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Gay Men's Health Crisis
AIDS Drug Interactions: Part I
Gabriel Torres, M.D.
August 1, 1994
GMHC Treatment Issues 1994 Jul 1; 8(6): 3

People with HIV commonly take several medications at the same time to fight both HIV and its related conditions. These drugs can interact with each other, leading to more toxic side effects and reduced effectiveness.

Some drug-drug interactions are related to the way drugs are absorbed by the gastrointestinal system. Absorption is highly dependent on stomach acidity and the rate of absorption, which may be affected by bouts of diarrhea. Drugs that are not absorbed well will not achieve sufficient levels in the blood to exert their effect. This can also happen if a coincident therapy increases or decreases the excretion or metabolism of the first drug.

Drugs with similar toxic effects, such as bone marrow suppression (myelosuppression), will usually result in combined toxicity. This can preclude taking both drugs together.

We will focus below on the most common drug-drug interactions. Readers can concentrate on the sections of greatest personal interest. Remember that there are thousands of other potential interactions that may or not be important for patients with HIV infections.

In this issue we cover interactions among antiretroviral drugs and drugs for PCP and fungal infections. Next month: drug interactions for toxoplasmosis, TB, MAC and CMV medications.

Antiretroviral Drugs 1. AZT (zidovudine, Retrovir): AZT's antiretroviral effects vary according to the levels achieved in the blood. Drugs that decrease AZT concentrations may result in a suboptimal antiretroviral effect. Insufficient viral inhibition and lack of a CD4 response may be a sign of this problem. Examples of drugs that lower AZT levels include rifabutin and clarithromycin, the two most common agents used for MAC prevention.

Other drugs may increase the amount of AZT in the blood. This reinforces AZT's suppression of bone marrow. The usual result is increased hematologic toxicity, i.e. such effects in the blood as anemia (low red blood cell counts) and neutropenia (low numbers of neutrophils, a type of infection-fighting white blood). Examples of drugs that increase AZT levels are Bactrim, fluconazole and probenecid.

Drugs with similar hematologic toxicity as AZT have to be used with caution, since if given together, they may lead to enhanced anemia or neutropenia. These drugs include ganciclovir, Bactrim, interferon, dapsone, sulfadiazine, pyrimethamine, pentamidine, flucytosine, and chemotherapies such as doxorubicin.

The combination of AZT and ganciclovir in particular is poorly tolerated due to the combined hematologic toxicity. In one study of patients receiving ganciclovir for CMV disease, 82 percent of those also treated with AZT developed hematologic side effects (anemia and neutropenia), which ranged from severe to life-threatening.[1] 2. ddI: Didanosine (Videx): ddI is another antiretroviral drug, which is used as a second-line agent for those who are intolerant to or failing AZT, or who have been on prolonged AZT therapy, where the drug may have lost its effect. ddI has the disadvantage that to be absorbed, it requires a buffer to counteract the stomach's acidity. Conditions or drugs that increase stomach acidity will lead to decreased absorption and lower blood levels. Substances that boost gastric acidity include acidulin, citrus juices and Coca-Cola.

The converse is also true: drugs that decrease gastric acidity will increase ddI's absorption and blood levels and heighten the risk of pancreatic damage (pancreatitis), neuropathy and other ddI side effects. Examples of drugs that lower gastric acidity are Tagamet, Pepcid, Zantac, Axid and Prilosec as well as antacids like Maalox, Mylanta, Tums, Rolaids and Riopan.

In addition, alcohol and oral ganciclovir both make ddI- associated pancreatitis more likely. Other drugs that make ddI-associated neuropathy more likely include vincristine, vinblastine, ddC, d4T, alcohol, Flagyl, INH and dapsone. The buffer that ddI comes mixed with can have negative effects on those drugs needing stomach acid for their absorption. These include: dapsone, ketoconazole, tetracyclines, ciprofloxacin, and ofloxacin. The lowered blood levels of these antibiotics will erase their therapeutic effect. The present recommendation is to schedule these antibiotics at least two hours before ddI.

3. ddC (zalcitabine, Hivid): ddC has relatively few drug-drug interactions, though it should not be given with other drugs that induce peripheral neuropathy. The risk of developing painful neuropathy is increased if ddC is taken at the same time as medications like ddI, vincristine, Flagyl and, to a lesser extent, INH and dapsone. The risk of pancreatitis with ddC is less than one percent, yet caution is still recommended when administering it in the presence of other pancreatitis- inducing drugs and alcohol.

4. d4T (stavudine, Zerit): d4T, like ddI and ddC, causes peripheral neuropathy and (less commonly) pancreatitis. Physicians should monitor the drug- drug interactions with the agents mentioned above that contribute to these conditions.

Drugs for PCP 1. Bactrim and Septra (trimethoprim-sulfamethoxazole combination, or TMP/SMX): This commonly used combination of antibiotics for the prevention and treatment of PCP has a variety of interactions and toxicities that need to be monitored. The most common side effect associated with the sulfa component is a skin rash, which is usually allergic in nature. It is also known that the drug can greaten the skin's sensitivity to ultraviolet light, and so excessive exposure to the sun should be avoided while taking the drug. Common drugs that have been reported to interact with TMP/SMX's liver effects include Coumadin (an anticoagulant) and Dilantin (an anticonvulsant).

Elevated potassium levels sometimes also occur when on TMP/SMX. High potassium may lead to abnormal heart rhythms and contractions. In the presence of kidney disease, TMP/SMX can accumulate and cause greater toxicity. Kidney-toxic drugs (e.g., amphotericin, foscarnet and aminoglycoside antibiotics (amikacin, gentamicin, paromomycin, streptomycin, etc.) pose a special problem for people taking TMP/SMX, as does potassium supplementation.

