318 Unit 4 Pharmacology of the Central Nervous System
Pharmacotherapy Illustrated 21.2
Alzheimer’s Drugs Work by Intensifying the Effect of Acetylcholine at the Receptor
1 Alzheimer’s disease
Characterized by abnormal structures in the brain:
• Neurons die
• The brain shrinks
• Memory is lost
Amyloid
plaques
Neurofibrillary Healthy neuronal structure
tangles
Unhealthy neuronal structure
2 Drug therapy focuses on restoring or enhancing Cholinergic neuron
acetylcholine’s role in the brain
• Cholinesterase inhibitors Pyruvate
e.g., donepezil
Normally: AcetylCoA Acetylcholine Normal role of
3 Factors responsible for brain cell death + (ACh) acetylcholine
include excessive transmission of glutamate 1 ACh is released. 1 in a vast array
Drug therapy: Choline of brain
• N-methyl-D-aspartate (NMDA) receptor drugs 2 ACh binds with functions,
e.g., memantine its receptor. Choline ACh 2 including the
Ac+etate ability to
Combination drug therapy: 3 The action of speak, move,
• Donepezil and memantine ACh is terminated 3 AChE see, think, and
by AChE. remember.
4 If AChE is
inhibited, ACh is
not broken down
as quickly and 4
produces a more
dramatic e ect.
AChE = acetylcholinesterase Cholinergic receptor
Neuron with
cholinergic receptor
Memantine (Namenda) was approved in 2003 for the Caution is indicated when memantine is given to
treatment of patients with moderate to severe AD. It acts by older adults or those with chronic kidney disease or sei-
a different mechanism than the centrally acting cholinester- zure disorder. No life-threatening adverse effects have
ase inhibitors. Memantine reduces abnormally high levels been identified. Occasional adverse effects have been
of glutamate, which is the major excitatory neurotransmit- reported, including dizziness, confusion, vomiting, head-
ter of the CNS. Chronic, high levels of brain glutamate have ache, cough, and hypertension. Because memantine and
been associated with the progression of AD and cell death. cholinesterase inhibitors act by different mechanisms,
Glutamate exerts its neural effects through interaction with they may be taken in combination. When taken together,
the N-methyl-D-aspartate (NMDA) receptor. Memantine these drugs do not interfere with each other’s absorption,
binds to the NMDA receptor, preventing glutamate from distribution, metabolism, or elimination. An extended
causing its excitatory actions and, theoretically, slowing release form (Namenda XR) offers the convenience of
nerve damage. once-daily dosing. Namzaric, a fixed-dose combination of
Chapter 21 Pharmacotherapy of Degenerative Diseases of the Central Nervous System 319
memantine and donepezil, was approved in 2015 to treat available in tablet, PO solution, and PO disintegrating
moderate to severe AD. tablet (Aricept ODT) forms. It has an extended duration of
action that allows for once-daily dosing. Donepezil is the
Other medication classes frequently prescribed for most frequent drug prescribed for AD.
symptoms associated with AD include antipsychotics, anti-
depressants, and antianxiety drugs. Agitation occurs in the There is no evidence that donepezil stops the destruc-
majority of patients with AD, which may be accompanied tion of neurons or that it alters the course of the underlying
by delusions, paranoia, hallucinations, or other psychotic dementia. It may, however, prolong the time between diag-
symptoms. Atypical antipsychotics such as risperidone nosis and the institutionalization of the patient. A caregiver
(Risperdal) and olanzapine (Zyprexa) may be used to con- must be present to assist the patient in adhering to the
trol these episodes. Conventional antipsychotics such as medication regimen.
haloperidol (Haldol) are occasionally prescribed, although
EPS often limit their use. The antipsychotic medications are Mechanism of Action: Donepezil raises ACh con-
presented in Chapter 20. centrations in the brain. Because the drug is moderately
selective for cholinesterase in the CNS, it produces fewer
Although not as common as agitation, anxiety and peripheral adverse effects than other drugs in this class.
depression occur in many patients with AD. Anxiolytics
such as buspirone (BuSpar) or benzodiazepines are used to Pharmacokinetics:
control anxiety. Mood stabilizers such as sertraline (Zoloft),
citalopram (Celexa), or fluoxetine (Prozac) are given when Route(s) PO
major depression interferes with daily activities. The stu-
dent should refer to Chapters 18 and 19 for information on Absorption Completely absorbed
these drugs.
Distribution Well distributed; crosses the
PROTOTYPE DRUG Donepezil (Aricept)
blood–brain barrier; 96% bound
Classification Therapeutic: Anti-Alzheimer’s drug
Pharmacologic: Reversible to plasma proteins
cholinesterase inhibitor Primary metabolism Hepatic; metabolized to active
Therapeutic Effects and Uses: Donepezil was ap- metabolites
proved to treat symptoms of AD in 1996. The drug is
Primary excretion Primarily renal; some feces
Onset of action 3–4 h
Duration of action Half-life: 10 h, if single dose; 70
h if multiple dose
Adverse Effects: Common adverse effects of done-
pezil that cause discontinuation of therapy are diarrhea,
CONNECTIONS: Complementary and Alternative Therapies
Ginkgo Biloba for Treatment of Dementia
Description Evidence
Ginkgo biloba is one of the oldest species of trees in the world, In U.S. studies, 240 mg of ginkgo taken daily has been shown to
with fossils of the tree dating back to the dinosaurs. Ginkgo improve mental functioning and stabilize AD in patients with mild
seeds and leaves have been used in traditional Chinese medi- cognitive impairment and dementia (Solfrizzi & Panza, 2015).
cine for thousands of years. The tree is now planted throughout Some studies have suggested that ginkgo may provide additional
the world, including the United States. positive effects in patients already taking AD drugs (Canevelli et al.,
2014). The mechanism of action seems to be related to neuropro-
History and Claims tective effects on brain cells (University of Maryland Medical
Center, 2015). Ginkgo has also been studied for the treatment of
In Chinese medicine, ginkgo was used to treat asthma, tinnitus, intermittent claudication, age-related macular degeneration
hypertonia, and angina. In Western medicine, the focus has (AMD), glaucoma, Raynaud’s phenomenon, anxiety, and premen-
been on treating depression and memory loss. In Germany, an strual syndrome, although results from these studies are mixed.
extract of ginkgo biloba is approved for the treatment of
dementia. Patients should consult with their healthcare provider
before taking this herb. Although most people can take ginkgo
Standardization without problems, those who are also taking anticoagulants,
aspirin, or NSAIDs may have an increased risk for bleeding.
Ginkgo biloba extract is often standardized to contain Because the FDA does not approve herbal products, ginkgo
24% ginkgo flavonoids and 6% terpenoids. A typical dose is and other herbs have not undergone the same scrutiny given to
120–240 mg/day. newly developed medications.
320 Unit 4 Pharmacology of the Central Nervous System
nausea, and vomiting. Donepezil exhibits typical cholin- donepezil. Approved in 2001, it is indicated for mild to
ergic effects such as diaphoresis, bradycardia, salivation, moderate symptoms of dementia. Like other AD medica-
and muscle weakness. Other possible adverse effects are tions, it does not alter the progression of the disease. It is
anorexia, muscle cramps, fatigue, arthralgia, abnormal available in immediate and extended release (ER) forms.
dreams, and headache. Many of these adverse events will This drug was originally named Reminyl, but to avoid pre-
diminish with continued therapy or by using a lower dose scribing errors with the drug Amaryl (an antidiabetic
of the drug. Potential life-threatening adverse effects in- drug), the FDA ordered the name changed to Razadyne.
clude atrial fibrillation, sinus bradycardia, and seizures.
Abrupt discontinuation of the drug results in a sudden The most frequent adverse effects are nausea and vom-
decline of cognitive function and an increase in behavioral iting. The drug may be administered with food or with an
disturbances. antiemetic to reduce these effects. Other adverse reactions
include diarrhea, bradycardia, chest pain, fatigue, anemia,
Contraindications/Precautions: The only contrain- syncope, vertigo, headache, insomnia, or tremor. Anorexia
dication to the use of donepezil is hypersensitivity to the and weight loss are possible and may be serious effects in
drug. There is a risk of GI bleeding, especially in patients patients who are debilitated. In addition, it is not recom-
with a history of peptic ulcers or chronic use of nonsteroi- mended for use in individuals with severe hepatic or renal
dal anti-inflammatory drugs (NSAIDs). It should be used dysfunction or in children or a lactating woman. It must be
with caution in patients with hyperthyroidism or hepatic used cautiously in individuals with respiratory disease,
dysfunction, or those who are lactating. Increased numbers bradycardia, cardiac conduction disorders, seizure history,
of seizures have been recorded in patients taking donepe- history of GI bleeding, peptic ulcer disease, or asthma. It is
zil, especially in those patients with a history of seizures. a pregnancy category C drug.
Drug Interactions: Donepezil is metabolized by Rivastigmine (Exelon): Like other drugs in this class,
CYP450 enzymes (CYP2D6 and CYP3A4), and drugs that rivastigmine inhibits brain cholinesterase more than
enhance or inhibit these enzymes have the potential to in- heart or skeletal muscle cholinesterase. Approved in
teract with donepezil. Decreased effects of donepezil will 2000, it is used to treat mild to moderate symptoms of
occur with concurrent administration of phenytoin, phe- dementia associated with AD and PD. It has similar
nobarbital, rifampin, dexamethasone, and carbamazepine. effectiveness to donepezil. Rivastigmine is given PO
Concurrent use of NSAIDs may lead to GI ulceration and with food to prevent nausea and vomiting, which fre-
bleeding. Synergistic effects will occur with cholinergic quently occur with this medication. Liquid preparations
agonists, cholinesterase inhibitors, and succinylcholine. should be mixed only with water, soda, or juice. A once-
Because it is a cholinergic agonist, donepezil will decrease daily transdermal patch of rivastigmine is available for
the effects of anticholinergic drugs. Metabolism of done- both PD and AD.
pezil may be inhibited by quinidine and ketoconazole.
Herbal/Food: None known. Rivastigmine is contraindicated in patients with hyper-
sensitivity to rivastigmine or carbamate. Nausea, vomiting,
Pregnancy: Category C. anorexia, and diarrhea occur in a significant number of
patients. The transdermal patch form of the drug causes a
Treatment of Overdose: Overdosage will result in lower incidence of GI adverse effects. Other common
signs of cholinergic crisis, such as nausea, vomiting, bra- adverse effects include headache, vertigo, abdominal pain,
dycardia, respiratory depression, hypotension, and sei- and confusion. Cautious use is indicated when given to
zures. Anticholinergic drugs such as 1 to 2 mg IV atropine patients with a hypersensitivity to cholinesterase inhibi-
may be administered to reverse some of the overdose tors; cardiac, pulmonary, renal, or hepatic disease; diabetes;
symptoms. GI disorders; concurrent use of other cholinergic or anti-
cholinergic drugs; PD; seizure history; or concurrent use of
Nursing Responsibilities: Key nursing implications NSAIDs. No potential life-threatening adverse effects have
for patients receiving donepezil are included in the Nurs- been identified. It is a pregnancy category B drug.
ing Practice Application for Patients Receiving Pharmaco-
therapy for Neurodegenerative Disorders. Multiple Sclerosis
Drugs Similar to Donepezil (Aricept) 21.11 Multiple sclerosis is a chronic,
neurodegenerative disease that is treated with
Other cholinesterase inhibitors used to treat the symptoms immunomodulator drugs.
of AD are galantamine and rivastigmine.
Multiple sclerosis (MS) is a neurodegenerative disease
Galantamine (Razadyne): Galantamine is an oral cholin- characterized by demyelination, the destruction or
esterase inhibitor that has the same uses and actions as removal of the myelin sheath from a nerve or nerve fiber.
Chapter 21 Pharmacotherapy of Degenerative Diseases of the Central Nervous System 321
The destruction is secondary to an inflammatory response and any changes in personality or behavior. A diagnosis is
that leads to random areas of demyelination, known as made after other neurologic disorders have been ruled out.
plaques, in the white matter of the CNS. The exact cause of Imaging studies such as MRI are useful in identifying the
MS is unknown. It is believed that a pathogen, such as a areas of demyelination in the brain.
latent virus, may trigger an abnormal autoimmune
response in patients who are genetically susceptible. MS is Like other neurodegenerative disorders, there are no
a leading cause of neurologic disability in the 20- to drugs available that can cure MS or reverse the progressive
40-year-old age group, although it may affect individuals demyelination of nerves. Existing drugs for MS are only
of any age (Figure 21.1). partially effective and some have serious adverse effects. In
general, pharmacotherapy has the following three goals:
MS has a typical pattern of progression that is charac-
terized by periods of symptom exacerbation alternating • Modify the progression of the disease.
with periods of remission during which symptoms com- • Treat acute exacerbations.
pletely disappear. Remissions may last several months or • Manage symptoms.
even years. Less commonly, progression may be continu-
ous without any clear remission periods. Drugs for modifying the progression of MS: Although
Diagnosis of MS is often difficult because its symptoms the exact etiology of MS remains unknown, it is considered
mimic those of other neurologic disorders. The early symp-
toms are frequently vague and nonspecific and include an autoimmune disease. The body has mounted an immune
weakness, visual disturbances, paresthesias, mild affective
disturbances, and difficulty with bladder control. Cogni- attack against its own tissues, in this case, the myelin sur-
tive impairment is common. It should be determined if the
symptoms are worsening or are intermittent. Also of note is rounding nerves. Strategies for slowing the progression of
whether the activity level of the patient has decreased,
along with worsening fatigue, things that aggravate the MS have therefore focused on modifying the abnormal
symptoms (e.g., hot showers or baths, overexertion, stress),
immune response of these patients through the application
of immunomodulators. Immunomodulator is a general
term that refers to drugs that affect body defenses. There
are two basic types of immunomodulators: those that stim-
ulate or boost the immune response and those that suppress
some aspect of immune function. Both types are used in
MS pharmacotherapy. For detailed informa-
tion on the immunomodulators, refer to
(a) Normal neuron Muscle Chapter 42.
Neuron The immunomodulators are used to pre-
Myelin sheath
vent exacerbations in patients with MS.
Immunomodulators are initiated soon after
Rapid conduction the diagnosis of MS is confirmed because
early control of disease activity has been
demonstrated to delay the progressive phase
of MS and prolong the ability of patients to
remain actively involved in daily activities.
(b) Early stage of multiple sclerosis T cells and monocytes Treatment should continue indefinitely and
attacking myelin sheath
only be changed or stopped if toxicity devel-
ops or there is no apparent benefit. Doses of
these drugs are listed in Table 21.7.
Slowed conduction The immunomodulators have equal effi-
cacy in treating MS. Selection is frequently
based on the clinical experiences of the health-
care provider and patient tolerance. They all
are expensive, with monthly costs exceeding
(c) Late stage of multiple sclerosis Fibrotic $4000. Interferon beta-1a (Avonex, Rebif),
region
peginterferon beta-1a (Plegridy), interferon
Slowed or no
conduction beta-1b (Betaseron, Extavia), glatiramer
Figure 21.1 Multiple sclerosis. (Copaxone, Glatopa), and ocrelizumab (Ocre-
vus) are immunomodulators used as first-line
therapy to modify the progression of MS. With
the exception of ocrelizumab, these drugs
require frequent self-administration, which
increases the risk for injection-site reactions or
322 Unit 4 Pharmacology of the Central Nervous System
Table 21.7 Drugs for Modifying the Progression of Multiple Sclerosis
Route and Adult Dose (Maximum Dose
Drug Where Indicated) Adverse Effects
alemtuzumab (Lemtrada) IV (two infusions, 12 months apart): first Infections, rash, headache, pyrexia, nasopharyngitis, fatigue
daclizumab (Zinbryta) course 12 mg/day for 5 days; second course
12 mg/day for 3 days Cytopenias, infusion reactions, serious infections, increased risk
of malignancies, serious autoimmune conditions
Subcutaneous: 150 mg once monthly
Skin infections, nasopharyngitis, upper respiratory tract infection,
rash
dimethyl fumarate (Tecfidera) PO: 120 mg bid for 7 days, then 240 mg bid Hypersensitivity reactions, immune-mediated disorders, severe
hepatotoxicity, serious infections, depression, suicide ideation
Flushing, abdominal pain, diarrhea, and nausea
fingolimod (Gilenya) PO: 0.5 mg once daily Lymphopenia
Headache, back pain, diarrhea, elevated liver transaminase
glatiramer (Copaxone, Glatopa) Subcutaneous: 20 mg daily or 40 mg Macular edema, bradycardia and other dysrhythmias
3 times/wk
Local reactions, arthralgia, back pain, flulike symptoms, infection,
anxiety, vasodilation, chest pain, palpitations, rash, pruritus,
diarrhea, nausea, dyspnea, rhinitis
interferon beta-1a (Avonex, Rebif) and IM: 30 mcg/wk Asthenia, lymphadenopathy
peginterferon beta-1a (Plegridy) Subcutaneous (Rebif): 4.4–44 mcg 3 times/wk Myalgia, upper respiratory tract infection, flulike symptoms,
Subcutaneous (Plegridy): 63 mg once on day injection-site reactions, headache, fever, nausea, chills
interferon beta-1b (Betaseron, Extavia) 1; 94 mcg on day 15; 125 mcg on day 29 and Hepatotoxicity, leukopenia, myelosuppression, severe depression
mitoxantrone (Novantrone) thereafter q2wk (suicide risk), seizures, anaphylaxis
Subcutaneous: 0.0625–0.25 mg every other day Nausea, vomiting, diarrhea, cough, headache, abdominal pain,
fever, alopecia
IV: 12 mg/m2 every 3 months (max: lifetime
dose 140 mg/m2)
natalizumab (Tysabri) IV: 300 mg infused over 1 h every month Myelosuppression, renal failure, hepatotoxicity, cardiotoxicity
(heart failure, MI, fetal harm)
Headache, depression, fatigue, menstrual dysfunction
ocrelizumab (Ocrevus) IV: 300 mg followed by 300 mg 2 wk later; Anaphylaxis (rare), infections
teriflunomide (Aubagio) subsequent dosing is 600 mg every 6 months Respiratory and skin infections
PO: 7–14 mg once daily Infusion reaction, possible malignancies and teratogenicity
Alopecia, diarrhea, influenza, nausea, paresthesia
Severe hepatotoxicity, teratogenicity, leukopenia, severe skin
reactions
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
abscess formation. The recent development of oral drugs Mechanism of Action: The mechanism of action by
for MS will likely lead to additional first-line drugs that which IFN beta-1b produces improvements in the symptoms
slow the progression of the disease. of MS is unknown. It is believed to act by suppressing the
activity of T cells and reducing the inflammatory actions of
PROTOTYPE DRUG Interferon Beta-1b (Betaseron, cytokines, which are substances secreted by activated T cells.
Extavia)
Pharmacokinetics: Subcutaneous
Classification Therapeutic: Drug for relapsing forms of Route(s)
multiple sclerosis Absorption 50% absorbed
Distribution
Pharmacologic: Immunomodulator Crosses the blood–brain barrier
Primary metabolism poorly; crosses placenta and
Therapeutic Effects and Uses: Approved in 1993, enters breast milk
interferon (IFN) beta-1b is produced by recombinant DNA Primary excretion
technology and is very similar to natural IFN. It was one Onset of action Rapidly metabolized in body
of the first drugs developed that was found to slow the Duration of action tissues
progression of MS. Patients taking IFN beta-1b experience
fewer relapses and a reduction in brain lesions characteris- Unknown
tic of MS. This drug is available by subcutaneous injection
for the treatment of patients with relapsing MS. 6–12 h
Half-life: 8 min–4 h
Chapter 21 Pharmacotherapy of Degenerative Diseases of the Central Nervous System 323
Adverse Effects: Adverse effects are very common adverse effects, it is reserved for patients who have had an
with IFN beta-1b. Most patients taking interferon beta-1b inadequate response to at least two other MS medications.
will experience transient flulike symptoms: Analgesics and The medication carries black box warnings regarding an
antipyretics may be premedicated on injection days to re- increased risk for hepatic injury and immune-related dis-
duce these symptoms. Injection-site reactions also occur orders. Its use is contraindicated in patients with preexist-
in the majority of patients. Patients should be monitored ing hepatic impairment or a history of autoimmune
closely for depression and suicidal ideation. Injection-site disorders. Prescribers must complete special training and
inflammation occurs in most patients and may progress pharmacies must be certified to dispense daclizumab. The
to necrosis. Other common adverse effects include leuko- drug has not been assigned a pregnancy category.
penia, headache, insomnia, asthenia, increased liver en-
zymes, rash, peripheral edema, and malaise. Dimethyl fumarate (Tecfidera): Approved in 2013,
dimethyl fumarate is used for treating relapsing forms of
Contraindications/Precautions: The only contra- MS. Given PO, its mechanism of action is unknown.
indication is history of hypersensitivity to interferon beta, Adverse effects include mild to moderate flushing, abdom-
albumin, or mannitol. inal pain, diarrhea, and nausea. Lymphocyte counts should
be monitored during therapy because dimethyl fumarate
Drug Interactions: Zidovudine (AZT) levels may in- can cause significant lymphopenia. This drug is pregnancy
crease to toxic levels during therapy. Herbal/Food: None category C.
known.
Fingolimod (Gilenya): Approved in 2010, fingolimod has
Pregnancy: Category C. a unique mechanism of action in that it blocks the capacity
of lymphocytes to exit lymph nodes. Because they remain
Treatment of Overdose: Treatment for overdose of in the nodes, there are fewer lymphocytes in peripheral tis-
this drug has not been documented. sues, including the CNS. The drug can reduce lymphocyte
counts to 60% of baseline values within 4 to 6 hours after a
Nursing Responsibilities: Key nursing implications single dose. Fingolimod is approved for the treatment of
for patients receiving interferon beta-1b are included in the patients with relapsing forms of MS. A major advantage is
Nursing Practice Application for Patients Receiving Phar- that the drug is given PO with once-daily dosing. Unfortu-
macotherapy for Neurodegenerative Disorders. nately the drug has the potential to cause serious dys-
rhythmias: Patients must be carefully monitored for
Drugs Similar to Interferon Beta-1b bradycardia and other cardiac rhythm abnormalities dur-
(Betaseron, Extavia) ing therapy. Due to the diminished lymphocyte count,
patients are at risk for infections. Macular edema is an
Other drugs used to treat the relapsing symptoms of MS adverse effect that is especially troublesome in patients
are alemtuzumab, daclizumab, dimethyl fumarate, fingoli- with a history of uveitis or diabetes. The most common
mod, glatiramer, IFN beta-1a, mitoxantrone, natalizumab, adverse effects are headache, influenza, diarrhea, back
and teriflunomide. pain, cough, and elevated liver transaminase levels. Fingo-
limod is pregnancy category C.
