Question

As a first year student during your allocation at Cancer Hospital, your fellow first year student nurses from another college have asked you to explain the classifications of various Cytotoxic drugs that they see being administered to patients. But as a bright Pharmacology student, you also decide to explain in details how to manage a patient on Cytotoxic drugs.
In each class write Mechanism of action & Drug name, Presentation, Indication, Dose (adult and Paediatric), Side effects and Nursing Implications

Answer 1

Classification of cytotoxic agents

Alkylating agents
• Cyclophosphamide
• Ifosfamide
• Temozolomide
Anti- Metabolites
• Capecitabine
• 5- Fluoro Uracil
• Methotrexate
• Gemcitabine
• Pemetrexed
Anti-Tumour antibiotics
• Bleomycin
• Doxorubicin ( + pegylated liposomal)

Epirubicin

Mitomycin

Plant Alkaloids/ Microtubule Inhibitors
• Cabazitaxel
• Docetaxel
• Eribulin
• Etoposide
• Irinotecan
• Paclitaxel
• Vincristine
• Vinorelbine
DNA Linking Agents
• Carboplatin
• Cisplatin
• Oxaliplatin
Biological Agents + Targeted Agents
• Afatinib
• Bevacizumab
• Cetuximab
• Crizotinib
• Denosumab
• Erlotinib
• Gefitinib
• Imatinib
• Nintedanib
• Pazopanib
• Pertuzumab
• Rituximab
• Sunitinib
• Sorafenib
• Trastuzumab
• Trastuzumab emtansine (TDM-1)

Bisphosphonates
• Pamidronate
• Zoledronic acid
Immunotherapy
• Ipilimumab
• Nivolumab
• Pembrolizumab
Hormones/other
• Abiraterone
• Anastrozole
• Bicalutamide
• Buserelin
• Cyproterone acetate
• Degarelix
• Enzalutamide
• Exemestane
• Fulvestrant
• Letrozole
• Medroxyprogesterone
• Octreotide
• Tamoxifen
• Anti-androgens - Bicalutamide, Cyptoterone acetate
• LHRH agonists - Goserelin, Leuprolin, Triptorelin

MECHANISM OF ACTION

ALKYLATING AGENTS

MECHANISM OF ACTION:

Classic alkylating agents interfere with DNA replication by crosslinking DNA strands, DNA strand breaking, and abnormal pairing of base pairs. They exert their lethal effects on cells throughout the cell cycle but tend to be more effective against rapidly dividing cells.

Because alkylating agents are active against cells in G0, they can be used to debulk tumours, causing resting cells to be recruited into active division. At this point, those cells are vulnerable to the cell cycle-specific agents. These agents are active against lymphomas, Hodgkin's disease, breast cancer, and multiple myeloma.

SIDE EFFECTS

Major toxicities occur in the haematopoietic, gastrointestinal and reproductive systems. Individuals treated with these agents are also placed at a higher risk of developing secondary malignancies. Examples include Cyclophosphamide, Ifosfamide, Chlorambucil, Busulfan and Melphalan.

The nitrosureas are a subgroup of the alkylating agents. They also interfere with DNA replication and repair. They are highly lipid soluble and readily cross the blood-brain barrier. An example is Carmustine.

Another subgroup of alkylators called Platinum-containing compounds include agents such as Cisplatin, Carboplatin and Oxaliplatin.¹²  Their cytotoxic properties also extend to alteration of the cell membrane transport systems and suppression of mitochondrial function.

ANTIMETABOLITES

MECHANISM OF ACTION

Antimetabolites interfere with DNA and RNA synthesis by acting as false metabolites, which are incorporated into the DNA strand or block essential enzymes, so that DNA synthesis is prevented. Most agents are cell cycle phase specific for S phase. These agents are most effective when used against rapidly cycling cell populations and are consequently more effective against fast-growing tumours than slow-growing tumours. Major toxicities occur in the haematopoietic and gastrointestinal systems. Examples include Methotrexate, 5-Fluorourocil and Cytosine Arabinoside.

Hypomethylating agents represent a class of drugs that may restore normal gene function to genes responsible for cell division and differentiation. Hypomethylating agents may function as biological response modifiers by affecting cytokine cell signaling. These agents may be identified as antimetabolites and they include 5-azacytidine and Decitabine.

ATI-TUMOR ANTIBIOTICS

MECHANISM OF ACTION

Antitumour antibiotics (also called Anthracyclines) interfere with RNA and DNA synthesis. Most drugs are cell cycle non-specific.

SIDE EFFECTS

Major toxicities occur in the haematopoietic, gastrointestinal, cardiac and reproductive systems. Cardiac toxicity may be manifested as acute changes in the electrocardiograph (ECG) and arrhythmias. Individuals with preexisting heart disease are most at risk. Examples include Bleomycin, Daunorubicin, and Doxorubicin.

PLANT ALKALOIDS

MECHANISM OF ACTION

Plant alkaloids bind to microtubule proteins during metaphase, causing mitotic arrest. The cell cannot divide and dies. This group is mainly cell cycle phase specific for M phase.

