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68 Cards in this Set
- Front
- Back
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MOA vincristine
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Plant alkaloid from periwinkle plant. Cell cycle specific -(M) phase. Inhibits tubulin polymerization, disrupting formation of microtubule assembly-> arrest in cell division & cell death. May also inhibit DNA, RNA, & protein synthesis.
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Mech resistance vincistine
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Overexpression of P170 glycoprotein encoded by the multidrug-resistant gene-> efflux of drug & dec intracellular drug accumulation. Cross-resistance w/ other natural products (taxanes, epipodophyllotoxins, anthracyclines, & actinomycin-D. Mutations in alpha & beta tubulin dec affinity to vincristine.
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Absorption vincristine
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Not available for oral use and administered only by the IV route.
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Distribution Vincristine
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Widely & rapidly distributed into body tissues w/i 30 minutes of administration. Poor cross the BBB
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Metabolism vincristine
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Liver P450. Majority (80%) excreted in bile and feces. Only 15%–20% recovered in urine. Terminal half-life is long (85 hr)
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Indications vincristine
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Acute lymphoblastic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, Multiple myeloma, Rhabdomyosarcoma, Neuroblastoma, Ewing’s sarcoma, Wilms’ tumor, Chronic leukemias, Thyroid cancer, Brain tumors
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MOA Vinorelbine
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Semisynthetic alkaloid from vinblastine. Cell cycle specific- (M) phase. Inhibits tubulin polymerization, disrupting formation of microtubule. High specificity for mitotic microtubules w/ lower affinity for axonal microtubules. May also inhibit DNA, RNA, & protein synthesis.
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Mech resistance vinorelbine
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Overexpression of P170 glycoprotein-> enhanced efflux of drug. Cross-resistance observed w/ other natural products (taxanes, epipodophyllotoxins, anthracyclines, actinomycin-D). Mutations in alpha & beta tubulin proteins w/ dec binding affinity to vinorelbine.
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Absorption vinorelbine
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Oral bioavailability varies from 27% to 43%, depending on the formulation. Peak plasma concentrations achieved w/i 2 hours of an oral dose
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Distribution vinorelbine
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Widely & rapidly distributed into most body tissues w/ a large apparent volume of distribution (> 30 L/kg). Extensive binding to plasma proteins (about 80%).
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Metabolism vinorelbine
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Liver P450. Small quantities of at least one metabolite, desacetyl vinorelbine, have antitumor activity similar to that of parent drug. Majority excreted in feces via the enterohepatic biliary system (50%). About 15%–20% of the drug is eliminated by the kidneys. Prolonged terminal half-life of 27–43 hours secondary to relatively slow efflux of drug from peripheral tissues.
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Indications vinorelbine
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Non–small cell lung cancer, Breast cancer, Ovarian cancer, Hodgkin’s lymphoma.
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Special considerations vinorelbine
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Caution w/ abnormal liver fcn (toxicity enhanced) - reduce dose. Caution in patients previously treated w/ chemo and/or radiation due to marrow reserve may be compromised. Infused as a rapid push in a free-flowing IV line to avoid extravasation. Flushing with sterile water, elevation of the extremity, and local application of ice are recommended. Avoid eye. Pregnancy category D. Avoid Breast-feeding
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Toxicity vinorelbine
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Myelosuppression. Neutropenia is most commonly observed. Nausea/vomiting. Constipation (35%), diarrhea (17%), stomatitis (< 20%), & anorexia (< 20%). Vesicant. Neurotoxicity. lower affinity for axonal microtubules. Inc risk in patients with preexisting neuromuscular disease.
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MOA etoposide
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"Plant alkaloid from the mandrake plant. Cell cycle specific- late S- and G2-phase. Inhibits topoisomerase II by stabilizing the topoisomerase II-DNA complex & preventing the unwinding of DNA.
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Mech resistance etoposide
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"Multidrug-resistant phenotype w/ inc expression of P170-> drug efflux. Cross-resistant to vinca alklaloids, anthracyclines, taxanes, & other natural products. Dec expression of topoisomerase II. Mutations in topoisomerase II w/ dec binding affinity to drug. Enhanced activity of DNA repair enzymes.
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Absorption of etoposide
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Bioavailability of oral capsules 50%, oral dose needs to be twice that of an IV dose. Oral bioavailability is nonlinear & dec w/ higher doses of drug (> 200 mg). Presence of food and/or other anticancer agents does not alter drug absorption.
