2.4 Folic Acid Analogs

Question 1

What are the 5 different classes of chemotherapy?

Answer 1

• Alkylating agents
  - Antimetabolites
• Topoisomerase inhbitors
• Mitotic inhibitors
• Anti tumour antibiotics

Question 2

What are 3 different classes of antimetabolite?

Answer 2

• Folic acid analogs
• Pyrimidine analogs
• Purine analogs

Question 3

Name 4 folic acid analogs?

Answer 3

• Methotrexate
• Pralatrexate
• Pemetrexed
• Raltitrexed

Question 4

What is the mode of action of folic acid antagonists?

Answer 4

Folic acid antagonists

Inhibit the conversion of dihydrofolate to tetrahydrofolate by competitively inhibiting dihydrofolate reductase and….

blocking thymidylate synthesis

This reduces the number of co-enzymes needed for cell replication during the S phase of the cell cycle.

Question 5

Which part of the cell cycle does folic acid analogs target?

Answer 5

S Phase
When DNA synthesis is maximum?

Question 6

When we say that methotrexate is a folic acid analogue what does that mean?

Answer 6

Methotrexate has a similar chemical profile to the folic acid analog.

Question 7

Typical dose of methorexate in cancer

Answer 7

> = 500mg/m2

Question 8

Methotrexate route of elimination

Answer 8

90% of clearance is via the kidney?

Question 9

What is the major challenge of using high dose methotrexate?

Answer 9

Methotrexate can be nephrotoxic.

Crystalisation of methotrexate in the renal tubular lumen can lead to tubular toxicity

The first sign is increased serum creatinine levels

Question 10

What problem can this nephrotoxicity lead to?

Answer 10

AKI

Question 11

What other side effects are commonly associated with high dose methotrexate?

Answer 11

• Nausea and Vomiting
• Myelosupression
• Mucositis
• Skin toxicity
• Liver toxicity

Question 12

What interventions might be undertaken to overcome the challenges of using high dose methotrexate?

Answer 12

Suspend any medication that interferes with the elimination of HDMTX via the kidney

e.g. Check OTC medicines for use of drugs such as Naproxen sodium, which can delay elimination of HDMTX for hours

More than 90% of MTX is eliminated via the kidney
To minimise the risk of AKI, ensure patient is **adequately hydrated **before and after treatment

The solubility of MTX is low at an acidic PH, this leads to crystallization of MTX in the renal tubules place the patient at risk of AKI

To minimize give IV bicarbonate to raise ph to a urine ph of > 7 before administration

If the urine ph falls to 6.5 ort less give more bicarbonate

If toxicity levels become too high, then use leucovorin as rescue medication

Nausea and vomiting - 5 HT3 antagonist

Question 13

What monitoring would you recommend for a patient on high dose methotrexate?

Answer 13

• Serum Creatinine
• eGFR
• Blood Urea Nitrogen
• Liver enzyme tests