MS drugs Flashcards
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
New antibody therapies (umabs)
-Alemtzumab (Compath)
-Rituximab (Rituxan)***
-Ofatumumab (Kesimpta)
Alemtuzumab (Compath)
-targets CD52
-effective in early phase but not degenerative
Rituximab (Rituxan)
-targets CD20 (B cell marker)
-aka OCRELIZUMAB
-approved for non-hodgkin lymphoma and rheumatoid arthritis
-off label for MS
-stops RRMS, effective for some PPMS pt
-infusion q6months
Ofatumumab (Kesimpta) and Ublituximab (Briumvi)
-also target CD20
Ocrelizumab (Ocrevus) aka Rituximab (Roche) MOA
-mAb targets CD20 (mature B cell marker)
-doesnt bind CD20 on stem or plasma cells = key immune functions stay intact
-decrease progression in PPMS (first example 18)
-dec relapse rate in RRMS)
Experimental MS drugs
-autologous hematopoietic stem cell transplants
-T-cell therapy
-ANTISNESE OLIGONUCLEOTIDES
-repositioned drugs
-drugs w different MOAs
autologous hematopoietic stem cell transplants
-immature stem cells removed from bone marrow and expanded
-pt immune system eliminated by irradiation
-stem cells introduced into pt to re-stablish healthy immune system (wont get rejected)
-best for pt w aggressive RRMS < 50 yo
T-cell therapy for MS
-ATA188 T cells against EBV cells
ANTISENSE OLIGONUCLEOTIDES
-ATL1102
-target VLA-4
-predicted to have sma eoutcome as natalizumab
Repositioned drugs for MS
-simvastatin (antiinflammatory effects)
-clemastine (allergy drug that can help in myelin repair
Drugs w different MOAs
-inhibitors of Bruton’s tyrosine kinase (evobrutinid, fenibrutinib, remibrutinib)
-lipoic acid (antioxidant activity)
Which of the following drugs is (are) active in both the periphery
and the CNS?
(A) dimethyl fumarate
(B) natalizumab
(C) rituximab
(D) teriflunomide
(E) none of the above
dimethyl fumarate
