Oncology Pharm Flashcards
1
Q
Log Kill Hypothesis
A
Cytotoxic drugs= first order kinetics
- Given dose, constant fraction of cells killed (not fixed number)
- Toxicity to normal tissues= major dose-limiting factor
- Need multiple cycles of chemo to eradicate tumor (ex: only killing 20% of cancer with each dose)
2
Q
Gompertzian Kinetics
A
Increased doubling time as tumor burden increases
- Takes longer time for tumor to enlarge as it gets larger
- Subclinical–> diagnosis–> symptoms–> death
- Increases in cellularity occur over longer periods of time
3
Q
Adjuvant therapy
A
Used after surgery or radiation therapy
- Eradicate residual tumor
4
Q
Neoadjuvant therapy
A
Used before surgery/radiation
- Shrink tumor to make surgical removal easier
5
Q
Alkylating agents
A
MOA: Alkylate DNA (N7 of guanine)
- DNA cross-linked, strand breaks, inhibits replication, transcription
- No cell cycle specificity
Includes:
- Nitrogen mustards
- Nitrosoureas
- Platinum Analogues
- Others
Toxicity: Dose limiting: - myelosuppression (febrile neutropenia) - Mucositis - Nausea and vomiting - Alopecia - Infertility - Secondary leukemias
6
Q
Nitrogen mustards
A
Includes: bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine (first anticancer drug- mustard gas–> lymphopenia), melphalan
7
Q
Cyclophosamide
A
Broad spectrum nitrogen mustard
Prodrug. Activated by liver to active and toxic metabolites
IV and PO
Adverse effects:
- Hemorrhagic cystitis: production of acrolein causes irritation to bladder wall.
Treatment for AEs:
- Adequate hydration, Mesna with high doses
8
Q
Ifosfamide
A
Analog of cyclophosphamide.
Also requires hepatic activation to same active metabolites
- Less potent, requires 4 x dose for efficacy
Adverse effects:
- Increased production of acrolein accumulates in bladder and causes hemorrhagic cystitis
- Administer with Mesna (IV/PO), hydration important.
9
Q
Melphalan
A
Nitrogen mustard
Oral and IV
High dose used for Bone marrow transplant
10
Q
Bendamustine
A
Nitrogen mustard: combination alkylating agent and purine analog
11
Q
Nitrosoureas
A
Nitrogen mustard
- Lipophilic, good CNS penetration
- Delayed myelosuppression, 4 week nadir
AEs:
Severe N/V, pulmonary toxicity, hepatotoxicity
Carmustine implant: Gliadel Wafer
12
Q
Dacarbazine
A
Other alkylating agent with CNS penetration
13
Q
Temozalmide
A
Alkylating agnet
Oral, converts to Dacarbazine
14
Q
Platinum Analogs
A
Binds to and causes double-stranded DNA breaks
15
Q
Cisplatin
A
Platinum analogs
AEs: Nephrotoxic, ototoxic, N/V
- Avoid with hydration, antiemetics
16
Q
Carboplatin
A
Platinum analog
AE:
- Myelosuppression
- less N/V, neuropathy, nephrotoxicity than cisplatin
Dosed NOT by weight
17
Q
Oxaliplatin
A
Platinum analog
AE: acute: cold induced neuropathy, cumulative peripheral neuropathy,
18
Q
Topoisomerase inhibitors
A
MOA:
Topoisomerases (I and II) are nuclear enzymes that unravel DNA for repair and replication
Specifically they participate in DNA replication and repair by:
- cleaving and resealing the phosphodiester bonds that comprise the backbone of DNA (Topo II)
- unwinding DNA (Topo I)
Inhibiting topoisomerases can induce DNA damage such as unrepairable strand breaks leading to cell apoptosis
19
Q
Anthracycline
A
Topoisomerase II inhibitor
MOA:
- High affinity binding to DNA
- Intercalates between base pairs, inhibits the activity of enzymes involved in DNA replication (topoisomerase II)
- Anthracyclines form free radical compounds that damage biological macromolecules
AEs:
- Specifically can cause CHF when cumulative dose reached
- As dose approached, must monitor ejection fractions
20
Q
Camptothecins:
A
Topoisomerase I inhibitor
21
Q
Topotecan
A
Topoisomerase I inhibitor:
AE: dose-limiting marrow suppression
22
Q
Irinotecan
A
Topoisomerase I inhibitor
AE:
