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PR3136 > Clinical Pharmacology of Anti-Cancer Agents > Flashcards

Clinical Pharmacology of Anti-Cancer Agents Flashcards

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
Q

Etoposide ADR (1)

  • topo ll inhibitor
A

Myelosuppression

- dose limiting

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26
Q

Anthracyclines example (1)

A

Doxorubicin

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27
Q

MOA of Anthracyclines (3)

A
  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
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28
Q

Anthracyclines (Doxorubicin) ADR (3)

A
  1. Myelosuppression
    - dose limiting
  2. Cardiotoxicity
  3. Urine discoloration (red)
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29
Q

Prevention of cardiotoxicity from anthracyclines (doxorubicin) (2)

A
  1. Fractionate doses
  2. Prolong infusion
  3. Liposomal form
30
Q

Antimetabolites types (2)

A
  1. Folate antagonist

2. Pyrimidine & Purine analogues

31
Q

MOA of antimetabolites (2)

A
  • 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
Q

Cytostatics

A
  • anti-metabolites
  • antimicrotubules
  • targeted therapy
33
Q

Methotrexate ADR (2)

A
  1. Dose limiting myelosuppression
  2. Escapes into third space (eg ascites)
    - increase risk of toxicity
34
Q

Methotrexate MOA (4)

A
  • 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
Q

Methotrexate (3)

  • other uses
  • distribution
  • overdose treatment
A
  • 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
Q

Pyrimidine analogues examples (2)

A
  1. 5-Fluorouracil
  2. Capecitabine
    - oral form of 5-FU
37
Q

5-Fluorouracil ADR (5)

A

Bolus administration

  1. Leukopenia
  2. Thrombocytopenia
  3. Anemia

Continuous infusion

  1. Hand-foot syndrome (Palmar Plantar Erythrodysethesias)
  2. Diarrhoea
38
Q

Capecitabine indications (2)

A
  1. Colorectal cancer

2. Breast cancer

39
Q

Capecitabine advantage (1+3)

A

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
Q

Capacitabine ADR (1)

A
  1. Hand-foot syndrome (Palmar Plantar Erythrodysethesias)

- dose limiting

41
Q

Anti-microtubules types & its MOA (2)

A
  1. Vinca alkaloids
    - inhibit polymerisation
  2. Taxanes
    - preferentially bind to microtubules shifting microtubules towards polymerisation
    - stabilise against depolymerisation
42
Q

Vinca alkaloids ADR (3+1+1)

A
  1. Very low ematogenic
  2. Vesicants
  3. Alopecia

Vincristine :
1. Peripheral neuropathy

Vinblastine & Vinorelbine :

  1. Neutropenia & thrombocytopenia
    - dose limiting
43
Q

Taxanes ADR (2+2)

A

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
Q

Endocrine therapies types (4)

A
  1. Antiestrogen
    - selective estrogen receptor modulators
    - pure antiestrogen
  2. Aromatase inhibitors
    - steroidal inhibitors
    - non-steroidal inactivators
  3. LHRH agonists
  4. Anti-androgens
45
Q

Tamoxifen MOA (3)

A
  • 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
Q

Why aromatase inhibitor is used in post-menopausal women only?

A
  • post menopausal women do not produce estrogen
  • estrogen comes from conversion from androstenedione
  • inhibit estrogen production
47
Q

Targeted therapies (2)

A
  • 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
Q

Targeted therapies types (3)

A
  1. TKI/VEGFR inhibitors
  2. TKI inhibitors
  3. Monoclonal antibodies
49
Q

Pertinent issues with targeted therapies (5)

A
  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
Q

Nomenclature of monoclonal antibodies (origin) (4)

A

Mouse :
- momabs

Chimeric (34% mouse) :
- ximabs

Humanised (10% mouse) :
- zumabs

Fully human :
- mumabs

51
Q

Types of antibodies require pre-med to prevent hypersensitivity (2)

A
  1. Mouse (-momabs)

2. Chimeric (-ximabs)

52
Q

Nomenclature of antibodies (target) (3)

A

Monoclonal :
- mab

Raf kinase inhibitor :
- rafenib

Tyrosine kinasee inhibitor :
- tinib

53
Q

Rituximab MOA (3)

A

Active immunotherapy

  1. Antibody Dependent Cell Cytotoxicity (ADCC)
  2. Complement Dependent Cytotoxicity (CDC)
  3. Apoptosis
54
Q

Rituximab ADR (1)

A

Infusion related reactions

  • fever, chills, rigors
  • bronchospasm
  • hypotension
55
Q

Rituximab antibodies origin

A
  • ximab
  • chimeric
    Hence req pre-medications
56
Q

Immunotherapies types (2)

A
  1. Active
    - act on immune systems & cells
  2. Passive
    - act on tumor
57
Q

Examples of targeted therapies (3)

A
  1. Rituximab
    - stimulate ADCC, CDC & apoptosis
  2. Bevacizumab
    - VEGFR inhibitor
  3. Trastuzumab
    - HER2/Neu receptor antagonist
58
Q

Ipilimumab MOA

A
  • blocks CTLA-4 inhibitory signals on T cells
  • allows Cytotoxic T Lymphocytes (CTL) to destroy the cancer cell
  • immune active
59
Q

Ipilimumab antibodies origin

A
  • mumab

- fully human

60
Q

PD-1 inhibitors act on _

A

T cells

PD-1 receptors on T cells

61
Q

PD-L1 inhibitors act on _

A

Tumor cells

PD-L1 ligand on tumour cells

62
Q

Immunotherapies ADR

A

Immune-related ADR
- over-stimulation of immune system
- inflammation
eg hypophysitis, pneumonitis, hepatitis, pancreatitis

63
Q

Management of hyper-active immune system

A

Immunosuppressants

64
Q

General toxicities of Alkylating agents (5)

A
  1. Dose limiting myelosuppression
  2. Mucositis
  3. CINV
  4. Neurotoxicity
  5. Alopecia
65
Q

Taxanes examples (2)

A
  1. Paclitaxel

2. Docetaxel

66
Q

Aromatase inhibitors examples (3)

A
  1. Anastrozole
  2. Letrozole
  3. Exemestane
67
Q

Vesicant

A

Tissue necrosis & formation of blisters

68
Q

Anti-estrogen vs Aromatase inhibitor

A

Anti-estrogen
eg tamoxifen
- pre & post menopausal

Aromatase inhibitor
eg analestrozole, letrozole & exemestane
- post menopausal

69
Q

SERM

A

Selective Estrogen Receptor Modulators

- both antagonist & agonist depending on the receptors

70
Q

Advice for patients taking Capecitabine (2)

A
  • 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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