicines, but
most likely there is a need for professional intervention for patients who take
both allopathic and alternative medicines.
Pharmacists are in a unique position to be a first-line counselor for
patients seeking information on drug/herb interactions, especially when it
comes to warfarin use. 4
The
fact that 60-67% of Americans are doing something “alternative” with their
healthcare lends to the fact that people are not going to stop taking
supplements, herbs and botanicals because they might harbor an adverse effect. On the contrary, it is more prudent to
recognize the fact that consumers like taking supplements but lack the
professional intervention to take them prudently, especially when they are on
prescription medications.
Here
are some of the main herbal products that may potentiate
adverse events when taken concomitantly with warfarin:
·
Ginkgo
(Ginkgo biloba)- Has
anticoagulant activity, inhibits platelet aggregation, and can prolong bleeding
time. Contraindicated when taken with anticoagulant drugs and antiplatelet
agents. 5
·
Garlic
(Allium sativum)- Has anticoagulant activity, inhibits platelet
aggregation, and may increase the risk
of bleeding. Contraindicated when taken with
anticoagulant drugs and antiplatelet agents.5
·
Feverfew
(Tanacetum parthenium) -
Inhibits platelet aggregation in vitro and may increase the bloodstream concentration of heparin. Has anticoagulant activity and inhibits
platelet aggregation. Contraindicated
when taken with anticoagulant drugs and antiplatelet
agents.6
·
Ginseng,
Panax (Panax ginseng)- Has anticoagulant activity, inhibits platelet
aggregation, and is reported to alter levels of warfarin
in vivo. May cause a reduction in blood coagulation. Use with caution. 7
·
Green
Tea (Camellia sinensis) - Has anticoagulant activity,
inhibits platelet aggregation and thromboxone formation. Drink sparingly when taking warfarin.7
·
Horse
Chestnut (Aesculus hippocastanum)
- Has anticoagulant activity (via coumarin constituents) and inhibits platelet
aggregation.7
·
Guggul
(Commiphora mukul)- Has
anticoagulant and antiplatelet activity due to
inhibition of platelet aggregtion.7
·
Cat’s
Claw (Uncaria tomentosa) - has
anticoagulant and antiplatelet activity. Use with caution.7
·
Ginger
(Zingiberis rhizoma) - Inhibition
of platelet activity. Use with caution.8
·
Chamomile
(Matricariae flos)- Has coumarin constituents. Use
with caution.8
·
Fenugreek
Seed (Foenugraeci semen) - Has coumarin
constituents. Use with caution.8
·
Pau
d’arco (Tabebuia impetiginosa)- Has coumarin constituents. Use with caution.8
·
Licorice
root (Liquiritiae radix)- Inhibition
of platelet activity. Use with caution.8
·
St
John’s wort (Hypericum) - Associated
with a decrease in the effectiveness of warfarin.1
Nutritional Considerations
One
of the first dietary aspects that arise when a patient is prescribed warfarin (Coumadin) is to avoid
or limit foods that are high in vitamin K content. Vitamin K levels are inversely proportional
to the efficacy of drugs such as anticoagulants.9 Vitamin K is found
in broccoli, brussel sprouts, spinach, cauliflower,
green leafy vegetables, and egg yolks.10 This does not mean that the
patient needs to avoid these foods entirely (especially salads), but they
should be consumed in sensible moderation and keep to a steady level of the
dietary amounts of these foods. Keep in
mind that vitamin K is necessary in blood clotting (a protective mechanism of
the body) and small amounts are essential to survival or a patient could easily
bleed to death. Eat a normal, balanced diet that is low-fat
and high fiber, where maintaining a consistent amount of vitamin K. Avoid drastic changes in dietary habits, such
as eating large amounts of leafy green vegetables. Avoid eating more than 60 grams of onions a
day, which can have fibrinolytic activity. Avoid excess
garlic, ginger and avocado.11
Figure 2:
Average Vitamin K Content of Selected Foods (Estimated Safe and Adequate Daily
Dietary Intake for Adults:70-140 µg)1
Coenzyme
Q10 (ubidecarenone) resembles vitamin K (chemically)
and may also reduce the effectiveness of warfarin
treatment.9 If the patient is
already on Coenzyme Q10 therapy before initiating warfarin
therapy, then discontinuing supplementation of CoQ is
not recommended. However, for a patient
originally starting warfarin dosing, it is advisable
not to initiate CoQ supplementation. The minerals calcium, magnesium, and
potassium play a crucial role in moderating heart activity. Too little of these
minerals can cause arrhythmias. (And too much can also be a problem, especially
with calcium.) Magnesium administered intravenously can correct tachycardia and
many other arrhythmias. You can get dietary magnesium from nuts, beans,
soybeans, bran, dark green vegetables, and fish. Many fruits and vegetables
supply potassium. Be aware that you can deplete your stores of magnesium and
potassium by ingesting too much salt or saturated fat, as well as by overusing
diuretics or laxatives.11
Absorption and activity of warfarin may be
decreased by iron, magnesium, and zinc.
