Chemotherapy drugs Flashcards
1
Q
How do cancers differ?
A
- based on:
- phenotype
- aggressiveness
- responsiveness to drugs
2
Q
How are cancers treated? (3)
A
- surgery
- radiation
- pharmacologic agents
3
Q
What are the different response criterias that the cancer can have to the treatment?
A
- 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
4
Q
What is the cycle the cell goes through from one mitotic division to the next?
A
- 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
5
Q
What are the 7 classes of chemotherapy drugs?
A
- 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)
6
Q
Why are anti cancer drugs given in combination?
A
to delay drug resistance, decrease toxicity, and improve cancer cell death
7
Q
Toxicity Summary (side effects) of chemotherapy drugs
A
- *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
8
Q
What is extravasation?
Symptoms?
A
- 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
9
Q
Which chemotherapies most commonly extravate?
A
anthracyclines
vinca alkaloids
taxanes
10
Q
What are the Alkylating agents?
(3)
A
- Nitrogen mustards ( Cyclophosphamide)
- Nitrosureas (Carmustine)
- Platinum compounds (Cisplatin, Carboplatin)
11
Q
What is the MOA of Alkylating Agents?
A
- 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
12
Q
What are the toxicities of Alkylating agents?
A
- 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
13
Q
Which alkylating agent has similar pulmonary toxicity to bleomycin?
A
Carmustine- pulmonary toxicity similar to bleomycin 20-30% with mortality 24-90%
14
Q
What are the toxicities of Platinum Compounds?
A
- 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
15
Q
Which Alkylating agent is dose limited because of nephrotoxicity?
A
cisplatin
16
Q
Which alkylating agent is dose limited for peripheral neuropathy?
A
oxaliplatin
17
Q
What are the Antimetabolite drugs? (3)
A
- Folate Analogues- Methyltrexate
- Pyrimidine analogues- Fluorouracil
- Purine analogues- Mercaptopurine
18
Q
What is the MOA of Antimetabolites?
A
- 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
19
Q
What is the Folic acid Analog?
MOA?
A
- 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
20
Q
What are the toxicities for Methotrexate?
A
- 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
21
Q
What is the common Pyrimidine analog?
MOA?
A
- Fluorouracil (5-FU)
- Inhibits thymidylate synthetase which inhibits nucleotide production, which inhibits DNA synthesis
22
Q
What are the toxicities of Fluorouracil?
A
- 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
23
Q
What are the Topoisomerase inhibitors? (2)
MOA?
A
- 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
24
Q
Topoisomerase inhibitors inhibit topoisomeraste I and II. What does Topoisomerase II do?
A
- relaxes the DNA supercoil and breaks the strand for replication
- also critical to the DNA strand being put back together
25
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
26
What are some protective therapies that can be used agains the cardiotoxicity of antrhracyclines?
* Dexrazoxane- prevents free radical formation
* Ace inhibitors?
27
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
28
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**
29
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
30
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
31
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
32
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
33
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
34
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
35
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
36
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)
37
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
38
What is Gleevec (Imantinib)?
* A Monoclonal antibody
* tyrosine kinase inhibitor/antibody that can treat cancer when tyrosine kinase is mutated to always be "on"
39
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
40
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
41
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
