Pharmacology Iii - Antimetabolites

Front 1

Name the 3 main classes of Antimetabolites.

Back 1

Pyrimidine analogues
Folate antagonists
Purine analogues

Front 2

What are the 3 main Pyrimidine analogue agents?

Back 2

Fluorouracil (5-FU)
Gemcitabine
Cytarabine

Front 3

What are the 2 main Folate antagonists?

Back 3

Methotrexate
Pemetrexed

Front 4

What are the 3 main Purine analogues?

Back 4

Mercaptopurine
Thioguanine
Fludarabine

Front 5

What phase do antimetabolites specifically inhibit?

Back 5

S phase

Front 6

What are the 3 main toxicities associated with antimetabolites?

Back 6

Myelosuppression
GI distrubances
Dermatological disturbances
Hepatic
Pulmonary
Dermatologic

Front 7

What is 5-FU indicated for?

Back 7

GI cancer
Breast cancer
Head/neck cancer

Front 8

What is 5-FU's MOA?

Back 8

Pyrimidine analog resembling uracil - falsely incorportes into DNA to inhibit synthesis and replication

Front 9

What are 5-FU's two active metabolites?

What is the inactive metabolite and how is it converted to this?

Back 9

5-FUTP - inhibits DNA synthesis
5-FUMP - inhibits thymidylate synthetase - DNA synthesis
Inactive form via enzyme DPD

Front 10

What is Leucovorin? What is its significance in anti-cancer therapy?

Back 10

It is reduced folate
Co-administration with Flurouracil enhances the activity of fluorouracil.
This occurs because Leucovorin stabilizes the binding of 5-dUMP (active metabolite) to thymidylate synthetase. This however is also associated with greater toxicity

Front 11

What is Capecitabine?

Back 11

The prodrug of 5-FU

Front 12

What is the mechanism of resistance for 5-FU?

Back 12

Increase Thymidylate synthetase
Decreased activation to active metabolite

Front 13

What is Gemcitabine and what are its 3 indications?

Back 13

Pyrimidine analog
Pancreatic cancer
Lung cancer
Bladder cancer

Inserts as false pyrimidine - blocks DNA synthesis

Front 14

What metabolite of Gemcitabine is the actual inhibitor of DNA synthesis?

Back 14

Gemcitabine triphosphate

***5-FU is given as an infusion
Gemcitabine is given as a bolus

Front 15

What is Cytarabine indicated for?

Back 15

Acute Leukemia
Lymphoma

Also inserts falsely as a pyrimidine and blocks DNA synthesis

Front 16

What is the actual metabolite of Cytarabine that exhibits anti-DNA synthesis effect?

What enzyme converts Cytarabine to this active form?

Back 16

Cytarabine triphosphate

Nucleoside diphosphate kinase

Front 17

What is the main mechanism of resistance associated with Cytarabine?

Back 17

Increased levels of Cytidine deaminase and Deoxycytidylate deaminase - two enzymes that convert Cytarabine to inactive forms.

Front 18

What toxicity is unique to Cytarabine amongst the anti-metabolite class?

Back 18

Central nervous system toxicities
Ocular toxicity

Front 19

What is the mechanism of resistance involved with Cytarabine?

Back 19

Increased DNA Polymerase
Increase Inactivation by cytidine deaminase

Front 20

What are the two folate antagonist agents?

Back 20

Methotrexate
Pemetrexed

Front 21

What is Methotrexate indicated for?

Back 21

Acute Leukemia
Lymphoma
Breast Cancer
CNS Malignancies

Front 22

What is the MOA of these agents?

Back 22

Mimic folate
Binds to/inhibits Dihydrofolate Reductase
Decreases the production of reduced folate (tetrahydrofolate) needed for DNA synthesis
Also inhibits thymidylate synthetase

Front 23

What toxicity is unique to this agent?

Back 23

Acute Renal Failure
CNS toxicity

Front 24

Why is Leucovorin administered after Methotrexate?

Back 24

A Leucovorin Rescue occurs that rescues normal cells from death and reduces toxicity
Cancer cells lack the transport carrier system to utilize leucovorin rescue

Front 25

What is Pemetrexed indicated for?

Back 25

Lung cancer
Bladder cancer

Front 26

What is given with Pemetrexed to reduce bone marrow suppression?

Back 26

Folic acid and Vitamin B12

Front 27

What is the mechanism of resistance for folate antagonists?

Back 27

Increased synthesis of dihydrofolate reductase

Front 28

What are the two main Purine analog agents?

Back 28

Fludarabine
Mercaptopurine

Front 29

What is the indication of Fludarabine?

Back 29

Hematologic malignancies

Front 30

What is the MOA of Fludarabine?

Back 30

Inhibits DNA polymerase alpha
Inhibits ribonucleotide reductase
Inhibits DNA primase

Falsely incorporates itself into DNA

Also is metabolized to triphosphate active form

Front 31

What clinical pearl is important for Fludarabine?

Back 31

Fludarabine inhibits T-cells an dincreases the risk of opportunistic infection. Anti-infectives given prophylactically

Front 32

What is the main indication of Mercaptopurine?

Back 32

ALL - used a lot in children with this disease

Front 33

What is the active form of 6-Mercaptopurine?

Back 33

Azathioprine --> 6 - MP --> 6 -thioguanine nucleotides (triphosphate form) --> incorporated into DNA/RNA

Front 34

What is the drug-drug interaction with Mercaptopurine

Back 34

Xanthine Oxidase Inhibitors - Allopurinol

Xanthine Oxidase metabolized mercaptopurine. If inhibited, MC levels rise