Use of these minerals, either in a multi-vitamin/mineral form or separately,
should be spaced at least two hours apart from the use of anticoagulants.9 It would be best for a patient taking a
multi-vitamin/mineral formula to choose one without vitamin K.
Vitamin
E has been shown to improve circulation in the coronary and peripheral blood
vessels as well as lowering total blood cholesterol levels; both high
cholesterol and poor circulation are risk factors for heart disease. 12 Vitamin
E supplements are safe and beneficial for most people (up to 1000 IU/day)-but
there is a caveat when taking it with an anticoagulant drug. Vitamin E, like aspirin, acts as a blood
thinner, and because vitamin E may promote bleeding, it shouldn’t be taken
prior to surgery, and should be taken in smaller doses when taken along with an
anticoagulant drug. Multiple vitamins
usually contain smaller amounts of vitamins E (40-100 IU). It would be safe to consider recommending
that a patient on anticoagulant therapy not exceed a daily intake of 100-200 IU
of vitamin E.13
Warning Signs
Warfarin has a narrow therapeutic range (index),
and caution should always be observed when this drug is administered to any
patient, especially the elderly, the disabled, or a person with any physical
condition where added risk of hemorrhage is present. Since warfarin
therapy must be individualized for each patient according to the particular
patient’s PT/INR response to the drug, practically any drug, herb, nutrient, or
food may lead to complications or even danger.
Always contact the physician to report any
illness, such as diarrhea, fever, or infection.
Notify the physician immediately if any unusual bleeding or symptoms
occur. Signs and symptoms of bleeding include: pain, swelling or discomfort,
prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding,
nosebleeds, bleeding from gums from brushing, unusual bleeding or bruising, red
or dark brown urine, red or tar black stools, headache, dizziness, or weakness.1
Patients taking non-steroidal anti-inflammatory drugs (NSAIDS) should consult
their physician if they have a bleeding disorder or are taking anticoagulant
therapy.
The
pharmacist is the best suited health professional to counsel both patients and
other health professionals on the concomitant use of prescription and
alternative medicines. The fact that
many complementary herbs, botanicals, nutrients, and even foods have a negative
effect on warfarin is a fact that all pharmacists
should be aware of. It is not practical
to just say “no” to all alternative medicines in conjunction with warfarin, because there are a myriad of supplements that
help patients in many other ways. Herbs,
botanicals, and vitamins have an important place in health. If a patient is not on warfarin,
then an herb like ginkgo biloba works exceedingly
well to help remove plaque from the arteries. It can be used effectively in
such conditions as claudication (painful walking), Meniere ’s syndrome, and Alzheimer’s Disease. However,
knowing the interaction between ginkgo and warfarin
and alerting the patient could save their life.
If a patient slowly is weaned off warfarin
therapy by the physician, then perhaps ginkgo would be a suitable herb to
introduce at a later time.
If American pharmacists were more astute in the
area of alternative medicines and therapies, then perhaps this problem would
not be so poignant. The public should
be alerted to always talk to their pharmacist or physician before taking any
supplement along with prescription drugs.
The onus is on the practicing pharmacist to better educate himself or herself in this timely area of specialization and
on the nation’s schools of pharmacy to better train their students to be the
“experts” in all areas of medicine- allopathic and/or alternative.
References
1.
Coumadin
[package insert]. Wilmington, Delaware. Dupont Pharma.
Jan. 2001.
2.
DePiro,
JT. Pharmacotherapy: A Pathophysiologic Approach.
2nd edition. 1993. Appleton & Lange, Norwalk, CT. p.324.
3.
Ibid, DePiro,
p. 325.
4.
LaValle,
JB. Potential Herb/Drug Interactions. America’s Pharmacist. April 2000. pp.
29-31.
5.
Anticoagulants:
Warfarin. Natural Digest. 2(5). p. 16.
6.
Blumenthal,
M. (Ed.): The Complete German Commission E
Monographs: Therapeutic Guide to Herbal
Medicines. American Botanical Council, Austin, TX.
1998.
7.
Ibid, LaValle.
p. 31.
8.
Ibid, Blumenthal.
p. 3.
9.
Nutriceutica [Computer information program]. Version
2001b. Van Nuys, CA: The JAG Group; 1999.
10.
Anticoagulants: Warfarin.
Natural Digest. 2(5). p.23.
11. Health Center. WebMD Corporation. 2001. Available
at: http://www.webmd.com Accessed:
August 12, 2001.
12.
Mann, D.
Vitamin E to the Rescue. Better
Nutrition. August 1999.
13.
Reader’s Digest. Why You Need Vitamin E.
Reader’s Digest Association, Inc., Pleasantville, NY. August, 1998.
14. Ihnat, MA.
Anticoagulant Notes. Pharm.D. Class 424 level. Duquesne University,
2000.
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