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TH Questions > Chapter 16 > Flashcards

Chapter 16 Flashcards

1
Q

Define and distinguish pharmacokinetics from pharmacodynamics

A

PK - study of the time course of drug and metabolite levels in different body fluids and tissues. Includes drug absorption, distribution, metabolism, and elimination (ie what the body does to drug)

PD - study of drug’s effect or response at the cellular level (ie what drug does to body)

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2
Q

Define bioavailability

A

the amount of drug that is available after oral administration divided by the amt available after IV administration

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3
Q

Metabolism primarily occurs in the liver and has 2 phases (I and II) - describe both

A

Phase I consists of oxidative and reductive reactions via cytochrome p450 system. Can lead to activation of pro-drug, or create active metabolites.

Phase II is conjugation that leads to inactive metabolites that can be eliminated from the body by biliary or renal excretion.

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4
Q

Describe the area under the curve. Some drug effects correlate w/ AUC (name 2) while others correlate more w/ duration of exposure over a threshold level (name 2).

What are 2 independent determinants of AUC?

A

AUC = measure of total drug exposure of blood or tissue. Obtained by plotting concentration of the agent as a function of time and obtaining AUC by integration.

AUC - nb for effects of alkylators and cisplatin
Time over threshold nb for antimetabolites, taxanes, TOPO I inhibitors

2 independent determinants of AUC = dose and clearance

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5
Q

Describe the volume of distribution

A

A hypothetical volume required to dissolve the total amt of drug at the same concentration as is found in the blood immediately after injection.

Large Vd represents extensive binding of the drug in tissue (ex: vincas)

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6
Q

How do alkylating groups work?
There are 2 main groups of alkylating agents based on the # of functional groups they have - what are these groups?
Which have the ability to crosslink?
What is the primary mechanism by which alkylators cause lethal toxicity to the cell?

A

Through covalent binding of alkyl groups (-CH2Cl) to intracellular macromolecules.
They generate highly reactive positively charged intermediates which combine w/ an electron rich group.
Can have 1 or 2 reactive groups..mono vs bi functional alkylators
Bifunctional can crosslink making them more clinically useful.
Lethal dt alkylation of DNA bases

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7
Q

Name 3 mechanisms of resistance to alkylators

A
  1. decreased transport across cell membrane
  2. increased intracellular thiol concentration such as glutathione which results in these cmpds interacting w/ alkylators instead of DNA
  3. increased enzyme detoxification of reactive intermediates
  4. alterations in DNA repair enzyme (ex- guanine O6 alkyltransferase)
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8
Q

There are 3 classes of alkylating agents. Name them and the drugs in each class. How many reactive groups are their in each? What is the most common alkylation site for the group that contains cyclophosphamide?

A

1 - Nitrogen Mustards. Most clinically useful.
Meclorethamine, cyclophosphamide, chlorambucil, ifosfamide, melphalan.
Bifunctional. N-7 guanine.

2 - Nitrosoureas.
CCNU (mono), BCNU (bi/IV only), streptozotocin

3 - Other
Busulfan (forms DNA crosslinks) - high dose BMT
Procarbazine - synth derivative of hydrazine
DTIC
Temozolamide

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9
Q

Alkylators (are or are not) cell cycle phase specific? Effectiveness of alkylators is related primarily to (AUC or peak dose)?

A

are not cell cycle phase specific

AUC

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10
Q

What tumor type is associated w/ previous administration of these agents?

Nitrogen mustard and melphalan
Cytoxan

A

AML for the mustards

bladder cancer for cytoxan

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11
Q

Describe how cytoxan is metabolized in the body including which metabolites are active vs inactive. Which is the most active form?

A

Cytoxan - parent compound (inactive) - requires metabolism by hepatic oxidases to form the alkylating intermediate PHOSPHORAMIDE MUSTARD.

Cytoxan is metabolized into 4-HYDROXYCYCLOPHOSPHAMIDE and ALDOPHOSPHAMIDE (exist in equilibrium)

Most active - phosphoramide mustard

p329 16.4

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12
Q

Why is cytoxan considered to be platelet and stem cell sparing?

A

due to higher concentration of ALDEHYDE DEHYDROGENASE which inactivates the drug intracellularly in early progenitor cells

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13
Q

What is the name of the metabolite of cytoxan that causes bladder irritation? What drug is used to prevent this and how does it work?

A

Acrolein - direct irritant to bladder mucosa
Mesna - coadministered w/ all patients receiving ifos

Mesna is a sulfydryl containing compound which conjugates acrolein in the urinary tract and protects the bladder from irritation.

