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Lehne: Pharmacology for Nursing Care, 8th Edition

Chapter 23: Drugs for Multiple Sclerosis


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Chapter 23 begins with a review of the pathophysiology of multiple sclerosis and the
factors that affect loss of sensory and motor neurons. The diseases proposed
etiology also is discussed.

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disorder that


damages the myelin sheath of neurons in the central nervous system (CNS).
The pathologic hallmark of MS is the presence of multifocal regions of
inflammation and myelin destruction in the CNS.
As a result of demyelination, axonal conduction is slowed or blocked, giving rise
to a host of neurologic signs and symptoms.
When inflammation subsides, damaged tissue is replaced by astrocyte-derived
filaments, forming scars known as scleroses (from which the diseases name is
derived).
It is important to note that, in addition to stripping off myelin, inflammation may
injure the underlying axon and may damage oligodendrocytes, the cells that
produce CNS myelin.
Axonal injury also can occur in the absence of inflammation and can be seen
early in the course of the disease.
The mechanism appears to be autoimmune: Cells of the immune system
mistakenly identify components of myelin as foreign and mount an attack against
them.
The most likely causes of MS are genetics, environmental factors, and microbial
pathogens. When inflammation subsides, some degree of recovery occurs, at least
in the early stages of the disease. Three mechanisms are involved: (1) partial
remyelination, (2) functional axonal compensation (axons redistribute their
sodium channels from the nodes of Ranvier to the entire region of demyelination),
and (3) development of alternative neuronal circuits that bypass the damaged
region.
People with MS can experience a wide variety of signs and symptoms. Depending
on the site of CNS demyelination, a patient may experience paresthesias, muscle
or motor problems, visual impairment, bladder and bowel symptoms, sexual
dysfunction, disabling fatigue, emotional lability, depression, cognitive
impairment, slurred speech, dysphagia, dizziness, vertigo, neuropathic pain, and
more. The intensity of these symptoms is determined by the size of the region of
demyelination.

The chapter then describes the four subtypes of MS and the tests used to diagnose
the disorder.
Copyright 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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MS has four subtypesrelapsing-remitting, secondary progressive, primary


progressive, and progressive-relapsingwhich are defined by the clinical course
the disease follows.
Relapsing-remitting MS is characterized by recurrent, clearly defined episodes of
neurologic dysfunction (relapses) separated by periods of partial or full recovery
(remissions).
Secondary progressive MS occurs when a patient with relapsing-remitting MS
develops steadily worsening dysfunction, with or without occasional plateaus,
acute exacerbations, or minor remissions.
In primary progressive MS, symptoms grow progressively more intense from the
outset, although some patients may experience occasional plateaus or even
temporary improvement.
Progressive-relapsing MS, which is rare, is much like primary progressive MS but
with acute exacerbations superimposed on the steady intensification of symptoms
Diagnosis of MS is based on the clinical presentation and laboratory data.
Additional diagnostic tools can help confirm a suspected diagnosis of MS.
Important among these are magnetic resonance imaging (MRI), cerebrospinal
fluid (CSF) tests, and measurement of the visual evoked potential (VEP). In
patients with MS, drugs are used to (1) modify the disease process, (2) treat acute
relapses, and (3) manage symptoms. No drugs can cure MS.

The chapter then reviews the two groups of drugs used to treat the symptoms of MS,
reduce the frequency and severity of relapse, and treat acute episodes.

