Antimetabolites 

• Introduction 

• Illustrated mechanism of action 

• Examples of Medication Brand Names (with Images)

• Indication

• Side Effects 

• Precautions & Contraindications 

• Monographs

• Reference

Antimetabolites are drugs that resemble natural metabolites in structure and interfere with normal cellular metabolism by inhibiting the synthesis or utilization of essential metabolites. They disrupt critical intracellular reactions, particularly DNA and RNA synthesis, thereby halting cell growth and division.

These compounds are widely used in chemotherapy because they selectively target rapidly dividing cancer cells by mimicking purine or pyrimidine bases, preventing their incorporation into DNA during replication. This leads to inhibition of DNA synthesis and triggers cell death (apoptosis). Antimetabolites also have applications in immunosuppression and as antibiotics by targeting bacterial metabolism.

Common examples include methotrexate (a folic acid analog) and 5-fluorouracil (a pyrimidine analog), which are used to treat various cancers and autoimmune diseases. Their mechanism involves competitive inhibition of enzymes involved in nucleotide biosynthesis or fraudulent incorporation into nucleic acids, causing structural abnormalities and cell death.

In summary, antimetabolites are vital anticancer agents that disrupt essential metabolic pathways in cells, making them effective in controlling cancer progression and other diseases.

Antimetabolites work by mimicking essential metabolites needed for DNA/RNA synthesis, disrupting cancer cell replication through two primary mechanisms:

1. Competitive enzyme inhibition

Folate antagonists (e.g., methotrexate) block dihydrofolate reductase (DHFR), halting tetrahydrofolate production required for thymidine synthesis

Purine/pyrimidine analogues (e.g., 6-mercaptopurine) inhibit enzymes like HGPRT, disrupting nucleotide synthesis

2. Fraudulent incorporation into nucleic acids

Pyrimidine analogues (e.g., 5-fluorouracil) mimic uracil/thymine, causing DNA/RNA chain termination or dysfunction

Purine analogues (e.g., cladribine) integrate into DNA, inducing structural defects and apoptosis

These agents target the S phase of the cell cycle, exploiting cancer cells' rapid DNA replication needs Resistance can occur via enzyme upregulation or reduced drug activation

Examples:

5-FU: Masquerades as uracil, inhibits thymidylate synthase

Cytarabine: Mimics cytidine, disrupts DNA polymerase

Gemcitabine: Delays DNA chain termination

Their specificity for dividing cells makes them effective against fast-growing tumors

Indications for use of antimetabolites :

 • Breast cancer

 • Colorectal cancer

 • Lung cancer

 • Leukemias

 • Ovarian cancer

 • Other solid tumors and hematologic malignancies

Because antimetabolites include a variety of drugs, side effects may differ between drugs. If you’re going to take a particular antimetabolite to treat cancer, you should talk to your doctor about the common side effects of that drug.

In general, side effects found in many antimetabolites include:

• Nausea, vomiting, or loss of appetite

• Tiredness, weakness, or sore muscles

• A headache and dizziness

• Inflammation of the mouth and lips

• Higher levels of liver enzymes, which can be a sign of inflamed or injured liver cells

• Hair loss

• A rash or dry and cracked skin

• Diarrhea or constipation

• Vision changes or light sensitivity

• Lower white blood cell counts that may make infection more likely.

Precautions of Antimetabolites

•  Hydration: Adequate hydration is essential, especially with drugs like clofarabine, to prevent dehydration caused by vomiting and diarrhea.

•  Monitoring: Regular monitoring of complete blood count (CBC), liver function tests (LFTs), and kidney function (serum creatinine, BUN) is necessary to detect myelosuppression, hepatotoxicity, and nephrotoxicity early.

• Avoid Sun Exposure: Some antimetabolites, such as methotrexate, increase photosensitivity, so patients should avoid direct sunlight or use protective measures.

•  Pregnancy and Breastfeeding: Antimetabolites can cause fetal harm and are generally contraindicated during pregnancy and breastfeeding. Women of childbearing potential should avoid pregnancy, and men should avoid fathering children during treatment

•  Drug Interactions: Careful consideration is needed when co-administering with drugs like warfarin or phenytoin due to increased toxicity risk and altered drug levels.

•  Discontinuation: Treatment should be discontinued if severe renal or hepatic toxicity develops.

Contraindications of Antimetabolites

•  Hypersensitivity: Patients with known hypersensitivity to a specific antimetabolite should not receive that drug.

•  Pregnancy and Lactation: Due to teratogenicity and potential fetal harm, antimetabolites are contraindicated in pregnant or breastfeeding women.

• Severe Hepatic or Renal Impairment: Patients with significant liver or kidney dysfunction require caution or avoidance of these drugs because of impaired metabolism and excretion, increasing toxicity risk.

•  Pre-existing Bone Marrow Suppression: Since antimetabolites cause myelosuppression, they are contraindicated or used with extreme caution in patients with severe baseline bone marrow suppression.

•  Active Infections: Immunosuppression caused by antimetabolites can worsen infections, so active infections are a relative contraindication

Summary of Common Side Effects Related to Precautions

1. Myelosuppression (leukopenia, neutropenia, thrombocytopenia)

2. Gastrointestinal toxicity (nausea, vomiting, diarrhea, mucositis)

3.  Hepatotoxicity (elevated bilirubin, liver fibrosis)

4.  Renal toxicity (elevated creatinine, renal failure)

5.  Pulmonary toxicity (pneumonitis)

6. Neurological toxicity (headache, somnolence, chemical arachnoiditis with intrathecal use)

7.  Dermatologic reactions (rash, photosensitivity, palmar-plantar dermatitis)

8. Cardiovascular effects (angina-like chest pain, EKG changes)

In conclusion, antimetabolites require careful patient selection and monitoring to mitigate risks. They are contraindicated in pregnancy, hypersensitivity, and severe organ dysfunction, and precautions include hydration, monitoring blood counts and organ function, avoiding sun exposure, and managing drug interactions