Alemtuzumab (Lemtrada): Alemtuzumab is a monoclonal
antibody against CD52 approved in 2014 for relapsing Glatiramer (Copaxone, Glatopa): Approved in 1996, glat-
forms of MS. Because of the potential for serious adverse iramer is one of several first-line drugs in the treatment of
effects, it is used for patients who have had an inadequate relapsing MS, including patients who have experienced
response to at least two other MS medications. It is given their initial clinical episode of the disease. The drug
by two IV infusions, 12 months apart. Because nearly all reduces the annual relapse rate for MS and the generation
patients experience infusion reactions, premedication with of new lesions in the brain. It is believed to dampen the
a high-dose corticosteroid just prior to alemtuzumab dos- immune response by activating suppressor T cells. It is
ing is necessary. This drug comes with several black box administered daily by the subcutaneous route. The most
warnings including an increased risk for cytopenias common adverse effects are injection-site reactions, vaso-
(including fatal pancytopenia), infusion reactions (some of dilation, weakness, dyspnea, and chest pain, which are
which have been fatal), serious infections (including Pneu- usually transient. The drug is pregnancy category B.
mocystis jiroveci), and malignancies (including thyroid can-
cer, melanoma, and lymphoproliferative disorders). This IFN beta-1a (Avonex, Rebif) and PEG IFN beta-1a (Plegridy):
medication is pregnancy category C. Approved in 1996, IFN beta-1a is structurally identical to
the natural IFN produced by the body. IFN beta-1a
Daclizumab (Zinbryta): Approved in 2016, daclizumab is decreases the frequency of clinical exacerbations and
a monoclonal antibody that blocks the interleukin-2 recep- slows the progression to physical disability. The drug acts
tor called CD25. Because of the potential for serious
324 Unit 4 Pharmacology of the Central Nervous System
by inhibiting the release of proinflammatory cytokines pregnancy rated but animal data suggests it may cause
that initiate the autoimmune reaction leading to MS. IFN fetal harm.
beta-1a also changes the blood–brain barrier and reduces
T-lymphocyte migration into the brain, thereby reducing Teriflunomide (Aubagio): Approved in 2012, terifluno-
inflammation. It is available by the subcutaneous (Rebif) mide is an oral drug for treating relapsing forms of MS. It
and IM (Avonex) routes. Peginterferon beta-1a (Plegridy) is an active metabolite of leflunomide (Arava), a drug for
has the same actions but has a longer duration of action treating rheumatoid arthritis. Teriflunomide acts by sup-
that allows for dosing once every 2 weeks. Adverse pressing the division of B and T cells. Teriflunomide is
effects are similar to those of other IFNs, with flulike generally well tolerated; however, some serious toxicities
symptoms being observed in the majority of patients. are associated with the drug. It carries a black box warning
Patients should be monitored for depression and suicidal that severe, and sometimes fatal, liver injury may occur. In
ideation. Decreased peripheral blood counts, including addition, the drug may cause birth defects and is preg-
thrombocytopenia and leukopenia, have been reported. nancy category X. This drug is eliminated very slowly and
Rare cases of severe hepatotoxicity, including some cases may take 8 to 24 months to be completely excreted from
requiring liver transplantation, have been reported in the body.
patients taking IFN beta-1a. In 2014 the long-acting form
of the drug, Plegridy, was approved. This drug is preg- Drugs for treating acute exacerbations of MS: Acute
nancy category C. exacerbations of the disease are treated with high-dose
corticosteroid therapy with prednisone or methylprednis-
Mitoxantrone (Novantrone): Mitoxantrone is an immuno- olone. The recommended length of treatment is no longer
modulator that is approved to treat acute myelogenous than 3 weeks and no more than 3 times a year. Although
leukemia, prostate cancer, and chronic, progressive relaps- very high doses are administered, the short-term use of
ing forms of MS. In treating MS, mitoxantrone acts by sup- corticosteroids does not usually cause significant adverse
pressing B and T lymphocytes and macrophages. Fatigue effects (see Chapter 68). Another drug that can be used to
and GI-related adverse effects are common. The most seri- treat an acute exacerbation is IV gamma globulin. This has
ous toxicities are myelosuppression and cardiotoxicity. The proven to be a successful treatment for patients who are
drug carries a black box warning that it may result in unresponsive or unable to tolerate corticosteroids.
potentially fatal heart failure as long as several years after
therapy is discontinued. It is only administered by IV infu- Drugs for managing symptoms of MS: Many classes
sion. This drug is pregnancy category D. of medications may be ordered to manage symptoms of
MS including antianxiety drugs, antidepressants, anti-
Natalizumab (Tysabri): Natalizumab is a monoclonal psychotics, or sedative–hypnotics. These symptomatic
antibody that acts by preventing white blood cells from medications are used to treat other conditions and are
migrating to the CNS. This inhibition reduces the inflam- discussed in other chapters of this text. The patient may
mation and demyelination of nerves in the brain. It is experience physical symptoms such as muscle spasticity
administered by IV infusion. Although effective for treat- or bladder or bowel dysfunction. Depression is common;
ing MS, its use is severely restricted due to a small risk of it may be the emotional response to a diagnosis of a
progressive multifocal leukoencephalopathy (PML), a rare chronic, progressive, potentially debilitating disease, or it
and sometimes fatal demyelinating disease of the CNS. may be secondary to damage to mood-regulating neu-
Restrictions limit the prescribers to those who have special rons as the disease progresses. Chronic pain may require
training in PML. In addition, only certain pharmacies can the use of analgesics. Approved in 2010, dalfampridine
distribute the drug. The drug carries a black box warning (Ampyra) is specifically indicated to improve walking in
for its risk of producing PML. Additional details on the patients with MS.
monoclonal antibody class of drugs may be found in
Chapter 42. Natalizumab is pregnancy category C. Pain is experienced in up to 86% of patients with MS
but it is not always well classified. Research is ongoing to
Ocrelizumab (Ocrevus): Approved in 2017, ocreli- develop a classification system (Truini, Barbanti, Pozzilli,
zumab is a monoclonal antibody that binds to the CD20 & Cruccu, 2013). Determining the cause of pain leads to
receptor on B lymphocytes. The binding results in the more effective treatment strategies. For example, neuro-
immune destruction of these cells. It is the only drug pathic pain caused by plaques in the spinal cord may
approved to treat primary progressive MS, a form of the respond to drugs such as amitriptyline or carbamaze-
disease that steadily worsens, without relapses. The pine. Pain due to muscle spasms related to MS may be
most common adverse effects include infusion reactions, treated with baclofen and gabapentin. Because many
respiratory infections, and skin infections. An increased patients with MS have mixed types of pain, thorough
risk of malignancies has been reported. The drug is not assessment is needed in order to determine the most
effective therapy.
Chapter 21 Pharmacotherapy of Degenerative Diseases of the Central Nervous System 325
PharmFACT in 1995, riluzole (Rilutek) has been shown to extend survival
by reducing the degeneration of neurons. It is estimated that
Although it most commonly occurs in adults, it is estimated survival is prolonged by only 3 months. Riluzole is a tablet
that 8,000 to 10,000 children have MS in the United States. that is given every 12 hours on an empty stomach. Seizures
Children have symptoms similar to those of adults but are the only life-threatening adverse effect. Common adverse
present with a higher incidence of seizures and mental status effects include headache, dizziness, poor concentration, con-
changes (National Multiple Sclerosis Society, n.d.). fusion, anxiety, hypotension, and edema.
Amyotrophic Lateral Sclerosis Approved in 2017, edaravone (Radicava) has been shown
to slow the progression of ALS and help individuals to pre-
21.12 The pharmacotherapy of amyotrophic serve function for a longer period of time. Administered by IV
lateral sclerosis is limited to a few drugs. infusion, edaravone is administered for 14 consecutive days,
followed by a 2-week drug-free period. All cycles thereafter
Amyotrophic lateral sclerosis (ALS), commonly known as are infused for 10 days, followed by a 2-week drug-free
Lou Gehrig’s disease, is the most common degenerative period. The most common adverse effects include bruising,
disease of the motor neurons. Its symptoms include weak- difficulty walking, and headache. This drug is not pregnancy
ness and atrophy of the muscles of the legs, hands, and rated but it may cause fetal harm based on animal data.
forearms that spread to all muscles of the body. Sensory
and cognitive functions are not affected. It usually occurs The patient with ALS experiences painful muscle spas-
in middle age and progresses rapidly to death in 2 or 3 ticity. Treatment with muscle relaxants such as baclofen
years due to respiratory failure or pneumonia. There is no (Lioresal) may bring some relief (see Chapter 23). Anticho-
known cause or curative treatment for the disease. About linergic drugs such as trihexyphenidyl or benztropine may
10% of cases have a familial history of the disorder. be administered to decrease saliva production. Rimabotu-
linumtoxinB (Myobloc) may be used off-label to reduce
Few drugs have FDA approval for treating patients with saliva secretion for up to 3 months. Opioids may be neces-
ALS, and none of them is able to cure the disease. Approved sary to treat severe pain late in the progress of the disease.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy for Neurodegenerative Disorders
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including cardiovascular, musculoskeletal diseases, or glaucoma. Obtain a drug history including allergies, current
prescription and OTC drugs, and herbal preparations. Be alert to possible drug interactions.
• Obtain a history of the current disease and symptoms, exacerbating conditions, and ability to carry out ADLs, particularly mobility and eating. Consider
safety concerns and whether alternative care environments are needed.
• Evaluate appropriate laboratory findings such as hepatic or renal function studies.
• Obtain baseline vital signs, bowel sounds, urinary output, muscle strength, and mental status as appropriate.
• Assess for disturbances in thought processes, perception, verbal communication, affect, behavior, interpersonal relationships, and self-care. Use
objective screening tools such as the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the Mini-Mental State
Examination (MMSE), or as per healthcare agency.
• Obtain a history of depression or sleep disorders and current treatments used.
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Assess for desired therapeutic effects (e.g., decreased tremors, bradykinesia, or rigidity, decreased agitation, fearfulness, and maintenance of current
functioning level).
• Continue periodic monitoring of vital signs, mental status, motor function, and the ability to carry out ADLs.
• Assess for and promptly report adverse effects: hypotension, increasing tremors, dizziness, salivation, anorexia, dysphagia, nausea, vomiting, diarrhea,
changes in heart rate or rhythm, or changes in mental status, including agitation or confusion.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient, family, or caregivers that gradual improvement in PD
• Continue frequent assessments as above for therapeutic effects. Drug symptoms may be noted. The patient should report continued or
increasing symptoms similar to those noted before drug therapy was
therapy may take several weeks or months to have full effect. Support initiated.
the patient in self-care activities as necessary until improvement is
observed. (The ability to carry out ADLs gradually improves with • In AD, teach the patient, family, or caregivers that these drugs delay
consistent usage of drug therapy in PD. Continued tremors, rigidity, or the progression of symptoms but do not treat or cure the underlying
other symptoms may require dosage adjustment. Symptoms help disease process. Increasing symptoms or a decrease in the ability to
determine the stage of the disease in AD and whether the medication perform self-care activities should be reported.
remains therapeutic.)
(continued )
326 Unit 4 Pharmacology of the Central Nervous System
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Minimizing adverse effects: • Instruct the patient with PD to call for assistance prior to getting out of
• Ensure patient safety; monitor motor coordination and ambulation, eating, bed or attempting to walk alone if bradykinesia, rigidity, or tremors are
particularly severe.
or other essential motor activities. Lifespan: Be particularly cautious with
older adults who are at increased risk for falls. (Gradual improvement in • Assess the ability of the patient, family, or caregivers to safely carry out
symptoms may be noticed over time, but the drug does not cure the ADLs at home, including previously safe activities such as cooking,
underlying disorder, and symptoms may wax and wane over the course walking alone, and living alone. Report changes that may require early
of the drug regimen. Particular care with ambulation is required in PD intervention to the provider. Explore the need for additional healthcare
because bradykinesia and rigidity may increase the risk of falls.) referrals.
• Continue to monitor vital signs. Take blood pressure lying, sitting, and • Teach the patient to rise from lying to sitting or standing slowly to avoid
standing to detect orthostatic hypotension. Lifespan: Be particularly dizziness or falls. If dizziness occurs, the patient should sit or lie down
cautious with older adults who are at increased risk for hypotension. and not attempt to stand or walk until the sensation passes.
Notify the healthcare provider if blood pressure decreases beyond
established parameters or if hypotension is accompanied by reflex
tachycardia. (Orthostatic hypotension is a common adverse effect and
may increase the risk of falls or injury.)
• Monitor for behavioral changes. (Drug therapy may increase the risk of • Teach the patient, family, or caregivers to watch for and report
agitation, confusion, depression, or suicidal thoughts, and may cause immediately any signs of changes in behavior or mood such as
other mood disturbances such as aggressive behavior.) increased aggression or confusion. Provide additional healthcare
referrals as required for a support group, counseling, or respite care.
• Carefully evaluate and report dose-related symptoms such as • Instruct the patient, family, or caregivers to be aware of newly
increased tremors and rigidity before the next dose is due or greatly occurring muscle twitching, including blepharospasm (in the muscles
increased symptoms unrelated to the timing of dose. (In PD, the return of the eyelids), greatly increasing tremors, rigidity, sweating, or other
or gradual increase of symptoms as the next dose comes due may symptoms, and to report them immediately.
signal a wearing-off effect and the dose may need to be increased, the
interval of dosage adjusted, or an adjunctive drug added. A significant • Encourage the patient, family, or caregivers to maintain a symptom
and sudden increase in symptoms may signal an overdose or on–off diary if effects seem to diminish as the next dose is due. Review the
syndrome where symptoms dramatically increase. If symptoms are diary with the patient on each healthcare visit.
significant, hospitalization may be required to assess for the reason
behind the exacerbation.)
• Evaluate nutritional intake. (Absorption of levodopa taken for PD • Teach the patient to take medication for PD on an empty stomach or
decreases with high-protein meals or high consumption of foods or to avoid taking it with a high-protein meal. Avoid excessive
vitamins that contain vitamin B6 [pyridoxine]. Symptoms may consumption of vitamin B6-rich foods such as bananas, wheat germ,
dramatically increase if absorption is impaired because the dose does fortified cereals, green vegetables, meat, and legumes, and avoid
not adequately absorb during the expected time. Patients with multivitamins that contain vitamin B6.
neurodegenerative disease may eventually experience difficulty in
feeding themselves or with swallowing. Weigh the patient weekly to • Teach the family or caregivers to assist the patient with AD with eating
assess the effects of dietary intake.) and to offer fluids on a regular basis.
• Monitor hepatic and renal function laboratory values periodically. (A • Teach the patient, family, or caregivers about the importance of
decrease in these functions may slow metabolism and excretion of the returning for follow-up laboratory studies.
drug, possibly leading to overdose or toxicity.)
• Monitor for other drug-related changes. (PD replacement drug therapy • Advise the patient that urine or sweat may darken and that undershirts
may cause darkening of urine and perspiration.) or dress shields may help to avoid staining of clothing.
• Evaluate the family or caregivers for signs of stress, fatigue, • Encourage the family or caregivers to discuss concerns related to their
or other effects related to caring for the patient with a own health, financial status, or other issues.
neurodegenerative disease. (Caring for a patient with
neurodegenerative disease is challenging and difficult. • Provide additional healthcare referrals as required for a support group,
Additional social and financial resources may be needed, counseling, or respite care.
including alternative care environments.)
Patient understanding of drug therapy: • The patient, family, or caregivers should be able to state the reason for
• Use opportunities during administration of medications and during the drug, appropriate dose and scheduling, and what adverse effects
to observe for and when to report them.
assessments to discuss the rationale for the drug therapy, desired
therapeutic outcomes, commonly observed adverse effects,
parameters for when to call the healthcare provider, and any necessary
monitoring or precautions. (Using time during nursing care helps to
optimize and reinforce key teaching areas.)
Patient self-administration of drug therapy: • Instruct the patient in proper administration guidelines. Encourage the
• When administering the medications, instruct the patient, family, or patient, family, or caregivers to maintain a medication log, noting symptoms
or adverse effects along with the dose and timing of medications.
caregiver in proper self-administration of the drugs and the need for
regular, consistent dosing. (Utilizing time during nurse administration of • Patients taking injectable drug forms for the treatment of MS (e.g.,
these drugs helps to reinforce teaching.) interferon beta-1b [Betaseron]) should report increasing redness, pain,
or blackening of the injection site, which may indicate that tissue
necrosis is occurring.
Chapter 21 Pharmacotherapy of Degenerative Diseases of the Central Nervous System 327
Understanding Chapter 21
Key Concepts Summary 21.7 Several miscellaneous dopaminergic drugs are
used as adjuncts to levodopa therapy.
21.1 Degenerative diseases of the central nervous
system are characterized by irreversible and 21.8 Anticholinergic drugs are the oldest of the
progressive loss of neuronal function. antiparkinson drugs and are effective at reducing
tremor.
21.2 Parkinson’s disease is a progressive
neurodegenerative disorder characterized by 21.9 Alzheimer’s disease, the most common dementia,
abnormal motor movement. leads to a progressive loss of cognitive function.
21.3 Parkinson’s disease is caused by a lack of 21.10 Pharmacotherapy of Alzheimer’s disease
sufficient amounts of dopamine produced by the produces only modest results and is ineffective at
substantia nigra. stopping the progression of the disorder.
21.4 The drugs used for Parkinson’s disease help to 21.11 Multiple sclerosis is a chronic, neurodegenerative
alleviate symptoms but do not cure the disease. disease that is treated with immunomodulator
drugs.
21.5 Replacement therapy with levodopa is the most
effective therapy for treating Parkinson’s disease. 21.12 The pharmacotherapy of amyotrophic lateral
sclerosis is limited to a few drugs.
21.6 Dopamine agonists may be used as monotherapy
for early symptoms of Parkinson’s disease or as
adjuncts to levodopa in patients with advanced
disease.
CASE STUDY: Making the Patient Connection
Remember the patient “Mary Lee” at the decreasing mental acuity over the past year. Mary’s physi-
beginning of the chapter? Now read the cal examination is negative, but the healthcare provider
remainder of the case study. Based on suspects that she is experiencing the early stage of AD.
the information presented within this Mary is started on Aricept, 5 mg at bedtime.
chapter, respond to the critical thinking
questions that follow. Critical Thinking Questions
Mary Lee is a 76-year-old retired high school principal with 1. What information should be included in the initial
a PhD in educational administration. She has been married assessment by the nurse and the provider in order to
to Robert for almost 50 years, and they have three grown determine a diagnosis for Mary?
children who live within 25 miles of them. Mary’s physical
health has been good. She has mild hypertension and had 2. What recommendations will the healthcare provider
colon cancer successfully removed 20 years ago. She has an most likely make to Mary and her husband?
annual physical examination and cancer screenings as rec-
ommended for her age. Robert makes an appointment with 3. What should Robert be alert for with regard to the
Mary’s healthcare provider, because he has noticed signs of donepezil?
Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study felt more tired than usual, and he noticed a slight tremor,
especially when he became fatigued. Michael’s wife
Michael, at 45 years of age, could not believe his ears when pointed out that his “hand shakes” were getting worse.
the healthcare provider told him he had PD. “Isn’t that an Like many people first diagnosed with a degenerative
old person’s disease?” he asked. However, he knew some-
thing had been very wrong for about 3 months. At first he
328 Unit 4 Pharmacology of the Central Nervous System
nervous system disease, Michael has many questions and medication work? What is the advantage of combining
concerns. Following are just a few of his questions. As his the two medications?
nurse, how would you respond?
3. What drug-related adverse effects would you discuss
1. What physiologic problem causes PD and what is the with Michael?
etiology of this disease? How could a nurse describe
this etiology to Michael? Answers to Additional Case Study questions are available on
the faculty resources site. Please consult with your instructor.
2. Eventually, Michael is prescribed levodopa and carbi-
dopa (Sinemet) for his parkinsonism. How does this
Chapter Review has which of the following advantages? (Select all that
apply.)
1. The patient is receiving levodopa and carbidopa for
parkinsonism. Which drug would the nurse expect 1. It is not associated with hepatotoxicity.
to be added to the patient’s drug regimen to help 2. It is taken once per day.
control tremors? 3. It may be used safely in patients with peptic
1. Amantadine (Gocovri) ulcer disease.
2. Benztropine (Cogentin) 4. It may be used safely in patients with
3. Haloperidol (Haldol)
4. Donepezil (Aricept) cardiac disease.
5. It may increase the time between diagnosis and
2. Which statement, if made by the patient, would
alert the nurse that the antiparkinson medication when memory care is needed.
is effective?
5. The nurse knows an advantage to rivastigmine
1. “I’m sleeping a lot more, especially during the (Exelon) over other cholinesterase inhibitors is that it:
day.”
1. Has no significant drug interactions.
2. “My appetite has improved.” 2. Does not cause cholinergic adverse effects.
3. “I’m able to shower by myself.” 3. Is absorbed best on an empty stomach.
4. “My skin doesn’t itch anymore.” 4. Does not alter glucose control in patients
3. The nurse is counseling the caregivers of a patient with diabetes.
with Alzheimer’s disease. Which statement, if made
by a caregiver, would indicate that the session had 6. Interferon beta-1b (Betaseron) has been ordered for
been effective? the patient with MS. The nurse will instruct the
patient on possible adverse effects that may be man-
1. “I should give this medication as symptoms of aged symptomatically by the patient. These include
Alzheimer’s disease become noticeable.” (select all that apply):
2. “If constipation occurs, I will notify the healthcare 1. Flulike symptoms.
provider immediately.” 2. Insomnia.
3. Depression.
3. “The medication may improve symptoms but will 4. Rashes.
not cure the disease.” 5. Pain at the injection site and blackening of the
4. “I will take the patient’s vital signs before every surrounding skin.
dose of the medication.”
See Answers to Chapter Review in Appendix A.
4. The nurse knows that the use of donepezil (Aricept)
to treat the symptoms of early Alzheimer’s disease
References Canevelli, M., Adali, N., Kelaiditi, E., Cantet, C., Ousset,
P. J., & Cesari, M. (2014). Effects of Ginkgo biloba
Alzheimer’s Association. (2016). 2016 Alzheimer’s disease supplementation in Alzheimer’s disease patients
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facts/overview.asp
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receiving cholinesterase inhibitors: Data from the Solfrizzi, V., & Panza, F. (2015). Plant-based nutraceutical
ICTUS study. Phytomedicine, 21, 888–892. doi:10.1016/j. interventions against cognitive impairment and
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(2015). Anticholinergic burden in Parkinson’s disease JAD-141887
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Parkinson’s Disease Foundation. (n.d.). Statistics on
Parkinson’s. Retrieved from http://www.pdf.org/en/ University of Maryland Medical Center. (2015). Ginkgo
parkinson_statistics biloba. Retrieved from http://umm.edu/health/
medical/altmed/herb/ginkgo-biloba
Selected Bibliography Feinstein, A., Freeman, J., & Lo, A. C. (2015). Treatment of
progressive multiple sclerosis: What works, what does
Alzheimer’s Association. (n.d.). Treatments for sleep changes. not, and what is needed. The Lancet Neurology, 14,
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disease_10429.asp#top
Nolden, L. F., Tartavoulle, T., & Porche, D. J. (2014).
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neuropharm.2013.07.004
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Bezard, E. (2014). Slowing of neurodegeneration in
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“I’m not sure I can cope with my child
having a seizure disorder. The schedule
for giving the medicines seems daunting
to me. I’m not sure I’ll know what to do when
he has a seizure or how the medicines work.”
Patient “Jorge Alvarez’s” mother
Chapter 22
Pharmacotherapy of Seizures
Chapter Outline Learning Outcomes
cc Characteristics of Seizure Disorders After reading this chapter, the student should be able to:
cc Classification of Seizure Disorders
1. Understand the causes of epilepsy.
Generalized Seizures
Partial Seizures 2. Differentiate among the following terms: epilepsy,
cc Antiepileptic Drugs seizures, and convulsions.
Barbiturates
Benzodiazepines 3. Describe how the presentation and
PROTOTYPE Diazepam (Valium), p. 342 pharmacotherapy of epilepsy change throughout
Hydantoins the lifespan.
PROTOTYPE Phenytoin (Dilantin, Phenytek), p. 344
Dibenzazepines 4. Differentiate the signs, symptoms, and treatment of
PROTOTYPE Carbamazepine (Carbatrol, Tegretol, the different types of seizure disorders.
Others), p. 346
Succinimides 5. Compare and contrast the pharmacotherapy of
PROTOTYPE Ethosuximide (Zarontin), p. 347 generalized and partial seizures.
Miscellaneous Antiepileptics
PROTOTYPE Gabapentin (Neurontin), p. 348 6. Identify factors that influence the selection of a
PROTOTYPE Valproic Acid (Depacon, specific antiepileptic drug by the healthcare
Depakene, Depakote), p. 349 provider.
Other Miscellaneous Drugs
7. Describe the nurse’s role in the pharmacologic
management of seizures.
8. For each of the classes shown in the chapter outline,
identify the prototype and representative drugs and
explain the mechanism(s) of drug action, primary
indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
9. Apply the nursing process to care for patients
receiving pharmacotherapy for seizures.
330
Chapter 22 Pharmacotherapy of Seizures 331
Key Terms febrile seizures, 336 preeclampsia, 333
generalized seizures, 334 seizure, 331
absence seizures, 335 infantile spasm, 336 simple partial seizures, 335
atonic seizures, 335 Lennox–Gastaut syndrome, 336 status epilepticus, 336
automatisms, 336 myoclonic seizures, 335 tonic–clonic seizures, 334
complex partial seizures, 336 partial (focal) seizures, 335
convulsions, 332 postictal state, 335
eclampsia, 333
epilepsy, 331
The word epilepsy is derived from the Greek word epilepsia, malfunction, and an alteration in motor activity. The many
meaning “to take hold” or “seize.” Epilepsy is a neurologic diverse symptoms of seizure are caused by abnormal neu-
condition characterized by recurrent seizures that affects ronal discharges within the different regions of the brain.
approximately 2 million Americans. Research in the past Abnormal neuronal discharges can be measured as sharp
two decades has resulted in the development of new drugs spikes or waves on an electroencephalogram (EEG), which
to treat epilepsy and other seizure disorders. In this chapter is a valuable tool in diagnosing seizure disorders.
the student will study the current medications for seizures
and understand the nurse’s role in the administration and When a patient presents with symptoms of a seizure, it
patient education associated with the medication regimen. is important to identify the cause of seizure activity so that
an appropriate treatment plan can be implemented. Epilep-
Characteristics of Seizure tic seizures are sometimes symptoms of an underlying dis-
Disorders order such as a brain tumor, head trauma, brain aneurysm,
stroke, alcoholism, or infectious disease of the brain. The
22.1 Epilepsy is characterized by recurrent diagnosis of epilepsy always begins with a search for an
seizures caused by disturbances in the electrical underlying disorder that could explain the seizures.
activity of the brain. Table 22.1 lists common etiologies for seizure disorders.
Successful treatment of the underlying condition often
Epilepsy is a disruption of the activity of clusters of neu- eliminates the seizure activity. If a brain abnormality
rons in the brain that is characterized by two or more sei- remains after the acute seizure has resolved, recurrent sei-
zures. A seizure is a disturbance of the brain’s electrical zures are likely.
activity that may result in loss of consciousness, sensory
In 50% to 70% of cases, the etiology of a seizure is idio-
pathic; no specific cause can be identified. These patients
Table 22.1 Etiology of Seizure Disorders
Etiology Pathophysiology
Fever Rapid increase in body temperature may result in febrile seizure. This is particularly noted in infants and toddlers.
Infectious disease
Metabolic disorders Meningitis and encephalitis, which are infections of the brain, result in brain inflammation and seizure development.
Miscellaneous causative agents Alteration in the fluid and electrolyte levels can result in seizure development.
Hypoglycemia, hyponatremia, and water intoxication contribute to the alteration in electrical impulse transmission at the
Neoplastic disorders cellular level.
Trauma
Medication used to treat mood disorders and psychotic episodes and local anesthetics produce increased levels of
Vascular disorders stimulatory neurotransmitters or toxicity.
Drug abuse, such as cocaine addictions, alters the neurotransmitters in the brain and produces seizures.
Alcohol and sedative–hypnotic drug withdrawal can result in seizure activity.
Both benign and malignant brain lesions, particularly those that grow rapidly, prevent adequate oxygenated blood
supply to the brain tissue and contribute to increased intracranial pressure, which results in seizure development.
