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BCN EXAM 4 > MS drugs > Flashcards

MS drugs Flashcards

1
Q

what change in channels/receptors are seen with MS?

A

increased intracellular calcium and sodium in MS

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2
Q

BNDF

A

produced by T and B cells
neuroprotective
glatiramer acetate increases BDNF production by lymphocytes and therefore contributes to neuroprotection

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3
Q

ASIC-1

A

acid-sensing ion channel is upregulated in active MS/EAE lesions
allows the influx of sodium and calcium
amiloride antagonizes ASIC-1 and ameliorates disease in EAE

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4
Q

TRPM4

A

transient receptor potential melastatin 4 opens via increased intracellular calcium and decreased ATP concentrations
leads to Na and Ca accumulation
glibenclamide blocks TRPM4 and acts neuroprotectively in EAE

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5
Q

RRMS - relapse remitting MS

A

have an attack, go into complete or partial remission then have the symptoms return

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6
Q

PPMS - primary progressive MS

A

continually decline and have no remissions
may be temporary relief in symptoms
few pts have malignant MS which is where they have a quick decline which leaves them severely disabled or even lead to death

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7
Q

SPMS - secondary progressive MS

A

stage of MS starts with RRMS symptoms and continues on to show signs of PPMS

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8
Q

PRMS - Progressive relapsing MS

A

rare form but here it takes a progressive route made worse by acute attacks
20% of pts with MS have a benign form
show little progression after the first attack

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9
Q

Pathogenesis of MS

A

EBV - 2nd most implicated factor , sometime after birth and must continue until ~15 yrs
1st - Vitamin D - involved in immune development and maturation, associated with autoimmunity, coupled to the solar cycle,

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10
Q

Pathogenesis due to Low Vitamin D

A

smoke exposure increases vit D breakdown in Macrophages
vit D dep rickets type I
low intake or sun exposure
impaired expression of HLA-DRB1 *1501 which can impair presentation by MHC II
decreased in vit D dep regulation of E2 - related inflammatory signaling
increase MMP-9 and increases BBB permeability to pro-inflammatory immune cells

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11
Q

Pathogenesis due to EBV infection

A

Low vit D can decrease anti viral and anti microbial defenses
impaired IL 10 signaling -> increased pro inflammatory cytokine profile
immmune targeting of EBV antigens leads to cross reactivity with myelin peptides
replication leads to periodic activation of immune responses

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12
Q

Immunoregulatory ______ receptors are present on T cells

A

Vitamin D

vitamin D interacts with the immunomod. effects of estrogen and testosterone

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13
Q

reduced serum vit D levels are shown to predict

A

accumulation of new lesions

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14
Q

High vit D linked to

A

decreased relapse risk

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15
Q

Early MS treatment

A 
initiation of therapy with an immunomodulator is advised as soon as possible following definite dx of MS with a relapsing course 
reduce relapses
delay disease progression 
delay disability 
alleviate symptoms
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16
Q

_____ of therapy is key to preventing disability

A

timing

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17
Q

Current therapies

A 
corticosteroids 
Interferon beta - betaseron,avonex, rebif, plegridy 
glatiramer acetate - copaxone 
natalizumab - tysabri 
mitoxantrone 
fingolimod - gilenya 
teriflunomide - aubagio 
dimethly fumarate - tecfidera 
alemtuzuab - lemtrada
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18
Q

First line MS therapy

A 
interferon beta-1b 
peginterferon beta-1a
glatiramer acetate 
similar efficacy for relapse rate reduction 
generally very safe and well tolerated 
all above require self injection
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19
Q

Oral first line MS therapy

A

fingolimod - gilenya
teriflunomide - aubagio
dimethyl fumarate - tecfidera

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20
Q

Second line MS therapy

A

Alemtuzumab
Natalizumab
Mitoxantrone
generally indicated for persons with suboptimal response to first line agents
require IV infusion
associated with life threatening adverse events

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21
Q

Corticosteroids

A

symptomatic management
used in moderate to severe exacerbations
IV methylprednisolone 500 mg/day for 5 days followed by oral prednisone (optional)
hasten clinical recovery
delay recurrence of neuro events
does not alter the course of MS

