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PR3136 > Pharmacology of anti-cancer drugs > Flashcards

Pharmacology of anti-cancer drugs Flashcards

1
Q

Cell cycle (phase) specific agents

A
  • Toxic to proportion of cells in part of cell cycle in which agent is active
  • Toxicity greatest during S phase of DNA synthesis
  • “continuous infusion” for > exposure
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2
Q

Cell cycle (non-phase) specific agents

A
  • Exert cytotoxic effect throughout cell cycle, including resting phase
  • cell kill proportional to dose

Agents:

  • alkylating agents
  • anthracycline antibiotics
  • antitumor antibiotics
  • nitroureas
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3
Q

Anticancer drug toxicities

A

Acute toxicities

  • Due to inhibition of host cell division
  • Tissue with fast renewal cell populations most susceptible

Delayed toxicities

  • Occurs mths to years after treatment
  • Infertility, sec malignancies
  • Drug-specific toxicity
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4
Q

List Alkylating Agents (Classes & Options)

A

Nitrogen mustards:

1) Cyclophosphamide
2) Ifosfamide

Platinum Analogues (Forms reactive electrophile that covalently binds to DNA):

1) Cisplatin
2) Carboplatin
3) Oxaliplatin

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5
Q

MOA of Alkylating Agents

A
  • Alkylation of DNA
  • Major cytotoxic effect results from formation of a +vely charged carbonium ion which binds to electron-rich nucleophilic sites
  • Cytotoxic effects from binding to reactive molecules on DNA
  • > Inhibit DNA replication & transcription
  • > Mispairing of DNA
  • > Strand breakage
  • In general do not show cross-resistance
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6
Q

Toxicity of Alkylating Agents

A

Dose-limiting toxicity: Myelosupression
- Neutropenia with a nadir at 6-10days & recovery in 14-21 days
(Exception: Nitrosureas class - nadir 28-35, recovery 42)

Other:

  • Mucositis
  • N/V
  • CINV
  • Neurotoxicity
  • Alopecia

Long-term: Pulmonary fibrosis, infertility, sec leukemias

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7
Q

[Alkylator] Cyclophosphamide

A
  • Plasma-protein binding
  • Metabolism: Microsomal enzymes in the liver (cytochromeP450 (CYP) pri CYP2B6)
  • Prodrug to be activated by liver
  • Excretion: Renal

Use:

i) Lymphomas, breast cancer
ii) Bone marrow transplants (high dose)

Toxicities:

  • N/V (dose-related)
  • Emetogenic potential
  • SiADH
  • Hemorrhagic cystitis (cause: acrotein)
  • myelosupression
  • cardiac dysfunction (high-dose)
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8
Q

[Alkylator] Ifosfamide

A
  • Analogue of Cyclophosphamide that is activated in liver by CYP3A4 to hydroxyifosfamide (dose adj for hepatic impairment)
  • Not prodrug

MOA:

  • Inter- and intra- strand cross-links
  • Cytotoxic action is pri through DNA crosslinks, alkylation at guanine N-7 positions

Metabolism: Activated by hepatic metabolism
Excretion: Urine

Use:

i) Testicular cancer
- VIP regimen + mesna, etoposide, cisplatin
ii) Diffuse large B-cell lymphoma
- RICE regimen + mesna, etoposide, carboplatin, rituximab

Administration notes:

  • MUST give mesna
  • Vigorous hydration with 1.5-2L of NS pre- & post-hydration
  • Increase fluid intake

Toxicities: N/V, CNS toxicity, Dose-limiting hemorrhagic cystitis (mesna), nephrotoxicity, neurotoxicity

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9
Q

Ifosfamide Neurotoxicity (Presentation, Cause, Management)

A

Presentation:

  • Hallucinations, confusion, somnolence
  • Usually 2-5days after initiation

Cause:
- Accumulation of chloroacetaldehyde

Management:

