MS (MC) - Block 1 Flashcards by Hannah Lapos

What are the tx options for acute exacerbations?

Start with corticosteroids
Mild: Oral prednisone or prednisolone
Severe, acute: IV methylprednisolone (Solu-Medrol)

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MOA of steroids?

Inhibit leukocyte infiltration at site of inflammation, interfere with mediators of inflammatory responses and suppress humoral immune responses
* Reduce edema in area of demyelination
* Reduce BBB abnormalities and reduce CSF IgG synthesis

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What are the adrs for Steroids?

Cushing’s syndrome (chronic use)
GI distress
Impaired skin healing
Hypertension
Adrenal insufficiency
Hyperglycemia, steroid diabetes

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What are the cautions of long term steroid use?

Not used for prevention (or disease modifying therapy)

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Are disease modifying therapies a cure for MS?

Not a cure still prone to relapse and progressive damage

All are immunomodulating agents

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What are ABC therapies?

β-interferons and copaxone (ABCs of MS therapy):
* Home injectable treatments for relapsing-remitting MS (RRMS)
* likely shift from Th1 (pro-inflammatory) to Th2 (anti-inflammatory) cytokine profile

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Interferon β-1b

Brand, Structure, MOA, ADR, Monitor, stabilizer

Betaseron, Extavia
Structure: 165 amino acid analog of human Interferon-β
* Cys17 -> Ser
* Also not glycosylated
* Produced in recombinant E.coli

MOA:
* Decreased expression of pro-inflammatory cytokines
* Decreases expression of class II MHC antigens
* Inhibition of helper T-cells

ADR: Inj site rednness and swelling, flu-like sx
* Therapy may cause patients to feel worse initially -> Can apply ice before and after to injection site to decrease redness/pain
* NSAIDs at regular intervals for 24 hrs after administration may help with flu-like symptoms

Moniotr:
* CBC, platelets, LFTs 1,3, 6 months
* THyroid function preiodically

Stabilizer: dextrose and albumin

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Interferon β-1a

Brand, Structure, Stabilizers, ADR, Dosing, Monitoring

Avonex, Rebif
Structure: Same amino acid sequence as human IFN-β
Stabilizer: Albumin, sodium chloride and phosphate buffer (do not shake)
ADR: Inj site rednness and swelling, flu-like sx
Dosing:
* Avonex: QW IM
* Rebif: 3W SC

Monitoring: Hb, liver and thyroid function, blood chemistries

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Plegridy

MOA

Pegylated interferon β-1a: PEG is attached to interferon -> longer duration SQ 2W

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Glatiramer Acetate

Brand, MOA, Indication

Copaxone
MOA: Mix of synthetic polypeptides that modifies immune processes responsible for MS (TH1 to TH2 shift)
* Might also serve as decoy to locally generated auto-antibodies

Indication: Decreases frequency of attacks and severity of disability in RRMS (minimal disabilitiy)

ADR: generally well tolerated, inj site reaction
* Immediate post inj rx: facial flushing, chest pain, dyspnea, throat constriction, palpitations, anxiety (Usually benign and self-limiting)

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Glatiramer Acetate Injection

Brand

Glatopa: generic equialent to Copaxone

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Describe the number of inj for ABCs?

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What is an examples of home injectable therapy?

Ofatumumab (Kesimpta)

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Ofatumumab

Brand, MOA

Kesimpta
MOA: Fully human 149 kDa IgG1κ anti-CD20 Mab
* Binds to CD20 on B–cells -> B-cell lysis

ADR: Upper respiratory tract infections, inj-related rx
* Progressive multifocal leukoencephalopathy (PML), Hepatitis B virus (HBV) reactivation

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What are the benefits of oral MS tx?

Increased adherence and easier admin

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Describe the MOA of Sphingosine 1-phosphate (S1P) receptor modulator?

Causes internalization of receptor:
* Blocks release of lymphocytes from lymph nodes and thymus, reducing number in the blood
* Prevents activated and autoreactive cells from migrating to the CNS

What are the S1P receptor modulators?

Fingolimod
Siponimod
Ozanimod
Ponesimod

S1P Receptor Modulators

ADR, Metabolism

ADR: HA, high BP, abnormal liver tests, increased infection
Metabolsim: CYP450s
* Siponomod – contraindicated in patients with CYP2C93/3 genotype (may require reduced dosing)

What are cardiac effects of S1P receptor modulators?