Head injuries may result in increased intracranial pressure, which results in seizure development.
Exposure to toxic fumes or substances, or ingestion of poisons, can result in trauma to brain tissue and resultant
seizures.
Hypoxia of brain tissue disrupts the electrical transmission of impulses contributing to seizure development. Carbon
monoxide poisoning reduces the oxygen-carrying ability of the blood and results in cerebral hypoxia. The related
ischemia of brain tissue alters the electrical transmission of impulses and contributes to seizure development.
Other vascular causes of seizures include hypotension, stroke, shock, and cardiac dysrhythmias.
332 Unit 4 Pharmacology of the Central Nervous System
may have a lower tolerance to environmental triggers, and first seizure before age 10. Because of this, epilepsy is con-
seizures may occur when they are sleep deprived, are sidered a major disorder of childhood. Fortunately, many
exposed to strobe or flickering lights, or have a fluid and patients who have childhood epilepsy experience a reduc-
electrolyte imbalance. Diagnostic tests such as complete tion in symptoms as they age, and some will no longer
blood count (CBC), serum lead levels, and blood glucose are require pharmacotherapy as adults. In addition to child-
important in excluding the systemic causes of seizures. Vir- hood, epilepsy manifests with higher frequency during
tually anything that changes the homeostatic environment pregnancy and in older adults. Treatment of epilepsy dif-
of neurons in the brain has the potential to cause seizures, fers throughout the lifespan.
thus complicating the diagnosis and treatment of epilepsy.
Women, pregnancy, and lactation: The pharmacother-
It is important to distinguish between the terms convul- apy of epilepsy in women with childbearing potential can
sion and seizure. Most often, patients associate epilepsy be challenging. These patients require special education to
with convulsions, which are involuntary, violent spasms of prevent conception during AED pharmacotherapy or to
the large skeletal muscles of the face, neck, arms, and legs. safely prevent seizures during pregnancy.
Convulsions are a characteristic sign of tonic–clonic sei-
zures. Many forms of epilepsy, however, do not involve Some AEDs interact with oral contraceptives, dimin-
convulsions. For example, absence seizures do not involve ishing the effectiveness of birth control pills. AEDs that are
any dramatic movement of the limbs and may be barely inducers of hepatic CYP450 enzymes will increase the
noticeable by those observing the affected individual. metabolism of contraceptive hormones, thus decreasing
Thus, it may be stated that all convulsions are seizures, but their effectiveness in preventing conception. Antiseizure
not all seizures are convulsions. Because of this difference, drugs that induce CYP450 include phenobarbital, carbam-
drugs used to treat epilepsy are best described as antiepi- azepine, oxcarbazepine, topiramate, and phenytoin. To
leptic drugs (AEDs) or antiseizure medications, rather than prevent an unplanned pregnancy, the patient should
anticonvulsants. receive a higher dose of oral contraceptive and be instructed
to use a backup method of birth control such as condoms.
PharmFACT Therapy with antiseizure drugs that do not induce CYP450
enzymes, such as valproic acid or gabapentin, may be an
Adults with early Alzheimer’s disease who have epilepsy option for these women.
present with cognitive decline almost 7 years earlier (age 64)
than those who do not have epilepsy (age 71). The start of Pregnancy is a major concern for women with seizure
seizure activity coincides with the beginning of cognitive disorders. Women with epilepsy have a higher risk for
decline (Vossel et al., 2013). delivering a child with congenital abnormalities, and many
of the AEDs have the potential to produce teratogenic
Seizures have the potential to significantly impact effects. The risk of birth defects is further increased because
one’s quality of life. They may cause serious injury if they some AEDs cause folic acid (folate) deficiency, a condition
occur while someone is driving a vehicle or performing a that has been associated with increased risk of neural tube
potentially hazardous activity. Without pharmacotherapy, defects in the embryo. Folic acid supplements (0.4–4 mg/
epilepsy can severely limit participation in school, employ- day) should always be recommended for women who are
ment, and social activities and affect self-esteem. Chronic considering pregnancy and those who become pregnant.
depression may accompany poorly controlled seizures. The use of vitamin supplementation will also reduce the
Proper treatment, however, can reduce or completely elim- risk of developing cardiac abnormalities and cleft lip or
inate seizures in many patients. Important considerations palate. Single-drug therapy should be used whenever pos-
in nursing care include identifying patients at risk for sei- sible because therapy with multiple AEDs results in a
zures, documenting the pattern and type of seizure activity, higher risk of birth defects. Doses are reduced to the lowest
and implementing safety precautions. In collaboration possible level that effectively controls the seizures. AEDs
with the patient, healthcare provider, and pharmacist, the such as lamotrigine, gabapentin, and zonisamide should be
nurse is instrumental in achieving positive therapeutic out- considered because they appear to have a lower risk of
comes during AED therapy. The nurse must educate teratogenicity.
patients that effective seizure control is usually achieved
through a combination of pharmacotherapy and support Women who have epilepsy have a reduced fertility
from family and caregivers. rate. Epilepsy and AEDs can disrupt the hypothalamus–
pituitary axis, causing menstrual irregularities. The length
22.2 Seizure disorders differ throughout of the menstrual cycle in these patients may vary from 23 to
the lifespan. 35 days, and 40% of women with epilepsy have polycystic
ovaries. Many women who have epilepsy do not ovulate.
Seizure disorders occur throughout the lifespan. Of those Genital blood flow is diminished and libido is reduced,
who experience seizures, about half will experience their contributing to a reduction in the frequency of intercourse.
Chapter 22 Pharmacotherapy of Seizures 333
During pregnancy, some of the enzyme-inducing terminate seizures. Magnesium sulfate acts by decreasing
AEDs cross the placenta and induce hepatic enzyme the amount of acetylcholine liberated from the motor nerve
metabolism in the fetal liver. This decreases the circulating terminals and produces a peripheral neuromuscular block-
vitamin K levels, posing an increased risk of hemorrhage in ade. It also has the therapeutic effect of increasing uterine
the newborn. It is recommended that prenatal vitamin K be blood flow. Because seizures may extend beyond labor and
prescribed to women who are taking AEDs during preg- delivery, magnesium sulfate therapy may continue for
nancy to prevent hemorrhagic disease in the newborn; 24 hours postpartum or until the HTN resolves.
10 to 20 mg of vitamin K should be administered daily dur-
ing the last 4 months of pregnancy. The issue of maternal AEDs during lactation has been
addressed by a number of research studies. Many studies
Gestational epilepsy is a rare condition in which the have confirmed the safety of AEDs taken during lactation,
patient experiences her first seizure during pregnancy. Sei- especially when considering the substantial benefits to the
zures in a pregnant patient who has never been diagnosed neonate derived from breastfeeding. It is likely that the
with epilepsy may indicate the development of preeclamp- amounts of AEDs secreted in breast milk are too low to
sia or eclampsia. Preeclampsia usually begins after the cause ill effects in the baby. Follow-up studies performed
20th week of pregnancy and is diagnosed by blood pres- 6 years after breastfeeding confirm that breastfeeding does
sure of 140/90 mmHg or higher on two separate occasions, not affect the cognitive development of children exposed to
and 300 mg of protein is found in the urine over a 24-hour AEDs in breast milk (Haunt, 2016). The exception is valpro-
period. The rate of preeclampsia in the United States is ate, which may have a higher risk than other AEDs.
approximately 5% to 7% of all pregnancies, affecting about
1 in every 2000 to 3000 deliveries. CONNECTION Checkpoint 22.1
Eclampsia occurs when hypertension (HTN) contin- From what you learned in Chapter 8, how does each of the following
ues to worsen during pregnancy. Eclampsia is associated affect the amount of drug that passes to the infant during lactation:
with seizures and a high risk of cerebral edema, which can lipid solubility of the drug, drug ionization, and drug half-life? An-
result in coma. If the baby is of proper gestational age, swers to Connection Checkpoint questions are available on the faculty
delivery is the treatment of choice for eclampsia. When the resources site. Please consult with your instructor.
pregnant woman is diagnosed with preeclampsia or
eclampsia and delivery is not imminent, intravenous (IV) Childhood: Seizures in children are either idiopathic or
magnesium sulfate may be administered to prevent or acquired. Children with idiopathic seizures often have a
CONNECTIONS: Complementary and Alternative Therapies
The Ketogenic Diet
Description drugs. The diet appears to be equally effective for every seizure
type, although those with drop attacks (atonic seizures) may be
The ketogenic diet is used when seizures cannot be controlled the most rapid responders. It also helps children with Lennox–
through pharmacotherapy or when the adverse effects of an Gastaut syndrome and shows promise in babies with infantile
AED medication are unacceptable. Before AEDs were devel- spasms. Adverse effects include hyperlipidemia, constipation,
oped, this diet was a primary treatment for epilepsy. vitamin deficiencies, kidney stones, acidosis, and, possibly,
slower growth rates.
History and Claims
Not all patients respond to the diet. Several studies sug-
The ketogenic diet may be used for babies, children, or adults. gest that response within the first 3 to 6 months may indicate
With adults, however, it is harder to develop the ketones that are that the diet has positive results, whereas those patients who fail
necessary for the diet. to respond in that time period are not likely to respond with con-
tinued diet therapy for longer periods (Lambrechts et al., 2015;
Standardization Vehmeijer, van der Louw, Arts, Catsman-Berrevoets, &
Neuteboom, 2015).
The ketogenic diet is a stringently calculated diet that is high in fat,
moderate in protein, and low in carbohydrates. It limits water intake The parents of children who follow the diet may have con-
to avoid ketone dilution and carefully controls caloric intake. Each flicted feelings about feeding their children high-fat foods and
meal has the same ketogenic ratio of 4 g of fat to 1 g of protein and the controlled nature of the diet. Encouraging parents to view
carbohydrate. Extra fat is usually given in the form of cream. the diet as medicine, planning ways that the family can have
similar, ketogenic alternatives that make meals more inclusive,
Evidence and recognizing that food can have significant meanings, both
positive and negative, may make dietary treatment more suc-
Research suggests that the diet produces a success rate, in cessful (Webster & Gabe, 2016).
some cases, that is equivalent to that of modern antiepileptic
334 Unit 4 Pharmacology of the Central Nervous System
family history of epilepsy or have an associated serious Older patients with memory deficits may have diffi-
neurologic abnormality, such as mental retardation or cere- culty remembering to take their AEDs. The nurse should
bral palsy. Febrile seizures are another form of idiopathic teach these patients and their caregivers that these medi-
seizure that occurs in children under the age of 2 years. cines must be taken on a regular basis, at the same time
Seizures represent the most common serious neurologic each day, for the most effective seizure prevention. If a dose
problem affecting children, with an overall incidence of is forgotten, the nurse should teach these patients not to
approximately 1% for idiopathic epilepsy. take a double dose of an AED because this could cause seri-
ous CNS toxicity. Furthermore, patients need to under-
Acquired seizure disorders may result from injury to stand that waiting until the first sign of a seizure before
the brain during the prenatal, antenatal, or postpartum taking their AED is ineffective at stopping the seizure
periods. Infants whose mothers have been exposed to cyto- because the drug will not be absorbed quickly enough.
megalovirus during pregnancy are at increased risk of
developing an acquired seizure disorder. Other causes of Classification of Seizure Disorders
acquired seizures include head trauma, metabolic imbal-
ances, exposure to toxins, and infection. 22.3 Most seizures are classified as generalized
or partial.
Seizure treatment for infants and children is usually
accomplished with pharmacotherapy. The most commonly Seizures begin with the firing of hyperexcitable neurons
prescribed pediatric AEDs include phenobarbital, valproic in the brain. The area where the abnormal electrical activ-
acid, phenytoin, carbamazepine, felbamate, lamotrigine, ity starts is known as an abnormal focus (plural = foci). As
and topiramate. To maintain optimal seizure control, the these neurons discharge impulses, the patient begins to
dosage of AEDs should be increased during periods of exhibit the characteristic signs and symptoms of epilepsy.
rapid growth and development. The specific symptoms depend on the nature of the dis-
charge: the location of the abnormal focus in the brain and
Nonpharmacologic treatments for epilepsy are avail- the extent of the discharge. Because symptoms vary
able. One such alternative therapy is the ketogenic diet. widely from patient to patient, there are many ways to
The beneficial effects of this diet occur when ketones are classify seizures. It is important to identify and classify the
eliminated from the body, thus decreasing seizure activity. type of seizure experienced by the patient because this
Other forms of seizure treatment include surgical interven- determines which drugs will be prescribed. There are two
tion with an excision of a circumscribed area of the brain broad categories of seizure activity: generalized and par-
affected by the seizure activity. The implantation of a vagal tial. Preferred drugs for the management of seizures are
nerve stimulator in the brain is a type of therapy that deliv- shown in Table 22.2.
ers electrical signals to the vagus nerve to reduce the fre-
quency of seizures. Generalized Seizures
Older adults: Seizure disorders in the older adult are In generalized seizures, multiple foci spread abnormal
often associated with an underlying comorbid condition. neuronal discharges across both hemispheres of the brain
Stroke accounts for one third of new-onset cases and is the simultaneously. The patient often experiences loss of con-
most common risk factor for the development of epilepsy sciousness, and the seizure may occur with or without
after age 60. Other conditions associated with epilepsy in convulsions. The four primary types of generalized sei-
the aging patient include progressive Alzheimer’s disease, zures are tonic–clonic seizures, absence seizures, atonic
subdural hematoma from a head injury due to falling, cen- seizures, and myoclonic seizures.
tral nervous system (CNS) infection, and brain tumors.
Tonic–clonic seizures, also referred to as grand mal
Older adults often take multiple medications that can seizures, are the type of seizure most associated by the pub-
contribute to seizure activity. It is vital to regularly monitor lic with epilepsy. It is the most common type of seizure in
the liver and kidney functions of the older patient when every age group. The seizure may be preceded by an aura,
administering multiple medications because impairment a warning that a seizure is imminent, that some patients
may lead to toxic serum drug levels and possible seizures. describe as a spiritual feeling, flash of light, or special noise.
Neurologists consider the aura to be part of the actual sei-
The nurse needs to assess the patient’s therapeutic zure. Loss of consciousness and intense muscle contrac-
response to the AEDs and also monitor the serum drug tions indicate the tonic phase. A hoarse cry may occur at
level. The clinical response should be used to guide the the onset of the seizure due to air being forced out of the
needed dosage changes. When possible, only a single AED lungs, and patients may temporarily lose bladder or bowel
is prescribed because the use of multiple AEDs increases control. Breathing may become shallow and even stop
the risk of adverse drug events. In most patients, therapy
with AEDs begins with low doses followed by careful mon-
itoring for drug effectiveness. Gradual dosage changes are
made based on clinical outcomes.
Chapter 22 Pharmacotherapy of Seizures 335
Table 22.2 Drugs Used for the Management of Seizures
Type of Seizure First-Line Drugs* Alternative Drugs
Generalized Seizures ethosuximide, lamotrigine, valproic acid clonazepam
Absence clonazepam, valproic acid
Atonic valproic acid lamotrigine, levetiracetam, topiramate
Myoclonic carbamazepine, lamotrigine, valproic acid
Tonic–clonic clonazepam, lamotrigine, phenobarbital, topiramate
Partial Seizures clonazepam, diazepam, levetiracetam, oxcarbazepine, phenobarbital,
Complex partial phenytoin, topiramate, zonisamide
Simple partial carbamazepine, lamotrigine, phenytoin gabapentin, oxcarbazepine, phenobarbital, pregabalin, tiagabine,
carbamazepine, lamotrigine, phenytoin, valproic acid topiramate, zonisamide
Other Seizures
Alcohol withdrawal brivaracetam, clorazepate, diazepam, felbamate, gabapentin,
Febrile levetiracetam, oxcarbazepine, phenobarbital, pregabalin, tiagabine,
Infantile spasms topiramate, zonisamide
Lennox–Gastaut
Status epilepticus lorazepam or diazepam carbamazepine
acetaminophen for prophylaxis diazepam, phenytoin
adrenocorticotropic hormone (ACTH) none
benzodiazepines, valproic acid felbamate, rufinamide
lorazepam diazepam, phenobarbital, phenytoin, valproic acid
*Selection of first-line drugs varies according to patient age and comorbid conditions, prescriber experiences, institution, and geographic region.
momentarily. The clonic phase is characterized by alternat- Myoclonic seizures are generalized seizures charac-
ing contraction and relaxation of muscles that are charac- terized by jerking body movements, usually involving the
teristic of convulsions. The seizure usually lasts 1 to muscles of the neck, shoulders, and upper arms. Major
2 minutes, after which the patient becomes drowsy and muscle groups contract quickly, usually for only a few sec-
disoriented and sleeps deeply. The period following the onds, and patients appear unsteady and clumsy. These
seizure is known as the postictal state. patients do not lose consciousness but may fall or drop
whatever they might be holding. Most patients with myo-
Absence seizures, formerly known as petit mal sei- clonic seizures also exhibit tonic–clonic or absence seizures,
zures, most often occur in children and last only a few or both. Myoclonic seizures usually begin around puberty
seconds. Approximately half of the patients with absence and comprise 5% to 10% of all epilepsies. Although these
seizures may also experience at least one tonic–clonic sei- seizures continue for the life of the patient, they can be con-
zure. Absence seizures involve a reduction of normal trolled with pharmacotherapy. Valproic acid has been the
brain activity. Staring and transient loss of responsive- traditional preferred drug for myoclonic seizures but
ness are the most common signs, but there may be slight newer AEDs such as topiramate and lamotrigine are being
motor activity with eyelid fluttering or muscular jerking increasingly prescribed.
movements. These episodes are subtle and can be mis-
taken for daydreaming or inattention, such as is seen in Partial Seizures
attention-deficit/hyperactivity disorder (ADHD). Chil-
dren with absence seizures may experience poor aca- Partial (focal) seizures involve a limited portion of the
demic performance because these episodes can occur brain, with the abnormal neuronal discharges starting on
several times per day. Most children who experience one side and traveling only a short distance before they
absence seizures will “outgrow” the disorder and become stop. Many partial seizures do not involve loss of con-
seizure free in adulthood. sciousness or convulsions, although discharge may begin
as a partial seizure and become a generalized seizure.
Atonic seizures are sometimes known as drop attacks, Some symptoms are subtle and reflect the simple nature of
due to the fact that the patient will stumble and fall for no neuronal misfiring in limited areas of the brain, whereas
apparent reason. The episode is brief, lasting only a few other symptoms may be more complex.
seconds. The patient loses control of muscle function
throughout the body. During the episode of weakness, the Simple partial seizures have an onset that begins at a
patient’s head will droop forward or the trunk muscles will small, regional focus. Patients with simple partial seizures
not support the patient, thus causing the drop attack. experience a wide array of symptoms depending on the
Although the seizure itself causes no serious harm, the specific region of the brain affected. If the motor cortex is
patient is at risk of injury due to falls.
336 Unit 4 Pharmacology of the Central Nervous System
affected, jerky, rhythmic contractions of a specific muscle However, some forms of this disorder do not involve con-
group are noted. Seizures affecting the sensory cortex are vulsions and may resemble simple partial or complex par-
less noticeable to an observer. Patients may feel for a brief tial seizures. When generalized tonic–clonic seizures are
moment that their precise location is vague, they may hear prolonged or continuous, the time in which breathing is
or see things that are not present, or they may have an affected by muscle contraction is lengthened and hypoxia
upset stomach. Senses of hearing, taste, smell, or sensation may develop. The continuous muscle contraction also can
may be affected. Other patients become emotional and lead to hypoglycemia, acidosis, and hypothermia due to
experience a sense of joy, fear, or grief. Consciousness is increased metabolic needs, lactic acid production, and heat
retained during the seizure, although the patient may loss during contraction. If untreated, status epilepticus
express amnesia about the event. Numerous AEDs are could lead to brain damage and death. Medical treatment
available to treat simple partial seizures. involves administration of AEDs by the IV route. In the
home setting, valproic acid or diazepam can be adminis-
Complex partial seizures (formerly known as psycho- tered by the rectal route.
motor or temporal lobe seizures) originate from a single
focus, usually in the temporal lobe of the brain. Patients Infantile spasm, also called West syndrome, usually
exhibit sensory, motor, or autonomic symptoms with some occurs in the first year of life and is characterized by a sud-
degree of altered or impaired consciousness. Total loss of den bending forward, body stiffening, or arching of the
consciousness may not occur during a complex partial sei- torso. Infantile spasms may occur in clusters, often with
zure, but a brief period of somnolence or confusion may several dozen separated by 5 to 30 seconds. Infants who
follow the episode. Complex partial seizures are usually experience infantile spasms often have some degree of
preceded by an aura that may be described as an unpleas- mental and developmental delays. Adrenocorticotropic
ant odor or taste, colored spots, unexplained fear, or tin- hormone (ACTH) and prednisone are preferred drugs for
gling. Seizures may start with a blank stare and proceed to the treatment of infantile spasms.
repetitive arm movements, leg movements, head rolling,
chewing, lip-smacking, or swallowing. These repetitive Lennox–Gastaut syndrome is considered a mixed sei-
movements are called automatisms. Most patients will be zure that has characteristics of tonic–clonic, atonic, and
unresponsive to verbal commands and act as if they are atypical absence seizures. The cause of this syndrome is
having hallucinations. Complex partial seizures occur in unknown. This seizure disorder has a mean age of onset of
about 35% of patients with epilepsy. Numerous AEDs are 26 to 28 months and is often associated with mental retar-
available to treat complex partial seizures. dation and mood instability. In older children, this type of
epilepsy is associated with personality disorders and psy-
22.4 Some types of seizures are called special chotic episodes. The preferred drugs for Lennox–Gastaut
epileptic seizures or are unclassified. syndrome include benzodiazepines and valproic acid,
although newer AEDs such as rufinamide are being increas-
Not all seizure disorders can be classified neatly into the ingly prescribed. Seizures associated with Lennox–Gastaut
two broad categories of generalized and partial. These syndrome are often resistant to pharmacotherapy.
“other” types of seizures are referred to as special or
unclassified epileptic seizures. 22.5 The selection of antiepileptic drug therapy
is dependent on seizure type and characteristics.
Febrile seizures are most likely to occur in the 3-month
to 5-year age group. As many as 5% of children experience The choice of AED medication is highly individualized for
febrile seizures. These seizures are associated with high each patient and is dependent on many factors, including
fever and are characterized by tonic–clonic motor activity the type of seizure; the patient’s medical history, including
lasting 1 to 2 minutes with rapid return of consciousness. the characteristics and length of the seizure; the results
They usually occur only once during any given illness. of the EEG and other diagnostic laboratory studies; and
Febrile seizures may be generalized (occur once and the presence of comorbid medical conditions. To prevent
quickly resolve) or complex partial (occur multiple times in adverse drug effects, the prescriber initially chooses the
24 hours and are prolonged). Pharmacotherapy with AEDs lowest, effective dose of an AED and increases it as neces-
is not necessary with most febrile seizures. Prevention of sary. Serum drug levels may be obtained to assist the
the onset of fever with acetaminophen is the best method healthcare provider in determining the most effective drug
for controlling this disorder. concentration. To prevent adverse effects and possible sei-
zure onset, the discontinuation of an AED or significant
Status epilepticus is a medical emergency that occurs dose reductions are extended over 6 to 12 weeks. Drugs for
when a seizure continues for more than 30 minutes or when the different types of seizures are listed in Table 22.2.
two or more sequential seizures occur without full recov-
ery of consciousness between them. Status epilepticus is In most cases, effective seizure management can be
sometimes classified as a generalized form of epilepsy obtained by using a single AED. If seizure activity contin-
because tonic–clonic symptoms are usually exhibited. ues, the initial drug is gradually discontinued and replaced
Chapter 22 Pharmacotherapy of Seizures 337
by a medication from a different class. Some patients multiple mechanisms, and a few have unknown mecha-
require multiple AEDs for effective seizure control. How- nisms. These mechanisms are shown in Pharmacotherapy
ever, certain AED drug combinations have the potential to Illustrated 22.1. The basic mechanisms are:
increase the incidence of seizures; thus it is important for
the nurse to consult current literature for drug compatibil- • Electrolyte movement
ity and administration guidelines. At the initiation of phar- Inhibition of the influx of sodium into neurons
macotherapy, the patient must be carefully assessed for Inhibition of the influx of calcium in neurons
adverse effects, particularly increased CNS depression,
and advised not to drive or engage in hazardous activities • Neurotransmitter balance
until drug levels have stabilized. An increase in the activity of GABA in the brain
Blocking of glutamate receptors in the brain.
Patients who remain symptom free for prolonged
periods often believe that they have “outgrown” their sei- Control of electrolyte movement: In their resting state,
zures and therefore no longer require medication. neurons are surrounded by a high extracellular concentra-
Although this may indeed be the case, the nurse should tion of sodium, calcium, and chloride ions. Potassium lev-
teach patients to never stop taking AEDs without the guid- els are higher inside the cell. An influx of sodium or
ance of their healthcare provider. In general, withdrawal calcium into the neuron enhances neuronal activity,
of antiepileptic medications is attempted only after the whereas an influx of chloride ions has an inhibitory effect.
patient has been seizure free for at least 3 years. The with- This affords several mechanisms to dampen abnormal
drawal of medications requires close monitoring by the neuronal activity.
patient’s healthcare provider, and doses must be reduced
slowly, one medication at a time, over a period of several The primary target for many AEDs is the sodium chan-
months. If seizures recur during the withdrawal process, nel. The sodium channel on the neuronal plasma mem-
pharmacotherapy is resumed with the same medication brane must open, allowing sodium to rush into the cell, for
previously prescribed. The nurse must educate the patient an action potential to be generated and propagated. Phe-
and family to maintain strict adherence to the pharmaco- nytoin, lamotrigine, and carbamazepine bind to the sodium
therapy regimen. Periodic serum drug levels can assist the channel, inactivating it and preventing the passage of
nurse in assessing adherence: Low serum drug levels in a sodium ion into the neuron. This slows the excitability of
patient claiming to be taking his or her medication may neurons, dampening the flow of abnormal, repetitive
indicate nonadherence to therapy. discharges.
