Topoisomerase Inhibitors Flashcards

1
Q

What does topoisomerase do?

A

Cuts DNA strands to relieve tension and allow the strand to unwind.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What do topoisomerase inhibitors do?

A

Bind to the toperisomerase after it has cut the strand once to prevent the strand from unwinding, decreasing DNA synthesis. Kills rapidly dividing cells.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are irinotecan and topotecan?

A

Toperisomerase I inhibitors; camptothecin analogs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the brand name of irinotecan?

A

Camptosar, CPT-11

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the brand name of topotecan?

A

Hycamtin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the active metabolite of irinotecan?

A

SN-38

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What formulation is irinotecan available in now?

A

Liposomal

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What formulations is topotecan available in?

A

IV and PO

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the toxicities of irinotecan?

A

Early diarrhea, late diarrhea, and hallmark toxicities

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

When does irinotecan’s early diarrhea occur?

A

During infusion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the characteristics of irinotecan’s early diarrhea?

A

Cholinergic storm (SLUD - salivation, lacrimation, urination, defecation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is used to treat the cholinergic storm of irinotecan’s early diarrhea?

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

When does irinotecan’s late diarrhea occur?

A

~12 to 24 hours after the infusion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is used to treat irinotecan’s late diarrhea?

A

Loperamide 4 mg initially, then 2 mg Q2H until no loose stools for 12 hours

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

True or false. A patient may exceed the OTC of loperamide when treating irinotecan’s late diarrhea.

A

True. May exceed OTC max dose of 16 mg/day, but not for longer than 48 hours without medical supervision

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are some of the hallmark toxicities seen in irinotecan?

A

Myelosuppression, diarrhea, a little nausea, a little mucositis

17
Q

What converts irinotecan to SN-38?

A

Carboxylesterase

18
Q

What converts irinotecan to its two inactive metabolites?

A

CYP 3A4

19
Q

What converts irinotecan’s two inactive metabolites to SN-38?

A

Carboxylesterase

20
Q

What makes SN-38 inactive (SN-38G)?

A

UGT 1A1 (glucoronidase enzyme)

21
Q

Where is beta glucoronidase produced?

A

The intestines

22
Q

What does beta glucoronidase do?

A

Converts SN-38G back to SN-38 (reabsorbs). Can cause more myelosuppression

23
Q

How are SN-38 and SN-38G eliminated?

A

Fecally

24
Q

How can elevated bilirubin affect irinotecan pharmacokinetically?

A

Greater toxicity. Seen in hepatic dysfunction and Gilbert’s syndrome

25
Q

How does smoking affect irinotecan pharmacokinetically?

A

Induces the effect of UGT 1A1, leading to decreased toxicity (better tolerated) /effect (UGT inducer)

26
Q

What drugs are UGT inducers?

A

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.

27
Q

What does it mean if a patient is UGT 1A1*28 deficient?

A

More susceptible to irinotecan toxicities, diarrhea, and myelosuppression. Need a 20-25% dose reduction

28
Q

What education is important for patients with diarrhea while on irinotecan?

A

Importance of staying hydrated

29
Q

How can you remember that irinotecan is a toperisomerase I inhibitor?

A

Irinotecan begins with the Roman numeral I

30
Q

What does toperisomerase II do?

A

Ligates two strands of DNA and results in re-ligation afterwards. Cuts two strands, unwinds, and re-ligates.

31
Q

How do toperisomerase II inhibitors work?

A

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.

32
Q

What are epipodophyllotoxins?

A

Toperisomerase II inhibitors derived from the natural toxins of the American Mayapple

33
Q

What are two examples of epipodophyllotoxins?

A

Etoposide and teniposide

34
Q

What is etoposide’s brand name?

A

Toposar, VP-16

35
Q

What is etoposide phosphate’s brand name?

A

Topophos

36
Q

How is etoposide phosphate different from etoposide?

A
  • 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
37
Q

What formulations is etoposide available in?

A

IV and PO.

38
Q

What is the IV rate of administration for etoposide?

A

Usually 30-60 minutes. Rate limited by hypotension

39
Q

What is the unique toxicity of etoposide and what causes it?

A

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.