MS Pharmacology

Major classes of cytokines

• interferons

• tumour necrosis factors

• interleukins (IL)

• colony-stimulating factors

4 Strategies to inhibit cytokine action

1. Antibody binds to cytokine

2. Antibody binds to cytokine receptor

3. Soluble receptor binds to cytokine

4. Receptor antagonist

   

Auto-immune theory of MS

• T-helper cells (CD4+) become autoreactive in periphery

• Activated T-cells bind to BBB epithelial cells and produce enzymes that break down barrier

• Activated T-cells enter CNS and produce cytokines that worsen BBB damage

• This allows B cells, complement, macrophages, etc. to enter the CNS

• Activated T-cells also promote cytokine production from neuronal support cells

What is thought to trigger T-cell autoreactivity in the periphery in MS?

Possibly due to viral infection whose proteins mimic myelin proteins

What enzymes are produced by T-cells to break down the BBB?

Matrix metalloproteinases (part of ADAM family of proteases)

What cytokines are produced by T-cells that enter through the BBB in MS?

• IL 1,2,12,17,23

• TNF alpha

• Interferon

What are symptomatic treatment for MS used for?

• tremor and spasticity

• sleep disturbances

• bladder dysfunction

• fecal incontinence

• pain

• depression

• sexual dysfunction

What are the first generation MS therapies?

• corticosteroids

• Interferon

• Glatiramer

Which corticosteroids are used in MS?

IV methylprednisolone for 3-5 days to resolve acute attacks, followed by oral prednisone

(oral methylprednisolone and dexamethasone are also used)

Which interferons are used as treatment for MS?

Interferons Beta1b and Beta1a

Function of interferons as treatment for MS

• decrease T-cell proliferation

• decrease T-cell movement from periphery to CNS

• decrease pro-inflammatory cytokine release from T-cells

• promote anti-inflammatory cytokine release

• additional neuro-protective activity

AEs of interferons

Flu-like symptoms (give Tylenol or NSAIDs pre-administration)

Glatiramer MOA

• peptides act as a decoy for immune system which prevents some of the damage to myelin proteins

• bind to MHC and interfere with binding to myelin basic protein

• induction of antigen-specific T-cells

• alter balance from pro-inflammatory Th1 cells to regulatory Th2 cells

Benefits of Glatiramer

Decrease exacerbations of relapsing-remitting type MS by ~30% as well as reduction in new onset CNS lesions

AEs of Glatiramer

• lipo-atrophy / skin dimpling at injection site

• short-lived chest tightness and SOB

• flushing

• anxiety

Second generation MS therapies

• Fingolimod and other S1P receptor agonists

• Natalizumab

Fingolimod class

Sphingosine-1-phosphate (S1P) receptor agonist

FIngolimod MOA

Prevents lymphocytes from leaving lymph nodes and spleen (lymphocytes are trapped in periphery and cannot reach the CNS)

AKA lymphocyte homing

How is fingolimod activated?

Given as prodrug and activated by sphingosine kinase-2 to form fingolimod-phosphate

How is fingolimod administered?

Orally

AE of fingolimod

• generally well-tolerated

• lymphopenia

• may cause increased LFTs

• can cause heart block/bradycardia with first dose

How do other S1P receptor agonists compare to fingolimod?

Others are more selective agonists at S1P receptor

Natalizumab MOA

Antibody directed against adhesion molecule integrin (alpha-4 chain of VLA-4 integrin dimer) to prevent cell-to-cell binding - including binding and recognition to BBB

Why is Natalizumab considered to be second line treatment?

Reports of progressive multifocal leukoencephalopathy (PML) including deaths

AEs of Natalizumab

• PML

• chest tightness

• urticaria

• anaphylaxis

• antibody development against drug

Third gen MS therapies

• Alemtuzumab

• Ocrelizumab

• Teriflunomide

• Diethyl fumarate

Alemtuzumab MOA

Antibody against CD52 - results in overall reduction of B and T cell levels

AEs of alemtuzumab

• infections

• rash

• headache

• fatigue

Ocrelizumab MOA

Anti-CD20 antibody

Ocrelizumab AE

• infection

• myelosuppression

Teriflunomide is the active metabolite of what drug?

Leflunomide (blocks pyrimidine synthesis)

AE of teriflunomide

• GI effects

• rash

• hair loss/thinning

Diethyl fumarate MOA

• Unknown

• may activate nuclear factor (erythroid-derived 2) -like 2 (NRF-2) to promote antioxidant effects

• reduction in some cytokine levels

AE of diethyl fumarate

• flushing

• rash

• GI effects

MOA of Cladribine

Purine analogue that is activated within cells to cladribine triphosphate - results in strand breaks and ultimately apoptosis

Mitoxantrone MOA

Inhibits DNA and RNA synthesis in leukocytes as well as inhibiting topoisomerase II

When is mitoxantrone indicated?

For relapsing-remitting attacks and secondary progressive MS in patients resistant to other immunomodulators

Upper-limit of mitoxantrone

Upper-limit accumulated dose of 140mg/m2

(can cause acute mucositis, myelosuppression, arrhythmias, and other cardiac ADRs)

• Can also cause secondary acute myelogenous leukemia in ~1/400 MS patients

Ofatumumab MOA

Human IgG1 that binds CD20 (different binding site that rituxumab)

AE of ofatumumab

• immunosuppression

• opportunistic infection

• myelosuppression

Supportive therapies for muscle spasms in MS

• Baclofen

• Tizanidine

• Botox

• Diazepam or other BDZ

• Cannabinoids

Balcofen MOA

GABA-B receptor agonist

Tizanidine MOA

Alpha-2 adrenergic receptor agonist

Supportive therapies for fatigue in MS

• Amantadine

• Modafinil

• Methylphenidate

Supportive therapies for walking speed in MS

Fampridine

Fampridine MOA

• Potassium channel antagonist with some selectivity for Kv1-type potassium channels

• may also increase calcium channel activity

(both lead to increase in neurotransmitter release at neuromuscular junction)

How is fampridine sometimes classified?

Sometimes referred to as a “convulsant” (however seizures are not an ADR at normal dose)

Supportive therapies for bladder spasticity in MS

• Botox

• Oxybutinin

• Tolterodine

• Mirabegron

Supportive therapies for pain management in MS

• neuropathic pain meds (gabapentin, pregabalin, duloxetine)

• muscle relaxants

• cannabinoids