SIDE EFFECTS

Major toxicities occur in the haematopoietic, integumentary, neurologic and reproductive systems. Hypersensitivity reactions also may occur during administration of these agents.This group contains three subgroups:

• the vinca alkaloids e.g. vincristine and vinblastine
• the epipodophyllotoxins e.g. etoposide and teniposide
• the taxanes e.g. paclitaxel and docetaxel.

MISCELLANEOUS AGENTS : differ from any of the major classes of cytotoxic agents.
Common miscellaneous agents are asparaginase and hydroxyurea.

Topoisomerase inhibitors prevent realigning of DNA strands and maintain single-strand breaks.

SIDE EFFECTS

Major toxicities occur in the haematopoietic and gastrointestinal systems. Examples include irinotecan and topotecan.

HORMONAL AGENTS

MECHANISM OF ACTION

alter the internal / extracellular environment. Most agents are cell cycle phase non-specific. Breast, thyroid, prostate and uterine cancers are examples of tumours that are sensitive to hormonal manipulation. With these diseases, the action of hormones or hormone antagonists depends on the presence of hormone receptors in the tumours themselves (i.e. oestrogen receptors in breast cancers). There are individual classifications of hormonal agents:

• adrenocorticoids, eg. prednisone
• androgens, eg. testosterone propionate
• oestrogens, eg. diethylstilbestrol
• selective oestrogen receptor modulators, eg. tamoxifen citrate
• selective aromatase inhibitors, eg. anastrozole
• progesterones, eg. megestrol acetate
• antitestosterone , eg. flutamide
• SIDE EFFECTS

Major toxicities occur in the gastrointestinal, sexual / reproductive systems and mood and sleep pattern changes.

Chemotherapy

In chemotherapy, antineoplastic agents are used in an attempt to destroy tumor cells by interfering with cellular functions, including replication.

• Goal. The goal of treatment is the eradication of enough tumor so that the remaining tumor cells can be destroyed by the body’s immune system.
• Proliferating cells. Actively proliferating cells within a tumor are the most sensitive to chemotherapeutic agents.
• Nondividing cells. Nondividing cells capable of future proliferation are the least sensitive to antineoplastic medications and consequently are potentially dangerous.
• Cell cycle-specific. Cell cycle-specific agents destroy cells that are actively reproducing by means of the cell-cycle; most affect cells in the S phase by interfering with DNA and RNA synthesis.
• Cell cycle-nonspecific. Chemotherapeutic agents that act independently of the cell cycle phases are cell cycle nonspecific, and they usually have a prolonged effect on cells, leading to cellular damage and death.

Antineoplastic Agents

Chemotherapeutic agents are also classified by chemical group, each with a different mechanism of action.

• Alkylating agents. Alters DNA structure by misreading DNA code, initiating breaks in the DNA molecule, cross-linking DNA strands
• Nitrosoureas. Similar to the alkylating agents, but they can cross the blood-brain barrier.
• Topoisomerase I inhibitors. Induce breaks in the DNA strand by binding to enzyme topoisomerase I, preventing cells from dividing.
• Antimetabolites. Antimetabolites interfere with the biosynthesis of metabolites or nucleic acids necessary for RNA and DNA synthesis.
• Antitumor antibiotics. Interfere with DNA synthesis by binding DNA and prevent RNA synthesis.
• Mitotic spindle poisons. Arrest metaphase by inhibiting mitotic tubular formation and inhibiting DNA and protein synthesis.
• Hormonal agents. Hormonal agents bind to hormone receptor sites that alter cellular growth; blocks binding of estrogens to receptor sites; inhibit RNA synthesis; suppress aromatase of P450 system, which decreases level.

Nursing Management in Chemotherapy

Nurses play an important role in assessing and managing many of the problems experienced by patients undergoing chemotherapy.

• Assessing fluid and electrolyte balance. Anorexia, nausea, vomiting, altered taste, mucositis, and diarrhea put patients at risk for nutritional and fluid electrolyte disturbances.
• Modifying risks for infection and bleeding. Suppression of the bone marrow and immune system is expected and frequently serves as a guide in determining appropriate chemotherapy dosage but increases the risk of anemia, infection, and bleeding disorders.
• Administering chemotherapy. The patient is observed closely during its administration because of the risk and consequences of extravasation, particularly of vesicant agent.
• Protecting caregivers. Nurses must be familiar with their institutional policies regarding personal protective equipment, handling and disposal of chemotherapeutic agents and supplies, and management of accidental spills or exposures.

Current dosing methodology based on BSA fails to uniformly explain the therapeutic failure, toxicity, and disposition of cytotoxic drugs, so there have been attempts to replace the BSAbased approach with alternative methods that better account for interindividual differences (Page et al., 1988;Gurney, 1996;Ratain, 1998;de Jongh et al., 2001;Felici et al., 2002;Bins et al., 2014). Several alternative dosing methods, such as flat-fixed dosing, fixed dosing for BSA clusters, toxicity-adjusted dosing, therapeutic drug monitoring, glomerular filtration rate (GFR)adjusted dosing, and retrospective dosing, have been proposed to standardize drug exposure, but all of these methods have limitations