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PHARMACOLOGY - Antiviral, Classic Chemo, ADME > Targeted Drugs > Flashcards

Targeted Drugs Flashcards

1
Q

What is the use of mAb drug contingent upon. Why?

A
  • Test for the Presence of the Target on the Cancer

why:
- Must test because these targets are present on normal tissues too. For the drug to kill the tumor before killing the patient, the tumor must overexpress the receptor

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2
Q

What 3 general types of mAb drugs are there?

A

Naked - nothing else attached to them
Conjugated - carry a toxic agent
Bispecific - bring immune cells into proximity with cancer cells

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3
Q

CD20 specific mAbs

  • Name Them.
  • MOA
  • Adverse Effects
  • Administration
A

Rituximab, Ofatumumab

MOA:
binds CD20 having 2 effects:
1) CD20 stimulation triggers Apoptotic Pathway
2) IgG can Fix Complement with Fc region

Adverse Effects:
This causes B cell Depletion

Administration:
- IV or SubQ

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4
Q

Diseases Treated with CD20 drugs.

- Name Drugs

A

Rituximab:

  • Chronic Lymphocytic Leukemia (CLC)
  • Non-Hodgkin’s Lymphoma (NHL)

Ofatumumab:
- CLL

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5
Q

CTLA-4 specific mAb

  • Name.
  • MOA
  • Administration
A

Ipilimumab

MOA:
- Immunostimulant binds CTLA-4 blocking CD80/CD86 from binding allos T cells to proliferated because no Treg suppression

Administration:
- IV or SubQ

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6
Q

Disease treated with Ipilimumab.

- what target it is specific for?

A

Melanoma

  • CTLA-4 blocking Treg peripheral tolerance mechanism
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7
Q

EGFR drugs (not including Her-2 drugs)

  • Name Them
  • MOA
  • Administration
A

Cetuximab and Panitumumab

MOA:
- Bind causing Apoptosis or ADCC

Administration:
- IV or SubQ

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8
Q

What is the adverse effect of the EGFR drugs INCLUDING the HER-2 drugs?
- NAME all of these.

A

ALL:
- Photosensitivity

Her-2 specifically:
- Cardiac Toxicity

EGFR:

  • Cetuximab
  • Panitumumab

Her-2:

  • Tratuzumab
  • Pertuzumab
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9
Q

Her-2 Drugs

  • Name them.
  • MOA
  • Administration
A

Traztuzumab and Pertuzumab

MOA:
Traztuzumab
- Inhibits Stimulatory Signal by binding HER-2 causing a downregulation of HER-2 and ACCUMULATION OF p-27 causing cell cycle arrest.
- Also apoptosis, ADCC

Pertuzumab:
- Blocks Heterodimerization of HER-2 and HER-3

Administration:
- IV or SubQ

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10
Q

EGFR drugs (including Her-2 drugs):

  • Cancer Treated
  • NAME THEM.
A

EGFR:
Cetuximab - colorectal, Head and Neck (H and N)
Panitumumab - Colorectal

Her-2: (traztumab, Pertuzumab)
Both treat breast cancer

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11
Q

VEGF drugs

  • MOA
  • Toxicity
  • Delivery
A

Bevicizumab

MOA:
- Anti-Angiogenesis

Toxicity:

  • Cardiac
  • Pulmonary
  • GI perforation

Delivery:
- IV or SubQ

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12
Q

What types of cancer are treated with VEGF inhibitors?

- Name the drug.

A
  • Colorectal
  • Non-small cell lung carcinoma (NSCLC)
  • Large solid tumors

Bevicizumab

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13
Q

Why is VEGF and effective target for large tumors?

A

Large tumors get hypoxic and need more BVs:
- HIF-1alpha unbinds from VHF which usually targets HIF-1alpha to the 26S proteasome

  • Free HIF-1alphs is then able to translate the nucleus and upregulate VEGF signaling
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14
Q

Are mAb drugs ever given orally?

A
  • No they would degrade rapidly in the stomach
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15
Q

Penetrance into the tumor is vital to fighting it. How are mAbs engineered so that they’re better equipped to penetrate?

