MS drugs

Question 1

what change in channels/receptors are seen with MS?

Answer 1

increased intracellular calcium and sodium in MS

Question 2

BNDF

Answer 2

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

Question 3

ASIC-1

Answer 3

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

Question 4

TRPM4

Answer 4

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

Question 5

RRMS - relapse remitting MS

Answer 5

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

Question 6

PPMS - primary progressive MS

Answer 6

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

Question 7

SPMS - secondary progressive MS

Answer 7

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

Question 8

PRMS - Progressive relapsing MS

Answer 8

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

Question 9

Pathogenesis of MS

Answer 9

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,

Question 10

Pathogenesis due to Low Vitamin D

Answer 10

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

Question 11

Pathogenesis due to EBV infection

Answer 11

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

Question 12

Immunoregulatory ______ receptors are present on T cells

Answer 12

Vitamin D

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

Question 13

reduced serum vit D levels are shown to predict

Answer 13

accumulation of new lesions

Question 14

High vit D linked to

Answer 14

decreased relapse risk

Question 15

Early MS treatment

Answer 15

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

Question 16

_____ of therapy is key to preventing disability

Answer 16

timing

Question 17

Current therapies

Answer 17

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

Question 18

First line MS therapy

Answer 18

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

Question 19

Oral first line MS therapy

Answer 19

fingolimod - gilenya
teriflunomide - aubagio
dimethyl fumarate - tecfidera

Question 20

Second line MS therapy

Answer 20

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

Question 21

Corticosteroids

Answer 21

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

Question 22

Interferon beta mechanism of action

Answer 22

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

Question 23

Avonex

Answer 23

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

Question 24

Rebif

Answer 24

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

Question 25

Betaseron

Answer 25

``` 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 ```

Question 26

Side effects of interferons

Answer 26

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

Question 27

Copaxone

Answer 27

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

Question 28

Glatiramer acetate mechanism of action

Answer 28

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

Question 29

Th2 activity in CNS

Answer 29

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

Question 30

side effects of glatiramer acetate

Answer 30

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

Question 31

Fingolimod (FTY720)

Answer 31

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

Question 32

Fingolimod MOA

Answer 32

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

Question 33

Pharmocokinetics of Fingolimod (Gilenya)

Answer 33

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

Question 34

_______ increases fingolimod AUC by 70%

Answer 34

Ketoconazole

Question 35

Fingolimod safety

Answer 35

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

Question 36

Fingolimod warning

Answer 36

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

Question 37

Fingolimod is more affective at reducing relapse rates than

Answer 37

IFN beta 1a IM

Question 38

Dimethyl Fumarate (Tecfidera)

Answer 38

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

Question 39

_______ has a greater affect than glatiramer

Answer 39

Tecfidera

Question 40

Tecfidera side effects

Answer 40

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

Question 41

Teriflunomide (Aubagio)

Answer 41

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

Question 42

Teriflunomide (Aubagio) side effects

Answer 42

diarrhea, nausea, hair loss and abnormal hepatic biochemistry

Question 43

Cellular effects of Teriflunomide

Answer 43

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

Question 44

Alemtuzumab

Answer 44

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

Question 45

Alemtuzumab side effects

Answer 45

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

Question 46

Alemtuzumab boxed warning

Answer 46

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

Question 47

Natalizumab (Tysabri)

Answer 47

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

Question 48

Mechanism of Natalizumab

Answer 48

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

Question 49

Progressive multifocal leukoencephalopathy (PML) etiologies

Answer 49

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

Question 50

Antineoplastic: Mitoxantrone (Novantrone)

Answer 50

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

Question 51

Side effects Mitoxantrone (Novantrone)

Answer 51

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

Question 52

Contraindications Mitoxantrone (Novantrone)

Answer 52

L. ventricular ejection fraction

Question 53

Tx for spasticity

Answer 53

physical therapy, baclofen, diazepam, dantrolene

Question 54

Tx for paroxysmal phenomena

Answer 54

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

Question 55

Tx for Fatigue

Answer 55

amantidine

Question 56

Tx for depression

Answer 56

anti depressant

Question 57

Tx for sexual dysfunction

Answer 57

behavioral therapy viagra muse

Question 58

Tx for urinary dysfunction

Answer 58

detrol, ditropan, botox

Question 59

Dalfampridine (amypyria)

Answer 59

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

Question 60

Miconazole

Answer 60

for athlete's foot | may aid in MS treatment