36-39 Pharmacology of MS drugs Flashcards

1
Q

3 categories of MS treatment

1) treatment of ___ attacks
2) disease ___ therapies
3) ___ therapies

A

1) acute
2) modifying
3) symptomatic

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2
Q

treatment of acute attacks (3)

A
  • methylprednisolone
  • prednisone
  • adrenocorticotropic hormone (ACTH)

ACTH is expensive (rarely used)

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3
Q

disease modifying therapies

reduce ___ rates, may slow the ___ of disability
- generally used to treat ___ rather than ___ forms of MS

A

relapse, progression
- relapse, progressive

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4
Q

disease modifying therapies - examples

1st line (4)

A
  • interferon B1a
  • interferon B1b
  • glatiramer acetate
  • fingolimod
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5
Q

disease modifying therapies - examples

2nd line (2)

A
  • natalizumab
  • mitoxantrone
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6
Q

disease modifying therapies - examples

new drugs (3)

A

teriflunomide
dimethyl fumarate
cladribine

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7
Q

primary corticosteroids for acute attacks

MOA:
- up-regulating anti - ___ genes
- down-regulating ___ -inflammatory genes
- alleviating ___ in ___ areas

A
  • inflammatory
  • pro
  • edema, demyelinated
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8
Q

interferon B1a and B1b drugs

first line drugs
MOA: act in the ___ and at the ___
- inhibition of ___ lymphocytes - T cells, dendritic cells
- inhibition of BBB penetration by ____ matrix metalloproteinase

clinical features
- delay conversion of ___ to clinical MS
- efficacy reduced by neutralizing ___

A

periphery, BBB
- autoreactive
- decreasing
- CIS
- antibodies

lymphocytes - T cells and dendritic cells

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9
Q

interferon B1a drugs (2)

A

Avonex
Rebif

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10
Q

interferon B1b drugs (2)

A

Betaseron
Extavia

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11
Q

Glatiramer acetate (Copaxone)

first line
MOA: ___ polypeptide, mimics ___ properties of myelin basic protein
- modulation of APCs such as dendritic cells, leading to decreased ___ activation

clinical features
- delay conversion of ___ to clinical MS

A

synthetic, antigenic
- T cells
- CIS

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12
Q

fingolimod (Gilenya)

first line
MOA: ___ receptor ___
- stimulation of ___ survival, remyelination
- interference with ___ movement out of lymphoid organs

clinical features
- first oral drug approved for RRMS, superior to IFN-B
- SE: cardiotoxicity, fatal viral encephalitis (HSV or Varicella-Zoster), and progressive multifocal ___ (PML), a potentially lethal brain infection

A

sphingosine-1-phosphate (S1P), agonist
- oligodendrocyte survival
- lymphocyte
- leukoencephalopathy

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13
Q

natalizumab (Tysabri)

second line
MOA: monoclonal antibody specific for ___ integrin
- ___ integrin pairs with ___ integrin to produce very late antigen (VLA-4)
- inhibition of VLA-4 binding to its ligand ( ___ on CNS vascular endothelium) and interferes with ___ and ___ cell movement into the CNS

clinical features
- superior effects vs first line DMDs
- SE: development of ___
- induces the development of ___ antibodies leading to ___ reactions

A

a4
- a4, B1
- VCAM-1, B, T
- PML
- neutralizing, allergic

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14
Q

mitoxantrone (Novantrone)

second line
MOA: antracenedione with ___ activity

reduces lymphocyte numbers by
- causing DNA stand ___ via ___
- delaying DNA ___ via inhibition of ___ II

clinical features
- first ___ drug licensed for SPMS
- SE: cardiotoxicity and malignancies (mutagenic activity)
- can be used as ___ therapy and then replaced with IFN-B or GLAT

A

cytotoxic
- breaks, intercalation
- repair, topoisomerase
- cytotoxic
- induction

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15
Q

teriflunomide (Aubagio)

MOA: ___ agent that inhibits dihydroorotate dehydrogenase, an enzyme involved in de novo ___ biosynthesis
- inhibition proliferation of peripheral ___

clinical features
- reduces ___ rates, MRI endpoints
- primary risks are hepatotoxicity and ___