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22
Q

Interferon beta mechanism of action

A

reduce the production of TNFa and T cells known to induce damage to myelin
reduce inflammation by switching cytokine production from type 1 (pro inflam) to type 2 (anti inflam) and increasing levels of IL10
decrease antigen presentation to reduce the attack on myelin barrier, by affecting adhesion molecules, chemokines and proteases

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23
Q

Avonex

A 
interferon beta 1a
relapsing forms of MS
30 mcg IM once/wk 
reduces the rate of clinical relapse 
delays the increase in volume of lesions 
may delay progression of disability
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24
Q

Rebif

A 
interferon beta 1a
relapsing/remitting forms of MS 
22 or 44 mcg SC 3x/wk 
decreases frequency of relapse 
delays the increases in the volume of lesions 
may delay progression of disability
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25
Q

Betaseron

A 
interferon beta 1b 
relapsing forms of MS 
8 million IU SC every other day 
reduces rate of clinical relapse 
reduces development of new lesions 
delays the increase in the volume of lesions
26
Q

Side effects of interferons

A

common: flu like symptoms, chills, fever, muscle aches, asthenia (weakness), betaseron and rebif have injection site reactions
uncommon: severe depression, suicide, seizures, cardiac effects, anemia, elevated liver enzymes, severe hepatic injury including cases of hepatic failure, has been reported in patients taking Avonex

27
Q

Copaxone

A

glatiramer acetate
reduction of frequency of relapses in patients with RRMS
20 mcg SC once daily
reduces the frequency of exacerbations
moderately reduces the development of new lesions

28
Q

Glatiramer acetate mechanism of action

A

synthetic chain of four amino acids
resembles myelin basic protein
blocks immune system from attacking myelin
switches immune response from Th1 to Th2 which could reduce myelin damage

29
Q

Th2 activity in CNS

A

release IL4, IL10 and BDNF causing bystander suppression effect and neuroregeneration

30
Q

side effects of glatiramer acetate

A

injection site reaction
chest pain (transient 20-30mins)
N&V - uncommon
dizziness

31
Q

Fingolimod (FTY720)

A

sphingosine 1 phosphate receptor (S1P-R) modulator
sequesters circulating lymphcytes into secondary lymphoid organs
peripheral reduction of CD3, 4, 8, 19, 45RA (naive T cell) 45RO (memory T cells)
no effect on lymphocyte induction, proliferation, or memory function
inhibit production of IL-17
crosses BBB and may be neuroprotective

32
Q

Fingolimod MOA

A

traps circulating lymphocytes in perpheral lymph nodes
binds the receptor, receptor is internalized, prevents cell from leaving because requires this receptor on the surface to leave the lymph node

33
Q

Pharmocokinetics of Fingolimod (Gilenya)

A

A: bioavailabilty 93%
D: Vd -1200 L, greater than 99.7% protein bound
M: forms active metabolite fingolimod phosphate. oxidation primarily via CYP 4F2, fatty acid like degradation to inactive metabolites
E urine 81%, feces 5% T1/2 = 6-9 days

remains in blood up to 2 months after discontinuation
other immunosuppressants should be avoided or used with caution during this time

34
Q

_______ increases fingolimod AUC by 70%

A

Ketoconazole

35
Q

Fingolimod safety

A

transient reduction in HR on initiationof treatment
elevated BP
elevated liver enzymes
macular edema

36
Q

Fingolimod warning

A

bradycardia (1-6 hours after first dose)
AV block
BP increases
macualr edema
malignancies (mostly skin cancer)
peripheral blood lymphocyte count reductions (MOA)
ALT increases
mild forced expiratory volume reductions
drug interactions (ketoconazole, antineoplastic/immunosuppressive drugs) vaccines, drugs affecting HR

37
Q

Fingolimod is more affective at reducing relapse rates than

A

IFN beta 1a IM

38
Q

Dimethyl Fumarate (Tecfidera)

