Persons with HIV infection are often taking three, four or even more antiretroviral medications. In addition they may be taking a number of drugs to prevent or treat opportunistic infections, or other medical conditions they may have. Most people taking complicated antiretroviral regimens are aware that these drugs may interact with each other, or other medications they may be taking. What many do not realize however, is that their HIV medications may interact with herbal treatments or supplements. While sometimes these interactions are beneficial, they may also be detrimental, causing either decreased effectiveness or increased toxicity of the HIV medications. As an example, St. John’s wort (Hypericum perforatum), a popular herb used to treat depression, was recently found to have an important interaction with Crixivan (indinavir), a protease inhibitor (see complementary therapies, pages 24-26). St. John’s wort decreased indinavir drug levels, which could potentially lead to antiretroviral resistance or treatment failure. The same effect has been shown with drugs similarly metabolized, like cyclosporin, a medication used to prevent organ rejection after transplantation. St. John’s wort has been shown to decrease levels of this drug, which could potentially result in transplant rejection. The consequences of drug interactions can sometimes be serious.

In the absence of specific information on interactions between herbs and antiretrovirals, it helps to know something about the mechanisms responsible for these interactions. Drug interactions occur by 4 major mechanisms.

1. Altered drug absorption
2. Altered renal (kidney) elimination of drugs
3. Additive effects or toxicities (pharmacodynamic interaction)
4. Altered hepatic (liver) metabolism of drugs

The first three account for a relatively small number of problems, while the fourth is the major culprit in drug interactions with HIV medications. The potential seriousness of a drug interaction depends in part on which drugs are involved. Some drugs have what is called a "narrow therapeutic margin" which means that there is a relatively small difference between the amount of drug needed to achieve its beneficial effect and that causing adverse or unwanted effects. Classic examples of drugs falling in this category are anticoagulants (blood thinners like warfarin), which can cause bleeding if the relative amount of drug is increased as a result of a drug interaction, anticonvulsants (anti-seizure medications such as phenytoin) and the heart drug digoxin.

1) ABSORPTION

When drugs are given orally they are usually absorbed into the bloodstream through the stomach. Changes in drug absorption may be due to alterations in pH, or acidity of the stomach, or by drugs binding together in the stomach to form complexes which cannot then be absorbed, for example because the molecule is too large to pass through the intestinal wall. Common examples include antacids, which increase stomach pH, and iron supplements, which can bind to some antibiotics, such as ciprofloxacin or tetracycline.

Another issue for absorption is the "motility of the gastrointestinal tract", in other words, how fast or slow your guts are moving. If you have diarrhea, the drugs or herbs are moving through your system quickly and may have less time to be absorbed. Laxatives or bulk-forming agents speed up intestinal transit, and might interfere with intestinally absorbed drugs. Common stimulant laxative herbs are anthranoid-containing plants like senna, frangula, yellow dock and Chinese rhubarb, as well as cascara sagrada and aloe vera leaf. Bulk-forming agents include guar gum and psyllium. The clinical significance of these interactions is not clear.

2) ELIMINATION

Drug interactions due to alterations in elimination of drugs through the kidney can only occur if a drug is primarily eliminated from the body through the kidney. If a drug or herb causes decreased kidney function, levels of the drugs eliminated through the kidneys may be increased as a result. Few drugs used to treat HIV infection fall in this category-foscarnet, which is used to treat cytomegalovirus infections is an example of a drug used in HIV therapy that may be toxic to the kidney. Herbs containing diuretic properties, such as cornsilk, dandelion, and juniper can increase the toxicity of lithium, a drug used to treat bipolar disorder.

3) PHARMACODYNAMIC INTERACTIONS

Some drugs (and herbs) that may be given together have similar beneficial effects, or similar toxic effects- this is called a pharmacodynamic interaction. For example, two antiretroviral drugs may both cause the side effects of peripheral neuropathy, increasing the likelihood of that side effect developing. Many drug-herb interactions fall in this category. For example herbs that have sedative properties, such as kava, nettle and sage may increase the sedative effects of some sleeping medications. Herbs that have antiplatelet activity, such as ginkgo biloba, ginger, ginseng, and garlic may increase the risk of bleeding in patients taking traditional drugs with antiplatelet activity or blood thinners. Herbs that can increase blood pressure, such as blue cohosh, ginger, licorice and bayberry can interfere with the effectiveness of drugs used to treat high blood pressure.

4) LIVER METABOLISM

The most complicated drug interactions, and those with the greatest significance for antiretroviral medications, are those resulting in altered liver metabolism of drugs. The activity of liver enzymes which are responsible for breaking down drugs can be increased (induced) or decreased (inhibited) by drugs or herbs. St. John’s wort is an example of an inducer - by increasing the rate of metabolism of indinavir, the blood levels, and effectiveness, of indinavir may be decreased. Many antiretroviral medications are enzyme inducers, enzyme inhibitors, or even both at the same time! The resulting drug interactions are complex, and not always predictable.

Ritonavir, a protease inhibitor, is a powerful inhibitor of liver metabolizing enzymes, and can dramatically increase the blood levels of other drugs metabolized by the same enzymes. This interaction can be used to our benefit, so that lower doses of the drugs affected are required to achieve the same effect. If dose adjustments are not made however, toxic levels of the affected drug could result. Nevirapine, another antiretroviral is an enzyme inducer, and can decrease the blood levels of other drugs metabolized by the same enzymes. If we know how each drug is metabolized and how it affects metabolizing enzymes, we can predict the response and be prepared.

Many drugs in a wide variety of therapeutic categories are metabolized by liver enzymes and subject to this type of interaction. These include drugs used to treat anxiety and insomnia (diazepam and some of its relatives), drugs used to treat depression, some antiarrhythymics (used to treat abnormal heart rhythms), oral contraceptives, painkillers and recreational drugs. For this reason everybody who is treating you should know what drugs (traditional and recreational) or herbs you are taking.

Unfortunately there is little information available on how most herbal products are metabolized, or how they affect the liver’s ability to metabolize other drugs. Many herbs have multiple ingredients and each may have a different effect, complicating the issue even more. One thing that is known is that the most important pathway for drug metabolism is the family of enzymes known as cytochrome P-450. More than 50% of metabolized drugs are substrates for (metabolized by) the 3A4 enzyme, and this enzyme is certainly the most common for HIV drugs. Common herbals and foods that are known to interact with the CYP system and potentially alter the rate at which many drugs are metabolized are: grapefruit juice (a powerful inhibitor) and St. John’s wort, cruciferous vegetables like brussel sprouts, cabbage and broccoli, red wine, ethanol, cigarette smoke and charcoal grilled beef (all inducers). Of these, only grapefruit juice and St. John’s wort have been specifically shown to cause problems.

COMMON MEDICINAL PLANTS REPORTED TO INTERACT WITH PHARMACEUTICALS

A recently published comprehensive search of interactions between commonly used medicinal plants and pharmaceutical drugs published in clinical reports suggest potential interactions with the following herbals: betel nut; chili pepper (capsicum); Danshen; Devils claw; dong quai; eleuthero or siberian ginseng; garlic; gingko; ginseng, guar gum, harela or bitter melon, liquorice, papaya, psyllium, St. John’s wort; Saiboku-to (Asian herbal mixture); Shankhaspushpi (Ayurvedic mixed-herb syrup); Sho-saiko-to or xiao chai hu tang (Asian herbal mixture); tamarind; valerian; and yohimbine.