Disease-modifying drugs can reduce the frequency and severity of relapses, the
development of brain lesions, and future disability, and they may help maintain
quality of life. In addition, they may prevent permanent damage to axons.
The two main groups of disease-modifying drugs are immunomodulators and
immunosuppressants. The immunomodulatorsinterferon beta, glatiramer
acetate, natalizumab, and fingolimodare much safer than mitoxantrone (the
major immunosuppressant in use) and therefore are generally preferred.
All patients with relapsing-remitting MS, regardless of age, frequency of attacks,
or level of disability, should be treated with one of the immunomodulators.
Treatment should begin as soon as possible after relapsing-remitting MS has been
diagnosed, because early treatment can help prevent axonal injury and thereby may
prevent permanent neurologic deficits. Treatment should continue indefinitely.
Interferon beta can benefit certain patients with secondary progressive MS,
specifically those who still have acute relapses. For these individuals,
interferon beta can reduce the severity and frequency of attacks and the
development of MRI-detectable brain lesions.
Mitoxantrone can reduce the clinical attack rate and the development of new brain
lesions and slow the progression of disability in secondary progressive MS.
However, although the drug is effective, cardiotoxicity precludes its long-term
use.
Copyright 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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Mitoxantrone is the only disease-modifying drug approved for progressiverelapsing MS. Unfortunately, its benefits generally are modest.
No disease-modifying therapy has been shown effective against primary
progressive MS.
A short course of a high-dose IV glucocorticoid is the preferred treatment of an
acute relapse. Glucocorticoids suppress inflammation and can thereby reduce the
severity and duration of a clinical attack.
Acute relapse may also be treated with IV gamma globulin. This option can be
especially helpful in patients intolerant of or unresponsive to glucocorticoids.

The chapter then discusses the immunomodulators and their possible side effects.

Seven immunomodulators are available: glatiramer acetate, natalizumab,


fingolimod, and four preparations of interferon beta.
Except for natalizumab, all of these drugs are recommended as first-line therapy for
patients with relapsing-remitting MS and for patients with secondary progressive
MS who still experience acute exacerbations.
Natalizumab is reserved for patients with relapsing-remitting MS who have not
responded to at least one of the other four drugs.
All of the first-line immunomodulators have nearly equal efficacy, reducing the
relapse rate by about 30%.
Natalizumab is more effective than the first-line drugs, reducing the relapse rate
by 68%, but it also is more dangerous.
Interferon beta is a naturally occurring glycoprotein with antiviral,
antiproliferative, and immunomodulatory actions.
In patients with MS, interferon beta is believed to help in two ways: (1) It
inhibits the migration of proinflammatory leukocytes across the blood-brain
barrier, thereby preventing these cells from reaching neurons of the CNS, and
(2) it suppresses T-helper cell activity.
Two forms of interferon beta are used clinically: interferon beta-1a and interferon
beta-1b. Both forms are manufactured using recombinant DNA technology.
Interferon beta products are approved for relapsing forms of MS. These drugs can
reduce the frequency and severity of attacks and the number and size of MRIdetectable lesions and delay the progression of disability.
Interferon beta-1b also is approved for patients with secondary progressive MS.
Interferon beta generally is well tolerated, although side effects are common:
flulike reactions occur often; the drug can injure the liver and suppress bone
marrow function; and subcutaneous injection can cause pain, erythema, bumps, and
itching. Also, interferon beta has been loosely associated with depression.
Like all other foreign proteins, interferon beta is immunogenic and thus can
stimulate the production of antibodies against itself. If present in sufficiently high
titers, these neutralizing antibodies can reduce the clinical benefits.

The chapter continues with a discussion of individual drugs and their side effects.

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

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Glatiramer acetate, also known as copolymer-1, is used for long-term therapy of