A

exact mechanism of action is unclear
inhibits expression of proinflammatory adhesion molecules and chemokines
suppresses macrophage function
increases Nrf2 DNA binding (possible neuroprotective)
suppresses inflammatory activation of astrocytes and C6 glioma cells
oral med - 2x/day - used for psoriasis

39
Q

_______ has a greater affect than glatiramer

A

Tecfidera

40
Q

Tecfidera side effects

A

most frequent: flushing and diarrhea

some cases of nasopharygitus and headaches

41
Q

Teriflunomide (Aubagio)

A

once daily oral med
reversibly inhibits mitochondrial enzymes dihydro-orotate dehydrogenase (DHODH) which plays role in pyrimidine synthesis needed for DNA replication
hinders T and B cell proliferation and function in response to autoantigens, drug functions as a disease modifying therapy for MS

42
Q

Teriflunomide (Aubagio) side effects

A

diarrhea, nausea, hair loss and abnormal hepatic biochemistry

43
Q

Cellular effects of Teriflunomide

A

inhibits JAK-STAT thus prevents IL17 and TNF release
inhibits DHODH prevents pyrimidine –> no glycoproteins, phospholipids, salvage pathway –> affects cell-cell contact, adhesion, diapedesis, cell membranes, second messengers, proliferation and Ab secretion

44
Q

Alemtuzumab

A

more recent drug
binds CD52 on B cells
given just two times, first IV over 4 hrs for 5 days in a row, Second tx is for 3 days one year later

45
Q

Alemtuzumab side effects

A

rash, HA, fever, N&V, fatigue, nasal congestion, insomnia,

46
Q

Alemtuzumab boxed warning

A

serious autoimmune conditions - thrombocytopenia, antiglomerular basement membrane disease leading to kidney damage
BM suppression
serious or fatal infection
infusion reactions
higher risk of cancer - thyroid, melanoma

47
Q

Natalizumab (Tysabri)

A 
monthly intravenous (IV) infusion 
selective adhesion molecule (SAM) inhibitor 
monoclonal antibody against alpha 4 integrin
48
Q

Mechanism of Natalizumab

A

blocks the recruitment of T cells which enter the CNS and recruit additional inflammatory cells and lead to the destruction of myelin sheaths

49
Q

Progressive multifocal leukoencephalopathy (PML) etiologies

A

rare demyelinating disorder
JC virus
Immunosuppressed patients - AIDS, taking immunosuppressant medication before taking Natalizumab (increases risk)
Taking natalizumab and Tysabri may increase risk as well

50
Q

Antineoplastic: Mitoxantrone (Novantrone)

A

reduction of relapse rate and clinical disability in patients with SPMS, PRMS, or worsening RRMS
short IV infusion for 5-15 mins every 3 months
reduces exacberation rate
prolongs time to first treated relapse
improves EDSS scores vs. baseline
inhibits or prevents the development of any uncontrolled new or abnormal growth such as a neoplasm or tumor
suppresses B cell and T cell immunity

51
Q

Side effects Mitoxantrone (Novantrone)

A

BM suppression - neutropenia, thrombocytopenia and acute myelogenous leukemia
Cardiac toxicity - CHF, decreased L ventricular ejection fraction
increased liver enzymes
nausea
alopecia (hair loss)

52
Q

Contraindications Mitoxantrone (Novantrone)

A

L. ventricular ejection fraction

53
Q

Tx for spasticity

A

physical therapy, baclofen, diazepam, dantrolene

54
Q

Tx for paroxysmal phenomena

A

Trigeminal neuralgia, pain, tonic, seizures,

carbamazepine, neurontin, phenytoin

55
Q

Tx for Fatigue

A

amantidine

56
Q

Tx for depression

A

anti depressant

57
Q

Tx for sexual dysfunction

A

behavioral therapy
viagra
muse

58
Q

Tx for urinary dysfunction

A

detrol, ditropan, botox

59
Q

Dalfampridine (amypyria)

A

improves walking speed/ gait difficulties
Mechanism: K+ channel blockade - enhances axonal conduction
side f/x - seizures

60
Q

Miconazole

A

for athlete’s foot

may aid in MS treatment

BCN EXAM 4 (8 decks)

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