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Distribution of etoposide
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Rapidly distributed into all body fluids & tissues. Large fraction protein bound (90%–95%)- albumin. Dec albumin levels result in a higher fraction of free drug a potentially higher incidence of host toxicity.
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Metabolism of etoposide
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The liver via glucuronidation to hydroxy acid metabolites, which are less active than the parent compound. 30%–50% excreted in urine & 2%–6% excreted in stool via biliary excretion. Elimination half-life ranges from 3 to 10 hours.
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Indications of etoposide
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Germ cell tumors, Small cell lung ca, Non–small cell lung ca, Non-Hodgkin’s lymphoma, Relapsed Hodgkin’s lymphoma, Gastric cancer, High-dose therapy in transplant for breast cancer, lymphoma, & ovarian cancer.
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Special considerations of etoposide
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abnormal renal & liver fcn. Infuse 30–60 minutes to avoid the risk of hypotension. Anaphylaxis, extravasation. Pregnancy category D.
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Toxicity of etoposide
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"Myelosuppression. Leukopenia more common than thrombocytopenia. Nausea/vomiting (more common w/ oral admin), Anorexia, Alopecia, Mucositis & diarrhea.
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MOA Doxorubicin (adriamycin)
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"Anthracycline antibiotic. Intercalates into DNA-> inhibit DNA synthesis & fcn. Inhibits transcription through inhibition of DNA-dependent RNA polymerase. Inhibits topoisomerase II by forming a cleavable complex w/ DNA & topoisomerase II-> DNA breaks. Form oxygen-free radicals-> single & double-stranded DNA breaks w/ subsequent inhibition of DNA synthesis & fcn.
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Mech of resistance doxorubicin
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"Inc P170 levels-> drug efflux. Dec topoisomerase II. Mutation in topoisomerase II w/ dec binding affinity to doxorubicin. Inc expression of sulfhydryl proteins, including glutathione & glutathione-dependent proteins.
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Absorption doxorubicin
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Not absorbed orally.
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Distribution doxorubicin
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Widely distributed to tissues. Does not cross the blood-brain barrier. About 75% of doxorubicin & its metabolites are bound to plasma proteins.
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Metabolism doxorubicin
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Liver to the active hydroxylated metabolite, doxorubicinol. About 40%–50% of drug eliminated via biliary excretion in feces. Less than 10% of drug cleared by kidneys. Prolonged terminal half-life of 20–48 hours.
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Indications doxorubicin
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"Breast cancer, Hodgkin’s and non-Hodgkin’s lymphoma, Soft tissue sarcoma, Ovarian cancer, Non–small cell and small cell lung cancer, Bladder cancer, Thyroid cancer, Hepatoma, Gastric cancer, Wilms’ tumor, Neuroblastoma, Acute lymphoblastic leukemia.
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Toxicity doxorubicin
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"Myelosuppression (leukopenia), Nausea and vomiting, Cardiotoxicity, Strong vesicant, Hyperpigmentation of nails, rarely skin rash, & urticaria. Radiation recall skin reaction can occur at prior sites of irradiation. Inc hypersensitivity to sunlight, Alopecia, Red-orange discoloration of urine.
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MOA bleomycin
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Small peptide. Iron as cofactor binds DNA-> generates activated oxygen-free radical species-> single- and double-strand DNA breaks
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Mech of resistance bleomycin
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Inc drug inactivation via inc expression of bleomycin hydrolase. Inc expression of DNA repair enzymes resulting in enhanced repair of DNA damage. Dec drug accumulation through altered uptake of drug.
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Absorption bleomycin
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Poor oral bioavailability. After IM administration, peak levels obtained in about 60 minutes but reach only one-third the levels achieved after an IV dose. When admin in intrapleural space for treatment of malignant pleural effusion (pleurodesis), approx 45%–50% absorbed in systemic circ
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Metabolism bleomyin
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After IV admin, rapid biphasic disappearance from circ. The terminal half-life is approx 3 hrs in patients w/ normal renal fcn. Rapidly inactivated in tissues, by bleomycin hydrolase. Elimination via the kidneys, with 50%–70% excreted unchanged in urine.