Many patients with epilepsy attempt a nondrug treat- Calcium channels are found at the synaptic terminals.
ment, with stress management techniques and prayer When opened, calcium enters the presynaptic neuron,
being the most common alternative therapies. Other thera- causing the release of stored neurotransmitter into the syn-
pies utilized to manage epilepsy include herbal supple- aptic cleft. Blocking calcium channels prevents the release
ments, chiropractic care, acupuncture, and yoga. The of the neurotransmitter and dampens impulse conduction.
implementation of the ketogenic diet can produce positive The AEDs believed to block calcium channels include etho-
effects in some patients by decreasing seizure activity. suximide, gabapentin, pregabalin, and lamotrigine.
However, the use of alternative therapies alone for the
management of epilepsy is not considered effective and Neurotransmitter balance: Drugs that enhance or
should be discouraged by the nurse. inhibit neurotransmitter activity in the CNS will affect
neuronal firing. The neurotransmitter most affected by
PharmFACT AEDs is gamma aminobutyric acid (GABA), the primary
inhibitory neurotransmitter in the brain. Increasing the
Contrary to popular belief, it is impossible to swallow the activity of GABA in the CNS will decrease neuronal firing,
tongue during a seizure, and one should never force an thus suppressing seizure activity. AEDs accomplish this
object into the mouth of someone who is having a seizure suppression by means of several mechanisms, as illus-
(Epilepsy Foundation of America, 2014). trated in Figure 22.1:
22.6 Antiepileptic drugs act by suppressing • Increased synthesis or amount of GABA in the pre-
abnormal neuronal discharges. synaptic nerve terminal. Some drugs block the meta-
bolic breakdown of GABA or enhance its formation.
All antiepileptic medications suppress neuron discharges, An example is valproic acid.
thus preventing the abnormal focus from forming or
spreading across the cerebrum. AEDs suppress abnormal • Activation of GABA receptors. Some drugs mimic
discharges by at least four mechanisms. The study of AEDs GABA and occupy its receptor on the postsynaptic
is complicated because some of these drugs act through membrane, causing the same inhibitory effect as
GABA. This is achieved by stimulating an influx of
chloride ion, which causes the neuron to have greater
338 Unit 4 Pharmacology of the Central Nervous System
Pharmacotherapy Illustrated 22.1
Mechanisms of Action of Antiepileptic Drugs
1 Blockade of sodium channels
• Carbamazepine
• Phenytoin
• Valproic acid
Excitatory Na+
neuron Na+ Na+
Sodium channel 1 Inhibitory
neuron
2 Potentiation of GABA receptor 2 GABA
• Barbiturates
• Benzodiazepines GABA Ca2+
channel Ca2+ Ca2+
3 Blockade of calcium channels Calcium channel 3
• Ethosuximide
• Lamotrigine
4 Antagonism of glutamute receptor 4
• Felbamate NMDA receptor
• Topiramate
Postsynaptic
neuron
difficulty achieving an action potential. Examples A second neurotransmitter affected by AEDs is gluta-
include barbiturates, benzodiazepines, topiramate, mate, the primary excitatory neurotransmitter in the brain.
and felbamate. By blocking glutamate receptors (known as N-methyl-D-
• Blocked reuptake of GABA. After GABA produces its aspartate [NMDA] receptors), these drugs serve as antago-
action at the synapse, it is normally pumped back into nists to glutamate and suppress neuronal firing. Examples
the presynaptic neuron, which terminates its action. include topiramate and felbamate.
Drugs that block this reuptake will keep GABA on its
receptors for a longer time, thus causing more neuro- Antiepileptic medications are difficult to classify.
nal inhibition. An example is tiagabine. One method is by mechanism of action; however, many
AEDs act by multiple means and a few have unknown
Chapter 22 Pharmacotherapy of Seizures 339
GABA synapse bradycardia, syncope, and hypotension.
(Inhibitory) Patients with impaired hepatic, respira-
tory, renal, and cardiovascular function
A should not receive barbiturates, or the
B doses should be lowered to prevent tox-
icity. Barbiturates also possess a high
Presynaptic Postsynaptic potential for drug dependence, and the
neuron neuron nurse must be certain that this fact is
included as part of patient and care-
= GABA C giver teaching.
= GABA receptor
= Drug molecule This section highlights only the anti-
seizure properties of barbiturates. These
A Increased GABA production in nerve terminal drugs are also classified as sedative–hyp-
Example: Valproic acid notics, and a prototype feature for phe-
nobarbital can be found in Chapter 18.
B Activation of GABA receptors Nursing responsibilities, lifespan and
Examples: Benzodiazepines, barbiturates diversity considerations, and patient and
family education for this drug class may
C Blocked reuptake at GABA transporter also be found in Chapter 18. Mephobar-
Example: Tiagabine bital was withdrawn from the United
States market in 2012.
Figure 22.1 Mechanisms of action of antiepileptic drugs that affect GABA. Phenobarbital: Phenobarbital is effec-
tive for long-term management of tonic–
mechanisms. Another classification scheme groups these clonic seizures and partial seizures. It can be administered
drugs into “newer” and “older” generations, but there is in patients with status epilepticus or febrile seizures or to
no clear distinction between the groups. Grouping by treat eclampsia. It is relatively ineffective in treating
type of seizure is not possible because most of these med- absence seizures. Phenobarbital has largely been replaced
ications are useful against more than one type. This text by safer AEDs, although it is still considered an important
uses a combination of chemical classes and mechanisms drug for neonatal seizures.
of action. The student should be aware, however, that Oral (PO) administration of phenobarbital may take
other classifications will be encountered in clinical prac- several weeks for an optimal level of antiseizure activity to
tice. The AEDs are listed in Table 22.3. be achieved. The advantages of phenobarbital are that it is
relatively inexpensive and long acting, and it can suppress
Antiepileptic Drugs seizures without causing major sedation with careful selec-
tion of dosage. The sedation effect of the drug is prominent
22.7 Barbiturates are traditional drugs for at the initiation of therapy but often diminishes as treat-
tonic–clonic seizures that have been replaced ment progresses.
by newer and safer medications. Phenobarbital is a major inducer of hepatic CYP450
The barbiturates have been used to treat seizures for enzymes and will markedly increase the metabolism of
almost 100 years. Barbiturates act biochemically in the other drugs metabolized by these enzymes. This results in a
brain by enhancing the inhibitory action of GABA, the significant potential for drug interactions with other medi-
neurotransmitter responsible for suppressing abnormal cations metabolized in the liver. Phenobarbital also increases
neuronal discharges. its own metabolism, which leads to significant tolerance as
therapy progresses. Phenobarbital is pregnancy category D.
Although barbiturates are still prescribed for epilepsy, Women of childbearing potential who are taking barbitu-
newer drugs have largely replaced them as first-line drugs rates should use two methods of birth control.
for this indication. Barbiturates have several major disad-
vantages. As a class, they have a low margin of safety and Primidone (Mysoline): Primidone is a barbiturate that is
can cause profound CNS depression, including sedation, metabolized in the liver to phenobarbital, which is respon-
coma, and death. Barbiturates will yield significant seda- sible for many of its pharmacologic effects. It is effective
tion when combined with alcohol, antidepressants, and for treating all types of seizures except absence seizures. It
other CNS depressants. Children may exhibit hyperkine- has no approved indications other than seizure. The
sis rather than sedation. Cardiovascular and respiratory actions and adverse effects of primidone are equivalent to
adverse effects include respiratory depression, those of phenobarbital. It is pregnancy category D.
340 Unit 4 Pharmacology of the Central Nervous System
Table 22.3 Drugs for Seizures
Drug Route and Dose (Maximum Dose Where Indicated) Adverse Effects
Barbiturates
phenobarbital Adult: PO: 50–100 mg bid–tid Drowsiness, dizziness, nausea, vomiting, sedation, confusion,
primidone (Mysoline) IV/IM: 200–600 mg (max: 20 mg/kg) unsteady gait, lethargy, paradoxical excitement, pain at the
Child: PO/IV: 3–8 mg/kg or 125 mg/m2/day injection site, hypotension with IV administration
Adult: PO: 100–250 mg bid–tid (max: 2 g/day) Agranulocytosis, angioedema, Stevens–Johnson syndrome (SJS),
Child younger than age 8: PO: 50–250 mg tid (max: 2 g/day) respiratory depression, bradycardia, CNS depression, coma
Benzodiazepines
clobazam (Onfi) PO: 5–10 mg/day gradually increased to a target dose of Sedation, headache, drowsiness, weakness, vertigo, ataxia,
clonazepam (Klonopin) 20–40 mg/day paradoxical excitement, short-term amnesia
Adult: PO: 1.5 mg/day gradually increased until seizures are Coma, respiratory depression, cardiac arrest, suicidal ideation,
controlled (max: 20 mg/day) blood dyscrasias, physical dependence, cardiovascular collapse
(diazepam), status epilepticus with abrupt withdrawal
Child younger than age 10: PO: 0.01–0.03 mg/kg/day
gradually increased until seizures are controlled (max: 0.2 mg/
kg/day)
clorazepate (Tranxene) Adult: PO: 7.5 mg tid (max: 90 mg/day)
Child ages 9–12: PO: 3.75–7.5 mg bid (max: 60 mg/day)
diazepam (Valium) Status epilepticus: Adult: IV/IM: 5–10 mg, repeat if needed at
10- to 15-min intervals up to 30 mg
Child: IV/IM: 0.2–1 mg slowly q2–5min up to 5–10 mg
lorazepam (Ativan) Adult: IV: 4 mg injected slowly at 2 mg/min; may repeat dose
once after 10 min (max: 8 mg during any 12-h period)
Status epilepticus: Child: IV: 0.1 mg/kg slowly over 2–5 min;
may repeat with 0.05 mg in 10–15 min (max: 4 mg/dose)
Hydantoins
fosphenytoin (Cerebyx) Adult: IV loading dose: 10–20 mg phenytoin equivalents/kg Hypotension, nystagmus, ataxia, lethargy, confusion, slurred
administered at 100–150 mg phenytoin equivalents/min speech, dizziness, nervousness, headache, nausea, vomiting,
phenytoin (Dilantin, Maintenance IV dose: 4–6 mg PE/kg/day gingival hyperplasia, rash, somnolence
Phenytek)
Adult: PO (extended release): 100 mg tid, then adjust for Seizures, dysrhythmias, blood dyscrasias, systemic lupus
seizure control (max: 600 mg/day) erythematosus, cardiac arrest, cardiovascular collapse, coma,
IV: 10–15 mg/kg loading dose, then 100 mg tid toxic epidermal necrolysis, SJS, osteomalacia
Child: PO (extended release): 5 mg/kg/day
Dibenzazepines
carbamazepine Adult: PO: 200 mg bid gradually increased to 800–1200 mg/day Dizziness, headache, ataxia, fatigue, rash, pruritus, dry mouth,
(Carbatrol, Tegretol, Child younger than age 6: PO: 10–20 mg/kg/day gradually nausea, vomiting, diplopia, abnormal gait
others) increased weekly (max: 35 mg/kg/day)
Child ages 6–12: PO: 100 mg, gradually increased to 400–800 mg SJS, aggravated absence seizures, hallucinations, aplastic
eslicarbazepine anemia, agranulocytosis, heart block, respiratory depression,
(Aptiom) PO: 400 mg once daily gradually increased to 1200 mg once exfoliative dermatitis, suicidal ideation, status epilepticus (with
daily abrupt withdrawal)
oxcarbazepine (Oxtellar Adult: PO: 300 mg bid (max: 2400 mg/day as monotherapy)
XR, Trileptal) Child ages 4–16: PO: 8–10 mg/kg/day (max: 600 mg/day)
Succinimides
ethosuximide (Zarontin) Adult: PO: 250 mg bid (max: 1.5 g/day) Drowsiness, headache, diarrhea, nausea, vomiting
Child ages 3–6: PO: maintenance dose 20 mg/kg/day
Anorexia, SJS, psychosis, blood dyscrasias, systemic lupus
methsuximide PO: 150–300 mg/day (max: 1.2 g/day) erythematosus, suicidal ideation
(Celontin)
Miscellaneous Antiepileptic Drugs
brivaracetam (Briviact) PO, oral solution, and IV: 50 mg bid Drowsiness, dizziness, nervousness, nausea, vomiting, fatigue
Suicidal ideation, psychoses
ezogabine (Potiga) Adult: PO: 100 mg tid gradually increased to 200–400 mg tid Dizziness, fatigue, blurred vision, diplopia, vertigo, tremor
Retinal abnormalities, confusion, memory impairment, urinary
retention, psychosis, prolongation of QT interval
Chapter 22 Pharmacotherapy of Seizures 341
Table 22.3 Drugs for Seizures (continued)
Drug Route and Dose (Maximum Dose Where Indicated) Adverse Effects
felbamate (Felbatol) Adult: PO: 1200 mg/day gradually increased to 3600 mg/day Headache, dizziness, blurred vision, nausea, vomiting, anorexia
Child ages 2–14: PO: 15 mg/kg/day (max: 45 mg/kg/day) Liver failure, aplastic anemia
gabapentin (Neurontin) Adult: PO: 300 mg tid gradually increased to 1800–2400 mg/ Dizziness, drowsiness, fatigue, weight gain, ataxia, diplopia,
day nystagmus, tremor, impaired concentration, dry mouth, flulike
Child ages 3–12: PO: 10–15 mg/kg/day gradually increased to syndrome
40 mg/kg/day
Increased frequency of partial seizures, blurred vision,
unintentional injury, suicidal ideation
lacosamide (Vimpat) Adult: PO: 50 mg bid gradually increased to 200–400 mg/day Dizziness, headache, diplopia, nausea
Suicidal ideation, prolongation of QT interval, syncope,
hypersensitivity reactions
lamotrigine (Lamictal) Adult: PO: 25–50 mg/day gradually increased to 150–500 mg/ Dizziness, headache, ataxia, drowsiness, insomnia, tremor, rash,
day (max: 700 mg/day without concurrent valproic acid, diplopia, blurred vision, flulike symptoms, infection, nausea,
200 mg/day with valproic acid) vomiting, back pain
Child ages 2–16: PO: 0.2–1 mg/kg/day gradually increased to
1–5 mg/kg/day (max: 15 mg/kg/day without valproic acid; SJS, toxic epidermal necrolysis, emotional lability (children),
5 mg/kg/day or 250 mg/day with concurrent valproic acid) suicidal ideation
levetiracetam (Keppra) Adult (regular release): PO: 500 mg bid; gradually increased to Drowsiness, headache, dizziness, nervousness, flulike
3 g/day symptoms, vomiting, anorexia, asthenia
Adult (extended release): PO: 1000–3000 mg once daily
Child ages 4–16: PO: 20 mg/kg/day; gradually increased to Emotional lability and personality disorder (children),
60 mg/kg/day unintentional injury, suicidal ideation, blood dyscrasias
pregabalin (Lyrica) PO: 150 mg/day gradually increased to 600 mg/day Dizziness, confusion, drowsiness, fatigue, weight gain, ataxia,
diplopia, nystagmus, tremor, impaired concentration, dry mouth
Increased frequency of partial seizures, blurred vision,
unintentional injury, angioedema, suicidal ideation
rufinamide (Banzel) Adult: PO: 400–800 mg/day gradually increased to 3200 mg/ Dizziness, headache, somnolence, nausea, fatigue
day
Child ages 4 and older: PO: 10 mg/kg/day gradually increased Suicidal ideation, shortening of QT interval, hypersensitivity
to 45 mg/kg/day or 3200 mg/day, whichever is less reactions
tiagabine (Gabitril) Adult: PO: 4 mg/day gradually increased to 56 mg/day Dizziness, asthenia, tremor, somnolence, nervousness, difficulty
Adolescent ages 12–18: PO: 4 mg/day gradually increased to concentrating
32 mg/day
Vasodilation, HTN, palpitations, tachycardia, syncope, peripheral
edema
topiramate (Topamax, PO: 50 mg/day gradually increased to 400 mg/day Paresthesia, anorexia, weight loss, fatigue, dizziness,
Trokendi XR, Others) somnolence, nervousness, psychomotor slowing, difficulty with
memory or concentration, confusion
Acute myopia with closed-angle glaucoma, oligohidrosis and
hyperthermia, suicidal ideation, hyperammonemia with
encephalopathy
valproic acid Adult/child: PO/IV: 10–15 mg/kg/day gradually increased Nausea, vomiting, abdominal cramps, anorexia, dyspepsia,
(Depacon, Depakene, to 60 mg/kg/day drowsiness, dizziness, asthenia, insomnia, weight gain
Depakote)
Deep coma, hallucinations, hyperammonemia,
thrombocytopenia, blurred vision, hepatotoxicity, pancreatitis,
bone marrow depression, prolonged bleeding time
vigabatrin (Sabril) Adult: PO: 500 mg bid gradually increased to 1500 mg/day Fatigue, somnolence, nystagmus, tremor, vision changes,
memory impairment, weight gain, arthralgia, abnormal
coordination
Depression, psychosis, confusion, severe rash, anemia, suicidal
ideation
zonisamide (Zonegran) Adult: PO: 100 mg/day gradually increased to 200–400 mg/day Dizziness, ataxia, drowsiness, fatigue, anorexia,
speech abnormalities and difficulty in concentrating or
remembering, flulike symptoms, headache, abnormal gait,
gingivitis, rhinitis
Severe rash including SJS, kidney stones, depression,
psychosis
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
342 Unit 4 Pharmacology of the Central Nervous System
PharmFACT to prevent seizures in patients who have received toxic
substances or during the acute phase of alcohol or benzo-
Twenty to thirty percent of patients with epilepsy also have diazepine withdrawal. Oral diazepam may be combined
psychiatric disturbances, the most common of which is with other AEDs in the treatment of refractory seizures. A
mood or anxiety disorder. The risk of suicide in patients with newer indication for diazepam is the oral prophylaxis of
epilepsy is about 13%, which is almost twice that of the febrile seizures in children ages 6 months to 5 years.
general population (Algreeshah, 2016).
Diazepam has a large number of other indications. It
22.8 Benzodiazepines are important drugs in was once widely prescribed for the management of anxiety
the treatment of status epilepticus. disorders, although it has largely been replaced by other
drugs such as alprazolam (Xanax). It is administered prior
Benzodiazepines are the first-line drugs for the treatment to procedures such as cardioversion or endoscopy to pro-
of certain anxiety disorders and are one of the most widely vide relaxation or sedation. Oral or parenteral diazepam
prescribed drug classes in the United States. Detailed may be administered for muscle relaxation in patients with
information about the benzodiazepines used for anxiety acute inflammation, trauma, tetanus, or spasticity.
and a prototype feature for lorazepam (Ativan) are
included in Chapter 18. The remainder of this section Mechanism of Action: Diazepam enhances the ac-
focuses on the antiseizure properties of drugs in this class. tion of GABA in the brain, thus inhibiting the abnormal
neuronal discharges characteristic of seizures.
Benzodiazepines control seizures by acting in the lim-
bic, thalamic, and hypothalamic regions of the CNS. All Pharmacokinetics: IV, IM, PO, rectal
drugs in this class act by enhancing the inhibitory action of Route(s)
GABA. They accomplish this by increasing the affinity of Absorption Rapidly absorbed by the GI
GABA for its receptors. tract; erratic absorption with IM
Distribution administration
The applications of benzodiazepines in the treatment
of seizure disorders are limited. The parenteral benzodiaz- Primary metabolism Widely distributed; crosses the
epines diazepam (Valium) and lorazepam are utilized in Primary excretion blood–brain barrier and the
the treatment of status epilepticus. Clonazepam (Klonopin) Onset of action placenta; 99% bound to protein
and clorazepate (Tranxene) are used for specific types of
seizures, usually when other drugs have proven Duration of action Hepatic
ineffective.
Renal
When giving these medications by the IV route, the
patient is administered oxygen, and resuscitation equip- IV: 1–5 min; IM: 15–30 min; PO:
ment should be readily available. IV administration of 30–60 min
diazepam or lorazepam for status epilepticus should be
given in a large vein and the drug should not be mixed Half-life: 20–50 h
with other drugs or IV fluid additives. These drugs have
a tendency to precipitate from solution and are irritating Adverse Effects: The most serious adverse effect of
to veins. Close monitoring of the respiratory and cardio- diazepam is cardiovascular collapse. The nurse should as-
vascular systems is necessary for the early recognition sess for hypotension, tachycardia, and edema, which are
of adverse effects associated with respiratory depres- precursors to cardiovascular collapse. CNS adverse effects
sion or cardiovascular collapse. Benzodiazepines should include drowsiness, fatigue, ataxia, dizziness, and vertigo.
never be discontinued abruptly because status epilepti- Diazepam can cause urinary retention and menstrual ir-
cus may result. regularities. The major respiratory adverse effect is laryn-
geal spasm and cough. Benzodiazepines are Schedule IV
PROTOTYPE DRUG Diazepam (Valium) drugs and possess a risk for substance abuse in susceptible
individuals (see Chapter 27).
Classification T herapeutic: Antiepileptic drug, antianx-
iety drug, skeletal muscle relaxant Contraindications/Precautions: Diazepam should
not be administered to patients with depressed vital signs,
Pharmacologic: Benzodiazepine, GABA those in shock, or those with acute alcohol intoxication.
receptor agonist It is also contraindicated in the presence of closed-angle
glaucoma because it can increase intraocular pressure. Di-
Therapeutic Effects and Uses: Diazepam was origi- azepam should be used cautiously in patients with depres-
nally approved by the U.S. Food and Drug Administration sion and myasthenia gravis, and a reduced dose should be
(FDA) in 1963. In antiseizure therapy, the primary indica- administered in patients with impaired hepatic or renal
tion for diazepam is status epilepticus. It may also be used function. Patients who have respiratory disorders such as
chronic obstructive pulmonary disease (COPD) should be
monitored closely due to the risk of respiratory depression.
Chapter 22 Pharmacotherapy of Seizures 343
After prolonged therapy, abrupt discontinuation of diaz- Clonazepam (Klonopin): Approved in 1975, clonazepam
epam may precipitate withdrawal symptoms, including is an oral benzodiazepine with strong antiseizure proper-
seizures in patients with epilepsy. The drug can cause birth ties. It is approved for the prophylaxis of absence seizures,
defects and should not be administered to pregnant pa- Lennox–Gastaut syndrome, akinetic and myoclonic sei-
tients unless benefits clearly outweigh the potential risks. zures, and nocturnal myoclonus. Its primary use as an
Diazepam is not recommended during lactation because AED is to treat refractory myoclonic seizures. Clonazepam
the drug is secreted in breast milk and may cause CNS de- is also approved for the treatment of panic disorder, with
pression in the neonate. or without agoraphobia. It is occasionally prescribed off-
label for other anxiety disorders, insomnia, and restless leg
Drug Interactions: Diazepam is metabolized by he- syndrome.
patic CYP450 enzymes and may interact with drugs that
inhibit these enzymes. Other CNS depressants, including Like other drugs in the class, the most common
alcohol, will intensify the sedative effects of diazepam. adverse effect is sedation. Hyperactivity, restlessness, irri-
Concurrent administration with cimetidine will increase tability, and cardiovascular or respiratory depression are
the plasma levels of diazepam. Administration of diaz- possible. If given for an extended period, the patient may
epam with antiparkinsonism medications may worsen the require an increase in dose due to the development of tol-
severity of Parkinson’s disease symptoms. Diazepam when erance. Tolerance also develops to the sedative side effects
administered with phenytoin will result in increased phe- of the drug. Therapeutic serum levels are 20 to 80 mg/mL.
nytoin levels and possible toxicity. Diazepam should never Clonazepam is pregnancy category C and a Schedule IV
be administered within 14 days of a monoamine oxidase controlled substance.
inhibitor (MAOI) due to the risk of hypertensive crisis.
Herbal/Food: Kava and valerian administered with di- Clorazepate (Tranxene): Approved in 1972, clorazepate is
azepam will result in additive sedative effects. Echinacea approved for the pharmacotherapy of anxiety, partial sei-
may lower the serum levels of diazepam. Grapefruit juice zures, and seizures associated with acute ethanol with-
increases the peak serum concentrations of diazepam by as drawal. It may be used off-label to treat insomnia.
much as two times. Clorazepate is administered PO and has a long duration
of action. The actions of clorazepate are the same as those
Pregnancy: Category D. of diazepam because the two drugs share the same active
metabolite. It is not a first-line drug for epilepsy but it
Treatment of Overdose: Flumazenil (Romazicon) is may be used as an adjunct to control partial seizures. Most
administered for overdosage of diazepam. This medica- adverse effects are CNS related and include mental
tion is a specific benzodiazepine receptor antagonist that depression, confusion, fatigue, tremor, and vertigo. Like
reverses the CNS depression from diazepam. diazepam, clorazepate is a Schedule IV drug and is preg-
nancy category D.
Nursing Responsibilities: Key nursing implica-
tions for patients receiving diazepam are included in the Lorazepam (Ativan): Approved in 1977, lorazepam is a
Nursing Practice Application for Patients Receiving Phar- first-line drug for treating status epilepticus because it per-
macotherapy for Seizures and in the Nursing Practice sists in the cerebrospinal fluid (CSF) longer than diazepam.