  • Caution in elderly/renal dysfunction/concurrent adm of CNS active drugs
  • Increase infusion time
  • Decrease dose/discontinue treatment
  • Methylene blue (case report)
  • -> Inhibits MAO metabolism to chloroacetaldehyde
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10
Q

Why must Mesna be administered with Ifosfamide

A

Hemorrhagic cystitis

  • To protect bladder lining by neutralising acrotein
  • 20% of Mesna equiv to Ifosfamide dose, give another dose @ 4 & 8h
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11
Q

[Alkylator] Cisplatin

A

Use: Wide range of solid tumours

Administration notes:

  • Vigorous hydration with adequate urine flow rate (>100mL/h) for administration
  • Pre- & post- hydration with KCl & MgSO4

Not recommended
- SCr < 1.5mg/dL

Toxicities

i) CINV (dose-limiting acute & delayed)
- -> Accompany with anti-mimetics

ii) Cisplatin-induced Nephrotoxicity
- -> Deterioration of renal function & electrolyte wasting

iii) Ototoxicity (may be irreversible)

iv) Peripheral neuropathy
- Limit cumulative doses/decrease dose/discontinue treatment
- med to reduce neuropathic pain
- Switch to carboplatin

v) Irritant to veins

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12
Q

How to prevent Cisplatin-induced Nephrotoxicity

A
  • Avoid in renal dysfunction (CrCl <30)
  • Hydrate with at least 1-2L 0.9% NaCl IV pre- & concurrent with cisplatin, with K+ & Mg2+ supplementation
  • Maintain urine output > 100mL/h
  • Prolong infusion time
  • Provide mannitol and/or furosemide (diuresis)
  • Amifostine (Radical scavenger - To reduce reactive metabolites)
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13
Q

[Alkylator] Carboplatin

A

Use:

  • Wide range of solid tumours
  • Peripheral neuropathy w cisplatin

Toxicities

  • Dose-limiting myelosupression (esp thrombocytopenia)
  • Hypersensitivity (after 6-7doses of carboplatin)

Compared to cisplatin…
- Lower incidence of nephrotoxicity, ototoxicity, delayed N/V

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14
Q

[Alkylator] Oxaliplatin

A

Use: Colorectal cancer
- Only stable in D5W (make sure not administered tgt with normal saline)

Toxicities:

i) Cumulative peripheral neuropathy
- Acute (1st 2days): Reversible, pri peripheral symptoms exacerbated by cold air
- Persistent (>14days): Interferes with daily activities eg. writing, buttoning & swallowing. Symptoms may improve upon discontinuing
ii) Myelosupression
iii) Nephrotoxicity (< than cisplatin)
iv) Hypersensitivity

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15
Q

List Enzyme Inhibitors (Classes & Options)

A

Topoisomerase I Inhibitors (Cleave single-strand DNA):
- Irinotecan

Topoisomerase II Inhibitors (Forms complex, cause double-stranded DNA breaks)
- Etoposide, Anthracyclines

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16
Q

[Enzyme Inhibitors] Irinotecan

A

MOA: Inhibit topoisomerase I, I + SN-38 (active metabolite) bind to topoisomerase I-DNA complex, prevent religation -> DNA breakage & cell death

Type: Cell cycle phase-specific agent (S-phase)

Use: Metastatic colorectal cancer

PK:

  • High inter-pt variability
  • Metabolism: Hepatic (converted to SN-38 by hepatic carboxylesterase enzymes)
  • Excretion: Biliary & urinary excretion

Toxicities:

  • Dose-limiting diarrhoea
  • Cholinergic syndrome (pre-medicate with IV or SC atropine)
  • Diarrhoea
  • UGT1A1 deficiency
  • -> Homozygous for UGT1A1*28allele: Reduce starting dose
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17
Q

[Enzyme Inhibitors] Etoposide

Forms: IV/PO

A

Use: Wide range of solid tumours

Administration:

