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Pharmacology II > Exam 4 - Chemo drugs > Flashcards

Exam 4 - Chemo drugs Flashcards

1
Q

Children’s Oncology Group Study (COG)

A
  • Randomized controlled study to test different drugs (on different arms) and compare outcomes
  • Helps develop better treatment plans in the long run
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2
Q

Stages of Tumor Formation

A
  1. Hyperplasia - increase in size/number of cells (Ex: muscle cells).
  2. Metaplasia - once cell type changes to another; may see LOSS of FXC. (Ex: chronic smokers, lungs are exposed to hot gases. Ciliated cells are not there anymore, so they become scar tissue).
  3. Dysplasia - Lose uniformity and orientation of cells. May be reversible, but closer towards unchecked growth.
  4. Neoplasia - uncoordinated growth; lose response to suppressor genes.
    >Immortalization of Telomerase.
    >P53 triggers apoptosis of cells normally. Without this, you have unregulated growth.
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3
Q

How do you describe a benign tumor?

A
  • Localized, enclosed in fibrous capsule
  • Can be removed surgically
  • Good prognosis
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4
Q

How do you describe a malignant tumor?

A
  • Spreads and destroys adjacent tissue
  • No capsule, high metastasis
  • Fatal
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5
Q

Tumor Grading System

A

Grade 1: Closely resembles tissue of origin. Retains specialized function.

Grade 2: Moderately differentiated, less tissue of origin, increased mitosis

Grade 3: Poorly differentiated, tumor doesn’t resemble tissue of origin, increased variation, increased mitosis.

Grade 4: Very poorly differentiated, no resemblance to tissue of origin, highly variable, enhanced mitosis, metastatic.

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6
Q

Principles of Therapy (7)

A
  1. Single “clone-ogenic” tumor stem cell has potentil for unlimited replication.
  2. Different tumors have different growth patterns, which change based on disease.
  3. Gompertzian cell growth
  4. Treatment should involve removal of the tumor as the first step.
  5. Drug conc., exposure time, and freq. of administration is critical for effectiveness.
    - Maximize drug concentration
    - Protect patient
  6. Early detection (pt. ed., screening, etc.).
  7. Toxicity
    Neoplastic cells: desired effect.
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7
Q

Well-differentiated

A

Cells targeted more effectively.

As you lose the differentiation, it becomes harder to target cells.

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8
Q

Localized

A

Localized can be removed by surgery or radiation.

Disseminated, like leukemia, you need to do more drug therapy, bc its systemic.

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9
Q

Gompertzian Cell Growth

A

Each tumor takes a constant time to double its size. Growth fraction decreases as the tumor size increases.

Growth is initially rapid, then flattens out, because it outgrows the nutrient supply.

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10
Q

Time at diagnosis, how many tumor cells are there, approximately?

A

10^8 at Dx.

10^6 cells = 1 mm
10^9 cells = 1.24 cm = 1 gm
10^12 cells = 20 cm = 1 kg

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11
Q

First order cell kill:

A

Therapy gives you a fraction of the cells killed.

If you kill 99.9% of 10^12 cells, you still have 10^9 left of cells that can still grow.

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12
Q

Treatment should involve removal of tumor first.

When is surgery appropriate? Radiation? Chemo?

A

Surgery - well-localized and well-differentiated tumors.

Radiation - localized tumors, NOT easy to remove.
Ex: brain and pancreas.

Chemotherapy - Good for systemic cancers; will see systemic effects.Targets all rapidly dividing cells.

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13
Q

What happens in myelosuppression?

A
  • Severely immunosupressed
  • Develop neutropenic fever
  • Put on BSA

Fever might be the only sign of infection. Can get fungal infections, resistant bugs, and viruses.

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14
Q

What kind of fruit do you give to a myelosuppressed patient?

A
  • Orange or banana

- PEELED fruit

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15
Q

How do you AVOID checking temperature on neutropenic patient?

A

Rectum

  • Worried about perforation and translocation of GI bugs.
  • Can cause septicemia.
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16
Q

What are the dosage regimens?

A

High dose w/ intermittent schedule to allow for recovery of cells.

  • Time for maximum susceptibility where drug acts in cell cycle and where tumor is in growth curve.
  • Drugs given prolonged to hit the different cell cycles; want to hit when its dividing.
  • Depends where tumor is in growth curve (good flow slow growing tumors).
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17
Q

Cell Cycle

A
  • G0: resting phase, no division
  • G1: enzyme synthesis prior to DNA synthesis, 18-30 hours
  • S: DNA synthesis, 10-20 hours
  • G2: pre-mitotic phase, protein and RNA synthesis 2-10 hours
  • M-phase: Mitosis: cell division, 30-60 minutes.

Most non-malignant cells are in G0.
Anticancer drugs are not only selective for tumor cells. They target rapidly dividing cells as well.

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18
Q

Growth Fraction:

A

-Portion of cells actively dividing; early stages of growth

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19
Q

S fraction:

A
  • Cells in S-phase

- More cells in S-phase means its more aggressive

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20
Q

Doubling time:

A
  • Time necessary for tumor to double in volume.
  • As tumor gets bigger, doubling time starts to slow down.

-Short doubling times are found in more aggressive tumors.

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21
Q

How do we design our dosage regimens?

