Antimetabolites, Bleomycin,

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  1. What are the antimetabolites?
    • DNA synthesis inhibitors
    • Inhibit the actions of enzymes that are involved in the synthesis of DNA precursors and bases
  2. what are the categories of antimetabolites?
    • Folate analogues (aka Antifolates)
    • Pyrimidine analogues
    • Purine analogues
  3. what are the folate analogues drugs?
    Methotrexate (Novantrone)
  4. what are the Pyrimidine analogue drugs?
    • 5-Fluorouracil (5FU)  (Adrucil)
    •    #1 tx for colorectal CA
    •     Results in a deficiency of dTMP (deoxythymidine diphosphate)
    • Raltitrexed (Tomudex) ·        
    • Pemetrexed (Alimta)- non small cell lung CA·        
    • Cytarabine (Cytosar)· 
    • Gemcitabine (Gemzar)- pancreatic CA·
    • Capecitabine (Xeloda)
  5. what are the Purine analogs?
    • Mercaptopurine  (6- MP),  (Purinethol)
    • Fludarabine (Fludara) (Oforta)
    • Pentostatin (Nipent)
    • Cladribine (Litak) (Movectro)·        
    • Thioguanine (Tabloid)
  6. antimetabolites MOA-
    methotrexate (Novantrone):
    5- FU:
    • Methotrexate (Novantrone)
    •       Competitively inhibits DHFR
    • 5-Fluorouracil (5FU)  (Adrucil)·        
    •       Results in a deficiency of dTMP (deoxythymidine diphosphate)
    • Mercaptopurine ·        
    •        is metabolized to 6-thio-GTP·        
    •        is incorporated into RNA and DNA, halting further DNA and RNA synthesis
    •        6-thio-GTP can be incorporated into DNA and RNA, but because it is not a normal base, it halts further DNA and RNA synthesis.
    •        It is called a fraudulent nucleoside. – kills the cell
  7. Acute Myeloid Leukemia Tx regime:
    methotrexate intrathecal
  8. Kinetics-
    • cannot cross BBB, must inject it right into the brain – on exam ·        
    • Administrated orally, intravenously, intramuscularly, or intrathecally·
    • CNS entry must be achieved via intrathecal administration
    •      Does not cross the blood-brain barrier
    • Only a small fraction metabolized
    • Majority eliminated unchanged in the urine
    • Consider dose adjustments with renal impairment
  9. kinetics of mercaptopurine:
    • Available in oral dosage forms
    • Metabolized by the liver
    •     Xanthine oxidase
    •         One of the enzymes responsible for mercaptopurine metabolism ([] goes up)
    •         Inhibitors of this enzyme can lead to toxicity
    •             Ex.  Allopurinol   (allopurinol inhibits xanthine oxidase)
  10. Non-small cell lung CA tx:1st line
    • 1st line: Pemetrexed/ CISplatin, & hydration
    • Premedications: Vitamin B12, Folic acid, dexamethasone
  11. Indications for methotrexate:
    • Rheumatoid arthritis
    • Acute lymphoblastic leukemia   
    • Severe psoriasis·        
    • Non-Hodgkin's lymphoma
    • Osteosarcoma·        
    • Cancers of the breast, brain, head, and neck, ovary, bladder
  12. indications for Pemetrexed?
    • Mesothelioma
    • Non-small cell lung cancer (non-squamous)
  13. indication for Thioguanine, Mercaptopurine
    • Lymphoma
    • Thioguanine (AML), Mercaptopurine (ALL)
  14. indications for Fludarabine, Cladribine (HCL), Pentostatin, Cytarabine
    • Leukemia
    • Lymphoma
    • Brain (cytarabine only)
  15. indications for 5-FU?
    • Cancers of the breast, colon and rectum, stomach, head and neck, skin (noninvasive)
    • Actinic keratoses (thick, scaly, or crusty patches of skin)
  16. indications for Gemcitabine:
    Cancers of the pancreas, lung (non-small cell cancer), ovary, bladder, esophagus, head and neck
  17. Colon CA tx- 1st line:
    what can you substitute the 1st line for?
