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oncology > antimetabolites > Flashcards

antimetabolites Flashcards

1
Q

antimetabolite classes

A

fluoropyrimidines
folic acid analogues
deoxycytidine analogues
purine analogs

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2
Q

drugs in fluoropyrimidine class

A

5FU
capecitabine

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3
Q

drugs in folic acid analog class

A

methotrexate
pemetrexed

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4
Q

drugs in deoxycytidine analog class

A

cytarabine
gemcitabine
decitabine
azacitadine

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5
Q

drugs in purine analog class

A

6-mercaptopurine
fludarabine

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6
Q

define generally what an antimetabolite is

A

structurally related to natural compounds (metabolites) in the body
mostly affect DNA synthesis by inhibiting enzymes involved in nucleotide production, or act as false metabolites that incorporate into DNA/RNA

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7
Q

antimetabolites are ______-specific

A

cell cycle specific
s phase

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8
Q

describe generally what antimetabolite side effects are

A

rapidly dividing normal tissues are susceptible to side effects
bone marrow–> penias
GI–> mucositis, diarrhea

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9
Q

review of DNA/RNA structure

A

DNA: sugar is deoxyribose. T pairs with A, C pairs with G
RNA: sugar is ribose. U pairs with A, C pairs with G

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10
Q

how does dUMP differ from dTMP

A

a single methyl group

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11
Q

enzymes in the folic acid cycle that are inhibited by our drugs of interest

A

methotrexate inhibits dihydrofolate reductase
5FU inhibits thymidylate synthase

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12
Q

mechanism of fluorouracil (5FU)

A

a prodrug activated to 5F-dUMP. forms a ternary complex with thymidylate synthase (TS)– the irreversible inhibition of TS causes dTMP production to halt.

cells then die a “thymineless death” since they lack a critical nucleotide used in the synthesis of DNA

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13
Q

use of leucovorin in 5FU vs MTX

A

leucovorin can increase the activity in 5FU
but it is a rescue with MTX to decrease toxicity

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14
Q

important thing to know for the metabolism of 5FU

A

majority of 5FU dose is broken down by dihydropyrimidine dehydrogenase (DPD).

DPD exhibits pharmacogenetic variability: 3-5% of the population is “DPD deficient” and will experience severe toxicity following 5FU.

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15
Q

DPD pharmacogenetics for 5FU

A

homozygous variant has complete DPD deficiency: select alternate drug

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16
Q

5FU clinical uses

A

active against many carcinomas, such as colorectal, breast

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17
Q

how can 5FU be given

A

bolus or continuous IV infusions
note there are differences in toxicities and effectiveness

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18
Q

effectiveness and toxicity differences for bolus or CIVI 5FU

A

CIVI is more efficacious in colorectal cancer and associated with decreased risk of myelosuppression. but increased risk of HFS

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19
Q

more common with bolus 5FU

A

diarrhea, myelosuppressionm

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20
Q

more common with CIVI 5FU

A

hand foot syndrome

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21
Q

side effects of 5FU

A

hand foot syndrome
mucositis
diarrhea
myelosuppression
vein pigmentations (peripheral)
angina
photosensitivity

22
Q

drug interactions with 5FU

A

5FU potentiates warfarin effects
tamoxifen (VTE)
metronidazole (FU toxicity)
leucovorin (desirable effect)

23
Q

what is capecitabine and how is it activated

A

a 5FU prodrug that undergoes a series of 3 reactions before it is 5FU

1st hydrolyzed in liver by carboxylesterase to 5’-deoxy-5F-cytidine
2nd in the liver and tumor tissue by cytidine deaminase to 5’-deoxy-5F-uridine
3rd in the tumor by thymidine phosphorylase to 5FU

24
Q

when is capecitabine primarily used

A

colon, metastatic breast cancer

25
Q

capecitabine ADEs

A

HFS, diarrhea, myelosuppression, increased bilirubin, mucositis, anorexia, fatigue

26
Q

pearls for capecitabine

A

patients in the US have worse toxicity and require lower dose vs european patients (due to folic acid fortification of grains in the US)

take with water 30 minutes after a meal (food decreases absorption, more side effects without food)

dose reductions for renal impairment

27
Q

drug interactions with capecitabine

A

capecitabine potentiates warfarin effects
leucovorin/folic acid may increase the effect of capecitabine

28
Q

treatment for hand foot syndrome

A

resolves rapidly with dose-reduction or discontinuation
general supportive care: topical emollients/urea cream, immerse hands in cold water, avoid extreme temps/pressure/friction on skin, cushion sore skin with soft pads, topical wound care & consult a dermatologist for blistering/ulceration

29
Q

antidote for 5FU, capecitabine

A

uridine triacetate

30
Q

antidote for methotrexate

A

leucovorin, glucarpidase

31
Q

uridine triacetate

A

a prodrug of uridine, indicated for emergency treatment after fluorouracil or capecitabine overdose or toxicity within 96 hours

