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Blood and Lymphoid > Sketchy Pharm - Antineoplastics > Flashcards

Sketchy Pharm - Antineoplastics Flashcards

1
Q

Explain the biosynthesis pathway of pyramidine and purine synthesis.

A

Ribonucleotides are made first in a cell which are then converted into deoxyribonucleotides later, precursor for all ribonucleotides is UMP (Uridine Monophosphate).
UMP is phosphorylated to UDP

UDP is converted into dUDP (deoxyuridine monophosphate) by ribonucleotide reducatase.
dUDP is converted to dUMP by a kinase.
dUMP is then converted into dTMP via thymidine synthetase. (deoxythymidine monophosphate) In order to do this a methylated THF is required which is then converted to DHF (it loses 2 hydrogens and a carbon in the process of forming dTMP). dTMP is then used to make Thymidine.

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2
Q

Explain the folate cycle.

A
  • Methylated THF is converted to DHF when donating a carbon for a metabolic process like synthesis of thymidine.
  • DHF reductase then converts DHF into THF.
  • THF is then methylated.
  • This cycle continues on.
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3
Q

Explain the MOA of methotrexate.

A

Methotrexate is a folate analong, it irreversibly binds to DHF reductase enzyme, as a result no THF is formed and the folate cycle comes to a halt. There is a built up DHF in the cell.

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4
Q

What are the indications of methotrexate other than for cancer treatment?

A
  • Non surgical treatment for ectopic pregnancy during early phase
  • Abortion
  • It can be used to treat psoriasis and psoriatic arthritis.
  • Can be used to treat RA with DMARDS therapy.
  • Due to its immunosuppressive effect it is used for IBD, SLE, vasculitis, dermatomyositis
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5
Q

What are the side effects of methotrexate?

A
  • Bone marrow suppression, can lead to pancytopenia
  • Folate deficiency, this can cause megaloblastic anemia
  • Increased risk for infections
  • Pulmonary fibrosis - restrictive lung disease
  • Hepatotoxicity by directly damaging hepatocytes
  • Alopecia, stomatitis
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6
Q

What is leucovorin used for?

A

Leucovirin aka folinic acid restores folate levels as it does not require DHF reducatase, furthermore it restores DHF activity by displacing methotrexate from its binding site.It reverses the toxicity caused by methotrexate.

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7
Q

What is the MOA of 5FU?

A

It is metabolised in our body to fdUMP (5 florodeoxyuridine monophosphate)It is a cytotoxic pyramidine analog, forms a complex with thymidine synthetase (which converts dUMP to dTMP) and THF, inhibiting thymidine synthesis.This leads to a build of dUMP.Other metabolites of 5FU also inhibit other processes such as incorporating into growing RNA strands as 5UTP, it inhibits RNA processing and RNA translation, or can get incorporated into DNA as 5dUMP to inhibit DNA’s function

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8
Q

Side effects of 5FU.

A
  • The most significant complication of 5FU is due to the fact that it significantly damages the rapidly dividing cells of intestinal mucosa leading to exfoliation of these cells and causing severe diarrhea.
  • Other side effects are cutaneous complications – photosensitivity, rash and hyperpigmentation, myelosuppression & pancytopenia
  • Leucovorin does NOT rescue patient from 5-FU.
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9
Q

MOA of Hydroxyurea.

A

UMP is a precursor to all nucleotides. It is phosphorylated to UDP. UDP (uridine diphosphate) is the substrate for ribonucleotide reductase – UDP -> dUDP. (dUDP -> dUMP -> dTMP).Hydroxyurea inhibits ribonucleotide reductase, preventing UDP conversion into dUDP.

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10
Q

What is 5FU mainly used for?

A

Colorectal cancer.

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11
Q

What are some other usesof hydroxyurea?What are its side effects?

A
  • Used in reducing veno-occlusive disease like in sickle cell patients, through a poorly understood mechanism it increases the levels of HbF (fetal hemaglobin)
  • Diarrhea, mylosuppression and pancytopenia.
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12
Q

What phase of the cell cycle are methotrexate, 5FU and hydroxyurea effective in?

A

These are anti metabolites, so effective only during the S phase since this is when DNA synthesis takes place.

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13
Q

Explain the process of synthesis of purines.

A

Purines consist of ribose, nitrogenous base and a couple phosphates. Synthesis starts with ribose. Precursor to all purines is PRPP (Phosphoribosyl pyrophosphate)
PRPP is converted into IMP (Inosine monophosphate)
IMP is then converted either into AMP or GMP (adenosine monophosphate or guanosine monosphosphate)

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14
Q

MOA of Azathiopurine.