A

Combination therapy

  • Rare to see patient on one drug
  • Minimize resistance
  • Can use lowe doses of all drugs to limit toxicity

Adjuvant therapy

  • Lots of drugs used to treat and minimize toxic effects
  • Antiemetics
  • Stimulate bone marrow

Patients get a big course of chemo, which knocks down their cells. Then we give them growth factors to stimulate growth of their healthy cells.

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22
Q

Toxicity: Kills cells with highest growth rates. What’s affected?

A

Neoplastic cells: desired effect.

  • Bone marrow - willl cause myelosuppression and immune supression
  • GI tract - oral and intestinal ulceration (stomatitis)
  • Hair - Alopecia.
  • Decreased sperm production and menstrual irregularities.
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23
Q

If you see a patient with stomatitis and mucositis, what are you concerned about?

A

May need to switch them to parenteral nutrition, because they won’t want to eat.

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24
Q

How do cells generate resistance to chemo?

A
  • Drug not able to get into the cell (decreased uptake).
  • Metabolism of drug more quickly.
  • Able to repair DNA more quickly.

When you develop resistance, need to switch to a different type of therapy.

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25
Q

Cancer chemotherapy (Synthetic)

  • Alkylating agents
  • Antimetabolites
A
  • Alkylating agents: alkylate purine/pyrimidine bases, blocks DNA synthesis for cancer cells.
  • Antimetabolites: structural analogs of purines, pyrimidines, or cofactors needed for DNA synthesis; added to chain and prevent further replication.
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26
Q

Cancer chemotherapy (Natural)

  • Plant alkaloids
  • Antibiotics
  • Biological response modifiers
  • Hormonal agents
  • Immunostimulants
A

PA: inhibit mitotic spindle formation and topoisomerase II.

Abx: intercalate DNA base pairs and break strands.

BRM: antibodies, kinase and GF inhibitors.

HA: inhibit hormone sensitive tumor growth.

IM: stimulate immune system

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27
Q

Topoisomerase:

A

Cuts single strand breaks in DNA to unwind and relax the DNA.

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28
Q

What antibiotics target bacterial topoisomerase?

A

Flouroquinolones

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29
Q

What type of cancer chemotherapy has greater specificity for cancer cells?

A
  • Biological response modifiers
  • Hormonal agents
  • Immunostimulants

Have less side effects

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30
Q

ALKYLATING AGENTS

A

…

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31
Q

ALKYLATING AGENTS

Nitrogen Mustards

A
  • Mechlorethamine (Mustargen)
  • Cyclophosphamide (Cytoxan)
  • Ifosfamide (Ifex)
  • Chlorambucil (Leukeran )
  • Melphalan (Alkeran)

-Come from mustard seeds and mustard gas.

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32
Q

ALKYLATING AGENTS

Nitrosoureas

A
  • Carmustine (BCNU)
  • Lomustine (CCNU)
  • Streptozocin (Zanosar) (targets pancreatic b-cells)
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33
Q

ALKYLATING AGENTS

Other

A
  • Dacarbazine (DTIC)
  • Procarbazine (Matulane)
  • Temozolomide (Temodar)
  • Altretamine (Hexalan)
  • Busulfan (Myleran )
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34
Q

ALKYLATING AGENTS

Platinum coordination complexes

A
  • Cisplatin (Platinol)
  • Carboplatin (Paraplatin)
  • Oxaliplatin (Eloxatin)
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35
Q

Which nitrosureas agent causes Type 1 Diabetes?

A

Streptozocin

  • Targets pancreatic beta cells
  • Good for pancreatic cancer, deadly
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36
Q

What alkylating agent causes pulmonary toxicity?

A

Busulfan (Myleran)

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37
Q

General Properties of Alkylating Agents:

Nitrogen Mustards
Nitrosureas
Others
Platinum-based

A
  • Cytotoxic to rapidly dividing cells
  • Not cell-cycle specific (G1 and S)
  • Bind to purines and pyrimidines; so doesn’t have to be in a state where its actively dividing.
  • Carcinogenic
  • Teratogenic - Make sure patients are using protection to PREVENT pregnancy.

SE:

  • Bone-marrow suppression
  • Epithelial cell damage (oral & GI mucosa) - diarrhea, stomatitis
  • Amenorrhea, decreased spermatogenesis
  • CNS mediated nausea and vomiting
  • Secondary tumors (leukemia’s)
  • All can cause pulmonary fibrosis
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38
Q

Because AA cause pulmonary fibrosis, what do you need to monitor before/during/after drug?

A

Serial PFTs

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39
Q

Alkylating Agents MOA

Nitrogen Mustards
Nitrosureas
Other
Platinums

A
  • AA bind to the nitrogen atoms of guanine, adenosine, and cytosine (DNA)
  • Formation of cross links with adjacent bases, causes damage which inhibits DNA replication.
  • More DNA strand breaks, increases P53 gene activity (APOPTOSIS).
  • Mispairing can cause RNA polymerase to code for wrong DNA and lead to cell death.
  • Depurination (removes purine from sugar backbone).
  • Ring cleavage increases, decreased periods of DNA synthesis phase.
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40
Q

Nitrogen Mustards

Where were they developed from?

