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PHARMACOLOGY - Antiviral, Classic Chemo, ADME > Antimetabolites > Flashcards

Antimetabolites Flashcards

1
Q

What antimetabolites work as folic acid analogs?

A

Methotrexate

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2
Q

What antimetabolites work as pyrimidine analogs?

A

Flurouracil (5-FU)
Capecitabine
Cytarabine (cytosine arabinoside)
Gemcitabine

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3
Q

What antimetabolites work as Purine Analogs?

A

6-Mercaptopurine (6-MP)
Thioguanine
Fludarabine

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4
Q

Methotrexate

  • Intake, Retention?
  • MOA
A

Taken in via ABC transporters and POLYGUTAMATED causing it to get trapped inside the cell (*this version is still effective)

  • Dihyrdofolate Reductase Inhibitor (DHFR)

Pyrimidine Synthesis Block:
- Thymidylate Synthase Inhibition (TS)

Purine Synthesis Block:
- Glycinamide Ribonucleotide Transformylase (GARFT) and ribonucleotide transformylase (AICARFT)

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5
Q

At Higher than usual doses what is the major adverse effect of methotrexate?

  • how do we combat this effect?
  • explain this processes
A

Bone Marrow Toxicity is High doses

Combat Effect by:
- LEUCOVORIN RESCUE

Leucovorin:
- aka Folinic Acid - does not need DHFR for conversion so purine and pyrimidine synthesis can resume

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6
Q

Why don’t other drugs that inhibit DHFR like Trimetoprim and Pyrimethamine get used for cancer?

A

They are target specifically for non-human DHFRs making them inaffective against cancer

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7
Q

How is Methotrexate Resistance conferred?

  • What are some other toxic effects of MTX besides bone marrow toxicity?
  • Elimination?
  • Drug -Drug interactions?
A

Resistance:

  • Less uptake by ABC trasporters
  • Less Polyglutamation
  • More DHFR production

Toxicity:

  • GI toxicity, N/V, abdominal pain
  • Pulmonary Infiltrates and Fibrosis

Elimination:
- Renal via GF and Tubules NSAIDs may inhibit Tubular secretion leading to Increased MTX toxicity

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8
Q

5-Fluorouracil; 5-FU [adrucil]
Method of Administration
MOAs

A

Delivered IV only

DNA synthesis Inhibition
- Inhibits Thymidine Synthase

Incorporation into DNA:
- Inhibits DNA synthesis

Translation inhibitor:
- Interferes with mRNA translation

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9
Q

What 3 antimetabolites cause hand and foot syndrome?

A
  • 5-Fluorouracil (IV)
  • Capecitabine (PO)
  • Cytarabine
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10
Q

5-Flurouracil

  • Resistance mechanisms
  • Toxicity
A

Resistance:

  • Thymidine Synthase Upregulation or Mutations
  • Decreased Activation of 5-FU

Toxicity:

  • Acute Chest pain
  • Other usual (myelosupp., GI, anemia, etc.)
  • HAND-FOOT SYNDROME

***Note: Hand and foot more common with acute drug infusions

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11
Q

What is hand and foot syndrome?

- cause?

A

Symptoms:

  • Redness of Hands and Feet
  • Tingling Sensations
  • Swelling
  • Blisters

Cause:
- Drug escapes from capillaries and irritates the skin in these areas of the body

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12
Q

Why would you use Levocovorin with 5-FU?

A
  • Drives Inhermediary Metabolism into Incorporating 5-FU (IV) in to Thymidine Synthase

**Remember Levocovorin is also used in Bone Marrow Rescue with Methotrexate

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13
Q

What is the oral version of 5-FU?

- differences in side effects?

A

Capecitabine [xeloda]
**essentially just a 5-FU pro-drug

  • Hand and Foot Syndrome occurs more frequently with this drug
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14
Q

What is the most specific of the Anti-metabolites for the S-phase of the cycle?

A

Cytarabine; ARA-c [cytosar]

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15
Q

Cytarabine; ARA-C [cytosar]
MOA
administration method?

A

MOA:

  • ARA-CTP (triphosphate)
  • Gets incorporated into growing chain and creates STERIC hinderance with 2’-hydroxyl

Administered:

  • IV
  • SC
  • ITH (intrahecally)
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16
Q

How is resistance to Cytarabine ARA-C conferred?

- Toxicity?

