Pharmacology Flashcards
Biochemical classification
Alkylating agents Topoisomerase inhibitors Targeted therapies Antimetabolites Anti-microtubules
MOA
Preferentially kill proliferating cells
Non-phase specific agents
Exert cytotoxic effect throughout cell cycle Cell kill proportional to dose Alkylating agents Anthracycline antibiotics Antitumor antibiotics Nitrosoureas
Nitrogen mustards
Cyclophosphamide Ifosfamide Bendamustine Chlorambucil Melphalan Mechlorethamine
Platinum analogues
Carboplatin
Cisplatin
Oxaliplatin
Alkylating agents MOA
Formation of positively charged carbonium ion which binds to electron-rich nucleophilic sites
Cytotoxic effects from:
- inhibition of DNA replication and transcription
- mispairing of DNA
- strand breakage
Alkylating agents toxicity
Myelosuppression*
- nadir at 6-10d, recovery in 14-21d (except nitrosourea)
Mucositis
CINV
Neurotoxicity
Alopecia
Long term (4y): pulmonary fibrosis, infertility, secondary leukemia
Cyclophosphamide
Must be activated in the liver to active metabolite
Indications:
- lymphomas and breast cancer (low doses)
- bone marrow transplants (high dose)
Cyclophosphamide toxicities
CINV (dose-related) SIADH Hemorrhagic cystitis (high doses/long term) Myelosuppression Cardiac dysfunction in high dose
Ifosfamide
Analogue of cyclophosphamide activated by CYP3A4
MOA through DNA crosslinks at guanine N-7 positions
Ifosfamide indications and administration
Testicular cancer VIP regimen
Diffuse large B-cell lymphoma RICE regimen
Must be administered with MESNA
Vigorous hydration with 1.5-2L of NS pre and post hydration; increase fluid intake
Ifosfamide toxicities
CINV
CNS Toxicity
Nephrotoxicity
Dose limiting haemorrhagic cystitis
Ifosfamide neurotoxicity
From accumulation of chloroacetaldehyde Presentation: - hallucinations - confusion - somnolence Symptoms begin 2-5d after start of ifosfamide
Ifosfamide neurotoxicity prevention/management
Caution in elderly patients, renal dysfunction Increase infusion time Avoid concurrent CNS active drugs Decrease dose/discontinue with onset Methylene blue antidote
Cisplatin
Indicated for solid tumours
CI in renal impairment (SCr < 1.5mg/dL)
Vigorous hydration required
Must be given with antiemetic
Cisplatin toxicity
Dose limiting acute and delayed CINV - Must always be given with antiemetics Ototoxicity (high peak doses) Peripheral neuropathy - Limit cumulative doses - Decrease dose or discontinue treatment - Substitute with carboplatin Irritant to veins Nephrotoxicity
Cisplatin induced nephrotoxicity prevention strategies
Hydration w at least 1-2L 0.9% NaCl IV pre and concurrent, with K and Mg supplementation Maintain urine output 100mL Provide mannitol/furosemide Prolong infusion time (24h) Amifostin
Carboplatin
Indicated for solid tumours
Dose = AUC x (GFR + 25)
- AUC = 2 for weekly; 5/6 for every 3 weekly
Carboplatin toxicities
Dose limiting myelosuppression (thrombocytopenia)
Hypersensitivity after 6-7 doses
Lower incidences of nephro and ototoxicity, CINV
Oxaliplatin
Indicated for colorectal cancer
Stable only in D5W
Oxaliplatin toxicity
Cumulative peripheral neuropathy from injury to small sensory fibres
- Acute occurs in first 2 days, reversible and exacerbated by cold surfaces
- Persistent (paresthesia) lasts > 14d, may improve upon discontinuation
Myelosuppression
Nephrotoxicity
Hypersensitivity
Irinotecan
Inhibition of topoisomerase I
Cell cycle phase specific (S phase)
Irinotecan toxicities and management
Dose limiting diarrhoea
- Loperamide 4mg at earliest sign, followed by 2mg PO q2h until diarrhea free for 12h
Cholinergic syndrome
- premedicate w IV/SC Atropine 0.25-1mg)
UGT1A1 deficiency - reduction in starting dose
Etoposide
Inhibition of topoisomerase II
Indicated for solid tumours
IV infusion at least 1h to avoid hypotension, <0.4mg/mL, non-PVC tubing
PO dose twice of IV
Etoposide toxicities
Dose limiting myelosuppression
Hypotension if infusion too quick
Anthracyclines
Doxorubicin Daunorubicin Epirubicin Idarubicin Liposomal doxorubicin Mitoxantrone
Anthracyclines MOA
Inhibition of topoisomerase II