    • OXALIplatin, Leucovorin, Fluorouracil.    mFOLFOX6
    • Can substitute capcitabine, bc it is a metabolite of 5-FU
    • 5 FU is gold standard
  18. SE for folate analogues:
    • Myelosuppression
    • Damage to GI epithelium
    • Stomatitis·        
    • Pneumonitis     
    • Nephrotoxicity       
    • Alopecia·        
    • Dermatitis ·        
    • Defective oogenesis or spermatogenesis
    • Hepatic:
    •     Acute: reversible elevations in liver enzymes
    •     Chronic: cirrhosis
  19. SE of purine analogues:
    • Myelosuppression
    •      Develops gradually
    •      Most severe with Thioguanine
    • Nausea and vomiting
    • Hepatotoxicity
    •       With Chronic mercaptopurine use
    • CNS
    •        Altered mental status and seizures
    •             Fludarabine
  20. Pyrimidine analogues (5-FU) SE:
    • Myelosuppression:
    •      Particularly cytarabine ·        
    • GI effects (severe diarrhea) and stomatitis –on exam
    • Palmar-plantar erythrodysesthesia( PPE)
    •      Aka “Hand-foot Syndrome” (24-40%)
    •          Drugs that causeHand-foot Syndrome :
    •       Xeloda® (capecitabine )
    •       Cytosar-U® (cytarabine)·        
    •       FUDR® (floxuridine)·        
    •       5-FU (fluorouracil)·         
    •       Idamycin® (idarubicin)
    •       Doxil® (liposomal doxorubicin)
    •       Sutent® (Sunitinib)
    •       Nexavar® (Sorafenib)
    •       Continuous infusion of (Adriamycin®) doxorubicin·        
    • Reversible hepatotoxicity ·        
    • CNS:
    •      When intrathecal administration or high plasma levels
    •     Cerebellar (ataxia)
    •     Cerebral (seizures, dementia, coma)
  21. chemo induced diarrhea drugs:
    Fluorouracil, capecitabine, methotrexate, cytarabine
  22. folate analogue (methotrexate) DI:
    • Tubular secretion plays a role in the excretion of methotrexate
    •      Agents that compete for secretion at the proximal tubule may reduce methotrexate clearance
  23. CI for folate analogue (methotrexate)?
  24. every person on 5-FU gets what drug?
    what is it? & what does it do?
    • Leucovorin (Folinic acid)- This increases effectiveness to kill ca
    • Reduced form of folic acid·        
    •     Decreases side effects of methotrexate (antifolate) (use with pentotrexate)
    •       Cirrhosis, pneumonitis
    • It is metabolized to mTHF·        
    •    This increases the cytotoxic effects of 5-FU by increasing and stabilizing the binding of FdUMP to thymidylate synthetase
  25. Pharmacogenetics of Thiopurine methyltransferase (TPMT):
    • Plays a role in the metabolic inactivation of mercaptopurine·        
    • Approximately 15% of Caucasians have reduced activity of this enzyme
    •     Greater risk for toxicity
  26. What is Dihydropyrimidine dehydrogenase (DPD)? on exam
    • One of the enzymes involved in the metabolic inactivation of 5-fluorouracil·        
    •      Korean patients tend to have higher DPD activity·        
    •      African Americans tend to have lower activity
    •          Increased 5-FU toxicity
  27. what is the mech of resistance for antimetabolites?
    • Reduced transport across cell membranes
    • Changes in the conformation of the DHFR enzyme
    • Increased concentrations of DHFR
    • Increased drug efflux
  28. what is description of Bleomycin?
    • Belongs to a family of glycopeptides
    • Exert a cytotoxic effect by damaging DNA
    • In the Anti-tumor Antibiotic class
  29. Bleomycin drugs?
    Bleomycin (Blenoxane®) – has low myleosuppression
  30. Bleomycin MOA?
    • Is an intercalator which inserts itself into the DNA structure which produces single and double stranded breaks
    • Skin and lung lack hydrolase which results in increased toxicities
    •     So SE on skin and lung
    • Bleomycin binds with FE(III)-OOH
  31. Indication for Bleomycin?
    • Lymphoma; “owl eyes”
    • Cancers of the head and neck, cervix, testicles, bladder
  32. CI for Bleomycin?
  33. what makes Bleomycin a good candidate for use in multi-drug regimes?
    • causes minimal bone marrow suppression
    • (unlike most cytotoxic agents)
  34. SE of Bleomycin?
    • Cutaneous-       
    •    Due to the lack of hydrolase activity
    •    Hyperpigmentation
    •    Hyperkeratosis
    •    Erythema
    •    Ulceration
    • Nausea, vomiting
  35. Serious SE of Bleomycin?
    • Interstitial pneumonitis or fibrosis: -on exam
    •     Very serious complication
    •         Fatal outcome in 1% of patients
    • Risk increases: Higher doses, Advanced age(>70 years), Preexisting pulmonary disease
    • Hypersensitivity reaction
  36. mech of resistance of Bleomycin?
    • Increased hydrolase activity
    • Leads to increased inactivation of bleomycin
    • Decreased uptake of bleomycin into cancer cells
    • Repair of DNA strand breaks
    • Inactivation of bleomycin
Card Set:
Antimetabolites, Bleomycin,
2013-07-15 02:22:00
Pharm Antimetabolites Bleomycin

Pharm exam
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