Chapter 23

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 23

Drugs for Multiple Sclerosis

2Copyright © 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.


Multiple Sclerosis (MS) Primary pathology of MS Inflammation mechanism Initiation of the autoimmune process After an acute attack Myelin sheaths of peripheral neurons


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.


Subtypes of MS Relapsing-remitting MS Secondary progressive MS Primary progressive MS Progressive-relapsing MS


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


Diagnostic Tools for MS Diagnosis of MS Diagnostic criteria: 1965, 2001, 2005, 2010 MRI CSF testing Visual evoked potential (VEP)


Fig. 23-1. Symptom patterns that define the four subtypes of MS.


Drug Therapy for MS Disease-modifying therapy

Not a cure, but a delay and a decrease in intensity and frequency

Immunomodulators and immunosuppressants


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)


Drug Therapy for MS Secondary progressive MS

Interferon beta Mitoxantrone

Primary progressive MS No drugs have shown effectiveness Promising studies (methotrexate, azathioprine,

cyclophosphamide) Progressive-relapsing MS

Mitoxantrone


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


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)


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


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


Glatiramer Acetate Therapeutic use

For long-term therapy of relapsing-remitting MS Description and mechanism

Protects myelin by inhibiting immune response to myelin basic protein

Adverse effects Well tolerated


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)


Disease-Modifying Drugs II: Immunosuppressants

Only one approved by the FDA: mitoxantrone More toxic than immunomodulators Produce greater suppression of immune

function


Mitoxantrone Therapeutic use

Decreases neurologic disability and clinical relapses Mechanism of action

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


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


Symptom Management Bladder dysfunction Bowel dysfunction Fatigue Depression Spasticity Sexual dysfunction Neuropathic pain Ataxia and tremor Cognitive dysfunction Dizziness and vertigo

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