A

Fc regions are often removed

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16
Q

How are mAb drugs metabolized and why is this an advantage?

- what can we do to slow down degradation in these?

A
  • Broken down by Lysosomal and Cytosolic processes
  • No CYP or Hepatic metabolism means no drug-drug interactions
  • mAbs can be formulated with PEG to prevent renal secretion
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17
Q

Besides adding PEG how is the half life of mAbs extended intrinsically?
- where is this receptor found usually?

A
  • FcRn (fetal Brambell receptor)
  • FcRn Receptor is found on the surface of Adult epithelial cells and monocytes (these cells bind the Fc region, endocytose, then recycle the mAb)
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18
Q

What are some of the general adverse effects of mAbs?

A
  • Anaphylaxis, Angioedema, Pulmonary Toxicity

- Depletions of Cell populations that express the same target as the tumor

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19
Q

What mAb drug causes increased oxidative stress in cardiac myocytes and cadiotoxicity?
- what is the intended target of this drug?

A
  • Trastuzumab [Herceptin] blocks HER2 activity

- Intended target is Breast Cancer Tissue, but Cardiac Myoctyes also express Her-2 so they get targeted too.

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20
Q

What mAb drug causes HTN, proteinuria, and thrombotic microangiopathy?

  • explain why?
  • what is the intended target of this drug?
A

Bevacizumab [avastin]

  • These are sides effects caused by Bevacizumab disrupting RENAL HOMOSTASIS
  • Intended target of Bevacizumab is VEGF
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21
Q

What mAb causes renal magnesium wasting and hypomagnesemia via effects on the distal convoluted tubule?

A

Cetuximab [Erbitux]

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22
Q

What mAbs work as checkpoint inhibitors to improve immune response to tumor cells?

  • what is their target?
  • idea behind these drugs?
A

CTLA-4 binding drugs:
- Ipilumumab - prevents CTLA-4 from binding B7 (CD80/86)

PD1 binding drugs:

  • Nivolumab
  • Pemmbolizumab
  • Prevents PD1 from repressing activation of T cells in 2˚ lymph tissue
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23
Q

What is a common cancer treated by the checkpoint inhibiting drugs?
- NAME these drugs.

A

melanoma

  • Ipilumumab
  • Nivolumab
  • Pemmbolizumab
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24
Q

What causes PD1 upreguation on peripheral tissues?

- when and why is this done?

A
  • PD-L1 gets up regulated to protect host tissue from getting attacked
  • PD-L1 binds PD-1 on T cells and downregulates them to keep them from affecting host tissue
  • IFN-gamma is believed to upregulate this response
25
Q

What are side effects of the checkpoint inhibiting antibodies that target PD-1 and CTLA-4.

  • Black Box Warnings?
  • NAME THESE DRUGS.
A

Autoimmune-type symptoms occur:

  • Dermatitis and TOXIC EPIDERMAL NECROLYSIS
  • Black Box Warnings - Endocrinopathies, diarrhea, Peripheral Neuropathy, Pregnancy, serious rash.
26
Q

What drugs act in immuno-stimulatory therapy?

A
  • Aldesleukin [proleukin]

- Interferon-alpha 2b [intron A]

27
Q

Aldesleukin

  • MOA
  • Aministration?
  • Toxicity (BBW/Contraindications)
A

MOA:
- Binds to IL-2 receptor inducing the proliferation and differentiation of B and T-cells, monocytes, macrophages, and CTLs including NK cells

Administration:
- IV or SC

Toxicity/BBW/Contradinications:

  • CNS impairment
  • Cardiac Disease
  • Pulmonary Disease
  • Renal Disease
28
Q

What is vascular leak syndrome (VLS)?

  • Drug that causes this?
  • Underlying Mechanism?
  • Organs involved?
A

Aldesleukin causes VLS

Increased Vascular Permeability leading to:

  • Hypotension
  • Pulmonary Edema
  • Liver Cell Damage
  • Renal Failure

Mechanism:

  • IL-2 binding to NK cells causing cytokine release
  • IL-2 binding to endothelial cells
29
Q

How does Interferon-alpha 2b work?