Finally, TMP/SMX increases the effect of the anticonvulsant Dilantin by inhibiting the liver's ability to break down the drug.

2. Pentamidine: Pentamidine is another drug for treating and preventing PCP. It is known to have many side effects, including low blood sugar, pancreatitis, low blood pressure, neutropenia, and elevation of liver enzyme and potassium levels in the blood. Generally it is felt that pentamidine should be dispensed with caution if given with other drugs that can damage the kidneys (for a list, see previous section). In addition, other substances that cause pancreatic damage, e.g. ddI, alcohol and rifampin, may also be dangerous if taken concurrently with pentamidine.

3. Dapsone: Dapsone is commonly used for PCP prophylaxis in sulfa- intolerant persons. It is known to interact with various drugs, including trimethoprim, rifampin, and probenecid. Rifampin can lower dapsone blood levels seven to ten fold, which can lead to subtherapeutic concentrations and breakthrough cases of PCP.[2] Some practitioners recommend taking higher doses of dapsone (100 mg per day) if the patient will receive rifampin or rifabutin at the same time. The combination of dapsone and trimethoprim raises the blood levels of both drugs and may produce excess toxicity by either compound. In one study, 30 percent of patients receiving trimethoprim with dapsone had to discontinue therapy because of toxic effects, whereas none of those receiving dapsone alone had to discontinue.[3] As mentioned earlier, stomach acid is necessary for dapsone's absorption. Drugs such as ddI, antacids, Tagamet, Zantac and Pepcid should not be administered concurrently. Metroka reported several cases of breakthrough PCP related to malabsorption of dapsone when taken along with ddI.[4] The present recommendation is to take dapsone two hours before ddI to avoid the drug-drug interaction and allow for full ddI absorption.

4. Clindamycin: The most common side effect of clindamycin is diarrhea, so other drugs that also cause diarrhea probably should be avoided. Overgrowth of a bacterium called Clostridium difficile is responsible for the diarrhea during clindamycin therapy. Clostridium infection can lead to a condition called pseudomembranous colitis, characterized by abdominal pain, blood diarrhea, fever and dehydration.

Clostridium requires direct treatment with oral vancomycin or Flagyl. Use of any agent that just slows intestinal motility may prolong or worsen pseudomembranous colitis by delaying elimination of the toxin made by the bacteria. Furthermore, use of antidiarrheal agents that contain kaolin or attapulgite (Kaopectate) may decrease the absorption of clindamycin, leading to subtherapeutic effects. Erythromycin also interacts with clindamycin, by interfering with its mechanism of action against bacteria.

4. Atovaquone (Mepron): This recently licensed oral drug is indicated for treatment of mild to moderate cases of PCP as well as for salvage treatment of toxoplasmosis. Its absorption is highly dependent on ingesting it with food, especially fatty food, which increases atovaquone's absorption four or five fold. Atovaquone is known to have many drug-drug interactions, some of which result in synergistic or additive effects against the toxoplasma parasite. It is known to be synergistic with rifabutin, pyrimethamine, clarithromycin and azithromycin against this parasite. Clinical trials of this combination are under way at present. In contrast, atovaquone should be used with caution along with rifampin and fluconazole since they can lower atovaquone blood levels. Atovaquone itself can lower AZT blood levels, though the clinical significance of this reduction remains unknown.

Antifungal drugs 1. Fluconazole: Fluconazole has many drug-drug interactions with a wide variety of agents, including those frequently taken concurrently by people with HIV. Some of the most common examples are as follows: a. Rifampin has been shown to decrease the half-life of fluconazole. Physicians may need to increase the usual dosage of fluconazole when they administer the two together.

b. Fluconazole may increase the blood levels of Dilantin, resulting in greater toxic effects from this drug. The Dilantin dose may need adjustment when this drug is given with fluconazole.

c. Levels of drugs used to control blood sugar are increased when given with fluconazole. Using fluconazole in conjunction with such drugs as tolbutamide, chlorpropamide, glyburide and gipizide can result in hypoglycemia (low blood sugar).

d. The metabolism of the common anticoagulant Coumadin is decreased by fluconazole so that taking both drugs together may prolong Coumadin's effect.

e. Blood levels of various drugs (rifabutin, AZT, Dilantin and cyclosporine) may increase when taken along with fluconazole. This may exacerbate their side effects.

2. Ketoconazole: This antifungal drug requires stomach acidity for absorption, and, here too, drugs that lower acidity will result in markedly lower ketoconazole blood levels. Ketoconazole also may alter the blood levels of either Dilantin or fluconazole, and taking these drugs together is not recommended. Taking the antihistamines Seldane and Hismanal along with ketoconazole is also not recommended. The outcome can be cardiac toxicity and arrythmias.

3. Amphotericin: Amphotericin is well known for its broad toxicity, which includes kidney damage, low blood potassium and anemia. Synthetic penicillins such as carbenicillin or ticarcillin may further reduce potassium levels when given with amphotericin. Medications that affect kidney function, such as foscarnet, aminoglycoside antibiotics and pentamidine, should be prescribed to patients on amphotericin with extreme caution.

1. Hochster H. et al. Annals of Internal Medicine. 1990; 113(2):111-7.

2. Physicians' Desk Reference. Medical Economics Data Productions Company, Montvale NJ. 1994; 48:1319.

3. Lee BL, et al. Annals of Internal Medicine. 1989; 110(8):606-11.

4. Metroka C, et al. New England Journal of Medicine. 1991; 325(10):737.

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