A

Azathiopurine is converted into 6MP (Mercaptopurine).6MP is activated by HPGRT (Hypoxanthine guanine phosporibosyl transferase). This then blocks synthesis of IMP from PRPP,leading to inhibiton of DNA and RNA synthesis. As a result the cell is arrested in S phase.

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15
Q

What are the indication for Azathiopurine?

A
  • 6MP treats hematologic malignancies (e.g. ALL).
  • Can also be used to treat autoimmune inflammatory conditions (e.g. graft rejection, SLE, autoimmune hemolytic anemia, RA [but not as effective as MTX for RA],
  • IBD [Crohn’s & UC].
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16
Q

What is the MOA, indication and side effects of Mycophenolate Mofetil?

A
  • Prevents formation of IMP to GMP, it is an IMP dehydrogenase inhibitor.
  • This leads to decreased B and T cell proliferation, decrease in antibodies production.
  • Can be used to treat autoimmune conditions (e.g. SLE, solid organtransplant rejection, Myasthenia Gravis, RA)
  • CAUTION: May cause GI distress (nausea, diarrhea, cramping), can cause myelosuppression -> infections.
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17
Q

What are the side effects of 6MP?

A
  • Myelosuppression, this can lead to infections and reactivation of latent viruses such as EBV
  • Pancreatitis and hepatotoxicity
  • 6-MP is inactivated by Thiopurine Methyl-Transferase & Xanthine Oxidase. It inhibits Xanthine Oxidase (just like allopurinol) and this leads to increase levels of purine analogues, including 6-MP -> ↑risk of side effects. Due to this, allopurinol has an ability to reduce the dose of 6MP in chemotherapy, sometimes it has to be reduced as much as 75%.
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18
Q

Name theNeolithic Antineoplastics.What is their MOA.

A

Cladribine, Cytarabine and Gemcitabine.They inhibit alpha and beta DNA polymerase, preventing DNA synthesis and repair, arresting cell in the S phase.

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19
Q

What is the MOA, indication and side effects of Cladribine?

A
  • Cladribine (“Clad” in bear skins) – cytotoxic purine analog. Resistant to purine deaminase (so it won’t get degraded) -> can reach very high intracellular levels (cytotoxic). Inhibits DNA polymerase α & β, preventing DNA synthesis and repair (S-Phase).
  • Is the drug of choice for treating Hairy Cell Leukemia (“clad in bear hair”), can also be used for other leukemias/lymphomas.
  • Side effects: Myelosuppression.
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20
Q

What is the MOA, indication and side effects of Cytarabine?

A
  • Cytarabine “Saber tooth” – cytotoxic pyrimidine analog. Does NOT affect folate cycle. Instead, it is converted into a triphosphate metabolite that competitively inhibits DNA polymerase α & β -> preventing DNA synthesis and repair (S-Phase).
  • Cytarabine is only active in hematologic malignancies* (e.g. AML, NHL).
  • CAUTION: myelosuppression
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21
Q

What is the MOA, indication and side effects of Gemcitabine?

A
  • Gemcitabine (“gems inside geode”) – cytotoxic pyrimidine analog. Inhibits DNA polymerase α & β -> preventing DNA synthesis and repair (S-Phase). Active against both hematologic malignancies and solid tumors.
  • CAUTION: myelosuppression
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22
Q

What is ofosfamide?

A

It is an alkylating agent, used in the treatment of testicular cancer

23
Q

MOA of cyclophosphamide.

A

Its a cytotoxic alkylating agent, it works by attaching an alkyl group to the Guanine in DNA, this leads to intra strand and interstrand cross links.

  • Hence it is cell cycle non specific, like all the other alkylating agents.
  • It is required to be activated by CYP450.
24
Q

What are the indication for cyclophosphamide?

A

Can be used for many hematologic and solid tumors.It is one of the most potent immunosuppressive therapies available (tx of nephrotic syndrome, vasculitis, autoimmune hemolytic anemia, RA etc).

25
Q

What are the side effects of cyclophosphamide?

A
  • Very cytotoxic – use is limited to SEVERE cases.
  • Myelosuppression – since cyclophosphamide is so strong, patients need CBC every few weeks to check myelosuppression. Pancytopenia is common.
    Hemorrhagic cystitis (metabolized by the kidney into Acroline -> excreted in urine -> renal cell death/necrosis). Acroline is toxic to uroepithelial cells.
  • Prevent hemorrhagic cystitis using aggressive hydration and Mesna “Maze” (binds and inactivates Acroline)
  • Causes a dose dependent effect of development of bladder cancer, usually high grade transitional cell carcinoma, this increased risk persists for years after discontinuation of the drug.
  • Cyclophosphamide can also induce hyponatremia due to SIADH (syndrome of inappropriate antiduretic hormone), this leads to marked water retention.
  • Cyclophosphamide can cause infertility and premature menopause.
  • Decrease in sperm count, and even azoospermia.
26
Q

MOA of busulifan.

