B35 Alkylating agents Flashcards Preview

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Flashcards in B35 Alkylating agents Deck (16)
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1
Q

Most common alkylating agent

A

Cyclophosphamide

2
Q

Cyclophosphamide

MoA and kinetics

A

It is a Prodrug, can be given Orally or IV.

Hydroxylated intermediates are made by liver CYP enzymes, then these are broken down to the active metabolites:

  • Phosphoramide mustard
  • Acrolein

Phosphoramide mustard reacts with DNA to create the crosslinks.

Cyclophosphamide and all its metabolites are excreted in urine.

3
Q

Cyclophosphamide
Indications
SEs

A

Rx:

1) Broad range of solid and blood tumors.
2) For very severe autoimmune syndromes

SEs:

  • Hemorrhagic cystitis from its Acrolein metabolite
  • Increased risk of bladder cancer after treatment
  • SIADH and hyervolemic hyponatremia
  • Potentially permanent infertility in both men and women, can induce premature menopause in women
  • Marrow suppression and infections, weekly blood counts needed.
4
Q

The other drug sharing its MoA with cyclophosphamide

A

Ifosfamide

5
Q

Ifosfamide

Kinetics, SEs

A

Unlike Cyclophosphamide, Ifosfamide can only be given by IV.

Its effect is the same, but generates different toxic metabolites than acrolein, still has hemorrhagic cystitis and all the same SEs.

Additionally, Has a high incidence of neurotoxicity

6
Q

List the alkylating agents

A

Mustard derivatives

  • Cyclophosphamide
  • Iphosphamide (Ifosfamide)

Nitrosureas

  • Carmustine
  • Lomustine
  • Stretozocin

Others:

  • Busulfan
  • Dacarbazine and Temozolomide
  • Thiotepa
  • Chlorambucil
7
Q

What are the 2 main nitrosourea drugs and their acronyms

A

Carmustine - BCNU, bis-chloroethylnitrosourea

Lomustine - CCNU

8
Q

Streptozocin

MoA and indications

A

A nitrosourea alkylating agent with selective and very high toxicity to pancreatic beta cells.

Used for islet cell cancers and in animal diabetes models

9
Q

Carmustine and Lomustine kinetics

A

Both are very lipophilic and readily penetrate the CNS.
Wide body distribution
Excreted by kidneys

Carmusine has to be IV

Lomustine must be given orally

10
Q

Camustine and Lomustine indications and SEs

A

Rx: Tumors of the CNS.

SEs;
-CNS side effects mainly....
Dizziness
Confusion
Ataxia
Convulsions
11
Q

Busulfan
MoA
Indications

A

Alkyl Sulfonate class drug,

Forms intrastrand DNA crosslinks

Rx:
It is severely toxic to bone marrow cells, and is used as a conditioning agent prior to bone marrow transplant

12
Q

Busulfan

SEs

A

Busulfan tan, Busulfan lungs

Significant lung toxicity, that can present a range of symptoms

  • Acute lung injury
  • Alveolar hemorrhage
  • Chronic interstitial fibrosis.

Busulfan tan - hyperpigmentation skin reaction.

marrow depletion and infections. 
secondary neoplasms (like all alkylating agents)
13
Q

What two alkylating agents generate the same active metabolite, and what is it?

What differs about their MoA?

A

Dacarbazine and Temozolomide

MTIC
which methylates DNA on O6 oxygen of guanine.

Temozolomide also inhibits the DNA repair enzyme that removes the methyl group from guanine.

14
Q

How do the kinetics of Dacarbazine and Temozolomide differ?

A

Dacarbazine is transformed to active MTIC by liver CYP enzymes

Temozolomide spontaneously generates MTIC at physiologic pH in solution.

Temozolomide also crosses into the CNS, and dacrbazine does not.

15
Q

Dacarbazine and Temozolomide
Indications
SEs

A

Dacarbazine: Melanoma, Hodgkin’s lymphoma

Temozolomide: Glioblastomas and Astrocytomas
also metastatic melanoma

SEs:
general chemo SEs, myelosuppression.

16
Q

What are the last other alkylating agents, and their use

A

Melphalan - multiple myeloma

Chlorambucil - CLL

Thiotepa - Conditioning agent prior to marrow transplant.