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RAMI ONC EXAM SBR
RAMI EXAM SBR
| Front | Back | More |
|---|---|---|
| Chemo man: Taxane | Alopecia | |
| Chemo man: Doxorubican | Alopecia, cardiotoxicity | |
| Chemo man: Cisplatin | Ototoxicity, nephrotoxicity | |
| Chemo man: Methotrexate | Stomatits/mucositis | |
| Chemo man: Vincristine | Peripheral neuropathy | |
| Chemo man: Bleomycin | Pulmonary pneumonitis | |
| Chemo man: Cyclophophamide | Hemorrhage cystitis | |
| Chemo man: Taxanes | Peripheral neuropathy | |
| Chemo man: Irinotecan | Intractable diarrhea | |
| Chemo man: 5-FU, 6-MP Methotrexate | Myelosupression | |
| Topoisomerase I | No ATP required, cuts double helix to unwind it Camptothecins: irnotecan, topotecan | durgs stabilize topo to cut cancerous and of course some normal DNA that are rapidly proliferating |
| Topoisomerase II | Requires ATP, cut DNA strand to unwind super coil alpha more prevalent in cancer cells, beta in normal cells Epipodophyllotoxins: etoposide, teniposide | durgs stabilize topo to cut cancerous and of course some normal DNA that are rapidly proliferating |
| Irinotecan (top I) | Prodrug (SN-38) active metabolite ADR:DIARRHEA and other acute cholinergic effects (treat w atropine), delayed SN-38 mucosal damage (treat w loperamide), Myelosuppression from SN-38 homo UGT1A1 28/6 more active CN-38 myelosuppresion risk, hetero = less | liposomal (PEG) form (Onivyde) has longer life and helps drug reach tumor before becoming CN-38 |
| Topotecan (top I) | ADRs: myelosuppression, diarrhea, mucosistis | |
| Etoposide (top IIa) | BOXED WARNING: bone marrow suppression, experienced physician use only | IV and PO, dose adjustment under 50 CrCl alopecia, NVD, anorexia, myelosuppresion |
| Teniposide (top IIa) | BOXED WARNING: bone marrow suppression, experienced physician use only | IV only, more lipophilic bc of solubility enhancer (kolliphor EL), 99% protein bound so interacts with highly protein bound drugs, caution w heparin and excessive agitation |
| Anthracyclines (rubcin) | stablize topoisomerase II Daunorubicin Doxorubicin Idraubicin Epirubicin red urine from double bonds on first ring | Natural products: Danuorubicin and Doxorubicin Natural product analogs: Idarubicin and Epirubicin Form oxygen free radicals that can cause cardiotoxicity (ECG changes) through fenton reaction w iron Catalase nutralizes 50% dose in hepatic dysfunction |
| Management of anthracyclines cardiotoxicity | Dexrazoxane, it chelates with iron so that iron does not form fenton reaction with rubicin drugs (anthracyclines) | delayed/chronic toxicity: limi tlifetime dose of anthracyclines other toxicities: severe myelosuppression, N/V, mucositis, alopecia, blistering and ulceration upon extravasation Aldoketoreductase and carbonyl reducase = rubicinol = CHRONIC toxicity |
| Daunorubicin and doxorubicin | daunorubicin has a smaller R group and become toxic faster doxorubicin has larger R group so has longer effect and takes longer before becoming toxic | liposomal Doxorubicin is even better with decrease in 2nd alc conversion, decreased extravasation, an increased uptake in tumor cells less in the heart |
| Epirubicin | less cardiotoxic than doxorubicin | rapidly eliminated due to flipped OH - H on bottom rubicin ring make ti less cardiotoxic, also has a large R group |
| Idarubicin | better intercalation into DNA from flatter D ring | large R group, removal of methyl (4-desmethoxydaunorubicin) on first ring increases antitumor activity on DNA |
| Mitoxantrone | cardiotoxicity greatly reduced from athracyclines but has the same MOA | resistant to NADPH/CYP450 limits ROS formation 3 rings instead of 4 makes in resistant due to intramolecular hydrogen bonding can give dark blue poop, sclera, nails |
| Bleomycin | inactivated by bleomycin hydrase, loses affinity to DNA, pulmonary and skin toxicity | no myelosuppression |
| Poly ADP-ribose polymerase (PARP) inhibitors - interferes with DNA repair | olaparib - tablet and capsule not interchangable rucaparib - high fat celays absorption niraparib talazoparib - 90h half life, excreted unchanged | bind to nicotinamide binding region, keeps PARP on DNA so it cannot repair itself ADRs: myelosuppression only work with mBRCA1/2 mutations |
| Antibody drug conjugates (ADC) | IV admin linker drugs, has bystander effect (kills neighboring antigen-negative cells) | |
