Topoisomerase Inhibitors Flashcards
What does topoisomerase do?
Cuts DNA strands to relieve tension and allow the strand to unwind.
What do topoisomerase inhibitors do?
Bind to the toperisomerase after it has cut the strand once to prevent the strand from unwinding, decreasing DNA synthesis. Kills rapidly dividing cells.
What are irinotecan and topotecan?
Toperisomerase I inhibitors; camptothecin analogs
What is the brand name of irinotecan?
Camptosar, CPT-11
What is the brand name of topotecan?
Hycamtin
What is the active metabolite of irinotecan?
SN-38
What formulation is irinotecan available in now?
Liposomal
What formulations is topotecan available in?
IV and PO
What are the toxicities of irinotecan?
Early diarrhea, late diarrhea, and hallmark toxicities
When does irinotecan’s early diarrhea occur?
During infusion
What are the characteristics of irinotecan’s early diarrhea?
Cholinergic storm (SLUD - salivation, lacrimation, urination, defecation)
What is used to treat the cholinergic storm of irinotecan’s early diarrhea?
Atropine (anti-cholinergic) - 0.25 mg to 1 mg IV. If cholinergic storm occurs once, patient must receive prophylactic treatment of atropine before every irinotecan dose.
When does irinotecan’s late diarrhea occur?
~12 to 24 hours after the infusion
What is used to treat irinotecan’s late diarrhea?
Loperamide 4 mg initially, then 2 mg Q2H until no loose stools for 12 hours
True or false. A patient may exceed the OTC of loperamide when treating irinotecan’s late diarrhea.
True. May exceed OTC max dose of 16 mg/day, but not for longer than 48 hours without medical supervision
What are some of the hallmark toxicities seen in irinotecan?
Myelosuppression, diarrhea, a little nausea, a little mucositis
What converts irinotecan to SN-38?
Carboxylesterase
What converts irinotecan to its two inactive metabolites?
CYP 3A4
What converts irinotecan’s two inactive metabolites to SN-38?
Carboxylesterase
What makes SN-38 inactive (SN-38G)?
UGT 1A1 (glucoronidase enzyme)
Where is beta glucoronidase produced?
The intestines
What does beta glucoronidase do?
Converts SN-38G back to SN-38 (reabsorbs). Can cause more myelosuppression
How are SN-38 and SN-38G eliminated?
Fecally
How can elevated bilirubin affect irinotecan pharmacokinetically?
Greater toxicity. Seen in hepatic dysfunction and Gilbert’s syndrome
How does smoking affect irinotecan pharmacokinetically?
Induces the effect of UGT 1A1, leading to decreased toxicity (better tolerated) /effect (UGT inducer)
What drugs are UGT inducers?
Carbamazepine, phenobarbital, and phenytoin. Have to give these patients a significantly higher dose or you will be under-dosing them by almost a factor of 2.5.
What does it mean if a patient is UGT 1A1*28 deficient?
More susceptible to irinotecan toxicities, diarrhea, and myelosuppression. Need a 20-25% dose reduction
What education is important for patients with diarrhea while on irinotecan?
Importance of staying hydrated
How can you remember that irinotecan is a toperisomerase I inhibitor?
Irinotecan begins with the Roman numeral I
What does toperisomerase II do?
Ligates two strands of DNA and results in re-ligation afterwards. Cuts two strands, unwinds, and re-ligates.
How do toperisomerase II inhibitors work?
Poison the toperisomerase II effect. Allows the strands to be cut and unwound, but prevents re-ligation from happening. Leads to S phase G2 cell cycle arrest of that interface, because inhibiting DNA synthesis. Rapidly dividing cells are more susceptible to toperisomerase II inhibition.
What are epipodophyllotoxins?
Toperisomerase II inhibitors derived from the natural toxins of the American Mayapple
What are two examples of epipodophyllotoxins?
Etoposide and teniposide
What is etoposide’s brand name?
Toposar, VP-16
What is etoposide phosphate’s brand name?
Topophos
How is etoposide phosphate different from etoposide?
- Increased solubility. Etoposide is lipophilic. The phosphate has alcohol in it to allow for better solubility.
- Allows for faster infusion. Etoposide alone, if given too fast, can cause hypotension because of its lipophilicity (hypotension is rate limiting)
- Still not used as commonly as etoposide because of its cost
What formulations is etoposide available in?
IV and PO.
What is the IV rate of administration for etoposide?
Usually 30-60 minutes. Rate limited by hypotension
What is the unique toxicity of etoposide and what causes it?
Secondary leukemia. Because DNA is left open and base pairs are exposed, more risk for mutations. Most often, the signature mutations seen are 11q23 (MLL gene) mutations.