- Toxicity

A

Works like endogenous Interferons:

  • Increased CD8+ activation
  • Promote NK ability to uses perofrin, granzyme, and FasL

Toxicity (BBWs):

  • Autoimmune disease
  • Cardiac Disease
  • Depression (suicidal idealization)
  • Infection
  • *Often causes elevated hepatic enzymes
30
Q

Sipuleuce-T [Provenge]

  • MOA
  • Adverse Effects
A

MOA:

  • Patient APCs are taken out and cultured with recombinant Prostatic Acid Phosphatase and GM-CSF
  • APCs take up the antigen and present it to T and B cells in the sample that are reinfused into the patient

**Goal - destroy cells that use this enzyme to make PSA which is linked to prostate cancer

Adverse Effects:

  • Mild Infusion Reactions (fever, chills, dyspnea)
  • Paresthesias, Citrate Toxicity
31
Q

How do the tyrosine kinase inhibitors differ from the mAb drugs?

  • how do they differ from alkylating agents and antimetabolites?
  • metabolism
A

mAb vs. TKI:
- They are small and orally bioavailable and metabolized by CYP3A4 (Drug-Drug interactions!)

TKI vs. other Chemo drugs:
- no reduction in white count make it hard to know if the drug is working

32
Q

What is the main problem with the TKIs not reducing the White count?

A

You don’t know if the drug is working and Dr’s might tend to underdose which can lead to resistance of the tumor towards the drug

33
Q

What is the classic way that resistance emerges against the Tyrosine Kinase inhibitors (TKIs)?
- what other features of TKs and their pathways give them the ability to resist TKIs?

A

Mutations in the ATP binding region of the Tyrosine Kinase Receptor prevents TKIs from binding and the cell resumes its proliferation

Others:
- Mutations downstream from TK receptors, such as those leading to constant activation of KRAS will nullify any effect of the drugs

34
Q

T or F: for most of the TKI drugs activity is limited to a specific TK.

A

False, TKIs are promiscuous because of how conserved the ATP binding region is from TK to TK and this can lead to adverse effects

35
Q

How should patients receiving treatment by TKs be monintored?

A

Endrocrine Function Monitoring:

  • Thyroid Function
  • Child Growth
  • Diabetes

**Women of Childbearing age need to be made aware of adverse effects

36
Q

Which of the TKIs produce stocking-glove syndrome?

A
  • Sunitinib
  • Sorafenib
  • Pazopanib
  • Vermurafenib
37
Q

What are some adverse affects of TKIs other than stocking-glove syndrome?
- name drugs specific to side effects.

A
  • Blood Dyscrasias (weird b/c not expected from targeted therapy)
  • QT prolongation
  • Cardiomyopathy (Trametinib and Dabrafenib)
  • Dermal Toxicity (Erlotinib, Gefitinib, Lapatinib)
38
Q

What TKIs and mAb have the affects of increased UV sensitivity in commmon?
- what pathway do ALL of these drugs act on.

A

EGFR pathway (so EPIDERMIS) is affected:

mAbs:

  • Cetuximab
  • Panitumumab

TKIs:

  • Erlotinib
  • Gefitnib
  • Lapatinib
39
Q

BE SURE TO GO BACK AND LOOK AT TKI CARDS IN THE OTHER DECK.

A

BE SURE TO GO BACK AND LOOK AT TKI CARDS IN THE OTHER DECK.

40
Q

What cancer is associated with the Sonic Hedgehog Signaling pathway?

  • when is this pathway usually active?
  • what drug targets this pathway?
A

Vismodegib [Erivedge]

Cancer:
- Basal Cell Carcinomas

  • Pathways involved in early development and regulates body patterning and organ development.
  • Goes Quiescent and is only involved in tissue repair after that
41
Q

What factors are produced as the end product of the Sonic Hedgehog pathway?

