Comprehensive Nursing Pharmacology Q 129
An adult patient has been taking a drug (Drug A) that is highly metabolized by the cytochrome p-450 system. He has been on this medication for 6 months. At this time, he is started on a second medication (Drug B) that is an inducer of the cytochrome p-450 system. You should monitor this patient for:
A. Increased therapeutic effects of Drug A.
B. Increased adverse effects of Drug B.
C. Decreased therapeutic effects of Drug A.
D. Decreased therapeutic effects of Drug B.
Correct Answer: C. Decreased therapeutic effects of Drug A.
Drug B will induce the cytochrome p-450 enzyme system of the liver; thus, increasing the metabolism of Drug A. Therefore, Drug A will be broken down faster and exert decreased therapeutic effects. Inducing the cytochrome p-450 system will not increase the adverse effects of Drug B. Cytochrome P450 (CYP) is a hemeprotein that plays a key role in the metabolism of drugs and other xenobiotics (Estabrook, 2003). Understanding the CYP system is essential for advanced practitioners (APs), as the consequences of drug-drug interactions can be profound.
Option A: Drug A will be metabolized faster, thus reducing, not increasing its therapeutic effect. A consequence of drug-drug interactions may include the augmentation of known potential side effects. Effects of CYP on drugs are not only limited to hepatic metabolism but also present in drug absorption by the small intestine. Drugs absorbed from the small intestine often undergo first-pass metabolism mediated by CYP3A4. Grapefruit juice, an inhibitor of CYP3A4, acts locally on the small intestine and inhibits enterocyte CYP3A4, which in turn results in higher systemic levels of CYP3A active drugs
Option B: Drug B induces the cytochrome p-450 system but is not metabolized faster. Thus, the therapeutic effects of Drug B will not be decreased. As our understanding of the CYP system has improved, new agents have extensive drug interaction studies performed before they reach the market. However, not all agents have been tested in combination. Sometimes, drug interactions are hypothesized based on known metabolic pathways. For example, tamoxifen is an estrogen receptor antagonist approved for use in patients with breast cancer. Its metabolism is complex and involves a number of CYP pathways, starting with activation through metabolism.
Option D: The clinical significance of CYP-mediated drug interactions can be more concerning among drugs with a narrow therapeutic window. This may require dosage adjustments for one or more agents. An example of an agent with a narrow therapeutic window is tacrolimus, which is used at some centers for the non–FDA-approved indication of immunosuppressant in hematopoietic stem cell transplant. Concurrent use of tacrolimus and omeprazole, a substrate for both CYP2C19 and CYP3A4, can result in increased tacrolimus concentrations, resulting in supratherapeutic levels and increased tacrolimus toxicity.