chemo agents Flashcards
(119 cards)
1
Q
What are the 8 classes of Chemo agents?
A
Alkylating, Anti-metabolite, Enzyme Inhibitors, Anti-microtubules, Endocrine Therapies, Targeted therapies, Immunotherapy, Miscellaneous
2
Q
What are the stages of the cell cycle?
A
1) Growth (G)
2) Synthesis (S)
3) Growth and preparation for mitosis (G1)
4) Cell division stage (M)
3
Q
What kind of cells do cell-cycle specific agent kill?
A
They preferentially kill proliferating cells
4
Q
How are cell-cycle specific agents administered?
A
Via continuous infusion to allow for exposure to more cells
5
Q
What kinds of cells do cell-cycle non specific agents kill?
A
Malignant and non-malignant cells
6
Q
Cell kill of cell-cycle non specific agent is proportionate to ____?
A
Dose
7
Q
What are the examples of acute toxicities caused by chemo?
A
Bone marrow suppression, Alopecia, Mucositis
8
Q
What kind of tissues are most vulnerable to acute toxicities?
A
Tissues with fast renewal cells such as bone marrow, skin, hair, GI mucosal cells
9
Q
What cause acute toxicities?
A
Inhibition of host cell division
10
Q
What are the examples of delayed toxicities caused by chemo?
A
Infertility
Anthracycline induced cardiotoxicities
MTX-induced pneumonitis
11
Q
Examples of alkylating agents?
A
Platinum analogues, Cyclophosphamide, Ifosfamide
12
Q
Examples of Platinum analogues?
A
Cisplatin (1st gen)
Carboplatin (2nd gen)
Oxaliplatin (3rd gen)
13
Q
MOA of alkylating agents?
A
1) Formation of positively charged carbonium ion that binds to electron-rich sites on biomolecules
2) Binding to reactive molecules on the DNA (N-7 of guanine)
3) DNA mispairing
4) DNA strand breakage
5) Inhibition of DNA transcription and replication
14
Q
Dose limiting toxicities of Alkylating agents?
A
Myelosuppression, nadir in 6-10 days, recovery in 14-21 days
Exception: Nitrosourea demonstrate delayed nadir and recovery.
15
Q
Do alkylating agent show cross resistance?
A
No, can switch to different class of alkylating agent if one is ineffective
16
Q
Alkylating agents differ greatly in?
A
PK, Lipid solubility, chemical reactivity and properties of membrane transport
17
Q
Cyclophosphamide is activated in ____?
A
The liver
18
Q
What are the products of cyclophosphamide activation?
A
Enzymatic: Carboxyphosphamide (Inactive)
Non-enzymatic: Acrolein, Phosphoramide mustard
19
Q
Main cytotoxic agent of cyclophosphamide?
A
Phosphoramide mustard
20
Q
Typical dose of cyclophosphamide? Indicated for?
A
600-750 mg/m^2
Indicated for lymphomas, breast cancer
21
Q
High dose of cyclophosphamide? Indicated for?
A
2g/m^2
Indicated for bone marrow transplant
22
Q
Toxicities of Cyclophosphamide?
A
N/V
Haemorrhagic cystitis
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
23
Q
Cyclophosphamide is excreted via?
A
Urine as active/ inactive metabolites
24
Q
Ifosfamide is activated in ____?
A
Liver via CYP3A4
25
MOA of Ifosfamide?
Cytotoxic activity arise from cross-linking of DNA by alkylation at N-7 of guanine. Inter-intra cross links in DNA causes cell death
26
Active metabolite of Ifosfamide?
Isophosphoramide mustard
27
Ifosfamide must be co-administered with?
Mesna
28
What is Mesna?
Mesna is a radical scavenger, must be administered with large dose of Ifosfamide
29
Toxicities of Ifosfamide?
Dose limiting haemorrhagic cystitis
Nephrotoxicity
N/V
CNS toxicity
30
MOA of platinum analogues?
Formation of reactive electrophile that covalently binds to DNA
31
Toxicities of Cisplatin?
1) Dose-limiting acute and delayed CINV
2) Cisplatin-induced Nephrotoxicity
3) Ototoxicity (may be irreversible)
4) Peripheral neuropathy (reversible)
32
When is the use of Cisplatin not recommended?
