Chemotherapy drugs Flashcards
How do cancers differ?
- based on:
- phenotype
- aggressiveness
- responsiveness to drugs
How are cancers treated? (3)
- surgery
- radiation
- pharmacologic agents
What are the different response criterias that the cancer can have to the treatment?
- Cure
- entirely free of disease, and has the same life expectancy as a cancer free individual
- complete response
- complete disappearance of all cancer without evidence of new disease for at least one month
- Partial response
- 50% decrease in tumor size or other objective markers
- Stable disease
- A patient whose tumor size neither grows nor shrinks by more than 25%
- Progression
- 25% increase in tumor size or development of new lesions while on treatment
What is the cycle the cell goes through from one mitotic division to the next?
- M (Mitosis)- 1.5-2 hr
- cell division
- G0 (resting)-
- cells not committed to cell division
- G1 (postmitotic)
- enzymes necessary for DNA synthesis are made
- S (synthesis)- 10-20 hours
- cell doubles its DNA
- G2 (premitotic)- 2-10 hours
- specialized proteins and RNA synthesis
What are the 7 classes of chemotherapy drugs?
- Alkylating agents
- antimetabolites
- antitumor antibiotics
- topoisomerase inhibitors
- tubulin binding drugs
- signal transduction modifiers
- Immunotherapy ( new approach that preserves normal cells and has very different adverse effects compared to traditional chemotherapy)
Why are anti cancer drugs given in combination?
to delay drug resistance, decrease toxicity, and improve cancer cell death
Toxicity Summary (side effects) of chemotherapy drugs
- *tissues with high number of proliferating cells
- Bone marrow suppression
- leukopenia, thrombocytopenia, anemia
- may require additional pre-op labs
- Gi tract damage
- N/V- electrolyte disturbances, hypovolemia
- Alopecia
- mucosal unceration
- Infertility, teratogenic effects
- urinary stones
- extravasation
- end organ damage and hepatic enzyme induction
- consider altered response to anesthetics
- promotion of secondary cancers
What is extravasation?
Symptoms?
- the escape of a chemotherapy drug into the extravascular space, either by leakage from a vessel or by direct infiltration
- symptoms:
- pain
- burning
- swelling
- redness
- lack of blood return
- may require skin graft/surgery
Which chemotherapies most commonly extravate?
anthracyclines
vinca alkaloids
taxanes
What are the Alkylating agents?
(3)
- Nitrogen mustards ( Cyclophosphamide)
- Nitrosureas (Carmustine)
- Platinum compounds (Cisplatin, Carboplatin)
What is the MOA of Alkylating Agents?
- Reactive alkyl groups form covalent bonds with nucleotide bases in DNA, RNA
- Ex: Crosslinks guanines on the DNA helix, makeing DNA “stuck” in supercoil
- if DNA cannot uncoil, it cannot replicate
- Disrupts DNA synthesis and cell division
What are the toxicities of Alkylating agents?
- Bone marrow suppression
- mucositis
- skeletal muscle weakness
- sz
- pneumonitis and pulmonary fibrosis
- pericarditis and pericardial effusion
- Inappropriate ADH secretion (water toxicity)
- uric acid induced nephropathy
- impaired pseudocholinesterase activity (2-3 weeks)
- ** the incidence of these toxicities varies among the different agents
Which alkylating agent has similar pulmonary toxicity to bleomycin?
Carmustine- pulmonary toxicity similar to bleomycin 20-30% with mortality 24-90%
What are the toxicities of Platinum Compounds?
- Nephrotoxicity
- cumulative and dose limiting- K and Mg wasting & decreased GFR
- hydration/supplemental electrolytes
- may be on lasix/mannitol to prevent
- hypomagnesium common (affects NMB sensitivity, cardiac dysrhythmia)
- Peripheral neuropathy
- presents as tingling around mouth, fingers, toes
- avoid cold contact
Which Alkylating agent is dose limited because of nephrotoxicity?
cisplatin
Which alkylating agent is dose limited for peripheral neuropathy?
oxaliplatin
What are the Antimetabolite drugs? (3)
- Folate Analogues- Methyltrexate
- Pyrimidine analogues- Fluorouracil
- Purine analogues- Mercaptopurine
What is the MOA of Antimetabolites?
