Pharmacology of anti-cancer drugs Flashcards
Cell cycle (phase) specific agents
- 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
Cell cycle (non-phase) specific agents
- Exert cytotoxic effect throughout cell cycle, including resting phase
- cell kill proportional to dose
Agents:
- alkylating agents
- anthracycline antibiotics
- antitumor antibiotics
- nitroureas
Anticancer drug toxicities
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
List Alkylating Agents (Classes & Options)
Nitrogen mustards:
1) Cyclophosphamide
2) Ifosfamide
Platinum Analogues (Forms reactive electrophile that covalently binds to DNA):
1) Cisplatin
2) Carboplatin
3) Oxaliplatin
MOA of Alkylating Agents
- 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
Toxicity of Alkylating Agents
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
[Alkylator] Cyclophosphamide
- 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)
[Alkylator] Ifosfamide
- 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
Ifosfamide Neurotoxicity (Presentation, Cause, Management)
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
Why must Mesna be administered with Ifosfamide
Hemorrhagic cystitis
- To protect bladder lining by neutralising acrotein
- 20% of Mesna equiv to Ifosfamide dose, give another dose @ 4 & 8h
[Alkylator] Cisplatin
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
How to prevent Cisplatin-induced Nephrotoxicity
- 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)
[Alkylator] Carboplatin
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
[Alkylator] Oxaliplatin
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
List Enzyme Inhibitors (Classes & Options)
Topoisomerase I Inhibitors (Cleave single-strand DNA):
- Irinotecan
Topoisomerase II Inhibitors (Forms complex, cause double-stranded DNA breaks)
- Etoposide, Anthracyclines
[Enzyme Inhibitors] Irinotecan
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
[Enzyme Inhibitors] Etoposide
Forms: IV/PO
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
[Enzyme Inhibitors] Anthracyclines
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
Anthracycline-induced Cardiotoxicity (RF, prevention)
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
List Antimetabolites (Classes & Options)
1) Folate Antagonists
- Methotrexate
2) Pyrimidine analogues
- 5-Fluorouracil
- Capecitabine
MOA of Antimetabolites
- 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
[Antifolate] Methotrexate
Forms: IV/IT/PO
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
[Pyrimidine Analogue] 5-Fluorouracil (5-FU)
Form: IV
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
[Pyrimidine Analogue] Capecitabine
Forms: PO (150, 500mg)
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
List Antimicrotubules (Classes & Options)
1) Vinca alkaloids (Inhibit polymerization)
2) Taxanes (Inhibit depolymerization)
[Vinca alkaloids] Vincristine, Vinblastine, Vinorelbine
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)
[Taxanes] Paclitaxel
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
[Taxanes] Docetaxel
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
MOA of Taxanes
- Bind preferentially to microtubules shifting t/w polymerization
- Stabilise against depolymerization
List Endocrine therapies (Classes & Options)
1) Antiestrogens
- Tamoxifen
2) Aromatase inhibitors
- Anastrozole
- Letrozole
- Exemestane
[Antiestrogens] Tamoxifen
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!)
[Aromatase Inhibitors] Anastrozole, Letrozole, Exemestane
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)
Treatment of Breast Cancer
Premenopausal diagnosis (Estrogen in ovary): - Tamoxifen ~5yrs
Postmenopausal diagnosis (Estrogen in peripheral tissues in body): - AI ~5yrs or Tamoxifen ~2-3yrs
Targeted therapy (What is it, Pertinent issues, Classifications)
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
[Small molecule drugs] BCR/ABL (Tyrosine kinase Inhibitors)
Eg. Imatinib, Dasatinib, Nilotinib
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)
[Small molecule drugs] EGF Tyrosine Kinase Inhibitors
Eg. Gefitinib, Erlotinib, Afatinib
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
Principles of managing Dermatological Toxicities
- Treatment shld not interfere with anti-tumour effects of EGFRi
- Minimal SE
- Ease of adm with rapid results
- Therapies tailored
[Monoclonal antibodies] Rituximab
Forms: IV/SC
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)
[Monoclonal antibodies] Bevacizumab
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
[Monoclonal antibodies] Trastuzumab
Forms: IV/SC
MOA: HER2/Neu receptor antagonist
Use: Breast, gastric cancer (if HER2+)
Toxicities:
- Cardiotoxicity
- Hypersensitivity
Types of immunotherapies
1) Passive (act on tumour)
2) Active (act on immune system itself)
[Immunotherapy] Ipilimumab
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
What is PD-1 (Programmed Cell Death)
Inhibitory signalling receptor expressed on activated T-cell
PD-1 Inhibitors
Pembrolizumab
Nivolumab
Cemipilimab
PD-L1 Inhibitors
Atezolizumab
Avelumab
Durvalumab
What are some immune-related adverse events & how to manage them?
- Pneumonitis, hepatitis, pancreatitis, motor & sensory neuropathies, arthritis, dermatitis, colitis, adrenal insufficiency, thyroiditis, hypophysitis
Manage: Immunosuppressants (eg. steroids)
