MS drugs Flashcards
(36 cards)
Categories of MS tx
- Acute attacks
- Disease-modifiying therapies (DMTs)
- Symptomatic therapies
Drugs used to treat acute attacks
-corticosteroids
-methylprednisolone (IV or oral)
-prednisone (oral)
-adrenocorticotopic hormone (ACTH) : rarely bc $$$
Corticosteroid MOA in MS
-acute attacks
-up-regulate anti-inflammatory genes
-down-regulate pro-inflammatory genes
-relieve edema in demyelinated areas
Disease modifying drugs for MS lines
- interferon B1a/b, glatiramer acetate, fingolimod
- natalizumab, mitoxantrone
new: teriflunomide, dimethyl fumarates, cladribine
-reduce relapse rates, may slow progression (used more for relapsing MS than progressive)
Interferon B1a (Avonex, Rebif) and Interferon B1b (Betaseron, Extavia) MOA
-act in periphery and BBB
-inhibit T cells and dendritic cells (periphery)
-inhibit BBB penetration by dec matrix metalloproteinase (MMP)
Interferon B1a (Avonex, Rebif) and Interferon B1b (Betaseron, Extavia)
-first line DMTs
-good safety profile
-alleviation in subset of pt
-delay conversion of CIS to MS
-EFFICACY REDUCED BY NEUTRALIZING ANTIBODIES
Glatiramer acetate (Copaxone) MOA
-synthetic polypeptide
-mimics antigenic properties of myeline protein
-modulation of APCs like dendritic cells = dec T cell activation
Glatiramer acetate (Copaxone)
-first line DMT
-black box warning for anaphylaxis!
-alleviation in some pt
-delays conversion of CIS to MS
Fingolimod (Gilenya) MOA
-sphinosine-1-phosphate (S1P) agonist
-stimulate oligodendrocyte survival and remyelination
-interfere w lymphocyte movement out of lymphoid organs
Fingolimod (Gilenya)
-first line DMT
-first oral approved for RRMS, better than IFNB
-SE: cardiotoxicity, fatal viral encephalitis (HSV or Varicella-Zoster)
-also progressive multifocal leukoencephalopathy (PML) (lethal brain infection)
Natalizumab (Tysabri) MOA
-mAb specific for a4 integrin
-a4 pairs w B1 to produce very late antigen (VLA-4)
-mAb blocks VLA-4 binding to it ligand (VCAM-1 on CNS vasc endothelium)
=interferes w B and T cell proliferation
Natalizumab (Tysabri)
-second line
-superior effects compared to first line (dec lesions, relapses)
-risk of PML
-induces development of neutralizing antibodies = allergy
Mitoxantrone (Novantrone) MOA
-anthracenedione w CYTOTOXIC activity
-reduce lymphocyte numbers by DNA strand breaks via intercalation and delaying DNA repair via topoisomerase II
Mitoxantrone (Novantrone)
-second-line
-first cytotoxic drug for SPSM
-cardiotoxicity and malignancies
-can be used as induction therapy and then replaced w IFN-B or GLAT
Teriflunomide (Aubagio) MOA
-CYTOTOXIC that inhibits dihydroorotate dehydrogenase (enzyme involved in de novo pyrimidine biosynthesis)
-inhibits proliferation of peripheral activated B and T cells
Teriflunomide (Aubagio)
-new drug
-reduce relapse rates, MRI endpoints
-primary risk: hepatotoxicity and teratogenicity
Dimethyl (tecfibera), Diroximel (Vemerity), Monomethyl (Bafiertam) fumarate MOA
-metabolized by esterases in the GI tract, blood, tissue
-activate Nrf2-mediated cellular antioxidant responses and anti-inflammatory pathways (active form drug is monomethyl ester)
-may promote remyelination
-suppress activated T cells, dendritic cells in the periphery
Dimethyl (tecfibera), Diroximel (Vemerity), Monomethyl (Bafiertam) fumarate
-new oral, delayed release drugs
-moderate side effects but also PML risk
Nrf2 antioxidant response pathway in astrocytes (not on exam)
-Nrf2 normally targeted for destruction as a result of its interaction with Keap1 (antagonist that promotes Nrf2 ubiquitylation)
-when cell is exposed to toxins or oxidative stress, Keap1 becomes covalently modified on key cysteine residues
-covalently modified Keap1 can no longer promote Nrf2 ubiquitylation, and thus Nrf2 accumulates and enters the nucleus, where it activates transcript of genes regulated by the antioxidant response element (ARE)
-genes under control of the ARE include genes encoding enzymes involved in (enzymes part of the phase II response):
1. glutathione biosynthesis
2. detoxification (glutathione-S-transferase or GST)
sphingosine 1-phosphate (S1P) agonists drugs
-siponimod (BAF312) (Mayzent)
-Ozanimod (Zeposia)
-Ponesimod (Ponvory)
-also fingolimod
sphingosine 1-phosphate (S1P) agonists MOA
-same as fingolimod
-may stimulate oligodendrocyte survival, remyelination
-interference w lymphocyte movement out of lymphoid organs
sphingosine 1-phosphate (S1P) agonists indication
-indicated for RRMS and SPMS
Cladribine (Mylinax) MOA
-taken up in cells bypurine nucleoside transporters
-in cells w high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated to triphosphate form (2-chlorodeoxyadenoside –> 2-chloro-dATP)
-2-chloro-dATP damages DNA ad interferes w DNA metabolism
=cell death = lymphocyte depletion
Clabridine (Mylinax)
-oral
-intially chemo to tx hairy cell leukemia
