Enzyme Inhibitors

Question 1

Enzyme Inhibitors class, MOA and example of drugs

Answer 1

Topoisomerase I Inhibitors

• Cleavage of single-strand DNA
• Topotecan, Irinotecan

Topoisomerase II Inhibitors
- Form a complex and cause double-strand DNA breaks - Etoposide, Teniposide, Anthracyclines

Question 2

Function of topoisomerases

Answer 2

Topoisomerases are required for the transcription and replication of cellular genetic materials

Question 3

Topotecan class

Answer 3

Topoisomerase I Inhibitors

Question 4

Irinotecan class

Answer 4

Topoisomerase I Inhibitors

Question 5

Etoposide class

Answer 5

Topoisomerase II Inhibitors

Question 6

Teniposide class

Answer 6

Topoisomerase II Inhibitors

Question 7

Anthracyclines class

Answer 7

Topoisomerase II Inhibitors

Question 8

Irinotecan ADR

Answer 8

•Cholinergic syndrome can occur: 
-	Salivation/sweating 
-	Lacrimation 
-	Urination 
-	Diarrhoea  
Therefore routinely pre-medicate w/atropine 

•Myelosuppression

•Diarrhea –manifest early and late
– Diarrhea treat with loperamide: 4 mg at earliest sign of diarrhea, followed by 2 mg PO q 2 hours until diarrhea free for 12 hours
– NOTE: Loperamide package insert will discourage against such high doses –however, intensive therapy is recommended for patient with diarrhea caused by irinotecan therapy

•UGT1A1 deficiency –problematic! –> drug not excreted out of body.

Question 9

Etoposide ADR

Answer 9

dose limiting myelosuppression (primarily neutropenia) and hypotension if infuse too quickly

Question 10

Anthracyclines

Three Mechanism of actions:

Answer 10

Anthracyclines
Three Mechanism of actions:
1. Induce formation of covalent topoisomerase II DNA complexes –this inhibition prevents the relegation of DNA during DNA replication causing DNA strand breaks
2. Intercalations between base pairs in the DNA are formed causing DNA breaks
3. Metabolized in the liver to form oxygen free radicals –can add to cytotoxicity

Question 11

Anthracyclines toxicities

Answer 11

Toxicities
•Dose limiting myelosuppression–primarily neutropenia
•Alopecia
•Acute nausea and vomiting
•Vesicant –related to extravasation
•Can cause red discoloration of urine, require patient education
• cardiotoxicity

Question 12

Pathophysiology of anthracycline-induced cardiotoxicity

and Risk factor

Answer 12

Pathophysiology of anthracycline-induced cardiotoxicity
•Acute (24 hours): Arrhythmias, Pericarditis
•Subacute (weeks to months): Tachycardia
•Late (> 5 years): Cardiomyopathy

Risk factors:

1. Cumulative doses
2. Administration schedule (high peaks)
3. Age
4. Mediastinal radiation (eg during breast cancer)
5. Known cardiac disease

Question 13

How to prevent anthracycline-induced cardiotoxicity?

Answer 13

How to prevent anthracycline-induced cardiotoxicity?
Limit cumulative dose 
•Doxorubicin = 450-550 mg/m2 
•Daunorubicin= 450-550 mg/m2 
•Epirubicin= 900 mg/m2
•Idarubicin= PO: 540 mg/m2IV: 150 mg/m2 

Administration schedule
•Fractionate doses
•Prolonged infusion

Less cardiotoxic anthracycline/analogue
•Mitoxantrone
•Liposomal doxorubicin (Caelyx®)

• Use Dexrazoxane(cardiac protectant)
• All patients should have a baseline MUGA to evaluate left ventricular ejection fraction (LVEF)before starting anthracyclines

Question 14

Limit cumulative dose

•Doxorubicin

Answer 14

Limit cumulative dose

•Doxorubicin = 450-550 mg/m2

Question 15

Limit cumulative dose

Daunorubicin

Answer 15

•Daunorubicin= 450-550 mg/m2

Question 16

Limit cumulative dose

Epirubicin

Answer 16

•Epirubicin= 900 mg/m2

Question 17

Limit cumulative dose

Idarubicin

Answer 17

•Idarubicin= PO: 540 mg/m2IV: 150 mg/m2