- Diarrhea is a dose limiting side effect
1. Early form - Cholinergic syndrome treated with IV atropine
2. Late form - Direct GI toxicity. Loperamide 4 mg x 1, 2 mg q2hr.
- May cause serious dehydration
23
Q
Bleomycin
A
Glycopeptide antibiotic
MOA: Bleomycin produces single and double strand breaks in DNA through the production of highly reactive free radicals
Toxicity:
- Pulmonary fibrosis (avoid cumulative dose >400 units, current radiation/oxygen).
- Hyperpigmentation, rash, fever, allergic rxn.
24
Q
Vinca Alkaloids
A
Vinblastine, vincristine, vinorelbine
MOA:
Inhibit microtubule function in M phase
- inhibit the formation of tubulin, which prevents polymerization into microtubules
- CAN’T FORM
Toxicity:
- All vesicants
Vincristine:
- neurotoxicity, constipation
- Max dose 2 mg/week
Vinblastine/vinorelbine:
- Myelosuppression
- Less neurotoxicity
25
Docetaxel, Paclitaxel
Taxanes
MOA:
Inhibit microtubule function in M phase
- bind to beta tubulin and stabilize the alpha and beta tubulin heterodimers, preventing the breakdown of microtubules
- CAN'T BREAK DOWN
AEs:
Require premedication with steroids due to solubilizing agents
Paclitaxel: Neuropathy, Albumin-bound paclitaxel (Abraxane), no solubilizer
Docetaxel: Fluid retention syndrome: dex 8 mg PO BID x 3 days
Cabazitaxel: Crosses BBB, not affected by P-glycoprotein
26
Ixabepilone
Epothilones
MOA:
Inhibit microtubule function in M phase
- bind to beta tubulin and stabilize the alpha and beta tubulin heterodimers, preventing the breakdown of microtubules
AEs:
Require premedication with steroids due to solubilizing agents
Ixabepilone: Distinct tubulin binding site, not effected by Pgp
27
Antimetabolites
MOA:
1. Mimic nucleotide cousins
2. S-phase specific
3. One or combination:
- inhibiting enzymes involved in nucleotide synthesis
- inhibiting enzymes involved in DNA replication
- replacing naturally occurring nucleotides in DNA that is actively being replicated. This serves to disrupt the natural structure of DNA, causing apoptosis.
28
Methotrexate
MOA: inhibitors dihydrofolate reductase
- decreases reduced folates, inhibits thymidylate synthase
ROA: IM, IV, IT< PO
PK: cleared renally, can accumulate in 3rd spaces
- Avoid in CHF, liver failure, renal failure causing ascites
AEs:
Mucositis, pneumonitis, renal failure, increased LFT’s
29
Purine analogs
Thioguanine (6-TG) and mercaptopurine (6-MP)
- Oral agents
- Metabolized by xanthine oxidase
AEs: Cause liver toxicity, mucositis
Fludarabine, cladrabine, pentostatin
AEs: Immunosuppression (lymphopenia)
Nelarabine
AEs: Neurotoxicity is dose-limiting
30
Cytarabine (Ara-C)
| Gemcitabine
Pyramidine analog
MOA: Analogue of cytidine
AEs:
1. Flu-like syndrome, rash
2. High dose: (HiDAC)
- Marrow suppression
- Cerebellar toxicity (ataxia)
- Conjunctivitis: steroid eye drops
Gemcitabine= same MOA
31
Fluorouracil
Pyramidine analog
Converted to 5-FdUMP causing inhibition of thymidylate synthase, thymidine depletion, apoptosis
Toxicity: dose, frequency-dependent
- Intermittent bolus: myelosuppression
- Continuous: Hand-foot syndrome (rashes)
* Administration of leucovorin potentiates effects.