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Indications bleomycin
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Hodgkin’s disease & non-Hodgkin’s lymphoma, Germ cell tumors, Head and neck cancer, Squamous cell carcinomas of the skin, cervix, & vulva, Sclerosing agent for malignant pleural effusion & ascites.
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Toxicity bleomycin
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Skin reactions, pulmonary, fever/chills
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MOA L-asparaginase
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Purified from Escherichia coli and/or Erwinia chrysanthemi, Tumor cells lack asparagine synthetase & require exogenous sources of L-asparagine. Hydrolyzes circ L-asparagine to aspartic acid & ammonia-> Deplete L-asparagine-> rapid inhibition of protein synthesis. Cytotoxicity of drug correlates well w/ inhibition of protein synthesis.
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Mech resistance L-asparaginase
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Inc expression of the L-asparagine synthetase gene. Facilitates cellular production of L-asparagine from endogenous sources. Formation of antibodies against L-asparaginase, resulting in inhibition of function.
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Metabolism L-asparaginase
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Not well characterized. Minimal urinary and/or biliary excretion occurs. Plasma half-life depends on formulation of drug: 40–50 hours for E. coli–derived L-asparaginase & 3–5 days for polyethylene glycol (PEG)-asparaginase.
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Indications L-asparaginase
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Acute lymphocytic leukemia.
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Toxicity of L-asparaginase
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Hypersensitivity rxn (skin rash/urticaria, Anaphylactic rxn-> resuscitation equoment @ bedside). Fever, chills, nausea/vomiting. Neurologic toxicity, including lethargy, confusion, agitation, hallucinations, and/or coma.
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Mech of resistance Interferon-Alpha
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Development of neutralizing antibodies & Dec expression of cell surface receptors to interferon-alpha
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Absorption Alpha-Interferon
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No oral use. Admin only via parenteral route. Approximately 80%–90% absorbed into the systemic circ after IM or SC injection. Peak plasma levels achieved in 4 hours after intramuscular injection & 7 hours after SC admin
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Metabolism Alphs-Interferon
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Catabolized by renal tubule cells to various breakdown products. Elimin through the kidneys by both glomerular filtration & tubular secretion. Hepatic metabolism & biliary excretion play only a minor role in drug clearance. Elimin half-life is approx 2–7 hours & depends on the route of admin
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Indications Alpha-Interferon
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Malignant melanoma (adjuvant), Chronic myelogenous leukemia (chronic phase), Hairy cell leukemia, AIDS-related Kaposi’s sarcoma, Cutaneous T-cell lymphoma, Multiple myeloma, (Low-grade) non-Hodgkin’s lymphoma, Renal cell ca, Hemangioma.
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Special Considerations Alpha-Interferon
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Pre-existing cardiac, pulmonary, CNS, hepatic, and/or renal impairment. Contraindicated in patients w/ history of autoimmune disease, autoimmune hepatitis, or in those who have received immunosuppressive therapy for organ transplants.
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Toxicity Alpha-Interferon
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"Flu-like symptoms (Incidence dec w/ subsequent injections), controlled w/ acetaminophen and/or indomethacin. Fatigue & anorexia are dose-limiting w/ chronic admin. Somnolence, confusion, or depression. Patients > 65yo much more susceptible to the neurologic sequelae
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MOA interleukin 2
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Stim of T-cell immunity & induction of a massive acute phase reaction.
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Indications interleukin 2
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Experimental, Renal cell carcinoma, Melanoma, Others
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Side effects of interleukin 2
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Systemic (chills, fever, pruritus, weight gain), Neurological (disorientation, somnolence, coma), Cardiac (hypotension), Respiratory (pulmonary edema), Hematologic (myelosuppression), Hepatic (hyperbilirubinemia), Renal (oliguria), GI( nausea/vomiting, diarrhea)
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MOA cisplatin
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"Covalently binds DNA w/ preferential binding to the N-7 position of guanine & adenine. Reacts w/ 2 diff sites on DNA to produce cross-links, either intrastrand (> 90%) or interstrand (< 5%). Form DNA adducts-> inhibition of DNA synthesis, function & transcription. Binding to nuclear & cytoplasmic proteins may result in cytotoxic effects.
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Mech resistance cisplatin
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Dec drug accum due to alterations in cellular transport. Inc inactivation by thiol-containing proteins such as glutathione & glutathione-related enzymes. Inc DNA repair enzyme activity. Deficiency in mismatch repair (MMR) enzymes
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Absortion cisplatin
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Not absorbed orally. Systemic absorption is rapid & complete after intraperitoneal (IP) administration.