Mesna is inactive in plasma and converted to active form ONLY in urine so it doesn’t interfere w/ cytotoxicity

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14
Q

Describe the 2 states that platinum agents are found in.
Which group does the clinically useful drugs belong to?
Cell cycle phase specific or not?

A

2+ (II) and 4+ (IV) oxidations states w/ 4 or 6 bonds respectively.
Useful drugs are part of the II group.
They have 4 attached chemical groups - 2 are carrier groups and are chemically inert; 2 are leaving groups available for reactions.
The chlorine groups are leaving groups and either displaced by nucleophilic groups on DNA or are replaced by OH after interacting w/ water.

NON-specific.

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15
Q

What is the preferred site of DNA binding for cisplatin?

A

N7 position of guanine and adenine

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16
Q

How is carbo different from cisplatin structurally?

A

Instead of chlorine leaving groups, carbo has cyclobutanedicarboxylate leaving groups. This leads to less reactive compound w/ less toxicity.

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17
Q

Name a 3rd member of the platinum group not yet used clinically in vet med

A

Oxaliplatin

Lobaplatin

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18
Q

Platinum groups are excreted mainly by what route?

Which members of this groups are significantly bound by plasma proteins?

A

Kidneys
Cisplatin is rapidly/reversibly bound.
Oxaliplatin also binds plasma proteins.

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19
Q

Describe 3 mechs of resistance to platinums

A

Reduced platinum-DNA adduct formation
Increased repair or tolerance of platinum-DNA adduct
Increased binding to scavengers such as glutathione

20
Q

Name the major cisplatin toxicities

A

emesis, kidney damage, neurotox, ototox

21
Q

Which two DNA bases are purines? Which are pyrimidines?
Describe which pair up on opposite strands in the DNA ladder. What base exists in RNA but not DNA? What base does it replace?

A

Purines - adenine guanine
Pyrim - thymine, cytosine
Normally G w C and A w T
In RNA, uracil replaces thymine

22
Q

Antimetabolites are cell cycle phase specific or non-specific?
These drugs are typically not carcinogenic - why?
Do they work based on AUC or time over threshold concentration?

A

Specific
No not bind/dmg DNA - only inhibit synht or base formation
Time over threshold is most nb for effect

23
Q

Methotrexate is an analog of ___. That substance is reqd in its reduced form for transfer of methyl groups in the synthesis of which DNA bases (name two)? And in the conversion of ___ to ___ which is a reaction catalyzed by the enzyme ___. Methotrexate does this by inhibiting ___.

A 
Folic acid.
Purines A & G.
dUMP to dTMP
thymidylate synthase
DHFR
24
Q

How does methotrexate enter the cell, what prevents methotrexate efflux leading to increased concentrations in the cell?
Efficacy of cell kill correlates with (exposure duration over certain threshold or peak level)?

A

Active transport
The drug is then polyglutamated in the cell preventing efflux.
Efficacy of cell kill correlates w/ exposure to greater than a certain level rather than peak level.

25
Q

Methotrexate toxicity can be reversed w/ which drug?

A

leucovorin - reduced folate

26
Q

How is mtx excreted?

A

renal

27
Q

5FU resembles what bases?
How does it inhibit RNA and DNA synthesis?
Cell cycle phase specific or not?

A

Thymidine and Uracil

Creates 5FUTP which is incorporated into RNA causing errors in base pairing during transcription; 5fdump inhibits irreversibly thymidylate synthase leading to depletion of dTMP

DNA effects are S phase specific but RNA effects are not, not well understood which is more nb

28
Q

Where is 5FU metabolized?

Name one other drug that if given concurrently it increases tox.

A

liver

leucovorin

29
Q

In humans, PPD has been described after 5FU administration. What is this and what med in vet med has this been associated with?

A

redness and peeling of skin on palms/soles

Doxil

30
Q

Capecitabine is a derivative of ____

A

fluoropyrimidine

31
Q

describe premetrexed MOA

A

Thymidylate synthase inhibitor (folate based similar to MTX) which depletes dTMP stores needed for DNA synthesis. Also inhibits DHFR renal excretion (at least 1 paper on this).

32
Q

Describe the metabolism of Ara-C in cells

A

Ara-C - (cytidine deaminase) - Ara-U
- (deoxycytidine deaminase) - Ara-CMP –>

Ara-CMP - (dCMP deaminase) - Ara-UMP
- (dCMP Kinase) - Ara-CDP –>

Ara-CDP - (NDP Kinase) - Ara-CTP - INHIBITS DNA SYNTHESIS

*on boards 16.13

33
Q

How does ara-C lead to cell death?