A

Nitrogen Mustards
(Alkylating agents)

  • Mechlorethamine
  • Cyclophosphamide
  • Ifosfamide
  • Chlorambucil
  • Melphalan
  • WW1: Mustard gas
  • Strong vesicant
  • Worry about extravasation
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41
Q

Vesicant:

A
  • Causes vesicles (blistering) and skin damage
  • Extravasation to underlying tissue can cause damage.
  • Port needed; to have central access.
  • Warm compress
  • Cold compress
  • Solvents
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42
Q

Mechlorethamine (Mustargen)

A
  • Nitrogen Mustard
  • Given IV

SE:

  • N/V “huge”
  • Myelosuppression
  • Stomatitis
  • Alopecia
  • ↓ reproductive functions

Myelosupression can cause them to die of secondary infections.

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43
Q

Cyclophosphamide (Cytotoxan)

A
  • Nitrogen Mustard
  • Oral, IV, (metabolic activation)
  • Used in breast, lung, testicular, ovarian cancer, CLL

SE:

  • Drug is broken down into acrolein molecule, which causes hemorrhagic cystitis.
  • Binds to sides of bladder and breaks down tissue.
  • Antidote: Mercaptoethane sulfonate (MESNA)
  • N/V, alopecia
  • Immunosupression
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44
Q

What causes hemorrhagic cystitis?

A

Cyclophosphamide (Cytotoxan)

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45
Q

How do you prevent hemorrhagic cystitis when giving Cyclophosphamide (Cytotoxan)?

A

Antidote: Mercaptoethane sulfonate (MESNA)

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46
Q

Ifosfamide (Ifex)

A
  • Nitrogen Mustard
  • CYP3A4 metabolic activation
  • Used for sarcoma, testicular cancer
  • Same toxicities as Cyclophosphamide (less potent)

SE:

  • Neurotoxicity: hallucination, confusion, and worsening depression.
  • Cystitis (MESNA can be hung to prevent damage in the first place).
  • Increased PLT suppression
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47
Q

Melphalan (Alkeran)

A
  • Nitrogen Mustards
  • Used for multiple myeloma, bone marrow transplants
  • Orally , IV

Toxicity

  • Bone marrow suppression
  • No alopecia
  • LESS N/V
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48
Q

Chlorambucil (Leukeran)

A
  • Nitrogen Mustards
  • Given orally, slow depression of bone marrow

Limited toxicity?

  • GI discomfort
  • Pulmonary fibrosis
  • Seizures’
  • Dermatitis
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49
Q

Nitrosureas

  • Carmustine
  • Lomustine
  • Streptozocin
A
  • MOA: Alkylate DNA and carbamoylate proteins.
  • Bind to proteins to inhibit their function, which results in DNA damage.

-Lipophillic: can get into the blood-brain barrier to reach brain tumors, melanoma, non-Hodgkin’s lymphoma

SE:

  • MORE myelosuppression
  • Pulmonary fibrosis
  • Secondary Leukemia
  • Renal toxicity
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50
Q

Dacarbazine (DTIC) (IV) (Triazene)

Procarbazine (Matulane) (oral) (Methylhydrazine)

A

-MOA: Activation by CYP P-450 system to Diazomethane (MTIC), cytotoxic agent

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51
Q

What toxicity is seen with Dacarbazine and Procarbazine?

A

SE:

  • Nausea and vomiting - SEVERE!!!
  • High emetogenicity, will change drugs used to treat.
  • Myelosuppression
  • Alopecia
  • Flu-like syndrome, fever, chills, muscle pain
  • CNS depression (procarbazine)
  • Renal and Hepatotoxicity
  • Leukogenic (procarbazine)
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52
Q

What drug causes CNS depression and is leukogenic?

A

Procarbazine!

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53
Q

Temozolomide (Temodar) (PO)

A

-Drug of choice for malignant gliomas together with radiation
-Mechanism similar to Dacarbazine
Prodrug.

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54
Q

Altretamine (Hexalan) (oral)(Ethylenimines)

A
  • Activated to alkylating agent by enzyme.
  • Second line agent for ovarian cancer

SE:
-Neurotoxicity: ataxia, depression, confusion, hallucinations

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55
Q

Busulfan (Myerlan, Busulfex) (oral)(Alkyl sulfonates)

MOA, SE

A
  • Alkyl sulfonate acts like mustards
  • Acute myelosuppression

SE:

  • Seizures
  • PULMONARY FIBROSIS!!
  • Busulfan lung, 3 years fatal
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56
Q

Cisplatin (IV)(Platinum Complexes)

MOA, uses

A
  • MOA: Cross-link nitrogen on guanine or adenine within same strand.
  • Sensitizes some tumors to radiation; give doses of chemo before a pt gets radiation. Make cancer cells rapidly divide again to get a higher fraction for radiation to hit.
  • Reacts with sulfhydryl groups
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57
Q

Cisplatin (Platinol-AQ)(Platinum Complexes)

Toxicity

A
  • SEVERE Nausea, vomiting
  • NEPHROTOXICITY
  • Ototoxicity - hair cell damage (baseline follow up hearing tests needed)
  • Mild myelosuppression

-Sulfhydryl rescue - Na Thiosulfate to limit toxicity; helps detoxify toxic compounds.

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58
Q

How do we avoid nephrotoxicity for patients on Cisplatin?

A
  • NEPHROTOXICITY
  • Hydrate patient (1-2 liters of saline)
  • Amifostine (Ethyol) thiophosphate: renal protective agent
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59
Q

What is a sulfhydryl rescue?

