Pharm- Folate & Purine Antimetabolites Flashcards
Methotrexate
Anti-Folate Drug
Methotrexate Distinctions
MTX inhibits DHFR -> blocks synthesis of thymidine, methionine, & serine. Metabolite MTX(glu)n inhibits GAR & AICAR transformylase -> blocks synthesis of purines
Pemetrexed
Anti-folate drug
Pemetrexed Distinctions
multiple sites of action: potent inhibitor of thymidylate synthase & GAR transformylase. 1000x less potent inhibition of DHFR compared to MTX. Can circumvent MTX resistance
MTX Therapeutic uses
pediatric leukemias (ALL); primary CNS lymphoma; NHL; Choriocarcinoma (monotherapy); component of therapy in colon, GI, breast, H & N
Pemetrexed Therapeutic uses
Malignant pleural mesothelioma - rare cancer associated with asbestos exposure- combo w/ cisplatin. Also used in refractory non-small cell lung cancer (NSCLC)
High Dose MTX (HDMTX) Therapeutic uses
CNS prophylaxis in pts with leukemia & high-risk lymphoma. Dose of MTX must be followed with 2-3 day rescue with leucovorin. Rescue depends on rapid clearance of MTX by kidneys (hydration & alkaline urine)
-depleting folate to such a high degree
Intermediate Dose MTX Therapeutic uses
Malignant gestational trophoblastic disease (GTD)- ex choriocarcinoma. Pts seldom require aggressive hydration, urinary alkalinization or leucovorin rescue
Low dose MTX Therapeutic uses
intrathecal for CNS prophylaxis; iv for bladder, desmoid tumors; oral for ALL, APL
MTX Preg Category D- Dose Limiting Toxicity
BM suppression (thrombocytopenia; neutropenia); mucositis. Toxicity profile varies with dose. HDMTX regimen risks renal crystalluria of MTX and renal failure. HDMTX requires leucovorin rescue
Pemetrexed Preg Category D- Dose Limiting Toxicity
BM suppression. Caution in pts with even mild, moderate renal insuff (ex: co-tx with NSAIDs)
Purine Antimetabolites
6-mercaptopurine, 6-thioguanine, Fludarabine, Cladribine
6-mercaptopurine & 6-thioguanine distinctions
inhibits purine ring biosynthesis & nucleotide interconversion -> disrupts DNA and RNA integrity
Fludarabine distinctions
tumor cell kinases convert 2-F-araA to nucleotide triphosphates -> inserted into DNA, RNA, and disrupt DNA & RNA synthesis
Cladribine distinctions
tumor cell kinases convert it to nucleotide analogs; inhibits DNA synthesis; also potent inhibitor of ribonucleotide reductase
6-mercaptopurine therapeutic uses
maintenance of remission in ALL
6-thioguanine therapeutic uses
Acute non-lymphocytic leukemia (w/ daunorubicin & cytarabine)
Fludarabine therapeutic uses
CLL; also effective against hairy cell leukemia, indolent NHL
Cladribine therapeutic uses
Hairy cell leukemia; also effective against NHL; CLL
6-mercaptopurine dose limiting toxicity
myelosuppresion; dose adjustment with allopurinol or febuxostat (xanthine oxidase inhibitor); hepatotoxicity (jaundice)
6-thioguanine dose limiting toxicity
myelosuppression; hepatotoxicity with long term use
Fludarabine dose limiting toxicity
myelosuppression; opportunistic infxs.
IV only to avoid intestinal bacteria generating toxic fluoroadenine
Cladribine dose limiting toxicity
myelosuppression; drug fever
High dose MTX metabolism/clearance
Hepatic metabolism -> renal elimination -> leads to crystalluria tubular obstruction
pemetrexed has a neglible effect on?
DHFR, unlike MTX
pemetrexed survival benefit with cisplatin in?
malignant pleural mesothelioma
what inactivation 6-MP?
hepatic inactivation by TPMT & XO
what activates 6-MP to TIMP?
HPRT in cells (tumor and normal)
what activates TIMP to active metabolites in cells?
IMPDH and TMPT
1st pass effect on 6-MP
sets up problem of 6-MP overexposure due to inhibition of XO by gout medications: allopurinal and febuxostat
tumor lysis syndrome
hyperkalemia, hyperphosphatemia (hypocalcemia), hyperuricemia
simultaneous admin of allopurinol and 6-MP limit what?
hyperuricemia which causes the urate crystal that cause damage
6-thioguanine
bypasses the XO inactivation step so there are no drug interactions with XO inhibitors
-6-TG activated by HPRT, inactivated by TPMT
cell cycle specific drugs are?
schedule dependent. duration and timing of drug admin affect efficacy more than dose
vincristine neuropathy
more common & worse than vinblastine