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PR3136 > Clinical Pharmacology of Anti-Cancer Agents > Flashcards

Clinical Pharmacology of Anti-Cancer Agents Flashcards

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1
Q

Chemotherapy Agents classes (8)

A
  1. Alkylating agents
  2. Enzyme inhibitors
  3. Anti-metabolites
  4. Anti-microtubules
  5. Endocrine therapies
  6. Targeted therapies
  7. Immunotherapies
  8. Miscellaneous
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2
Q

Chemotherapy agents killing (2)

A
  • preferentially kill proliferating cells

- non-specific agents kill both normal & malignant cells

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3
Q

Chemotherapy agents classification based on cell-cycle (2)

A
  1. Cell-cycle phase specific
  2. Cell-cycle non-phase specific
    eg ifosfamide
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4
Q

Cell-cycle phase specific (3)

A
  • toxicity to the proportion of cells in part of the cell cycle in which the agent is active in
  • toxicity is the greatest during the S phase of DNA synthesis
  • administrations as continuous infusion allows exposure to more cells in the specific cycle
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5
Q

Cell-cycle non-phase specific (2)

A
  • exert their cytotoxic effect throughout the cell cycle, including resting phase
  • cell killing is proportional to dose
    eg alkylating agents
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6
Q

Alkylating agents types (2)

A
  1. Nitrogen mustards
    - cyclophosphamide
    - ifosfamide
  2. Platinum analogues
    - carboplastin
    - cisplatin
    - oxaliplatin
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7
Q

Alkylating agents MOA

A
  • formation of positively charged carbonium ion
  • binds to neutrophilic sites on biological molecules eg DNA
  • cytotoxic effects :
    1. Inhibition of DNA replication & transcription
    2. Mispairing of DNA
    3. Strand breakage
  • no cross-resistance
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8
Q

Cyclophosphamide ADR (5)

A
  1. Myelosuppression
  2. Cardiac dysfunction
    - high dose
  3. Ematogenic potential / CINV
    - dose related
  4. Haemorrhagic cystitis
    - due to active metabolite acrolein
    - high dose
    - long term
  5. SIADH
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9
Q

Cyclophosphamide (2)

A
  • prodrug

- metabolised to active metabolites (acrolein & phosphoramide mustard)

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10
Q

Ifosfamide

A
  • prodrug
  • metabolised to isophosphoramide mustard, acrolein & chloroacetaldehyde
  • cell cycle specific but phase non-specific
  • MUST administer with mesna
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11
Q

Administration of Ifosfamide (3)

A
  • administer with mesna (radical scavenger) to reduce the risk of haemorrhagic cystitis
  • vigorous hydration with 1.5-2L of normal saline pre & post hydration
  • increase oral fluid intake
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12
Q

Ifosfamide ADR (5)

A
  1. N/V
  2. CNS toxicity
  3. Nephrotoxicity
  4. Neurotoxicity
    - due to accumulation of chloroacetaldehyde
    - 2-5 days onset
  5. Haemorrhagic cystitis (dose related)
    - use mesna for prevention
    - vigorous hydration w NS pre & post
    - increase oral fluid intake
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13
Q

Neurotoxicity clinical presentation (3)

A
  1. Hallucinations
  2. Confusion
  3. Somnolence

2-5 days after initiation of Ifosfamide due to accumulation of chloroacetaldehyde

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14
Q

Antidote for neurotoxicity from Ifosfamide

A

Methylene blue

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15
Q

Platinum analogues examples (3)

A
  1. Cisplatin
  2. Carboplatin
  3. Oxaliplatin
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16
Q

Platinum analogues ADR

  • Cisplatin (2)
  • Carboplatin (1)
  • Oxaliplatin (1)
A

Cisplatin :

  1. CINV
    - dose limiting
    - acute & delayed
  2. Nephrotoxicity
    - most

Carboplatin : Myelosuppression
- esp thrombocytopenia

Oxaliplatin : Peripheral neuropathy

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17
Q

Topoisomerase l inhibitor act on __

A

Single strand DNA

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18
Q

Topoisomerase ll inhibitor act on __

A

Double stranded DNA

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19
Q

Topoisomerase purpose as a normal cell function

A
  • relieve the tension created by unwinding the DNA
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20
Q

Topoisomerase l example (1)

A

Irinotecan

- cell cycle phase specific

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21
Q

Topoisomerase ll examples (2)

