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CMOD Pharm > Alkylating Agents > Flashcards

Alkylating Agents Flashcards

1
Q

Classes of DNA alkylating agents

A
  1. Nitrogen mustards –> cyclophsophamide, ifosfamide, mechlorethamine, melphalan
  2. Alkyl sulfonates –> Busulfan
  3. Nitrosoureas –> Carmustine and Lomustine
  4. Triazenes –> Dacarbazine
  5. Hydrazines –> Procarbazine
  6. Platinum drugs –> Cisplatin and carbaplatin
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2
Q

Alkylating agents attach to what atom on guanine?

A

N7; most nucleophilic nitrogen due to planar lone pair and lack of steric hindrance

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3
Q

How do alkylating agents kill cancer cells?

A

Alkylating agents overwhelm the DNA repair machinery due to the rapid rate of DNA synthesis and cells die

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4
Q

4 main nitrogen mustards?

A

Cyclophosphamide, ifosfamide, mechlorethamine, and melphalan

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5
Q

Nitrogen mustard alkylating agent that requires metabolic activation (2)

A

Cyclophosphamide, Ifosfamide

Leads to unique mechanism of resistance –> down regulation of enzymes that convert to active form

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6
Q

Unusual toxicities of cyclophosphamide (4)

A

1) Lung fibrosis,
2) renal failure,
3) urotoxicity (hemorrhagic cystitis),
4) CHF

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7
Q

Drug given with cyclophosphamide to prevent hemorrhagic cystitis (urotoxicity)

A

Mesna –> acrolein is breakdown product of cyclophosphamide. Acrolein complexed by mesna to prevent toxic action

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8
Q

Melphalan unusual toxicities

A

Lung fibrosis

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9
Q

Alkyl sulfonates

A

Busulfan

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10
Q

Busulfan unique toxicities (2)

A

1) Veno-occlusive disease of the liver –> increased by coincident CYP inhibitors.
2) Asthenia and hypotension resembling Addison’s disease

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11
Q

Nitrosoureas

A

Carmustine (BCNU) and Lomustine (CCNU)

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12
Q

Unique mechanism of BCNU/carmustine

A

Carbamoylate proteins and alkylate DNA –> little cross-resistance with other DNA alkylating agents

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13
Q

Unique property of BCNU and CCNU

A

Lipophilic and non-ionized –> can cross BBB to enter CNS

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14
Q

BCNU (carmustine) unique toxicities

A

Hepatic veno-occlusive disease, CNS dysfunction; seizures, dementia

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15
Q

BCNU (carmustine) unique toxicities –> HE CORRECTED THIS LATER

A

CNS dysfunction; seizures, dementia

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16
Q

Platinum drugs

A

Cisplatin, carboplatin

17
Q

Cisplatin/carboplatin mechanism

A

INTRAstrand DNA cross-linking of guanine –> disrupts DNA replication and transcription –> induces apoptosis

18
Q

Unique toxicities of cisplatin

A

Ototoxicity (kills hair cells of inner ear –> tinnitus (archer)), renal toxicity, and peripheral neuropathy

19
Q

Rescue therapy used with cisplatin

A

1-2L of forced hydration and amifostine (cytoprotective agent, free radical scavenger)

20
Q

Dose-limiting toxicity of carboplatin

A

Peripheral neuropathy

21
Q

Drug in Triazene class

A

Dacarbazine

22
Q

Dacarbazine mechanism

A

Methylation of DNA –> can see resistance with removal of methyls

23
Q

Drug in hydrazine class

A

Procarbazine –> requires metabolic activation

24
Q

Unusual toxicities of procarbazine

A

Weak monoamine oxidase inhibitor and nausea/headache while drinking alcohol
Causes male infertility

25
Q

Cancer resistance mechanisms

A
  1. Increased DNA repair (alkylating and cisplatin)
  2. Thiol trapping agents (alkylating, bleomycin, and cisplatin)
  3. Decreased drug accumulation through p-gp pumps
26
Q

Treatment of acute emesis from chemo

A

Seretonin receptor antagonist, neurokinin-1 (NK-1) antagonist, and corticosteroids

27
Q

2 drugs given and their actions to prevent tumor lysis syndrome

A

Allopurinol–> inhibit Xanthine oxidase

Rasburicase–> convert uric acid to more soluble Allantoin

28
Q

Is cardiomyopathy (CHF) from Cyclophosphamide permanent or reversible? (long term or short term?)

A

reversible when the drug is removed (no long term consequences if survive initial bout)

29
Q

What specifically from Cyclophosphamide creates hemorrhagic cystitis?

A

Acrolein

30
Q

What CYP activates cyclophosphamide?

A

CYP2B

31
Q

Why is it so advantageous that Cyclophosphamide can be given PO?

A

because alkylating agents can cause a vesicant reaction (damage the endothelium) upon IV administration

32
Q

What alkylating agents have CNS toxicity?

A

Ifosfamide- causes altered mental status, ataxia, and seizures
Carmustine (BCNU)- convulsions and encephalopathy

33
Q

What 2 alkylating agents can cause Renal toxicity?

A

Cyclophosphamide and Ifosfamide

34
Q

What alkylating agents cause pulmonary dysfunction?

A

Cyclophosphamide, Melphalan, and Busulfan (but all show some amount of pulm tox)

35
Q

Which alkylating agents show renal toxicity?

A

Cyclophosphamide, Ifosfamide, Cisplatin, Carboplatin

36
Q

Which of the platinum drugs has the worst renal toxicity?

A

Cisplatin

37
Q

Only nitrogen mustard given orally

A

cyclophosphamide (Wiki says melphalan can be oral too)

38
Q

what is unique about platinum drug peripheral neuropathy?

A

they accumulate in the ganglion cells and induce apoptosis

CMOD Pharm (8 decks)

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