Application for Patients Receiving Pharmacotherapy for Whereas diazepam remains active in the brain for 30 to
Anxiety or Sleep Disorders in Chapter 18. 60 minutes, lorazepam may prevent seizures for up to
12 hours. It is also used to prevent or treat seizures associ-
Drugs Similar to Diazepam (Valium) ated with acute ethanol withdrawal. When given orally,
lorazepam is indicated for the short-term management of
Clobazam, clonazepam, clorazepate, and lorazepam are anxiety disorders or anxiety associated with depressive
benzodiazepine antiepileptic medications. symptoms. It is the most potent of the benzodiazepines
and has the ability to produce skeletal muscle relaxation,
Clobazam (Onfi): Clobazam was approved for the U.S. sedation, and a hypnotic state. Oral, IM, and IV forms are
market in 2013 and is available PO for one specific indica- available. Lorazepam is pregnancy category D and a
tion: seizures associated with Lennox–Gastaut syndrome Schedule IV controlled substance. A prototype feature for
in patients 2 years of age or older. The drug exhibits the lorazepam is presented in Chapter 18.
adverse effects typical of benzodiazepines, especially seda-
tion, which can be profound when the drug is used with CONNECTION Checkpoint 22.2
alcohol or other CNS depressants. Stevens–Johnson syn-
drome (SJS) is a serious, though rare, adverse effect. Toler- In addition to epilepsy, what are other indications for benzodiaze-
ance to the sedation effect, as well as the antiepileptic pines? Answers to Connection Checkpoint questions are available on
effect, occurs with continued therapy. Clobazam is preg- the faculty resources site. Please consult with your instructor.
nancy category C and a Schedule IV controlled substance.
344 Unit 4 Pharmacology of the Central Nervous System
22.9 Hydantoins are effective in the although it is not approved for these indications (see
management of most types of seizures Chapter 37). Other off-label indications for phenytoin
but have many adverse effects. include the treatment of migraines, diabetic neuropathy,
and neuropathic pain.
First used in 1938, phenytoin (Dilantin) became a preferred
drug for many types of epilepsy because it provided effec- Mechanism of Action: Phenytoin inhibits seizure
tive seizure prevention without the serious CNS depres- activity by delaying the influx of sodium ions in neurons,
sion and abuse potential associated with barbiturates. thus slowing the propagation and spread of abnormal dis-
Despite having many drawbacks, phenytoin remains an charges. Unlike some AEDs, phenytoin does not elevate
important drug in the pharmacotherapy of seizures. the seizure threshold.
Hydantoins act by delaying the influx of sodium ions Pharmacokinetics: PO, IV
across neuronal membranes in the brain. Sodium ion move- Route(s)
ment is the major factor determining the initiation and Absorption Slowly but completely absorbed
propagation of a neuron action potential. Hydantoin medi- in the GI tract
cations do not block the sodium channels but instead Distribution
desensitize them. Total blockage of sodium channels would Enters the CSF; crosses the
cause neuronal activity to cease as is seen with the admin- Primary metabolism placenta; secreted in breast
istration of local anesthetics. At high doses, the hydantoins Primary excretion milk; 95% bound to protein
begin to exert excitatory CNS effects and can induce Onset of action
seizures. Hepatic
Duration of action
PROTOTYPE DRUG Phenytoin (Dilantin, Phenytek) Renal
Classification Therapeutic: Antiepileptic drug PO (with loading dose):
Pharmacologic: Hydantoin, neuronal 30–120 min
sodium channel modulator Half-life is highly variable,
ranging from 7 to 42 h with an
Therapeutic Effects and Uses: Available since the average of 24 h
1930s phenytoin is approved for the prophylactic therapy
of all types of seizures except absence seizures. Phenytoin Adverse Effects: Phenytoin can be a very toxic drug
has been used to prevent seizures that might occur during and patients must be monitored carefully during therapy.
neurosurgery or eclampsia. The IV form of phenytoin is CNS adverse effects are relatively common and include
effective in treating generalized convulsions due to status lethargy, headache, drowsiness, and dizziness. High doses
epilepticus. The action of IV phenytoin is not immediate; can cause nystagmus, confusion, ataxia, coma, and sei-
therefore, an IV benzodiazepine should be administered zures. Cardiovascular adverse effects include bradycardia,
prior to, or concurrently with, IV phenytoin to achieve ventricular fibrillation, hypotension, and phlebitis. Gastro-
faster seizure control. Phenytoin injections must always intestinal (GI) adverse effects include gingival hyperpla-
be performed slowly (not to exceed 50 mg/min in adults) sia (swelling of the gums), weight loss, and liver necrosis.
to prevent cardiovascular collapse. Phenytoin (Phenytek) Hematologic adverse effects include agranulocytosis, leu-
is an extended release form of the drug that allows once- kopenia, thrombocytopenia, and aplastic anemia. Rashes
daily dosing. and serious dermatologic conditions occur in 5% to 10% of
patients taking the drug. Abrupt discontinuation of phe-
Patients taking phenytoin must be closely monitored nytoin can induce status epilepticus. Black Box Warning:
and the dosage adjusted based on clinical response and When IV infusion rates exceed 50 mg/min in adults, the
laboratory results. The therapeutic serum range is narrow, patient is at risk for hypotension and dysrhythmias. Care-
10 to 20 mcg/mL, and small increases in dose can produce ful cardiovascular monitoring is needed during and after
large changes in the serum concentration. Thus, the patient IV administration.
should be educated on the importance of maintaining a
strict schedule for administration of the medication and for Contraindications/Precautions: Patients who have
keeping all laboratory appointments. The brand of phenyt- developed a rash, sore throat, fever, oral ulcers, or other
oin should not be changed without approval of the health- hypersensitivity reactions to a hydantoin should not re-
care provider because differences in bioavailability among ceive phenytoin. This medication is contraindicated in
brands have been noted. patients who have experienced seizures caused by hypo-
glycemia. Phenytoin should be administered cautiously
Phenytoin is a Class 1B antidysrhythmic and may be to patients with impaired liver or kidney function because
used to treat ventricular tachycardia (especially those these may increase the serum concentration of phenytoin
induced by digoxin) or paroxysmal atrial tachycardia, to toxic levels. Patients with serious cardiovascular signs
and symptoms such as dysrhythmias, bradycardia, and
Chapter 22 Pharmacotherapy of Seizures 345
heart failure must be monitored carefully during therapy. site of injection) for several minutes to hours following the
Patients with blood dyscrasias should not receive phe- IV dose. Fosphenytoin carries the same black box warning
nytoin because this drug can worsen these conditions. as phenytoin. The drug is pregnancy category D.
Phenytoin is a known teratogen and should not be admin-
istered to pregnant patients unless the seizures cannot be 22.10 Carbamazepine is a first-line drug
managed by safer drugs. The drug is secreted in breast for treating many tonic–clonic and partial
milk, although it may be used during lactation, if neces- seizures.
sary, to control serious seizures.
The dibenzazepines are a small class of drugs that have
Drug Interactions: Because phenytoin strongly in- important applications to seizure management. These
duces hepatic CYP3A4 enzymes, the metabolism of many drugs have three rings in their structures, which makes
other drugs may be affected, and drug–drug interactions them chemically related to the tricyclic antidepressants
are common. Phenytoin increases the metabolism of corti- (see Chapter 19). The drugs in this class, carbamazepine
costeroids, warfarin, and oral contraceptives, thus render- (Carbatrol, Tegretol), eslicarbazepine (Aptiom), and oxcar-
ing these drugs less effective. Chronic alcohol ingestion, bazepine (Oxtellar XR, Trileptal), have similar pharmaco-
carbamazepine, and barbiturates can increase the metabo- logic activity.
lism of phenytoin, thus decreasing the antiseizure effects
of phenytoin. Amiodarone, chloramphenicol, diazepam, CONNECTIONS: Treating the
valproic acid, isoniazid, omeprazole, and ticlopidine will Diverse Patient
increase phenytoin levels when administered concurrently.
Herbal/Food: The administration or consumption of foods Post-Traumatic Epilepsy in Veterans with
that contain folic acid, calcium, and vitamin D will de- Traumatic Brain Injury
crease the absorption of phenytoin. Ginkgo may decrease
the antiseizure effectiveness of phenytoin. Epilepsy can develop after any form of head trauma. For sol-
diers returning from war and conflict, seizures and epilepsy
Pregnancy: Category D. related to traumatic brain injury (TBI) can occur from both
closed and open head wounds. As a result of recent military
Treatment of Overdose: Overdoses of phenytoin are conflicts, TBI in veterans has increased. The risk for post-
treated with activated charcoal with gastric lavage. traumatic epilepsy (PTE) appears to be directly related to the
severity of the TBI (Chen et al., 2014; Pugh et al., 2015).
Nursing Responsibilities: Key nursing implications
for patients receiving phenytoin are included in the Nurs- Pugh et al. (2015) found that the risk for epilepsy following
ing Practice Application for Patients Receiving Pharmaco- TBI was 18 times greater than for veterans without TBI. The
therapy for Seizures. authors also found statistically significant associations between
epilepsy and headache, mental health conditions such as
Drugs Similar to Phenytoin bipolar disorder and schizophrenia, and substance abuse dis-
(Dilantin, Phenytek) order (p. 35). Epilepsy was also more common in younger vet-
erans under the age of 50. Chen et al. (2014) found that
Fosphenytoin is the only other hydantoin. psychogenic nonepileptic seizures may be occurring, rather
than PTE, a finding not inconsistent with high levels of post-
Fosphenytoin (Cerebyx): Approved in 1996, fosphenytoin traumatic stress disorder (PTSD) in veterans.
is a prodrug that is converted to phenytoin following
metabolism. Given only by the parenteral route, it is con- PTE in the wounded veteran population significantly
sidered functionally equivalent to phenytoin; their actions affects their ability to reenter civilian life as productive members
and adverse effects are the same. Doses on the label are of society. Depending on whether or not the PTE is controlled,
indicated as phenytoin equivalents (PE). Indications for normal life activities such as driving and employment using
fosphenytoin include tonic–clonic seizures, status epilepti- skills learned in the armed services, for example, automotive or
cus, and seizure prophylaxis during neurosurgery. Because aviation jobs, may be difficult or impossible to obtain or main-
the drug is converted to phenytoin, therapeutic serum lev- tain. Nurses should be aware of the stigma of epilepsy in all
els of phenytoin may be monitored during therapy. Advan- patients, but especially for veterans returning from combat with
tages of fosphenytoin over phenytoin include more rapid head wounds. Reentry into society may be difficult for any vet-
IV administration (important during status epilepticus), eran with wounds related to combat. However, when a closed
ability to be administered by the IM route, and less pain head injury has resulted in PTE and negatively affects the ability
and phlebitis at the injection site. The adverse effects are to function normally in society, the veteran, who may look nor-
the same as IV phenytoin, except that fosphenytoin may mal, has sustained a significant wound that cannot be seen.
cause intense burning, itching, and paresthesia (not at the By providing teaching and care, and by working with veterans’
support groups, nurses can help ease the transition for these
veterans when they return home.
346 Unit 4 Pharmacology of the Central Nervous System
The mechanisms of action of the dibenzazepines are clinical outcomes and drug serum levels. The therapeutic
incompletely understood. Like phenytoin, they affect the serum concentrations usually range from 4 to 12 mcg/mL.
sodium channels in cortical neurons, slowing the propaga- Several weeks of therapy may be required before the opti-
tion and spread of repetitive action potentials. These drugs mal dose is determined and the effective plasma drug con-
have other actions, however, that are unexplained by the centration achieved.
sodium channel mechanism, including analgesic, anticho-
linergic, antidysrhythmic, antidepressant, and sedative Mechanism of Action: Carbamazepine inhibits so-
effects. They also have muscle relaxant and neuromuscu- dium channels, blocking the repetitive, sustained firing
lar-blocking properties. Doses for the dibenzazepines are of neurons that is characteristic of epilepsy. Other mecha-
listed in Table 22.3. nisms are likely but are incompletely understood.
PROTOTYPE DRUG Carbamazepine (Carbatrol, Pharmacokinetics: PO
Tegretol, Others) Route(s)
Absorption Slowly absorbed across the
Classification Therapeutic: Antiepileptic drug Distribution GI tract
Pharmacologic: Dibenzazepine,
Primary metabolism Widely distributed; enters
neuronal sodium channel modulator Primary excretion the CSF; crosses the
Onset of action placenta; secreted in breast
Therapeutic Effects and Uses: Approved by the Duration of action milk; 75–85% bound to
FDA in 1968, carbamazepine is one of the most widely proteins
prescribed AEDs in the world because of its effectiveness
and relative safety. It is indicated for the management of Hepatic (induces CYP450
generalized tonic–clonic seizures, partial seizures with enzymes)
complex symptomatology, and mixed seizure patterns.
It is ineffective against absence seizures. Carbamazepine Primarily renal with some
may be administered as monotherapy or in combination in feces
with other AEDs. Carbamazepine is also approved for the
treatment of acute mania associated with bipolar disorder, Slow and variable
either as monotherapy or in combination with lithium
(see Chapter 19). Carbamazepine is available as an ex- Half-life: 14–16 h; 35–40 h for
tended release form (Tegretol XR and Carbatrol CR), and extended release
as a multiphasic extended release form (Equetro). In 2016
an IV form (Carnexiv) was approved to treat generalized Adverse Effects: Carbamazepine is well tolerated;
tonic–clonic seizures or partial seizures when oral admin- adverse effects are usually transient and diminish as
istration is not feasible. therapy progresses. The most frequently observed ef-
fects include drowsiness, dizziness, ataxia, and nausea
Prior to its use as an AED, carbamazepine was and vomiting. Transient sedation is common at the onset
approved to treat pain associated with trigeminal neural- of therapy or after dosage increases. Other CNS effects
gia. It remains one of the most effective drugs for this include confusion, blurred vision, lethargy, and visual
condition. Off-label uses of carbamazepine include the disturbances, although the patient usually develops tol-
treatment of neuropathic pain associated with diabetic erance to these effects. Other possible adverse effects
neuropathy and post-herpetic pain. The drug is also used include myalgia, leg cramps, carbamazepine-induced
off-label to treat hiccups and for the management of systemic erythematosus, heart block, aplastic anemia,
severe symptoms of dementia such as aggression and respiratory depression, phototoxicity, urticaria, and alo-
agitation, which are seen in some patients with Alzheim- pecia. Elevated hepatic enzymes occur during therapy,
er’s disease. although the patient is usually asymptomatic for hepatic
disease. A few rare cases of serious hepatic impairment
Although carbamazepine is structurally similar to the have been documented. Some patients have reported uri-
tricyclic antidepressants, it does not produce the antide- nary retention and frequency, and male patients may ex-
pressant effects of drugs in that class. The medication is perience impotence. Black Box Warning: Aplastic anemia
metabolized in the liver to an active metabolite and is a and agranulocytosis have been reported with this drug.
potent inducer of CYP450 enzymes that will increase its Serious and sometimes fatal dermatologic reactions, in-
own metabolism. Long-term administration of carbamaze- cluding toxic epidermal necrosis and SJS, have also oc-
pine will result in the need to increase the dose because its curred with carbamazepine. Patients testing positive for
half-life becomes shortened. the HLA-B 1502 gene (usually found in people of Asian
ancestry) are at higher risk for severe dermatologic reac-
For all indications, therapy with carbamazepine must tions and should not receive this drug unless the benefit
be monitored carefully and the dosage adjusted based on clearly outweighs the risk.
Chapter 22 Pharmacotherapy of Seizures 347
Contraindications/Precautions: Patients who are Oxcarbazepine (Oxtellar XR, Trileptal): Although oxcar-
hypersensitive to tricyclic antidepressants should not bazepine is similar to the tricyclic antidepressants, it does
take carbamazepine. Patients who have been diagnosed not possess antidepressant activity. Approved in 2000,
with increased intraocular pressure, systemic lupus ery- oxcarbazepine can be administered as monotherapy or in
thematosus, cardiac disease, hepatic disease, and liver combination with other medications in the treatment of
disease should not take carbamazepine. This medica- partial seizures, with or without secondary generalization.
tion is contraindicated with HTN. Older adults should Off-label uses include the treatment of neuropathic pain
be monitored closely if they possess a history of cardiac and bipolar disorder. A major advantage of oxcarbazepine
disease because a major adverse effect is heart block. over carbamazepine is that drug interactions appear less
Carbamazepine causes multiple birth defects in labora- significant and monitoring of drug plasma levels and
tory animals. If used during pregnancy, monotherapy is hematologic values is generally not necessary. Although it
recommended because the use of two or more AEDs in- induces CYP450 enzymes, it is not as strong an inducer as
creases the risk of teratogenesis. carbamazepine and it does not induce its own metabolism.
An extended release form of the drug (Oxtellar XR) is
Drug Interactions: Carbamazepine induces the activ- available for once-daily dosing.
ity of several hepatic CYP450 enzymes, which can result in
decreased serum concentrations of AEDs and other drugs For checking adherence with the drug regimen or in
metabolized by the liver. Increased carbamazepine lev- overdose situations, the therapeutic serum concentration
els have been noted when the drug is administered with of the drug is 12 to 30 mcg/mL. Adverse effects are similar
verapamil, erythromycin, ketoconazole, or nefazodone. to those of carbamazepine, with dizziness, drowsiness,
Patients who take carbamazepine with anticoagulants headache, and ataxia being the most common effects. Seri-
will experience decreased hypoprothrombinemic effects. ous adverse effects include suicidal ideation, agranulocyto-
Carbamazepine may decrease the effectiveness of oral sis, hyponatremia, and severe dermatologic reactions. A
contraceptives. Herbal/Food: Ginkgo may decrease the an- serious and sometimes fatal adverse event called drug
tiepileptic effectiveness of carbamazepine. Grapefruit juice reaction with eosinophilia and systemic systems (DRESS)
and St. John’s wort induce CYP450 enzymes and can de- has been reported with oxcarbamazepine. Oxcarbamaze-
crease serum carbamazepine levels. pine is pregnancy category C, although caution should be
used during pregnancy because this drug is closely related
Pregnancy: Category D. structurally to carbamazepine, which is category D.
Treatment of Overdose: Activated charcoal and gas- 22.11 Succinimides are the first-line drugs for
tric lavage are administered with carbamazepine overdose. the pharmacotherapy of absence seizures.
Nursing Responsibilities: Key nursing implications Succinimides form a small group of AEDs that suppress
for patients receiving carbamazepine are included in the the influx of calcium into neurons during neuronal trans-
Nursing Practice Application for Patients Receiving Phar- mission. This is believed to increase the electrical threshold
macotherapy for Seizures. of the neuron, which reduces the likelihood of abnormal
action potentials. Recent research has questioned this
Drugs Similar to Carbamazepine (Carbatrol, mechanism of action, and the actual mechanism of antiepi-
Tegretol, Others) leptic activity of this group remains largely unknown.
Despite the small size of the class and their unknown
Other dibenzazepines include eslicarbazepine and mechanism of action, these drugs have important roles in
oxcarbazepine. the pharmacotherapy of absence seizures.
Eslicarbazepine (Aptiom): One of the newer AEDs, esli- PROTOTYPE DRUG Ethosuximide (Zarontin)
carbazepine was approved in 2013 for the treatment of
partial-onset seizures. It is usually used as an add-on treat- Classification Therapeutic: Antiepileptic drug
ment to therapy with other drugs in this class. It has a long Pharmacologic: Succinimide, neuronal
half-life that allows for once-daily dosing. Eslicarbazepine
and oxcarbazepine have very similar actions and adverse calcium channel modulator
effects because both are converted to the same active
metabolite. Common adverse effects include dizziness, Therapeutic Effects and Uses: Ethosuximide is the
somnolence, nausea, headache, vomiting, blurred vision, only drug in this class that is commonly prescribed. Ap-
and tremor. Serious adverse effects include suicidal ide- proved in 1960, it is a preferred drug for managing absence
ation, agranulocytosis, hyponatremia, and severe derma- seizures. Because ethosuximide is ineffective in treating
tologic reactions. This drug is pregnancy category C. simple or complex partial seizures and tonic–clonic sei-
zures, combination pharmacotherapy is needed to manage
mixed seizures.
348 Unit 4 Pharmacology of the Central Nervous System
Ethosuximide is only administered by the oral route. frequency. Isoniazid administered in combination with eth-
Therapeutic serum concentrations range from 40 to osuximide can result in increased serum ethosuximide lev-
100 mcg/mL, although dosing is usually based on clinical els. Carbamazepine will cause a decrease in ethosuximide
response rather than serum levels. It may take 4 to 7 days serum levels. Concurrent use of valproic acid will inhibit the
before optimal therapeutic levels are attained. metabolism of ethosuximide, leading to possible toxicity.
Herbal/Food: Unknown.
Mechanism of Action: Ethosuximide depresses
the motor cortex by delaying the calcium influx into the Pregnancy: Category C.
neuron.
Treatment of Overdose: Activated charcoal and gas-
Pharmacokinetics: PO tric lavage are administered with ethosuximide overdose.
Route(s)
Absorption Readily and completely Nursing Responsibilities: Key nursing implications
absorbed for patients receiving ethosuximide are included in the
Distribution Nursing Practice Application for Patients Receiving Phar-
Widely distributed; very small macotherapy for Seizures.
Primary metabolism amounts bound to proteins;
Primary excretion crosses the placenta and is Drugs Similar to Ethosuximide (Zarontin)
secreted in breast milk
Onset of action Methsuximide is the only other drug in this class.
Duration of action Hepatic
Methsuximide (Celontin): Like ethosuximide, methsuxi-
Primarily renal, with some in mide is indicated for the management of absence seizures.
feces and bile This drug is rarely used in clinical practice because it is less
effective and more toxic than ethosuximide. It has the
Peak: 4 h same indications and adverse effects as ethosuximide. This
drug is pregnancy category C.
Half-life: 30 h in children; 60 h
in adults 22.12 Several miscellaneous drugs are
important in treating epilepsy.
Adverse Effects: The most common adverse effects
of ethosuximide are GI related, including anorexia, nau- As explained in Section 22.6, it is difficult to classify AEDs
sea, vomiting, abdominal pain, and diarrhea. Adverse because many act by multiple mechanisms, whereas others
CNS events include drowsiness, dizziness, ataxia, confu- are unique and are the only drug in a class. Several of these
sion, and night terrors. Hematologic toxicity may include “miscellaneous” drugs are widely used. Following the dis-
agranulocytosis, pancytopenia, and aplastic anemia. Der- cussion of the two prototypes, other miscellaneous drugs
matologic effects include rash, pruritus, and exfoliative and their indications are described.
dermatitis. Like many AEDs, this drug may increase the
risk of suicidal ideation. PROTOTYPE DRUG Gabapentin (Neurontin)
Contraindications/Precautions: Ethosuximide is Classification Therapeutic: Antiepileptic drug
contraindicated in patients who have a known sensitivity Pharmacologic: GABA analog
to succinimides. It should be administered with caution to
patients with liver or kidney impairment. Administration of Therapeutic Effects and Uses: Gabapentin consists
ethosuximide may increase the frequency of tonic–clonic sei- of a molecule of the neurotransmitter GABA with an at-
zures. Patients with blood dyscrasias or bone marrow sup- tached side chain. The side chain makes the molecule lipid
pression should not receive this drug because it can worsen soluble so that it readily crosses the blood–brain barrier.
these conditions. Safety has not been established for the ad- Approved in 1993, gabapentin is used in combination with
ministration of this medication during pregnancy. Although other AEDs to control partial seizures with or without
small amounts of the drug are secreted in breast milk, the secondary generalization. Doses are based on therapeutic
drug is believed to be compatible with breastfeeding. response, making it unnecessary to measure serum drug
levels during therapy. It is available as capsules, as tablets,
Drug Interactions: Ethosuximide can participate in and as an oral solution.
many drug–drug interactions. When used in combination
therapy with other AEDs, serum drug levels should be Therapy with gabapentin has been found to benefit a
regularly monitored. CNS depressants and ethanol may number of other conditions. Gabapentin (Gralise) is
cause additive sedation. Use of ethanol may also reduce approved for the treatment of post-herpetic neuralgia and
the effectiveness of the antiseizure medication. Ethosuxi- gabapentin (Horizant) for restless leg syndrome. Gabapen-
mide administered concurrently with phenobarbital, phe- tin is used off-label for other conditions with neuropathic
nothiazines, or tricyclic antidepressants can increase seizure
Chapter 22 Pharmacotherapy of Seizures 349
pain such as diabetic neuropathy. In fact, the drug is prob- Drug Interactions: A major advantage of gabapentin
ably prescribed more often for the treatment of neuropathic is that it does not induce CYP450 enzymes, and thus it ex-
pain than for epilepsy. Hot flashes are reduced in approxi- hibits fewer drug interactions than many other AEDs. No
mately 50% of the women taking the drug. It has been des- interactions with carbamazepine, phenobarbital, phenyt-
ignated as an orphan drug for the treatment of amyotrophic oin, or valproic acid have been observed. Morphine and
lateral sclerosis (ALS). Some research has suggested that hydrocodone may cause additive CNS depression when
gabapentin is useful in treating trigeminal neuralgia, pares- administered with gabapentin. Herbal/Food: The adminis-
thesia, spasticity, and ocular ataxia in patients with multi- tration of ginkgo with gabapentin may result in decreased
ple sclerosis. anticonvulsant effects. The use of valerian is contraindi-
cated due to the risk of additive sedation.
