Antimetabolites

Question 1

What is an antimetabolite

Answer 1

A drug that interferes with one or more enzyme or their reactions that are necessary for DNA synthesis. they affect DNA synthesis by acting as a substitute to the actual metabolites that would be used normal metabolism

Question 2

Methotrexate

Answer 2

A folate antagonist, given at low doses it is an effective immunosupressant. has short half life (6-12hrs) but is retained within cells for much longer. for immune suppression weekly doses of 10-30mg are given weekly or via subcutaneous injection. body will mistake methotrexate for folic acid.

Question 3

Potential mechanisms of action for methotrexate

Answer 3

Inhibition of DHFR
-irreversible binding to dhfr and prevention of activation of folic acid, an important cofactor in purine synthesis
inhibiton of AICAR transformylase
- inhibition of purine biosynthesis and acccumulation of adenosine.
inhibiting MTHFR
- inhibiting formation of pyrimidine bases (thymine)

Question 4

The pathway of purine and pyrimidine synthesis (look at diagram)

Answer 4

Methotrexate will enter the cell via the RFC carrier. Once inside the cell methotrexate has a number of glutamic acid residues added to it to form methotrexate polyglutamate this occurs under the influence of the enzyme FPGS, the consequences of adding glutamic acid residues to methotrexate polyglutamate is much much more polar and therefore less likely to diffuse out of the cell. So the intracellular half life of methotrexate glutamate is very long. The MTX-PGs inhibits the enzymes TYMS, DHFR, ATIC

Question 5

Resultant effects of methotrexate

Answer 5

DNA is deprived therefore t cell and b cell proliferation and activation is inhibited
- adenosine is a potent antinflammatory agent so those effects
inhibiton of neutrophil activation(phagocytosis)
-apoptosis of activated cd4 and cd8 t cells.

Question 6

methotrexate side effects

Answer 6

nausea,vomiting, diarrhoea, agranulocytosis, anaemia ,cirrohis (liver) and alopecia