MedChem of MS

Pathology of MSDemyelinated areas (plaques/lesions) in the CNS:Loss of myelin + oligodendrocytesWhite/grey matter (lesions)Brain and spinal cordEarly MS: axons/neurons preservedOngoing MS: axons/neurons lost Brain atrophy + ventricular enlargement

Clinical Course Categories of MS

Relapsing-Remitting MS (RRMS)

The most common form, characterized by temporary
periods of relapses and remissions

Secondary Progressive MS (SPMS)

Sxs worsen more steadily over time w/wo the
occurrence of relapses and remissions
-most ppl who are diagnosed w/ RRMS will --> SPMS

Primary progressive MS (PPMS)

Uncommon, slowly worsening sxs from the onset w NO relapses or remissions

Progressive Relapsing MS (PRMS)

Rare form of MS, steadily worsening disease
state from the onset

Disease Course of MS

Pre-symptomatic

Episode immune attack/inflammation
of myelin
-Below clinical threshold
-Initial axonal loss

Relapsing-remitting

Same as pre +
-sometimes above clinical threshold
-axonal loss continues

Primary/Secondary Porgressive

-Mainly due to continuous axonal loss
-Above clinical threshold

MS Categorization

Early

-Immune cell infiltration from periphery via:
-BBB, subarachnoid space, choroid plexus
-Peri immune cells + activated CNS resident microglia + astrocytes promote:
-Demyelination, oligo injury, axonal injury

Late

-Fewer immune cell infiltration (adaptive immune cell exhaustion)
-Chronic CNS inflammation+ neurodegeneration
-Mutual stim b/w astrocytes/microglia may produce a vicious cycle

Treatment :D

Treatment of exacerbations (early RRMS):

Disease modification treatment

Interferon-B1a/B1b

Indication: Relapsing MS
-Reduce MRI lesion activity
-reduce brain atrophy
-inc time to reach clinic def MS
-decrease relapse rate
-reduce risk of sustained disability progression

MOA:
-Immunomodulation
-reduces inflammatory response

Agents:
B1a (glycosylated):
-Avonex, Rebif
B1b (non-glycol):
-Betaseron, Extavia
Pegylated-IFNB1a:
-Plegridy

ADEs:
-Flu-like sxs
-depression
-Caution: dev. of neutralizing antibodies (NABs) --> dec efficacy overtime

Antibodies

Alemtuzumab

Indication: High efficacy for relapsing MS
-Use after inadeq response to 2 other drugs

MOA:
-CD52 monoclonal antibody
-depletes T+B cells

ADEs:
-Infusion Associated Rxn (IAR) in 90% of pts
-Mild-mod: headache, rash, pyrexia, N, resp/urinary tract infections
-Increased herpes infection risk (prophylactic acyclovir txt)
-secondary autoimmune disease mainly changing thyroid func (30-40% of pts)

Natalizumab

Indication: Relapsing MS

MOA:
-Humanized IgG monoclonal antibody
-binds to interns, reduces lymphocyte entry through BBB

ADEs:
-IAR
-Risk of PML (progressive multifocal leukoencephalopathy) due to human polyomavirus (check pts)
-risk of immune reconstitution inflammation syndrome (IRIS) when D/C due to PML
-depression, infection, fatigue

Human Polyomavirus (John Cunningham (JC) Virus):infected by inhalationresides in bone marrow/kidneysreactivated by immunosuppressionEnters CNS --> attacks oligodendrocytes --> causes PML

Ocrelizumab

Indication: MS or PPMS

MOA:
-IgG monoclonal antibody
-Target CD20 on surface of B cells
-Induce B cell self-destruction

ADEs:
-Infused-related reaction
-Infections

Ofatumumab

Indication: Relapsing MS or SPMS

MOA:
-IgG, CD20
-Bind to CD20 --> Ab-depnd cytolysis

ADEs:
-Hepatitis B reactivation
-Progressive PML

S1P Receptor modulators

MOA:
-Sphingosine 1-phosphate receptor modulators
-Bind to S1P1R/S1P5R --> sequesters lymphocytes in lymph nodes/thymus/GI tract --> reduces circ. T cells/macrophages --> reduce CNS infiltration of immune cells

Fingolimod: Relapsing MS

ADEs:
-Heart toxicity:
-Bradycardia (1st dose monitor)
-QTc prolongation, other arrhythmias, need heart monitor for 6h after 1st dose
-CI: I/III anti arrhythmic drugs, 2/3 AV block, prolonged QTc, recent cardiac diseases

Siponimod: MS/SPMS
** similar to Fingolimod

Ozanimod: MS/SPMS

ADEs:
-somnolence, fatigue, headache, dizziness, bradycardia, HTN, liver injury, N

Other classes:

Glatiramer Acetate (Copaxone)

MOA:
-Mimics myelin basic protein of the myelin sheath --> decoy to T-cell attack

-Mixture of polypeptides containing L-Glu, L-Lys, L-Ala, L-Tyr

Indication: Relapsing MS

Teriflunomide

Indication: Relapsing MS

MOA:
-Reduce inflammation
-Reduce pyrimidine synthesis --> reduce T/B cell proliferation --> reduce lymphocytes in CNS

ADEs:
-Liver toxicity (CI in hepatic imp)
-Teratogenicity

Mitoxantrone

Indication: SPMS, PRMS, or worsening RRMS (LAST RESORT)

MOA:
Binds to+ breaks DNA --> reduce lympho proliferation

ADEs:
-Bone marrow suppression
-Neutropenia
-Menstrual disorder

Cladribine

Indication: MS, SPMS (used when other txt unacceptable)

MOA:
-Adenosine analog --> inhibits nucleoside metabolism --> toxic to B/T cells --> red lympho counts

ADEs:
-Cytotoxic
-Malignancies
-Lymphopenia/hematologic toxicity
-Infections
-Liver injury
-Cardiac failure
-Risk of teratogenicity

Fumarates:

Dimethyl fumarate: Relapsing MS, SPMS

Metabolized by esterase in liver and GI tract to active MMF

Diroximel fumarate: Relapsing MS, SPMS

Less likely to cause GI ADEs due to substitution of methanol with inert 2-hydroxyethyl succinamide

Monomethyl fumarate: Relapsing MS, SPMS

Unknown MOA, may decrease blood vessel permeability. Eliminated mainly as CO2.

Symptomatic therapies