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PHRM 845: Therapeutics III > Multiple Sclerosis > Flashcards

Multiple Sclerosis Flashcards

1
Q

What is Multiple Sclerosis?

A
  • An immune-mediated [inflammatory] disorder involving destruction of the myeline sheath that surrounds neuronal axons - leaves scar
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2
Q

What is the ‘Charcot Triad’?

A
  • Nystagmus
  • Intention Tremor
  • Telegraphic Speech
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3
Q

What are the symptoms of Mulitple Sclerosis?

A
  • Common: Visual problems, Numbness tingling, fatigue, motor weakness, difficutly walking, dizziness, vertigo,…
  • Less Common: tremor, seizures, speech and swallowing issues, headache…
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4
Q

What are some of the enivornmental risk factors of MS?

A
  • Age, geography, decreased Vit D, smoking, genetic factors…
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5
Q

What is important to understand about viral infections and how they relate to MS?

A
  • Infections may INCREASE the risk of MS by activating autoreactive immune cells - increasing the immune response
  • Increase IgG, Antibody titers, childhood infections
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6
Q

How is Epstein-Barr Virus involved in developing MS?

A
  • activation of autoreactive T- and B-cells [Molecular Mimicary]
  • HLA phenotype with anti-EBNA antibodies
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7
Q

What are the different clinical forms of MS?

A
  • Relapsing-Remitting MS: RRMS
  • Secondary Progessive MS: SPMS
  • Primary Progressive MS: PPMS
  • Clinically Isloated Syndrome: CIS
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8
Q

What is the Clinically Isolated Syndrome [CIS]?

A
  • It is the first initial inflammatory response
  • Resulting in demyelination
  • Most likely will become MS
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9
Q

What is Relapsing-Remitting MS [RRMS]?

A

-The MOST COMMON
- Has a flair up of symptoms which crosses the clinical threshold then remission occurs, repeating the process
- RRMS to SPMS

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10
Q

What is Secondary Progressive Remission [SPMS]?

A
  • Have very little Relapsing-Remitting phase BUT becomes very increasing disability
  • Slow neurological decline
  • Less inflammation
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11
Q

What is Primary Progessive Remission [PPMS]?

A
  • Just a constant increasing of disability; very closly related to SPMS
  • Occurs later in the disease
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12
Q

What is involved in the progressive phases?

A
  • Cytodegeneration [loss of myelin, axons, oligodendrocytes]
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13
Q

Describe the Autoimmune phase of MS?

A

-

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14
Q

Describe the Degenerative phase of MS?

A

-

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15
Q

Briefly describe the Autoimmune response in MS?

A
  • Neuron leaks out ANTIGENS that pass through the BBB to DENDRITIC CELLS activating T-CELLs
  • The T-Cells use A4-INTEGRIN to pass through the BBB
  • CD8+ T-Cells attack OLIGODENDROCYTES while CD+ T-Cells bind to MIRCOGLIAL CELLS releasing CYOTKINES
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16
Q

How do macrophages harm the myelin sheath?

A
  • They get recruited to the lesion and release harmful cytotoxic agents that harm the lesion [Reactive oxygen and nitrogen; glutamate]
  • Phagocytosis
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17
Q

What happens to action potentials in zones of demyelination?

A
  • In demyelinated zones, the action potential becomes slower and will become nothing
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18
Q

What is the normal process of an action potentail?

A
  • The action potential will travel quickly down the insulated axon [because of the myelin]
  • Node of Ranvier: demyelinated segment - has Na channels that reactive the action potential
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19
Q

What is the process of which we can remyelinate the demyelinated sections?

A
  • Oligodendrocytes form the myelin sheath on the axon
  • White matter inflammation will cause the break down of the myelin sheath [oligodendrocytes]
  • Remyelination occurs with the recruitment of OPC; increasing the Oligodendrocytes production
  • Astrogliosis causes the increase in astrocytes = scars
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20
Q

Briefly explain remyelination simply?

A
  • White Matter Inflammation/Breakdown
  • OPC recuitment
  • Astrocytes formation [Scars]
  • New Myelin is thinner and weaker
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21
Q

How does remyelination fail within MS?

A
  • Ongoing inflammation and the demyelination of the axon/neurons
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22
Q

What are some example therapies for MS?

A

Targeting Immune System
- T cell Binding/Penetration of BBB [a4-Intrgrin antibodies; IFN-b][
- T cell/APC interaction [APLs - copaxone; statins]
- Cytokines [IL-23 antibodies; osteopontin]

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23
Q

Example why gadolinium [Gd] in MS?

A
  • Visualization tool that will penetrate the brain where the BBB is compromised
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24
Q

What is Guillain-Barre Syndrome?

A
  • Autoimmune attack on the peripheral nerves by circulating antibodies, causing demyelination
  • Very slow recovery and death is caused by respiratory issues
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25
Q

What are the 3 categories of treatment in MS?

