Question
A 29-year-old woman with a history of autoimmune disease develops progressive kidney failure and is diagnosed with immune-mediated nephritis on biopsy. She is started on immunosuppressive therapy. Within a few days, she develops visible blood in urine, and a protective drug is administered to counter this adverse effect.
What is the primary mechanism of action of the drug responsible for this complication?
A. Blocks spindle formation during mitosis
B. Causes DNA strand breakage directly
C. Raises pH inside antigen-presenting cells
D. Prevents folate metabolism
E. Forms covalent bonds between DNA strands
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Answer
E. Forms covalent bonds between DNA strands
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Explanation
The drug described is cyclophosphamide, an alkylating agent commonly used in severe autoimmune diseases such as lupus nephritis. It works by cross-linking DNA strands, which prevents DNA replication and leads to cell death, particularly in rapidly dividing immune cells.
A key adverse effect is haemorrhagic cystitis, caused by the toxic metabolite acrolein, which irritates the bladder mucosa → leading to macroscopic haematuria.
This complication is prevented or treated with Mesna, which binds acrolein and neutralizes its toxic effects.
Other options:
Microtubule inhibition → vinca alkaloids
DNA degradation → bleomycin
Increased lysosomal pH → hydroxychloroquine
DHFR inhibition → methotrexate
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Cheat Sheet (Exam Gold 🔥)
Cyclophosphamide
Class: Alkylating agent
Mechanism: DNA cross-linking → inhibits replication
Uses: SLE, vasculitis, cancers
Toxicity:
Haemorrhagic cystitis (→ acrolein)
Myelosuppression
Infertility
Prevention: Mesna + hydration
Key Association:
Cyclophosphamide → haematuria → Mesna
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Flash Cards
Q1: What is the mechanism of cyclophosphamide?
A: DNA cross-linking → prevents replication
Explanation: Alkylates DNA → inhibits cell division
Q2: What causes haemorrhagic cystitis in cyclophosphamide?
A: Acrolein metabolite
Explanation: Toxic to bladder epithelium
Q3: What drug prevents cyclophosphamide-induced cystitis?
A: Mesna
Explanation: Binds and detoxifies acrolein
Q4: Which drug inhibits DHFR?
A: Methotrexate
Explanation: Blocks folate metabolism → ↓ DNA synthesis
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MCQs (High-Yield + Challenging)
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MCQ 1
A patient on immunosuppressive therapy develops haematuria. Which metabolite is responsible?
A. Formaldehyde
B. Acrolein
C. Nitrosourea
D. Methotrexate polyglutamate
Answer: B
Explanation: Acrolein is the toxic metabolite causing bladder irritation.
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MCQ 2
Which drug acts by increasing lysosomal pH and interfering with antigen processing?
A. Methotrexate
B. Cyclophosphamide
C. Hydroxychloroquine
D. Bleomycin
Answer: C
Explanation: Hydroxychloroquine alters antigen presentation.
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MCQ 3
Which of the following is FALSE regarding cyclophosphamide?
A. Causes DNA cross-linking
B. Used in lupus nephritis
C. Causes haemorrhagic cystitis
D. Mechanism involves microtubule inhibition
Answer: D
Explanation: Microtubule inhibition is seen with vincristine, not cyclophosphamide.
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MCQ 4
A chemotherapeutic agent causes pulmonary fibrosis. What is its mechanism?
A. DNA cross-linking
B. DNA strand degradation
C. DHFR inhibition
D. Microtubule stabilization
Answer: B
Explanation: Bleomycin degrades DNA → lung fibrosis.
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MCQ 5
Which drug prevents DNA synthesis by inhibiting folate metabolism?
A. Methotrexate
B. Cyclophosphamide
C. Cisplatin
D. Vinblastine
Answer: A
Explanation: Methotrexate inhibits DHFR → ↓ thymidine synthesis.
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MCQ 6
Which cytotoxic drug is most associated with cardiomyopathy?
A. Bleomycin
B. Doxorubicin
C. Cyclophosphamide
D. Cisplatin
Answer: B
Explanation: Anthracyclines cause dose-dependent cardiotoxicity.
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Summary for Quick Exam Revision
Cyclophosphamide is an alkylating agent that exerts its immunosuppressive and cytotoxic effects by cross-linking DNA, thereby preventing replication and inducing apoptosis in rapidly dividing cells. It is widely used in severe autoimmune conditions like lupus nephritis and vasculitis. A hallmark adverse effect is haemorrhagic cystitis caused by the toxic metabolite acrolein, which damages bladder epithelium and leads to macroscopic haematuria. This complication is effectively prevented by mesna, which binds and neutralizes acrolein, along with adequate hydration. Other important toxicities include myelosuppression and infertility. In contrast, methotrexate inhibits dihydrofolate reductase, hydroxychloroquine increases lysosomal pH, bleomycin causes DNA strand breaks leading to pulmonary fibrosis, and vinca alkaloids inhibit microtubules. Recognizing drug mechanisms alongside their characteristic toxicities is crucial for exam success and clinical practice.