A
  • Give Na Thiosulfate; donates sulfur groups to detoxify toxic compds.
  • Ex: Cisplatin
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60
Q 
Platinum ComplexesCarboplatin (Paraplatin)  
MOA, Toxicity
A

-MOA: Requires activation, slower, less reactive than Cisplatin

Toxicity:

  • Moderate nausea, vomiting
  • MORE myelosuppression
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61
Q

Oxaliplatin (Eloxatin)

Uses, SE

A

-Used for GI and colorectal, ovarian, head and neck cancer

SE:
-Peripheral neuropathy!! “Stocking glove” pattern.

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62
Q

How do you develop resistance to chemotherapy drugs?

A

↓ Ability to enter cells
Efflux pumps

↓ Activation and conversion of pro-drugs
Drugs not activated; less effective.

↑ Intracellular glutathione to bind Alkylating agent before it hits the DNA

↑ DNA repair mechanisms
Upregulated to overcome alkylation effects

Resistance develops rapidly when used ALONE. Need to use MULTIPLE DRUGS to avoid resistance!!!!!!!!!

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63
Q

ANTIMETABOLITES

A

Used in combination with alkylating agents.

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64
Q

Folic Acid Analogs

A

Methotrexate (Trexall, Rheumatrex)

  • Also used in RA.
  • Immune suppression

Trimetrexate (Neutrexin)- PJP
Pemetrexed (Alimta)

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65
Q

Pyrimidine Analogs

A
  • 5-Flurouracil (5-FU)
  • Floxuridine (FudR)
  • Capecitabine (Xeloda)
  • Cytarabine (ara C, Cytosine arabinoside)
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66
Q

Purine Analogs

A
  • Mercaptopurine(Purinethol)
  • Fludarabine (Fludara)
  • Cladribine (Leustatin)
  • Thioguanine (analog of guanine)
  • Pentostatin (Nipent)
67
Q

What’s used a lot for the leukemia kids?

A

Methotrexate

68
Q

Antimetabolite MOA

What phase of cell division do they target?

A
  • All are structural analogs of naturally occurring bases or intermediates
  • Inhibit enzymes or substitute for naturally occurring bases.

“Strand terminators”

  • Work during S-phase!!
  • Can also impair nucleotide synthesis in G1
69
Q

Methotrexate (Trexall, Rheumatrex)

MOA, Uses

A
  • Folic acid analog
  • First cure of a solid tumor! (choriocarcinoma)
  • MOA: High affinity for dihydrofolate reductase; it inhibits DHF reductase from DHF to THF conversion.
  • This prevents production of thymidine, cysteine, and methionine, so they can’t be incorporated into the DNA.

-Used for RA, lupus, transplant patients (need immunosupression to prevent organ rejection).

70
Q

Resistance mechanism of MTX:

A

If DHF is being blocked by methotrexate, the enzyme can be upregulated to overcome the methotrexate inhibition.

Or make new enzymes with different conformations (less affinity for methotrexate).

71
Q

How does Methotrexate get to the site of action?

A
  • MTX looks like DHF (needed for DNA synthesis)
  • MTX has a preferential uptake in cancer cells, because they’re trying to produce a high amount of DNA than other cells.

-MTX gets in and then glutamyl residues are added so it won’t escape.

72
Q

Leucovorin (Folinic Acid)

A
  • Rescue agent after a patient has had a high dose methotrexate.
  • Normal cells have DHF inhibited, so you give them the active form (folinic acid) to make their DNA.

SUM:

  • Give a high dose MTX, which will inhibit the cancer cells rapidly dividing via uptake of the drug.
  • Then leucovorin used to rescue the healthy cells.
73
Q

If you have an overdose of methotrexate, what do you give the patient?

A
  • Folinic acid will help to reverse the effects of MTX.

- Active form their cells can’t make themselves.

74
Q

MTX

Administration, uses

A
  • Indications: oral, IV
  • Used in acute lymphoblastic leukemia (ALL) in children

-Inhibits cell-mediated immune reactions. Low doses in organ transplants, psoriasis, rheumatoid arthritis

75
Q

Dose difference of MTX:

A

Doses in RA are smaller; don’t need to wipe out immune system. Just need to inhibit a little.
Ex: 25mg

Cancer: knock out all immune cells inducing neutropenia and allowing cells to repopulate.
Ex: 10g in a single dose IV.

76
Q

MTX toxicity

A
  • Hepatotoxicity
  • Bone marrow suppression
  • GI/ oral epithelial ulceration
  • Alopecia
  • Teratogenic, has been used with Misoprostol as abortifacient
  • PREGNANCY TEST NEEDED BEFORE ADMIN.
77
Q

What do you monitor for MTX?

A
  • Risk of hepatotoxicity
  • Monitor liver function tests
  • AST/ALT
  • PT/INR (will rise if liver doesn’t produce clotting factors).
78
Q

How is MTX excreted?

How do you prevent crystallization of the drug and nephrotoxicity?

