The Clinical Guide to Supportive and Palliative Care for HIV/AIDS

A Clinical Guide to Supportive and Palliative Care for HIV/AIDS • Chapter 27: Pharmacologic Interactions of Clinical SignificanceSignificant Induction Interactions: Cigarette Smoking,Benzodiazepines, Rifampin and Narcotic Analgesics26 picasSimilar to theophylline, the inducing effects of smoking are associated with decreased drowsinessin patients taking diazepam and chlordiazepoxide. In a comprehensive in-hospital drugsurveillance program comparing 2274 nonsmokers, light smokers and heavy smokers receivingbenzodiazepines, smokers generally required larger doses of benzodiazepines to achieve a sedativeand/or anxiolytic effect. 15Rifampin is one of the most powerful inducers of the cytochrome P450 enzyme system and canimpair the efficacy of some benzodiazepines based on this activity. When co-administered withrifampin to ten healthy volunteers in a double-blind cross-over study, the AUC of midazolam wasdecreased 96% while the hypnotic effects were nonexistent in all ten subjects. Similar studieswith triazolam and rifampin gave similar results, with markedly decreased effects of triazolamin the presence of rifampin based on standardized psychomotor tests.It is also well known that rifampin, like benzodiazepines, increases the rate of metabolism ofmany opioids and may induce withdrawal symptoms in patients. 16Drug Interactions of Clinical Significance Involving WarfarinThe anticoagulant effects of warfarin, as measured by increases in prothrombin time, havebeen reported to be increased two-fold by the presence of fluconazole (Diflucan) and three-foldby ketoconazole (Nizoral). Clearances of both isomers of warfarin were reduced even by doses offluconazole as low as 100mg/day for seven days. 17Numerous other reports tend to substantiate the effects of erythromycin in enhancing thehypoprothrombinemic effects of warfarin when given in combination. Two-fold increases inprothrombin time were reported after seven days but there have been few reports of bleedingcomplications.The clinical relevance of this interaction depends on a number of factors such asage of patient, concurrent drug therapy, rate of clearance of warfarin and ability to transfer drugmetabolism to other non-inhibited pathways. This interaction has not been observed withazithromycin; as with erythromycin, caution is advised with clarithromycin therapy in this setting.Omeprazole, another drug commonly used by patients for palliative care, has been shown toinhibit the metabolism for warfarin, an interaction that is most likely mediated by CYP3A4. Thisinteraction is usually observed after several days of taking omeprazole, is dose-related, and maynot necessarily abate upon discontinuation of the agent. Lansoprazole (Prevacid) appears notto have this interaction and offers a comparable alternative treatment. 18As a general rule, patients with clotting disorders, those awaiting surgical procedures, and thoseon anticoagulant therapy should be cautioned against the use of herbs such as garlic, papaya,ginseng (Pannax species), Devil’s claw (Harpagophytum procumbens), Danshen (Salviamittiorhiza), ginkgo (Ginkgo biloba), Don quai (Angelica sinensi). 11 Where patients insist oncontinuing with these medications along with their herbal remedies, their bleeding times shouldbe more closely monitored. Since most of these herbs interfere with platelet aggregation, notthe coagulation cascade, they will neither affect prothrombin time, partial thromboplastin (PTT)nor the international normalized ration (INR). It is also worthy to note that since many herbalsubstances contain anticoagulant substances, patients on warfarin should as a precautionarymeasure, have their INRs measured within seven days of starting any herbal remedy.XXVIIU.S. Department of Health and Human Services • Health Resources and Services Administration • HIV/AIDS Bureau 567