  • IV infusion at least 1h to avoid hypotension (usually 2h)
  • IV solution diluted to <0.4mg/mL
  • Non-PVC tubing

Toxicities:
- Dose-limiting myelosuppression (pri neutropenia) & hypotension if infused too quickly

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18
Q

[Enzyme Inhibitors] Anthracyclines

A

MOA:

1) Form covalent topoisomerase II DNA complexes
2) Intercalation between base pair in DNA
3) Metabolised in liver to form O2 free radicals

Toxicities

  • Dose-limiting myelosupression
  • Cardiotoxicity (perform baseline MUGA/ECHO)
  • Alopecia
  • Acute N/V
  • Vesicant
  • -> Can cause red discolouration of urine, require pt education
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19
Q

Anthracycline-induced Cardiotoxicity (RF, prevention)

A

RF:

  • Cumulative doses
  • Adm schedules (high peaks)
  • Age
  • Mediastinal radiation
  • Known cardiac disease

Administration schedule:

  • Fractionate dose (multiple doses over few days)
  • Prolong infusion

Prevention:

1) Less cardiotoxic options
- Mitoxantrone
- Liposomal foxorubicin
2) Dexrazoxane (cardiac protectant)
3) Baseline MUGA/ECHO prior starting to evaluate LVEF

20
Q

List Antimetabolites (Classes & Options)

A

1) Folate Antagonists
- Methotrexate

2) Pyrimidine analogues
- 5-Fluorouracil
- Capecitabine

21
Q

MOA of Antimetabolites

A
  • Structurally related to naturally occurring compounds in the body

Inhibit cell growth & proliferation by

i) Compete for binding sites on enzymes
ii) Incorporate directly into DNA or RNA

22
Q

[Antifolate] Methotrexate

Forms: IV/IT/PO

A

Indications: ALL, breast, head&neck, CTCL, lung, osteosarcoma, NHL, bladder, CNS, acute promyelocytic leukemia, soft tissue sarcoma, GVHD prophylaxis

MOA:

  • Irreversibly binds to dihydrofolate reductase (inhibits folic acid -> tetrahydrofolate)
  • Tetrahydrofolate required for purine & thymidylate synthesis
  • Deficiency of thymidylate & purines
  • > Decrease DNA synthesis, repair, cellular replication

Toxicities:

  • *Dose-limiting myelosupression
  • Nephrotoxicity
  • Mucositis
  • Diarrhoea
  • Hepatitis
  • Pulmonary pneumonitis
  • CNS toxicities

Caution:

  • Avoid administration of drugs that interfere with methotrexate excretion
  • *Pts with ascites/pleural effusions @ high risk of methotrexate toxicity (M escapes into 3rd spaces)

Essentials to know:

  • Wide range of doses
  • Non-oncology uses common (rheumatoid arthritis)
  • High doses require TDM & folinic acid rescue
  • High interpt variability in time to peak conc
  • Absorption highly variable, dose-dependent
23
Q

[Pyrimidine Analogue] 5-Fluorouracil (5-FU)

Form: IV

A

Use: Breast, colon, rectal, pancreatic & gastric cancer, anal, bladder, cervical, esophageal, head & neck, hepatobiliary, penile, thymic cancer, adenocarcinoma of unkown pri & neuroendocrine

MOA: Acts as false pyrimidine (analogue of pyrimidine uracil)

  • Interpt variability in dihydropyrimidine dehydrogenase (DPD) activity
  • > Diff in toxicity

Toxicities (dependent on duration of tx & rate of administration):

  • Dose-limiting leucopenia, thrombocytopenia, anaemia (w bolus adm)
  • Dose-limiting hand-foot syndrome & diarrhoea (w continuous infusion)
  • Skin discolouration, nail changes
  • Photosensitivity
  • Neurologic toxicity
  • Vasospastic angina
24
Q

[Pyrimidine Analogue] Capecitabine

Forms: PO (150, 500mg)