- Antimetabolites are structural analogues of natural metabolites, such as nucleic acid synthesis inhibitors
- They ultimately inhibit replication or repair of DNA by one of the following mechanisms
- Direct inhibition of enzymes needed for DNA replication or repair
- incorporation of the antimetabolite, which is structurally similar to nucleotites, directly into DNA
What is the Folic acid Analog?
MOA?
- Methotrexate
- Folate must be taken up by the cell and reduced to FH2, then FH4 by dihydrofolate reductase in order to produce nucleosides
- Methotrexate has a higher affinity for dihydrofolate reductase than FH2, thereby preventing its reduction to FH4
What are the toxicities for Methotrexate?
- Pulmonary fibrosis (8%) and/or non cardiogenic pulmonary edema
- Neutropenia and thrombocytopenia
- mucositis and GI ulceration
- GI perforation possible
- Renal toxicity (10%)
- alkalinize urine and hydrate
- Hepatic toxicity
- often reversible
What is the common Pyrimidine analog?
MOA?
- Fluorouracil (5-FU)
- Inhibits thymidylate synthetase which inhibits nucleotide production, which inhibits DNA synthesis
What are the toxicities of Fluorouracil?
- increased risk of MI for 1 week after administration
- myelosuppression (leukopenia, thrombocytopenia, and anemia)
- alopecia
- neurologic defects
- ataxia (cerebellum)
- GI toxicity
- d/c if stomatitis/mucousitis/diarrhea
- pt at risk for GI ulceration and perforation
- Hand-and-foot syndrome
- tingling, redness, burning, flaking, swelling and blistering of the palms and soles
What are the Topoisomerase inhibitors? (2)
MOA?
- Anthracyclines (Doxorubicin, Daunorubicin)
- Non-anthracyclines (Bleomycin)
- Inhibition of topoisomerase I and II and intercalation with DNA, causing double stranded DNA to break and inhibits DNA and RNA synthesis
- Makes hydroxyl free radicals
- free radical production is greatly stimulated by the interaction of doxorubicin with iron
Topoisomerase inhibitors inhibit topoisomeraste I and II. What does Topoisomerase II do?
- relaxes the DNA supercoil and breaks the strand for replication
- also critical to the DNA strand being put back together
What are the Antracyclines drugs? (2)
What are their toxicities?
- Bone marrow suppression
- Red/orange color urine and sweat
- cardiotoxicity
- may be more sensitive to cardiac depressive side effects of anesthetics even if normal resting echo
- free radical production causes myocardial damage
- Acute (10%): tachycardia, arrhythmias
- chronic (2% with 60% fatality): severe cardiomyopathy/CHF
What are some protective therapies that can be used agains the cardiotoxicity of antrhracyclines?
- Dexrazoxane- prevents free radical formation
- Ace inhibitors?
What is the Water Soluble Glycopeptide?
MOA?
- Bleomycin
- Topoisomerase inhibition + binds DNA and chelates iron leading to the formation of free radicals that cause single and double strand DNA breaks
Explain the pulmonary toxicity related to Bleomycin
- 4% (1% life threatening)
- lungs take up high concentrations of drug and lack hydroloase enxyme to inactivate bleomycin
- Risk increases with: increased cumulative dosing, age, chest radiation, pulmonary co-morbidity, oxygen exposure, other chemotherapy drugs, genetics
- discontinue if: dry cough, dyspnea, tachypnea and infiltrates on CXR
- may progress to pulmonary fibrosis and death
- decreased diffusion capacity
- keep FiO2 concentration at or below 30% during anesthesia if possible
Which cancer patients might have a hypersensitivity reaction to Bleomycin?
