PHRM 845: Therapeutics III > Multiple Sclerosis > Flashcards

Multiple Sclerosis Flashcards

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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
What are the 3 categories of treatment in MS?
- Acute attacks, Disease-Modifying Treatment, Symptomatic
26
What are the drugs used to treat Acute Attacks?
- Corticosteroids [Methyprednisolone, Prednisone, ACTH - Act by up-regulating anti-inflammatory genes and down-regulating pro-inflammtory genes = DECREASE INFLAMMATION
27
What are the Disease modifying drugs in MS?
- First Line: Interferon B1a, Interferon B1b, Glatiramer Acetate, Fingolimod - Second Line: Natalizumab, Mitoxantrone - New Drugs: Teriflunomide Dimethyl Fumarate, Cladribine
28
What is the function of the Interferons?
- MOA: inhibit lymphocytes in periphery [T Cells; Dendritic Cells] and inhibits BBB penetration [decrease in matrix matalloproteinase] - delays the CIS - Decrease Antibodies
29
What is the function of Glatiamer Acetate?
- 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
What is the function of Fingolimod?
- 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
What is the function of Natalizumab?
- 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
What is the function of Mitoxantrone?
- 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
What is the function of Terifluomide?
- MOA: Cytotoxic Agent that inhibits dihydroorotate dehydrogenase that inhibits proliferation of peripheral lymphocytes [B- and T-Cells] - SE: Hepatotoxicity and Teratogenicity
34
What is the function of Dimethyl Fumarate?
- 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
What is the function of the new "imods"? [Siponimod, Ozanimod, Ponesimod]
- 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
What is the function of Cladribine?
- 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
What is the function of Ocrelizumab [Rituximab] in MS?
- 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
What is the function of Firategrast in MS?
- MOA: Small molecule that targets a4-Integrin, limiting the movement of B- and T-Cells into the CNS
39
What is the function of Amiloride in MS?
- 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
What is the function of Laquinimod in MS?
- MOA: produces immunomodulatory effects and may up-regulate brain derived neurotrophic factors in the CNS; increasing to Neuroprotective effects
41
What is the diagnostic for Multiple sclerosis?
- NO single feature - Dissemination in Time & Dissemination in Space
42
What is Dissemination in Time in Multiple Sclerosis?
- The time between new lesions; damage that happens more than once
43
What is Dissemination in Space in Multiple Sclerosis?
- Multiple lesions in 2 of 4 CNS regions; damage that is in more than one place
44
What are the different types of Multiple Sclerosis?
- Clinically Isolated Syndrome [CIS], Relapsing Remitting MS [RRMS], Secondary Progessive MS [SPMS], Primary Progressive MS [PPMS], Progressive Relapsing MS [PRMS]
45
What is Clinically Isolated Syndrome [CIS] in Multiple Sclerosis?
- The firest demyelinating event that occurs; inflammation that crosses the threshold
46
What is Relapsing Remitting Multiple Sclerosis [RRMS]?
- RRMS: Relapses and partial to complete remissions of the inflammation during the disease; slowly progressing over time - Most Common
47
What is Secondary Progressive Multiple Sclerosis [SPMS]?
- SPMS: Usually starts out as RRMS with less relapses/remissions overtime to where there is none and its constant disabilty
48
What is Primary Progressive Multiple Sclerosis [PPMS]?
- PPMS: Start out with the slow progression over time BUT there are NO relapses/remissions that occur ever
49
What is Progressive Relapsing Multiple Sclerosis [PRMS]?
- PRMS: Starts out as PPMS [slow progression with constant disability] but laters has relapses with NO remission
50
What is the EDSS in multiple sclerosis?
- The Expanded Disability Status Scale: Measures the degree of disability
51
What are the different ranks of the EDSS
- 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
What are some of the goals of treatment for Multiple Sclerosis?
- Start Early [Hopefully stall the deneurogeneration], Acute Treatment [treat relapses better and promote complete remission], Disease Modifying Drugs [Start at CIS]
53
What is the treatment for the acute attacks in Multiple Sclerosis?
- High dose Corticosteroids is the 1st line - Methylprednisolone 500-1000mg IV daily - OUTPATIENT: Prednisone 1250mg every other day x 5 doses
54
What are some of the markers that show treatment failure in Multiple Sclerosis?
- No decrease in Relapse rate [hard to determine] - Acquiring Disabilities [EDSS INCREASE] - MRI Activity [more and more lesions forming]
55
What are the oral medications that are used in treating Multiple Sclerosis?
- Dimethyl Fumurate, Fingolimd, Ozanimod, Ponesimod, Siponimod, Terfluonimide
56
What are the injectable medications that are used in treating Multiple Sclerosis?
- Interferon b1a, Peginterferon b1a, Interferon b1b, Glatiramer Acetate
57
What are the infusion medications that are used in treating Multiple Sclerosis?
- Alemtuzumab, Natalizumab, Ocrelizumab
58
What is Progressive Multifocal Leukowncephalopathy [PML]?
- 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
What type of vaccines can and/or should be given to a patients that has multiple sclerosis?
- 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
What are the important things to note about using Dimethyl Fumarate in Multiple Sclerosis?
- Capsule SHOULD NOT be opened - Monitor for Hepatotoxicity and increase risk of infections - PML
61
What isimportant to know about the Sphingosine-1-Phosphate Receptor modulators in Multiple Sclerosis?
- 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
What is important to know about Glatiramer Acetate in Multiple Sclerosis?
- Injection site reactions: Flushing, Sweating, Dyspnea, Chest Pain, Anxitey, Itching - Rotate injection sites: DECREASE Lipoatrophy - Maybe used in pregnancy
63
What is important to know about Interferons in Multiple Sclerosis?
- 1st line treatment - Can develop flu like symptoms - pretreat with acetaminophen or an NSAIDS - Depression, Suicidal Thinking
64
What is important to note about taking teriflunomide during pregnancy in Multiple Sclerosis?
- CONTRAINDICATED - Takes 2 years to fully eliminate; take cholestyramine or activated charcoal for 2 week elmination
65
What is important to note about taking mitoxatrone during pregnancy in Multiple Sclerosis?
- Contraceptive and negative test required
PHRM 845: Therapeutics III
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