32
Capecitabine
Pyramidine analog
Oral agent converted to fluorouracil
- Activated by tumor cells
AEs:
- Hand-foot syndrome, GI
33
5-Azacitidine
| Decitabine
```
DNA hypomethylators
MOA:
1. Inhibits DNA methyltransferase
2. Hypomethylates DNA
3. Activates "silenced" tumor suppressor genes
- Inhibits angiogenesis, metastasis
- Allows apoptosis
```
34
Monoclonal antibodies: types
1. Disrupt signal transduction:
- Bevacizumab: neutralize ligand
- Cetuximab, panitumumab: inhibit extracellular receptors
2. Direct cytotoxicity:
- Rituximab, alemtuzumab
- Completment-dependent, antibody-dependent, induction of apoptosis:
3. Delivery of cytotoxic agents:
- Tositumomab, Irbitumomab: Radioactive moieties
- Brentuximab, Vedotin: antineoplastic
35
Monoclonal antibodies: nomenclature
First part= specific to drug
Second part= target
- Li(m)= immune system
- tu(m)= miscellaneous tumor
- ci(r)= circulatory
Third part= source
- a= rat
- e= hamster
- i= primate
- o= mouse
- u= human
- xi= chimeric
- zu= humanized
Last part= mab
36
Rituximab
MOA: anti-CD20 antibody (found on all B lymphocytes)
Uses: CD20 seen in > 90% of B-cell NHL and leukemias
AEs:
- Infusion reactions (human better tolerated)
- Tumor lysis syndrome
- Respiratory, renal failure
*Ofatumumab= binds to different epitope on CD20
37
Alemtuzumab
MOA:
- Anti CD52 antibody; CD52 is expressed on most normal and malignant B and T lymphocytes, NK cells, monocytes, and macrophages
Uses:
- Refractory CLL, T-cell leukemia
AEs:
- Infusion reactions, anaphylaxis
- Profound, prolonged immunosuppression, HSV and PCP prophylaxis recommended
38
Ibritumomab
MOA: Radioactive immunoconjugate with anti-CD20 antibody attached to radioactive moeity
Uses:
- Relapsed and/or refractory CD20-positive, follicular NHL
AEs:
- Avoid in patients with > 25% involvement of the bone marrow by lymphoma and/or impaired bone marrow reserve.
39
Tositumomab
MOA: Radioactive immunoconjugate with anti-CD20 antibody attached to radioactive moeity
Uses:
- Relapsed and/or refractory CD20-positive, follicular NHL
AEs:
- Avoid in patients with > 25% involvement of the bone marrow by lymphoma and/or impaired bone marrow reserve.
40
Brentuximab
MOA:
- Anti-CD30 antibody attached to monomethyl auristatin E (MMAE)
- MMAE is a mitotic spindle poison
Uses:
- Hodgkin, anaplastic large cell lymphoma
AEs:
- Infusion reactions, myelosuppression, peripheral neuropathy
41
Denileukin Diftitox
MOA:
Anti CD25 antibody (IL2 receptor) attached to diphtheria toxin
Uses:
Persistent or recurrent cutaneous T-cell lymphoma
AEs:
Infusion reactions, vascular leak, flu-like syndrome, hepatotoxicity
42
Trastuzumab/Pertuzumab
```
MOA:
MOA:
Anti HER2/neu receptor antibody
HER2 overexpressed on 25 – 30% of breast cancers
Binding results in apoptosis and ADCC
```
Uses:
Breast cancers
AEs:
- Infusion related reactions, anaphylaxis
- Cardiotoxicity (CHF), especially when used with cyclophosphamide or an anthracycline
- Renal insufficiency, Stevens-Johnson syndrome
43
Cetuximab/Panitumab
MOA:
Anti-EGFR antibody
Uses:
- EGFR over expressed in many solid tumors
- Binding results in inhibition of proliferation, growth, metastasis, and angiogenesis
- Enhanced response to chemotherapy and radiation
AEs:
- Infusion related reactions, anaphylaxis
- Skin toxicity, may be severe
44
Bevacizumab
MOA:
Anti VEGF antibody
Uses:
Inhibits formation of new blood vessels in primary and metastatic tumors
AEs:
- Infusion reactions, anaphylaxis
- GI perforations and impaired wound healing
- Bleeding, arterial thrombosis, hypertension, CHF
- Tracheoesophageal fistulas
45
Ipilimumab
MOA:
Binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
Blockade of CTLA-4 augments T-cell activation and proliferation
AEs:
can result in severe and fatal immune-mediated adverse reactions due to T-cell activation.