relapsing-remitting MS. Glatiramer can reduce the frequency and severity of
relapses and the development of MRI-detectable lesions and delay the progression
of disability.
In patients with MS, glatiramer promotes a T-cell shift; that is, it reduces the
production of proinflammatory TH1 cells and increases production of antiinflammatory TH2 cells. The anti-inflammatory cells migrate across the bloodbrain barrier at sites of inflammation and then suppress the inflammatory attack
on myelin.
Glatiramer is generally well tolerated. Injection-site reactionspain, erythema,
pruritus (itching), and induration (pitting)are most common.
About 10% of patients have a self-limited postinjection reactioncharacterized
by flushing, palpitations, severe chest pain, anxiety, laryngeal constriction, and
urticariathat typically lasts 15 to 20 minutes.
Natalizumab is a recombinant monoclonal antibody. Protective restrictions have
been placed on who can prescribe, dispense, administer, and receive the drug,
because it poses a risk of progressive multifocal leukoencephalopathy (PML), a
severe infection of the brain.
Natalizumab is approved only for monotherapy of relapsing forms of MS.
In studies, natalizumab reduced the annualized rate of relapse by 68% and the
number of new or enlarging brain lesions by 83%. However, owing to the risk
of PML, natalizumab should be reserved for patients who have not responded
to at least one of the first-line agents, and it should not be combined with other
disease-modifying drugs.
Natalizumab prevents circulating leukocytes (T cells and monocytes) from
leaving the vasculature, thereby preventing these cells from migrating to sites
where they can do harm.
The most common reactions are headache and fatigue. Other common reactions
include abdominal discomfort, arthralgia, depression, diarrhea, gastroenteritis,
urinary tract infections, and lower respiratory tract infections. The most serious
effects are PML, liver injury, and hypersensitivity reactions.
Fingolimod is a first-in-class sphingosine 1-phosphate receptor modulator and the
first oral disease-modifying agent for MS.
The drug is approved for reducing the frequency of MS exacerbations and
delaying disability in patients with relapsing forms of the disease.
Fingolimod can cause significant adverse effects. Accordingly, it should be
reserved for patients who cannot tolerate injections or have not responded well to
other immunomodulators.
Fingolimod binds with high affinity to a class of molecules known as sphingosine
1-phosphate (S1P) receptors on lymphocytes, causing their sequestration in
lymph nodes. This leaves fewer lymphocytes in the peripheral blood, reducing the
inflammation that underlies neuronal injury.

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

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Fingolimod can cause multiple adverse effects. The most common are headache,
diarrhea, cough, back pain, influenza, and elevation of liver enzymes. The most
serious are bradycardia, macular edema, infection, fetal harm, and liver injury.
Fingolimod causes a 20% to 30% decrease in circulating lymphocytes and thus
increases the risk of infection.
Fingolimod is teratogenic and embryolethal in animals at doses equivalent to
those used clinically; there are no well-controlled studies in pregnant women.
Women of child-bearing age should be informed of the risk of fetal harm and
advised to use two effective forms of contraception both during treatment and for
2 months after the cessation of therapy.
Fingolimod can cause a dose-dependent decrease in lung function.

The chapter continues with a discussion of immunosuppressants, noting that only


one has been approved for the treatment of MS.

Mitoxantrone is the only immunosuppressant approved for the treatment of MS.


The drug poses a significant risk of toxicity and therefore generally is reserved for
patients who cannot be treated with safer agents.
Mitoxantrone is approved for reducing neurologic disability and clinical relapses in
patients with worsening relapsing-remitting MS, secondary progressive MS, and
progressive-relapsing MS.
The drug may delay the time to relapse and the time to disability progression. In
addition, it may reduce the number of new MRI-detectable lesions.
Mitoxantrone is a cytotoxic drug that binds with DNA and inhibits topoisomerase
II. These actions inhibit DNA and RNA synthesis and promote cross-linking and
breakage of DNA strands.
In patients with MS, mitoxantrone suppresses production of immune system cells
(B lymphocytes, T lymphocytes, and macrophages), thereby reducing
autoimmune destruction of myelin.
Mitoxantrone can cause a variety of adverse effects; myelosuppression,
cardiotoxicity, and fetal injury are the greatest concerns.
Because mitoxantrone is especially toxic to tissues with a high percentage of
dividing cells, it can cause reversible hair loss and injury to the gastrointestinal
(GI) mucosa. The drug also can cause nausea, vomiting, menstrual irregularities,
and symptoms of allergy. In addition, mitoxantrone can impart a harmless, bluegreen tint to the skin, sclera, and urine; patients should be forewarned.

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