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100 Cards in this Set
- Front
- Back
properties of MS (including diagnosis, cause, disease duration, etc.) (5)
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•Chronic, unpredictable disease of the CNS
•Variable from patient to patient •Lifelong disease (does not kill the patient or shorten life but pt may die of co-morbidities) •Exact cause of disease still unknown •Diagnosis of exclusion!!! |
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4 subsets of MS and incidence relatively
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1) most are relapsing-remitting- attacks then fine (flat line/periods of stability- never go back to baseline)
2) then primary progressive (aggressive/no recovery) 3) Secondary progessive disease (1/2 pts with relapsing/remitting will go on to this type of disease- turns into progressive disease) 4) then progressive relapsing |
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age of onset of MS
gender (2) |
20-50 yo (child bearing age)
female > male but male more disabling (primary progressive |
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genetics/triggers of MS (3)
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Multiple genes involved
•Plus virus •Plus environmental factor |
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risk factors/helpful factors of MS (6)
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•Sunlight exposure and vitamin D decrease risk
•Vitamin D intake •Cigarette smoking- worsens •Dietary fat- worsens •Dietary antioxidants- slows progression •Sex hormone- estrogen worsens progression |
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latitude and MS
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higher latitudes = higher prevalence...might be due to sunlight
if kids...born in northern latitude move to texas or w/e they adopt risk of texas |
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viruses and MS patients titres (2)
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Peripheral blood antibody titers to many viruses are elevated in MS
•Sometimes detected in CSF |
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5 viruses linked to MS
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Varicella zoster
•Vaccinia •Rubella •Epstein-Barr •Human herpes virus 6 (HHV-6) |
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pathophys of MS (5)
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1.Autoimmune response to trigger
2.Myelin seen as foreign antigen 3.T cells cross blood brain barrier → attack myelin → additional T-cell activation 4.Cytokines released, causing myelin and axonal damage 5) signal interrupted as it goes down damaged mylein |
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2 "components" to the pathophys damage of MS and what characteristics of MS they coincide with
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•Inflammatory component- Coincides with relapsing features of the disease
•Neurodegenerative component (axons and neurons)- coincides with Progressive, slow, worsening of disease |
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damage to CNS with MS (5) types of dmg i guess
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•Permanent damage accumulates
•If patient stable but untreated, damage continues to build •Macroscopic and microscopic damage •White inflammatory lesions on MRI scan •Up to 70% of brain tissue is abnormal (microscopic dmg) |
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sx of MS starting with highest incidence (6)
typical presentation in a pt |
Variable:
Fatigue- most common Difficulty walking stiffness/spasms cognitive bladder pain (paresthesia, neuralgia) mood problems vision problems (inflamed optic neuritis) just...anything nerve related (see list) |
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what is the EDSS? describe the scoring a little
used for what |
EDSS- disability status scale
0-4 = no disability/normal/not much difference 6 = assistance required to walk 7 = wheelchair 9 = highest...confined to bed 10 = death done in neuro clinic to guide therapy |
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tx goals of MS (5)
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•Reduce number of relapses
•Prevent disability progression •Minimize new MRI lesions •Manage symptoms •Restore functions •Maintain or improve quality of life |
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definition of acute relapse (4) + sx type, duration, frequency
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•IS a Exacerbation or attack
•with new or recurring symptoms •Lasting more than 24 hours •Separated by 1 month |
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what is NOT rec'd for acute relapse (2)
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•Low-dose oral steroids not recommended- not effective
•Chronic daily corticosteroids not rec'd; does not affect rate of relapse |
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regimen for acute relapse/drug/route
another more conservative approach |
•Methylprednisolone 500-1000 mg IV q24h x 3-5 days ± prednisone taper x 1-3 weeks
•another approach is to Wait and see if minor relapse (just sensory sx, not physical disability) |
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main 3 AE with IV methylpred (for acute relapse)
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•Adverse effects: GI distress, hyperglycemia is big, mood swings
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what is optic neuritis
relationship to MS |
inflammation of optic nerve
"hallmark" sx of MS?? |
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ONTT trial- what was it measuring, what were the arms, what did it show
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ONTT (optic neuritis trial)
tx'd with low dose pred oral (1mg/kg/day) methyl pred IV placebo 6 month visual assesssments- primary endpoints: visual field and contrast sensitivity found oral pred same as placebo- only beneficial was IV high dose methylpred |
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doses of methylpred used in ONTT trial
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Methylprednisolone 1 g/day IV x 3 days, then prednisone 1 mg/kg/day po x 11 days
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ONTT iv HD steroids results
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•Visual function recovered faster with IV therapy
•At 6 months- improved BETTER •Improved visual fields •Improved contrast sensitivity •Improved color •Visual acuity same |
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in ONT if steroids ineffective? what to do? (evidence and frequency/number of tx)
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Consider plasma exchange (PLEX)
•Small studies show benefit1-2 •Faster symptom resolution in relapsing forms of MS •Typically q48h x 7 treatments |
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1st line Disease Modifying Therapies- type of drug
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Immunomodulators in relapsing-remitting MS
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clinical benefits of DMTs (6)
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•↓ number of relapses, severity
•↑ time between relapses •↑ number of patients relapse-free •↓ disability and worsening on neuro exam •↑ quality of life •↓ MRI lesion formation, size, and severity |
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4-5 DMTs for MS
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interferons
enter rest |
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what are interferons? (2)
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Family of naturally occurring proteins
•Respond to viral infection and other biologic agents |
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3 groups of interferons
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IFN-1a/b??
