A 24-year-old woman of Ashkenazi Jewish descent presents with recurrent bloody diarrhea and abdominal pain. She says she feels well otherwise. Review of systems is significant for a 4 kg weight loss over the past month. Physical examination is significant for multiple aphthous oral ulcers. Colonoscopy reveals a cobblestone pattern of lesions of the mucosa of the intestinal wall with skip lesions involving the terminal ileum and colon. The patient is informed of the diagnosis and medication to treat her condition is prescribed. On a follow-up visit 6 weeks later, the patient presents with non-productive cough, chest pain, dyspnea on exertion, and worsening oral lesions. A chest radiograph reveals a diffuse interstitial pattern. Which of the following enzymes is inhibited by the medication most likely prescribed for her initial diagnosis?

Hypoxanthine guanine-phosphoribosyltransferase (HGPRT)

A 9-month-old boy is brought to the pediatrician because he cannot sit on his own without support and has involuntary movements. He was born vaginally with no complications at full term. There is no history of consanguinity among parents. On physical examination, it was noticed that he is a stunted infant with generalized hypotonia and severe generalized dystonic movements. The mother says that she has noticed the presence of orange sand in his diapers many times. Laboratory evaluation revealed elevated uric acid levels in both blood and urine. Which of the following enzymes is deficient in this patient?

Hypoxanthine-guanine phosphoribosyltransferase

Inosine monophosphate dehydrogenase

Orotate phosphoribosyltransferase

A 60-year-old female presents to her gynecologist with bloating, abdominal discomfort, and fatigue. She has a history of hypertension and takes hydrochlorothiazide. Physical exam reveals ascites and right adnexal tenderness. Initial imaging reveals a mass in the right ovary and eventual biopsy of the mass reveals ovarian serous cystadenocarcinoma. She is started on a chemotherapeutic agent with plans for surgical resection. Soon after starting the medication, she develops dysuria and hematuria. Laboratory analysis of her urine is notable for the presence of a cytotoxic metabolite. Which of the following mechanisms of action is consistent with the medication in question?

Platinum-based DNA cross-linking agent

An 18-month-old boy is brought to the physician because of walking difficulties. His mother says that he cannot walk unless he is supported. She has also noted orange, sandy residues in his diapers. Over the past year, she has frequently caught him pulling his toenails and chewing the tips of his fingers. Examination shows scarring of his fingertips. Muscle tone is decreased in the upper and lower extremities. He cannot pick up and hold small objects between the tips of the index finger and the thumb. The most appropriate pharmacotherapy for this patient's condition inhibits which of the following conversions?

Hypoxanthine to inosine monophosphate

Orotate to uridine monophosphate

A 67-year-old woman who was diagnosed with cancer 2 months ago presents to her oncologist with a 6-day history of numbness and tingling in her hands and feet. She is concerned that these symptoms may be related to progression of her cancer even though she has been faithfully following her chemotherapy regimen. She is not currently taking any other medications and has never previously experienced these symptoms. On physical exam, she is found to have decreased sensation to pinprick and fine touch over hands, wrists, ankles, and feet. Furthermore, she is found to have decreased reflexes throughout. Her oncologist assures her that these symptoms are a side effect from her chemotherapy regimen rather than progression of the cancer. The drug most likely responsible for her symptoms has which of the following mechanisms?

Prevention of nucleotide synthesis

Antimetabolites for USMLE Step 3: High-Yield Pharmacology Lessons

Antimetabolites - Cellular Copycat Sabotage

*Analogs of normal metabolites that sabotage nucleic acid synthesis. They are cell cycle-specific, primarily targeting the S-phase.

Folate Analog: Methotrexate
Purine Analogs: 6-Mercaptopurine, Azathioprine
Pyrimidine Analogs: 5-Fluorouracil, Cytarabine

⭐ Leucovorin (folinic acid) must be given with high-dose Methotrexate. It bypasses the inhibited DHFR enzyme, rescuing bone marrow and GI cells from toxicity.

Folic Acid Analogs - The Folate Fake-Out

Mechanism: Competitively inhibit Dihydrofolate Reductase (DHFR), blocking DHF → THF conversion. This depletes Tetrahydrofolate (THF), a vital cofactor for purine and thymidylate synthesis, halting DNA replication (S-phase specific).
Key Drug: Methotrexate (MTX)
- Uses: Leukemias (ALL), lymphomas, choriocarcinoma; also rheumatoid arthritis, psoriasis.
- Toxicity: Myelosuppression, mucositis, hepatotoxicity, pulmonary fibrosis.
- Rescue: Leucovorin (folinic acid) bypasses the DHFR block to save normal cells.

⭐ High-dose methotrexate therapy mandates leucovorin rescue to prevent fatal myelosuppression by replenishing the folate pool downstream.

📌 Methotrexate Makes Myelosuppression, Mucositis. Rescue with Leucovorin.

Pyrimidine Analogs - Corrupting the Code

Analogs of cytosine, thymine, and uracil that inhibit DNA and RNA synthesis, primarily by blocking thymidylate synthase or by fraudulent incorporation into DNA.

Drug	Mechanism of Action	Key Uses	Unique Toxicities
5-Fluorouracil (5-FU)	Inhibits thymidylate synthase → ↓ dTMP ("thymineless death").	Colorectal, pancreatic, stomach, topical (basal cell)	Myelosuppression, hand-foot syndrome, diarrhea.
Capecitabine	Oral prodrug of 5-FU.	Breast, colorectal cancer	📌 5-FU for 5-fingers (Hand-Foot Syndrome).
Cytarabine (ara-C)	DNA chain termination via DNA polymerase inhibition.	AML, Lymphomas	📌 Cytarabine causes Cytologic (pancytopenia) & Cerebellar toxicity.

5-FU and Leucovorin synergy in DNA damage

Purine Analogs - Purine Poison Pills

Drugs: Azathioprine, 6-Mercaptopurine (6-MP), Cladribine, Fludarabine.
Mechanism of Action:
- Azathioprine & 6-MP: Prodrugs metabolized by HGPRT to active forms. They inhibit de novo purine synthesis by blocking PRPP amidotransferase.
- Cladribine & Fludarabine: Mimic adenosine; inhibit DNA polymerase and induce DNA strand breaks.
Clinical Use:
- 6-MP: Acute Lymphoblastic Leukemia (ALL).
- Cladribine: Hairy Cell Leukemia.
- Fludarabine: Chronic Lymphocytic Leukemia (CLL).
- Azathioprine: Immunosuppression (e.g., IBD, Rheumatoid Arthritis).
Toxicity: Myelosuppression, GI distress, hepatotoxicity.

⭐ Co-administration of Allopurinol with 6-MP or Azathioprine dramatically increases drug levels and toxicity, as Allopurinol inhibits their breakdown by Xanthine Oxidase. Requires significant dose reduction.

📌 Mnemonic: Azathioprine and 6-MP are XO-rated (metabolized by Xanthine Oxidase).

High-Yield Points - ⚡ Biggest Takeaways

Antimetabolites are S-phase specific agents that mimic metabolic molecules to disrupt nucleotide synthesis.

Methotrexate toxicity is managed with leucovorin rescue; key side effects include nephrotoxicity and mucositis.

Reduce 6-Mercaptopurine dose with allopurinol to prevent life-threatening toxicity.

5-Fluorouracil is a key drug for solid tumors, notably causing hand-foot syndrome and myelosuppression.

Cytarabine is a mainstay for AML and can cause dose-dependent cerebellar ataxia.

Myelosuppression is the major dose-limiting toxicity for most antimetabolites.

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