Folic acid analogues

Folic acid analogues

Although researchers have developed many folic acid analogues, the early compound methotrexate remains the most commonly used.

Pharmacokinetics

Methotrexate is well absorbed and distributed throughout the body. It can accumulate in any fluid collection, such as ascites or pleural or pericardial effusion, possibly resulting in prolonged elimination and higher than expected toxicity, especially myelosuppression. At usual dosages, it doesn’t enter the CNS readily.

 

Metabolism and excretion

Although methotrexate is metabolized partially, it’s excreted primarily unchanged in urine.

 

A disappearing act

Methotrexate exhibits a three-part disappearance from plasma; the rapid distributive phase is followed by a second phase, which reflects kidney clearance. The last phase, the terminal half-life, is 3 to 10 hours for a low dose and 8 to 15 hours for a high dose.

 

Pharmacodynamics

Methotrexate reversibly inhibits the action of the enzyme dihydrofolate reductase, thereby blocking normal folic acid processing and thus inhibiting DNA and RNA synthesis. The result is cell death. Folinic acid is used in high-dose methotrexate therapy to help prevent cell death.

Pharmacotherapeutics

Methotrexate is especially useful in treating:

• acute lymphoblastic leukemia (abnormal growth of lymphocyte precursors, the lymphoblasts), the most common leukemia in children
• acute lymphocytic leukemia (abnormal growth of lymphocytes); methotrexate may be given as treatment or prophylaxis for meningeal leukemia
• CNS diseases (given intrathecally, or through the spinal cord into the subarachnoid space)
• choriocarcinoma (cancer that develops from the chorionic portions of the products of conception)
• osteogenic sarcoma (bone cancer)
• malignant lymphomas
• cancers of the head, neck, bladder, testis, and breast.

Unconventional treatment

The drug is also prescribed in low doses to treat such disorders as severe psoriasis, graft versus host disease, and rheumatoid arthritis that don’t respond to conventional therapy.

 

Drug interactions

Methotrexate interacts with several other drugs:

• Probenecid decreases methotrexate excretion, increasing the risk of methotrexate toxicity, including fatigue, bone marrow suppression, and stomatitis (mouth inflammation).
• Salicylates and nonsteroidal anti-inflammatory drugs, especially diclofenac, ketoprofen, indomethacin, and naproxen, also increase methotrexate toxicity.
• Cholestyramine reduces absorption of methotrexate from the GI tract.
• Concurrent use of alcohol and methotrexate increases the risk of liver toxicity.
• Taking co-trimoxazole with methotrexate may produce blood cell abnormalities.
• Penicillin decreases renal tubular secretion of methotrexate, increasing the risk of methotrexate toxicity. 

Warning!

Adverse reactions to methotrexate

Adverse reactions to methotrexate include:

• bone marrow suppression
• stomatitis
• pulmonary toxicity, exhibited as pneumonitis or pulmonary fibrosis
• skin reactions, such as photosensitivity and hair loss.

Kidney concerns

With high doses, kidney toxicity can also occur with methotrexate use. During high-dose therapy, leucovorin (folinic acid) may be used in a technique known as leucovorin rescue to minimize adverse reactions.

The spine of the matter

Adverse reactions to intrathecal administration (through the dura into the subarachnoid space) of methotrexate may include seizures, paralysis, and death. Other less severe adverse reactions may also occur, including headaches, fever, neck stiffness, confusion, and irritability.