IFN-2 (gamaa) |
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what does interferon beta do (4)
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•Enhances of suppressor T-cell activity
•Reduces proinflammatory cytokine production •Downregulates antigen presentation •Inhibits lymphocyte migration into CNS |
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idk...list of FDA approved meds for MS...
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betaseron- now has generic (oldest)
avonex copaxone rebif tysabri gilenya aubagio extavia** idk this is betaseron as a generic...or something |
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interferon beta-1b: name of drug
contains what made from what |
betaseron/extavia
•Recombinant DNA from E. coli •Contains human albumin- NO JENOVAS WITNESS |
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beta(b1)seron- dosing and route
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•Dose = 0.25 mg SQ q48h
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6 ADR from betaseron
1 ADR that applies to all interferons |
•Most common ADRs: Injection site reaction/necrosis (lipoatrophy), lymphopenia, asthenia (weakness), flu-like symptom complex, headache, and pain
•All interferons have increased risk of depression and suicide |
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names for interferon beta 1a (2 of them)
similarity to human IFN-b, and contains what what is it made from |
Rebif/avonex (not bioequivalent)
•Recombinant DNA from genetically engineered from chinese hamster ovary cells!! •Identical to natural human IFN-β has human albumin |
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6 most common ADR with IFN-b-1a
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•Injection site reactions (most problematic with 1a), fatigue, flu-like illness, headache, abnormal LFTs, depression
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IFN-b-1a routes of admin (2)
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•Rebif SQ
•Avonex IM |
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monitoring for IFN-b-1a/1b
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CBC with platelets and LFTs at baseline, at 1 month, then q3months x 1 year, and q6months thereafter
due to transaminitis (2/3 of pt with elevated LFTs) most common with betaseron and rebif but also with avonex Thyroid too must be monitored (can cause hypothyroid) watch for immunogenecity (neutralizing ab that make drug ineffective) |
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IFN b 1a/1b pregnancy category
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C
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IFN b 1a/1b DDIs?
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DDIs: no formal drug interaction studies conducted...body has interferons so probably not?
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counseling points
and storage (betaseron, avonex, rebif) |
SQ or IM injection technique
•Storage •Betaseron & Extavia: room temp. •Avonex: refrigerator, good for 7 days at room temp. •Rebif: refrigerator, good for 30 days at room temp. |
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INCOMIN study: type of study, studying what type of MS
Arms duration |
Prospective, randomized, multicenter study
•Relapsing-remitting MS duration 2 years arms- betaseron vs. avonex (1a) |
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INCOMIN study primary endpoints (2)
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Proportion of patients free from relapses
•Free from new proton density lesions on MRI |
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results of INCOMIN
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proportion of pts relapse free: betaseron looks better...
pts remaining lesion free: same |
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EVIDENCE trial: type of trial, arms, duration
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Randomized, controlled, multicenter trial for relapsing/remit MS comparing rebif to avonex for 24 weeks (both 1a)
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EVIDENCE primary endpoint
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Proportion of patients who were relapse free at 24 weeks
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results of EVIDENCE (2)
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avonex worse than rebif for recurrence of relapses
HOWEVER rebif more portent...more adverse effects |
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2 effects of neutralizing ab on interferons
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Reduce bioavailability and clinical efficacy of interferons
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betaseron, avonex, rebif and incidence of creating neutralizing antibodies
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betaseron has highest risk of neutralizing antibodies- avonex lowest risk
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what is copaxone (generic name and structure)
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Random polymer of 4 amino acids
glatiramer acetate |
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MoA of copaxone (3)
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•Mechanism of action not fully understood
•Modifies immune processes •Induces and activates suppressor T cells |
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dosing of copaxone
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20 mg sq q24h
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storage of copaxone
how long is it good for |
Store in refrigerator
•Good for 1 month at room temperature |
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advantages of copaxone (3)
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•No routine laboratory monitoring
•Pregnancy category B •Useful in patients with depression (not an interferon) |
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disadvantages of copaxone (3)
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•first dose usually given in clinic: ~ 10% of patients experience a one-time, transient (less than 20 minute) reaction consisting of chest tightness, flushing, and dyspnea beginning several minutes after injection (heart attack-y)
•Lipoatrophy may occur at injection site •Immunogenicity potential |
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copaxone: DDIs, renal function
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•No formal drug interactions studies conducted
•Not tested in patients with impaired renal function |
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AE of copaxone (9) 2 main ones
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injection site reactions**, chest pain with first dose
vasodilatation, infection, pain, nausea, arthralgia, anxiety, and hypertonia (these might just be related to disease state) |
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4 first line agents for MS
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avonex
betaseron rebif copaxone |
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trial comparing all 4 first line agents- type of study
primary endpoint |
Retrospective, open-label study
reduction of relapse rates at 24 months |
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first line agents- WHICH WAS BEST?? in trial..
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copaxone won
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newer first line? agent for MS
route |
Teriflunomide (Aubagio)
oral- ONLY ORAL AGENT |
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what is teriflunomide (structure)
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Active metabolite of lefluonomide
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teriflunomide- dosing used in trials
results of trials |
Teriflunomide 7 or 14 mg po daily vs. placebo x 2 years
•30% decrease in annual relapse rate |
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AE of teriflunomide (3)
monitoring |
N/V/D, ↑ LFTs, alopecia
•Monthly LFTs for at least 6 months |
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teriflunomide- preg cat
issues with pregnancy (how long dose it last?) drug you can give to help clear drug |
Pregnancy category X for both men and women
•Detectable up to 2 years after last use •Cholestyramine can increase CL |
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2nd line therapy for MS
used only as... |
Natalizumab (Tysabri)
Monotherapy only with REMS program |
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why was tysabri pulled off market
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toxicity: PML- posterior multifocal L..? when used as dual therapy
attack of the body against neurons (viral?) |
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what is natalizumab (2)
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•Recombinant humanized monoclonal antibody to α4 integrin
•Adhesion molecule expressed on leukocytes that allows the binding to blood vessels and penetration into body organs |
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MoA of natalizumab (2)
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•Specific MOA not fully defined
•Thought to prevent leukocytes from crossing blood brain barrier |
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AE of natalizumab: long ass list
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Headache, fatigue, arthralgia, UTI, lower respiratory tract infection
gastroenteritis, vaginitis, depression (not to same extent as interferon) didn't talk about these: pain in extremity, abdominal discomfort, diarrhea, and rash |
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AFFIRM Trial (2)
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natalizumab 300 mg IV q4weeks for 2 years
reduced relapse by 68%!!! |
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natalizumab storage
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Refrigerate
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dosing of natalizumab
administer within how long infusion time monitor for what |
300 mg IV q4weeks
•Administer within 8 hours of preparation •Infuse over 1 hour •Monitor for infusion reaction |
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natalizumab monitoring (2)
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infusion reaction
LFTs monthly |
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major precautions of natalizumab (2)
must be enrolled in what program |
•Increased risk for infection
•BBW: Risk of progressive multifocal leukoencephalopathy (PML) •Must be enrolled in Tysabri Outreach: Unified Commitment to Health (TOUCH) program- pt, prescriber and parmacy must be enrolled |
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tysabri only to be used for...
assess risk for what before giving CI with what drug |
•For use in relapsing MS in patients with inadequate response or intolerance to other therapies
•Assess for risk of PML •Contraindicated with immunosuppressants |
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tysabri only to be dispensed where?
who must be enrolled |
Only dispensed at registered infusion centers
•Doctors, pharmacies, and patients must be enrolled |
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what is gilenya (generic, and what is it) (3)
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Fingolimod
•Sphingosine analogue •Modulates sphingosine-1-phosphate receptor to alter lymphocyte migration •Lymphocytes sequestered in lymph nodes and can't get into CNS |
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gilenya route of admin
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oral!
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TRANFORMS trial
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gilenya- showed it halved relapse rate compared to IF
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common AE of gilenya (6)
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headache, influenza, diarrhea, back pain, LFTs, cough
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gilenya- must get baseline what? (4) and their assoc. AEs
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CBC (leukopenia) /LFT/ocular exam (macular edema)/EKG (bradycardia/AV block)
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5 CIs to gilenya
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if ACS or TIA/CVA within 6 months, HF, QTc prolongation, preexisting 2nd-3rd degree heart block or antiarrhythmic use
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why gilenya sucks
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TOO MANY AEs
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infections and gilenya- 2 you have to worry about, and one...other...not infection..thing
how to prevent.. |
Tumor development
Varicella- someone died in trial from this •Zoster vaccination > 1 month BEFORE starting fingolimod •PML |
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Mitoxantrone (Novantrone) line of therapy
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2nd-line therapy in relapsing forms of MS
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mitoxantrone- what is it? (type of...class..of drug)
MoA (3) |
Anthracycline- CHEMO WOO
•Inhibits B-cell, T-cell, and macrophage proliferation •Impairs antigen presentation •Decreases IFN-γ, TNF-α, and IL-2 |
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ok mitoxantrone is an anthracycline...remember the major dose limiting shit with this drug?
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Lifetime maximum of 140 mg/m² due to cardiotoxicity which can occur at any time but significantly increased with increased cum dose
so..never really caught on. pretty last line. |
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cardiotox issues with mitoxantrone- what happens?
assess for what at baseline avoid if... |
•Heart failure months to years after stopping
•Assess for cardiovascular problems with baseline EKG and LVEF •Avoid if EF < 50% |
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how is mitoxantrone dosed
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5-15 minute infusion q3months- so cheaper
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AE of mitoxantron 7
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chemo! so...
Nausea, alopecia, infections, EKG abnormalities, diarrhea, back pain, headache |
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5 precautions with mitoxantrone
what must you monitor |
HF, CV disease, LVEF < 50%, blood abnormalities, liver disease (how it's cleared)
Monitor LFTs |
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consensus algorithm for MS (4 steps and when you would give each drug)
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consensus for MS (2008)
1) start with IFN beta or copaxone (either is fine) 2) initiate if definite dx of relapse/remit MS (remember dx of exclusion) or if high risk pt with first attack (optic neuritis) 3) then natalizumab if inadequate response/unable to tolerate 1st line 4) reserve mitoxantrone for worsening disease despite tx or secondary progressive MS |
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other drugs that have been studied in MS (6)
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•Alemtuzumab
•Azathioprine- feh •Cyclophosphamide •Daclizumab- pulled off market •Rituximab- quasi decent data |
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Dalfampridine (Ampyra™) what dis (moa...what it for)
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Potassium-channel blocker which increases conductivity of demyelinated nerve fibers → increased walking speed
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dosing of dalfampridine
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Extended-release 10 mg tablet po bid
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CI of dalfampridine (2)
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•CrCl < 50 mL/min
•History of seizures |
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dalfampridine availability
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Available March 2010 via specialty pharmacies
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economic burden of ms- how much per pt per year
what components make up this cost (3) |
47000$ per patient per year
50% due to direct med/non-med costs loss of productivity makes up a third of it 10% on informal care |
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insurance barriers for MS (5)
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most formularies only have 1 or 2 DMTs- with financial penalties for not using preferred agent
many insurances don't have coverage of injectable drugs some require pt to go on drug holiday periodically to demonstrate need for drug... some require documentation of continued attack- if absence of attacks they make you stop it..which makes no sense arbitrary restrictions ceiling on cost of tx? idk what this means she didn't talk about it |
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some arbitrary restriction placed on MS pt by insurance (4)
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ambulatory! so no coverage!
full recovery after attack = no more drug age- not old enough requiring 2 relapses in past year before drug is covered |