- Lymphoma pts
- fever, chills, confusion, hypotension, wheezing
- test dose recommended for lymphoma pts before standard doses
There are two types of Tubulin-binding drugs. Which are the ones that prevent assembly?
MOA?
- Vinca Alkyloids
- Vincristine, Vinblastine, Vinorelbine
- Binds to tubulin to block microtubules assembly, preventing polymerization of dimers
- cell division is arrested during metaphase and leads to apoptosis
What are the toxicities of Tubulin Binding drugs?
- Vincristine
- very little bone marrow suppression
- hyponatremia (inappropriate ADH secretion)
- peripheral neuropathy via damate to neurotubules in almost 100% of pts
- gets worse with surgery/anesthesia
- Vinblastine/Vinorelbine
- bone marrow suppression
What are some of the peripheral neuropathy problems seen with Vincristine?
- Sensory loss, weakness, autonomic dysfunction
- constipation, sinus tachycardia, dry mouth, urinary retention, reflex loss, laryngeal and extraocular dysfunction
- usually slowly resolves after treatment
- uncertain safety with regional anesthesia
- reduce LA doses
- use ultrasound guidance to avoid intraneural injection
- no vasoconstrictor additives
What are the Tubulin-Binding drugs that prevent disassembly?
MOA?
- Taxanes- Paclitaxel, Docetaxel
- Stabilizes microtubule bundles and prevents disassembly (by preventing depolymerzation), inhibiting cell devision and producing apoptosis
What are the toxicities of Taxanes?
- Peripheral neuropathy- especially hands and feet
- nuscle and joint pain
- hypersensitivity reactions (25-30% of pts)
- cardiac
- bradycardia, heart block, MI
- myelosuppression
- neutropenia develops in almost all pts
- 1% sepsis related death
- 11% if liver disease present
- neutropenia develops in almost all pts
What are the Signal transduction Modulators?
MOA?
- Antiestrogens (Tamoxifen)
- Antiandrogens (Flutamide)
- Disrupt aberrant growth factor:receptor interactions in cancerous cells preventing intracellular signaling that leads to cellular proliferation and survival
- or target mutated receptors that give a signal to proliferate even without any growth factors bound
Tamoxifen is an anti-hormone drug. How does it work?
Side effects?
- acts as an estrogen antagonist in certain cells (breast and ovarian) and and estrogen agonist in other cells (uterus, liver, bone)
- Side effects related to agonist activity:
- DVT, endometrial cancer, menopausal symptoms, increased bone density (beneficial), andimproves serum cholesterol panel (beneficial)
What are the two Signal Transduction Modulators?
- Monoclonal Antibodies: target specific proteins expressed on immune cells, or that promote pro-survival signaling in cancer cells
- flu like symptoms common
- Aromatase Inhibitors: enzyme that converts androgens to estrone peripherally
- helps to decrease estrone levels in some post-menopausal women with breast ca
What is Gleevec (Imantinib)?
- A Monoclonal antibody
- tyrosine kinase inhibitor/antibody that can treat cancer when tyrosine kinase is mutated to always be “on”
What is the Anti-angiogenic?
- Bevacizumab (trade name Avastin)
- Monoclonal antibody that blocks angiogenesis
- Inhibits vascular endothelial growth factor-A
- Without vascularization, tumors cannot survive
What are some of the other agents? (2)
- Immunotherapy- flu like symptoms
- dendritic cells loaded with tumor lysate
- vaccines targeting tumor-specif epitopes
- chimeric antigen receptor Tcells
- autoimmune reactions are major concert with these approaches
- Biologically directed therapy
- Engineered viruses
What are some general guidelines for chemotherapy?
- these drugs are mutagenic, carcinogenic, and teratogenic
- protect yourself!
- avoid contact with the skin, eyes, and mucous membranes
- follow hospital protocols
