Anthracyclines Flashcards
How many rings are chained in the anthracycline structure?
Four
What drug class is mitoxantrone? How many rings are chained in its structure?
Anthracendione; three
Which anthracycline is the prototype and most frequently used in the class?
Doxorubicin
What is doxorubicin’s brand name?
Adriamycin
What is a nickname for doxorubicin? Why is it called that?
“The Red Devil”; bright red coloring
What is the predominant mechanism of action of anthracyclines?
Toperisomerase II inhibition
How does toperisomerase II inhibition work in anthracyclines?
Covalently binds to toperisomerase II and DNA, but ultimately prevents re-ligation (like etoposide)
Is toperisomerase II inhibition in anthracyclines cell cycle specific or cell cycle non-specific?
Cell cycle specific
What are the other two mechanisms of action for anthracyclines?
DNA intercalation and free radical production
What is DNA intercalation?
The insertion of a drug (or something else) in between DNA base pairs. Results in single and double strand DNA breaks
Is DNA intercalation in anthracyclines cell cycle specific or cell cycle non-specific?
Cell cycle non-specific
What is free radical production?
Free radical production mediated by both enzymes and iron complexes. Reactive intermediates are then capable of damaging intracellular proteins and metabolites that can covalently bind to DNA. Historically believed to be a driving mechanism of the class’ cardiotoxicity and vesicant properties.
Is free radical production in anthracyclines cell cycle specific or cell cycle non-specific?
Cell cycle non-specific
What are the hallmark toxicities seen in anthracyclines?
Fair amount of myelosuppression and N/V, mucositis, and alopecia
What side effect of anthracyclines are you expected to know?
Cardiotoxicity. Decreased left ventricular ejection fraction (LVEF). This is a class effect, and risk increases with cumulative exposure (lifetime maximum exposure)
What is another significant side effect of anthracycline?
Vesicant - causes tissue necrosis with extravasation
What is a side effect caused only by doxorubicin and daunorubicin?
Red-colored urine/tears following administration
What anthracycline side effects are more likely if given via bolus?
Myelosuppression and cardiotoxicity
Secondary leukemia is associated with anthracyclines. Which gene is typically mutated?
MLL gene mutations (same as etoposide)
What is the approximate standard dose of doxorubicin and daunorubicin?
50-60 mg/m2
What is the maximum cumulative lifetime maximum for doxorubicin and daunorubicin?
400-550 mg/m2
What is the approximate standard dose of idarubicin?
12 mg/m2
What is the maximum cumulative lifetime maximum of idarubicin?
150 mg/m2
What is the approximate standard dose of epirubicin?
100 mg/mg2
What is the maximum cumulative lifetime maximum of epirubicin?
900 mg/m2
What dose range should be considered as the danger zone for anthracycline cardiotoxicity?
The cumulative lifetime max dose range
True or false. Use beyond the max lifetime dose is never indicated.
False. Use beyond may be indicated at times, such as when the patient was once treated for one cancer and now has a secondary cancer. Risk of death from cancer outweighs the risk of heart failure.
What is the brand name of liposomal doxorubicin?
Doxil
How does liposomal doxorubicin differ from conventional doxorubicin?
- Leads to lower Cmax but longer exposure
- Different toxicity profile - less N/V, myelosuppression, and cardiotoxicity, but more dermatologic toxicity such as mucositis and hand-foot syndrome (hand-foot can be dose limiting)
How are the MOAs of mitoxantrone and anthracyclines similar?
Primarily toperisomerase II inhibitors; DNA intercalation
How are the MOAs of mitoxantrone and anthracyclines different?
Mitoxantrone has less free radical production than anthracyclines
How is the toxicity profile of mitoxantrone different than anthracyclines’?
- Less cardiotoxicity (still has some!)
- Less severe vesicant properties
What is considered the antidote of anthracyclines?
Dexrazoxane
How does dexrazoxane work?
Has chelating properties to prevent iron-mediated free radical production
What are the two different brand name formulations of dexrazoxane?
Zinecard and Totect
What is Zinecard approved for?
Limit cardiotoxicity of doxorubicin (cardioprotective)
- considered in patients with 300 mg/m2 lifetime exposure
- does appear to decrease the effectiveness of doxorubicin, so not used often (usually only in pediatric formulations)
What is Totect approved for?
Treat anthracycline extravasation
- extravasation is initially treated with ice (slows free radical cascade and decreases blood flow to the area)
- remove ice at least 15 minutes before administration to increase blood flow to the area
What should be monitored in patients taking anthracyclines?
- LVEF assessment at baseline (to ensure don’t have HF) - can be done via echocardiogram or multi-gated acquisition study (MUGA)
- Signs/symptoms of extravasation - treat with ice then dexrazoxane
- CBC (done will all myelosuppressive agents) - typical WBC nadir (lowest point) - 10 to 14 days
- LFTs - dose reductions for t. billi > 1.2 (normal = 1) per package insert ((elevated bilirubin means not excreted as well in the feces))
