Multiple Sclerosis (Khan)

Cause of MS?

unknown→ but genetic/viral links

Symptoms of MS?

• dysarthria (speech problems)

• optic neuritis

• fatigue

• spasms

• incontinence

• depression

Pathogenesis of MS:

What do white blood cells do in MS?

How do MS lesions arise?

What happens to the BBB?

• WBCs (B and T lymphocytes) involved in adaptative immunity attack the CNS

• MS lesions arise from destruction of oligodendrocytes (what makes the myelin) or direct myelin destruction

• BBB is destroyed as well (allows WBCs to easily get in and attack)

Steroids used for acute attacks of MS are used _____ dose for _____ duration.

a. high dose, short duration

b. high dose, long duration

c. low dose, short duration

d. low dose, long duration

a.

What group on methylprednisolone is required for activity?

unsaturated system (C4-5)

What groups on methylprednisolone increase GC activity?

• double bond on C1-2 (increases GC activity, decreases MC activity)

• a-hydroxyl at C17 (increases GC activity)

• b-hydroxyl at C11 (increases GC activity)

• methyl group at C6 (increases GC/MC ratio)

MOA of glucocorticoids:

1. steroid in circulation bound to CBG (aka protein bound in blood)

2. enters cell and binds to CYTOPLASMIC RECEPTOR

3. receptor changes conformation

4. steroid-receptor complex translocates to nucleus

5. receptor dimerizes, binds to GRE (DNA)

6. results: increase/decrease in transcription

(note: BINDS in the cytoplasm, ACTS in the nucleus)

ADRs of glucocorticoids:

• mood disturbances

• hyperglycemia

• GI

• infection risk

• metallic taste

What ADR is associated with long term systemic steroid use?

HPA suppression (basically when natural cortisol production is shut down)

What drugs are ONLY used for tx of acute attacks with MS?

• glucocorticoids (methylprednisolone, prednisone)

• ACTH (corticotropin)

ACTH is part of a precursor molecule to what? which is the precursor to what hormone?

ACTH→ POMC→ MSH hormone

MOA of ACTH:

• acts on what receptors?

  • what type of receptor? G protein? ionotropic?

• activates or inhibits AC?

• increases or decreases cAMP?

• stimulates production of what?

• results?

• acts on melanocortin receptor (MC2)

  • which is a GPCR

• activates AC → increases cAMP

• stimulates: cortisol, androgen, and mineralocorticoid secretion

• results: immunosuppression, adrenal suppression?

ADRs of ACTH:

electrolyte and psych disturbances

MOA of Interferon B (IFN-β):

• results?

1. DIMERIZATION: IFN-β binds to receptor, dimerization occurs

2. PHOSPHORYLATION: receptor phosphorylated, activates mobile tyrosine kinase JAK

3. STAT PHOSPHORYLATION: JAK phosphorylates STAT molecules

4. TRANSLOCATION: STAT-P dimerization occurs→ translocation to nucleus

5. gene expression effected

6. RESULTS:

   • decrease immune cell BBB adhesion/penetration

   • reduces inflammation

   • increase neurotrophic factors

ADRs of Interferon B (IFN-β):

• Flu-like symptoms

• Severe depression

• Injection site necrosis

• Elevated liver enzymes

• Thyroid dysfunction

• Others: leukopenia, pain

Which fumerates are prodrugs? which is the actual drug?

• prodrugs: dimethyl fumarate and diroximel fumerate

• actual drug/active metabolite: monomethyl fumarate

MOA of Fumerates:

• activates what?

• results?