A

It’s a cytotoxic alkylating agent, forms intra strand cross links

27
Q

Name Nitrosoureas drugs and their MOA.What are they used for and their associated side effects?

A
  • Ends with a suffix ‘mustine -carmustine & lomustine.
  • Streptozotocin is one of the naturally ocurring agents
  • Require a biotransformation via non enzymatic hydroxylation in the liver, once active they can cross the blood brain barrier and hence are used to treat brain tumors like gliobastoma multiforme
  • MOA involves cytotoxic alkylating agent
  • Side effects are CNS effects such as dizziness, convulsions, ataxia, could be anything.
28
Q

What are the indications of busulifan?

A

It has a strong property of myelosuppression, one of its uses involves as a conditioning agent prior to BM transplant, especially in leukemias/lymphomas patients

29
Q

What are the side effects of bisulifan?

A
  • Myelosuppression
  • Associated with lung toxicitythis can express itself as acute lung injury, interstitial fibrosis and alveolar hemorrhage.
  • Hyper pigmentation, called ‘bisulfan tan’.
30
Q

Name the platinum analogs used in chemotherapy and their MOA.

A

Cisplatin, Carboplatin and Oxaliplatin.Their MOA is not properly understood, it is belived they insert themselves in the DNA, cause interstrand and intrastrand linkages by cross linking within themselves.

31
Q

What are platinum analogs useful against?

A

They are effective against a broad range of cancers including small cell and non small cell carcinomas, testicular cancers etc.

32
Q

What are the side effects of platinum analogs?

A
  • Neurotoxicity, leading to Ototoxicity (->sensineuroal hearing loss & tinnitus).Outer hair cells in the organ of Corti are targeted leading to high frequency hearing loss. All side effects are less likely with Carboplatin & Oxaliplatin.
  • Cisplatin causes peripheral neuropathy (paresthesia, numbness and pain) in a stocking glove distribution.
  • Cisplatin is also especially nephrotoxic -> AKI, ATN (muddy brown casts on urinalysis)
  • Amifostine – organic thiophosphate agent that can protect against Cisplatin nephrotoxicity. Binds to and inactivates the toxic metabolites of Cisplatin. Also scavenges free radicals made by Cisplatin in renal tissue.
  • Primary approach to reduce Cisplatin-induced nephrotoxicity is IV Saline fluids (due to cost of Amifostine).
  • Main toxicity associated with other drugs like carboplatin are myelosuppression.
33
Q

Name a few antibiotics that are used for chemotherapy.

A

Bleomycin, Actinomycin D, Daunorubicin and Doxorubicin.

34
Q

What is the MOA, indications and side effects associated with Bleomycin?

A
  • Bleomycin is a small peptide that has an Iron-binding site at one end and a DNA-binding site on the other -> binds to DNA and then forms free radicals that cleave DNA.
  • As a result cell is arrested in G2 phase specifically.
  • Useful for Hodgkin’s and Non-Hodgkin’s Lymphoma, along with solid malignancies.
  • Causes dose limiting toxicity is due to pulmonary toxicity (usually pneumonitis, pulmonary infiltrates). In some cases pulmonary toxicity can be fatal.
  • Can also cause hyperpigmented atrophic striae, rash, & exfoliation.
  • Can also cause mucositis and stomatitis (mucosal inflammation of the mouth).
  • Can cause alopecia.
  • Has only a LOW risk of myelosuppression.
35
Q

What is the MOA, indications and side effects associated with Anthracyclines?

A

Anthracyclines were initially isolated from actinomyces bacteria. MOA involves:

  • Make free radicalsthrough an Iron-dependent reductive process (like bleomycin). High affinitybinding for DNA intercalation (fit into DNA) -> prevent DNA and RNA synthesis.
  • Block Topoisomerase II
  • Doxyrubicin specifically is a very common drug used for solid and hematologic malignancies. Associated with dose dependent irreversible cardiotoxicity due to build of free radicals in cardiomyocyte mitochondria -> manifests as dilated cardiomyopathy.
  • Dexrazoxane “up on the deck with a razor” – an Iron Chelator -> prevents Anthracycline-induced cardiotoxicity.
  • Other side effects are myelosuppression, mucositis & stomatitis, alopecia
36
Q

What are the indications and side effects of Etoposide and Teniposide?What are the indications and side effects of Irinotecan and Tepotecan?

