36-39 Pharmacology of MS drugs Flashcards
3 categories of MS treatment
1) treatment of ___ attacks
2) disease ___ therapies
3) ___ therapies
1) acute
2) modifying
3) symptomatic
treatment of acute attacks (3)
- methylprednisolone
- prednisone
- adrenocorticotropic hormone (ACTH)
ACTH is expensive (rarely used)
disease modifying therapies
reduce ___ rates, may slow the ___ of disability
- generally used to treat ___ rather than ___ forms of MS
relapse, progression
- relapse, progressive
disease modifying therapies - examples
1st line (4)
- interferon B1a
- interferon B1b
- glatiramer acetate
- fingolimod
disease modifying therapies - examples
2nd line (2)
- natalizumab
- mitoxantrone
disease modifying therapies - examples
new drugs (3)
teriflunomide
dimethyl fumarate
cladribine
primary corticosteroids for acute attacks
MOA:
- up-regulating anti - ___ genes
- down-regulating ___ -inflammatory genes
- alleviating ___ in ___ areas
- inflammatory
- pro
- edema, demyelinated
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 ___
periphery, BBB
- autoreactive
- decreasing
- CIS
- antibodies
lymphocytes - T cells and dendritic cells
interferon B1a drugs (2)
Avonex
Rebif
interferon B1b drugs (2)
Betaseron
Extavia
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
synthetic, antigenic
- T cells
- CIS
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
sphingosine-1-phosphate (S1P), agonist
- oligodendrocyte survival
- lymphocyte
- leukoencephalopathy
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
a4
- a4, B1
- VCAM-1, B, T
- PML
- neutralizing, allergic
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
cytotoxic
- breaks, intercalation
- repair, topoisomerase
- cytotoxic
- induction
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 ___
cytotoxic, pyrimidine
- lymphocytes
- relapse
- teratogenicity
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 ___
esterases
- Nrf2, anti-inflammatory
- remyelination
- T, dendritic
- PML
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
- ubiquitylation
- Keap1
- glutathione
- II
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 ___
fingolimod
- oligodendrocyte
- lymphocyte
- RRMS, SPMS
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
- lymphocytes, monocytes
- DNA, lymphocytes
new antibody therapies
alemtuzumab (Compath)
MOA: targets ___ (pan-leukocyte marker)
- effective in treating the ___ phase of MS, but not the degenerative phase
CD52
- early
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 ___
CD20
- Ocrelizumab
- PPMS
CD20
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
rituximab
- humanized, CD20, B cells
- PPMS
- RRMS
T or F: Ocrelizumab binds to CD20 in stem cells and plasma cells
FALSE
only binds to CD20 on mature B cells
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
- immature
- irradiation
- RRMS
drugs in late stage clinical trials
T cell therapy
- ATA188, an EBV T cell formulation that targets ___ infected cells
Epstein-Barr virus
drugs in late stage clinical trials
antisense oligonucleotides
- ATL1102, an ASO targeting VLA-4
- predicted to have the same outcome as ___
natalizumab
drugs in late stage clinical trials
repositioned drugs
- ___ - a cholesterol-lowering drug with anti-inflammatory effects
- ___ - an allergy drug that apparently promotes myelin repair
- simvastatin
- clemastine
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
- Burton’s
- lipoic
