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Hem Onc > Antimetabolites > Flashcards

Antimetabolites Flashcards

1
Q

3 types of antimetabolites

A

Folate analogs
Pyrimidine analogs
Purine analogs

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2
Q

Folate analogs [drug names]

A

Methotrexate
Pemetrexed
Pralatrexate

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3
Q

Pyrimidine analogs [drug names]

A

Fluorouracil
Capecitabine
Cytarabine
Gemcitabine

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4
Q

Purine analogs [drug names]

A 
Thioguanine 
Mercaptopurine 
Fludarabine 
Cladribine 
Pentostatin
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5
Q

What form of folate is essential in humans?

A

Tetrahydrofolate

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6
Q

Folate analogs [MOA]

A

inhibition of dihydrofolate reductase (DHFR is enzyme that turns folic acid to dihydrofolate and then to tetrahydrofolate)
inhibition of thymidylate synthase

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7
Q

Folate analogs [PK]

A

Lipophobic –> will not cross BBB

Renally eliminated

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8
Q

Folate analogs [DDIs]

A

anything that reduces renal blood flow – NSAIDs, nephrotoxic drugs, cisplatin

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9
Q

Folate analogs [ADEs]

A

methotrexate – mucositis and myelosuppresion

pregnancy category X

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10
Q

Folate analogs [Treating ADEs]

A

Folinic Acid [Leucovorin]
Fully reduced folate coenzyme; will decrease MOA so avoid if possible
Reverses myelosuppression & mucositis caused by methotrexate because substitutes for 5,10-methylene-THF

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11
Q

Folate analogs [Mechanisms of Resistance]

A

SLC19A1 mutations [brings methotrexate INTO cell]
DHFR mutations [alters binding affinity of drug and increased expression of DHFR]
Folylpolyglutamate synthetase mutations
Increased expression of efflux transporters (ABCs)
Enhanced expression of thymidylate synthase

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12
Q

Folate analogs [PGx]

A

SLC19A1 allows entrance of methotrexate INTO cell

Amplification = more drug to cell

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13
Q

How many times are folate metabolites used to transfer methyl groups in nucleic acid synthesis?

A

purines: 2
pyrimidines: 1

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14
Q

What is the result of polyglutamylation of methotrexate?

A

More like to stay INSIDE cell

More likely to inhibit thymidylate synthase

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15
Q

Why is leucovorin used to treat methotrexate toxicity?

A

ENHANCES thymidylate synthase activity –> substitutes cofactor

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16
Q

Pyrimidine Analogs [subcategories]

A

Thymidylate Analogs

Fluoropyrimidine Analogs

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17
Q

Thymidylate analogs [MOA]

A

dUMP —> dTMP

enzyme: Thymidylate Synthase
cofactor: 5,10-methyl THF

donate methyl group from 5,10-methyl THF to dUMP to get dTMP

18
Q

Thymidylate analogs [drug names]

A

Capecitabine
5-Fluorouracil [5-FU]

**Capecitabine is a prodrug that is converted to 5-FU

19
Q

Fluoropyrimidine analogs [MOA]

A

Inhibition of thymidylate synthase
Inhibition of RNA processing
Incorporation into DNA (rare but still happens)

20
Q

Fluoropyrimidine analogs [PK]

A

give IV because these drugs are orally unpredictable

21
Q

Fluoropyrimidine analogs [Metabolism]

A

Metabolized by LIVER
Mediated by DPD (dihydropyrimidine dehydrogenase)
**MORE clearance = LESS adverse effects; inactive DPD–> MORE risk of adverse effects

22
Q

Fluoropyrimidine analogs [ADEs]

A

Capecitabine and 5-FU: myelosuppression, mucositis, hand & foot syndrome (swelling/pain)

5-FU only: diarrhea

23
Q

Fluoropyrimidine analogs [Mechanisms of Resistance]

A

Mutations in activating enzymes (b/c PRODRUGS)
Mutations in thymidylate synthase
Insufficient 5,10-methylenetetrahydrofolate (cofactor–> cannot form inhibitory complex; can add leucovorin to enhance 5-FU efficacy)

24
Q

Leucovorin

A

Folinic Acid
Will REVERSE methotrexate toxicity
Will ENHANCE fluoropyrimidine analog activity

25
Q

How does leucovorin enhance 5-FU activity?

A

Can substitute as 5,10-methylene-THF and act as a cofactor to form inhibitory complex if insufficient amount available

26
Q

Cytidine Analogs [drugs]

A

Cytarabine

Gemcitabine

27
Q

Cytarabine [MOA]

A

due to trans -OH substituted for cis form, competes with dCTP for incorporation and causes DNA polymerase to be unable to synthesize more DNA

enters cell via hENT1 (nucleoside transporter)
converted Ara-C to Ara-CMP by enzyme deoxycytidine kinase (CdK)

28
Q

Gemcitabine [MOA]

A

gemcitabine –> FdCMP via CdK
FdCDP inhibits ribonucleotide reductase (RNR)
FdCTP competes with dCTP for incorporation and stop DNA polymerase

29
Q

Cytidine analogs [PK]

A

GIVE IV –> cytidine deaminase is high in GI tract; this enzyme degrades the drug; will not work as well

30
Q

Cytidine analogs [ADEs]

A

Cytarabine and Gemcitabine: myelosuppression

Cytarabine ONLY: mucositis, hand & foot syndrome, visual disturbances

31
Q

Cytidine analogs [Mechanisms of Resistance]

A

Loss of function deoxycytidine kinase (CdK)
Increased expression of cytidine deaminase or dCMP deaminase (metabolizes to non-toxic metabolites/degrades drug)
Mutations in hENT1 (helps drug enter cell )

32
Q

Which folate metabolite is responsible for transfer of methyl group resulting in dUMP —> dTMP

A

5,10-methylene THF

33
Q

Purine analogs [drug names]

A

Thioguanine
Mercaptopurine
Fludarabine
Cladribine

34
Q

Thioguanine [MOA]

A

thioguanine –> 6-thioGMP via hypoxanthine guanine phosphoribosyl transferase (HGPRT) which
inhibits IMP dehydrogenase, which is the RLS of GTP synthesis–> loss of GTP pools, causing DNA damage

35
Q

Mercaptopurine [MOA]

A

marcaptopurine –> 6-thioIMP via HGPRT, which inhibits PRPP glutamyl amidotransferase de novo purine synthesis; deplete ALL purine pools

36
Q

Thiopurine methyltransferase (TPMT) and thiopurines

A

TPMT is the inactivating enzyme – low [TPMT] = high [drug] = increased ADE

37
Q

6-thiopurines [Mechanisms of Resistance]

A

Loss of HGPRT function
Decreased drug uptake or increased efflux
Impaired recognition of DNA breaks
Impaired mismatch repair machinery

38
Q

Adenine analogs [drug names]

A

Cladribine

Fludarabine

39
Q

Fludarabine [MOA]

A

needs to be dephosphorylated to get INTO cell and then phosphorylated again once inside

inhibit DNA polymerase, DNA primase, DNA ligase and RNR

40
Q

Cladribine [MOA]

A

inhibition of RNR

incorporation into DNA –> strand breaks

41
Q

Adenosine Deaminase

A

Fludarabine and Cladribine are resistant to adenosine deaminase metabolism due to Cl and F groups on purine ring

Hem Onc (8 decks)

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