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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
capecitabine ADEs
HFS, diarrhea, myelosuppression, increased bilirubin, mucositis, anorexia, fatigue
26
pearls for capecitabine
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
drug interactions with capecitabine
capecitabine potentiates warfarin effects leucovorin/folic acid may increase the effect of capecitabine
28
treatment for hand foot syndrome
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
antidote for 5FU, capecitabine
uridine triacetate
30
antidote for methotrexate
leucovorin, glucarpidase
31
uridine triacetate
a prodrug of uridine, indicated for emergency treatment after fluorouracil or capecitabine overdose or toxicity within 96 hours
32
MOA of uridine triacetate
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
adverse effects of uridine triacetate
nausea, vomiting, diarrhea if they vomit within 2 hours of dose, give an extra dose ASAP
34
methotrexate MOA
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
affinity of dihydrofolate reductase
greater affinity for MTX than folic acid so large doses of folic acid will not revere the effects of MTX
36
methotrexate uses
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
methotrexate ADEs
RENAL DYSFUNCTION: 2% incidence-- can subsequently delay MTX elimination (EMERGENCY) also: myelosuppression, mucositis, LFTs transient increase, nausea/vomiting
38
methotrexate ADME/PK
-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
how can you prevent toxicity to normal rapidly growing tissues with MTX
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
how do you avoid AKI with MTX
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
why would you give IV fluids with NaHCO3 (sodium bicarbonate) for methotrexate
alkalinizes urine-- enhances MTX solubility-- prevents crystallization of MTX in urine
42
methotrexate renal dose reductions
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
drug interactions with high dose MTX
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
what is glucarpidase, how does it work
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
glucarpidase dosing, ADEs
50 u/kg IV over 5 mins x 1 continue IV fluids, urine alkalinization, leucovorin rescue ades are minimal: flushing, HA, paresthesia
46
glucarpidase and leucovorin... together?
glucarpidase degrades leucovorin-- do not give leucovorin within 2 hours before/after glucarpidase
47
immunoassay method for quantification of MTX
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
what is pemetrexed
a multi-targeted "dirty" antifolate
49
pemetrexed activity
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
what is the meaning of the multiple mechanisms for pemetrexed
overcomes MTX resistance mechanisms: inhibits additional targets other than DHFR
51
pemetrexed clinical pearls
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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