Mechanism of Action: The exact mechanism of an-
ticonvulsant action for gabapentin is unknown. Although Pregnancy: Category C.
closely related structurally to GABA, it does not appear to
bind to GABA receptors or to prevent endogenous GABA Treatment of Overdose: Overdose results in dys-
from binding. It does not appear to affect the binding of pnea, sedation, double vision, and slurred speech. Renal
other neurotransmitters such as serotonin, dopamine, glu- dialysis can be utilized to treat gabapentin overdose.
tamate, or histamine. It likely affects calcium channels but
its exact mechanism has not been determined. Nursing Responsibilities: Key nursing implications
for patients receiving gabapentin are included in the Nurs-
Pharmacokinetics: PO ing Practice Application for Patients Receiving Pharmaco-
Route(s) therapy for Seizures.
Absorption 50–60% is absorbed from the GI
Distribution tract PROTOTYPE DRUG Valproic Acid (Depacon,
Depakene, Depakote)
Primary metabolism Crosses the blood–brain barrier
Primary excretion and the placenta; readily passes Classification T herapeutic: Antiepileptic drug,
Onset of action into the CSF; secreted in breast antimanic drug
Duration of action milk; very small amounts
bound to proteins Pharmacologic: GABA agonist
Not metabolized Therapeutic Effects and Uses: Approved in 1978,
valproic acid has become a preferred drug for treating
Excreted unchanged by the many types of epilepsy. This medication has several trade
kidneys names and formulations, which can cause confusion when
studying it.
1h
• Valproic acid (Depakene) is the standard form of the
Half-life: 5–6 h drug given by the oral route.
Adverse Effects: Gabapentin is well tolerated, with • Valproate sodium (Depacon) is the sodium salt of val-
CNS symptoms such as drowsiness, fatigue, nystag- proic acid given orally or IV.
mus, and dizziness being the primary adverse effects.
The administration of gabapentin can lead to increased • Divalproex sodium (Depakote ER) is a sustained
frequency of viral infections, weight gain, and gastric release combination of valproic acid and its sodium
upset. Behavioral problems such as hostility, emotional salt in a 1:1 mixture. It is given orally and is available
lability, impaired cognition, aggressiveness, and hyper- in an enteric-coated form.
kinesia have been reported in the pediatric population
ages 3 to 12. All three formulations of the drug form valproate
after absorption or on entering the brain. The pharmaco-
Contraindications/Precautions: Gabapentin should kinetics of each form varies, and they are not interchange-
not be administered during pregnancy or lactation unless able. In this text, the name “valproic acid” is used to
the benefits of pharmacotherapy outweigh the risks. It describe all forms of the drug, unless specifically stated
should not be administered in patients who have experi- otherwise.
enced a hypersensitivity reaction to GABA-related medica-
tions. It should be used cautiously with status epilepticus Valproic acid is administered as monotherapy or in
and with older adults. Gabapentin should be used with combination with other AEDs to treat absence seizures and
caution in patients with chronic kidney disease because complex partial seizures. Depakote ER is also approved for
the drug could accumulate to toxic levels. The drug should the prevention of migraines and mania associated with
be discontinued gradually to prevent withdrawal-associ- bipolar disorder. Off-label indications include severe
ated seizures. behavioral disturbances such as agitation due to dementia,
Alzheimer’s disease, or explosive temper in patients with
350 Unit 4 Pharmacology of the Central Nervous System
ADHD; persistent hiccups; and status epilepticus refrac- and autoimmune deficiency syndrome. Patients with
tory to IV diazepam. Dosage adjustments for valproic acid known or suspected pancreatitis should not receive this
are usually based on patient response; normal serum drug drug because life-threatening pancreatitis has been re-
levels for epilepsy are 50 to 100 mcg/mL. In 2007, the FDA ported. Valproic acid should be administered cautiously
approved Stavzor, a soft gelatin capsule of valproic acid. in patients with a low serum albumin or chronic kidney
The capsule dissolves in the small intestine, rather than the disease. Extreme caution should be used in treating pa-
stomach, thus reducing nausea and vomiting, which are tients under age 2 because fatal hepatotoxicity has been
common adverse effects of the drug. reported. The drug should not be administered to pa-
tients with known hepatic impairment. Abrupt discon-
Mechanism of Action: Valproic acid increases con- tinuation may cause status epilepticus. This drug is a
centrations of the inhibitory neurotransmitter GABA in the known teratogen and should be used during pregnancy
brain. Abnormal neuron discharges are suppressed, lead- only when benefits of therapy clearly outweigh the risk
ing to decreased seizure activity. of birth defects.
Pharmacokinetics: IV, PO Drug Interactions: Valproic acid inhibits CYP450 en-
Route(s) zymes, which can result in many drug–drug interactions.
Absorption Rapidly absorbed in the GI Valproic acid administered concurrently with alcohol and
tract other CNS depressants may result in additive sedation.
Distribution Patients taking enzyme-inducing AEDs such as carbam-
Crosses the placenta and is azepine, phenytoin, and phenobarbital will metabolize
Primary metabolism secreted in breast milk; 80–90% valproic acid more rapidly, and dosage adjustment will
Primary excretion bound to protein be necessary. Valproic acid may increase the serum lev-
Onset of action els of tricyclic antidepressants, requiring a reduction in
Duration of action Hepatic antidepressant dosage. Aspirin increases the serum drug
levels of valproic acid and should not be administered
Renal and GI tract concurrently. Isoniazid will elevate serum valproic acid
levels. Cholestyramine will decrease absorption of val-
15–30 min proic acid. Cimetidine will increase valproic acid levels
and will place the patient at risk for hepatotoxicity. Val-
Half-life: 5–20 h proic acid should not be administered with topiramate
due to an increased risk of hyperammonemic encepha-
Adverse Effects: Valproic acid is well tolerated in most lopathy. Herbal/Food: Ginkgo may decrease the antiepi-
patients and adverse effects rarely cause discontinuation leptic effects of valproic acid.
of therapy. The most common adverse effects are GI re-
lated, such as nausea, vomiting, diarrhea, abdominal pain, Pregnancy: Category D.
and diminished appetite. An enteric-coated formulation of
valproic acid can be used to reduce these uncomfortable Treatment of Overdose: The effects from overdose
effects. These effects are usually transient and not severe. of valproic acid may be serious and include sedation, heart
CNS adverse effects such as headache, tremor, dizziness, block, deep coma, and death. Naloxone (Narcan) is uti-
and sedation occur in about 25% of patients. High doses lized to reverse the CNS depression, and hemodialysis can
of valproic acid cause diminished platelet aggregation, lower drug serum levels. Caution must be used when ad-
which can result in prolonged bleeding and clotting times. ministering naloxone because this drug may also reverse
Bone marrow depression, photosensitivity, and pulmonary the antiseizure action of valproic acid.
edema are rare potential adverse effects. Valproic acid may
cause hyperammonemic encephalopathy, especially in Nursing Responsibilities: Key nursing implications
combination with topiramate, which requires discontinu- for patients receiving valproic acid are included in the
ation of valproic acid therapy. Black Box Warning: Serious Nursing Practice Application for Patients Receiving Phar-
hepatotoxicity has been reported in infants younger than macotherapy for Seizures.
age 2 taking valproic acid. Life-threatening pancreatitis has
occurred as a result of valproic acid administration. When Other Miscellaneous Drugs
given during pregnancy, valproic acid can produce neural
tube defects and children exposed while in utero demon- Brivaracetam (Briviact): Approved in 2016, brivaracetam
strate lower cognitive scores. is one of the newest drugs for treating partial-onset sei-
zures. This drug acts by a similar mechanism of action to
Contraindications/Precautions: Patients with levetiracetam, although its dose is 10 times lower than the
hypersensitivity to any formulation of valproic acid older medication. It is used as an add-on when other AEDs
should not be administered this drug. Other contrain-
dications include significant hepatic impairment, bleed-
ing disorders, cirrhosis, congenital metabolic disorders,
Chapter 22 Pharmacotherapy of Seizures 351
are unable to successfully control seizures. The patient however, and patients who are taking potent inducers of
should be carefully monitored for sedation and suicidal CYP450 enzymes (e.g., carbamazepine, phenytoin, and
ideation during therapy. Brivaracetam may be adminis- phenobarbital) will metabolize the drug more rapidly.
tered by either the PO or IV route. This drug is pregnancy Doses of lamotrigine will need to be increased in these
category C. patients to produce an optimal antiseizure response. On
the other hand, valproic acid will reduce the elimination of
Ezogabine (Potiga): Ezogabine was approved in 2011 for lamotrigine, and the dose of lamotrigine should be reduced
the adjunctive treatment of partial-onset seizures in adults. to prevent toxicity. Oral contraceptives reduce serum levels
The drug acts by stabilizing potassium channels in the of lamotrigine, and the dosage of the AED will need to be
brain, which reduces brain excitability. The drug should be adjusted when therapy with the hormones is initiated or
used with caution in patients with benign prostatic hyper- discontinued and during the “pill-free” week of the month.
plasia because it may cause urinary retention. Dizziness, Lamotrigine is one of the preferred drugs for managing
somnolence, and fatigue are common side effects during epilepsy in pregnant women.
therapy. Ezogabine carries a black box warning that the
drug may cause retinal abnormalities and vision loss. All Lamotrigine is generally well tolerated by patients.
patients should receive baseline and periodic ophthalmic The most common adverse effects are drowsiness, dizzi-
examinations while taking this drug. Ezogabine is a Sched- ness, ataxia, headache, diplopia, blurred vision, nausea,
ule V drug and is pregnancy category C. vomiting, and rash. Patients should be monitored for the
development of suicidal ideation. Over 10% of patients tak-
Felbamate (Felbatol): Approved in 1993, felbamate is an ing this AED will develop a rash, which normally occurs
oral drug that is effective against most types of seizures. during the first 2 to 8 weeks of therapy. This drug carries a
Serious adverse effects, however, limit its use to severe black box warning that serious dermatologic toxicity,
partial seizures and the treatment of partial and general- including SJS, has been reported, especially in children.
ized seizures associated with Lennox–Gastaut syndrome Lamotrigine should be discontinued at the first sign of any
in children who have not responded to other therapies. type of rash. This drug is pregnancy category C.
Although the incidence of these adverse effects is rare,
they may be serious or fatal. More common adverse effects Levetiracetam (Keppra): Levetiracetam is available for
include nausea, vomiting, anorexia, drowsiness, dizziness, both PO and IV routes and is utilized in the therapy of the
insomnia, and vision changes. This drug carries a black following seizures: adjunctive therapy for partial seizures
box warning that fatal aplastic anemia and fatal hepatic in adults and children ages 4 years and older, adjunctive
failure have been associated with felbamate use. Baseline therapy for myoclonic seizures in adults and adolescents
and periodic hematologic and hepatic laboratory tests ages 12 years and older, and adjunctive therapy of primary
should be conducted. This drug is pregnancy category C. generalized tonic–clonic seizures in adults and children
ages 6 years and older. Approved in 1999, the mechanism
Lacosamide (Vimpat): Lacosamide is a miscellaneous of its antiseizure activity is unknown. Levetiracetam is
AED used in the management of partial-onset seizures in excreted unchanged by the kidneys; thus dosage should be
adults whose seizures are not well controlled by other reduced in patients with chronic kidney disease (CKD).
medications. Approved in 2008, its most frequent adverse Few significant drug interactions have been recorded. In
effects include diplopia, headache, dizziness, and nausea. 2008, an extended release form of the drug (Keppra XR)
Patients with cardiac conduction abnormalities should be was approved to treat partial-onset seizures.
carefully monitored during therapy. This drug is preg-
nancy category C. Levetiracetam is well tolerated, with the most common
adverse effects being drowsiness, dizziness, infections,
Lamotrigine (Lamictal): Approved in 1994, lamotrigine headache, and asthenia. The nurse must teach the patient
is an oral drug indicated for the adjunctive therapy of to exercise care in performing tasks because an increase in
partial seizures, Lennox–Gastaut syndrome, absence sei- unintentional injuries is associated with levetiracetam use.
zures, and tonic–clonic seizures in adults and pediatric Pediatric patients exhibit a relatively high incidence of
patients 2 years of age or older. It is also used in the behavioral effects, including agitation, nervousness, hyper-
maintenance therapy of bipolar disorder. Lamotrigine kinesia, hostility, depression, and emotional lability. Leveti-
inhibits the release of glutamate in neurons and inhibits racetam is pregnancy category C.
flow through sodium ion channels, which stabilizes neu-
ronal membranes. Lamotrigine is rapidly absorbed, 55% Pregabalin (Lyrica): Approved in 2004, pregabalin is an
bound to plasma proteins, and almost entirely excreted oral AED that is very similar to gabapentin. Pregabalin is
by the kidneys. indicated for the adjunctive therapy of adult patients with
partial-onset seizures. Like gabapentin, it is used more
Lamotrigine does not induce or inhibit hepatic meta- often for its other approved indications: the management
bolic enzymes. It is metabolized by CYP450 enzymes, of neuropathic pain associated with diabetic peripheral
352 Unit 4 Pharmacology of the Central Nervous System
neuropathy, post-herpetic neuralgia, and fibromyalgia. tremor, asthenia, abdominal pain, and difficulty with con-
Off-label uses include the therapy of anxiety and social centration or attention. As with other AEDs the nurse
phobia. The safety of pregabalin in pediatric patients has should teach patients to avoid injury due to possible seda-
not been established. Although its mechanism of action tive effects. Although tiagabine suppresses seizures in
has not been clearly demonstrated, it is thought to act by patients with epilepsy, it has been found to increase new-
increasing GABA levels by reducing the calcium channel onset seizures when given to patients without epilepsy (for
function of neurons in the brain. This drug does not affect off-label indications). Because of this, the FDA and the
CYP450 enzymes; thus it has fewer drug–drug interactions manufacturer have advised prescribers not to administer
than many other AEDs. Pregabalin is not bound to plasma tiagabine for any indication other than partial seizures in
proteins and is excreted in an unmetabolized form by the patients 12 years and older. An additional FDA warning
kidneys. Dose reduction in patients with CKD is necessary advises healthcare providers to monitor carefully for any
to avoid toxicity. increase in suicidal behavior or ideation. Tiagabine is preg-
nancy category C.
Pregabalin is well tolerated by most patients. Dizzi-
ness and drowsiness are the most common adverse effects Topiramate (Topamax, Trokendi XR, Others): Approved in
and these may affect 20% to 40% of patients taking prega- 1996, topiramate has become an important medication in
balin, especially at high doses. Other common adverse treating a broad range of seizure types in adults and chil-
effects of pregabalin are blurred vision, lethargy, dry dren. It may be used as monotherapy or in combination
mouth, peripheral edema, weight gain, and difficulty with with other AEDs. The drug is usually well tolerated, with
concentration or attention. Concurrent administration with the most frequent adverse effects being dizziness, fatigue,
other CNS depressants can lead to increased sedation. paresthesia, anorexia, weight loss, and psychomotor slow-
Because pregabalin is a Schedule V controlled substance ing. Newer, extended release forms (Qudexy XR, Trokendi
that may cause physical and psychologic dependence, it XR) offer the convenience of once-daily dosing. During
should be used with caution in patients with a known or therapy, patients should be monitored for visual changes,
suspected history of substance abuse. Pregabalin is preg- glaucoma, metabolic acidosis, cognitive dysfunction, and
nancy category C. suicidal behavior. Adequate fluid intake should be encour-
aged to prevent kidney stone formation. Because this drug
Rufinamide (Banzel): Rufinamide is an oral drug can decrease sweating, the patient may be susceptible to
approved in 2008 for the adjunctive treatment of seizures hyperthermia during hot weather. Topiramate is preg-
associated with Lennox–Gastaut syndrome. It is well toler- nancy category D and may increase the risk of oral clefts in
ated, with dizziness, headache, and fatigue being common children exposed to the drug while in utero.
adverse effects. The drug acts by regulating the activity of
sodium channels in the brain. It is contraindicated in Vigabatrin (Sabril): Available PO, vigabatrin was
patients with familial short ST syndrome. Rufinamide is approved in 2009 for adjunctive therapy of refractory com-
pregnancy category C. plex partial seizures in adults. Because of potential serious
adverse effects, vigabatrin is available in a restricted distri-
Tiagabine (Gabitril): Tiagabine is given by the oral bution program and is only prescribed when patients have
route for the adjunctive treatment of partial seizures in not responded adequately to other medications. This drug
patients who have not responded to therapy with other contains a black box warning that permanent vision loss
AEDs. Safety in patients under age 12 has not been can occur during therapy. Other serious adverse effects
established. Approved in 1997, it acts by inhibiting include anemia, confusion, and memory impairment.
GABA reuptake into the presynaptic neuron. Tiagabine Vigabatrin is pregnancy category C.
is extensively metabolized by CYP3A enzymes. Patients
who are taking potent inducers of CYP450 enzymes Zonisamide (Zonegran): Approved in 2000, zonisamide is
(e.g., carbamazepine, phenytoin, and phenobarbital) an oral sulfonamide that is effective in combination with
will metabolize tiagabine more rapidly. Doses of other AEDs for partial seizures in adults. Safety in patients
tiagabine will need to be increased in these patients to under age 16 has not been established although the drug is
produce an optimal antiseizure response. Tiagabine sometimes used off-label in children. It produces antiepi-
itself does not induce CYP450 enzymes; thus it has fewer leptic effects by inhibiting sodium and calcium channels in
drug–drug interactions than many other AEDs. brain neurons. Zonisamide has a long half-life and 2 weeks
Tiagabine is 98% bound to plasma proteins and is elimi- may be required before optimal antiseizure activity is
nated in both the urine and feces. achieved.
Approximately 10% to 20% of patients taking tiagabine Zonisamide is well tolerated by most patients. The
experience adverse effects that require discontinuation of most common adverse effects are dizziness, ataxia, drows-
therapy. The most common adverse effects are dizziness, iness, fatigue, anorexia, speech abnormalities, and difficulty
lethargy, confusion, somnolence, nausea, irritability,
Chapter 22 Pharmacotherapy of Seizures 353
in concentrating or remembering. Because many patients carbamazepine, phenobarbital, and valproic acid will
are allergic to sulfonamides, it is important to assess these decrease the half-life of zonisamide. Doses of zonisamide
patients for sulfonamide hypersensitivity prior to the will need to be increased in these patients to produce an
administration of the medication. Sulfonamides can cause optimal antiseizure response. Zonisamide itself does not
fatal skin reactions, including SJS. The medication should induce CYP enzymes; thus it has fewer drug–drug interac-
be administered cautiously in patients who are receiving tions than many other AEDs. Zonisamide is pregnancy
drugs that inhibit or reduce CYP3A4 enzymes; phenytoin, category C.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy for Seizures
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including hepatic, renal, cardiovascular, or neurologic disease, mental status, closed-angle glaucoma, pregnancy, or
breastfeeding. Obtain a drug history including allergies, current prescription and over-the-counter (OTC) drugs, and herbal preparations. Be alert to
possible drug interactions.
• Obtain a seizure history (e.g., frequency, duration, physical symptoms, preseizure symptoms that occur, and length of postictal period).
• Obtain baseline vital signs, weight, and, in pediatric patients, height.
• Obtain a developmental history in pediatric patients (e.g., DDST-II level of growth and development, and school performance).
• Evaluate appropriate laboratory findings (e.g., CBC, electrolytes, hepatic or renal function studies).
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Assess for desired therapeutic effects (e.g., diminished or absence of seizure activity).
• Continue periodic monitoring of CBC and liver and renal function studies.
• Assess vital signs and weight periodically or if symptoms warrant. Assess height and weight in all pediatric patients.
• Assess for and promptly report adverse effects: excessive dizziness, drowsiness, lightheadedness, confusion, agitation, palpitations, tachycardia,
blurred or double vision, continuous seizure activity, skin rashes, bruising or bleeding, abdominal pain, jaundice, change in color of stool, flank pain,
and hematuria.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient, family, or caregiver to keep a seizure diary of
• Continue assessments as above for therapeutic effects. (Antiseizure frequency, type, length, preseizure symptoms, and postictal period.
drugs may not completely resolve symptoms but frequency and
severity of seizures should be diminished.)
Minimizing adverse effects: • Teach the patient to rise from lying or sitting to standing slowly to
• Continue to monitor vital signs, mental status, coordination, and avoid dizziness or falls. If dizziness occurs, the patient should sit
or lie down and not attempt to stand or walk, until the sensation
balance periodically. Ensure patient safety; monitor ambulation until passes. Lifespan: Teach the patient, family, or caregiver to
effects of the drug are known. Lifespan: Be particularly cautious with be especially cautious with the older adult who is at greater risk
the older adult who is at increased risk for falls. (Antiseizure drugs may for falls.
cause drowsiness and dizziness, hypotension, or impaired mental and
physical abilities, increasing the risk of falls and injury.) • Instruct the patient to call for assistance prior to getting out of bed or
attempting to walk alone, and to avoid driving or other activities
requiring mental alertness or physical coordination until the effects of
the drug are known.
• Lifespan: Continue to monitor height, weight, and developmental • Teach the patient’s family or caregiver to keep regularly scheduled
level in pediatric patients. In the school-age child, assess school appointments with the healthcare provider and report any
performance. (Adverse effects of antiseizure drugs or unresolved developmental lags or concerns.
seizures may hinder normal growth and development.)
• Continue to monitor drug levels, CBC, renal and hepatic function, and • Instruct the patient on the need to return periodically for laboratory
pancreatic enzymes. work.
• Diverse Patients: Some antiseizure drugs induce or inhibit CYP450 • Diverse Patients: Teach all patients, but especially ethnically diverse
enzymes and may interact with other drugs. Ethnically diverse patients, to observe for less than optimal effects and report promptly.
populations may also experience less than optimal effects of the drug.
(Antiseizure drugs require periodic evaluation of drug levels to correlate • Instruct the patient to carry a wallet identification card or wear medical
level with symptoms. Antiseizure drugs may cause hepatotoxicity and identification jewelry indicating a seizure disorder and antiseizure
valproic acid may cause pancreatitis as an adverse effect.) medication.
• Teach the patient to promptly report abdominal pain, particularly in the
upper quadrants, changes in stool color, yellowing of sclera or skin, or
darkened urine.
• Assess for changes in level of consciousness, disorientation, • Instruct the patient, family, or caregiver to report increasing lethargy,
confusion, or agitation. (Neurologic changes may indicate disorientation, confusion, changes in behavior or mood, slurred
overmedication or adverse drug effects.) speech, or ataxia immediately.
(continued )
354 Unit 4 Pharmacology of the Central Nervous System
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Assess for changes in visual acuity, blurred vision, loss of peripheral • Instruct the patient to report any visual changes or eye pain
vision, seeing rainbow halos around lights, acute eye pain, immediately.
accompanied by nausea and vomiting, and report immediately.
(Increased intraoptic pressure in patients with closed-angle glaucoma
may occur in patients taking benzodiazepines.)
• Assess for bruising, bleeding, or signs of infection. (Antiseizure drugs may • Teach the patient to report any signs of increased bruising, bleeding, or
cause blood dyscrasias and increased chances of bleeding or infection.) infections (e.g., sore throat and fever, or skin rash) promptly.
• Monitor for dermatologic effects including red or purplish skin rash, • Teach the patient to wear sunscreen and use protective clothing for
blisters, and sunburn. Immediately report severe rashes, especially sun exposure and to avoid tanning beds. Immediately report any
associated with blistering. (Carbamazepine may cause significant sunburn or rashes.
dermatologic effects including SJS.)
• Monitor affect and emotional status. (Antiseizure drugs may increase • Instruct the patient, family, or caregiver to report significant mood
the risk of mental depression and suicide. Concurrent use of alcohol or changes, especially depression, and to avoid alcohol and other CNS
other CNS depressants increases the effects and the risk.) depressants while taking the drug.
• Assess the condition of gums and oral hygiene measures. (Hydantoins • Instruct the patient to maintain excellent oral hygiene and keep
and phenytoin-like drugs may cause gingival hyperplasia, increasing regularly scheduled dental appointments.
the risk of oral infections.)
• Encourage appropriate lifestyle and dietary changes: increased intake • Encourage the patient to decrease or abstain from caffeine, nicotine,
of foods that are rich in vitamins K, D, and B, and folic acid, lowered and alcohol, and to increase the intake of foods that are rich in vitamins
caffeine intake including OTC medications that contain caffeine, and K, D, and B, and folic acid.
limited or no alcohol intake. (Caffeine and nicotine may decrease the
effectiveness of the benzodiazepines. Barbiturates, drugs with GABA • Advise the patient to discuss all OTC medications with the healthcare
action, and hydantoins and phenytoin-like drugs affect the absorption provider to ensure that caffeine or alcohol is not included in the
of vitamins K, D, and B, and folic acid. Alcohol and other CNS formulation.
depressants may increase the adverse effects of antiseizure drugs.)
• Lifespan: Monitor children for paradoxical response to barbiturates. • Instruct the patient, family, or caregiver to notify the healthcare provider
(Hyperactivity may occur.) if the patient exhibits hyperactive behavior.
• Lifespan: Assess women of childbearing age for the possibility of • Discuss pregnancy and family planning with women of childbearing
pregnancy, and plans for pregnancy, breastfeeding, and contraceptive age. Explain the effect of medications on pregnancy and breastfeeding
use. (Antiseizure medications are category D in pregnancy. AEDs are and the need to discuss any pregnancy plans with the healthcare
known to decrease the effectiveness of oral contraceptives and provider. Discuss the need for additional forms of contraception,
additional forms of contraception should be used.) including barrier methods.