A

-Actively secreted into proximal tubule, monitor renal function

  • Can precipitate out and damage kidneys if you have acidic urine.
  • Give sodium bicarbonate with it to alkalinize and not have the crystals precipitating out.
79
Q

Pemetrexed (Altima)

A

-Activity against mesothelioma, lung cancer

SE:

  • Pruritic rash
  • Severe myelosuppression
80
Q

MTX

A

Folic acid antagonist

81
Q

5-Fluorouracil (Adrucil)

Drug type, MOA

A
  • Pyrimidine analog
  • Uracil with fluorine in position 5 of uracil ring; precursor to thymidine
  • MOA: attaches to deoxyribose to form fdUMP; competes with deoxy-uracil monophosphate to inhibit thymidylate synthase.
  • Less thymidine incorporated into DNA; more damage, less mitosis
82
Q

Cytarabine (Cytosar-U)

Drug type

A
  • Pyrimidine analog

- Cytosine analog in which natural ribose replaced by D-arabinose (sugar)

83
Q

5-Fluorouracil (Adrucil)

Administration

A
  • IV and topical
  • Short half-life
  • Can be infused over 5 days; target cells in S phase ONLY.
  • Better for slow growing tumors
84
Q

When is 5-Fluorouracil (Adrucil) topical formulation used?

A

Non-invasive skin cancers

85
Q

Other preps of 5-Fluorouracil:

  • Floxuridine (FUdR)
  • Capectabine (Xeloda)
A

Floxuridine (FUdR)

  • FU + deoxyribose
  • Metastatic CA of colon

Capectabine (Xeloda)

  • prodrug of FUdR
  • Used for NONresponsive metastatic breast/colorectal cancer.
86
Q

Toxicity of 5FU

A
  • Myelosuppression
  • Alopecia
  • Mucosal damage (oral and GI)
  • Hepatotoxicity

-Hand-foot syndrome – pain and sensitivity of palms and soles more frequently with Capecitabine (Xeloda)

87
Q

Cytarabine (Cytosine arabinoside, AraC)

A
  • MOA: Cytosine with D-arabinose sugar, which is phosphorylated to AraCTP.
  • When put into DNA, arabinose can’t be elongated.
  • Termination of DNA chain.

Admin:

  • 5 to 7 days, for slow growing tumors
  • S phase
88
Q

Cytarabine (Cytosine arabinoside, AraC)

SE

A

SE:

  • Stomatitis
  • Potent myelosuppression!
  • Hepatotoxicity
89
Q

Gemcitabine (Gemzar) (IV infusion)

MOA, Admin, Toxicity

A
  • MOA: Di-fluoro analogue of cytidine, when incorporated into DNA terminates strand.
  • Increases apoptosis

-Admin: I-V on days 1, 8, 15 of 28 day cycle (most likely to hit S phase on these days).

Toxicity

  • Myelosuppression
  • Flu-like syndrome
  • Potent radiation sensitizer
90
Q

Thioguanine

A
  • Purine analog
  • Thio analog of guanine
  • Uses: acute lymphoblastic leukemia
  • SE: myelosuppression, GI effects
91
Q

Fludarabine (Fludara)

A
  • Purine analog
  • Fluorinated adenosine arabinose inhibits DNA polymerase

-Uses: chronic lymphocytic leukemia, lymphoma, nausea, vommitting

92
Q

Cladribine (Leustatin)

A
  • Purine analog
  • Inhibits DNA Polymerase
  • Uses: hairy cell leukemia
  • SE: N/V, myelosupression
93
Q

6-Mercaptopurine MOA

A

-Purine analog

  • MOA: Thio analog of hypoxanthine, converted into nucleotides, inhibit DNA synthesis.
  • Phosphorylated to add sugar and form thio-IMP; inhibits andenosine and xanthene formation.

Prevents DNA synthesis. Can be incorporated into RNA…

94
Q

6-mercaptopurine

Admin, Metabolism, Toxicity

A
  • Oral and IV
  • Uses ACL and AML

Two pathways for metabolism:
P-450
1. Xanthine oxidase - converts purines into uric acid; can see hyperuricemia, hyperuricosuria.
*Exacerbates gout.
2. Allopurinol - xanthine oxidase inhibitor; given to increase 6 MP levels and decrease uric acid levels.

Toxicity:

  • Mild myelosuppression
  • Anorexia
  • Long term hepatotoxcicity
  • Opportunistic infections
95
Q

What do you worry about compounding?

A

-Worry about who is making the drug; hazardous, teratogenic drug.

  • Crushing tablets can cause aerosolization of particles.
  • Need PPE.
  • Done in a hood with negative pressure.
96
Q

ANTIBIOTICS

97
Q

Antibiotics

  • Names
  • Derived from bacteria
A
  • Daunorubicin (Cerubidine)
  • Doxorubicin (Adriamycin) - bright red
  • Dactinomycin (Actinomycin D, Cosmegen)
  • Idarubicin (Idamycin)
  • Bleomycin (Blenoxane)
  • Mitomycin (Mutamycin)
  • Mitoxantrone (Novantrone)
98
Q

Antibiotics

Origin, MOA

A
  • Products of Streptomyces (soil fungus).
  • Too toxic to use as antibiotics

-MOA: Directly bind DNA or intercalate between pairs, causes breaks which prevents replication.

99
Q

What are Daunorubicin, Doxorubicin, and Idarubicin used for?

A

“Anthracycline antibiotics” -

  • Hematological and solid tumors
  • Leukemia kids

These 3 drugs are the ones with lifetime doses!

100
Q

What is dactinomycin used for? Plicamycin? Mitomycin?

A

Dactinomycin - Ewing’s sarcoma, Wilm’s tumor

Plicamycin - testicular cancer

Mitomycin - stomach, pancreas, lung

101
Q

Dactinomycin (Actinmycin D) (Cosemgen)

A
  • MOA: intercalates DNA, single strand breaks.
  • One of the most potent tumor agents.

