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Flashcards in MS drugs Deck (60):
1

what change in channels/receptors are seen with MS?

increased intracellular calcium and sodium in MS

2

BNDF

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

3

ASIC-1

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

4

TRPM4

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

5

RRMS - relapse remitting MS

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

6

PPMS - primary progressive MS

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

7

SPMS - secondary progressive MS

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

8

PRMS - Progressive relapsing MS

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

9

Pathogenesis of MS

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,

10

Pathogenesis due to Low Vitamin D

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

11

Pathogenesis due to EBV infection

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

12

Immunoregulatory ______ receptors are present on T cells

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

13

reduced serum vit D levels are shown to predict

accumulation of new lesions

14

High vit D linked to

decreased relapse risk

15

Early MS treatment

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

16

_____ of therapy is key to preventing disability

timing

17

Current therapies

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

18

First line MS therapy

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

19

Oral first line MS therapy

fingolimod - gilenya
teriflunomide - aubagio
dimethyl fumarate - tecfidera

20

Second line MS therapy

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

21

Corticosteroids

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

22

Interferon beta mechanism of action

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

23

Avonex

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

24

Rebif

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

25

Betaseron

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

Side effects of interferons

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

Copaxone

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

Glatiramer acetate mechanism of action

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

Th2 activity in CNS

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

30

side effects of glatiramer acetate

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

31

Fingolimod (FTY720)

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

Fingolimod MOA

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

Pharmocokinetics of Fingolimod (Gilenya)

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

_______ increases fingolimod AUC by 70%

Ketoconazole

35

Fingolimod safety

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

36

Fingolimod warning

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

Fingolimod is more affective at reducing relapse rates than

IFN beta 1a IM

38

Dimethyl Fumarate (Tecfidera)

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

_______ has a greater affect than glatiramer

Tecfidera

40

Tecfidera side effects

most frequent: flushing and diarrhea
some cases of nasopharygitus and headaches

41

Teriflunomide (Aubagio)

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

Teriflunomide (Aubagio) side effects

diarrhea, nausea, hair loss and abnormal hepatic biochemistry

43

Cellular effects of Teriflunomide

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

Alemtuzumab

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

Alemtuzumab side effects

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

46

Alemtuzumab boxed warning

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

Natalizumab (Tysabri)

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

48

Mechanism of Natalizumab

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

49

Progressive multifocal leukoencephalopathy (PML) etiologies

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

Antineoplastic: Mitoxantrone (Novantrone)

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

Side effects Mitoxantrone (Novantrone)

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

52

Contraindications Mitoxantrone (Novantrone)

L. ventricular ejection fraction

53

Tx for spasticity

physical therapy, baclofen, diazepam, dantrolene

54

Tx for paroxysmal phenomena

Trigeminal neuralgia, pain, tonic, seizures,
carbamazepine, neurontin, phenytoin

55

Tx for Fatigue

amantidine

56

Tx for depression

anti depressant

57

Tx for sexual dysfunction

behavioral therapy
viagra
muse

58

Tx for urinary dysfunction

detrol, ditropan, botox

59

Dalfampridine (amypyria)

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

60

Miconazole

for athlete's foot
may aid in MS treatment