  • what drug targets this pathway?
  • Cancer associated with re-emergence of this path?
A

Vismodegib [Erivedge]

  • Bcl-2
  • VEGF
  • *Both of these are very advantageous for a tumor cell
    • BASAL CELL CARCINOMAS often use this path
42
Q

Vismodegib

  • cancer targeted?
  • what pathway does it act on?
  • Most Common Side Effects?
  • BBWs?
A
  • Acts on SMO in the Sonic Hedgehog pathway that produces Bcl-2 and VEGF
  • Targets BASAL CELL CARCINOMAS

most common side effects:
- Alopecia

BBWs:

  • INTRAUTERINE FETAL DEATH
  • MALE-MEDIATED TERATOGENICITY
  • PREGNANCY
43
Q

How do the mTOR inhibiting drug work?

- Name the drugs.

A

Form Three Way:
- FK + BP-12 + mTOR

Drugs:

  • Temsirolimus
  • Sirolimus
  • Everolimus
44
Q

What are the end products of the mTOR path that makes it advantageous for cancers to up-regulate this path?

A

mTOR end pdts:

  • Nutrient Uptake
  • Angiogenesis
  • Ribosome Biogenesis
  • Cell Growth and Proliferation
45
Q

What drug prevents IkB-alpha (inhibitor of NFkB) from getting targeted for breakdown?
- How does it do this?

A

Bortezomib - prevents targeting of IkB-alpha to the 26S proteosome by INHIBITING THE 26S proteosome

  • This Prevents NFkB from getting released and promoting cell proliferation
46
Q

Besides IkB-alpha what else gets targeted to the 26S proteosome?

A

HIF-1alpha gets targeted to the 26S proteosome in normal cells

47
Q

What is the method of administration for Bortezomib?

- toxicity?

A

Bortezomib:
- IV or SC injection

Toxicity:

  • Cardiotoxicity
  • Sensory and Motor Neuropathy
  • Hypotension
48
Q

What is the problem with using single targets, especially with RTKs?

A

Often more than one RTK can converge on a single pathway.

  • This means we would need to treat multiple RTKs to truly shut down the pathway
49
Q

Can Targeted therapies erradicate cancer?

A

NOOOO

50
Q

What drugs are given to fight Advanced renal cell carcinoma?

A

MTOR inhibitors:

Termsirolimus
Everolimus

51
Q

Which of the TKI drugs target the thyroid as a side effect?

  • Commonly?
  • Less Commonly?
A

Common:
Sorafenib
Imatinib
Sunitinib

Moderate: 
Dasatinib
Erlotinib
Nilotinib
Pazopanib
52
Q

Which of the TKI drugs are associated with cardiomyopathy and QT prologation?

A
  • Trametinib

- Dabrafenib

53
Q

Which of the TKI drugs are associated with dermal toxicity?

A
  • Erlotinib
  • Gefitinib
  • Lapatinib

(mAbs Cetuximab and Panitumumab also cause this)

54
Q

Which of the TKI drugs act on BRAF?

  • V600E or V599E?
  • side effects?**
A

V600E

  • Dabrafenib (QT prolongation)
  • Vemurafenib (Stocking glove syndrome)

V599E
- Sorafenib (Stocking Glove Syndrome, Common Thyroid Dysfunction)

55
Q

Which of the TKI drugs act on VEGFR?

- side effects?**

A

Pazopanib (Stocking Glove Syndrome)

Sunitinib (Stocking Glove Syndrome, Common Thyroid Dysfunction)

56
Q

Which of the TKI drugs act on EGFR?

- side effects?**

A

Erlotinib (DERMAL TOXICITY, Sometimes Thyroid Dysfunction)

Gefitinib (DERMNAL TOXICITY)

Lapatinib (DERMAL TOXICITY)

57
Q

Which of the TKI drugs act on Bcr-abl mutant cells?

- side effects?**

A

Nilotinib (Sometimes Thyroid Dysfunction)

Imatinib (Common Thyroid Dysfunction)

58
Q

Crizotinib

  • target
  • cancer treated
A

Crozotinib
- Tyrosine Kinase Inhibitor

  • EML4-ALK ADENOCARCINOMAS (usually found in non-smokers)

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

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