A
  1. Etopiside

2. Doxorubicin (Anthracyclines)

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22
Q

MOA of topoisomerase l & ll inhibitors

A
  • cause single/double DNA stand breaks

- prevent religation of DNA strand resulting in DNA breakage & cell death

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23
Q

Irinotecan ADR (2)

  • topo l inihibitor
A
  1. Diarrhoea
    - dose limiting
    - manifest early & late
    - treated with high dose loperamide (1st dose 4mg, subsequent doses 2mg q2h until diarrhoea free for 12h)
  2. Cholinergic syndrome (SSLUD)
    - pre-medicate w SC Atropine
  3. UGT1A1 deficiency
    - reduce starting dose
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24
Q

Cholinergic syndrome (5)

A

SSLUD

  1. Salivation
  2. Sweating
  3. Lacrimation
  4. Urination
  5. Diarrhoea
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25
Etoposide ADR (1) - topo ll inhibitor
Myelosuppression | - dose limiting
26
Anthracyclines example (1)
Doxorubicin
27
MOA of Anthracyclines (3)
1. Induce formation of covalent topoisomerase ll - DNA complexes - inhibition prevents the religation of DNA - leading to DNA strand breaks 2. Intercalations between base pairs causing DNA breaks 3. Metabolised in the liver to form oxygen free radicals - additional cytotoxicity
28
Anthracyclines (Doxorubicin) ADR (3)
1. Myelosuppression - dose limiting 2. Cardiotoxicity 3. Urine discoloration (red)
29
Prevention of cardiotoxicity from anthracyclines (doxorubicin) (2)
1. Fractionate doses 2. Prolong infusion 3. Liposomal form
30
Antimetabolites types (2)
1. Folate antagonist | 2. Pyrimidine & Purine analogues
31
MOA of antimetabolites (2)
- analogues to naturally occurring compounds found in the body eg amino acids, DNA, RNA 1. Compete for binding sites on enzymes - inhibit synthesis of critical metabolites eg pyrimidines eg methotrexate 2. Incorporate directly into DNA/RNA eg pyrimidine analogues Net effect is inhibit cell growth & proliferation
32
Cytostatics
- anti-metabolites - antimicrotubules - targeted therapy
33
Methotrexate ADR (2)
1. Dose limiting myelosuppression 2. Escapes into third space (eg ascites) - increase risk of toxicity
34
Methotrexate MOA (4)
- irreversible bind & inhibit dihydrofolate reductase - inhibit conversion of folic acid to tetrahydrofolate - results in deficiency of thymidylate & purines - decrease DNA synthesis, repair & cellular replications
35
Methotrexate (3) - other uses - distribution - overdose treatment
- non-oncology usages are common eg rheumatoid arthritis (RA) - escapes into third spaces (increase risk of toxicity for obese/ascites patients) - antidote for overdose : folinic acid
36
Pyrimidine analogues examples (2)
1. 5-Fluorouracil 2. Capecitabine - oral form of 5-FU
37
5-Fluorouracil ADR (5)
Bolus administration 1. Leukopenia 2. Thrombocytopenia 3. Anemia Continuous infusion 1. Hand-foot syndrome (Palmar Plantar Erythrodysethesias) 2. Diarrhoea
38
Capecitabine indications (2)
1. Colorectal cancer | 2. Breast cancer
39
Capecitabine advantage (1+3)
Minimal systemic exposure of active drug - selectively activated by tumor cells - thymidine phosphorylase (TP) enzyme required to convert capecitabine to active fluorouracil are reported to be higher in tumour cells than tissue cells - minimal side effects compared to 5-FU
40
Capacitabine ADR (1)
1. Hand-foot syndrome (Palmar Plantar Erythrodysethesias) | - dose limiting
41
Anti-microtubules types & its MOA (2)
1. Vinca alkaloids - inhibit polymerisation 2. Taxanes - preferentially bind to microtubules shifting microtubules towards polymerisation - stabilise against depolymerisation
42
Vinca alkaloids ADR (3+1+1)
1. Very low ematogenic 2. Vesicants 3. Alopecia Vincristine : 1. Peripheral neuropathy Vinblastine & Vinorelbine : 1. Neutropenia & thrombocytopenia - dose limiting
43
Taxanes ADR (2+2)
Paclitaxel (2) 1. Hypersensitivity - premed with H1, H2 blocker & corticosteroids 2. Myelosuppression Docetaxel (2) 1. Edema - premed with dexamethasone - 8mg BD 1 day before & 2 days after 2. Neutropenia
