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PHARMACOLOGY - Pulmonary > Alkylating Agents > Flashcards

Alkylating Agents Flashcards

1
Q
A
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2
Q

What 2 groups of drugs act on DNA?
- how do these groups differ?

A

Antimetabolites:
- Inhibit DNA synthesis

Alkylating Agents:
- Damage DNA structure

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3
Q

How does overall goal of cancer treatment changed in the recent years?

A

Older Drugs:
- Targeted proliferating cells and are toxic

Newer Drugs:
- Target growth of the cancer cell

**The newer drugs are insanely expensive

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4
Q

What tissues are most affected by chemotherapy?

A
  • Blood and Bone Marrow
  • Epithelial Lining of the oral cavity
  • Gastrointestinal tract
  • Growing hair
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5
Q

Dose dependent nausea and vomiting is a common side effect of chemotherapy.
- explain the 2 different processes that cause this effect.

A
  1. CHEMOTRIGGER zone in the base of the 4th ventricle in the GI tract
  2. Psychological Aspects of Impending therapy can also cause this
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6
Q

What is the difference between adjuvant and neoadjuvant therapy?

A

Adjuvant Therapy: - Given After Surgery or RadiationNeo-aduvant Therapy: - Given Before surgery or Radiation

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7
Q

When are the following used:

  • Surgery
  • Radiation
  • Chemotherapy
A

Surgery:
- Solid tumor can be cut out

Radiation:
- Tumors in difficult to reach locations

Chemotherapy:
- Best option in blood cancers and metastases, can be just as adjuvant or neo-adjuvant

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8
Q

What is biological therapy? - when can it be used?

A

Biological Therapy:
- Targeted approach using mAbs etc. Only can be used if patient is positive for the epitope that the drug targets

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9
Q

In addition to their affects on rapidly dividing cell populations, what are some of the toxicities caused by anti-cancer drugs?

A
  • Secondary Malignancies
  • Organ Toxicity
  • Sterility
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10
Q

What is Tumor Lysis Syndrome (TLS)?
- what type of cancers does this occur with?

A

Large Tumors may lyse quickly releasing their contents into the bloodstream

3 Main Downstream Effects:
• Volume Depletion and Obstruction of Renal Tubules with Debris

  • Purine Nucleotides, Potassium, and Proteins reach high conc. in blood
  • Uric acid may be deposited causing Gout
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11
Q

How do we manage the effects of TLS?

A

Management:

  • Hydration
  • Acid/Base Correction
  • BICARB to ALKALINIZE the urine
  • DRUGS that prevent PRECIPITATION
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12
Q

What compound are we most worried about precipitating out in the kidneys in TLS?

  • what drugs can we give to prevent this?
  • how do they work?
  • method of administration?
A

Uric Acid Crystals

Allopurinol (PO) works on Xanthine Oxidase to PREVENT formation of uric acid

Rasburicase (IV) works on Urate Oxidase to convert uric acid that is formed into Allantoin

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13
Q

NOTE:
1) not every chemo drug can be used against every type of tumor

2) Small structural changes in drug can greatly change the spectrum of antitumor activity

A

NOTE:
1) not every chemo drug can be used against every type of tumor

2) Small structural changes in drug can greatly change the spectrum of antitumor activity

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14
Q

Is Cyclophosphamide a biologically active agent?

  • if not what is needed for its activation?
  • where is this done?
  • What affect does it have on this tissue?
A

No it must first be converted to an active agent in the liver by CYP2B.
- active agent exists in an equilibrium with between 2 active forms (cyclic and non-cyclic)

*This is done in the liver and the liver itself is protected because the active compound is inactivaed to a 4-keto product

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15
Q

What 2 toxic agents are the actived products of cyclophosphamide turned into?

A
  1. Acrolein
  2. Phosphoramide Mustard
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16
Q

What is the general method used by the Bis(chloroethyl)amine alkylating agents to mess up DNA?

