WBR0156
| Author | PageAuthor::William J Gibson |
|---|---|
| Exam Type | ExamType::USMLE Step 1 |
| Main Category | MainCategory::Pharmacology |
| Sub Category | SubCategory::Musculoskeletal/Rheumatology |
| Prompt | [[Prompt::A 43-year-old woman presents to her primary care physician for increasingly severe joint pain and fatigue over the past three months. She feels significant joint stiffness in the morning, which improves throughout the day. She describes her pain as a persistent, dull pain that “hurts all over”. On physical examination, the physician notes mild joint swelling around the knee and ulnar deviation of the fingers. Laboratory testing reveals a positive ELISA for anti-IgG antibodies. The patient is started on a first-line disease-modifying drug, but three weeks later is found to be critically leukopenic. Which of the following medications can be used to specifically reverse the effects of the administered drug?]] |
| Answer A | AnswerA::Infliximab |
| Answer A Explanation | [[AnswerAExp::Infliximab is an antibody directed against TNF-alpha, indicated for use in Rheumatoid arthritis, Crohn’s disease and ankylosing spondylitis. All anti-TNF-alpha agents increase the risk of reactivation TB. While Infliximab can be used to treat Rheumatoid arthritis, it cannot rescue the toxic effects of methotrexate.]] |
| Answer B | AnswerB::Leucovorin |
| Answer B Explanation | [[AnswerBExp::Leucovorin is equivalent to activated folinic acid. It can be administered to “rescue” the effects of Methotrexate. Methotrexate competitively inhibits folic acid binding to Dihydrofolate reductase, an enzyme responsible for the conversion of dihydrofolic acid to the activate form, tetrahydrofolic acid. Tetrathydrofolic acid is an essential substrate for the synthesis of thymidylate, which is in turn required for DNA synthesis. Leucovorin administration bypasses this step in thymidine synthesis and thereby reverses the effect of methotrexate.]] |
| Answer C | AnswerC::Vitamin K |
| Answer C Explanation | [[AnswerCExp::Vitamin K is used to reverse the effects of Warfarin.]] |
| Answer D | AnswerD::Protamine |
| Answer D Explanation | [[AnswerDExp::Protamine is used to reverse the effects of heparin.]] |
| Answer E | AnswerE::Naloxone |
| Answer E Explanation | [[AnswerEExp::Naloxone is used to reverse the effects of morphine overdose.]] |
| Right Answer | RightAnswer::B |
| Explanation | [[Explanation::The patient in this vignette is suffering from rheumatoid arthritis (RA), an autoimmune inflammatory disease which commonly presents as systemic joint pain. A positive rheumatoid factor (anti AgG antibody) is 80% sensitive and 90% specific for RA. RA is two to three times more prevalent in females than males. Rheumatoid arthritis tend to affect the MCP and PIP joint of the hand and spares the DIP. Swelling of the MCP joint can cause the ulnar deviation of the fingers seen in this patient.
RA is treated with a combination of analgesics and disease-modifying antirheumatic drugs (DMARDs). The first-line disease modifying drug for RA is methotrexate. Methotrexate competitively inhibits folic acid binding to Dihydrofolate reductase, an enzyme responsible for the conversion of dihydrofolic acid to tetrahydrofolic acid. Cells require tetrahydrofolic acid to make thymidine, one of the four critical nucleosides in DNA synthesis. Robbed of thymidine, fast-growing cancer cells can no longer replicate DNA and die. There is some debate about the cell physiologic basis for methotrexate activity in rheumatoid arthritis. Leucovorin is equivalent to activated folinic acid. It can be administered to “rescue” the effects of Methotrexate. Methotrexate competitively inhibits folic acid binding to Dihydrofolate reductase, an enzyme responsible for the conversion of dihydrofolic acid to tetrahydrofolic acid. Leucovorin administration bypasses this step in thymidine synthesis and thereby reverses the effect of methotrexate. Stoller RG, Kaplan HG, Cummings FJ, Calabresi P. A clinical and pharmacological study of high-dose methotrexate with minimal leucovorin rescue. Cancer Res. 1979;39(3):908-12.]] |
| Approved | Approved::Yes |
| Keyword | WBRKeyword::Rheumatoid arthritis, WBRKeyword::RA, WBRKeyword::Methotrexate, WBRKeyword::Chemotherapy, WBRKeyword::Side effect, WBRKeyword::Myelosuppression, WBRKeyword::Leukopenia, WBRKeyword::Drug, WBRKeyword::Pharmacology, WBRKeyword::Antidote |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |