MS (MC) - Block 1 Flashcards
What are the tx options for acute exacerbations?
Start with corticosteroids
Mild: Oral prednisone or prednisolone
Severe, acute: IV methylprednisolone (Solu-Medrol)
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
What are the adrs for Steroids?
- Cushing’s syndrome (chronic use)
- GI distress
- Impaired skin healing
- Hypertension
- Adrenal insufficiency
- Hyperglycemia, steroid diabetes
What are the cautions of long term steroid use?
Not used for prevention (or disease modifying therapy)
Are disease modifying therapies a cure for MS?
Not a cure still prone to relapse and progressive damage
All are immunomodulating agents
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
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
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
Plegridy
MOA
Pegylated interferon β-1a: PEG is attached to interferon -> longer duration SQ 2W
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)
Glatiramer Acetate Injection
Brand
Glatopa: generic equialent to Copaxone
Describe the number of inj for ABCs?
What is an examples of home injectable therapy?
Ofatumumab (Kesimpta)
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
What are the benefits of oral MS tx?
Increased adherence and easier admin
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
- Increases risk of progressive multifocal leukoencephalopathy (PML)
- Risk includes having antibodies to John Cunningham Virus (JCV)
What are the sx of PML?
- Personality changes
- Changes in thinking and memory
- Onset of seizures
- 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