• Avoid abrupt discontinuation of therapy. (Status epilepticus may occur • Instruct the patient to take the drug exactly as prescribed and to not
with abrupt discontinuation.) stop it abruptly.
• Provide emotional support and appropriate referrals as needed. • Teach the patient, family, and caregiver about support groups, and
(Treatment with antiseizure drugs may require using combinations of make appropriate referrals as needed.
drugs, and seizure activity may diminish but may not be resolved. Social
isolation and low self-esteem may occur with continued seizure disorder.)
• Closely monitor the IV infusion site when using IV antiseizure drugs. All IV • Teach the patient to report pain or burning at the IV site or in the
drips should be given via infusion pump. (Benzodiazepines, hydantoins, extremity with the IV immediately.
and barbiturates are irritating to the vein. Blanching and pain at the IV
site are an indicator of extravasation; the IV infusion should be
immediately stopped and the provider contacted for further treatment
orders. Infusion pumps will allow precise dosing of the medication.)
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during administration of medications and during the drug, appropriate dose and scheduling, what adverse effects to
observe for and when to report them, and the anticipated length of
assessments to discuss the rationale for drug therapy, desired medication therapy.
therapeutic outcomes, commonly observed adverse effects,
parameters for when to call the healthcare provider, and any necessary
monitoring or precautions. (Using time during nursing care helps to
optimize and reinforce key teaching areas.)
Patient self-administration of drug therapy: • Teach the patient to take the medication:
• When administering the medication, instruct the patient, family, or • Exactly as ordered and the same manufacturer’s brand each time
the prescription is filled. (Switching brands may result in differing
caregiver in proper self-administration of the drug, e.g., take the drug pharmacokinetics and alterations in seizure control.)
as prescribed and do not substitute brands. (Utilizing time during nurse • Read label directions for how to take the medication. Some forms
administration of these drugs helps to reinforce teaching.) may not be opened or chewed; others require chewing thoroughly.
When in doubt, consult a pharmacist or other healthcare provider.
• Take a missed dose as soon as it is noticed but do not take double
or extra doses to “catch up.”
• Take with food to decrease GI upset.
• Do not abruptly discontinue the medication.
Chapter 22 Pharmacotherapy of Seizures 355
Understanding Chapter 22
Key Concepts Summary 22.8 Benzodiazepines are important drugs in the
treatment of status epilepticus.
22.1 Epilepsy is characterized by recurrent seizures
caused by disturbances in the electrical activity of 22.9 Hydantoins are effective in the management of
the brain. most types of seizures but have many adverse
effects.
22.2 Seizure disorders differ throughout the lifespan.
22.10 Carbamazepine is a first-line drug for treating
22.3 Most seizures are classified as generalized many tonic–clonic and partial seizures.
or partial.
22.11 Succinimides are the first-line drugs for the
22.4 Some types of seizures are called special epileptic pharmacotherapy of absence seizures.
seizures or are unclassified.
22.12 Several miscellaneous drugs are important in
22.5 The selection of antiepileptic drug therapy is treating epilepsy.
dependent on seizure type and characteristics.
22.6 Antiepileptic drugs act by suppressing abnormal
neuronal discharges.
22.7 Barbiturates are traditional drugs for tonic–clonic
seizures that have been replaced by newer and
safer medications.
CASE STUDY: Making the Patient Connection
Remember the patient discharge, which is diagnostic of a tonic–clonic seizure. The
“Jorge Alvarez” at the laboratory studies performed on Jorge included a serum
beginning of the chapter? lead level to rule out lead intoxication and a serum glucose
Now read the remainder level to rule out hypoglycemia. Both the lead level and
of the case study. Based blood glucose were in the normal range.
on the information pre-
sented within this chap- Jorge has been started on the following medications to
ter, respond to the critical assist in controlling his tonic–clonic seizures: carbamaze-
thinking questions that pine (Tegretol) 300 mg PO tid and phenytoin (Dilantin)
follow. 120 mg PO tid.
Jorge Alvarez is a 3-year-old boy who has been hospital- Critical Thinking Questions
ized following a seizure. Since being admitted 2 days ago,
he has experienced three subsequent tonic–clonic seizures 1. Jorge’s mother expresses concern about what to do if
lasting 2 to 2.5 minutes each. Prior to having a seizure, he has a seizure. Create a list of home safety tips that
Jorge notices a flash of light. He then loses consciousness, could be given to her.
emits a hoarse cry, and has intense muscle contractions.
During the clonic phase he is incontinent of bowel and 2. What will you instruct Jorge’s mother about with
bladder. His postictal phase is characterized by drowsi- regard to his medication administration?
ness, disorientation, and deep sleep.
Answers to Critical Thinking Questions are available on the
On admission Jorge was scheduled for a sleep-and- faculty resources site. Please consult with your instructor.
awake EEG. His EEG revealed a high-voltage spike
356 Unit 4 Pharmacology of the Central Nervous System
Additional Case Study 2. What adverse effects are associated with this drug?
3. Why should Matt inform his dentist that he is
Matt has had epilepsy since childhood. It seems that his
current medications are no longer keeping him seizure free. now on valproic acid?
Valproic acid (Depakene) is being added to Matt’s medica-
tion regimen. How would you respond to the following Answers to Additional Case Study questions are available on
questions from Matt about this new medication? the faculty resources site. Please consult with your instructor.
1. How does valproic acid (Depakene) work to prevent
seizures?
Chapter Review 3. Stroke and decreased motor function
4. Sedation and falls
1. A 10-year-old child has been evaluated for a learning
disability and has been diagnosed with absence sei- 4. A 23-year-old patient has been taking gabapentin
zures. Ethosuximide (Zarontin) has been ordered and (Neurontin) for control of partial seizures. He is
the nurse is teaching the patient and family about the admitted to the emergency department with slurred
drug. Because of the patient’s age, it is important to speech, dyspnea, reports of double vision, and seda-
include instructions to: tion. The admitting nurse suspects the patient has:
1. Curtail after-school sports activities because the 1. Not taken his drug for several days.
drug’s metabolism may be increased with physical 2. Taken an overdose of the drug, either
activity.
unintentionally or deliberately.
2. Increase intake of calcium-rich foods and vitamin D 3. Taken the drug with grapefruit or grapefruit juice.
to prevent bone loss. 4. Continued to smoke despite prior patient
3. Monitor height and weight weekly to be sure GI education that smoking interacts with the drug.
side effects are not hindering nutrition and normal
growth. 5. The nurse, who is monitoring a patient taking phe-
nytoin (Dilantin), has noted symptoms of nystag-
4. Increase fluid intake to avoid dehydration caused mus, confusion, and ataxia. Considering these
by the drug. findings, the nurse would suspect that the dose of
the drug should be:
2. The nurse is caring for a 42-year-old patient who
was recently diagnosed with partial seizures and 1. Reduced.
has been prescribed oxcarbazepine (Trileptal). 2. Increased.
Which laboratory study would the nurse expect 3. Maintained.
to be ordered? 4. Discontinued.
1. CBC with differential 6. Carbamazepine (Tegretol) has been prescribed for a
2. Serum albumin and glucose levels 24-year-old patient for the control of partial seizures.
3. Sedimentation rate and platelet count The nurse will teach the patient to immediately
4. Serum sodium and renal function studies report:
3. An 80-year-old patient is prescribed carbamazepine 1. Blurred vision.
(Tegretol) for a newly diagnosed seizure disorder. The 2. Leg cramps.
nurse will implement safety measures because this 3. Blister-like rash.
patient is at an increased risk for which adverse 4. Lethargy.
effects with the administration of this drug?
See Answers to Chapter Review in Appendix A.
1. Dementia and confusion
2. Insomnia and forgetfulness related to sleep
deprivation
Chapter 22 Pharmacotherapy of Seizures 357
References Pugh, M. J. V., Orman, J. A., Jaramillo, C. A., Salinsky, M.
C., Eapen, B. C., Towne, A. R., … Grafman, J. H. (2015).
Algreeshah, F. S. (2016). Psychiatric disorders associated with The prevalence of epilepsy and association with
epilepsy. Retrieved from http://emedicine.medscape. traumatic brain injury in veterans of the Afghanistan
com/article/1186336-overview#a1 and Iraq wars. Journal of Head Trauma Rehabilitation, 30,
29–37. doi:10.1097/HTR.0000000000000045
Chen, L. L., Baca, C. B., Choe, J., Chen, J. W., Ayad, M. E.,
& Cheng, E. M. (2014). Posttraumatic epilepsy in Vehmeijer, F. O., van der Louw, E. J., Arts, W. F., Catsman-
Operation Enduring Freedom/Operation Iraqi Berrevoets, C. E., & Neuteboom, R. F. (2015). Can we
Freedom in veterans. Military Medicine, 179, 492–496. predict efficacy of the ketogenic diet in children with
doi:10.7205/MILMED-D-13-00413 refractory epilepsy? European Journal of Paediatric
Neurology, 19, 701–705. doi:10.1016/j.ejpn.2015.06.004
Epilepsy Foundation of America. (2014). Seizure first aid.
Retrieved from http://www.epilepsy.com/learn/ Vossel, K. A., Beagle, A. J., Rabinovici, G. D., Shu, H., Lee,
treating-seizures-and-epilepsy/seizure-first-aid S. E., Naasan, G., … Mucke, L. (2013). Seizures and
epileptiform activity in the early stages of Alzheimer
Haunt, S. (2016). Antiepileptic medications and disease. JAMA Neurology, 70, 1158–1166. doi:10.1001/
breastfeeding: Better news than expected? Epilepsy jamaneurol.2013.136
Currents, 16, 84–86. doi:10.5698/1535–7511-16.2.84
Webster, M., & Gabe, J. (2016). Diet and identity: Being a
Lambrechts, D. A., de Kinderen, R. J., Vies, H. S., de Louw, good parent in the face of contradictions presented by
A. J., Aldenkamp, A. P., & Majole, M. J. (2015). The the ketogenic diet. Sociology of Health & Illness, 38,
MCT-ketogenic diet as a treatment option in refractory 123–136. doi:10.1111/1467-9566.12330
childhood epilepsy: A prospective study with 2-year
follow-up. Epilepsy & Behavior, 51, 261–266.
doi:10.1016/j.yebeh.2015.07.023
Selected Bibliography Strozzi, I., Nolan, S. J., Sperling, M. R., Wingerchuk, D. M.,
& Sirven, J. (2015). Early versus late antiepileptic drug
Bryson, A. S., & Carney, P. W. (2015). Pharmacotherapy for withdrawal for people with epilepsy in remission.
epilepsy in the elderly. Journal of Pharmacy Practice and Cochrane Database of Systematic Reviews, 2, Art.
Research, 45, 349–356. doi:10.1002/jppr.1135 No. CD001902. doi:10.1002/14651858.CD001902.pub2
Lee, S. K. (2014). Old versus new: Why do we need new Tolaymat, A., Nayak, A., Geyer, J. D., Geyer, S. K., &
antiepileptic drugs? Journal of Epilepsy Research, 4, Carney, P. R. (2015). Diagnosis and management of
39–44. doi:10.14581/jer.14010 childhood epilepsy. Current Problems in Pediatric and
Adolescent Health Care, 45, 3–17. doi:10.1016/j.
Moshé, S. L., Perucca, E., Ryvlin, P., & Tomson, T. (2015). cppeds.2014.12.002
Epilepsy: New advances. The Lancet, 385, 884–898.
doi:10.1016/S0140-6736(14)60456-6 Vajda, F. J., O’Brien, T., Lander, C., Graham, J., &
Eadie, M. (2014). The efficacy of the newer antiepileptic
Ochoa, J. G., & Riche, W. (2016). Antiepileptic drugs. drugs in controlling seizures in pregnancy. Epilepsia,
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article/1187334-overview
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diagnosis and management. American Journal of medications. Mental Health Clinician, 3, 88–95.
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Smith, G., Wagner, J. L., & Edwards, J. C. (2015). CE: Yo, D. Y. (2016). Epilepsy and seizures. Retrieved from
Epilepsy update, part 1: Refining our understanding of http://emedicine.medscape.com/
a complex disease. American Journal of Nursing, 115(5), article/1184846-overview
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34–44. doi:10.1097/01.NAJ.0000466314.46508.00
“I was lifting concrete blocks
to build a landscaping wall in
my front yard yesterday. When I
woke up this morning, I couldn’t
bend down to put on my pants
after my shower. My back hurts
so bad I can hardly walk.”
Patient “Andrew Eskew”
Chapter 23
Pharmacotherapy of Muscle
Spasms and Spasticity
Chapter Outline Learning Outcomes
cc Etiology and Pathophysiology of Muscle Spasms After reading this chapter, the student should be able to:
and Spasticity
1. Compare and contrast the etiology and
cc Nonpharmacologic Therapies for Muscle Spasms pathophysiology of muscle spasm and
and Spasticity muscle spasticity.
cc Pharmacotherapy of Muscle Spasms 2. Describe the nonpharmacologic management of
Centrally Acting Skeletal Muscle Relaxants muscle spasms and muscle spasticity.
PROTOTYPE Cyclobenzaprine (Amrix), p. 363
3. Identify drug classes used to treat muscle spasms
cc Pharmacotherapy of Muscle Spasticity and spasticity.
Direct-Acting Skeletal Muscle Relaxants
PROTOTYPE Dantrolene (Dantrium, Revonto), p. 366 4. Compare and contrast the actions of the centrally
acting and direct-acting skeletal muscle relaxants.
cc Skeletal Muscle Relaxants as Surgical Adjuncts
5. Explain the role of skeletal muscle relaxants as
surgical adjuncts.
6. Describe the nurse’s role in the pharmacologic
management of muscle spasms and muscle
spasticity.
7. For each of the classes shown in the chapter outline,
identify the prototype and representative drugs and
explain the mechanism(s) of drug action, primary
indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
8. Apply the nursing process to care for patients
receiving pharmacotherapy for muscle spasms
and spasticity.
358
Chapter 23 Pharmacotherapy of Muscle Spasms and Spasticity 359
Key Terms muscle spasms, 359 muscle spasticity, 359
dystonia, 360
malignant hyperthermia, 367
The administration of drugs to relieve muscle spasms and Table 23.1 Medications That May Cause Myopathy as an
musculoskeletal pain dates back to the early 19th century
when scientists discovered curare, a substance used for Adverse Effect
hundreds of years by Amazon Indians as a poison on
arrows. Although everyone experiences muscle aches and Drug Class Example(s)
pains from time to time, these symptoms often resolve Alzheimer’s drug
without pharmacotherapy. There are some conditions, Antifungals donepezil (Aricept)
however, where medications may be used to relieve pain-
ful muscle pain, spasm, or spasticity. This chapter exam- Antihyperlipidemics fluconazole (Diflucan), ketoconazole
ines how these drugs produce their actions and their (Nizoral)
applications to the pharmacotherapy of muscle Antineoplastics
conditions. statins (Crestor, Lipitor, Zocor), niacin,
Antiulcer drugs: proton pump red yeast rice
Etiology and Pathophysiology inhibitors
of Muscle Spasms and Spasticity Asthma drugs cisplatin (Platinol), imatinib (Gleevec),
vincristine
23.1 Whereas muscle spasms are often caused Calcium channel blockers
by overuse of skeletal muscle, muscle spasticity Diuretics esomeprazole (Nexium), omeprazole
involves damage to motor nerves. (Prilosec)
Immunosuppressants
Intense skeletal muscle contractions can cause severe pain albuterol (Proventil, Ventolin),
and disability. Abnormal contractions may be classified as terbutaline (Brethine)
spasms or spasticity. Although both may occur in the same
patient, the etiology, pathogenesis, and treatment strate- nifedipine (Procardia)
gies differ for the two conditions.
furosemide (Lasix), hydrochlorothiazide
Muscle spasms: Muscle spasms are involuntary con- (Microzide)
tractions of skeletal muscles that are usually localized to a
specific muscle group. As the affected muscles strongly corticosteroids, leflunomide (Arava)
contract and tighten, the spasm causes sudden, intense
pain, which gradually diminishes after a few minutes. as shown in Table 23.1. Signs of drug-induced myopathy
Patients may refer to the condition as a charley horse or usually develop slowly after several months of drug ther-
cramp. In addition to causing intense pain, chronic or apy. The most important class causing this pathology is
severe spasms can impair joint mobility. the statins, which are widely used to lower blood choles-
terol levels. Statins can cause a severe form of myopathy
When treating a patient with muscle spasms, it is called rhabdomyolysis that may cause significant disabil-
important to identify their cause. The etiology of muscle ity and morbidity. Most drug-induced myopathies are
spasms may involve many body systems, including the reversible in their early stages. If a medication is sus-
nervous, musculoskeletal, endocrine, and cardiorespira- pected of causing myopathy, the dose is lowered or the
tory systems. The most common etiology of muscle spasm drug is discontinued.
is overuse of a skeletal muscle. When subjected to trauma
or overexertion, the muscle may spasm. If the history does Muscle spasticity: Muscle spasticity has a different eti-
not reveal muscle overuse or injury, the healthcare provider ology than muscle spasm. Muscle spasticity is a condition
will need to assess for possible metabolic or electrolyte caused by damage to upper motor neurons in the central
imbalances such as hypocalcemia, hypokalemia, or dehy- nervous system (CNS), which causes certain muscle
dration. Poor blood circulation to the legs, known as clau- groups to remain in a continuous state of contraction. The
dication, is a common cause of muscle cramping. patient may experience irritable deep tendon reflex activ-
ity, muscle spasms, involuntary jerking, and scissoring
Some medications may cause muscle spasms, muscle movements of the lower extremities. Patients with muscle
weakness, and other types of myopathy as adverse effects, spasticity are unable to voluntarily relax their limbs. Spas-
ticity, also referred to as hypertonia, causes pain that is
more intense than muscle spasm and produces greater
impairment of mobility.
Whereas muscle spasms occur most often with overex-
ertion, muscle spasticity is associated with neuromuscular
diseases that are the result of damage to neurons in the
region of the cerebral cortex that controls muscle move-
ments. Conditions most commonly associated with muscu-
lar spasticity include severe head or spinal cord trauma,
360 Unit 4 Pharmacology of the Central Nervous System
multiple sclerosis (MS), stroke, cerebral palsy (CP), trauma, is caused by the degeneration and loss of lower and upper
and amyotrophic lateral sclerosis (ALS). motor neurons in the CNS. The disorder is progressive and
fatal. Muscle relaxants may bring some pain relief during
Under normal conditions a muscle receives a balance periods of intense muscle spasticity.
of both excitatory and inhibitory signals from motor neu-
rons. When a muscle needs to contract, an impulse is sent Dystonia is a chronic neurologic disorder that is char-
from the brain or spinal cord down an excitatory motor acterized by involuntary muscle contraction that forces
neuron. When a muscle needs to relax, the brain sends a body parts into abnormal, painful movements or postures.
signal to the muscle through an inhibitory motor neuron. The condition may affect the entire body (generalized dys-
As a simple example, consider flexion and extension of the tonia), or it may be localized to a single body region (focal
elbow. Forearm flexion occurs when the biceps receives an dystonia) such as the arms, legs, trunk, neck, eyelids, face,
excitatory impulse; at the same time its antagonist, the tri- or vocal cords. Dystonia may occur secondary to other neu-
ceps, receives an inhibitory impulse. On extension, the rologic disorders such as MS, stroke, or CP. The impair-
opposite occurs: The biceps receives the inhibitory message ment in mobility and intense pain produced by muscle
while the triceps contracts after receiving the excitatory spasms and spasticity inhibits the patient’s ability to per-
message. Proper contraction of skeletal muscle thus form activities of daily living (ADLs). Generalized dysto-
involves a balance of signals from the CNS through both nias are treated with high doses of anticholinergic drugs
excitatory and inhibitory motor neurons. such as benztropine, benzodiazepines, and baclofen.
Patients with focal dystonia may obtain some relief with
Muscle spasticity from a spinal cord injury occurs botulinum toxin type A.
when there is an imbalance of excitatory and inhibitory sig-
nals. The area that is distal to the spinal cord injury or Dupuytren’s contracture is a condition of the hand in
lesion becomes disassociated from the inhibitory area of which a thick cord of connective tissue forms in the palm,
the brain, and the excitatory impulses dominate at the causing the fingers to curl inward. Although not usually
affected muscles. The muscles may go into spastic paraly- painful, the curling is progressive and can restrict motion
sis; flexor muscles become tight, and the muscles can be and use of the hand. This disorder is not caused by muscles;
extended only with great difficulty. Once extended, the therefore, traditional muscle relaxants and antispasmodics
muscles tend to immediately flex back. It is important to are ineffective. For severe cases, surgical removal of the con-
understand that although the obvious symptoms appear to nective tissue cord is performed. Collagenase (Xiaflex) is an
be muscle related, the cause of the spasticity is actually enzyme medication approved to treat this disorder. The
neurologic injury. enzyme is injected multiple times into the affected cord,
over a 4-week interval. The most frequently reported
In the advanced stages of MS, muscle spasticity is adverse effects are swelling of the affected hand, contusion,
caused by destruction of the myelin sheath, which inter- injection-site reaction or hemorrhage, and localized pain.
rupts the main motor pathways from the spinal cord to the
muscles. Spasticity results in a stiff, unbalanced gait and Nonpharmacologic Therapies
may eventually confine these patients to a wheelchair. for Muscle Spasms and Spasticity
Patients with MS are treated with a combination of medica-
tions including muscle relaxants, corticosteroids, and 23.2 Nonpharmacologic interventions
immunosuppressants (see Chapter 21). for treating muscle spasms and spasticity
are limited.
Approximately 35% of patients experience spasticity
following a stroke. If the brain area affected by the stroke is The therapeutic goals for treating muscle spasms or spas-
able to reestablish communication with the muscle, the ticity are to decrease discomfort and enhance mobility so
spasticity may be reversible and voluntary movement may that the patient is better able to perform ADLs. Nonphar-
be restored. In many cases, however, the spasticity becomes macologic complementary and alternative therapies
permanent and can be recognized by a clenched fist, per- (CATs) are sometimes implemented to achieve these goals.
manently flexed elbow, or pointed toes. When the spasms or spasticity are prolonged or disabling,
pharmacotherapy is initiated. A combination of CATs and
Cerebral palsy is a neurologic disorder that results in drug therapy is often the most effective treatment.
severe muscular spasticity, which can affect facial muscles,
cause an unsteady, scissoring gait, and result in painful Nonpharmacologic interventions that sometimes ben-
joint contractures and deformities. The primary cause of efit patients with muscle spasm or spasticity include the
spasticity associated with CP is congenital trauma to the application of heat or cold, massage, traction, and manipu-
brain or spinal cord. Pharmacologic options for treating CP lation. The application of heat or cold to the affected site
are limited. Intrathecal baclofen may be beneficial in reduc- will reduce or relieve the muscle spasm and pain. If the
ing severe spasticity. spasm has occurred due to overexertion, application of
Muscle spasms, spasticity, and twitching are also char-
acteristic of ALS, also known as Lou Gehrig’s disease. ALS
Chapter 23 Pharmacotherapy of Muscle Spasms and Spasticity 361
heat to the area can reduce cramping and relieve localized high-potency prescription drug containing 8% capsaicin
pain. If the spasms persist after 3 to 5 days, the application (Qutenza) is approved to treat neuropathic pain associated
of cold packs to the site may be used to slow the transmis- with post-herpetic neuralgia.
sion of pain impulses. The application of touch, massage,
and gentle pressure are sometimes effective at promoting A final nonpharmacologic therapy for muscle spasm is
musculoskeletal relaxation. Other nonpharmacologic tech- treatment with B complex vitamins, specifically pyridoxine
niques that may be useful include acupuncture, sensory (B6). In some patients, the B complex vitamins can reduce
nerve stimulation, and ankle splints for leg pain. both the intensity and duration of leg cramps.
The implementation of physical therapy is sometimes Pharmacotherapy of Muscle
effective for treating muscle spasticity. Routine and consis- Spasms
tent physical therapy exercises provide the patient with
increased muscle movement and decreased severity of 23.3 Nonsteroidal anti-inflammatory drugs
symptoms. Effective physical therapy exercises include and skeletal muscle relaxants are used to treat
muscle stretching, which assists in the prevention of con- muscle spasms.
tractures (permanent shortening of muscles). The imple-
mentation of muscle group strengthening and repetitive Muscle spasms, especially those caused by injury, are pain-
motion exercises may allow for safer ambulation. In ful and sometimes associated with inflammation. Nonste-
extreme cases, surgery may be necessary to release tendons roidal anti-inflammatory drugs (NSAIDs) such as aspirin,
or to sever the nerve–muscle pathway. naproxen, and ibuprofen are usually the first-line drugs
for treating minor to moderate pain due to muscle overex-
Herbal remedies are occasionally used to treat patients ertion. These drugs have the ability to relieve muscle pain
with muscle spasms. Black cohosh, first used for neuralgia and reduce inflammation around the injury site, which can
and muscular pain in the 1840s, may be applied topically to take pressure off the surrounding nerves and enhance
produce relaxation of muscles. Castor oil packs can be mobility. The pharmacology of NSAIDs is presented in
applied to the site of pain and muscle spasm. The castor oil Chapter 41.
should be warmed, soaked into a flannel, wool, or cotton
cloth, and then applied to the tonic muscle. Capsaicin, For more intense muscle spasms, muscle relaxants
derived from cayenne pepper, is applied topically as a may be prescribed. Although these drugs are not analge-
cream four times per day to increase mobility and reduce sics, they can promote pain relief by relaxing tight, con-
pain. It is important to instruct the patient to wear gloves tracted muscles without interfering with normal muscle
while applying capsaicin cream to prevent irritation of the function. When skeletal muscle relaxants are used in com-
skin on the hands and to avoid introducing the capsaicin to bination with NSAIDs, pain relief is greater than when
the eyes or other parts of the body not under treatment. A either drug is used alone.