1. activate Nrf-2 transcription pathway

2. results: increased expression of antioxidative enzymes and increase GSH (glutathione) biosynthesis
   

(FYI: oxidative stress is bad in MS bc it produces free radicals that further MS… here this drug increases antioxidants that will neutralize these free radicals)

In addition to the antioxidative effects, what else occurs as a result of Nrf-2 pathway activation with fumerates? leads to what side effect?

nACh agonist→ leads to ADR of cutaneous flushing

ADRs of Fumerates:

• cutaneous flushing

• hepatotoxicity

• neutropenia

What is the PREFERRED MS drug in PREGNANCY?

glatiramer acetate

MOA of Glatiramer acetate:

• mimics antigenic properties of myelin basic protein (MBP) (part of the myelin sheath)

• acts as decoy for immune attack on MBP

• BASICALLY: mimics a protein that makes up myelin and tricks the immune system into attacking it INSTEAD of myelin

ADRs of Glatiramer acetate:

• injection site rxns

• post infusion rxns (flush, diaphoresis, dypsnea)

• chest pain

• flu-like symptoms

List the Spingosine1P modulators:

• Fingolimod

• Ozanimod

• Siponimod

• Ponesimod

What is the ONLY Spingosine1P modulator that is a PRODRUG and needs phosphorylated?

Fingolimod

MOA of Spingosine1P modulators?

• bind to S1P1R receptor→ causes irreversible downregulation, internalization, and degradation of S1P1R

• results: blocks lymphocytes egress from lymph nodes

• basically: traps lymphocytes (B and T cells) in the lymph nodes so they can’t attack the CNS

ADRs of Spingosine1P modulators?

• bradycardia

• macular edema

• increased LFTs

What drug is contraindicated in pts. homozygous with CYP2C9*3/*3 genotype?

Siponimod

What drug is contraindicated with MAOIs?

Ozanimod (bc Ozanimod metabolite inhibits MAO)

What are the contraindications with Spingosine1P modulators?

cardiac issues→ arrhythmias, MI, stroke/TIA, HF

What facilitates the rapid removal of Teriflunomide?

activated charcoal and cholestyramine

MOA of Teriflunomide:

• inhibits synthesis of orotate (pyrimidine precursor)

  • inhibits the enzyme dihydrooorotate dehydrogenase

• results: decreased # of activated lymphocytes in CNS

BBW AND C/I of TERIFLUNOMIDE:

• PREGNANCY (cat X)

• HEPATOTOXICITY

MOA of Cladribine:

• prodrug activation?

• requires phosphorylation to its triphosphate (deoxyadenosine derivative)

• incorporates into DNA and causes DNA strand break→ apoptosis

For Cladribine:

• ADRs

• BBW

• C/I

• ADRs: infections, liver injury, heart failure

• BBW: malignancy, teratogenicity (must use contraception)

• C/I: malignancy, HIV, chronic infection

MOA of Mitoxantrone:

• intercalation with DNA (affects transcription / translation / replication)

• radical induced damage

• inhibits Top II

ADRs and BBW of Mitoxantrone:

• ADRs: cardiotoxicity, BMS, GI/cutaneous disturbances, alopecia

• BBW: cardiotoxicity, BMS, malignancy

MOA of Natalizumab (TYSABRI):

• results?

• binds to alpha-4 integrins and prevents interactions with VCAM-1 receptors on CNS vessel walls

• results: lymphocytes can’t get in the BBB

ADRs and BBW of Natalizumab:

• ADRs: infusion rxns, HA, fatigue

• BBW: progress multifocal leukoencephalopathy

  • viral infection of white matter in brain

MOA of Alemtuzumab:

• HUMANIZED mAb that binds to CD52 abs on B cells

• results: increases antibody-dependent cell mediated cytolysis →

  • B-cell depletion

BBW and C/I of Alemtuzumab:

• BBW:

  • infusion rxns

  • autoimmune conditions

  • stroke

  • malignancies

• C/I: HIV

What was the first drug approved for PPMS? (progressive primary MS)

Ocrelizumab

What drugs are CD20 targeting antibodies?

• Ocrelizumab

• Ofatumumab

• Ublituximab

What CD20 targeting antibody is C/I in active Hep B?

Ublituximab

MOA and ADRs of Dalfampridine:

• lowkey khan said not really even used anymore

• MOA: K+ channel blocker → increases conduction in damaged nerves

• ADRs: seizure

REVIEW

For each of the following mAb, what is their target?

• Natalizumab

• Alemtuzumab

• Ocrelizumab

• Ofatumumab

• Ublituximab

• Natalizumab- alpha-4 integrins

• Alemtuzumab- CD52

• Ocrelizumab- CD20

• Ofatumumab- CD20

• Ublituximab- CD20