| Vinca alkaloids - inhibit microtubule polymerization (prevent addition of subunit) | vincristine vinblastine vinorelbine | bind at the interface of two heterodimers ADR: neruopathy IV only intrathecal is fatal mictotubule binding affinity cristine>blastine>orelbine cristine has c/p neuropathy no myelosupression others are opposite |
| Taxanes - inhibit microtubule depolymerization | Paclitaxel - hypersensitivty reaction (Abraxane is alb-based paclitaxel that does nto cause hypersensivity - not interchanbgable) Docetaxel - hypersens Cabazitaxel - hypersens | bind to specific site on B-tubulin ADR: neruopathy, alopecia, peripheral neuropathy |
| Epothilones - inhibit microtubule depolymerization | xiabepilone | |
| nitrogen mustards | Cyclophosphamide 2A6, 3A4 Ifofamide -2A6, 3A4 Bendamustine - single and double crosslinking - 1A2 metabolism | prepare right before use because fast decomp, if 2 water molecules attach to beta carbons compound becomes inactive ADRS:melosuppression, cardiotox, hepatotox, urotox, pulmtox, malignancies |
| nitrosoureas | Carmustine Lomustine | high lipophilicity so good d for brain tumors Alkylating species: 2-chlorethyl and 2-hydroxyethyl carbocations​ ADRs: seizures, pulmornary fibrosis, prolonged myelosupression |
| alkylsulfonates | Bulsulfan | can cause hyperpigmentation (busulfan tan) |
| DNA methylators | Dacarbazine Procarbazine Temozolomide | O6-methylation MOA, resistance from repair )6 methylation by O6 alkylguanine DNA alkyltransferase |
| Organoplatinum compounds | Cisplatin Carboplatin Oxaliplatin | MOA: Intrastrand crosslinking not cell cycle specific |
| cyclophosphamide | mustard gas prodrug PO and IV give with mensa | acrolein metabolite: urotoxicity (hemorrhagic cystitis) and nephro toxic chloroacetaldehyde: nephro and neurotoxic aaziridinum ion leads alkylated and crosslinking give with MENSA |
| ifosfamide | mustard gas prodrug IV only give with mensa | same toxic metabolities prtonated 3 aziridine is active BOXED WARNING for bone marrow suppression, CNS toxicity, nephrotoxicity, hemorrhagic cystitis |
| Procarbazine | DNA METHYLATOR, methyl radical, inhibts MAO, used in hodgkins disase | diazene (2 N's) |
| dacarbazine | DNA methylator poor oral absorption Iv only, does not cross BBB | trazine (3 N's) |
| temozolomide | DNA methylator PO, readily passes BBB | trazine (3 N's) |
| cisplatin | organoplatinum compound | ADRs: nephro, neuro, ototoxicity, emesis, hypersensitivity reaction not cell cycle specific BW: severe renal toxicity, N/V, myelosuppression, dose dependent periphearl neuropathy |
| carboplatin | less reactive than cisplatin sensory neuropathy triggered/worsened by the cold | admin taxane drug before platinum to limit myelosuppression and enhance efficacy |
| nitrogen mustards vs organoplatins interacton with water | mustards are activated by water and organoplatins are activated by water as well | |
| primidine antagonists | Fluorouracil, capecitabine give with leucovirn/folic acid to increase binding to thymidylade synthase | both metabolized to active 5-FdUMP which inhibits thymidylate synthase thymidine phosphorylase makes capecitabine more cancer specific |
| purine antagonists | Mercaptopurine, thioguanine | |
| antifolates | Methotrexate, pemetrexed pemtrexed has higher affinity for tumor cells | MOA: inhibit dihydrofolate reducatse (DHFR) alkaline urine helps excrection Leucovotin is resume therapy for high dose MTX DDI with cisplatin, NSAIDs |
| DNA polymerase/DNA chain elongation inhibitors | pyrimidine analogs: cytarabine, gemcitabine | myelosuppression |
| DNA methyltransferase inhibitors | azacitidine, decitabine | |
| RESET Camptothecins (natural product analogs) (topo I) (topo posions) | Irinotecan - acute diarrhea is a cholinergic reaction Topotecan | Target S phase Irinotecan has pypiridene ring, topotecan has dimethyl amine group to increase water solubility + closed lactone ring make them good for injection Diarrhea and myelosupprion - SN-38 UGT1A1 28/6 causes toxic SN-38-O10 glucuronide |
| Epipodophyllotoxins (topo IIa) (natural product analog) (totpo posions) | Etoposide Teniposide | Target S phase lipophilicity (higher logP) enhances uptake reduce kolliphor El hypersensitivity by pretreating with steroid and antihistamine BBW: bone marrow suppression, experienced physician use |
| Antracyclines (anticancer antibiotic) | Doxorubicin (natural product) Danurubicin (natural product) Idarubicin (natural product analog) Epirubicin (natural product analog) | stabilize topo IIa all 4 rings structures with quinone and hydroquin in the middle that makes them liable to ROS Low catalase in cardiac tissue leads to additional ROS and fenton rxn with Fe Aldoketo/carbonyl reductase (AKR)(CBR) = rubicinol |
