Antimetabolite Pharmacology Dr. Bossaer Flashcards
MOA Methotrexate
Methotrexate looks similar to Folic Acid
Mtx blocks dihydrofolate reductase DHFR
What does the enzyme dihydrofolate reductase DHFR usually do?
DHFR reduces Dihydrofolate to Tetrahydrofolate
it is part of a cycle that produces purines and pyrimidine (base)
-> impairs DNA and RNA synthesis and proteins (lower methionine, serine production)
Methotrexate is hydrophilic or hydrophobic?
Pharmacokinetics: Methotrexate
Hydrophilic
at high doses: Accumulation in fluid reservoius
-pleural effusions (fluid in pleural cavity around the lungs)
-ascites (fluid in the stomach cavity in liver dysfunction)
How is Methotrexate eliminated?
Renal elimination (with ATP through an organic transporter)
Drug interaction: the elimination interferes with drugs that are also eliminated through the kidney (Penicillin, Bactrim, NSAIDs, Probenecid for gout) -> increase in Methotrexate concentration
What promotes the excretion of Methotrexate?
Urine alkalization because Methotrextae is a weak acid
the pH of urine is slightly acidic, by making it more basic it will be more soluble in the urine and can be flushed out
What happens with Methotrexate in an acidic environment?
Mtx is a weak acid -> an acidic environment it is unionized and causes Precipitation and crystallizes (at high doses)
in the kidney tubule, it causes an AKI
What are the toxicities of Methotrexate?
!!!
-Mucositis (inflammation of the mucous membrane of the mouth and GI tract)
-Myelosuppression (bone marrow suppression, low RBC)
-LFT elevation (transient unless used frequently for lupus or rheumatoid arthritis)
-Acute renal failure
-pulmonary toxicity (when used chronically)
What is often given with Methotrexate to prevent acute kidney injury?
IV fluids with an alkylating agent (sodium bicarbonate)
increases solubility and excretion
What dose of Methotrexate is usually used for cancer what has to be given with it?
> 1g/m2 IV (lethal)
give it with Leucovorin (reduced folic acid, folinic acid)
Leucovorin rescues the healthy cells that need folic acid, cancer cells die
also give IV fluids and alkalinizing agent to prevent AKI !!!
Monitor Mtx levels !!!
Why do we need high doses of Methotrexate?
Because cancer cells turn off the drug uptake of Methotrexate and folate (resistance)
What is the dose of Leucovorin?
10mg/m2 every 6h
dose adjusted based on Methotrexate levels
What is the goal urine output during treatment with Methotrexate?
Which IV fluid is preferred?
> 100ml/hr
use IV fluids containing NaHCO3- (bicarbonate)
Which drugs should be avoided when giving Methotrexate?
-Probenecid
-Penicillin
-Bactrim
-NSAIDs
-nephrotoxic drugs
-hold PPIs -> switch to H2R
Why does Leucovorin rescue healthy cells but not cancer cells?
Because the folate transporter in cancer cells is deactivated (mutations)
-normal dose of Leucovorin and Mtx can’t enter the cells
-high dose of Mtx enters the cell via passive diffusion
What is the antidote of Methotrexate in case of an overdose?
Glucarpridase (Voraxaze) KNOW the Brand name!!!
-hydrolyzes methotrexate
MOA of Pemetrexed (Alimta)
Anti-folate that inhibits multiple enzymes of the folate pathway:
-DHFR (dihydrofolate reductase)
-TS
-GARFT
-AICARFT
Which medication is administered before Pemetrexed?
1 week prior: reduces myelosuppression
-Folic acid 400-1000 mcg daily
-Vit B12 100 mcg every 9 weeks
1 day before: prevent skin reaction (desquamation)
-Dexamethasone 4 mg BID for 3 days (begin the day before Pemetrexed)
What is the MOA of 5-Fluorouracil
the metabolite of 5-FU inhibits Thymidylate synthase (less thymine)
-looks like Uracil -> false RNA base pair
How does Capecitabine (Xeloda) work?
it is a prodrug of 5-FU
gets converted by:
Carboxylesterase (liver)
Cytidine esterase (tissue and tumor) !!!
Thymidine phosphorylase (in the tumor) !!-> to 5-FU
it works more on tumor cells than in healthy cells due to enzymes being present in tumor cells
Toxicities of Bolus 5-FU
-Myelosuppression (more false DNA base pair)
-N/V
Toxicities of Capecitabine and continuous infusion dosing
-Mucositis
-Diarrhea
-Hand-foot syndrome (lost a few layers of skin of the palms and foot)
What is the difference in MOA between continuous infusion and Bolus infusion of 5-FU work in cancer therapy?
continuous infusion: Thymidine synthase (TS) inhibition
Bolus: primarily RNA false base pair
Which enzyme metabolizes 5-FU?