A
  • For etoposide and teniposide: solid and hematologic tumors, AE are myelosuppression and alopecia.
  • Tepotecan is indicated in ovarian and small cell lung CAs.
  • Irinotecan is effective in colon CA.
  • Both cause myelosuppression and severe diarrhea (damage to rapidly dividing gut epithelial/mucosal cells).
37
Q

What is the MOA, indications and side effects associated with Actinomycin D?

A
  • Intercalates into DNA -> blocks DNA and RNA synthesis.
  • Useful in pediatric malignancies (e.g. Wilm’s Tumor, Ewing Sarcoma, Rhabdomyosarcoma)
  • Myelosuppression, alopecia
38
Q

Name the topoisomerase inhibitors that are used as chemotherapeutic agents.What is their respective MOA.

A

Etoposide and Teniposide inhibit topoisomerase II - the function of this enzyme is to re-ligate double strand breaks to relieve supercoiling, when this is inhibited double strand breaks accumulate in DNA, leading to cell death.Irinotecan and Tepotecan inhibits topoisomerase I - this enzyme causes single strand breaks to relieve supercoiling. This induces DNA damage and cell death.

39
Q

In what stage of the cell cycle the cell is arrested by topoisomerase inhibitors?

A

S and G2 phase (in G2 phase DNA is checked for errors)

40
Q

What is the MOA of Vinchristine, Vinblastin and Taxanes.Name Taxanes.

A

Vincristine and Vinblastinarecytotoxic vinca alkyloid. Works by binding to tubulin building blocks and preventing their polymerization -> prevents microtubule formation -> prevents mitotic spindle assembly.As a result the cell is arrested in metaphase.Taxanes (e.g. paclitaxel, docetaxel, cabazitaxel) – cytotoxic plant alkaloids. Works by binding directly to microtubules and stabilize them -> prevents their depolymerization -> improper mitotic spindle function. Arrests cells in M phase.

41
Q

What are the indications and AE of Vinchristine, Vinblastin and Taxanes.

A
  • Vinchristine treats: ALL, Multiple Myeloma, HL, and NHL + numerous pediatric tumors. AE of Vinchristine:
  • Neurotoxicity -> peripheral sensory neuropathy (stocking & glove)//
  • Can cause autonomic dysfunction -> orthostatic hypotension, paralytic ileus*, and constipation.
    Alopecia, Mild myelosuppression in comparison to vinblastine. Vinblastin treats: hematologic and solid CAs,
  • AE involve more severe myelosuppression (“blasts your bones”),
    Alopecia.
  • Taxanes: Peripheral sensory neuropathy, alopecia, myelosuppression
42
Q

What is the suffix for tyrosine kinase inhibitors?

A

-tinib, ‘t’ for tyrosine kinase and ‘inib’ for inhibitor

43
Q

What is the MOA, indications and AE of Imatinib?

A

Imatinib targets specific TK to treat CML. Imatinib blocks the TK domain of the BCR/ABL (“BReakABLe”) fusion protein in CML. Most common cause of CML is t(9;22) aka Philadelphia chrosome.

  • CML is characterized by increase in number of immature white blood cells like granulocytes, eosinophils, neutrophils and basophils.
  • Imatinib also inhibits c-kit in Gastrointestinal Stromal Tumors (GIST).
  • AE: fluid retention -> ankle & periorbital edema.
44
Q

What are kinase inhibitors used for?

A

They can be used for a variety of hematologic and solid malignancy.

45
Q

What are the indications and side effects of Erlotinib?

A
  • Inhibits TK domain of EGFR. Treats solid tumors with EGFR overexpression. 1st line for non-small cell lung cancers.
  • AE: cutaneous adverse effects (acneiform rash) due to abundant EGFR expression in the skin, diarrhea – very common but not usually severe.
46
Q

What are the tyrosine kinase inhibitors that inhibit VEGF-R?What are their indications and AE

A

Sunitinib and Sorafinib.

  • Sorafenib is useful in RCC and Hepatocellular CA.
  • Sunitinib also treats RCC, as well as GIST.
  • Hyperkeratosis and rashes, and increased risk of hemorrhage (“bleeding wound”) by disrupting function of endothelial cells expressing VEGFR.
47
Q

Vemurafinib.

