Download Chapter 16 Cholinesterase Inhibitors

Chapter 23
Drugs for Multiple Sclerosis
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Multiple Sclerosis (MS)





Chronic, inflammatory, autoimmune disorder that
damages the myelin sheath of neurons in the CNS
Exact cause is unknown
MS causes a wide variety of sensory and motor
deficits
Most patients experience periods of acute clinical
exacerbations (relapses) alternating with periods of
complete or partial recovery (remissions)
Over time, symptoms usually grow progressively
worse.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
2
Multiple Sclerosis (MS)





Primary pathology of MS
Inflammation mechanism
Initiation of the autoimmune process
After an acute attack
Myelin sheaths of peripheral neurons
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
3
Drug Therapy for MS

1993: dramatic change occurred



First disease-modifying agent approved
Now disease progression can be slowed,
frequency and intensity of relapses
decreased, and permanent neurologic loss
delayed
Early treatment increases the chances of
significantly improving prognosis.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
4
Subtypes of MS




Relapsing-remitting MS
Secondary progressive MS
Primary progressive MS
Progressive-relapsing MS
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
5
Signs and Symptoms of MS

Symptoms vary depending on where CNS
demyelination occurs and the size of the
region of demyelination.








Paresthesias
Muscle or motor problems
Visual impairment
Bladder and bowel symptoms
Sexual dysfunction
Disabling fatigue
Emotional lability
Depression
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
6
Diagnostic Tools for MS





Diagnosis of MS
Diagnostic criteria: 1965, 2001, 2005, 2010
MRI
CSF testing
Visual evoked potential (VEP)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
7
Fig. 23-1. Symptom patterns that define the four subtypes of MS.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
8
Drug Therapy for MS

Disease-modifying therapy


Not a cure, but a delay and a decrease in intensity
and frequency
Immunomodulators and immunosuppressants
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
9
Drug Therapy for MS

Relapsing-remitting MS



This type benefits the most from therapy.
Treatment should begin as soon as diagnosed
and should continue indefinitely.
All patients (regardless of age) should receive
immunomodulators.
• Interferon beta-1a (Avonex)
• Interferon beta-1a (Rebif)
• Interferon beta-1b (Betaseron)
• Glatiramer acetate (Copaxone)
• Natalizumab (Tysabril)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
10
Drug Therapy for MS

Secondary progressive MS



Primary progressive MS



Interferon beta
Mitoxantrone
No drugs have shown effectiveness
Promising studies (methotrexate, azathioprine,
cyclophosphamide)
Progressive-relapsing MS

Mitoxantrone
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
11
Drug Therapy for MS

Treating an acute episode (relapse)



Short course of high-dose IV glucocorticoid
IV gamma globulin
Drug therapy of symptoms

All four subtypes have the same symptoms
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
12
Disease-Modifying Drugs I:
Immunomodulators





Seven immunomodulators currently available
Four preparation of interferon beta
All except natalizumab are recommended as
first-line therapy for all patients with
relapsing-remitting MS and for those with
secondary progressive MS who are
experiencing acute exacerbations.
Decrease relapse rate about 30%
Self-injected (except for fingolimod)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
13
Interferon Beta


Interferon is a naturally occurring glycoprotein
with antiviral, antiproliferative, and
immunomodulatory actions.
Therapeutic use



Reduces the frequency and severity of attacks
Reduces the number and size of MRI-detectable
lesions
Delays progression of disability
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
14
Interferon Beta

Adverse effects and drug interactions







Flu-like reactions
Hepatotoxicity
Myelosuppression
Injection-site reactions
Depression
Drug interactions
Preparation, dosage, and administration

Dispensed as single-use syringes and vials
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
15
Glatiramer Acetate

Therapeutic use


Description and mechanism


For long-term therapy of relapsing-remitting MS
Protects myelin by inhibiting immune response to
myelin basic protein
Adverse effects

Well tolerated
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
16
Natalizumab (Tysabril)





Introduced in 2004 and withdrawn a few months later
owing to three reports of progressive multifocal
leukoencephalopathy (severe brain infection)
Reintroduced in 2006 with protective restrictions on
who can prescribe, dispense, administer, receive it
Therapeutic uses – MS and Crohn’s disease
Prevents circulating leukocytes from leaving the
vasculature
Adverse effects – generally well tolerated (headache,
fatigue, abdominal discomfort, arthralgia, depression,
diarrhea, gastroenteritis, UTI, lower respiratory tract
infection)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
17
Disease-Modifying Drugs II:
Immunosuppressants



Only one approved by the FDA: mitoxantrone
More toxic than immunomodulators
Produce greater suppression of immune
function
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
18
Mitoxantrone

Therapeutic use


Mechanism of action


Decreases neurologic disability and clinical relapses
Binds with DNA and inhibits topoisomerase
Adverse effects and drug interactions




Myelosuppression
Cardiotoxicity
Fetal harm
Reversible hair loss, injury to GI mucosa, nausea/vomiting,
amenorrhea, allergy symptoms, blue-green tint to urine, skin,
and sclera
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
19
Mitoxantrone

Monitoring summary




Perform complete blood counts at baseline and
before each dose
Perform liver function tests at baseline and before
each dose
Perform a pregnancy test before each dose
Determine left ventricular ejection fraction (LVEF)
• Before the first dose
• Before all doses once cumulative dose has been
reached
• Whenever signs of congestive heart failure (CHF)
develop
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
20
Symptom Management










Bladder dysfunction
Bowel dysfunction
Fatigue
Depression
Spasticity
Sexual dysfunction
Neuropathic pain
Ataxia and tremor
Cognitive dysfunction
Dizziness and vertigo
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
21