46
Tyrosine Kinase Inhibitors
TKI: Two types: receptor based and cellular
- Dependent on activity/function of receptor (some are constitutively active, others are activated by other factors)
MOA:
These enzymes are involved in cellular signaling pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signaling
- Inhibitors occupy ATP binding site and prevent phosphorlyation of substrates
PK: All are CYP3A4 substrates
47
Erlotinib
Receptor-based TKI
MOA:
- Inhibit epidermal growth factor receptor (EGFR) TK
Uses: NSCLC (non-small cell lung cancer)
AEs:
Diarrhea, skin rash (correlates with efficacy)
Life-threatening interstitial pneumonitis
48
Imatinib
Intracellular TKI
MOA:
Inhibits BCR-ABL TK created by Ph chromosome translocation (9;22), PDGF, cKIT
Uses:
CML therapy
Nilotinib more potent than imatinib
Dasatinib also inhibits SRC kinase
AEs:
myelosuppression
49
Sutinib
Receptor based TKI including PDGF, VEGF
Uses:
Renal Cell Cancer
AEs:
GI, skin discoloration , fatigue, hypertension, bleeding, CHF
50
Sorafinib
Receptor based TKI including PDGF, VEGF
Used in RCC, Hepatocellular Cancer
Toxicities: GI, rash, hypertension, bleeding, hand-foot syndrome
51
Lapatinib
Receptor based TKI of EGFR and Her-2
Used Her2+ breast cancer
Toxicities: diarrhea, decreased LVEF, QT prolongation
52
Rapamycin
mTOR inhibitor
Mechanism:
Binds to FK Binding Protein
FKBP-drug complex inhibits mTOR kinase activity
Decreased production of Hypoxia Inducible Factor, VEGF, PDGF, TGF
53
Temsirolimus
mTOR inhibitor
Mechanism:
Binds to FK Binding Protein
FKBP-drug complex inhibits mTOR kinase activity
Decreased production of Hypoxia Inducible Factor, VEGF, PDGF, TGF
```
AEs:
Hyperglycemia
Increased triglycerides/cholesterol
Rash, asthenia, mucositis
Pulmonary syndrome (hypoxia, noninfectious infiltrates)
```
54
Differentiating agents
Clinical use:
- Acute promyelocytic leukemia is characterized by the t(15;17) translocation
- Produces PML-RAR receptor protein
- PML-RAR suppresses DNA transcription at normal retinoic acid levels
- Accumulation of promyelocytes (cell stopped in one stage of maturation
MOA:
Differentiating agents release block, allow cells to mature
55
All-trans-retinoic-acid (ATRA)
MOA:
ATRA provides high levels of retinoic acid
Induces differentiation and maturation of acute promyelocytic cells to normal myelocyte cells .
AEs:
- Differentiation syndrome.
- Fever, leukocytosis, dyspnea, weight gain, diffuse pulmonary infiltrates, and pleural and/or pericardial effusions.
- Observed with WBC > 10,000/mm3.
- Usually observed during the first month of therapy but may follow the initial drug dose.
* Drug causes increased maturation of neutrophils--> AEs related to increased circulating neutrophils
56
Arsenic trioxide
MOA:
Induces differentiation of APL cells by degrading the chimeric PML/RAR-α protein, resulting in release of the maturation block.
AEs:
Differentiation syndrome, QT prolongation
- Keep Mg and K within normal ranges
57
Thalidomide
lenalidomide
pomalidomide
Immunomodulatory agents
MOA:
Induce apoptosis, enhance T cell and NK cell cytotoxicity, inhibit angiogenesis
Used for multiple myeloma
AEs:
Thalidomide: sedation, constipation, rash, neuropathy
Lenalidamide: marrow suppression, thromboembolism
Restricted distribution system, teratogen.
58
Bortezomib
Proteosome Inhibitor
MOA:
Inhibits proteosome function. Prevents degradation of pro-apoptotic proteins
- Proteosome= "garbage disposer of cell"--> ubiquinate and degrade proteins
- IkB inhibits NFkB
- IkB normally broken down by proteosomes--> NFkB active--> cell proliferation
- Proteosome inhibition--> increased IkB--> decreased NFkB activity
- Accumulation of malformed proteins--> cell can't handle trash--> dies
Uses:
Highly active in multiple myeloma
AEs:
Toxicities include neuropathy and thrombocytopenia.