A

cytotoxic, pyrimidine
- lymphocytes
- relapse
- teratogenicity

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16
Q

dimethyl fumarate, diroximel fumarate, monomethyl fumerate

MOA: metabolized by ___ in the GI, blood, and tissues
- activate ___ mediated cellular antioxidant responses and ___ pathways
- may promote ___
- suppress activated ___ cells, ___ cells in the periphery

clinical features
- new oral, DR drugs
- SE: lymphocytopenia, and ___

A

esterases
- Nrf2, anti-inflammatory
- remyelination
- T, dendritic
- PML

17
Q

Nrf2 antioxidant response pathway in astrocytes

1) normally Nrf2 is broken down by interacting to Keap1 (promotes ___ )
2) when the cell is exposed to electrophilic toxins or stress, ___ becomes covalently modified and can no longer degrade Nrf2
3) Nrf2 builds up and enters the cell and activates genes that are regulated by the ___ response element (ARE)
4) genes under the control of ARE include genes that encode enzymes involving ___ biosynthesis and detoxification (GST). These enzymes are part of the phase ___ response

GST = glutathione-S-transferase

A
  • ubiquitylation
  • Keap1
  • glutathione
  • II
18
Q

siponimod, ozanimod, ponesimod

MOA: S1P receptor agonists (same mechanism as ___ )
- may stimulate ___ survival, remyelination
- interference with ___ movement out of lymphoid organs

clinical features
- indicated for ___ and ___

A

fingolimod
- oligodendrocyte
- lymphocyte
- RRMS, SPMS

19
Q

cladribine (Mylinax)

MOA:
- taken up in cells by purine nucleoside transporters
- in cells with a high ratio of deoxycytidine kinase to deoxynucleotidase ( ___ and ___ ), cladribine is phosphorylated to 2-chloro-dATP
- 2-chloro-dATP damages ___ and interferes with its metabolism resulting in cell death (decrease in ___ )

clinical features
- inititally used as a chemotherapeutic agent to treat hairy cell leukemia
- PO

A
  • lymphocytes, monocytes
  • DNA, lymphocytes
20
Q

new antibody therapies

alemtuzumab (Compath)
MOA: targets ___ (pan-leukocyte marker)
- effective in treating the ___ phase of MS, but not the degenerative phase

A

CD52
- early

21
Q

new antibody therapies (know this one)

rituximab (Rituxan, MabThera, Zytux)
MOA: targets ___ (B cell marker)
- also known as ___
- approved for non-Hodgkin lymphomas and rheumatoid arthritis
- stops RRMS, effective for some ___ patients

ofatumumab (Kesimpta) and ublituximab (Briumvi) also target ___

A

CD20
- Ocrelizumab
- PPMS

CD20

22
Q

ocrelizumab (Ocrevus), a.k.a ___
MOA:
- ___ monoclonal antibody that targets ___ , a marker of mature ___
- doesnt bind to stem cells or plasma cells, so that key immune functions arent messed with
- decrease disease progression in ___
- decrease relapse rate in ___

clinical features:
- administered via infusion every 6 months

A

rituximab
- humanized, CD20, B cells
- PPMS
- RRMS

23
Q

T or F: Ocrelizumab binds to CD20 in stem cells and plasma cells

A

FALSE
only binds to CD20 on mature B cells

24
Q

drugs in late stage clinical trials

autologous hematopoietic stem cell transplants
- ___ stem cells are removed from patient’s bone marrow and expanded
- patient’s immune system is eliminated by ___
- stem cells are introduced into the patient to re-establish healthy immune system
- best for patients with aggressive ___ and < 50 years old

A
  • immature
  • irradiation
  • RRMS
25
Q

drugs in late stage clinical trials

T cell therapy
- ATA188, an EBV T cell formulation that targets ___ infected cells

A

Epstein-Barr virus

26
Q

drugs in late stage clinical trials

antisense oligonucleotides
- ATL1102, an ASO targeting VLA-4
- predicted to have the same outcome as ___

A

natalizumab

27
Q

drugs in late stage clinical trials

repositioned drugs
- ___ - a cholesterol-lowering drug with anti-inflammatory effects
- ___ - an allergy drug that apparently promotes myelin repair

A
  • simvastatin
  • clemastine
28
Q

drugs in late stage clinical trials

drugs with mechanisms of action different from those of current therapies
- inhibitors of pro-inflammatory ___ tyrosine kinase (evobrutinib, fenibrutinib, remibrutinib)
- ___ acid, a supplement with antioxidant activity

A
  • Burton’s
  • lipoic