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 3-month-old boy is brought to the pediatrician by his mother after she notices orange sand–like crystalline material in her child’s diaper. He is not currently taking any medication and is exclusively breastfed. His immunizations are up to date. The doctor tells the mother that her son may have an X-linked recessive disorder. The boy is prescribed a medication that inhibits an enzyme responsible for the production of the crystals seen in his urine microscopy. Which of the following enzymes is the target of this medication?

Adenine phosphoribosyltransferase

Hypoxanthine-guanine phosphoribosyltransferase

An investigator is studying a drug that acts on the thyroid hormone pathway. Levels of serum free T3 and T4 in healthy participants are measured before and after administration of the drug. After administration, there is a decrease in the average serum free T3 level, while the average serum free T4 level is increased compared to initial serum studies. Inhibition of which of the following is the most likely mechanism of action of this drug?

Follicular iodotyrosine deiodinase

A drug that inhibits mRNA synthesis has the well-documented side effect of red-orange body fluids. For which of the following is this drug used as monotherapy?

Neisseria meningitidis prophylaxis

Methicillin-resistant staphylococcus aureus infection

Mycobacterium avium intracellulare infection

A 26-year-old G1P0 woman is brought to the emergency room by her spouse for persistently erratic behavior. Her spouse reports that she has been sleeping > 1 hour a night, and it sometimes seems like she’s talking to herself. She has maxed out their credit cards on baby clothes. The patient’s spouse reports this has been going on for over a month. Since first seeing a physician, she has been prescribed multiple first and second generation antipsychotics, but the patient’s spouse reports that her behavior has failed to improve. Upon examination, the patient is speaking rapidly and occasionally gets up to pace the room. She reports she is doing “amazing,” and that she is “so excited for the baby to get here because I’m going to be the best mom.” She denies illicit drug use, audiovisual hallucinations, or suicidal ideation. The attending psychiatrist prescribes a class of medication the patient has not yet tried to treat the patient’s psychiatric condition. In terms of this new medication, which of the following is the patient’s newborn most likely at increased risk for?

Right ventricular atrialization

Attention deficit hyperactivity disorder

A 44-year-old man, with a history of intravenous (IV) drug use, presented to the emergency department due to worsening non-productive cough, exertional dyspnea, and night sweats. His cough started 3 weeks ago and progressively worsened. He is homeless and well-known by the hospital staff. He was previously admitted to the hospital after an overdose of opioids. He takes no medication. At the hospital, the vital signs included: blood pressure 101/68 mm Hg, heart rate 99/min, respiratory rate 20/min, oxygen saturation of 91% on room air, and oral temperature of 37.4°C (99.3°F). His chest X-ray showed left perihilar shadowing. The laboratory results included: WBC count 8,800/mm3 Arterial pH 7.39 Rapid HIV testing positive with an elevated viral load PaCO2 41 mm Hg PaO2 76 mm Hg He was admitted for the treatment of presumed sepsis and pneumonia, and he was immediately started on IV ceftriaxone. An induced sputum specimen shows multiple kidney bean-shaped cysts that are approximately 5 um. These cysts stain positive with methenamine silver. What is the preferred antibiotic therapeutic regimen for this condition?

Intravenous liposomal amphotericin B with flucytosine

Isoniazid, rifabutin, pyrazinamide and ethambutol

Clindamycin and primaquine, with adjunctive prednisone

Antimetabolites (azathioprine, mycophenolate) for USMLE Step 3: High-Yield Pharmacology Lessons

Mechanism of Action - Purine Synthesis Sabotage

Core Principle: Both drugs disrupt the de novo purine synthesis pathway, which is essential for the proliferation of T and B lymphocytes, as they lack robust salvage pathways.
**Azathioprine (AZA):
- Prodrug converted to 6-mercaptopurine (6-MP).
- 6-MP is then converted into fraudulent nucleotides that inhibit multiple steps in purine synthesis.
**Mycophenolate Mofetil (MMF):
- Prodrug hydrolyzed to mycophenolic acid (MPA).
- MPA is a potent, reversible inhibitor of Inosine Monophosphate Dehydrogenase (IMPDH), a rate-limiting step in de novo guanosine synthesis.

⭐ Both drugs ultimately disrupt the de novo purine synthesis pathway, starving proliferating lymphocytes of necessary DNA building blocks.

Mycophenolate's inhibition of de novo purine synthesis

Pharmacokinetics - A Tale of Two Metabolites

Azathioprine (AZA): A prodrug, non-enzymatically cleaved to 6-mercaptopurine (6-MP).
- Activation: 6-MP is converted by HGPRT to active thioguanine nucleotides (TGNs), which disrupt DNA/RNA synthesis.
- Inactivation: Metabolized by two key enzymes:
  - Thiopurine S-methyltransferase (TPMT)
  - Xanthine Oxidase (XO)
- ⚠️ TPMT Deficiency: Genetic polymorphism can lead to ↓TPMT activity, causing ↑TGNs and severe, life-threatening myelosuppression. Screening is crucial.

⭐ Allopurinol, a xanthine oxidase inhibitor, dangerously increases azathioprine/6-MP levels, requiring a significant dose reduction (by ~75%).

Mycophenolate Mofetil (MMF): A prodrug, rapidly hydrolyzed to the active metabolite, mycophenolic acid (MPA).
- Mechanism: MPA is a selective, non-competitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH).
- Selectivity: IMPDH is vital for the de novo purine synthesis pathway, which lymphocytes exclusively rely on. This provides lymphocyte-specific cytotoxicity.

Azathioprine metabolism and mechanism of action

Clinical Use & Toxicities - Prescribing Points

Azathioprine (AZA)

Clinical Use:
- Autoimmune conditions (e.g., Rheumatoid Arthritis, IBD).
- Prophylaxis of organ transplant rejection.
Toxicities & Prescribing Points:
- Myelosuppression: Pancytopenia, especially in patients with low Thiopurine Methyltransferase (TPMT) activity.
  - ⚠️ Screen for TPMT deficiency before initiating therapy.
- GI Effects: Nausea, vomiting.
- Hepatotoxicity: Monitor LFTs.
- Drug Interaction: Allopurinol ↑ AZA toxicity by inhibiting xanthine oxidase. Must reduce AZA dose by ~75%.

Mycophenolate Mofetil (MMF)

Clinical Use:
- Prophylaxis of solid organ transplant rejection (kidney, heart, liver).
- Lupus nephritis.
Toxicities & Prescribing Points:
- GI Effects: Diarrhea and vomiting are very common.
- Myelosuppression: Primarily leukopenia. Monitor CBC.
- Infections: Increased risk of opportunistic infections (e.g., CMV).
- Teratogenicity:
  
  ⭐ Mycophenolate is highly teratogenic, requiring a negative pregnancy test before initiation and reliable contraception during treatment (REMS program).

High‑Yield Points - ⚡ Biggest Takeaways

Azathioprine, a prodrug of 6-mercaptopurine (6-MP), blocks de novo purine synthesis. Its toxicity is markedly increased by allopurinol.

Mycophenolate mofetil is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), selectively blocking lymphocyte purine synthesis.

The major dose-limiting toxicity for both is bone marrow suppression (pancytopenia).

Mycophenolate is strongly associated with GI distress (diarrhea) and is highly teratogenic.

Monitor for opportunistic infections, especially CMV with mycophenolate.

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