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HY points about each drug followed by a quiz at the end
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Methotrexate
Most important drug from “biochemistry pharm” for USMLE is methotrexate.
MOA of methotrexate? –> answer = dihydrofolate reductase inhibitor (competitive and reversible) –> leads to decreased THF production.
- HY for USMLE: methotrexate, trimethoprim (an antibiotic), and pyrimethamine (used in the treatment of toxoplasmosis) all inhibit dihydrofolate reductase.
Main side-effects of methotrexate? –> answer = pulmonary fibrosis + neutropenia (presents as mouth ulcers, fever, rash) + hepatotoxicity (increased LFTs).
Main use of methotrexate? –> answer = first-line disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis (RA).
- When we treat RA, we need to address the symptoms (i.e., pain relief) separate from the actual disease progression (DMARDs).
- For symptom relief, we use NSAIDs, followed by corticosteroids (prednisone).
- But independent of symptom relief, patient should be started on methotrexate to slow disease progression.
How to overcome toxicity of methotrexate? –> answer = folinic acid (not folic acid); this is aka leucovorin rescue.
5-fluorouracil (5-FU)
MOA of 5-FU? –> answer = thymidylate synthase inhibitor.
How to overcome toxicity of 5-FU? –> answer = oral thymidine.
Capecitabine
MOA of capecitabine? –> answer = metabolized into 5-FU.
How to overcome toxicity of capecitabine? –> answer = oral thymidine (same as 5-FU, since it’s metabolized into 5-FU).
6-mercaptopurine (6-MP)
MOA of 6-MP? –> answer = PRPP amidotransferase inhibitor (inhibits purine synthesis).
Important USMLE use for 6-MP? –> answer = can have utility in the treatment of acute lymphoblastic leukemia (ALL).
Which enzyme activates 6-MP? –> answer = HGPRT.
Which enzyme breaks down 6-MP? –> answer = xanthine oxidase –> drug cannot be simultaneously given to a patient on a xanthine oxidase inhibitor (i.e., allopurinol, febuxostat).
- Then you might ask: But why would a patient be on a xanthine oxidase inhibitor and 6-MP at the same time anyway? –> treatment of leukemia can cause tumor lysis syndrome, which releases uric acid into the blood, causing gout. Rather than giving a xanthine oxidase inhibitor, patients can be administered a urate oxidase analogue, such as rasburicase or pegloticase, both of which breakdown uric acid directly, rather than prevent its formation.
Azathioprine
MOA of azathioprine? –> answer = metabolized into 6-MP, which in turn inhibits PRPP-amidotransferase (inhibits purine synthesis).
- Same way capecitabine is a pro-drug of 5-FU (i.e., it is metabolized into 5-FU), azathioprine is a pro-drug of 6-MP.
- Therefore the rule about not combining xanthine oxidase inhibitors with 6-MP also applies to azathioprine.
Mycophenolate mofetil
MOA of mycophenolate mofetil? –> answer = inhibits IMP dehydrogenase.
Important USMLE use for mycophenolate? –> answer = lupus nephritis. Pretty much the only factoid you need to know about this one.
Ribavirin
MOA of ribavirin? –> answer = inhibits both RNA polymerase and IMP dehydrogenase.
What are two uses of ribavirin? –> answer = hepatitis C and RSV.
- Should be noted that ribavirin is almost always the wrong answer when selecting the treatment for RSV bronchiolitis, but the USMLE still wants you to know that it can be used in select cases. Answer “supportive care” for RSV on the USMLE.
Major side-effect of ribavirin? –> answer = hemolytic anemia.
Hydroxyurea
MOA of hydroxyurea? –> answer = ribonucleotide reductase inhibitor.
Major use of hydroxyurea? –> answer = increases HbF in sickle cell.
Leflunomide
MOA of leflunomide? –> answer = dihydroorotate dehydrogenase inhibitor.
Any notable use for leflunomide? –> can be used in RA if methotrexate is not effective as first-line DMARD.
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