When patient's SCr < 1.5 mg/dl
33
Preventive measures for Cisplatin-induced nephrotoxicity?
1) Avoid in patients with renal dysfunction
2) Hydration with at least 1.2L 0.9% NaCl IV pre and concurrent with Cisplatin, with Potassium and Magnesium supplementation
3) Use of osmotic diuretics (Mannitol/ Furosemide)
4) Maintain urine output >100ml/h
5) Prolong infusion time
6) Use amifostine (radical scavenger)
34
Disadvantages of Amifostine?
1) Expensive and myelosuppressive.
| 2) Might affect efficacy of Cisplatin
35
How is Carboplatin dosed?
Based on Calvert's equation
36
State the Calvert's equation
Dose = AUC * (GFR +25), where AUC=2 for weekly dosing, AUC= 5 or 6 for every 3 weekly dosing
37
Toxicity of Carboplatin?
Dose limiting myelosuppression, hypersensitivity
38
Benefits of Carboplatin over Cisplatin?
Carboplatin has lower incidence of Nephrotoxicity, delayed N/V, Ototoxicity
39
Indication of Cisplatin, Carboplatin, Oxaliplatin?
Cisplatin/ Carboplatin: Large range of solid tumour
| Oxaliplatin: Colorectal cancer
40
Oxaliplatin is only stable in?
D5W
41
Toxicity of Oxaliplatin
1) Cumulative peripheral neuropathy
2) Myelosuppression
3) Nephrotoxicity
4) Hypersensitivity
42
What are the enzymes that enzyme inhibitors anatagonise?
Topoisomerase I and II
43
Topoisomerase I inhibitors?
Irinotecan (CPT-11)
44
Which stage of the cell cycle does Irinotecan affects?
S phase
45
Active metabolite of Irinotecan
SN-38
46
MOA of Irinotecan
Binds to Topoisomerase I-DNA complex, prevents the relegation of DNA. Resulting in DNA breakage and cell death
47
Indication of Irinotecan?
Metastatic colorectal cancer
48
Excretion of Irinotecan?
Biliary and urinary
49
Toxicities of Irinotecan?
1) Dose-limiting Diarrhoea
2) Cholinergic syndrome
3) UGT1A1 deficiency
50
Management of Irinotecan dose-limiting diarrhoea?
Use Loperamide 4mg at earliest sign, 2mg q2h until diarrhoea free for 12 hours
51
Describe UGT1A1 deficiency
Patient with homozygosity for UGT1A1*28 allele has problem clearing the active metabolite SN-38
52
Management of Irinotecan cholinergic syndrome?
Routinely pre-med with IV/SC Atropine (0.25-1 mg)
53
Topoisomerase II inhibitors?
Etoposide, Anthracyclines
54
Examples of Anthracyclines?
1) Doxorubicin
2) Daunorubicin
3) Epirubicin
4) Idarubicin
5) Liposomal Daunorubicin
6) Mitoxantrone
55
Indication for Etoposide?
Wide range of solid tumour?
56
Availability of Etoposide?
IV (100mg injection), Oral (50mg Caplet)
57
Administration instructions for IV Etoposide?
1) Infused for at least 1 hour to avoid hypotension
2) Use non-PVC tubing
3) Diluted to concentration of <0.4mg/ml
58
Toxicities of Etoposide?
1) Dose-limiting myelosuppression
| 2) Hypotension if infused too quickly
59
MOA of Anthracyclines?
1) Induce formation of covalent topoisomerase II-DNA complexes, preventing relegation of DNA
2) Intercalation of base pairs in DNA
3) Metabolized in liver to form oxygen rich radicals
60
Toxicities of Anthracyclines?
1) Anthracycline-induced cardiotoxicity
2) Dose-limiting myelosuppression (primarily neutropenia)
3) Alopecia
4) Acute N/V
5) Vesicant
6) Red discolouration of urine
61
Before initiation of Anthracyclines what test must be performed?
Baseline MUGA/ECHO performed to evaluate left ventricular ejection fraction (LVEF).
If LVEF <40%, do not start
62
What causes Anthracycline-induced cardiotoxicity?
Formation of free radicals
63
Risk factors of Anthracycline-induced cardiotoxicity?
