Neoplasia Pharmacology PDF

NS2882 Neoplasia Pharmacology Anu [email protected]  Learning objectives ▪ Describe general principles of chemotherapy ▪ Explain the mechanism of action (MoA) of the various classes of cytotoxic drugs in the treatment of cancers ▪ Explain the gene...

NS2882 Neoplasia Pharmacology Anu [email protected]  Learning objectives ▪ Describe general principles of chemotherapy ▪ Explain the mechanism of action (MoA) of the various classes of cytotoxic drugs in the treatment of cancers ▪ Explain the general adverse effects of chemotherapeutics (include both immediate and delayed side effects) ▪ Identify certain issues associated with chemotherapy ▪ Explain why combination therapy is mostly preferred over single drug chemotherapy  General principles of Chemotherapy Cytotoxic agents : disrupt cancer cells. Also known as ‘antineoplastic’ agents; in layman’s language - ‘chemotherapy’, cytotoxics, chemotherapeutics … ❑ Transported through blood - has potential to reach each cancer cell Principle of Selective toxicity is applied to destroy abnormal cancerous cells while preserving normal cells - Antineoplastic agents target mostly ‘active proliferating property’ of malignant cells ❖ Can be given for many purposes: as curative, adjuvant, neo-adjuvant, palliative or for maintenance o May be administered in the hospital, clinic, or home setting by topical, oral, intravenous, intramuscular, subcutaneous, arterial, intracavitary, & intrathecal routes Revise Cell Cycle Note: There are two DNA checkpoints in a cell cycle - at the end of G1 & G2 phases. For extra information on Cell Cycle (Overview, Interphase) watch - https://youtu.be/gTZ_vj-HdzM  Antineoplastic agents Cell-cycle phase specific agents Cell-cycle phase 5. non-specific agents Plant alkaloids 4. Other antineoplastic agents: o Hormones, especially steroids and their 3. antagonists o Immunomodulatory drugs: Monoclonal antibodies and cytokines o Protein kinase inhibitors o Miscellaneous agents.  Alkylating Agents Mechanism of Action (MoA) – cause cross links (covalent bonds) between the DNA strands and make DNA non-functional; cell cannot function and replicate – induce apoptosis – The strands can no longer separate for replication/cause breakage of DNA To reduce urotoxic side effects Cause general adverse effects associated with (haematuria) Mesna is often used: cytotoxics (mentioned later) Has a free chemical group which binds to Potent vesicants toxic metabolites of alkylating agents in Can cause urotoxicity: Presents as haemorrhagic cystitis urinary tract →reduces damage to the caused by metabolites of the anti-cancer drug - E.g. Cyclophosphamide bladder and  bleeding  Alkylating Agents Nitrogen Mustards – Platinum Compounds Chlorambucil (T) Carboplatin (I) Cyclophosphamide (T, I) Cisplatin (I) Ifosfamide (I) Oxaliplatin (I) Melphalan (T, I) – Others Nitrosureas Busulfan (T,I) Lomustine (C) Procarbazine (C) Fotemustine (I) Thiotepa (I) Carmustine (I) Dacarbazine (I) Temozolomide (T, I) T= Tablet, I= Injection, C=Capsule  Antibiotic type cytotoxic agents Mechanism of Action ✓ Bind to DNA & cause intercalation between base pairs (prevent synthesis of DNA & RNA; induce breaks in the DNA) ✓ Generate free radicals which are destructive to DNA & cells ✓ Inhibit enzyme (topoisomerase II) required for DNA replication Common Examples: Anthracyclines Side effects Bleomycin (I) Doxorubicin (I) Dactinomycin (I) ▪ General adverse effects Daunorubicin (I) Mitomycin (I) Epirubicin (I) ▪ Cardiac toxicity T= Tablet, Idarubicin (I, C) I= Injection, C=Capsule ▪ Pulmonary fibrosis Mitozantrone (I)  Antimetabolites Cell-cycle phase specific agents - Mechanism of Action: Antimetabolites (folate, purine, adenosine, and pyrimidine analogs, and substituted ureas), which are structurally similar to naturally occurring metabolites required for DNA and RNA synthesis, exert their effects either by competing with or by substituting for normal metabolites ✓ Cause general cytotoxic adverse effects: bone marrow depression, damage to GI lining; Methotrexate can also induce pneumonitis and liver damage. 