A

Use: Colorectal, breast

MOA:

  • PO active prodrug of 5-FU (via 3step conversion) that is selectively activated by tumour cells
  • Systemic exposure of drug minimised (:

Toxicities:

  • Dose-limiting hand-foot syndrome (capecitabine > 5-FU), mucositis & diarrhoea
  • CINV
  • Vomitting
  • Fatigue
  • Rash

Notes:

  • High interpt variability
  • Given within 30mins after a meal
25
Q

List Antimicrotubules (Classes & Options)

A

1) Vinca alkaloids (Inhibit polymerization)

2) Taxanes (Inhibit depolymerization)

26
Q

[Vinca alkaloids] Vincristine, Vinblastine, Vinorelbine

A

In general…

  • Very low emetogenic potential
  • Vesicants (tissue necrosis/ formation of blisters)
  • Alopecia (hair loss)

Vincristine:

  • Peripheral neuropathy (numbness, tingling pain in extremities)
  • Ileus, constipation
  • (Rare) Bone marrow suppression

Vinblastine & Vinorelbine:

  • Dose-limiting neutropenia & thrombocytopenia
  • Neurologic toxicity & constipation (much < than vincristine)
27
Q

[Taxanes] Paclitaxel

A

Use: Breast & ovarian cancer

Premedication with:

  • H1-blocker, H2-blocker, Corticosteroids
  • Prevent hypersensitivity

Toxicities:

  • Myelosupression
  • Peripheral neuropathy
  • Hypersensitivity rxns
  • Mucositis
  • Asthenia (weakness, lack of energy & strength)
  • Alopecia
28
Q

[Taxanes] Docetaxel

A

Use: Breast & ovarian cancer

Premedication with:

  • Dexamethasone to reduce fluid retention
  • Prevent edema

Toxicities:

  • More neutropenia (dose-limiting)
  • Less peripheral neuropathy, hypersensitivity & asthenia than paclitaxel
29
Q

MOA of Taxanes

A
  • Bind preferentially to microtubules shifting t/w polymerization
  • Stabilise against depolymerization
30
Q

List Endocrine therapies (Classes & Options)

A

1) Antiestrogens
- Tamoxifen

2) Aromatase inhibitors
- Anastrozole
- Letrozole
- Exemestane

31
Q

[Antiestrogens] Tamoxifen

A

What: Selective estrogen receptor modulators (SERMs)

Use: Estrogen-receptor +ve Breast Cancer

MOA:
- Inhibit nuclear binding of estrogen receptor, block estrogen stimulating of breast cancer cells
–> Antiestrogenic @ breast epithelial cells (normal + cancer)
–> Estrogenic @ bone, lipids, endometrium
(Increased risk of endometrial cancer!)

32
Q

[Aromatase Inhibitors] Anastrozole, Letrozole, Exemestane

A

Reversible competitive inhibitor:
- Anastrozole, Letrozole
Irreversible inhibitor:
- Exemestane

Use: Estrogen-receptor +ve Breast Cancer (Post-menopausal ONLY)

Toxicities:

  • Fatigue
  • Hot flashes
  • Myalgia
  • Athralgia
  • Bone loss (supplement with Ca2+ & Vit D)
33
Q

Treatment of Breast Cancer

A 
Premenopausal diagnosis (Estrogen in ovary):
- Tamoxifen ~5yrs
Postmenopausal diagnosis (Estrogen in peripheral tissues in body):
- AI ~5yrs or Tamoxifen ~2-3yrs
34
Q

Targeted therapy (What is it, Pertinent issues, Classifications)

A

What:
- Drugs that interfere with specific molecules involved in tumour growth & progression

Pertinent issues:

i) Patient education (drug adherence, significance of food consumptions eg. avoid grapefruit juice)
ii) Long-term toxicities (unknown, pharmacovigilance)
iii) Toxicity & response issues
iv) Financial burden
v) DDI