A

Competitive inhibitor of DNA polymerase AND gets incorporated into DNA leading to cytotoxicity possibly by chain termination.
Concentration of ara-C then isn’t nb bc you want relatively high doses of Ara-CTP compared to dCTP

34
Q

Gemzar is metabolized in a similar fashion as ara-C. What is the end product in the cell of Gemzar metabolism? How does this inhibit DNA synthesis?

A

dFdCTP - inserted into the DNA strand leading to chain termination. Also inhibits cytidine deaminase, the primary enzyme responsible for Gemzar degradation leading to longer sustained levels in cells and stimulates deoxycytidine kinase (nb for activation)

35
Q

Name 3 purine antimetabolites

A

Azathioprine, 6-thioguanine, 6-mercaptopurine, fludarabine

36
Q

What is the normal fxn of DNA topoisomerases?
Differentiate bt types 1 and II.
Where do TOPO inhibitors interfere in this normal function?

A

Enzymes that relax supercoiled dsDNA to allow DNA replication and RNA transcription.
Topo I relieves torsional strain via ss nick, Topo II does it via ds nick.

After the DNA unwinds, the strands are also religated.

Inhibitors prevent the religation by binding and stabilizing the DNA/Topo complex

37
Q

Name 2 topo I inhibitors. Are they S phase specific?

A

camptothecin, topotecan, irinotecan

May be more active in S phase but not limited to S phase activity

38
Q

Tame 2 Topo II inhibitors

A

Etoposide, teniposide
Altho podophyllotoxin binds to tubulin and inhibits polymerization, these drugs act via topo II inhibition. MDR mediates resistance. Etoposide is much more effective as daily dosing than single dose.

39
Q

Name 4 members of the anthracycline/anthracenedione group of chemotherapeutics.
Describe at least 3 MOA for these drugs.

A

Daunorubicin, doxorubicin, idarubicin, epi, mito

MOA - interact w/ topo II inhibiting religation, DNA intercalation bt base pairs leading to unwinding of DNA, formation of free radicals such as superoxide O2 (which causes oxidative dmg to the cell membrane and DNA), effects on cell membrane

40
Q

How does cardiotoxicity form after doxorubicin exposure?
Cardiotoxicity is correlated to what aspect of the drug’s pharmacokinetics?
Drug efficacy is related to what aspect of drug pharmacokinetics?

A

Mech of tox is likely dt dmg to the SR mediated by formation of free radicals w/in the cardiac muscle. Toxicity is more related to the peak concentration of the drug rather than overall exposure (give over longer pd of time). Efficacy is associated w/ AUC.

41
Q

Describe vinca alkaloid MOA

A

bind to protein tubulin and inhibit polymerization to form microtubules which are nb for the mitotic spindle, separation of chromosomes and structural and transport functions in axons and nerves

42
Q

Describe the MOA of the taxanes
Name 2 drugs
How are they eliminated?

A

Paclitaxel and docetaxel
Bind tubulin at a different site; inhibit mtb disassembly which prevents normal growth and breakdown of mtbs
Liver metabolism

43
Q

MOA bleomycin

What is most serious tox associated w/ administration of this agent

A

Causes ds DNA breaks via binding, intercalation and unwinding of the double helix
Interstitial fibrosis of the lung - related to cumulative dose

44
Q

For the following molecular targeting agetns, list target adn what type of inhibitor they are (ie PTKI or MAB etc).
List at least 1 tumor they treat

Imatinib, Erlotinib, Gefitinib, Cetuximab, Bortezomib, Tipifarnib

A

Imatinib (gleevac) - protein TKI - inhibits Bcr-Abl fusion protein (Philadelphia chromosome) and c-kit and PDGF-R. In ppl w/ CML, dogs w MCT/gist (liver tox)

Erlotinib (Tarceva) - inhibit EGFR TKs - head and neck, gynecological, NSCLC

Gefitinib (Iressa) - as above

Cetuximab - mab against EGFR

Bortezomib (Velcade) - proteosome inhibitor - prostate, lung, MM

Tipifarnib (Zarnestra) - oral farnesyltransferase inhibitor - inhibits RAS signaling = pancreatic cell lines

45
Q

Name 4 drugs susceptible to MDR.

Name 4 classes of drugs NOT susceptible to MDR (p-glycoprotein)

A

Susceptible to MDR:
*Topo II (etoposide, teniposide), Vincas, Taxanes, Anthracyclines

Not Susceptible:
*Alkylators, platinums, antimetabolites, Topo I (camptothecin, topotecan, irinotecan)

TH Questions (21 decks)

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