59
Ruxolitinib
JAK inhibitor
| - Myelofibrosis
60
Vemurafenib
BRAF inhibitor
| - Melanoma with BRAF V600E mutation
61
Crizotinib
ALK inhibitor
| - ALK positive NSC lung cancer
62
Vismodegib:
Hedgehog inhibitor
- Basal cell skin cancer
- Embryotoxic and teratogenic
63
Dasatinib
Intracellular TKI
MOA:
Inhibits BCR-ABL TK created by Ph chromosome translocation (9;22), PDGF, cKIT
Uses:
CML therapy
Nilotinib more potent than imatinib
Dasatinib also inhibits SRC kinase
AEs:
myelosuppression
64
Nilotinib
Intracellular TKI
MOA:
Inhibits BCR-ABL TK created by Ph chromosome translocation (9;22), PDGF, cKIT
Uses:
CML therapy
Nilotinib more potent than imatinib
Dasatinib also inhibits SRC kinase
AEs:
myelosuppression
65
Gefitinib
Receptor-based TKI
MOA:
- Inhibit epidermal growth factor receptor (EGFR) TK
Uses: NSCLC (non-small cell lung cancer)
AEs:
Diarrhea, skin rash (correlates with efficacy)
Life-threatening interstitial pneumonitis
66
Ondansetron (Zofran®)
Granisetron (Kytril®)
Dolasetron (Anzemet®)
Palonosetron (Aloxi®)
Serotonin (5HT3) Antagonists
-setron drugs:
—Longest acting
MOA:
Inhibition of 5HT3 receptors on vagal afferent neurons in GI and in CTZ
** USED IN PREVENTION ONLY**
Efficacy improved when used with a steroid (20%)
Well tolerated, minimal side effects
Transient, non-significant ECG changes
67
Aprepitant, Fosaprepitant
Neurokinin-1 (NK-1) Receptor Antagonists
-prepitant drugs:
MOA:
selective, high affinity antagonist of human substance P at neurokinin 1 (NK1) receptors --> interferes with the substance P pathway
Drug Interactions with CYP450 system-reduce dose of dexamethasone
68
Corticosteroids for nausea
Dexamethasone, Methylprednisolone
MOA:?decrease 5HT3 release in gut/brain stem, ?antagonism of 5HT3 receptors, ?activate glucocorticoid receptors in brain
Generally well tolerated--elevated BS, insomnia, GI sxs, edema, weight gain, agitation
Used as single agent(low)/combined with aprepitant/5HT3 antagonists (moderate-high)
69
Prochlorperazine(Compazine®)
| Promethazine(Phenergan®)
Dopamine (D2) receptor antagonists: Phenothiazines
MOA: antagonize D2 receptors in CTZ
** USE IF ALREADY SICK**
Potent Antipsychotic agents
ADR: sedation, akathisia, dystonia
70
Metoclopramide
Dopamine (D2) receptor antagonist: Benzamide analog
MOA: stimulates gut motility; blocks intestinal 5HT2 receptors
Crosses Blood Brain Barrier = EPR’s (high doses)
- Prevention with diphenhydramine/lorazepam
Age-dependent reaction (younger 30%>elderly 2%)
Common: trismus, akathisia, dystonia
71
Haloperidol (Haldol®)
| Droperidol (Inapsine®)
Dopamine (D2) Receptor antagonists: Butyrophenones
MOA: antagonize D2 receptors in CTZ
*As effective as Phenothiazines with less incidence of EPRs/hypotension in delayed emesis
AEs:
Sedation and anticholinergic effects
Droperidol: cases of QT prolongation/TdP
72
Lorazepam
Benzodiazepine
MOA: no antiemetic properties; antegrade amnesia used for prevention
Place in therapy for anticipatory N/V
73
Dronabinol
| Nabilone
Cannabinoids for N/V:
MOA: agonism of cannabinoid(CB1) receptors in the CNS and gut; indirectly inhibit other neurotransmitters released in emesis process
Tolerance develops to adverse effects
Effective for moderate-high emetogenic regimens
Utilized in Refractory patients