A
  • Acute attacks, Disease-Modifying Treatment, Symptomatic
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26
Q

What are the drugs used to treat Acute Attacks?

A
  • Corticosteroids [Methyprednisolone, Prednisone, ACTH
  • Act by up-regulating anti-inflammatory genes and down-regulating pro-inflammtory genes = DECREASE INFLAMMATION
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27
Q

What are the Disease modifying drugs in MS?

A
  • First Line: Interferon B1a, Interferon B1b, Glatiramer Acetate, Fingolimod
  • Second Line: Natalizumab, Mitoxantrone
  • New Drugs: Teriflunomide Dimethyl Fumarate, Cladribine
28
Q

What is the function of the Interferons?

A
  • MOA: inhibit lymphocytes in periphery [T Cells; Dendritic Cells] and inhibits BBB penetration [decrease in matrix matalloproteinase]
  • delays the CIS
  • Decrease Antibodies
29
Q

What is the function of Glatiamer Acetate?

A
  • MOA: Synthetic polypeptide that mimics antigenic properties of myelin; modulates antigen-presenting cells = inhibiting lymphoctyes periphery [T Cells; Dendritic Cells]
  • Delays the CIS
  • Could be use in Pregnancy
  • Lipoatrophy
30
Q

What is the function of Fingolimod?

A
  • MOA: Sphingosine-1-Phosphate agonist; stimulates olgiodendrocyte survival in CNS; inhibits lymphocytes out of lymphoid organs in periphery
  • Approved for RRMS
  • SE: cardiotoxicity, fatal encephalitis, PROGESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY [PML]
31
Q

What is the function of Natalizumab?

A
  • MOA: a monoclonal antibody that acts on a4-integrin making VLA-4 which stops B- and T-Cells from crossing into BBB
  • SE: PML
  • Increases neutralizing antibodies
32
Q

What is the function of Mitoxantrone?

A
  • MOA: Reduces lymphocyte number by causing DNA breaks and delaying DNA repair via inhibiting topoisomerase II in the periphery [Cytotoxic Effect]
  • First Cytotoxic Drug for SPMS
  • Need a - Pregnancy test
33
Q

What is the function of Terifluomide?

A
  • MOA: Cytotoxic Agent that inhibits dihydroorotate dehydrogenase that inhibits proliferation of peripheral lymphocytes [B- and T-Cells]
  • SE: Hepatotoxicity and Teratogenicity
34
Q

What is the function of Dimethyl Fumarate?

A
  • MOA: Metabolizes esterases that will activate NrF2-mediated antioxidant responses and anti-inflammatory pathways and promote remyelination in CNS; suppress T-Cells/Dendritics Cells in the Periphery
  • SE: PML
35
Q

What is the function of the new “imods”?
[Siponimod, Ozanimod, Ponesimod]

A
  • MOA: Sphingosine-1-Phosphate Agonist; Stimulates oligodendrocyte survival in the CNS; inhibits lympocyte movement out of lymphoid organs peripherally
  • For RRMS and SPMS
  • SE: PML?
  • Ozanimod: AVOID with MAO-I
  • Siponimod: need 2C9 genotyping
36
Q

What is the function of Cladribine?

A
  • Phosphorylated to the triphosphate form of 2-chloro-dATP; 2-chloro-dATP damages DNA causing cell death and decrease in lymphocyte depletion
  • cytotoxic agent
37
Q

What is the function of Ocrelizumab [Rituximab] in MS?

A
  • Monoclonal antibody that targets CD20 [marker for mature B-Cells] so that immune functions are unperturbed
  • Decreases progression in PPMS and relapse rate in RRMS
38
Q

What is the function of Firategrast in MS?

A
  • MOA: Small molecule that targets a4-Integrin, limiting the movement of B- and T-Cells into the CNS
39
Q

What is the function of Amiloride in MS?

A
  • MOA: Small molecule that targets the ASIC-1, which is responsible for neurotoxic levels of Ca2+ in the CNS; Blocking this could increase neuroprotective effects
40
Q

What is the function of Laquinimod in MS?

A
  • MOA: produces immunomodulatory effects and may up-regulate brain derived neurotrophic factors in the CNS; increasing to Neuroprotective effects
41
Q

What is the diagnostic for Multiple sclerosis?

A
  • NO single feature
  • Dissemination in Time & Dissemination in Space
42
Q

What is Dissemination in Time in Multiple Sclerosis?

A
  • The time between new lesions; damage that happens more than once
43
Q

What is Dissemination in Space in Multiple Sclerosis?

A
  • Multiple lesions in 2 of 4 CNS regions; damage that is in more than one place
44
Q

What are the different types of Multiple Sclerosis?

A
  • Clinically Isolated Syndrome [CIS], Relapsing Remitting MS [RRMS], Secondary Progessive MS [SPMS], Primary Progressive MS [PPMS], Progressive Relapsing MS [PRMS]
45
Q

What is Clinically Isolated Syndrome [CIS] in Multiple Sclerosis?