Intercalations between base pairs
Metabolised in liver to form oxygen free radicals
Anthracyclines toxicity
Dose limiting myelosuppression Cardiotoxicity Alopecia Acute NV Vesicant Red discolouration of urine
Anthracyclines cardiotoxicity
Acute (24h): Arrhythmias, pericarditis
Subacute (weeks to months): tachycardia
Late (>5y): cardiomyopathy
Anthracyclines cardiotoxicity risk factors
Cumulative doses Administrative schedule Age Mediastinal radiation Known cardiac disease
Anthracycline-induced cardiotoxicity prevention
Baseline MUGA for LVEF Limit cumulative dose Less cardiotoxic anthracycline/analogue - liposomal doxorubicin - mitoxantrone Use dexrazoxane
Antimetabolites mechanism of action
Compete for binding sites on enzyme
- antifolate (mtx)
Incorporate directly into DNA or RNA
Methotrexate
Indicated for all cancers, GVHD, rheumatoid diseases
MTX toxicities
Dose limiting myelosuppression CNS toxicity Mucositis Pulmonary pneumonitis Hepatits Nephrotoxicity Diarrhoea
5-Fluorouracil
Pyrimidine analogue – acts as an antagonist
Available as injection
5-FU Toxicities
Myelosuppression with bolus administration
Hand-foot syndrome (PPE) and diarrhoea with continuous infusion
Skin discoloration
Nail changes
Photosensitivity
Neurologic toxicity
Vasospastic angina
Capecitabine
Pyrimidine analogue selectively activated by tumour cells
Indicated for breast and colorectal cancer
Administered with food
Capecitabine toxicity
Dose limiting hand-foot syndrome, mucositis and diarrhoea
CINV
Fatigue
Rash
Vinca alkaloids
Vincristine
Vinblastine
Vinorelbine
Vinca-induced toxicities
Vesicant Alopecia Constipation Vincristine - peripheral neuropathy (max 2mg/w) - ileus Vinblastine/Vinorelbine - dose limiting neutropenia and thrombocytopenia - neurologic toxicity
Taxanes and premedications
Paclitaxel - H1 blocker, H2 blocker, corticosteroids
Docetaxel - Dexamethasone
Paclitaxel toxicities
Myelosuppression - WBC nadie 8-11d, recovery 15-21d Peripheral neuropathy Myalgias Hypersensitivity reactions Mucositis
Docetaxel toxicities
More neutropenia
Alopecia
Less peripheral neuropathy, hypersensitivity reactions and asthenia
Tamoxifen
Selective estrogen receptor modulators
Indicated for estrogen-receptor positive breast cancer
Tamoxifen toxicities
Increased risk of endometrial cancer
agonistic effect on bone, lipids, endometrium
Hot flashes
Thromboembolic events
Aromatase inihibitors
Anastrozole
Letrozole
Exemestane
Reversible competitive inhibitor
Aromatase inhibitors SE
Fatigue
Hot flashes
Myalgia/Athralgia
Bone-related adverse effects
BCR/ABL tyrosine kinase inhibitor
Imatinib, Dasatinib, nilotinib
Indicated for leukemia, gastrointestinal stromal tumor
BCR/ABL tyrosine kinase inhibitor toxicities
CINV Dose limiting myelosuppression Fluid retention Increase in LFTs CYP3A4 interactions
EGFR tyrosine kinse inhibitors
Gefitinib
Erlotinib
Afatinib
Indicated for lung cancer, pancreatic cancer (erlotinib)
EGFR TK inhibitors SE
Dermatological toxicities - Pruritis - papulopustular rash - alopecia - Xerosis - Nail changes GI side effects -- diarrhoea
Rituximab considerations
Infusion related reactions - fever, rigors, bronchospams, hypotension
Premedicate with paracetamol and diphenhydramine
Start infusion slow and increase rate over time if no reactions
Bevacizumab
VEGF inhibitor
Indicated in colorectal, lung, kidney cancer
Bevacizumab CI
High risk of bleeds High risk of CNS metastasis Hypertension Proteinuria -- discontinue in nephrotic syndrome Risk of stroke
Trastuzumab
HER2/Neu receptor antagonist
Indicated for breast, gastric cancer (HER2+)
Trastuzumab toxicities
Cardiotoxicity
Hypersensitivity - premedicate with paracetamol
Ipilimumab
Blocks CTLA-4 inhibitory signal to kill cancer cells
Indicated for treatment of melanoma
SE: rash, diarrhoea, thyroid
PD-1 Inhibitors
Pembrolizumab
Nivolumab
Cemepilimab
PD-L1 inhibitors
Atezolizumab
Avelumab
Durvalumab
Immune related adverse effects
Hypophysitis Thyroiditis Pneumonitis Hepatitis Pancreatitis Adrenal insufficiency Colitis Motor and sensory neuropathies Dermatitis/rash Arthritis