Uses: rhabdomyosarcoma and Wilm’s tumor in children.

SE

  • Pancytopenia from myelosupression
  • Vesicants
  • Anorexia
  • N/V, alopecia, GI effects
102
Q

Daunorubicin (Cerubidine) and Doxorubicin (Adriamycin)

MOA, SE

A
  • MOA: intercalate into DNA to prevent uncoiling
  • Inhibits topoisomerase 2, which repairs strand breaks and unwinds DNA for replication.

SE:

  • N/V, myelosuppression
  • Cardiotoxicity!!!
  • STRONG vesicant properties; worry about extravasation. Cause severe ulceration and necrosis to tissue.

-Monitor: echocardiogram

103
Q

How does the metabolism of Daunorubicin (Cerubidine) and Doxorubicin (Adriamycin) cause cardiotoxicity?

A

-When metabolized, form free radicals.

  • Cardiac tissue is low in superoxide dismutase, which is repsonsible for dealing with free radicals.
  • Without superoxide dismutase, you can get free radicals which lead to cardiotoxicity.
104
Q

Doxyrubicin Dose

A
  • 550mg/m^2 of doxyrubicin in lifetime.

- Once exceed, need to try a new drug/regimen.

105
Q

What’s dark red?

A

Daunorubicin or Doxyrubicin

106
Q

What are 2 ways to limit cardiac toxicity of Daunorubicin or Doxyrubicin to try to give more drug to patient over their lifetime??

A
  • Amphotericin B (used for fungal infections); can implant drug into lipid bilayer to limit toxicity.
  • Lipid complexes aren’t taken into the heart cells.

-Can also give Dexrazoxane, which uses iron to chelate or bind to the free radicals to prevent damage.

107
Q

Mitoxantrone

A
  • Less cardiotoxic effects
  • Less potent chemo drug
  • Less free radicals, better tolerated..
108
Q

Bleomycin (Blenoxane)

MOA, target phase

A

-Developed from streptomyces
verticillus

  • MOA: flat ring structure that intercalates into DNA.
  • In presence of O2, metal complex produces free radicals to break DNA

-Specific for G2

109
Q

Bleomycin (Blenoxane)

Toxicity

A
  • Dry cough, leads to pulmonary fibrosis
  • Skin reactions, hyperpigmentation, blistering of skin
  • Low myelosuppression
  • Fever
  • Mild N/V, alopecia, mucosal ulceration
110
Q

ANTIMITOTICS

111
Q

Antimitotics
-Derived from natural products

  • Vinka alkaloids
  • Taxanes
  • Tecans
A 
VINKA ALKALOIDS
Vinblastine (Velban)
Vincristine (Oncovin, Vincasar)
Vinorelbine (Navelbine)
*CANNOT be given intrathecal

TAXANES
Paclitaxol (Taxol)
Docetaxel (Taxotere)

TECANS
Topetecan (Hycamtin)
Irinotecan (Camptosar)
Etoposide (Vepesid, Toposar, Etopophos)
Teniposide (Vumon)
112
Q

Biological Response Modifiers

A 
Inhibitors of growth factors
Imatinib  (Gleevec)
Gefitinib  (Iressa)
Erlotinib (Tarceva)
Bortezomib  (Velcade)
Antibodies to tumor cell antigens
Rituximab (Rituxan)
Alemetuzumab (Campath)
Tratuzumab (Herceptin)
Cetuximab (Erbituix)
Bevacizumab (Avastin)
Gemtuzumab Ozagamicin (Mylortarg)
113
Q

Antimitotic Drugs MOA

A
  • Interfere with mitotic process by altering spindle formation or degradation
  • M phase specific
  • Can also inhibit topoisomerase 1/2
  • S-G2 phase specific too
114
Q

What drugs inhibit the mitotic spindles?

A
  • Vinblastine > derived from periwinkle
  • Vincristine
  • Paclitaxel > derived from yew tree
  • Docetaxel
115
Q

What drugs inhibit topoisomerase I/II?

A

Etoposide > derived from mandrake plant
Teniposide - analog of etoposide
Topotecan - analog of etoposide

116
Q

Mitotic agents

A

Interfere with microtubules to prevent separation of DNA strands, which will arrest cell division and lead to apoptosis.

117
Q

Vinca alkaloids (IV)

Stop formation of?
Do they enter CNS?

A
  • Work on stopping formation of microtubules (Taxanes prevent disassembly).
  • Do NOT enter CNS!!
  • Extensive hepatic metabolism
  • Biliary excretion. Watch for hepatotoxicity.
118
Q

Top 2 drugs for leukemia?

A

Methotrexate and Vincristine

119
Q

Vinca Alkaloids Toxicity

A

Toxicity: Common to both agents

  • Hyperuricemia; prevented by allopurinol
  • Alopecia, stomatitis

-Strong vesicants, if out of vein use heat or hyaluronidase to disperse drug.

Cannot be given intrathecally, FATAL!

120
Q

How do you treat hyperuricemia from vinblastine or vincristine?

A

-Hyperuricemia; prevented by allopurinol

121
Q

What drugs are fatal if given intrathecally?