1) Cumulative doses
2) Age
3) Pre-existing cardiac disease
4) Administration schedule
5) Mediastinal radiation
64
Prevention of Anthracycline-induced cardiotoxicity?
1) Limit cumulative dose, involves lifetime tracking
2) Adjust administration schedule. Fractionate doses and prolong infusion
3) Use less cardiotoxic alternative such as Liposomal Daunorubicin, Mitoxantrone
4) Use Dexrazoxane, a cardiac protectant
65
Examples of Antimetabolites?
Anti-folate agent: MTX
| Pyrimidine analogues: 5-FU, Capecitabine
66
MOA of MTX?
Binds to Dihydrofolate reductase, prevents formation of tetrahydrofolate from folic acid. Hence, preventing formation of thymidylate and purines.
Lesser DNA synthesis, repair and cellular replication
67
Indication of MTX?
All cancers
68
Administration instructions for high dose (>1g/m^2) MTX?
Requires therapeutic drug monitoring and folinic acid rescue.
69
What kinds of drugs should be avoided with MTX?
1) NSAIDs
2) Penicillins
3) Salicylates
4) Omeprazole
5) Ascorbic acid (Vit C)
6) Probenecid, Sulfonamides
70
Excretion of MTX
Primarily renal via glomerular filtration and active tubular secretion
71
Toxicities of MTX?
1) Dose limiting myelosuppression
2) MTX-induced pneumonitis
3) Nephrotoxicity
4) Hepatitis
5) Diarrhoea
6) Mucositis
7) CNS toxicities
8) MTX can escape into third spaces. Patients with ascites, pleural effusion are at high risk for MTX toxicity
72
MOA of 5-FU?
Acts as a "false pyrimidine", inhibits the enzyme Thymidylate synthase, thus inhibiting formation of the DNA base thymidine
73
Indication of 5-FU?
Solid tumour cancers
74
Excretion of 5-FU
As respiratory CO2, and via biliary system
75
Toxicities of 5-FU
Depends on the duration and rate of administration
1) Dose-limiting leukopenia, thrombocytopenia, anemia in bolus administration
2) Dose-limiting hand-food symptoms and diarrhoea in continuous infusion
3) Skin discolouration
4) Nail changes
5) Photosensitivity
6) Neurologic toxicities
7) Vasospastic angina
76
MOA of Capecitabine?
Undergoes 3-step conversion to fluorouracil. Last step being phosphorylation by thymidine phosphorylase (TP). TP is found in higher levels in tumour cell
77
Indication of Capecitabine?
Solid tumour cancers
78
Toxicities of Capecitabine?
1) Dose-limiting hand foot syndrome (more in Capecitabine), mucositis, diarrhoea
2) CINV
3) Fatigue
4) Rash
79
Examples of Anti microtubule drug?
Vinca alkaloids, Taxanes
80
Examples of Vinca alkaloid?
Vincristine, Vinblastine, Vinorelbine
81
Examples of Taxanes?
Paclitaxel, Docetaxel
82
MOA of Vinca?
Inhibition of polymerisation by binding to Tubulin
83
MOA of Taxanes?
Inhibition of depolymerisation by binding to microtubules
84
Toxicities of Vinca (general)?
1) Alopecia
| 2) Vesicants
85
Benefit of Vinca?
Low emetogenic potential
86
Toxicities of Vincristine?
1) Peripheral neuropathy
2) Ileus
3) Constipation
87
Toxicities of Vinblastine, Vinorelbine?
1) Dose-limiting neutropenia, thrombocytopenia
2) Neurologic toxicity
3) Constipation
88
Premedication for Paclitaxel? Indicated for?
To prevent Hypersensitivity. Anti-histamines (H1 & H2), Corticosteroids
89
Premedication for Docetaxel? Indicated for?
To prevent Edema. Dexamethasone 8mg PO BD, start 1 day prior to treatment, continuing for 2 additional days
90
Toxicities of Paclitaxel?
1) Hypersensitivty
2) Myelosuppression (Less significant than Docetaxel)
3) Myalgias
4) Peripheral neuropathy
5) Mucositis (Seen more with prolonged infusion)
91
Toxicities of Docetaxel?
1) Myelosuppression (Neutropenia more significant than Paclitaxel)
2) Less peripheral neuropathy
3) Less hypersensitivity
4) Less asthenia
92
Examples of Endocrine therapies?