  • what is their target?
  • Different possibilities?
  • NAME THESE AGENTS
A

Target: - N7 GUANINE is the MAIN target (most approachable)
Possibilities:
- 2 moieties on each of the alkylating agents once the first alkylation has been performed the second group is free to produce:
a. Intrastrand Linkage
b. DNA cross-linking with the complementary strand
AGENTS:
• Cyclophosphamide
• Ifosfamide
• Mechlorethamine
• Melphalan

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17
Q

When are the Bis(chloroethyl)amine alkylating agents effective

  • To what cell populations are these drugs most toxic?
  • NAME THESE AGENTS.
A

Late G1-S is when cells are the MOST susceptible causes a G2 BLOCK (this is because DNA can’t be replicated with all of this cross-linking going on)

AGENTS:
• Cyclophosphamide
• Ifosfamide
• Mechlorethamine
• Melphalan

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18
Q

What are some of the adverse affects of Bis(chloroethyl)amine alkylating agents?
- NAME THESE AGENTS.

A

HEMORRAHAGIC CYSTITIS (give mesna to counter effect) and Renal Failure

  • Cyclophosphamide
  • Ifosfamide

Pulmonary Fiborsis

  • Cyclophosphamide
  • Melphalan Significant Vesicant Action
  • Mechlorethamine
    Rapid onset Congestive Heart Failure
  • Cyclophosphamid
    CNS - altered Mental Status, Seizures, Coma- Ifosfamide
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19
Q

What are some of the long term toxicities associated with ALL alkylating agents
- which of these show these adverse effects more frequently?

A

Lung Problems:
- Fibrosis, Cynaosis

2˚ Cancers:
- Leukemias and Solid Tumors

Teratogenicity:- 1/6 have malformed offspring

20
Q

What drug is given to try to reduce the hemmorhagic cystitis produced by Ifosfamide and Cyclophosphamide?

  • How is this drug administered?
  • what is the by product of the Bis(chloroethyl)amines that causes this symptom?
A

Acrolein (one of the cytotoxic metabolites of the activative Bis(choroetyl)amines) causes the damage

MESNA- along with good hydration this prevents Hemmorhagic Cystitis - Given IV or PO

21
Q

How do we keep Mesna from concentrating in the tumor and neutralizing acrolein that acts on the tumor cell?

A

Its concentrated in the kidney and bladder so it will likely avoid the cancer

22
Q

Besides being used for cancer what are two other uses for Cyclophosphamide?

A
  1. prepare pts. for Stem Cell Transplants
  2. Rheumatoid Arthritis (last resort)
23
Q

Alkyl Sulfonates:

  • Drug(s) in this class
  • Activation
  • Toxicity
A

Bulsulfan

Activation:
- Happens via simple Hydrolysis on contact with aqueous soln

Toxicities:

  • Pulmonary Fibrosis
  • GI damage
  • VENO-OCCLUSIVE DISEASE- ASTHENIA (Addison’s w/ normal cortisol)
24
Q

Nitrosoureas:

  • Drug(s) in this class
  • Administration
  • Special Features
  • alternative effects**
  • Toxicity
A

Carmustine (BCNU) - IV

Lomustine (CCNU) - POLipophilic - can cross BBB (given to treat brain tumors)

BCNU - Can Carbamoylate Proteins adding to toxicity - REDUCES CROSS RESISTANCE WITH OTHER ALKYLATING AGENTS

25
Q

How do the Nitrosureas differ from most alkylating agents?
- NAME THEM

A

They are LIPOPHILIC allowing BBB penetration

Names:

  • BCNU - Carmustine - IV
  • CCNU - Lomustine - PO
26
Q

What drugs are often given concurrently with the nitrosureas to treat brain tumors?
- Name the nitrosureas too

A

Vincristine and Temozolamide
Nitrosureas:
- BCNU - Carmustine - IV
- CCNU - Lomustine - PO

27
Q

Nitrosurea Toxicity

A

Lomustine and Carmustine: - Extensive Hepatic Metabolism CCNU

Lomustine (PO):

  • THROMBOCYTOPENIA (Bleeding risks)
  • Leukopenia

BCNU Carmustine (IV): - CNS - convulsion, encephalopathy- Endocrine Dysfunction with Brain Irradiation

28
Q

What alkylating agents from the Nitrosureas and from the Bis(chloroethyl)amines may induce negative CNS effects?

A

Nitrosureas - BCNU - Carmustine

Bis(chloroethyl)amines - Ifosfamide

29
Q

What strong alkylating agents are known to cause Hepatic Veno-Occlusive disease?