A

Vinblastine (Velban)
Vincristine (Oncovin, Vincasar)
Vinorelbine (Navelbine)

122
Q

Vincristine (Oncovin®)

SE

A
  • Peripheral neuropathies of hands and feet (motor and sensory).
  • Suppression of deep tendon reflexes
  • Cranial nerve damage may cause jaw pain, face palsies
  • Muscle weakness
  • Autonomic neuropathies
  • Minimal myelosuppression
123
Q

Vinblastine (Velban®)

A

Better tolerated than Vincristine
-Less neurotoxicity

Vinorelbine (Navelbine®) - not used as often

124
Q

Paclitaxel (Taxol)
Docetaxel (Taxotere)
MOA

A

-MOA: block degradation of microtubules in mitosis. Stops M-phase with apoptosis.

125
Q

Paclitaxel (Taxol)

Toxicity

A
  • Myelosuppression; biggest SE.
  • Hypersensitivity can develop
  • Stocking-glove neuropathy
  • Myalgia
126
Q

Docetaxol (Taxotere)

Toxicity

A
  • Less severe neuropathy
  • Less severe hypersensitivity
  • Edema
127
Q

Etoposide (VePesid)

Teniposide (Vumon)

A
  • Cell cycle specific for S-G2
  • MOA: Topoisomerase II inhibitors; block enzyme and lead to strand breaks.
  • Excreted unchanged in urine
  • Watch renal FXC
128
Q

Etoposide (VePesid)
Teniposide (Vumon)
Toxicity

A
  • SIGNIFICANT myelosuppression that is dose limiting
  • Check neutrophil count; pt must “meet counts” to get more chemo.

-Check specific gravity of urine to make sure drug won’t precipitate out.

129
Q

Irinotecan (Camptosar)
Topotecan (Hycampin)

MOA, Toxicity

A

-MOA: inhibit topoisomerase 1

Toxicity
-Diarrhea (Irinotecan)
-

130
Q

Irinotecan (Camptosar)
Topotecan (Hycampin)

MOA, Toxicity

A

-MOA: inhibit topoisomerase 1

Toxicity:

  • Diarrhea (Irinotecan&raquo_space;> Topotecan)
  • N/V, alopecia
131
Q

What has decreased choliensterase activity?

A

Irinotecan

132
Q

What causes diarrhea?

A

Irinotecan

133
Q

BIOLOGICAL RESPONSE MODIFIERS

A

…..

  • Specific at targetting cell
  • Less SE
134
Q

What has more toxicity - monoclonal antibodies and MTX?

A

Monoclonal antibodies have less, because tehy’re more targetted.

MTX is more toxic, affects every cell.

135
Q

Imatinib (Gleevec)

MOA, SE

A

-MOA: Decreases myeloid tyrosine kinase’s responsible for cell proliferation

Test to see if they express mutation. If they do, drug will work.

  • CML (BCR-ABL mutation)
  • CMML (EVT6-PDGFR mutation)

SE

  • N/V, edema
  • WELL TOLERATED
136
Q

Gefitinib (Iressa®)

MOA, SE

A
  • Affects epidermal growth factor, tyrosine kinase inhibitor
  • NSLC

SE:

  • N/V/D
  • Rash
  • Dry skin
137
Q

Erlotnib (Tarceva)

MOA, SE

A

-Affects HER1 (Erb1)/EGFR Tyrosine Kinase Inhibitors

SE:

  • Diarrhea
  • Rash
  • Elevated liver enzymes
138
Q

Lapatinib (Tykerb)

A
  • ErbB1 (HER1), ErbB2 (HER2) Tyrosine kinase Inhibitors
  • Increased time for tumor growth (4.4 months to 8 months)

SE:

  • Rash
  • Nausea
  • Fatigue
  • Anorexia
139
Q

Bortezomib (Velcade®)

MOA, SE

A
  • Proteasome inhibitor
  • Increase IkB and decrease NF-kB, NF-kB cell survivor promoter gene
  • Apoptosis
  • Multiple myeloma

Toxicity:

  • Fatigue
  • Thrombocytopenia
  • Neuropathy
  • Limb pain
140
Q

Antibodies

A
  • Rituximab (Rituxan)
  • Alemetuzumab (Campath)
  • Trastuzumab (Herceptin)
  • Cetuximab (Erbituix)
  • Bevacizumab (Avastin)
  • Gemtuzumab Ozagamicin (Mylortarg)

Cause:
Anaphylaxis and immune suppression

141
Q

Rituximab (Rituxan)

MOA

A

-MOA: against CD20 antigen to clear B cells. Prevents cell cycle activation, so cells can’t replicate.

Blocking CD20 can cause complement-mediated lysis of cells, apoptosis, and cytoxicity

142
Q

Rituximab (Rituxan)

Toxicity

A
  • Given as 4 weekly infusions
  • IV or subQ

Toxicity

  • infusion related flu syndrome
  • urticaria
  • bronchospasm
143
Q

Alemtuzumab(Camapth)

MOA, SE

A

-MOA: Binds CD 52 antigen on T and B lymphomas, induces cellular cytotoxicity

Toxicity:

  • Infusion reaction
  • Decreased T-cells
  • Opportunistic infections
144
Q

Trastuzumab(Herceptin)

A
  • MOA: Antibody to human epidermal growth factor 2 (HER2/neu, ErbB2)
  • Antibody prevents binding of growth factor, can also down-regulate growth factor receptor.