A
  • The firest demyelinating event that occurs; inflammation that crosses the threshold
46
Q

What is Relapsing Remitting Multiple Sclerosis [RRMS]?

A
  • RRMS: Relapses and partial to complete remissions of the inflammation during the disease; slowly progressing over time
  • Most Common
47
Q

What is Secondary Progressive Multiple Sclerosis [SPMS]?

A
  • SPMS: Usually starts out as RRMS with less relapses/remissions overtime to where there is none and its constant disabilty
48
Q

What is Primary Progressive Multiple Sclerosis [PPMS]?

A
  • PPMS: Start out with the slow progression over time BUT there are NO relapses/remissions that occur ever
49
Q

What is Progressive Relapsing Multiple Sclerosis [PRMS]?

A
  • PRMS: Starts out as PPMS [slow progression with constant disability] but laters has relapses with NO remission
50
Q

What is the EDSS in multiple sclerosis?

A
  • The Expanded Disability Status Scale: Measures the degree of disability
51
Q

What are the different ranks of the EDSS

A
  • 0: Normal
  • 1: NO disability
  • 2: Minimal disability
  • 3: Moderate disability
  • 4: Severe disability
  • 5: disability affects daily activities [cane]
  • 6: assistance to walk & work [walker]
  • 7: Restricted to [Wheelchair]
  • 8: Restricted to [Bed or wheelchair]
  • 9: Bedridden
  • 10: Death
52
Q

What are some of the goals of treatment for Multiple Sclerosis?

A
  • Start Early [Hopefully stall the deneurogeneration], Acute Treatment [treat relapses better and promote complete remission], Disease Modifying Drugs [Start at CIS]
53
Q

What is the treatment for the acute attacks in Multiple Sclerosis?

A
  • High dose Corticosteroids is the 1st line
  • Methylprednisolone 500-1000mg IV daily
  • OUTPATIENT: Prednisone 1250mg every other day x 5 doses
54
Q

What are some of the markers that show treatment failure in Multiple Sclerosis?

A
  • No decrease in Relapse rate [hard to determine]
  • Acquiring Disabilities [EDSS INCREASE]
  • MRI Activity [more and more lesions forming]
55
Q

What are the oral medications that are used in treating Multiple Sclerosis?

A
  • Dimethyl Fumurate, Fingolimd, Ozanimod, Ponesimod, Siponimod, Terfluonimide
56
Q

What are the injectable medications that are used in treating Multiple Sclerosis?

A
  • Interferon b1a, Peginterferon b1a, Interferon b1b, Glatiramer Acetate
57
Q

What are the infusion medications that are used in treating Multiple Sclerosis?

A
  • Alemtuzumab, Natalizumab, Ocrelizumab
58
Q

What is Progressive Multifocal Leukowncephalopathy [PML]?

A
  • Rare, reactivition of JCV; causing the cells that produce myelin to break down, looking similar to MS relapse
  • Patients MUST be tested for JCV
59
Q

What type of vaccines can and/or should be given to a patients that has multiple sclerosis?

A
  • Inactivated vaccines given 6 WEEKS before any drug therapy
  • Live, attenuated are not recommended [could still get the disease]
  • Varicella for those who haven’t have chicken pox with MS
60
Q

What are the important things to note about using Dimethyl Fumarate in Multiple Sclerosis?

A
  • Capsule SHOULD NOT be opened
  • Monitor for Hepatotoxicity and increase risk of infections
  • PML
61
Q

What isimportant to know about the Sphingosine-1-Phosphate Receptor modulators in Multiple Sclerosis?

A
  • Fingolimod, Ozanimod, Ponesimod, Siponimod
  • CONTRAINDICATED: arrhythmias; any CV issue in the last 6 months
  • Monitor: Bradycardia, Infections, Macular edema
  • Ozanimod: AVOID with MAO inhibitor
62
Q

What is important to know about Glatiramer Acetate in Multiple Sclerosis?

A
  • Injection site reactions: Flushing, Sweating, Dyspnea, Chest Pain, Anxitey, Itching
  • Rotate injection sites: DECREASE Lipoatrophy
  • Maybe used in pregnancy
63
Q

What is important to know about Interferons in Multiple Sclerosis?

A
  • 1st line treatment
  • Can develop flu like symptoms - pretreat with acetaminophen or an NSAIDS
  • Depression, Suicidal Thinking
64
Q

What is important to note about taking teriflunomide during pregnancy in Multiple Sclerosis?

A
  • CONTRAINDICATED
  • Takes 2 years to fully eliminate; take cholestyramine or activated charcoal for 2 week elmination
65
Q

What is important to note about taking mitoxatrone during pregnancy in Multiple Sclerosis?

A
  • Contraceptive and negative test required

PHRM 845: Therapeutics III (25 decks)

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