Explain why folic acid is given with methotrexate.

Understanding Methotrexate's Mechanism of Action

Methotrexate is a folate antagonist that primarily works by competitively inhibiting the enzyme dihydrofolate reductase (DHFR). DHFR is essential for reducing dihydrofolate (DHF) to tetrahydrofolate (THF), the active form of vitamin B9 (folate). Tetrahydrofolate is a critical coenzyme in the synthesis of purine and pyrimidine nucleotides, which are the building blocks of DNA and RNA, as well as in amino acid metabolism.

• In Cancer Treatment: By inhibiting DHFR, methotrexate depletes the cellular stores of THF, thereby blocking DNA synthesis, repair, and cellular replication. This action is particularly effective against rapidly dividing cancer cells.
• In Autoimmune Diseases: While the inhibition of DHFR plays a role, methotrexate's anti-inflammatory and immunosuppressive effects in conditions like rheumatoid arthritis and psoriasis are thought to involve multiple mechanisms. These include the inhibition of enzymes involved in purine metabolism leading to adenosine accumulation (which has anti-inflammatory properties), inhibition of T-cell activation, and suppression of intercellular adhesion molecule expression.

The Consequence: Folate Depletion and Side Effects

The therapeutic action of methotrexate, particularly its antagonism of folate metabolism, is not selective to diseased cells. It also affects healthy, rapidly dividing cells in the body, which rely on folate for normal function. This leads to a state of functional folate deficiency, resulting in a spectrum of undesirable side effects.

Common Side Effects of Methotrexate due to Folate Depletion:

• Gastrointestinal Issues: Nausea, vomiting, diarrhea, stomach pain, and painful mouth sores (stomatitis/mucosi-tis) are frequently reported.
• Hematological Toxicity: Bone marrow suppression, leading to anemia (low red blood cell count), leukopenia (low white blood cell count, increasing infection risk), and thrombocytopenia (low platelet count, increasing bleeding risk).
• Hepatic Toxicity: Elevated liver enzymes, indicating liver irritation or damage.
• Dermatological Issues: Hair thinning or loss, and increased sun sensitivity.
• Systemic Symptoms: Extreme tiredness, fatigue, headache, dizziness, and general malaise.

The Role of Folic Acid Supplementation

Folic acid is the synthetic form of folate (vitamin B9). Its co-administration with methotrexate is a strategic intervention to mitigate the adverse effects caused by methotrexate-induced folate depletion without compromising the drug's therapeutic efficacy in most cases (especially in autoimmune diseases).

How Folic Acid Helps:

1. Replenishes Folate Stores: Folic acid provides an exogenous source of folate, helping to restore adequate folate levels in healthy cells. This allows these cells to bypass some of the methotrexate-induced blockade in the folate pathway, enabling them to carry out essential metabolic processes like DNA repair and protein synthesis.
2. Reduces Side Effects: By counteracting folate deficiency, folic acid supplementation significantly reduces the incidence and severity of many methotrexate side effects, including:
   • Gastrointestinal symptoms (nausea, vomiting, diarrhea, mouth sores)
   • Liver enzyme elevations
   • Hematological abnormalities (e.g., anemia)
   • Fatigue and general discomfort
3. Improves Patient Adherence: The reduction in side effects makes methotrexate therapy more tolerable, leading to better patient adherence and persistence with treatment, which is crucial for achieving long-term disease control, particularly in chronic autoimmune conditions.
4. Maintains Efficacy (in Autoimmune Diseases): Importantly, research indicates that, for autoimmune diseases like rheumatoid arthritis, folic acid supplementation does not significantly diminish the anti-inflammatory and immunosuppressive efficacy of methotrexate. This is because the primary mechanisms of action in these conditions are not solely dependent on the complete inhibition of DHFR to the same extent as in high-dose chemotherapy for cancer. However, for high-dose methotrexate chemotherapy in cancer, the timing and type of folate rescue (e.g., folinic acid) are more critically managed to avoid interfering with antineoplastic effects.

The typical regimen involves taking folic acid (often 1 mg daily or 5-10 mg once weekly) on a different day than the methotrexate dose to optimize benefit and minimize any potential for interference, although some experts suggest daily dosing on all days except the methotrexate day. The specific dosage and timing are determined by the treating physician based on individual patient needs and methotrexate dosage.

Feature	Methotrexate (MTX)	Folic Acid Supplementation
Primary Mechanism	Inhibits Dihydrofolate Reductase (DHFR), blocking folate metabolism.	Provides exogenous folate, bypassing the DHFR inhibition in healthy cells.
Therapeutic Goal	Antineoplastic (cancer), Immunosuppressive, Anti-inflammatory.	Mitigates MTX side effects by preventing folate deficiency.
Impact on Folate	Causes functional folate deficiency by blocking its activation.	Replenishes folate levels in healthy tissues.
Targeted Cells	Rapidly dividing cells (cancer, immune cells, also healthy cells).	Primarily healthy cells to reduce systemic toxicity.
Effect on Treatment	Therapeutic drug.	Supportive therapy, improves tolerability and adherence.