  • What is Hepatic Veno-Occlusive Disease?
  • How long does it take for this to occur?
  • Signs that its happening
A

Busulfan or BCNU

What is it? - NONthrombotic occlusion caused by intimal edema venular wall fragmentation

How long:
- 2 to 10 weeks after starting therapy

Signs:
- Jaundice, Ascites, Hepatomegaly

30
Q

Platinum Compounds:

  • activation
  • MOA
  • Difference in crosslinking between these and other alkylating agents?
A

Cisplatin (IV) and Carboplatin (IV)

Activation:
- activated on contact with water

MOA:
- N7 Guanine attachment and Guanine-Adenine cross-links are formed

Difference:
- Less IntERstrand cross-linking

31
Q

What alkylating agents are activated on contact with water?

A
  • Busulfan
  • Plainum compounds (Cisplatin and Carboplatin)
32
Q

Cisplatin

  • Administration
  • Elimination
  • Toxicity**
  • Protection from Toxicty?
A

Administration:
- IV only

Elmination:
- Urinary mostly bound COVALENTLY to protein and peptides

Toxicity:
- NEPHROtoxic = DOSE LIMITING (most drugs myelosuppression is dose-limiting)

  • OTOTOXICITY (unilateral or bilateral)
  • Dose related - PROGRESSIVE Peripheral Neuropathy

Protection:

  • Forced Hydration
  • AMIFOSTINE (ETHYOL)
33
Q

What is Amifostine (ETHYOL)?
- Used with what drug?

A
  • Dephsphorylated active Free Thiol Metabolite
  • FREE RADICAL SCAVENGER

Used for protection of the Kidneys with Cisplatin

34
Q

Carboplatin [paralatin], what makes it better than the other drug in its class?
- Name that drug.

A

Carboplatin is better than cisplatin*

because it has much less toxicity associated with it

35
Q

Carboplatin [parplatin]- Toxicities
- Dose limiting toxicity?

A

Less: - oto, neuro, and nephrotoxicity that cisplatin

DOSE-LIMITING TOXICITY:

  • Myelosuppression

**Peripheral Neuropathy also an important toxicity

36
Q

What is the dose limiting toxicity of each of the platinum compounds?

A

Cisplatin:
- Nephrotoxicity

Carboplatin:
-Myelosuppresion

37
Q

Methylators of DNA:

  • Drug names?
  • activation?
A

Dacarbazine (DTIC) and Procarbazine (matulane)

**Must be Metabolically activated like Cyclophosphamide and Dacarbazine

38
Q

Dacarbazine (DITC)

  • activation
  • toxicity
A

Metabolic activation required

Toxicity:

  • Myelosuprresion
  • Thrombrocytopenia
  • Leukopenia
39
Q

How is resistance conferred against methylating agents

A

Methyl group is removed from O6 of guanine via AGT

40
Q

Procarbazine [matulane]

  • Activation
  • Unusual Toxicities?
A

Activation:
- DNA methylator via CYP activation

Unusual:
- Disulfram-like effect (remember cephalosporins do this too)

Toxicities:

  • MAO
  • hypertensive drug-drug reactions
  • Potent immunosuppression and Male infertility
41
Q

Why is it not sufficient just to damage DNA to get cancer to die?

A

Cells are equipped with lots of DNA repair tools that allow them to live on

42
Q

What are 3 main ways by which resistance often arises to cancer drugs?

A
  1. Increased DNA repair
  2. Thiol Trapping Agents (free radical scavengers)
  3. Decreased Drug Accumulation - MDR1 gene coding P-gp
43
Q

What are the combo is most commonly give to prevent emesis while giving chemo drugs?

A
  1. Serotonin Antagonist
  2. NK-1 Antagonist
  3. Corticosteriods
44
Q

What alkylating agents are the worst about causing Emesis?

A
  • Cisplatin
  • Mechlorethamine
  • Cyclophosphamide
  • Carmustin
  • Dacarbzine
45
Q

What alkylaing agens aren’t quite as bad about causing Emesis?

A
  • Cytarabine
  • Carboplatin
  • Ifosfamide
  • Cyclophosphamide
  • Anthracylcines, Irinotecan

PHARMACOLOGY - Pulmonary (30 decks)

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