Classifications:

1) Small molecule drugs (Inhibit cell proliferation by blocking IC signals that stimulate gene expression)
2) Monoclonal antibodies

35
Q

[Small molecule drugs] BCR/ABL (Tyrosine kinase Inhibitors)

Eg. Imatinib, Dasatinib, Nilotinib

A

Use:

1) Chronic myelogenous leukemia
2) Acute lymphoblastic leukemia
3) GI stromal tumour

Toxicities:

  • N/V
  • Dose-limiting myelosupression
  • Fluid retention
  • LFTs increase (assess hepatic functn beforehand)

Note;
- DDI (grapefruit juice incr plasma levels)

36
Q

[Small molecule drugs] EGF Tyrosine Kinase Inhibitors

Eg. Gefitinib, Erlotinib, Afatinib

A

Use:

1) Lung cancer
2) Pancreatic cancer (erlotinib only)

Toxicities:

i) Dermatological toxicities
- -> Pruritus (<1-2wks)
- -> Rash (1-2wks)
- -> Alopecia & xerosis (3-4wks)
- -> Nail changes (>4wks)
ii) GI (Diarrhoea - give loperamide)

  • EGFR+
    Eg. EGFR+ Lung Cancer
  • Mutation on axon 18-21
37
Q

Principles of managing Dermatological Toxicities

A
  • Treatment shld not interfere with anti-tumour effects of EGFRi
  • Minimal SE
  • Ease of adm with rapid results
  • Therapies tailored
38
Q

[Monoclonal antibodies] Rituximab

Forms: IV/SC

A

Target: CD20

Toxicities:

  • Infusion-related reactions (fever, chills/rigour, bronchospasm, hypotension)
  • -> Ab-antigen rxn on lymphocytes -> cytokine release

Note:

  • Pre-medicate with paracetamol & diphenydramine
  • Start infusion low & increase rate over time
  • Subsequent cycles can benefit from shorter infusion (90mins)
39
Q

[Monoclonal antibodies] Bevacizumab

A

MOA: EGF Inhibitor

Use: Colorectal, lung, kidney cancer

Toxicities:

  • Hemorrhage (avoid/discontinue in serious hemorrhage)
  • Increase risk of thrombotic events
  • Wound healing complications
  • GI perforations
  • -> Discontinue in pts with suspected GI perforations
  • Proteinuria

Avoid in:

  • High risk for bleeds/CNS metastasis
  • -> Watch hypertension, proteinuria, risk of stroke
40
Q

[Monoclonal antibodies] Trastuzumab

Forms: IV/SC

A

MOA: HER2/Neu receptor antagonist

Use: Breast, gastric cancer (if HER2+)

Toxicities:

  • Cardiotoxicity
  • Hypersensitivity
41
Q

Types of immunotherapies

A

1) Passive (act on tumour)

2) Active (act on immune system itself)

42
Q

[Immunotherapy] Ipilimumab

A

MOA: Block Cytotoxic T-Cell Lymphocyte associated Antigen (CTLA-4) inhibitory signal, allows CTLs to destroy cancer cells

Use: Melanoma

Toxicities (immunological-related):

  • rash
  • diarrhoea
  • thyroid
43
Q

What is PD-1 (Programmed Cell Death)

A

Inhibitory signalling receptor expressed on activated T-cell

44
Q

PD-1 Inhibitors

A

Pembrolizumab
Nivolumab
Cemipilimab

45
Q

PD-L1 Inhibitors

A

Atezolizumab
Avelumab
Durvalumab

46
Q

What are some immune-related adverse events & how to manage them?

A
  • Pneumonitis, hepatitis, pancreatitis, motor & sensory neuropathies, arthritis, dermatitis, colitis, adrenal insufficiency, thyroiditis, hypophysitis

Manage: Immunosuppressants (eg. steroids)

PR3136 (14 decks)

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