Page 26 Complete Your CE Test Online - Click Here Drugs that speed up the production of a certain CYP enzyme are called inducers of that enzyme. They speed up the metabolism of the enzyme substrate drugs. To compare this system to something simpler, think of a substrate drug as something that is dumped in a certain shower stall (i.e. a particular drug) for cleanup. Normally, the water (i.e. the enzyme) comes from the shower head and washes it away at a standard pace. But, an inhibitor can diminish the water flow so that it takes longer to wash out the substrate drug. A potent inhibitor can slow the shower down to a trickle, leaving the substrate drug around for a very long time. On the other hand, an enzyme inducer speeds ups the water flow for that stall (i.e. enzyme system), and washes out the substrate drug very quickly. Suddenly a person is getting much less of the drug because it is disappearing so fast. If the substrate is the kind of drug with noticeable therapeutic effects, the patient might report that it is not working well anymore. Someone taking imatinib will have the drug “washed out” by the enzymes induced by the phenytoin (inducer) s/he is also taking. Although the person is not likely to notice the difference in this case, it may affect treatment adversely by reducing the effectiveness of the imatinib. People who are genetically deficient in one or more of these enzymes may metabolize drugs differently even without a drug to cause an interaction. In the above analogy, the patient is missing the shower stall, but an enzyme deficient patient can get little or no effect from a prodrug that requires enzyme activity to be metabolized to its active form, such as tamoxifen or codeine. Torsades de Pointes (prolonged QT interval and cardiac arrhythmias) The NCCN guidelines mention concerns about the abilities of certain antiemetic drugs to prolong the QT interval, which can be dangerous especially to people with congenital QT prolongation or those taking other drugs which can also prolong the interval [204]. According to the CredibleMeds website, the following drugs are potential causes of Torsades de Pointes (TdP) in those with other risk factors for TdP such as [78]: ● ● Congenital prolonged QT interval. ● ● Congestive heart failure. ● ● Bradycardia. ● ● Low potassium or magnesium. ● ● Use of other drugs that also prolong QT interval. With any of the above risk factors, the following drugs are typically contraindicated: ● ● Ondansetron. ● ● Droperidol. ● ● Oxaliplatin. In treating cancer and N&V related to cancer drugs, there are a number of other medications that may affect QT interval enough to cause TdP or other arrhythmias in the presence of the risk factors for TdP as noted above, these drugs are not categorically contraindicated as of early 2016, but use caution with [78]: Antiemetic drugs: ● ● Granisetron. ● ● Olanzapine. ● ● Promethazine. Cancer treatment drugs: ● ● Arsenic trioxide. ● ● Bortezomib. ● ● Bosutinib. ● ● Ceritinib. ● ● Crizotinib. ● ● Dabrafenib. ● ● Dasatinib. ● ● Degarelix. ● ● Eribulin. ● ● Lapatinib. ● ● Lenvatinib. ● ● Leuprolide. ● ● Nilotinib. ● ● Osimertinib. ● ● Panobinostat. ● ● Pazopanib. ● ● Sorafenib. ● ● Sunitinib. ● ● Tamoxifen. ● ● Toremifene. ● ● Vandetanib. ● ● Vemurafenib. ● ● Vorinostat. It is important to continue to follow up on new drug additions to this list as new research is published. And of course, new drugs come out all the time that may add to this list as well. Nursing consideration: Avoiding drug combinations that interact via the CYP enzyme system can maintain effectiveness of drug treatments and reduce the incidence of drug toxicity events. Inherited genetic mutations can affect response to drug treatment Germline (inherited) mutations can also affect responses to treatment. For example, women who were born with CYP 2D6 mutations do not produce enough of the enzyme that metabolizes certain drugs (e.g. CYP 2D6 substrates) (see “Drug interactions” for more detail). Tamoxifen, which is a commonly used breast cancer treatment that greatly reduces recurrence in women with estrogen receptor-positive breast cancer, must be metabolized by the CYP 2D6 enzyme to its active form, endoxifen. Some studies suggest that women with a germline genetic mutation that lowers CYP 2D6 production do not get the same benefit from tamoxifen as women who metabolize the drug normally. There are other anti- estrogens for women who are not expected to respond to tamoxifen; specifically, the aromatase inhibitors such as anastrozole, letrozole, and exemestane can be used for ER-positive breast cancers. However, there is currently no requirement or recommendation from U.S. experts that women be tested to find out if their CYP 2D6 levels are adequate before starting tamoxifen [81]. Women who have higher CYP 2D6 levels due to a different genetic mutation may get higher levels of active drug, and may be more prone to side effects and toxicities. Unfortunately, there are other germline mutations that can cause problems in cancer treatment. People who have a dihydropyrimidine dheydrogenase (DYPD) mutation can have much higher toxicity and even fatalities with the commonly used cancer drug, 5-Fluorouracil. Thiopurine methyltranserase (TPMT) mutations, which affect about one in 300 people, can result in unexpected toxicity with mercaptopurines. People with UDP-glycosyl-transferase 1A1 mutations can have increased toxicity from irinotecan, with dose-limiting diarrhea and leukopenia. Those with methylenetetrahydrofolate reductase mutations (MTHFR) can have much worse toxicity to methotrexate [83]. Again, most of these problems are discovered after chemotherapy begins, if they are discovered at all. Many cancer treatment centers do not test for these genetic mutations even if they have to stop therapy. This is another reason it is so crucial to assess and document responses to cancer treatment. If treatment with the problem drug is allowed to progress in the face of these mutations, it can result in death (see “Resources for Nurses”). Hematopoietic stem cell transplants Hematopoietic stem cell transplants (HSCT) provide healthy blood- forming stem cells to replace cells that were destroyed by treatment (and sometimes by disease). The blood-forming stem cells that are used in transplants can come from bone marrow, the bloodstream, or umbilical cords. Transplants can be: ● ● Autologous, i.e. the stem cells come from the patient and are eventually infused into the same patient. ● ● Allogeneic, i.e. the stem cells come from someone else. The donor may be a blood relative but can also be an unrelated match, including banked cord blood from newborns. ● ● Syngeneic, i.e. the stem cells come from a patient’s identical twin. To reduce possible side effects and improve the chances that an allogeneic transplant will work, the donor’s blood-forming stem cells must “match” [196]. This matching involves human leukocyte antigens