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PHARMACOLOGY - Antiviral, Classic Chemo, ADME > Alkylating Drugs General Info > Flashcards

Alkylating Drugs General Info Flashcards

1
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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2
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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3
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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4
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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5
Q

What is the difference between adjuvant and neoadjuvant therapy?

A

Adjuvant Therapy:
- Given After Surgery or Radiation

Neo-aduvant Therapy:
- Given Before surgery or Radiation

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6
Q

When are the following use:

  • 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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7
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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8
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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9
Q

How and why do we measure a patients response to a drug?

A

How:

  • CT, PET, MRI
  • Tumor Markers
  • Quality of Life Improvement

Why:
- We want to justify use of a particular drug showing that it will increase life-span or make life for cancer patients more tolerable.

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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

4 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?

  • 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

What is the difference between a chemotherapy drug that is cell cycle phase specific and one that is not?

A

Cell Cycle Phase Specific drugs will only work on a fraction of the cells in a tumor that happen to be in that cell cycle phase while the drug is being administered

Non-specific drugs will work on cells in any part of the cell cycle

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14
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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15
Q

What are the 3 general Groups of Alkylating agents?

- how do their structures differ?

A

Chloroacetaldehydes (O=CH2CH2-Cl) :

  1. Bis(chloroethyl)amines (2 of these groups)
  2. Nitrosoureas

Alkylsulfonate (OSO2Me)

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16
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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17
Q

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

A
  1. Acrolein

2. Phosphoramide Mustard

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18
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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19
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 
- 
AGENTS:
• Cyclophosphamide 
• Ifosfamide 
• Mechlorethamine
• Melphalan
20
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

21
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

22
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 (more common of a side effect with ifosfamide)

MESNA

  • along with good hydration this prevents Hemmorhagic Cystitis
  • Given IV or PO
23
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

24
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)

25
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)
26
Q

Nitrosoureas:

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

Carmustine (BCNU) - IV
Lomustine (CCNU) - PO

Lipophilic - can cross BBB (given to treat brain tumors)

BCNU

  • Can Carbamoylate Proteins adding to toxicity
  • REDUCES CROSS RESISTANCE WITH OTHER ALKYLATING AGENTS
27
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
28
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
29
Q

Nitrosurea Toxicity

A

Lomustine and Carmustine:
- Extensive Hepatic Metabolism

CCNU Lomustine (PO):

  • THROMBOCYTOPENIA (Bleeding risks)
  • Leucopenia

BCNU Carmustine (IV):

  • CNS - convulsion, encephalopathy
  • Endocrine Dysfunction with Brain Irradiation
30
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

31
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

32
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

33
Q

What alkylating agents are activated on contact with water?

A
  • Busulfan

- Plainum compounds (Cisplatin and Carboplatin)

34
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)
35
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

36
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

37
Q

Carboplatin [parplatin]

  • Toxicities
  • Dose limiting toxicity?
A

Less:
- oto, neuro, and nephrotoxicity that cisplatin

DOSE-LIMITING TOXICITY:
- Peripheral Neuropathy = DOSE limiting

38
Q

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

A

Cisplatin:
- Nephrotoxicity

Carboplatin:
- Peripheral Neuropathy

39
Q

Methylators of DNA:

  • Drug names?
  • activation?
A

Dacarbazine (DTIC) and Procarbazine (matulane)

**Must be Metabolically activated like Cyclophosphamide and Dacarbazine

40
Q

Dacarbazine (DITC)

  • activation
  • toxicity
A

Metabolic activation required

Toxicity:

  • Myelosuprresion
  • Thrombrocytopenia
  • Leukopenia
41
Q

How is resistance conferred against methylating agents

A

Methyl group is removed from O6 of guanine via AGT

42
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
43
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

44
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
45
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
46
Q

What alkylating agents are the worst about causing Emesis?

A
  • Cisplatin
  • Mechlorethamine
  • Cyclophosphamide
  • Carmustin
  • Dacarbzine
47
Q

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

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

PHARMACOLOGY - Antiviral, Classic Chemo, ADME (18 decks)

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