General Mechanism of Action
Antimetabolites act as cellular saboteurs. Their pharmacodynamics is based on three main principles:
- Inhibition of synthesis: the drugs block the formation of natural DNA and RNA precursors.
- Competitive antagonism: substances enter into direct competition with normal metabolites for binding to enzymes.
- Synthesis of "false" nucleotides: by incorporating into the growing nucleic acid chain instead of the normal component, they terminate its further synthesis at a certain stage.
A crucial feature of the group is phase specificity. They act exclusively in the S-phase of the cell cycle. Resting cells (outside the proliferation phase) are insensitive to them. The result of antimetabolite action is an acute nucleotide deficiency, loss of replication capacity, and the triggering of apoptosis (programmed cell death).
Folic acid antagonists: Methotrexate
Folic acid is not synthesized de novo in the human body, but is critical for the creation of purines and thymidine. Methotrexate acts as its structural analogue and antagonist.
- Target: dihydrofolate reductase enzyme. Methotrexate has a significantly higher affinity for it than the natural substrate.
- Effect: the conversion of dihydrofolates to active tetrahydrofolic acid is blocked. A coenzyme deficiency occurs, leading to a sharp drop in the production of adenine, guanine, and thymidine.
- Application: as part of combination therapy — for treating oncology (leukemias, carcinomas), in low doses (monotherapy) — for rheumatoid arthritis, severe psoriasis, and Crohn's disease. When administered systemically, the drug does not cross the blood-brain barrier, so it is administered intrathecally to affect the CNS.
- Toxicity: myelosuppression (corrected by administration of leucovorin), nephrotoxicity (requires prophylactic urine alkalinization), risk of liver cirrhosis. Pregnancy is an absolute contraindication.
Purine antagonists
This group includes mercaptopurine (a thiol analogue of hypoxanthine) and its precursor, azathioprine.
Inside the cytoplasm, mercaptopurine is transformed into an active metabolite — 6-thioinosinic acid. It acts in two ways: it physically breaks the purine formation chain and creates a "false feedback" effect. The cell perceives this metabolite as an excess of adenosine and completely stops endogenous synthesis on its own.
- Metabolic features: the drug is inactivated by the enzyme xanthine oxidase. If the patient is simultaneously taking an inhibitor of this enzyme (allopurinol), metabolism slows down. To avoid severe toxicity, the dose of mercaptopurine must be reduced by 75%.
- Resistance: most often associated with a decrease in the activity of the HGPRT (hypoxanthine-guanine phosphoribosyltransferase) enzyme, which is needed to activate the drug. A deficiency of this enzyme is also observed in Lesch-Nyhan syndrome.
- Comparison: azathioprine has a more pronounced immunosuppressive effect, which is why it is the drug of choice as an immunosuppressant.
Pyrimidine antagonists
This subgroup includes drugs that disrupt pyrimidine base metabolism:
- Fluorouracil (5-fluorouracil): a uracil analogue in which a hydrogen atom is replaced by fluorine. Administered intravenously or topically (cannot be taken orally due to high toxicity to the gastrointestinal mucosa). Blocks the thymidylate synthase enzyme and also incorporates into the RNA structure. Used mainly for solid tumors of the gastrointestinal tract and breast. A specific side effect with prolonged use is palmar-plantar erythrodysesthesia ("hand-foot" syndrome).
- Cytarabine: a 2-deoxycytidine analogue (contains arabinose instead of ribose). Potently inhibits DNA polymerase and causes termination of DNA chain elongation. Used predominantly in hematological malignancies. In high doses, it can cause severe neurotoxicity (encephalopathy, paralysis).
- Gemcitabine: a fluorinated analogue of deoxycytidine. Competes with cytidine triphosphate and inhibits the enzyme ribonucleotide reductase. Specific side effects include flu-like syndrome and nephrotoxicity.
Briefly: answers to topical questions
What are the absolute contraindications to prescribing methotrexate?
An absolute contraindication to prescribing methotrexate is pregnancy. Other conditions as absolute contraindications are not described in the presented materials, but therapy requires strict monitoring due to high toxicity. In particular, the drug is excreted predominantly by the kidneys, so in renal failure, its concentration in the blood increases, leading to severe adverse reactions. Also, methotrexate can suddenly cause depression of the hematopoietic system even at standard therapeutic doses, requiring regular monitoring of a complete blood count.
In which specific diseases is azathioprine used as the drug of choice?
Azathioprine is the drug of choice as an immunosuppressant compared to mercaptopurine because it has a more pronounced immunosuppressive effect. The sources do not highlight specific nosologies for which azathioprine has a strictly established status as the drug of choice. The following indications are listed: organ transplantation, rheumatoid arthritis, systemic lupus erythematosus, and ulcerative colitis.
To avoid confusing the groups, pay attention to the names: drugs with the roots "-purine" and "-prine" (mercaptopurine, azathioprine) are purine analogues. The remaining representatives from the list (fluorouracil, cytarabine, gemcitabine) belong to pyrimidines.
Class and exam questions
Why is methotrexate inactive against resting cells?
The drug is a strict phase-specific agent. It acts exclusively during the S phase of the cell cycle when active DNA synthesis takes place.
Why is leucovorin prescribed during methotrexate therapy?
Leucovorin is used to correct drug toxicity. It helps protect healthy tissues, primarily reducing the risk of severe bone marrow suppression (myelosuppression).
Why is 5-fluorouracil not administered orally (per os)?
When taken orally, this drug exhibits extreme toxicity to the gastrointestinal mucosa, causing ulcerative lesions. Therefore, it is administered intravenously or applied topically.
How to avoid toxicity when co-administering mercaptopurine and allopurinol?
Allopurinol blocks xanthine oxidase, the enzyme that degrades mercaptopurine. To avoid dangerous overdosage, the dose of mercaptopurine must be preemptively reduced by 75%.
What else to study on this topic
- Mechanisms of cellular resistance to methotrexate (gene amplification and impaired membrane transport)
- Metabolic features of 5-fluorouracil and the role of the hepatic enzyme dihydropyrimidine dehydrogenase (DPD)
- Specific toxicity of pyrimidine analogues (hand-foot syndrome, encephalopathy)
- Clinical differences in the use of azathioprine and mercaptopurine
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