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.

3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Multiple Sclerosis (MS)  Primary pathology of MS  Inflammation mechanism  Initiation of the autoimmune process  After an acute attack  Myelin sheaths of peripheral neurons

4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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.

5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Subtypes of MS  Relapsing-remitting MS  Secondary progressive MS  Primary progressive MS  Progressive-relapsing MS

6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Diagnostic Tools for MS  Diagnosis of MS  Diagnostic criteria: 1965, 2001, 2005, 2010  MRI  CSF testing  Visual evoked potential (VEP)

8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Symptom patterns that define the four subtypes of MS.

9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Therapy for MS  Disease-modifying therapy  Not a cure, but a delay and a decrease in intensity and frequency  Immunomodulators and immunosuppressants

10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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 (Avonex) Interferon beta-1a (Rebif) Interferon beta-1a (Rebif) Interferon beta-1b (Betaseron) Interferon beta-1b (Betaseron) Glatiramer acetate (Copaxone) Glatiramer acetate (Copaxone) Natalizumab (Tysabril) Natalizumab (Tysabril)

11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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)

14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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)

18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Disease-Modifying Drugs II: Immunosuppressants   Only one approved by the FDA: mitoxantrone   More toxic than immunomodulators   Produce greater suppression of immune function

19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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 the first dose Before all doses once cumulative dose has been reached Before all doses once cumulative dose has been reached Whenever signs of congestive heart failure (CHF) develop Whenever signs of congestive heart failure (CHF) develop

21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Symptom Management   Bladder dysfunction   Bowel dysfunction   Fatigue   Depression   Spasticity   Sexual dysfunction   Neuropathic pain   Ataxia and tremor   Cognitive dysfunction   Dizziness and vertigo