Patient survey data from Canada, the U.S., and Australia show that one in five patients use prescription drugs concurrently with CAM. The inherent polypharmaceutical nature of complementary and alternative medicine increases the risk of adverse events if these complementary and alternative medicine either have pharmacological activity or interfere with drug metabolism. Since confirmed interactions are sporadic and based largely on case reports, advice to avoid certain drug-CAM combinations is based on known pharmacological and in vitro properties.
Known Hypersensitivity to Asteraceae
Cross-reactive sesquiterpene lactones are present in many, if not all, Asteraceae. Patients with known CAD from one plant may develop similar type IV reactions following contact with others. Affected patients are often advised to avoid contact with all Asteraceae, yet this advice is based on limited knowledge of cross-reactivity between relatively few members of this large family.
Some authorities recommend avoiding Asteraceae-derived complementary and alternative medicine if, for example, the patient is known to have IgE-mediated inhalant allergy to ragweed. While a reasonable approach, this ignores a number of important facts: (1) many atopic patients are unaware of their sensitization “profile”; (2) the degree of cross-reactivity among over 20,000 species of Asteraceae, and between Asteraceae and superficially unrelated plants, remains undefined; (3) even patients without defined sensitization to inhaled Asteraceae may react to complementary and alternative medicine like Echinacea; and (4) atopies are more likely than other patients to suffer allergic reactions to CAM, even with first known exposure. It thus seems more prudent to advise caution in all (not just a subset) of atopic subjects.
The presence of pyrrolizidine alkaloids in Echinacea together with reports of hepatitis have led to advice to avoid potentially hepatotoxic medication in combination with Echinacea, such as anabolic steroids, methotrexate, ketoconazole, or amiodarone. Perhaps more important is the potential for all of these substances to influence drug metabolism by inhibiting hepaticCYP3A4 activity.
Interference with Hepatic CYP3A4 Enzyme Activity
CYP3A4 is one of approximately 50 individual cytochrome P450 enzymes playing an important role in drug metabolism, an activity inhibited by Echinacea, milk thistle, and chamomile. In theory, these products could interfere with metabolism of medications such as calcium channel blockers, antihistamines, or antiretroviral agents as summarized in Table Medications Interacting with CYP3A4. Potential interactions are even more important when using medications like amiodarone, cisapride, carbamazepine, cyclosporine, warfarin, or antiretroviral agents, all of which have narrow therapeutic windows.
TABLE Medications Interacting with CYP3A4
Alprazolam, amiodarone, amitriptyline, astermizole, atorvastatin, budesonide, buprenorphine, busulphan, carbamazepine, cisapride, clarithromycin, clomipramine, clonazepam, clozapine, cocaine, cortisol, cyclophosphamide, cyclosporin, dapsone, dexamethasone, dextromethorphan, digitoxin, diltiazem, diazepam, doxorubicin, erythromycin, ethinyloestradiol, ethosuximide, etoposide, felodipine, fentanyl, fexofenadine, flutamide, ifosfamide, imipramine, indinavir, ketoconazole, loratadine, losartan, lovastatin, miconazole, midazolam, nifedipine, nelfinavir, oestradiol, omeprazole, ondansetron, paclitaxel, propafenone, quinidine, ritonavir, saquinavir, sertraline, simvastatin, tacrolimus, tamoxifen, teniposide, tetrahydrocannabinol, theophylline, trazadone, troleandomycin, verapamil, vinblastine, vincristine, warfarin
Amiodarone, cannabinoids, cimetidine, clarithromycin, clotrimazole, delavirdine, diltiazem, erythromycin, fluoxetine (due to norfluoxetine metabolite), fluvoxamine, grapefruit juice, itraconazole, ketoconazole, metronidazole, miconazole, nefazodone, paroxetine, protease inhibitors, troleandomycin
Feverfew inhibits cyclooxygenase and phospholipase A2, potentially increasing the risk of bleeding while taking oral anticoagulants or aspirin. Chamomile contains coumarins that may potentiate warfarin activity.
Autoimmune Disease and Chronic Infection
Because of its purported short-term immunostimulatory effect, some authorities recommend that Echinacea be avoided in patients with autoimmune disease (e.g., systemic lupus erytematosus, multiple sclerosis), or in those with chronic HIV infection or tuberculosis. Such statements are not evidence based. For example, while Echinacea-associated TNF release might conceivably aggravate rheumatoid arthritis, it could actually benefit patients with active tuberculosis, where TNF appears to exert a protective role.
Tissue Transplantation and Surgery
Because of its purported immunostimulatory effect, it is commonly recommended that Echinacea be avoided in patients undergoing organ transplantation, to reduce the risk of rejection. Similarly, Echinacea is thought to inhibit wound healing and thus might interfere with surgical recovery. Medications with a potential anticoagulant effect such as feverfew or chamomile should probably also be avoided.
Interaction with Alcohol, Diuretics, and Hypoglycemic Agents
Combining alcohol-containing tinctures of Echinacea with disulfuram or metronidazole is not advised by some authorities, although the amounts of alcohol ingested are such that the risk is remote. Artichoke and dandelion are purported to have diuretic activity and the latter may have some hypoglycaemic activity as well.