9  Antimetabolites Common Examples ❖Pyrimidine ‘Antagonists’ ❖Folic Acid ‘Antagonists’ Azacitidine (I) Methotrexate (I,T) Capecitabine (T) Pemetrexed (I) Cytarabine (I) Raltitrexed (I) Fluorouracil (I) Gemcitabine (I) ❖Purine ‘Antagonists’ Cladribine (I) Clofarabine (I) Fludarabine (I,T) T= Tablet, Mercaptopurine (T) I= Injection, Thioguanine (T) C=Capsule 10  Antimetabolites Certain Antimetabolites (5-Flourouracil) can also be used topically to treat certain skin cancers 11  Plant-derived anticancer drugs Topoisomerase inhibitors o MoA: Disrupt DNA replication, transcription, generates DNA single- & double-strand breaks, leading to apoptotic cell death; Cancer cells that are in S phase/G2 phase are mostly affected by topoisomerase inhibitors Mitotic inhibitors/poisons (Taxanes & Vinca alkaloids) o MoA: microtubule damaging agents; interfere with the metaphase of mitosis; stops cancer cell division & induces cell death Side effects: ▪ Cause general adverse effects associated with cytotoxics such as Bone marrow suppression, Damage to GI lining, development of secondary leukemia ▪ Peripheral Neuropathy; Pain, burning, tingling in extremities  Plant-derived anticancer drugs Topoisomerase I inhibitor Vinca alkaloids: Irinotecan (IV) Vincristine (IV) Topotecan (IV, C) Vinblastine (IV) Vinorelbine (IV) Topoisomerase II inhibitors Taxanes: Etoposide (T, IV) Paclitaxel (IV) Doxorubicin (IV) Docetaxel (IV) Epirubicin (IV)  Cytotoxic pharmacology – Adverse effects Cause damage to rapidly dividing normal cells in the body – hair follicles Cells with – skin cells rapid – cells lining the GI tract growth rates – bone marrow cells and – sex gametes division This produces a characteristic set of adverse effects (may be immediate or delayed) across many classes of cytotoxic agents  General adverse effects of cytotoxic drugs ✓ Bone marrow suppression ✓ Damage to GI epithelium ✓ Nausea and vomiting ✓ Sterility ✓ Depression of growth in children ✓ Loss of hair ✓ Impaired wound healing ✓ Carcinogenicity ✓ Teratogenicity ✓ Toxic effects on organs ❖ Side effects can be acute or late.  General adverse effects - immediate – Mouth ulcers & Oral mucositis Maintain oral hygiene Symptomatic treatment – topical or systemic analgesics – Skin blisters & necrosis Symptomatic treatment – emollients – Fatigue accumulation of toxic substances, lack of sleep &  RBC - Nausea & Vomiting The incidence, severity, onset and duration depends on a number of factors  General adverse effects - delayed ❖ Suppression of bone marrow ✓ Leucopoenia (decrease in WBC; within 1 to 2 weeks) ✓ Thrombocytopenia (decrease in platelets; in 2 to 3 weeks) ✓ Anaemia (decrease in RBC; after one or two months) Treated with Colony Stimulating Factors (G-CSFs), erythropoietin agonists Others: delayed nausea and vomiting, mucositis, alopecia, skin rashes, diarrhoea or constipation, and a variety of cumulative neurotoxicities. ❖ Chronic toxicities involve damage to organs such as the heart, liver, kidneys and lungs. Antineoplastic agents and their side effects  Issues Extravasation with cytotoxic agents – Inadvertent leakage of drug from vein into surrounding tissue – Can range from no damage, to pain, mild inflammation or severe ulcerative necrosis – Agents that are known to cause damage (vesicants) are usually administered via central venous catheter, slow IV push, short IV infusion – Use protocols to deal with the risk of extravasation – QH and eviQ protocols https://www.eviq.org.au/clinical-resources/extravasation ✓ These risks affect the patient and those who prepare them (i.e., pharmacists) and those who administer these agents (i.e., nurses); protocols include protective equipment required, correct disposal, dealing with bodily fluids.  Issues with cytotoxic agents Physical Stability Some cytotoxic agents are degraded by exposure to light and/or heat Makes the drug less effective May be prevented by covering IV bags to prevent exposure Resistance to Cytotoxic Drugs Like microbial organisms (e.g. bacteria), cancer cells can develop resistance to cytotoxic drugs This is overcome by optimising antineoplastic drug and use of combination therapy 20  Combination therapy When chemotherapy agents from different classes that act by distinct mechanisms are used has proven to be more effective than single –drug chemotherapy Combination therapy helps, ✓ to interrupt cell growth at multiple points in the cell cycle ✓ to decrease drug resistance ✓ to minimize drug toxicity ▪ Dose-dense chemotherapy: Administration of chemotherapeutic agents at standard doses with short time intervals between each cell cycle of treatment