Chemo Drugs 4 Flashcards
Methotrexate Class: Cycle specificity: Macromolecular target: Bioactivation: MOA: Pharmacokinetics and metabolism: Side effects:
Class: Antimetabolite, antifolate
Cycle specificity: CCS (S-phase)
Macromolecular target: Dihydrofolate reductase
Bioactivation:None
MOA:
- MTX enters cell via specific folate carrier protein and binds reversibly to DHFR
- Dihydrofolate accumulates and tetrahydrofolate declines
- Tetrahydrofolate serve as one carbon donors in the synthesis of purine rings
Pharmacokinetics and metabolism: yellow in solution. metabolized in body and excreted in the urine
Side effects:
- mild nausea and vomiting, stomatitis
- myelosuppression is dose limiting (reversible with rescue)
What happens if MTX and folic acid are polyglutamated by folylpolyglutamate synthetase? How are cells rescued?
- polyglutamated forms are retained within the cancer cells producing increased inhibitory effects on enzymes involved in purine synthesis and thymidylate synthesis
- normal cells do not form appreciable levels of MTX-polyglutamate
To rescue cells:
Tetrahydrofolate (leucovorin) is given
-if MTX is polyglutamated they are not rescued
-stop rescue when level is grater than 5X 10-7M at 48 hrs
Special features and dose modficaitons of MTX
- Protein bound
- if displaced from albumin may potentiate toxicity (aspirin, sulfonamides, penicillins) - Volume of distribution is total body water
- MTX gains access third space accumulations of fluid and will slowly leak out and cause prolonged tail of excretion: ascites and pleural effusions are relatively contraindicated - MTX is filtered, secreted and reabsorbed by the kidney
- use caution in patients with impaired renal function - MtX is excreted by the kidney as the salt of a weak acid
- asprin, penicillins are also excreted this ay and interfere with urinary excretion
- probenecid blocks the organic acid transport system and will also interfere with excretion - MTX solubility markedly increases in alkaline pH
- alkalinize urine to promote excretion-pH must be greater than 7 - penetrates CNS when given in high doses
- IV doses may provide protection to CNS against spread of tumor
-APPROVED FOR INTRATHECAL ADMINSITRAION
What is MTX used in?
Breast Cancer, Leukemia, Lymphoma, Brain tumors, RA, Psoriasis
Pemetrexed
Antifolate-disrupts folate dependent metabolic processes
- polyglutamated
- inhibits thymidylate synthesis
Used in : lung cancer and mesothelioma
Myelosuppression is dose limiting
Rash, stomatitis, and Diarrhea, Hand-foot sydnrome may occur
-pretreatment with parenteral vitamin B-12 and oral folic acid decreases the extent of myelosuppression
Cytarabine (cytosine arabinoside)
Class:
Cycle specificity:
Macromolecular target:
Bioactivation:
MOA:
Pharmacokinetics and metabolism:
Side effects:
Class: antimetabolite
Cycle specificity: CSS (s-phase)
Macromolecular target:DNA
Bioactivation: Successive phosphorylation via kinases to the triphosphate
MOA:
- taken up in cell via a carrier mediated nucleoside transport mechanism
- converted to the triphosphate via kinases
- ARA-CTP triphosphate is the main cytotoxic metabolite
- ARA-CTP inhibits DNA polymerase
- ARA-CTP is incorporated into DNA and inhibits template function and chain elongation
Pharmacokinetics and metabolism:
SHort HL and S phase dependent= Schedule dependent cytotoxicity
-metabolized by ubiquitous deaminase
Side effects:
- Nausea, Vomiting, hair loss, stomatitis
- Hepatic toxicty
- dose limiting myelosuppression
Special features and dose modifications of Cytarabine (cytosine arabinoside)
- INTRATHECAL use-for treatment of carcinomatous or lymphomatous meningitis
- Toxicity is myelosuppression and cerebellar toxicity and conjunctivitis
Cytarabine is used for what?
-exclusively Acute leukemia
3 + 7 induction regime (continuous 7 days)
Gemcitabine
myelosuppression dose limiting
-useful in pancreas and lung cancers
5-fluorouracil
Class:
Cycle specificity:
Macromolecular target:
Bioactivation:
MOA:
Pharmacokinetics and metabolism:
Side effects:
Class: antimetabolite
Cycle specificity: CCS (S-phase)
Macromolecular target: Thymidylate synthetase, RNA and DNA
Bioactivation: Successive phosphorylation to triphosphate and metabolism to FdUMP
MOA:
1A. Production of FdUMP inhibits thymidylate synthetase
1B. Tetrahydrofolate + FdUMP binds tightly to thymidylate synthase and decreases production of thymine nucleotides (thymineless death)
2. Sequential phosphorylation and incorporates into the RNA and DNA
Pharmacokinetics and metabolism: Extensively metabolized by the liver
Side effects:
- rash, stomatitis and diarrhea and mild myelosuppression
- Hyperpigmentation of the skin occurs and increased sensitivity to sunlight
- Chest pain (vasospasm)
- Cerebellar ataxia
- excess lacrimation
- hand foot sydnrome
What are special features of 5FU?
- given concomitantly with radiation therapy as a radiation sensitizer
- 5FU plus leucovorin is better than 5FU alone. response rates better but stomatitis and diarrhea are worse. leucovorin potentiates the cytotoxicity of 5FU
- Initial metabolism requires dihydropyrimidine dehydrogenase (DPH)
- different schedules of administration differ toxicity profiles
What are the uses of 5FU?
breast cancer, head and neck cancer, gastrointestinal cancers
Capecitabine
Prodrug of 5FU
- oral chemotherapy drug
- useful in gastrointestinal tract malignancies and breast cancer
Side effects: rash, hand foot syndrome, diarrhea, myelosuppression
6-mercaptopurine
Class:
Cycle specificity:
Macromolecular target:
MOA:
Pharmacokinetics and metabolism:
Side effects:
Class: antimetabolite
Cycle specificity: CCS
Macromolecular target: Enzyme inhibition and incorporation into RNA and DNA
MOA: 6 thioinosinic acid (active form) inhibits enzymes of de novo purine nucleotide synthesis
Pharmacokinetics and metabolism: 6 mercaptopurine is metabolized to inactive 6-thiouric acid by the enzyme xanthine oxidase
-dose reduction 50-75% when coadministered with allopurinol
Side effects: Myelosuppression is dose limiting
6 mercaptopurine is used for what?
childhood acute leukemia