44
Endocrine therapies types (4)
1. Antiestrogen - selective estrogen receptor modulators - pure antiestrogen 2. Aromatase inhibitors - steroidal inhibitors - non-steroidal inactivators 3. LHRH agonists 4. Anti-androgens
45
Tamoxifen MOA (3)
- selective estrogen receptors modulators (SERMs) - inhibit nuclear binding of the estrogen receptor & block estrogen stimulating breast cancer cells - indicated for treatment of estrogen-receptor positive breast cancer only
46
Why aromatase inhibitor is used in post-menopausal women only?
- post menopausal women do not produce estrogen - estrogen comes from conversion from androstenedione - inhibit estrogen production
47
Targeted therapies (2)
- block the growth & spread of cancer by interfering with specific molecules involved in tumor growth & progression - drug with a reference to a diagnostic test that must be performed for the patient to be eligible to receive the drug
48
Targeted therapies types (3)
1. TKI/VEGFR inhibitors 2. TKI inhibitors 3. Monoclonal antibodies
49
Pertinent issues with targeted therapies (5)
1. Patient education issues - drug adherence - significance of food consumptions 2. Long term toxicities - unknown as most drugs are new in the market - importance of pharmacovigilance 3. Toxicity & response issues - pharmacogenomics & biomarkers Hence need to do diagnostic test for eligibility 4. Financial burden - most are patented 5. DDI
50
Nomenclature of monoclonal antibodies (origin) (4)
Mouse : - momabs Chimeric (34% mouse) : - ximabs Humanised (10% mouse) : - zumabs Fully human : - mumabs
51
Types of antibodies require pre-med to prevent hypersensitivity (2)
1. Mouse (-momabs) | 2. Chimeric (-ximabs)
52
Nomenclature of antibodies (target) (3)
Monoclonal : - mab Raf kinase inhibitor : - rafenib Tyrosine kinasee inhibitor : - tinib
53
Rituximab MOA (3)
Active immunotherapy 1. Antibody Dependent Cell Cytotoxicity (ADCC) 2. Complement Dependent Cytotoxicity (CDC) 3. Apoptosis
54
Rituximab ADR (1)
Infusion related reactions - fever, chills, rigors - bronchospasm - hypotension
55
Rituximab antibodies origin
- ximab - chimeric Hence req pre-medications
56
Immunotherapies types (2)
1. Active - act on immune systems & cells 2. Passive - act on tumor
57
Examples of targeted therapies (3)
1. Rituximab - stimulate ADCC, CDC & apoptosis 2. Bevacizumab - VEGFR inhibitor 3. Trastuzumab - HER2/Neu receptor antagonist
58
Ipilimumab MOA
- blocks CTLA-4 inhibitory signals on T cells - allows Cytotoxic T Lymphocytes (CTL) to destroy the cancer cell - immune active
59
Ipilimumab antibodies origin
- mumab | - fully human
60
PD-1 inhibitors act on _
T cells PD-1 receptors on T cells
61
PD-L1 inhibitors act on _
Tumor cells PD-L1 ligand on tumour cells
62
Immunotherapies ADR
Immune-related ADR - over-stimulation of immune system - inflammation eg hypophysitis, pneumonitis, hepatitis, pancreatitis
63
Management of hyper-active immune system
Immunosuppressants
64
General toxicities of Alkylating agents (5)
1. Dose limiting myelosuppression 2. Mucositis 3. CINV 4. Neurotoxicity 5. Alopecia
65
Taxanes examples (2)
1. Paclitaxel | 2. Docetaxel
66
Aromatase inhibitors examples (3)
1. Anastrozole 2. Letrozole 3. Exemestane
67
Vesicant
Tissue necrosis & formation of blisters
68
Anti-estrogen vs Aromatase inhibitor
Anti-estrogen eg tamoxifen - pre & post menopausal Aromatase inhibitor eg analestrozole, letrozole & exemestane - post menopausal
69
SERM
Selective Estrogen Receptor Modulators | - both antagonist & agonist depending on the receptors
70
Advice for patients taking Capecitabine (2)
- rapidly & almost completely absorbed unchanged from GI tract but unclear absorption of drug with food - still recommend to take with food (30min after meal) as efficacy & safety studies are based on administration with food

PR3136 (19 decks)

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