CONNECTIONS: Using Research in Practice
Use of Intrathecal Baclofen to Treat Spastic Cerebral Palsy in Children
Between 70% and 90% of patients with CP have spasticity along report, one study assessed the effectiveness of implantable ITB
with other motor disorders. Prior treatment for CP patients with pumps over 6 months, and the four other studies looked at the
spasticity has included diazepam (Valium), dantrolene (Dantrium), short-term results of ITB on spasticity in children with CP. The
and oral baclofen (Lioresal). Because these drugs are given PO, results of both the short-term and longer term studies showed
they may cause significant systemic adverse effects such as improvement in comfort and ease of care and a small improve-
drowsiness, confusion, behavior changes, and hypotension. In ment in gross motor function and spasticity.
the early 2000s, the American Academy for Cerebral Palsy and
Developmental Medicine (AACPDM) performed a systematic Based on these findings, ITB may offer improved and tar-
review of treatment and noted beneficial effects of continuous geted treatment of the spasticity, pain, loss of ADL ability, and
intrathecal baclofen (ITB) in patients with spastic CP, but noted other effects of CP in children, especially for those who have not
that no well-controlled studies in children had been conducted. responded well or at all to traditional PO medications or surgery.
Nurses often provide the most direct support and connection to
A 2015 Cochrane report (Hasnat & Rice, 2015) confirmed families dealing with the long-term implications of CP. They can
the earlier studies’ reports of limited evidence that ITB is an provide education on the use and care of the ITB pump, site
effective therapy for reducing spasticity in children with CP. care, and drug effects to monitor for those families choosing this
Although the report found that the research was unsuitable to option. Nurses may also help educate school staff and nurses on
conduct a meta-analysis, the qualitative summary supported the the use and care of the pump and the monitoring required for
use of ITB as a treatment. Of the five studies reviewed in the adverse effects.
362 Unit 4 Pharmacology of the Central Nervous System
Pharmacotherapy Illustrated 23.1
Mechanism of Action of Drugs Used to Treat Muscle Spasms and Spasticity
Sensory Motor response to muscle:
perception of pain Spasm due to pain
Cerebral
cortex
Centrally acting drugs act
in the CNS by
• Reducing excitability
• Tizanidine
• Enhancing inhibition
• Baclofen
Spinal cord
Sensory Motor Neuromuscular junction
Neuromuscular blockers
• Succinylcholine
Direct-acting drugs
• Dantrolene
• Botulinum
Skeletal muscle
Stretch and pain receptors
The centrally acting skeletal muscle relaxants relieve The sedative effects may be beneficial in helping patients
muscle spasms by their actions in the CNS. They do not with muscle spasms or spasticity to obtain needed sleep.
directly affect the neuromuscular junction or muscles The centrally acting skeletal muscle relaxants include
themselves. The precise mechanism of action of centrally baclofen (Lioresal), cyclobenzaprine (Amrix), deutetraben-
acting skeletal muscle relaxants is unclear but it is believed azine (Austedo), tetrabenazine (Xenazine), and tizanidine
they help to restore the balance of excitatory and inhibitory (Zanaflex). Some drugs in this class are used for both mus-
impulses from motor neurons in the CNS. Like the benzo- cle spasms and spasticity. Mechanisms of action are shown
diazepines, they can produce significant drowsiness, espe- in Pharmacotherapy Illustrated 23.1. Doses of the centrally
cially if combined with alcohol or other CNS depressants. acting muscle relaxants are listed in Table 23.2.
Chapter 23 Pharmacotherapy of Muscle Spasms and Spasticity 363
Table 23.2 Centrally Acting Skeletal Muscle Relaxants
Drug Route and Adult Dose (Maximum Dose Adverse Effects
baclofen (Lioresal) Where Indicated)
Drowsiness, dizziness, weakness, fatigue, confusion, altered mental
carisoprodol (Soma) PO: 5 mg tid, increasing gradually to 40–80 mg/ status, nausea, vomiting, constipation, urinary frequency
day (max: 80 mg/day)
Intrathecal: 50-mcg bolus QT prolongation, dysrhythmias
Adult: PO: 250–350 mg tid Drowsiness, confusion, orthostatic hypotension, nausea, vomiting,
hiccups, vertigo, ataxia, tremor, syncope
chlorzoxazone PO: 250–500 mg tid–qid (max: 3 g/day) Anaphylactic shock, physical dependence, profound sedation
Drowsiness, dizziness, anorexia, heartburn, nausea, vomiting, diarrhea,
abdominal pain, lightheadedness, overstimulation, rash, pruritus,
urticaria, discoloration of urine
cyclobenzaprine (Amrix) PO: 5–10 mg tid for tablets; 15 mg once daily for Hepatotoxicity, jaundice, anemia, neutropenia
extended release capsules (max: 30 mg/day)
Drowsiness, xerostomia, dizziness, fatigue, nausea, constipation,
dyspepsia
deutetrabenazine (Austedo) PO (Austedo): 6 mg once daily (max: 48 mg/day) Tongue edema, potential for QT prolongation, hallucinations, serotonin
and tetrabenazine (Xenazine) PO (Xenazine): 12.5–50 mg/day in divided doses syndrome
Sedation, fatigue, insomnia, depression, akathisia, anxiety, nausea
metaxalone (Skelaxin) PO: 800 mg tid–qid
Neurologic malignant syndrome
Nausea, vomiting, GI upset, drowsiness, dizziness, headache, anxiety
methocarbamol (Robaxin) PO: 4 g/day maintenance dose Hemolytic anemia, jaundice, hepatotoxicity, anaphylaxis
IV/IM: 1–3 g once daily for 3 days
Drowsiness, dizziness, lightheadedness, fever, pruritus, rash,
syncope, thrombophlebitis, pain, blurred vision, headache,
tachycardia, syncope
orphenadrine PO: 100 mg bid Anaphylactic shock, sloughing of skin with extravasation
IM/IV: 60 mg q12h (max: 250 mg/day)
Dry mouth, drowsiness, weakness, dizziness, agitation, tachycardia,
syncope, palpitations, increased ocular tension, blurred vision, nausea,
vomiting, abdominal cramps, pruritus, urticaria
tizanidine (Zanaflex) PO: 4–8 mg q6–8h (max: 36 mg/day) Anaphylactic shock, hallucinations
Dry mouth, somnolence, asthenia, fatigue, back pain, dizziness, flulike
symptoms
Hepatotoxicity, hypotension, bradycardia, hallucinations
Note: Italics indicates common adverse effects. Underline indicates serious adverse effects.
Drugs from a number of other classes have been used PROTOTYPE DRUG Cyclobenzaprine (Amrix)
to treat and prevent muscle spasms. Calcium channel
blockers including diltiazem (Cardizem, Dilacor) and vera- Classification Therapeutic: Skeletal muscle relaxant
pamil (Calan) may be used off-label to prevent muscle Pharmacologic: Centrally acting
cramps. The mechanism for this action is unknown but
may be related to the drugs’ ability to dilate arteries and antispasmodic
bring additional oxygen to muscles.
Therapeutic Effects and Uses: Approved in 1977,
Benzodiazepines such as diazepam (Valium) are cyclobenzaprine is indicated for the short-term therapy
occasionally prescribed to relax skeletal muscle. Diaze- of acute musculoskeletal conditions that are unrelated to
pam may be used as an adjunct to relieve skeletal muscle CNS disease. Cyclobenzaprine is not effective for treating
spasms associated with CP, paraplegia, and tetanus. muscle spasm due to spinal cord injury or CP. The drug
Diazepam is a featured prototype drug for seizures in promotes skeletal muscle relaxation, thus decreasing mus-
Chapter 22. cle spasms and increasing joint mobility. The manufacturer
recommends that treatment not extend beyond 3 weeks.
CONNECTION Checkpoint 23.1 Fibromyalgia is an off-label indication for the drug.
Benzodiazepines are some of the most widely prescribed drugs. From Cyclobenzaprine is chemically related to the tricyclic
what you learned in Chapter 18, what are the major indications for antidepressants (TCAs) and it exhibits some antidepressant
drugs in this class? Answers to Connection Checkpoint questions are effects. The drug is available by immediate release tablet or
available on the faculty resources site. Please consult with your instructor. extended release capsule. Cyclobenzaprine is occasionally
abused as a recreational drug due to its sedative actions.
364 Unit 4 Pharmacology of the Central Nervous System
Mechanism of Action: The action of cyclobenzaprine other CNS depressants because significant sedation may
is thought to occur at the brainstem and spinal cord levels. occur. Phenothiazines and anticholinergic drugs will en-
The drug increases norepinephrine activity by blocking its hance the anticholinergic adverse effects and are contrain-
synaptic reuptake to produce an anticholinergic effect. Cy- dicated with cyclobenzaprine. Use with TCAs may result
clobenzaprine acts centrally and thus has no direct action in additive CNS depression and increased anticholinergic
on skeletal muscle. effects. A potentially fatal hypertensive crisis can occur if
cyclobenzaprine is used within 14 days of a monoamine
Pharmacokinetics: oxidase inhibitor. Serotonin syndrome has been reported
when cyclobenzaprine is coadministered with other drugs
Route(s) PO that increase serotonin such as selective serotonin reuptake
inhibitors (SSRIs), serotonin–norepinephrine reuptake in-
Absorption Well absorbed in the hibitors (SNRIs), TCAs, tramadol, bupropion, meperidine,
or verapamil. Herbal/Food: Additive CNS depression may
gastrointestinal (GI) tract occur if cyclobenzaprine is administered concurrently with
valerian or kava.
Distribution It is unknown whether the drug
Pregnancy: Category B.
crosses the placenta or is
Treatment of Overdose: Signs of overdose include
secreted in breast milk; 93% CNS depression and tachycardia. Physostigmine (Antilir-
ium) may be administered to reverse serious anticholiner-
bound to protein gic adverse effects. Overdose is generally not fatal.
Primary metabolism Extensive hepatic metabolism Nursing Responsibilities: Key nursing implications
for patients receiving cyclobenzaprine are included in the
via CYP450 enzymes to inactive Nursing Practice Application for Patients Receiving Phar-
macotherapy for Muscle Spasms and Spasticity.
metabolites
Drugs Similar to Cyclobenzaprine (Amrix)
Primary excretion Renal
The following medications are other centrally acting skele-
Onset of action 1h tal muscle relaxants: baclofen, carisoprodol, chlorzoxa-
zone, deutetrabenazine, metaxalone, methocarbamol,
Duration of action 12–24 h orphenadrine, tetrabenazine and tizanidine. Chlorphene-
sin (Maolate) is a centrally acting muscle relaxant that was
Adverse Effects: Commonly reported adverse effects removed from the market in the United States.
include drowsiness, dizziness, and xerostomia. Sedation
can be a limiting effect with the first few doses. Other Baclofen (Lioresal): Approved in 1977, baclofen is used
adverse effects of cyclobenzaprine include edema of the to reduce muscle spasticity in patients with injury or
tongue and face with sweating, myalgia, hepatitis, and disease of upper motor neurons such as that associated
alopecia. Potential cardiovascular adverse events include with MS, CP, ALS, and spinal cord trauma. Off-label
orthostatic hypotension, tachycardia, syncope, palpita- indications include the treatment of tardive dyskinesia
tions, and vasodilation. The patient may report having an related to long-term pharmacotherapy with antipsy-
unpleasant taste, a coated tongue with discoloration, vom- chotic drugs, persistent hiccups, and for management of
iting, anorexia, diarrhea with flatulence, or paralysis. neuropathic pain. The drug resembles the inhibitory
neurotransmitter gamma aminobutyric acid (GABA)
Contraindications/Precautions: Cyclobenzaprine and acts by inhibiting neuronal activity within the brain
should be used with great caution in patients older than and spinal cord. Baclofen is usually administered PO,
age 65 because this population is more likely to experi- but it can be administered by infusion delivered directly
ence confusion, hallucinations, and adverse cardiac events into the intrathecal space, using a small catheter and a
from the drug. Cyclobenzaprine also should be used cau- pump. This provides a direct route for the baclofen to
tiously in patients who have increased intraocular pres- reach its target sites in the spinal cord and brain. Because
sure, prostatic hyperplasia, urinary retention, and seizures. the baclofen is delivered continuously at its site of
Patients with hypersensitivity to TCAs should not receive action, very small amounts are needed to produce a
this drug. Like the TCAs, cyclobenzaprine can adversely therapeutic effect. The healthcare provider determines
affect the heart and therefore should be used with caution the amount of drug to be released by the pump and the
in patients with cardiovascular disease, including those
with heart failure or dysrhythmias with heart block. It is
contraindicated in patients who have QT interval prolon-
gation on the electrocardiogram (ECG) or who are in the
recovery phase of a myocardial infarction (MI). The drug is
metabolized in the liver and thus should be administered
cautiously to patients with hepatic impairment. Patients
with a history of hyperthyroidism should not be adminis-
tered cyclobenzaprine.
Drug Interactions: Cyclobenzaprine should not be
administered with alcohol, opioids, barbiturates, or any
Chapter 23 Pharmacotherapy of Muscle Spasms and Spasticity 365
dosing schedule. The pump must be refilled every 1 to 3 contain a black box warning regarding the risk for depres-
months and the battery lasts 5 to 7 years. Several months sion and suicidal thoughts. Tetrabenazine is pregnancy
of therapy may be required to achieve full therapeutic category C.
benefit from baclofen.
Metaxalone (Skelaxin): Approved in 1962, metaxalone is
Adverse effects related to the administration of baclofen administered PO and is indicated for the symptomatic
include drowsiness, dizziness, weakness, and fatigue. relief of muscle spasm and pain related to musculoskeletal
Abrupt discontinuation following prolonged therapy may conditions. It is ineffective in the treatment of spasticity-
cause high fever, seizures, severe rebound muscle spasticity, related neurologic disorders. The therapeutic effects of
and hallucinations. This drug is pregnancy category C. metaxalone are likely due to general CNS depression. Like
chlorzoxazone, metaxalone may cause liver injury and is
Carisoprodol (Soma): An older drug approved by the contraindicated in patients with hepatic impairment. It
U.S. Food and Drug Administration (FDA) in 1959, cariso- should not be administered to patients over age 65 due to
prodol is administered PO for the short-term therapy (up significant anticholinergic effects. Drowsiness, nausea and
to 3 weeks) of acute, painful musculoskeletal conditions. It vomiting, and anxiety are common adverse effects. This
is effective in relieving the pain, muscle spasms, and spas- drug is pregnancy category C.
ticity associated with CP. The drug produces significant
sedation in 40% of patients taking it and may cause signifi- Methocarbamol (Robaxin): Approved in 1957, methocar-
cant CNS and respiratory depression if taken with alcohol bamol has central sedative effects that likely are responsi-
or other CNS depressants. The general sedative nature of ble for its ability to reduce muscle spasms. It is used as an
the drug is likely responsible for its ability to relieve the adjunct to physical therapy interventions. It can be admin-
pain associated with muscle spasms. Although not a con- istered intravenously (IV) for the treatment of tetanus or
trolled substance, carisoprodol can cause physical depen- other acute musculoskeletal conditions. Methocarbamol
dence and has been abused by recreational drug users. The may cause significant dizziness and sedation and should
active metabolite of carisoprodol is meprobamate, a rarely not be taken with alcohol or other CNS depressants. It is
used antianxiety agent and a Schedule IV drug. The drug contraindicated in patients with chronic kidney disease. It
should be used with caution in patients with a history of should not be administered to patients over age 65 due to
substance abuse. The development of newer medications significant anticholinergic effects. This drug is pregnancy
and increased levels of carisoprodol abuse in recent years category C.
has led to less frequent prescribing of the drug. This drug
is pregnancy category C. Orphenadrine: Orphenadrine was approved in 1959. It is
administered PO or parenterally to relax skeletal muscles
Chlorzoxazone: Chlorzoxazone is an oral centrally act- and reduce pain. The drug has analgesic properties and
ing skeletal muscle relaxant administered for the symp- may be administered parenterally to produce local anes-
tomatic treatment of discomfort associated with acute, thetic effects. It may be used off-label as an adjunct in the
painful musculoskeletal conditions. It is ineffective in treatment of the muscular rigidity associated with
the treatment of spasticity related to neurodegenerative Parkinson’s disease. The most common side effect of
disorders such as CP. The actions of the drug may be orphenadrine is xerostomia. Orphenadrine is structurally
largely due to its sedative effects. It should not be com- very similar to diphenhydramine (Benadryl) and can cause
bined with alcohol or other CNS depressants. Chlorzoxa- prominent anticholinergic effects; therefore, it should not
zone is hepatotoxic and should not be used in patients be used with other anticholinergic drugs due to the risk for
with liver impairment. Other adverse effects include additive toxicity. Orphenadrine produces a mild to moder-
anorexia, nausea, vomiting, rash, and red-orange discol- ate euphoric effect that has led to its abuse. This drug is
oration of urine. Older adults may experience more pregnancy category C.
adverse CNS effects than younger patients. This drug is
pregnancy category C. Tizanidine (Zanaflex): Approved in 1996, tizanidine is a
centrally acting alpha2-adrenergic agonist that inhibits
Deutetrabenazine (Austedo) and tetrabenazine (Xenazine): motor neurons mainly at the spinal cord level. It has no
Deutetrabenazine (approved in 2017) and tetrabenazine direct effect on muscle fibers. Indicated for the manage-
(approved in 2008) have nearly identical chemical struc- ment of muscle spasticity, tizanidine is most effective in
tures and are used to reduce chorea movements in patients patients who have significantly diminished muscle tone,
with Huntington’s chorea. They act by depleting the including spasticity related to brain or spinal cord injury
amounts of dopamine, serotonin, and norepinephrine at or MS. Tizanidine is as effective as baclofen in treating
nerve terminals. The two drugs have identical actions and muscle spasticity and is considered a first-line drug. One
adverse effects except deutetrabenazine has a longer dura- disadvantage of tizanidine is that it has a short duration of
tion of action that allows once-daily dosing. Both drugs action that requires dosing every 6 to 8 hours.
366 Unit 4 Pharmacology of the Central Nervous System
The most common adverse effects of tizanidine Pharmacotherapy of Muscle
include xerostomia, fatigue, weakness, dizziness, and Spasticity
drowsiness. Hypotension is common at higher doses; the
drug is closely related to clonidine (Catapres), which is an 23.4 Direct-acting skeletal muscle relaxants
antihypertensive drug. Hallucinations are uncommon but are often used to relieve muscle spasticity.
patients with a history of psychosis should be carefully
monitored for this adverse effect. Tizanidine is hepato- Medications effective in the treatment of spasticity include
toxic and should not be used in patients with liver impair- muscle relaxants that act at the level of the CNS, neuro-
ment. Older adults, especially those with chronic kidney muscular junction, or muscle tissue. Some of the centrally
disease, may experience adverse effects such as drowsi- acting medications used to treat muscle spasms, such as
ness, dizziness, dry mouth, and asthenia. This drug is baclofen (Lioresal) and tizanidine (Zanaflex), are also effec-
pregnancy category C. tive in treating spasticity.
CONNECTION Checkpoint 23.2 Dantrolene (Dantrium, Revonto) and the botulinum
toxins act directly on skeletal muscle to relieve spasticity.
Cyclobenzaprine is very similar to the TCAs. From what you learned These are called direct-acting muscle relaxants or antispas-
in Chapter 19, describe the major indications (approved and off-label) ticity drugs. Dantrolene is the prototype for direct-acting
for the TCAs. Answers to Connection Checkpoint questions are avail- drugs. Doses of these drugs are listed in Table 23.3. The
able on the faculty resources site. Please consult with your instructor. mechanisms of action of direct-acting antispasmodics are
shown in Pharmacotherapy Illustrated 23.2.
PharmFACT
PROTOTYPE DRUG Dantrolene (Dantrium, Revonto)
The brain lesions of CP occur in the fetus and through age 3,
but the diagnosis may not be made until age 5 or later Classification Therapeutic: Direct-acting skeletal
(Abel-Hamid, 2016). muscle relaxant, antispasticity drug
Pharmacologic: Calcium release blocker
(skeletal muscle cells)
Table 23.3 Direct-Acting Skeletal Muscle Relaxants
Drug Route and Dose (Maximum Dose Where Indicated) Adverse Effects
abobotulinumtoxinA (Dysport)
Cervical dystonia: IM: 500 units, in divided doses Injection reactions, headache, dysphagia, muscle
incobotulinumtoxinA (Xeomin) Glabellar lines: IM: 50 units given in 5 equal doses weakness, pain, tenderness, bruising, flulike
Upper limb spasticity: IM: 100–400 units depending on muscle symptoms, dry mouth, ptosis of eyelids
onabotulinumtoxinA (Botox) injected
Spread of toxin to surrounding muscles,
onabotulinumtoxinA (Botox Cervical dystonia: IM:120 units anaphylaxis and other hypersensitivity reactions,
Cosmetic) Blepharospasm: IM: 10–50 units per eye in 6 injections (max: 50 difficulty swallowing or breathing (cervical dystonia
rimabotulinumtoxinB (Myobloc) units per eye) therapy), corneal ulceration (blepharospasm
dantrolene (Dantrium, Revonto) Upper limb spasticity: IM: 5–200 units depending on muscle injected therapy)
Cervical dystonia: IM: 198–300 units in divided doses (max: 50 units
per site)
Upper limb spasticity: IM: 75–360 units in divided doses (max: 50
units/site)
Axillary hyperhidrosis: IM: 50 units per site
Migraines: IM: 155 units in divided doses across specific head and
neck regions (max: 5 units per site)
Overactive bladder: 100–200 units across 20–30 injections sites in
the detrusor muscle
Glabellar lines: IM: 20 units divided among affected muscles
Cervical dystonia: IM: 2500–5000 units divided among affected Hypersensitivity, drowsiness, dizziness,
muscles lightheadedness, fatigue, speech disturbance,
insomnia, mental depression, blurred vision,
Spasticity: PO: 25 mg once daily (max: 100 mg bid–qid) diplopia, photophobia, vomiting, anorexia, GI
upset, crystalluria, urinary frequency, urinary
Malignant hyperthermia: IV push: 1 mg/kg; repeat as needed (max: retention, nocturia, enuresis, difficult erection
10 mg/kg); may continue PO at 1–2 mg/kg qid for 1–3 days
Muscle weakness, diarrhea, hepatic necrosis
Note: Italics indicates common adverse effects. Underline indicates serious adverse effects.
Chapter 23 Pharmacotherapy of Muscle Spasms and Spasticity 367
Pharmacotherapy Illustrated 23.2
Mechanism of Action of Direct-Acting Antispasmodics
1 Spasticity: Sarcomere contracting 2 Administration of antispasmodics Botulinum toxin A/B (Botox;
Myobloc) blocks release of ACh.
Dependent on calcium release Neuron Dantrolene (Dantrium) blocks
Symptoms: Axon calcium release within muscle.
• Pain Direction of Skeletal
• Immobility nerve signal muscle
• Inability to perform ADLs Cell body (effector)
Myofibrils
Sarcomere contracting Thick filaments Arrival of Synaptic
(myosin) nerve terminals
Tightened muscles Thin filaments impulse Neuromuscular
3 Sarcomere at rest (actin) junction
Vesicles
Myosin containing
"heads" neurotransmitter
molecules
Result of drug therapy:
• Reduced pain
• Mobility
• Greater range of muscle activity
Sarcomere at rest Synaptic Neurotransmitter
Relaxed muscles cleft receptors
Initiation of new
impulse
Therapeutic Effects and Uses: Approved in dangerous level. There is a strong genetic predisposition
1974, dantrolene is a direct-acting skeletal muscle re- to malignant hyperthermia, and patients with a family
laxant indicated for spasticity, especially for spasms history of the disorder should not receive drugs that have
of the head and neck muscles following a spinal cord the potential to cause this adverse effect. It is important
injury, stroke, and in cases of CP or MS. When admin- for the anesthesia provider and circulating nurse to have
istered PO, the drug induces relaxation of the skeletal phentolamine (Regitine) available in the event of extrava-
muscles. It may be used off-label to treat malignant sation of dantrolene.
neuroleptic syndrome or for the treatment of pain fol-
lowing heavy exercise. Mechanism of Action: Dantrolene is related to
phenytoin (Dilantin), an antiepileptic drug. Dantrolene
When administered IV, Revonto is a preferred drug directly relaxes spastic muscles by interfering with the re-
for treating malignant hyperthermia, a rare condition lease of calcium ions that have been stored in the sarco-
that is an adverse effect of succinylcholine (Anectine) plasmic reticulum of skeletal muscle.
and some general anesthetics. A patient with malignant
hyperthermia will experience a sudden onset of tachy- Pharmacokinetics: PO, IV
cardia, ventricular dysrhythmia, and hypotension. This Route(s)
is due to the rapid release of calcium ions in muscle Absorption Approximately 35% is slowly
cells, which produces hypermetabolism and intense and incompletely absorbed from
muscle rigidity. The muscle metabolic rate becomes so the GI tract
elevated that it quickly raises the body temperature to a
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(GNUR 294) 1 Adams, Michael Patrick_ Urban, Carol Quam - Pharmacology_ connections to nursing practice (2018_2019, Pearson) - libgen.li-1-400
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(GNUR 294) 1 Adams, Michael Patrick_ Urban, Carol Quam - Pharmacology_ connections to nursing practice (2018_2019, Pearson) - libgen.li-1-400
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