| Anthracenedione (anticancer antibiotic) | Mitoxantrone | stabilize topo IIa 3 ring structure causes intramolecular hydrogen bonding to limit ROS formation = reduced cardiotoxicity GLUcuronide conjugates make feces, sclera and nails dark blue |
| Bleomycin (anticancer antbiotic) | works withe O2 to form hydrogen peroxide (ROS) that reacts with guanine to break DNA strands | unlike anthras that hate ROS and make it on accident, bleomycin uses them to its advantage bleomycin is inactivated by bleomycin hydrase, pulmonary system and skin do not have large levels of bleo hydrase so experience toxicity no myelosuppression |
| Nitrogen mustards | Cyclophosphamide Ifosfamide Bendamustie | Aziridine products are responsible for DNA crosslinking Give with MENSA to mitigate urotoxicity BOXED WARNING: comes from Acrolein (uro/nephrotoxic) and chloroacetaldehyde (neuro/nephro toxic) formation |
| Nitrosoureas | Carmustine Lomustine | High lipophilicity, good for brain tumors ADRs; seizures, pulmonary fibrosis, prolonged myelosuppression Alkylating species: 2-chlorethyl and 2-hydroxyethyl carbocations​ |
| Alkylsulfonates | Busulfan | Useful in CML, can cause hyerpigmentation (busulfan tan) |
| DNA Methylators | Dacarbazine Procarbazine Temozolomide | add methyl group at O6 (O6 methylation) causes mutations and cell destruction |
| Organplatinum Compounds | Cisplatin - Carboplatin - less reactive than cisplatin Oxaliplatin - acute neuropathy worsend/triggered by the cold, QT prolongation | MOA: instrastrand DNA crosslinking, prevent DNA repair no alkylation, attaches directly to O6 of guanine use taxane before platinum to decreaese myelosuppression |
| Pyrimidine antagonists | Fluorouraci (5-FU) Capecitabine | MOA: metabolised to 5-FdUMP (active form) through ribonucleotide reductase and inhibits thymidylate synthase by binding to it an a cofactor Thymidine phosphorylase turns capecitabine into 5-FdUMP give with leucovorin to increase binding to target |
| Purine antagonists | Mercaptopurine - activated by HGPRT Thioguanine | Mercaptopurine MOA: inhibit amidophosphoribosyl transferase to inhibit natural (de novo) purine synthesis (allop) Thioguanine MOA: Putting 6-thioguanine nucleotides into DNA/RNA inhibits further elongation inactivated by TPMT and xanthine oxidase |
| Antifolates | Methotrexate Pemetrexed | MOAs: Inhibit dihydrofolate reductase (DHFR) - inhibits GAR formyltransferase to prevent de novo purine synthesis - and TS Uptake at RFC1 and PCFT, ion retained/trapped at FPGS (pemetrex higher affinity for all) alkaline urine helps MTX excretion |
| DNA polymerase/DNA chain elongation inhibitors (pyrimidine analogs) | Cytarabine Gemcitabine | MOA: drug in triphosphate form competes with dCTP deaminase = inactivates kinase = activates gemcitabine elimination is gender dependent |
| DNA methyltransferase inhibitors | Azacitidine Decitabine | MOA: prevent DNA and RNA hypermethylation activated through citidine kinases |
| Vinca alkaloids (natural product analog) | Vincristine -c/p nerotoxicity, constipation no myelosuppression Vinblastine - dose limiting toxic myelosuppression Vinorelbine - dose limiting toxic myelosuppression | MOA: inhibits microtubule polymerization ADRs: extravasation exacerbated by cold IV only intrathecal is fatal binding affinity rankings: vincristine>vinblastine>vinorelbine |
| Taxanes | Paclitaxel (natural produc) - kolliphor E pretreat all taxane with antihistamine - abraxane is the albumin bound paclitaxel that does not cause hypersensitivty (not interchangable) Docetaxel/Cabazitaxel (analog) - pretreat for hypersens via polysorbate | MOA: inhibits microtubule depolymerization HIs227 keeps faces separate bind to specific site on b-tubulin ADRs: alopecia, myelosuppressio CI neutrophil <1500, peripheral neuropathy cabazitaxel lowest P-gp activity better efficacy and resist |
| Epothilones | Ixabepilone | MOA: inhibits microtubule depolymerization inhibition causes neuropathy |
| PARP Inhibitors (poly ACP ribose polymerase) | Olaparib Rucaparib Nirasparib Talazoparib - worst myelosuppresion but all are supprssive | MOA: interferes with repair lads to build up of double strand breaks and lethal damage to cells (synthetic lethality) can only be used in mBRCA1/2 mutations many interactions in nicotinamide (pharmacophore) binding region MIMIC NAD |
| Antibody Drug Conjugates (ADC) | Tratuzumab | mAb-linker-drug delivery to cancer cell IV admin Bystander effect can kill neighboring cells in areas without antigen |
Created by:
beezy41