Bradycardia, prolongation of QT interval
* Requires cardiac monitoring for 6 hours after first dose
* Contraindicated in patients with cardiac conditions

Terflunomide

MOA, ADR

MOA: Inhibits dihydroorotate dehydrogenase (enzyme in pyrimidine synthesis) -> inhibits T-cell and B-cell division
* Decrease in number of activated lymphocytes in CNS
* active metabolite of leflunomide

ADR: elevation of liver enzymes, reduced WBC, teratogenic
* May be up to 2 years before plasma levels decrease to sufficient amount

Cladribine

MOA, ADR

MOA: Purine nucleoside analog prodrug – activated by deoxycytidine kinase
* Causes failure of DNA damage repair
* High levels of deoxycytidine kinase in T-cells and B-cells
* Reduces levels of pro-inflammatory chemokines

ADR: upper respiratory tract infection, lymphopenia, malignancy
CI: Patients who have reproductive potential with no effective contraception

Dimethyl fumarate

MOA, ADR

MOA: Prodrug converted to monomethyl fumarate
* May activate nuclear factor (erythroid-derived 2)-like 2 (NRF-2) transcriptional pathway that reduces oxidative stress from demylination and anti-inflammatory

ADR: flushing, lymphopenia, N, diarrhea

What is the active fumarate metabolite?

Monomethyl Fumarate

What are the fumarates>

Dimethyl Fumarate
Monomethyl Fumarate
Diroximel Fumarate

What is the difference betwen monomethyl and diroximel fumarate?

Diroximel fumarate = delayed-release oral capsules and metabolized to mono

MOA of Natalizumab

Humanized IgG4 monoclonal antibody binds to a4-subunit of a4b1 and a4b7 integrins expressed on leukocyte surface * Inhibits α4-mediated adhesion of leukocytes to cognate receptor * Blocks entry into brain

Natalizumab | ADR

1. Increases risk of progressive multifocal leukoencephalopathy (PML) 2. Risk includes having antibodies to John Cunningham Virus (JCV)

What are the sx of PML?

1. Personality changes 2. Changes in thinking and memory 3. Onset of seizures 4. Disturbances in vision

Alemtuzumab | MOA, DOsing, ADR

**MOA:** rDNA-derived humanized IgG1κ mAB specific for CD52 * Depletes autoimmune inflammatory T and B cells **Dosing:** Round 1 – one infusion/day on 5 consecutive days * Round 2 (1 year later and following years) – one infusion/day on 3 consecutive days **ADR:** Infusion rx, Graves * Patients become lymphopenic so monitor for opportunisitc infections and hematologic tox

Ocrelizumab | MOA, Monitoring, ADR

Humanized IgG Mab targeting CD20 on B lymphocytes **Monitoring:** B-cell depletion can increase risk of infections * If patients become hypogammaglobulinemic -> immunoglobulin replacement therapy **ADR:** infusion rx, increases risk of cancer

What is the MOA of chemotherapeutic agents?

Myelin damage caused by autoimmune response -> chemo can shorten attacks and slow progression by suppressing the immune system

Mitoxantrone | MOA, ADR, BBW

**MOA:** Suppressed activity of T-cells, B-cells and macrophages **ADR:** Serious side effects (last resort drugs) * N, alopecia, menstrual dx, infections **BBW:** leukemia, arrhythmias, cardiotox and CHF, hepatotox, and renal tox

What are considered first line chemo drugs (characterisitcs)?

Less potent and burden of tx

Summary of MS drugs?

What is the tx for spasticity?

Requires pharm but should avoid CNS muscle relaxants

What are the med for spaciticty?

Baclofen and dalfampridine

Baclofen | MOA, ADR, Counseling

**MOA:** GABAB receptor agonist * Inhibit presynaptic neurons – reduce Ca2+ influx and hyperpolarizing the cell via K+ efflux * Suppresses excitability by reducing calcium persistent inward currents in spinal motor neurons **ADR:** sedation, n, vertigo **Conseling:** withdrawl can occur * If abruptly discontinue can cause seizures, anxiety, tachycardia, hallucinations, increased spasticity

Dalfampridine | Indication, MOA, CI

**Indication:** manages walking impairment **MOA:** K+ channel blocker **CI:** Hx of seizures, moderate-severe renal impairment