A

Vemurafinib– NOT a ‘-tinib. Instead it inhibits BRAF Kinase (“Ben Franklin”). BRAF is a protein kinase involved in melanocyte proliferation. BRAF mutation V600E (“ve-mu-raf-inib”) is seen in 40-60% of patients w/ melanoma. Leads to improved survival and long-term outcomes in these patients.

48
Q

What are the suffix for monoclonal antibodies.What is the significance of this?

A

-mab = monoclonal Ab – means the Ab’s are from the same lineage and target the same antigen.“-xi”-mab = chimeric“-zu”-mab = humanizedChimericantibodies are morelikely to lead to serum sickness which is a type 3 hypersensitivity reaction that develops 7 to 10 days after the infusion of the drug.

49
Q

Rituximab.

A
  • Rituximab (a chimeric mab) – binds to CD20 of B-Cells -> good to treat CD20+ NHL, by binding to the CD20 receptor on B cells it activates a complement dependent AND cell dependent cytotoxicity.
  • Combined with other chemotherapeutics, can be used for CLL (“tapestry above”, this cancer consists of aberrant proliferation of B cells and T cells).
  • Treats RA (DMARD; usually used in combo w/ MTX), also good for microscopic polyangiitis and Wegener’s Granulomatosis.
  • Important to know that immunoglobulins level don’t change dramatically due to treatment with Rituximab, although repeated treatments with this agent can cause decrease in immunoglobulins.
    Adverse Effects:
  • Can cause late-onset neutropenia.
  • Can cause Hep-B reactivation.
  • Associated w/ increased risk of PML from reactivation of JC virus.
  • Infusion reaction due to ‘–mabs’ may cause headache, fever, skin rash, pruritis, dyspnea, and hypotension – thought to be due to Ab-Ag binding causing cytokine release - usually managed with NSAIDs.
  • Chimeric antibodies can cause Serum Sickness (Type 3 HS; tissue deposition) w/in 7-10 days. Symptoms include fever, rash, and athralgias that begin 7-10 days later. Due to the host creating antibodies against the –ximabs and causing immune complexes to form that deposit in tissues. Proteinuria and lymphadenopathy can also be seen.
50
Q

Cituximab.

A
  • Cetuximab “Tusks” – chimeric mab that targets EGFR (“giraffe”) which is a TK Receptor.
  • Good for use in solid tumors (e.g. squamous cell carcinoma of head and neck and colorectal cancer)
    Adverse Effects: Due to EGFR expression in the skin, cetuximab can cause a papulopustular acneiform rash. Can also cause infusion reaction
  • Cituximab is highly associated with infusion reaction.
  • Since Cetuximab is a chimeric ‘-mab’, it can cause Serum Sickness (w/in 7-10 days) but is less likely than Rituximab.
51
Q

Bevacizumab.

A

Bevacizumab “Beverage lady” – binds VEGF -> prevents it from binding to receptor -> anti-angiogenic drug (“chopped up red carrots”).Due to its anti-angiogenic action, it’s good for treatment of metastatic tumors (e.g. colorectal cancer, lung cancer). Also treats Wet Macular Degeneration.Adverse Effects:

  • Can cause poor wound healing, can cause bleeding/hemorrhagic events.
  • Can also increase risk of thrombotic events (angina, MI, strokes),
  • Gastrointestinal perforation (most often in setting of colorectal cancer). If a patient has acute abdominal pain while taking bevacizumab, think GI perforation.
52
Q

Alemtuzumab.

A
  • Alemtuzumab “Alms” – IgG –mab that binds to CD52 (found on B & T cells and NK cells & monocytes [mature lymphocytes + monocytes]). -> initiates a direct cytotoxic effect through complement activation & Ab-dependent apoptosis.
  • Good for use in CLL (chronic lymphocytic leukemia)
  • AE: Myelosuppression, infections, and even the emergence of autoimmune disorders. Infusion reactions (“chubby cherub w/ ivy”)
53
Q

Trastuzumab.

A
  • Trastuzumab “tapestry” – useful for HER2+TK (“Her 2 babies in the tire swing”) breast cancer. Works by binding to Growth Factor Receptor 2 (HER2, c-erbB2) -> inhibits MAPK & PI3K AKT intracellular signaling-> increasing degradation of HER2 and facilitating Ab-mediated cell death of tumor cells.
  • HER2 is over expressed in 20% breast cancers and some adenocarcinomas of ovaries, stomach, lung and salivary glands.
  • AE: can cause cardiotoxicity (decreased LVEF -> systolic heart failure (rare for it to progress to HF though).
  • Infusion reactions (“chubby cherub w/ ivy”).

Blood and Lymphoid (47 decks)

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