Toxicity:

  • Fever, chills (first dose 40% of patients)
  • N/V, HA
  • Dizziness
  • Dyspnea, cough
  • Cardiomyopathy
145
Q

Cetuximab(Erbitux)

MOA, SE

A

-MOA: Antibody to Epidermal growth factor receptor (HER1, ErbB1)

Toxicity: infusion reaction, skin rash (75%)

146
Q

Bevacizumab(Avastin®)

MOA, SE

A
  • MOA: Antibody to vascular-endothelial growth factor (VEGF) – responsible for angiogenesis.
  • When you block it, you cut off that blood supply so cells die off.

Toxicities:

  • Severe hypertension
  • Proteinuria
  • CHF
147
Q

If a patient getting Trastuzumab(Herceptin) gets a fever/chills; how do you treat?

A

Treat with acetaminophen, diphenhydramine and meperidine.

148
Q

Gentuzumab Ozogamicin

A

-MOA: Antibody to CD33 antigen linked to Ozogamicin (antitumor antibiotic).

Indications: CD33 positive Acute myelogenous leukemia (AML) in first relapse

Toxicity:

  • Infusion reactions
  • Hepatic and bone marrow suppression
149
Q

D,L-Asparaginase (Elspar)

MOA

A
  • MOA: Asparagine needed to produce protein in cell division.
  • Tumors have low levels of asparagine synthetase, so without asparagine they can’t make proteins; die off.

SE

  • allergic reaction
  • intracranial hemorrhage
  • pancreatitis
  • decreased clotting factors
  • ammonia toxicity
150
Q

Glucocorticoids

A
  • Supress WBC production
  • Prednisone, Dexamethosone
  • Tx leukemias
151
Q

Tamoxifen (Nolvadex)

A

-MOA: Estrogen partial agonist; competes with estrogen for receptor binding.

  • Antagonist in breast and bone (worry about osteopenia)
  • Agonist in uterus

Toxicity:

  • Hot flashes
  • N/V, myelosuppresion
  • DVT and PE (pro-estrogen effects)

Positive effects on cholesterol*
Toremifene (Fareston) - similar*

152
Q

Raloxifene (Evista)

A

-MOA: SERM

Estrogen effects in bone and CV. Antagonizes uterus and breast tissue.

  • Prevents breast cancer
  • Used in osteoporosis.
153
Q

Fulvestrant (Faslodex)

A
  • Monthly IM injection
  • Pure anti-estrogen (hot flashes)

Toxicity

  • Nausea
  • Pain
  • Vasodilation = HA
154
Q

Anastrozole (Arimidex)
Letrozole (Femara)
MOA, SE

A

-MOA: Aromatase inhibitors, inhibiting aromatase decreases production of estrogen.

SE:

  • Osteoporosis
  • Hair growth
  • Hot flashes/nausea
155
Q

Exemestane (Aromasin)

A
  • MOA: irreversible aromatase inhibitor
  • Decreases estrogen levels significantly
  • Used for treatment resistant patients
  • SE: hot flashes, edema fatigue, less frequent gynecological symptoms, more common visual disturbances and bone fractures
156
Q

Flutamide (Eulexin)
Nilutamide (Nilandron)
Biclutamide (Casodex)

A
  • Block androgen receptors and prevent testosterone from interacting
  • Proestrogenic effects

SE
-Gynecomastia

157
Q

Leuprolide (Lupron)

Goserelin (Zoladex)

A
  • MOA: Analogs of GnRH, occupy LHRH receptor in pituitary continuously, desensitize and inhibit release of FSH and LH.
  • FSH and LH responsible for testosterone release

Daily subQ or monthly depot

SE:
Impotence, hot flashes, gynecomastia, nausea, vomiting

158
Q

Immunotherapy

159
Q

Interferon alpha

A

Alpha 2A - Roferon-A Lysine 23
Alpha 2B - Intron -A Arginine 23

  • MOA: Increases cytotoxicity of natural killer cells
  • Increases phagocytic ability of macrophages
  • Increases ability of macrophage to present “processed antigen” to T-helper cells
  • SubQ
  • Recombinant form made in E. Coli.
160
Q

ADR Interferon Alpha

A
  • Flu-like symptoms, fever, chills, myalgia, headache, hair loss, diminish with time with daily administration
  • Dizziness, confusion, depression, aggressive behavior, decreased mental status, visual problems, coma
  • Contraindicated in pregnancy, no breastfeeding, passes to fetus
161
Q

Aldesleukin (IL-2)

MOA

A
  • Molecular messenger between leukocytes
  • IL-2 is a T cell growth factor, can inhibit cell proliferation by giving it.
  • MOA: stimulate proliferation and activation of lymphokine activated killer (LAK) cells and tumor infiltrating lymphocytes (TIL).
  • Turns on NK cells.

Recombinant products made in E. coli; expensive to produce.

162
Q

Aldesleukin (IL-2)

ADR

A
  • Flu-like syndrome: fever, chills, myalgia, nausea, vomiting
  • Capillary leak syndrome (87%) hypotension (70% require pressor therapy)
  • Arrhythmias, MI, heart failure
  • Pulmonary edema, failure
  • CNS - headache, dizziness, mental changes, seizures, coma (73% CNS edema)
  • Hepatotoxicity
  • Myelosuppression
163
Q

How do you treat capillary leak syndrome hypotension?

A

Dopamine and epinephrine

164
Q

What causes cappillary leak syndrome?

A

Aldesleukin (IL-2)

Pharmacology II (10 decks)

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