1) Antiestrogen
| 2) Anti-aromatase
93
Example of Antiestrogen agent?
Tamoxifen, a selective estrogen receptor modulator.
94
Indications for Tamoxifen?
1) Indicated for pre menopausal women with Estrogen-receptor positive breast cancer.
2) Advanced endometrial cancer
95
MOA of Tamoxifen?
Inhibits nuclear binding of the estrogen receptor, prevent estrogen from stimulating breast cancer cells
96
Antagonist and Agonist activity of Tamoxifen?
Antagonist: Breast epithelial cells (Cancer/ Non cancer)
Agonist: Bone, Lipids, Endometrium (Can increase risk for endometrium cancer)
97
Examples of Anti-aromatase agent?
1) Anastrozole
2) Letrozole
3) Exemestane
98
Group of patient anti-aromatase agent is used in?
Post-menopausal women
99
SEs of Anti-aromatase agents?
1) Hot flashes
2) Fatigue
3) Myalgia/ Arthralgia
4) Bone Loss
100
Two major classification of Targeted Therapies?
1) Small molecular drug
| 2) Monoclonal antibodies
101
TT-induced toxcities?
1) Cardiotoxicity
2) Neurotoxicity
3) Immunotoxicity
4) Hepatotoxicity
5) Pulmonary toxicity
6) GI toxicity
7) Dermatological toxicity
102
Examples of Small molecule drugs?
Epidermal growth factor tyrosine kinase inhibitors:
1) Gefitinib
2) Erlotinib
3) Afatinib
103
MOA of Epidermal growth factor tyrosine kinase inhibitors
Inhibits cell proliferation by blocking intracellular signals that stimulate gene expression.
1) Decrease proliferation
2) Decrease cell survival
3) Decrease growth factor
4) Decrease angiogenesis
5) Decrease metastasis
6) Increase Chemo/Radio sensitivity
104
Epidermal growth factor tyrosine kinase inhibitors are indicated for?
EGFR positive cancers (Lung, pancreatic (erlotinib only))
105
Toxicities of small molecule drugs?
1) Dermatological toxicities (Mild)
| 2) Diarrhoea
106
Management principle for toxicities of small molecule drugs?
1) Should not interfere with anti-tumour effects of EGFR-inhibitors
2) Minimal SEs
3) Tailored to type of clinical presentation
107
What are the agents used for dermatological toxicities?
1) Anti-microbials
2) Emollients/ Skin protectant
3) Antihistamines
4) Retinoids
5) Corticosteroids/ Immunomodulators
108
Examples of Monoclonal antibodies?
1) Rituximab
2) Bevacizumab
3) Trastuzumab
109
MOA of Rituximab?
Binds to CD20 receptors on malignant/ normal B cells leading to:
1) Apoptosis
2) Complement Dependent Cytotoxicity
3) Antibody-dependant cell-mediated cytotoxicity
110
Toxicities of Rituximab?
1) Infusion related reactions (Fever, chill/rigor, bronchospasm, hypotension)
2) N/V
3) Myelosuppression
4) Infections
111
Management of Infusion related reactions?
1) Pre-medicate with paracetamol, diphenhydramine
| 2) Start infusion slow and increase rate overtime
112
MOA of Bevacizumab?
Vascular endothelial growth factor inhibitor
113
Bevacizumab should be avoided in _____?
Patient with bleeding risk, CNS metastasis
114
MOA of Trastuzumab?
HER2/ Neu receptor antagonist
115
Indication for Trastuzumab?
Cancer with HER2 overexpression (Breast/ Gastric)
116
Toxicities of Trastuzumab?
Cardiotoxicity, hypersensitivity
117
Toxicities of Bevacizumab?
1) Increased risk of thrombotic events (Stroke)
2) Haemorrhage
3) Gastrointestinal perforation
4) Proteinuria
5) Wound healing complication
118
Examples of Immunotherapies?
1) Ipilimumab
2) PD-1 inhibitor
3) PD-L1 inhibitor
119
MOA of Ipilimumab?
Blocks cytotoxic T-cell lymphocyte associated antigen (CTLA-4) inhibitory signal, allowing CTL to kill cancer cells