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Distribution cisplatin
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Widely distributed to all tissues with highest concentrations in the liver & kidneys. Less than 10% remaining in the plasma 1 hour after infusion.
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Metabolism cisplatin
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Plasma concen decay rapidly. W/i the cytoplasm of the cell, low concentrations of chloride (4 mM) favor aquation rxn (the chloride atom is replaced by a water- highly reactive species). Clearance from plasma slow after1st 2 hrs due to covalent binding w/ serum proteins. Approx 10%–40% excreted in urine in 24 hours, w/ 35%–50% excreted in urine after 5 days of admin Approx 15% excreted unchanged.
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Indications cisplatin
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Testicular ca, Ovarian ca, Bladder ca, Head/neck ca, Esophageal ca, Small cell & non–small cell lung ca, Non-Hodgkin’s lymphoma, Trophoblastic neoplasms.
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toxicity cisplatin
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Nephrotoxic, nausea/vomiting, myelosupression, neurotoxicity, & ototoxicity
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MOA carboplatin
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Covalently binds to DNA w/ preferential binding to the N-7 position of guanine & adenine. Cross-links (intrastrand (> 90%) or interstrand (< 5%). DNA adducts-> inhibition of DNA synthesis & transcription. Binding to nuclear & cytoplasmic proteins may result in cytotoxic effects. Cell cycle–nonspecific agent.
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Mech resistance carboplatin
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Reduced accumulation of carboplatin due to alterations in cellular transport. Inc inactivation by thiol-containing proteins. Enhanced DNA repair enzyme activity. Deficiency in mismatch repair (MMR) genes
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Distribution carboplatin
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Widely distributed in body tissues. Crosses the blood-brain barrier & enters the CSF. Does not bind to plasma proteins & has an apparent volume of distribution of 16 L.
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Metabolism carboplatin
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No significant metabolism. Aquation rxn in the presence of low concentrations of chloride (slower than cisplatin). Extensively cleared by the kidneys, 60%–70% excreted in urine w/i 24 hours. Elimin is slower than cisplatin.
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Indications carboplatin
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Ovarian cancer, Germ cell tumors, Head and neck cancer, Small cell and non–small cell lung cancer, Bladder cancer, Relapsed and refractory acute leukemia, Endometrial cancer.
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Toxicity carboplatin
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Myelosuppression is significant and dose-limiting. Dose-dependent, cumulative toxicity is more severe in elderly patients. Thrombocytopenia is most commonly observed. Nausea and vomiting (sig less than cisplatin). Renal toxicity (sig less common than w/ cisplatin) Electrolyte imbalance (hypocalcemia, hypokalemia, hypomagnesemia, and hyponatremia)
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MOA hydroxyurea
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Cell cycle specific analog of urea (S-phase). Inhibits ribonucleotide reductase, which converts ribonucleotides to deoxyribonucleotides, critical precursors for de novo DNA biosynthesis & DNA repair.
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Mech resistance hydroxyurea
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Inc expression of ribonucleotide reductase due to gene amp, inc transcription, & post-transcriptional mechanisms.
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Absorption hydroxyurea
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Oral absorption is rapid & nearly complete w/ bioavailability b/w 80% & 100%. Peak plasma concentrations are achieved in 1–1.5 hours.
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Metabolism hydroxyurea
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Approx 50% metabolized in the liver. About 50% of drug is excreted unchanged in urine. The carbon dioxide that results from drug metabolism is released through the lungs. Plasma half-life is on the order of 3–4.5 hours.
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Indications hydroxyurea
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Chronic myelogenous leukemia, Essential thrombocytosis, Polycythemia vera, Acute myelogenous leukemia, blast crisis, Head and neck cancer (in combination with radiation therapy), Refractory ovarian cancer
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Toxicity hydroxyurea
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Myelosuppression. Dose-limiting toxicity. Leukopenia. Median onset 7–10 days w/ recovery of WBC counts 7–10 days after stopping drug. Median onset of thrombocytopenia & anemia usually by day 10. Effect on bone marrow may be more severe in patients previously treated w/ chemotherapy and/or radiation therapy. Nausea/vomiting. Generally mild. Incidence reduced by dividing the daily dose into 2 or 3 doses. Stomatitis also occurs.
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