DPD: Dihydropyrimidine dehydrogenase
deficiency can lead to life-threatening toxicities
-Neutropenia !!!
-Mucositis
-Diarrhea
-Neurotoxicity
What is the antidote of 5-FU in case of an overdose?
Uridine triacetae (Vistogard)
Supportive care for 5-FU side effects
Mucositis: Cryotherapy, ice chips (cooling causes vasoconstriction and less blood flow and drug exposure to the mouth)
Myelosuppression: CBC, temperature monitoring
Diarrhea: PRN anti-diarrheal
Avoid sun exposure
Supportive care for Capecitabine side effects
-Hand-Foot syndrome: topical emollient, diclofenac
-Diarrhea: PRN anti-diarrheal
-Avoid sun exposure
-Avoid enriched grains
think avoid Golf
How does Cytarabine work?
the compound looks like Cytosine with the sugar but it is phosphorylated
-> inhibits DNA polymerase, causing apoptosis in the S-phase
What is the usual dose of Cytarabine?
continuous infusion: 100-200 mg/m2 per day for a week
-can be given subcutaneously and intrathecally (spinal fluid)
-used for leukemia and lymphomas
Toxicites of Cytarabine
-Mucositis
-Myelosuppression
-alopecia
-N/V
-Cytarabine syndrome (rare) - corticosteroids is helpful
What is a high dose of Cytarabine (HiDAC)?
1000-3000 mg/m2
-used to overcome Cytarabine resistance
-but it will cause more CNS penetration
What are the toxicities of high doses of Cytarabine?
Cerebellar dysfunction: monitor CNS function during treatment (sobriety test multiple times, finger to the nose, write their name)
-chemical conjunctivitis/keratitis
use corticosteroid eye drops from start to 48h after treatment (prednisone, dexamethasone drops)
Gemcitabine cycle
the drug is cell cycle-specific!!
given on week 1 and week 2 (Week 3 OFF)
or Week 1, 2 and 3 (Week 4 OFF)
Toxicities of Gemcitabine
-Thrombocytopenia
-Hemolytic uremic syndrome (thrombotic thrombocytopenic purpura, rare)
MOA of 6-Mercaptopurine and 6-Thioguanine
Antipurines
both act as false DNA and RNA base pairs
-> inhibit purine synthesis
Indication of 6-Mercaptopurine and 6-Thioguanine
lymphocytic leukemia
Why are Lymphocytes more susceptible to anti-purines?
because they only use the denovo pathway to create purines, normal cells have a recycling pathway
blocking the denovo pathway causes cell death
Before using 6-mercaptopurine and 6-thioguanine patients need to be tested for what?
-TPMT testing
-> the drugs are metabolized by TPMT, if homozygous (deficient) reduce the dose by 90%
-NUDT15 testing
What should patients using 6-mercaptopurine and 6-thioguanine be counseled on?
avoid milk bc it contains Xanthine oxidase
Xanthine oxidase metabolizes 6-MP and 6-TG
Which drugs interact with 6-MP and 6-TG?
Xanthine oxidase inhibitors:
-Allopurinol
-febuxostat
->increase in 6-MP and 6-TG -> toxicity
Toxicities of 6-MP (Allopurinol induced)
Myelosupression (induced by the DDI with Allopurinol)
BUT
Allopurinol blocks the metabolic pathway and reduces hepatotoxicity (due to metabolites of 6-MP)
-> but needs 6-MP dose reduction to prevent myelosuppression)
MOA of Fludarabine
false base pair, inhibits DNA polymerase and ribonucleotide reductase
-not used a lot
Toxicities of Fludarabine
causes profound Lymphopenia -> so it works great for lymphocytic cancer
-lymphocytes takes time to recover
so prone to opportunistic infections: PCP, VZV/HSV
patients need prophylaxis !!
for PCP: Bactrim DS
for VZV/HSV: acyclovir, valacyclovir
Indication of Cladribine and Pentostatin
hairy cell leukemia
MOA of Cladribine and Pentostatin
Cladribine: DNA false base pair
Pentostatin: inhibits adenosine deaminase
Toxicities of Cladribine and Pentostatin
-profound lymphopenia
-opportunistic infection prophylaxis is needed !!
Brand name Pemetrexed
Alimta
Brand name capecitabine
Xeloda