A
  • Decreased Cellular Uptake
  • Decreased Phosphorylation to make ARA-CTP
  • Increased ARA-C —> ARA-UMP (inactive)

Toxicity:

  • Usual (Myelosupp., G.I. effects, thrombocytopenia)
  • STOMATITIS
  • Hepatic Enzyme Elevations
17
Q

Gemcitabine [gemzar]
MOA
Toxicity

A

MOA:

  • Must be TriPhosphorylated (like ARA-C)
  • 1 additional base pair added making repair more difficult
  • Better Penetration/Retention

Toxicity:

  • Same as all others
  • Pneumonitis
18
Q

Mercaptopurine [purinethol]
MOA
- Administration method?
- Reasons to Dose adjust?

A

MOA:

  • 6 Mecraptopurine (6-MP) gets converted to 6-thioinosine monophosphate by HGPRT
  • Ultimately because 6-thioguanine Monophosphate and inhibits DNA synthesis

Administration:
Oral

  • **Dose adustment:
    1) ALLOPURINOL - blocks 6-thiouric acid (side pdt) formation leading to Toxicity of 6-MP (reduce to 25% of original 6-MP dose)

2) TPMT - converts 6-MP to 6-methyl-MP, Activity of this enzyme is determined by SINGLE NUCLEOTIDE polymorphisms (3 levels of activity)

19
Q

Mechanisms of Resistance to Mercaptopurine (PO)?

- Toxicity?

A

Resistance:

  • Lowered of HGPRT
  • Less drug uptake, more efflux
  • Recognition of DNA breaks

Toxicity:

  • Bone marrow depression (like always) - DOSE LIMITING
  • Jaundice and Hepatic Enzymes may Increase
20
Q

How do you know how much Mercaptopurine to give someone?

A

***Do Genetic tests to see which version of TMPT they have (polymorphic gene with 3 different possible levels of activity)

(remember HGPRT is involved in Lesch-Nyhan syndrome)

21
Q

Thioguanine; 6-TG [tabloid]

  • MOA
  • resistance
  • Toxicity
A

MOA:
- Same as 6-MP EXCEPT NO 6-thiouric acid conversion so NO conflicts with Allopurinol

Resistance (same as 6-MP)

  • Lowered of HGPRT
  • Less drug uptake, more efflux
  • Recognition of DNA breaks

Toxicity:

  • Bone Marrow Suppression - DOSE LIMITING
  • Hepatic/Jaundice
22
Q

Hydroxyurea [hydrea]

  • MOA
  • resitance?
  • Toxicity
A

MOA:
- Free Radical Scavenger that grabs a free radical needed in the conversion of ribonucleotides to DEOXYribonucleotides (RATE LIMITING step)

Resistance:
- Upregulation of Ribonucleotide Reductase

Toxicity:

  • Bone Marrow Depressino
  • RASHES, ERYTHEMA, ULCERATIONS, SKIN CANCER, SKIN DARKENING
23
Q

What is the difference between Hydroxyurea and Antimetabolites?

A

Hydroxyurea doesn’t pretend to be a nucleotide or nucleotide intermediate it just inhibits the RATE LIMITING step in nucleotide synthesis

24
Q

Which of the drugs have resistance conferred against them by decreasing their activation?

A
  • Mercptopurine and Thioguanine (HGPRT and pathway)
  • Gemicitabine and Cytarabine ARA-C (triphos. activation)
  • 5-FU
25
Q

Which of the metabolites are resisted by inactivation?

A

Most Purine and Pyrimidine Antimetabolites

26
Q

How accumulation of drug within the cell prevented with the antimetabolites, MTX?

A

P-gp
- can efflux just about any drug out

MTX- polyglutamation is needed to keep it in the cell, if this doesn’t happen MTX is no longer effective

27
Q

What reproductive effects do most anti-cancer drugs have?

A
  • Most drugs are TERATOGENS

- Most also cause INFERTILITY

28
Q

What are some cancer drugs that may cause Red urine. Explain the difference in each.

A

Cyclophosphamide:
- causes hemorrhagic cystitis leading to RBCs in the urine

Doxyrubicin:
- causes red urine because its metabolites are red not because its causing disease

29
Q

T or F: the Platinum drugs are considered alkylating agents.

A

False, they are platininating agents, not alkylating agents

30
Q

T or F: in some cases cancer cells can just upregulate DNA excision repair mechanisms to remove antimetabolites and keep moving on.

A

True.

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

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