32
Q

MOA of uridine triacetate

A

5FU is built up to FUTP–> fraudulently incorporated into RNA, leading to cell death & toxicity

uridine triacetate is an acetylated prodrug of uridine–> converted to UTP in cells–> outcompetes FUTP for incorporation
prevents severe bone marrow and GI toxicity

33
Q

adverse effects of uridine triacetate

A

nausea, vomiting, diarrhea
if they vomit within 2 hours of dose, give an extra dose ASAP

34
Q

methotrexate MOA

A

similar in structure to folic acid: competes with 7,8-DHF for binding to dihydrofolate reductase, thereby preventing synthesis of THF–> prevents dTMP biosynthesis–> leading to inhibition of thymidylate synthase enzyme so tumor cells die a “thymine-less death”

35
Q

affinity of dihydrofolate reductase

A

greater affinity for MTX than folic acid
so large doses of folic acid will not revere the effects of MTX

36
Q

methotrexate uses

A

commonly used in a high dose for acute lymphoblastic leukemia as part of HyperCVAD regimen, osteosarcoma, primary CNS lymphoma

the high dose crosses the BBB and ALL has a tendency to relapse in the CNS so MTX can penetrate into there

37
Q

methotrexate ADEs

A

RENAL DYSFUNCTION: 2% incidence– can subsequently delay MTX elimination (EMERGENCY)
also: myelosuppression, mucositis, LFTs transient increase, nausea/vomiting

38
Q

methotrexate ADME/PK

A

-absorption PO is incomplete, dose dependent, saturable
-distribution: doses >1 gm/m2= good CNS penetration
-penetrates third space fluid collections slowly (exits these compartments slower)
-protein binding: other drugs like bactrim can displace MTX and increase toxicity
T1/2 is 8-15 hours

39
Q

how can you prevent toxicity to normal rapidly growing tissues with MTX

A

administer leucovorin rescue until MTX is cleared from the body
high doses (>1 gm/m2) of MTX may cross BBB but also require leucovorin rescue

40
Q

how do you avoid AKI with MTX

A

AKI is due to crystallization– need to make it more soluble. solubility of MTX is increased when pH is raised. Maintain a dilute urine (IV fluids containing NaHCO3) +/- furosemide

41
Q

why would you give IV fluids with NaHCO3 (sodium bicarbonate) for methotrexate

A

alkalinizes urine– enhances MTX solubility– prevents crystallization of MTX in urine

42
Q

methotrexate renal dose reductions

A

never give in the setting of AKI
dose reduction generally required for CrCL<100
if 70 mL/min- give 70% of the dose. monitor BUN/SCR and urine output closely (goal >150 mL/hr)

43
Q

drug interactions with high dose MTX

A

NSAIDs, penicillins, PPIs, bactrim all inhibit renal tubular secretion of MTX.

bactrim also competes for protein binding (increased free MTX) and additive antifolate effects)

NSAIDs also increase AKI risk

44
Q

what is glucarpidase, how does it work

A

for treatment of toxic plasma MTX concentrations (>1 micromolar) in patients w/ delayed clearance due to renal impairment

it is a carboxypeptidase enzyme that hydrolyzes the terminal glutamate from MTX– converts it to DAMPA (inactive metabolite)– provides a non-renal means of elimination in AKI.

> 97% reduction in MTX level within 15 minutes

45
Q

glucarpidase dosing, ADEs

A

50 u/kg IV over 5 mins x 1
continue IV fluids, urine alkalinization, leucovorin rescue
ades are minimal: flushing, HA, paresthesia

46
Q

glucarpidase and leucovorin… together?

A

glucarpidase degrades leucovorin– do not give leucovorin within 2 hours before/after glucarpidase

47
Q

immunoassay method for quantification of MTX

A

also detects DAMPA (the inactive metabolite)
overestimates true MTX level so do not measure MTX by immunoassay for first 48 hours (5 DAMPA half lives)

48
Q

what is pemetrexed

A

a multi-targeted “dirty” antifolate

49
Q

pemetrexed activity

A

inhibits dihydrofolate reductase but mostly its activity occurs by inhibiting thymidylate synthase and glycinamide ribonucleotide formyltransferase

as a result it inhibits purine nucleotide synthesis, thymidine nucleotides, protein synthesis

50
Q

what is the meaning of the multiple mechanisms for pemetrexed

A

overcomes MTX resistance mechanisms: inhibits additional targets other than DHFR

51
Q

pemetrexed clinical pearls

A

avoid NSAIDs, avoid if CrCL<45
to minimize myelosuppression and mucositis, folic acid 1 mg PO daily begin 1 week prior, continue for 3 weeks after therapy

admin vitamin B12 1 mg IM 1 week prior to first dose and every 3 cycles thereafter

to minimize skin rash: dexamethasone 4 mg PO BID day before, day of, day after

oncology (19 decks)

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